@article {pmid42574987,
year = {2026},
author = {Liu, Z and Li, P and Cecarini, V and Eleuteri, AM and Nan, B and Piao, C},
title = {Ginsenoside Rg2 attenuates Alzheimer-like phenotypes in 3xTg-AD mice: Associations with gut microbiota and brain metabolomic profiles.},
journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology},
volume = {160},
number = {},
pages = {158678},
doi = {10.1016/j.phymed.2026.158678},
pmid = {42574987},
issn = {1618-095X},
abstract = {BACKGROUND AND PURPOSE: Alzheimer's disease (AD) is the most common form of dementia. The microbiota-gut-brain axis represents a critical pathway bridging peripheral metabolic signals and central AD pathology. This study aimed to evaluate the effects of ginsenoside Rg2 on AD-like phenotypes in 3xTg-AD mice and to examine its associations with gut microbiota and brain metabolomic profiles.

STUDY DESIGN AND METHODS: A 3xTg-AD mouse model was used to assess the effects of Rg2 intervention in vivo. Behavioral performance was assessed using open field and water maze tests, Aβ and inflammatory factors were detected by ELISA, gut microbial changes were analyzed by 16S rRNA sequencing, and brain metabolic alterations were investigated using untargeted metabolomics.

RESULTS: The results showed that Rg2 improved behavioral performance in mice, reduced Aβ deposition in the brain, and decreased serum and brain tissue inflammatory factors. Rg2 treatment was associated with alterations in gut microbial community characteristics. Metabolomics indicated that Rg2 was associated with alterations in the brain metabolic profile, with differential metabolites mainly involved in energy and lipid metabolism as well as inflammation-related pathways. The correlation network further revealed a close relationship between microbiota, SCFAs and brain metabolites, inflammation and behavioral indicators.

CONCLUSION: Rg2 attenuated AD-related pathology and functional impairment in 3xTg-AD mice. These protective effects were accompanied by changes in gut microbiota composition, brain metabolic profiles, and the inflammatory microenvironment. This study provides multi-omics evidence supporting the potential of Rg2 as a natural product for AD intervention and highlights its associations with gut microbiota and brain metabolism.},
}

@article {pmid42575163,
year = {2026},
author = {Thurber, KR and Lee, M and Tycko, R},
title = {Brain-seeded 42-residue amyloid-β fibrils that resemble fibrils directly extracted from Alzheimer's disease brain tissue.},
journal = {Journal of molecular biology},
volume = {},
number = {},
pages = {169983},
doi = {10.1016/j.jmb.2026.169983},
pmid = {42575163},
issn = {1089-8638},
abstract = {Fibrils formed by the 42-residue amyloid-β peptide (Aβ42) are known to be polymorphic, with molecular conformations and supramolecular structures that depend on conditions of nucleation, growth, seeding, or other factors. Structural studies of Aβ42 fibrils that develop in human brain tissue have been based on two different approaches, either direct extraction and partial purification of fibrils from brain tissue for characterization by cryogenic electron microscopy (cryo-EM) or growth of fibrils in vitro from seeds in amyloid-containing brain tissue extracts for characterization by solid state nuclear magnetic resonance (ssNMR) or cryo-EM. To date, studies of brain-extracted and brain-seeded Aβ42 fibrils have produced qualitatively different sets of structures. Here we report structures of two new brain-seeded Aβ42 fibril polymorphs, derived from cortical tissue of an Alzheimer's disease (AD) patient, that share certain structural features with previously characterized polymorphs extracted from AD brain tissue. These structures contribute to our understanding of the relationships between brain-seeded and brain-extracted fibril structures and expand our understanding of the full range of polymorphism in amyloid-β fibrils.},
}

@article {pmid42575313,
year = {2026},
author = {Fang, J and Wang, X},
title = {Opposing kinase signaling may underlie the inverse relationship between cancer and Alzheimer's disease.},
journal = {Journal of proteomics},
volume = {},
number = {},
pages = {105723},
doi = {10.1016/j.jprot.2026.105723},
pmid = {42575313},
issn = {1876-7737},
abstract = {Cancer and Alzheimer's disease (AD) are leading causes of mortality and exhibit an inverse relationship, where AD patients have reduced cancer risk and vice versa. However, the molecular basis of this relationship remains poorly understood. We reanalyzed published proteomic and phosphoproteomic datasets to investigate this relationship. Differentially abundant proteins were identified in lung adenocarcinoma and glioblastoma samples relative to controls and compared with proteins altered in AD brains, revealing 37 proteins with opposing abundance patterns. Protein-protein interaction and pathway analyses revealed enrichment in kinase signaling and phosphorylation pathways. Phosphoproteomic analysis identified 52 differentially phosphorylated sites with opposing patterns, while kinase-substrate enrichment analysis identified 44 kinases with opposing inferred activity profiles. Integration of kinase activity and phosphosite data identified 29 kinase-phosphosite pairs, including 4 prioritized pairs with opposing patterns relevant to both diseases. Across seven independent cancer cohorts, 17 of 20 statistically significant phosphosite-cohort comparisons (85%) were concordant with the discovery findings, supporting reproducibility of the prioritized phosphosites. Together, these findings highlight opposing kinase signaling as a prominent feature of the inverse relationship and suggest potential biomarkers and therapeutic targets. This study provides a novel systems-level framework for investigating inverse relationships, supported by an R Shiny application for data exploration (https://advscancer.shinyapps.io/advscancer/). SIGNIFICANCE: This study presents an integrated proteomic and phosphoproteomic framework for investigating the inverse relationship between cancer and Alzheimer's disease (AD). By integrating differential protein abundance, phosphosite phosphorylation, inferred kinase activity, and curated kinase-substrate relationships, we identified opposing signaling patterns and prioritized four kinase-phosphosite pairs. Independent evaluation across seven CPTAC cancer cohorts supported the reproducibility of the prioritized phosphosite patterns. These findings provide insight into molecular processes potentially associated with the inverse relationship between cancer and AD, identify candidate biomarkers and therapeutic targets, and demonstrate the value of systems-level, data-driven approaches for investigating shared and opposing disease processes.},
}

@article {pmid42575342,
year = {2026},
author = {Lobyntseva, A and Guz, LS and Galushkin, A and Gozes, I},
title = {Dramatic sex differences leading to different brain disease presentation: The requirement for sex-specific medications with ADNP/davunetide as a case study.},
journal = {Frontiers in neuroendocrinology},
volume = {},
number = {},
pages = {101274},
doi = {10.1016/j.yfrne.2026.101274},
pmid = {42575342},
issn = {1095-6808},
abstract = {Focusing on the brain-essential gene revealed in our laboratory, activity-dependent neuroprotective protein (ADNP) and its neuroprotective site, the investigational drug davunetide (NAP), we discuss ADNP regulating steroid hormone biosynthesis and sex chromosome genes coupled with sex-dependent shuttling between the nuclei and cytoplasm. Further coupled with sex-dependent transcriptional control, ADNP/davunetide cytoplasmic microtubule/Tau targeting is translated into differential sex regulation of key cellular processes including neurogenesis, synaptic function, and axonal transport, then decoded into sexual dichotomy in multicellular processes directing sex-dependent behavioral outcomes. ADNP regulation of these sex-specific processes serves as a target for davunetide intervention, toward sex-directed precision medicine, revealing sexually dichotomized neuroprotection against tauopathy risk and progression spanning from coronary artery bypass grafting (CABG) to prodromal Alzheimer's disease, progressive supranuclear palsy (PSP), and schizophrenia, as well as the pediatric ADNP syndrome. Sex-specific intranasal bioavailability of davunetide, regulated by the estrous cycle, provides a mechanistic foundation for these differential outcomes.},
}

@article {pmid42575373,
year = {2026},
author = {Ding, G and Liu, Y and Zhao, Y and Chen, X and He, Y and Li, Y and Chen, N and Cui, J},
title = {Metabolic Vulnerability Indices and Alzheimer's Disease Risk: A Prospective Analysis of the UK Biobank Cohort.},
journal = {The Journal of nutrition},
volume = {},
number = {},
pages = {101777},
doi = {10.1016/j.tjnut.2026.101777},
pmid = {42575373},
issn = {1541-6100},
abstract = {BACKGROUND: Metabolic dysfunction is implicated in Alzheimer's disease (AD) pathogenesis. Branched-chain amino acids (BCAAs) have been prospectively linked to dementia risk, yet prospective associations of composite metabolic vulnerability indices with incident AD remain untested.

OBJECTIVE: To examine associations of the Metabolic Vulnerability Index (MVX), Inflammatory Vulnerability Index (IVX), and Metabolic Malnutrition Index (MMX) with incident AD in the UK Biobank.

METHODS: Among 367,715 dementia-free UK Biobank participants (mean age 56.93 years, 54.3% female; 2006-2010 baseline), incident AD was ascertained through hospital and death registry linkage. Fully adjusted Cox models (Model 3) constituted the pre-specified primary analysis; three Bonferroni-corrected tests (α = 0.0167) addressed multiple comparisons. Restricted cubic splines characterized association shape; interaction analyses examined potential effect modification by sex, age group, diabetes status, BMI, inflammatory status, and polygenic risk.

RESULTS: Over 13.7 years, 2,615 participants developed AD. Per 1-SD increase, MMX (HR = 1.16, 95% CI: 1.12-1.21, p = 4.93×10[-13]) and MVX (HR = 1.12, 95% CI: 1.07-1.17, p = 3.72×10[-6]) were each associated with higher AD risk, both meeting the Bonferroni-corrected threshold; IVX showed no association (p = 0.108). Associations were approximately linear and monotonically increasing. Sex-specific associations were observed for MMX (stronger in males, p-interaction = 0.004) and MVX (stronger in females, p-interaction = 0.003). Sensitivity analyses confirmed robustness.

CONCLUSION: MMX and MVX are independently associated with incident AD, supporting the clinical relevance of metabolic health monitoring in neurodegeneration risk stratification.},
}

@article {pmid42575375,
year = {2026},
author = {Ali, S and Ayaz, A and Zaman, W},
title = {Establishing causality for protein lactylation in Alzheimer's disease: site validation, evidence standards, and experimental priorities.},
journal = {Biochemical pharmacology},
volume = {},
number = {},
pages = {118343},
doi = {10.1016/j.bcp.2026.118343},
pmid = {42575375},
issn = {1873-2968},
abstract = {Protein lysine lactylation has emerged as a candidate interface between metabolic stress and Alzheimer's disease (AD), but the strength of individual claims varies. This focused review evaluates whether reported histone and non-histone lactylation events meet analytical and experimental requirements for causal interpretation. Direct AD evidence is more robust for plaque-associated microglial histone H4 lysine 12 lactylation (H4K12la)-pyruvate kinase M2 (PKM2) feedback in an amyloid model. Histone H3 lysine 18 lactylation (H3K18la)-nuclear factor-κB (NF-κB) signaling is supported principally in senescent microglia and ageing or AD-related models. Human tau K331 lactylation demonstrates disease-associated occurrence but not quantitative occupancy, temporal precedence or residue-specific necessity. Amyloid precursor protein (APP) K612 lactylation provides a potentially protective mechanism supported by site-resolved identification, cellular perturbation and in vivo rescue. Histone H3 lysine 9 lactylation (H3K9la) and additional substrates remain hypothesis-generating. We distinguish putative enzymatic L-lactylation from methylglyoxal-derived D-lactoylation and define minimum standards for antibody specificity, stereochemistry, site localization, occupancy, protein abundance, cell composition, post-mortem quality, isotope tracing, genetic substitution and rescue. A four-tier framework separates extrapolated evidence, human occurrence or relevant in vivo association, site-specific AD-model mechanisms supported by intervention and rescue, and quantified, cell-resolved, residue-causal evidence independently replicated in human-relevant systems. Six experimental stages are proposed for advancing a candidate site from detection to human relevance. Current evidence supports protein lactylation as a context-dependent disease-modifying layer rather than a single upstream driver. Therapeutic development should prioritize validated sites and biomarker-defined cell states rather than indiscriminate suppression of lactate metabolism or global lactylation.},
}

@article {pmid42575412,
year = {2026},
author = {Liu, Y and Peng, L and Li, M and Yan, W and Xiang, Q},
title = {Let-7d-5p improves mouse cognitive function by targeting bach1 in Alzheimer's disease.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115957},
doi = {10.1016/j.expneurol.2026.115957},
pmid = {42575412},
issn = {1090-2430},
abstract = {BACKGROUND: MicroRNAs (miRNAs) have emerged as critical modulators in Alzheimer's disease (AD) pathogenesis. The lethal-7 (let-7) family functions as key regulators of cell apoptosis, differentiation, and immune response. Herein, we explore the functions and underlying mechanisms of let-7d-5p in AD progression.

METHODS: Eight-month-old male APP/PS1 transgenic mice and wild-type C57BL/6 J mice were assigned to the model and control groups, respectively. Model mice received intrahippocampal injections of either a negative control adenovirus (Ad-NC) or a let-7d-5p overexpression adenovirus (Ad-let-7d-5p). The Morris water maze test was conducted to assess cognitive function. Hippocampal histopathological changes were evaluated using hematoxylin and eosin staining. Aβ deposition was detected via immunohistochemical staining. SH-SY5Y cells were transfected with let-7d-5p mimics prior to treatment with 10 μM Aβ1-42. Cell viability and apoptosis were examined using MTT assays and flow cytometry. The expression levels of let-7d-5p and bach1 were measured using RT-qPCR. Western blotting was conducted to evaluate bach1, Bcl-2, and cleaved caspase-3 protein levels. The binding relationship between let-7d-5p and bach1 was verified using luciferase reporter assays.

RESULTS: In vitro, Aβ1-42 treatment induced the downregulation of let-7d-5p and decrease of cell viability. However, overexpression of let-7d-5p significantly increased let-7d-5p level, enhanced cell viability and inhibited cell apoptosis of Aβ1-42-treated SH-SY5Y cells. Moreover, overexpression of let-7d-5p upregulated Bcl-2 protein levels and downregulated cleaved caspase-3 protein levels in Aβ1-42-treated SH-SY5Y cells. Furthermore, let-7d-5p overexpression ameliorated oxidative stress injury in Aβ1-42-treated SH-SY5Y cells. Importantly, bach1 upregulation counteracted the inhibitory effects of let-7d-5p overexpression on Aβ1-42-induced cellular injury. In vivo, let-7d-5p overexpression mitigated cognitive deficits of AD mice, as indicated by reduced escape latency and increased platform crossings. Additionally, let-7d-5p overexpression attenuated hippocampal histopathological changes and Aβ deposition in APP/PS1 mice. At the molecular level, let-7d-5p targeted bach1 3'UTR and repressed its mRNA and protein expression in vitro and in vivo. Rescue assays further validated that bach1 overexpression restored the protective effect of let-7d-5p on cognitive deficits and pathological injuries.

CONCLUSION: Let-7d-5p alleviates cognitive deficits in AD by inhibiting Aβ deposition and neuronal apoptosis through targeting bach1.},
}

@article {pmid42575452,
year = {2026},
author = {Dai, X and Ye, Z and Zhang, X and Huang, Y and Wang, C and Liu, Y and Gao, B and Zhang, J and Chen, X},
title = {SIK2-P300 axis Orchestrates the metabolic reprogramming and Immunological functions in microglia of Alzheimer's disease mice via a dual modulation of lactylation and Acetylation: An epigenetic Perspective.},
journal = {Brain, behavior, and immunity},
volume = {},
number = {},
pages = {106953},
doi = {10.1016/j.bbi.2026.106953},
pmid = {42575452},
issn = {1090-2139},
abstract = {Metabolic dysfunction in microglia is increasingly recognized as a core driver of Alzheimer's disease (AD) pathogenesis, and yet the underlying mechanisms remain elusive. Here, we identified salt-inducible kinase 2 (SIK2) as a critical metabolic checkpoint that was downregulated in microglia across the AD mouse models (5 × FAD, APP/PS1, and SAMP8). We found that a loss of SIK2 in microglia induced a pro‑inflammatory phenotype, thus impairing amyloid β-protein (Aβ) phagocytosis and rewiring glucose and lipid metabolism toward enhanced glycolysis and lipid accumulation. Mechanistically, SIK2 directly interacted with the histone acetyltransferase P300; SIK2 deficiency increased the activity of P300, elevating H3K9 acetylation and H4K8/12 lactylation at promoters of metabolic genes. The microglia‑specific SIK2 overexpression in the 5 × FAD mice mitigated cognitive deficits, Aβ pathology, neuroinflammation, and aberrant histone modifications. A pharmacological inhibition of P300 regained these protective effects. Our findings highlight the SIK2-P300 epigenetic axis as a key regulator of the metabolic homeostasis in microglia and a potential therapeutic target for AD treatments.},
}

@article {pmid42575718,
year = {2026},
author = {Dzib, E and Hernández-Ayala, LF and Silva-Aguirre, S and Galano, A},
title = {Rational Design of Multifunctional Tacrine Derivatives as Candidates for the Treatment of Alzheimer and Parkinson Diseases.},
journal = {ChemMedChem},
volume = {21},
number = {15},
pages = {e70429},
doi = {10.1002/cmdc.70429},
pmid = {42575718},
issn = {1860-7187},
support = {CBF2023-2024-1141//SECIHTI/ ; },
mesh = {*Tacrine/chemistry/pharmacology/chemical synthesis/therapeutic use/analogs & derivatives ; *Alzheimer Disease/drug therapy/metabolism ; *Drug Design ; Humans ; Monoamine Oxidase/metabolism/chemistry ; Acetylcholinesterase/metabolism/chemistry ; *Parkinson Disease/drug therapy/metabolism ; *Cholinesterase Inhibitors/chemistry/pharmacology/chemical synthesis/therapeutic use ; Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors/metabolism ; Structure-Activity Relationship ; *Monoamine Oxidase Inhibitors/chemistry/pharmacology/chemical synthesis ; Catechol O-Methyltransferase/metabolism ; Molecular Structure ; Molecular Docking Simulation ; Catechol O-Methyltransferase Inhibitors/chemistry/pharmacology/chemical synthesis ; },
abstract = {Alzheimer disease (AD) and Parkinson disease (PD) are multifactorial neurodegenerative disorders for which there is currently no therapy that prevents or slows their progress. Some drugs used to treat AD are inhibitors of acetylcholinesterase (AChE) and antagonists of N-methyl-D-aspartate receptor (NMDAr), while inhibitors of catechol-O-methyltransferase (COMT) and monoamine oxidase B (MAO-B) are used for PD. Tacrine was the first FDA (Food and Drug Administration) approved drug against AD. Although later withdrawn due to hepatotoxicity, it remains a pivotal scaffold for drug development. Herein, 1295 tacrine derivatives, meant to enhance therapeutic efficacy and safety of the parent compound, were designed through the CADMA-Chem protocol. The chemical space was screened using selection scores based on ADME properties, toxicity, and synthetic accessibility. Two derivatives with the best drug-like behavior were chosen for further investigation. Acid-base constants and reactivity descriptors were estimated for them. Our findings show that these derivatives are promising inhibitors of AChE, COMT, NMDAr, and MAO-B. Therefore, according to in silico predictions they are expected to be beneficial for AD and PD. One of the compounds investigated here is the first reported tacrine-derived compound with potential as COMT inhibitor.},
}

*Tacrine/chemistry/pharmacology/chemical synthesis/therapeutic use/analogs & derivatives
*Alzheimer Disease/drug therapy/metabolism
*Drug Design
Humans
Monoamine Oxidase/metabolism/chemistry
Acetylcholinesterase/metabolism/chemistry
*Parkinson Disease/drug therapy/metabolism
*Cholinesterase Inhibitors/chemistry/pharmacology/chemical synthesis/therapeutic use
Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors/metabolism
Structure-Activity Relationship
*Monoamine Oxidase Inhibitors/chemistry/pharmacology/chemical synthesis
Catechol O-Methyltransferase/metabolism
Molecular Structure
Molecular Docking Simulation
Catechol O-Methyltransferase Inhibitors/chemistry/pharmacology/chemical synthesis

@article {pmid42575772,
year = {2026},
author = {Russo, AG and Hawkshaw, MJ and Sataloff, RT},
title = {Voice Disorders as Early Biomarkers of Cognitive Decline.},
journal = {Journal of voice : official journal of the Voice Foundation},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jvoice.2026.07.037},
pmid = {42575772},
issn = {1873-4588},
abstract = {BACKGROUND: Dementia affects greater than 57 million people worldwide. With an aging population and limited disease-curing treatments available, early identification of biomarkers is crucial. The 2020 Lancet Commission identified hearing loss as the largest modifiable risk factor for dementia globally, and a randomized controlled trial found that hearing intervention reduced 3-year cognitive change in older adults who were at increased risk for cognitive decline. Similarly, studies have found that abnormalities in acoustic measures of voice are correlated with cognitive status and can potentially predict decline. The association between hearing loss and cognitive decline might have both social and neurological mechanisms. Dysphonia might pose similar problems. Socially, voice disorders may reduce engagement in social and cognitively stimulating activities. Neurologically, one example is in Parkinson's disease in which the vagus nerve is one of the earliest sites of Lewy body pathology in Braak staging, and dysphonia and dysarthria can precede motor symptoms by years. Voice changes have been associated with different neurological conditions such as amyotrophic lateral sclerosis, multiple system atrophy, and Alzheimer's disease. Despite this, no prior large-scale study has examined whether diagnosed voice disorders are associated independently with incident cognitive decline. Our study is the first to examine this potential association, using the TriNetX US Collaborative Health Network platform to compare patients with diagnosed voice disorders and matched controls, with a hearing loss cohort as a standard of comparison given that it is the largest established modifiable risk factor for dementia, as dysphonia is also a modifiable condition.

RESULTS: This study included 833,417 total patients in the voice disorders and control cohorts. Voice disorders were associated with a significantly elevated risk of incident cognitive decline compared to controls (HR=1.291, 95% CI 1.155-1.443, P<0.0001). Hearing loss alone was associated with a slightly lower risk of cognitive decline (HR=1.267, 95% CI 1.203-1.334, P<0.0001). Voice disorders without concurrent hearing loss were associated with an elevated risk of incident cognitive decline compared to hearing loss alone (HR=1.261, 95% CI 1.121-1.419, P=0.0001), while voice disorders with hearing loss were associated with the highest risk among all cohorts (HR=2.038 vs controls; HR=1.545 vs hearing loss). Both voice disorder subgroups did not differ when compared with each other (HR=1.088, P=0.376).

CONCLUSION: The results from our study indicate that voice disorders are associated with an elevated risk of incident cognitive decline and may represent a stronger early biomarker than hearing loss alone. These findings highlight otolaryngology and family medicine/internal medicine encounters as potential entry points for cognitive assessment, and early voice treatment needs to be investigated for possible beneficial cognitive effect.},
}

@article {pmid42575819,
year = {2026},
author = {Despa, F and Lashley, T},
title = {Amyloidogenic amylin signaling links diabetes to dementia pathogenesis.},
journal = {Trends in pharmacological sciences},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.tips.2026.07.009},
pmid = {42575819},
issn = {1873-3735},
abstract = {Recent studies identify amyloidogenic human amylin, secreted by the pancreas, as a potential link between type-2 diabetes and Alzheimer's disease. Evidence suggests that pathogenic amylin signaling impairs cerebral bioenergetics, promoting tau hyperphosphorylation and neurodegeneration. Selective targeting of circulating amyloidogenic amylin and its pathogenic signaling may enable biomarker development and disease-modifying therapies.},
}

@article {pmid42575873,
year = {2026},
author = {Frank, LE and Flack, N and Faulk, C and Block, AJ and Bartz, JC and Larsen, PA},
title = {Epigenetic changes associated with the progression of prion disease in Syrian hamsters (Mesocricetus auratus).},
journal = {Prion},
volume = {20},
number = {1},
pages = {52-65},
doi = {10.1080/19336896.2026.2710965},
pmid = {42575873},
issn = {1933-690X},
mesh = {Animals ; *Epigenesis, Genetic ; DNA Methylation/genetics ; *Prion Diseases/genetics/pathology ; Mesocricetus ; Cricetinae ; Disease Progression ; Brain/metabolism/pathology ; },
abstract = {Prion diseases are fatal neurodegenerative disorders characterized by abnormally folded prion proteins inducing misfolding of normal prion proteins, leading to neurotoxic fibrils and plaques. Epigenetic mechanisms, particularly DNA methylation, are increasingly implicated in prion-like diseases (e.g. Alzheimer's disease), but their role in prion pathogenesis remains unclear. To investigate, we used nanopore sequencing and RNAseq to measure genome-wide methylation and gene expression in the brains of Syrian hamsters (Mesocricetus auratus) experimentally infected with a hamster-adapted murine synthetic prion strain (n = 9) and age-matched mock-infected controls (n = 9) at 80, 120, and 160 days post-infection (dpi). We identified 1,586, 1,692, and 2,429 differentially methylated regions (DMRs) at 80, 120, and 160 dpi, respectively. Early- and mid-stage prion disease (80 and 120 dpi) skewed towards hypermethylation, whereas late-stage prion disease (160 dpi) skewed towards hypomethylation. Gene ontology (GO) of DMR-associated genes at 160 dpi included neuron regulation and signalling, neurodevelopment, and cellular stress pathways. We identified 178 differentially expressed genes (DEGs) at 80 dpi, 90 at 120 dpi, and 616 at 160 dpi. The majority of DEGs were downregulated at 80 dpi, and at 120 and 160 dpi, most were upregulated. Overlap in DEGs across timepoints was limited, and GO terms were related to upregulation of disease/injury response and cell death pathways in later timepoints. Overall, we found a stage-specific transcriptional shift from immune suppression to widespread immune and inflammation activation. These findings provide time-resolved data on methylation and transcriptional changes associated with impaired neuronal structure, function, and communication during disease.},
}

Animals
*Epigenesis, Genetic
DNA Methylation/genetics
*Prion Diseases/genetics/pathology
Mesocricetus
Cricetinae
Disease Progression
Brain/metabolism/pathology

@article {pmid42575875,
year = {2026},
author = {Satake, Y and Kanemoto, H and Taomoto, D and Takeda, K and Katakami, S and Kobayashi, M and Matsunaga, K and Isohashi, K and Suehiro, T and Yoshiyama, K and Ikeda, M},
title = {Progression to Dementia in Very Late-Onset Schizophrenia-Like Psychosis Stratified by Alzheimer's Disease and Lewy Body Disease Biomarkers: A Retrospective Cohort Study.},
journal = {Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society},
volume = {26},
number = {5},
pages = {e70205},
doi = {10.1111/psyg.70205},
pmid = {42575875},
issn = {1479-8301},
support = {TK21K15730//Japan Society for the Promotion of Science/ ; Overseas Study grant//SENSHIN Medical Research Foundation/ ; },
mesh = {Humans ; Disease Progression ; *Lewy Body Disease/diagnosis/psychology ; Retrospective Studies ; Female ; Biomarkers/blood ; Male ; *Alzheimer Disease/diagnosis/psychology ; *Schizophrenia/diagnosis ; Aged ; *Psychotic Disorders/diagnosis ; Age of Onset ; Aged, 80 and over ; *Dementia/diagnosis ; Japan ; },
abstract = {BACKGROUND: Very late-onset schizophrenia-like psychosis (VLOSLP) is clinically heterogeneous, and its relationship with dementia-related neurodegenerative disease remains unresolved. We examined whether Alzheimer's disease (AD) and Lewy body disease (LBD) biomarker status were associated with dementia progression in VLOSLP.

METHODS: We retrospectively identified patients who visited the University of Osaka Hospital between January 2018 and December 2023 and met criteria for VLOSLP. Twenty-two participants with AD and/or LBD biomarker data and at least one follow-up assessment within 775 days were classified as biomarker-negative (BMs-neg; n = 7) or biomarker-positive (BMs-pos; n = 15). Group comparisons were performed using Mann-Whitney U tests and Fisher's exact tests.

RESULTS: The BMs-pos group showed older onset age and lower memory scores than the BMs-neg group. Dementia progression was more frequent in the BMs-pos group than in the BMs-neg group, although the difference was not statistically significant (8/15 [53.3%] vs. 1/7 [14.3%]; p = 0.165; odds ratio 6.31; 95% CI 0.55-353.18). Five of eight participants with AD biomarker positivity progressed to AD dementia. Three of seven participants with LBD biomarker positivity progressed to dementia, including two diagnosed with dementia with Lewy bodies. Follow-up MMSE, CDR, and CDR-SB scores differed significantly between groups.

CONCLUSIONS: AD and/or LBD biomarker-positive VLOSLP may be associated with greater dementia progression and cognitive decline, although findings should be interpreted cautiously given the small sample size and retrospective design. These results support the clinical value of considering neurodegenerative biomarkers when evaluating the prognosis and underlying pathology of VLOSLP.},
}

Humans
Disease Progression
*Lewy Body Disease/diagnosis/psychology
Retrospective Studies
Female
Biomarkers/blood
Male
*Alzheimer Disease/diagnosis/psychology
*Schizophrenia/diagnosis
Aged
*Psychotic Disorders/diagnosis
Age of Onset
Aged, 80 and over
*Dementia/diagnosis
Japan

@article {pmid42575917,
year = {2026},
author = {Jacob, T and Schützmann, MP and Gerhards, L and Hruby, L and Leprivier, G and Tamgüney, G and Hoyer, W},
title = {Liquid-liquid phase-separated tau colocalizes with and stabilizes Aβ oligomers.},
journal = {Communications chemistry},
volume = {9},
number = {1},
pages = {},
pmid = {42575917},
issn = {2399-3669},
support = {726368//EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)/ ; },
abstract = {Protein aggregation is a hallmark of neurodegenerative diseases, where misfolded proteins accumulate into insoluble deposits. Emerging studies indicate that liquid-liquid phase separation (LLPS) may serve as a transient stage in the transition from monomers to amyloid fibrils for several proteins implicated in neurological disorders. In this study, we investigated the interplay between tau and off-pathway oligomers of amyloid-beta (Aβ), the two key proteins in Alzheimer's disease (AD). Our findings demonstrate that tau condensates act as reservoirs for Aβ oligomers under LLPS conditions. Inside the tau condensates, Aβ oligomers reduced tau dynamics and formed discrete puncta, indicating a conducive environment for Aβ oligomer clustering. In contrast, in the absence of LLPS conditions, tau and Aβ oligomers formed solid-like co-aggregates with distinct morphologies. Tau significantly affected the kinetics of Aβ assembly, stabilizing off-pathway oligomers and inhibiting their replacement by amyloid fibrils. Our results highlight interactions between higher-order assemblies of tau and Aβ that may contribute to AD pathology.},
}

@article {pmid42575945,
year = {2026},
author = {Keil, J and Hernandez-Urbina, V and Doherty, L and Bahmani, H and Holtkamp, M and Steinbart, D and Diall, AD and Hebel, JM and Brandt, C and Cloppenborg, T and Doll, A and Müschenich, M},
title = {High-frequency visual stimulation can increase medial temporal lobe ripple oscillation density.},
journal = {Communications medicine},
volume = {6},
number = {1},
pages = {},
pmid = {42575945},
issn = {2730-664X},
abstract = {BACKGROUND: Flickering visual stimulation can evoke neural oscillations, which can influence ongoing brain activity. Electrophysiological recordings of neural oscillations in the ripple band (80-180 Hz) show that these high-frequency oscillations occur in the neocortex and the hippocampus, that they phase-synchronize across long distances, and that ripple oscillations in the neocortex often precede those in the hippocampus during wakefulness. It is therefore possible that the neocortical ripple oscillations propagate beyond sensory areas to the hippocampus, inducing ripple oscillations.

METHODS: To test the hypothesis that neocortical ripple oscillations induced by visual stimulation induce hippocampal ripple oscillations, we conduct an exploratory experiment (N = 8) in humans, using ultra-high frequency visual stimulation to induce ripple oscillations recorded through electrodes implanted in or near the hippocampus. Although hippocampal ripple oscillations, so-called sharp-wave-ripples, mostly occur during quiet rest or slow-wave sleep, we aim to increase their abundance using visual stimulation during wakefulness in this exploratory study. We hypothesize that ultra-high frequency visual stimulation increases the number of sharp-wave-ripples relative to an eyes-open resting-state baseline.

RESULTS: In this exploratory and preliminary study, we observe significantly more sharp-wave-ripples per second during periods of stimulation compared to a resting-state baseline before and after the stimulation.

CONCLUSIONS: The increased number of sharp-wave ripples during stimulation suggests that ultra-high-frequency visual stimulation can be used as a safe noninvasive tool to influence sharp-wave ripples, which offers the potential to improve memory.},
}

@article {pmid42576087,
year = {2026},
author = {Oyedokun, PA and Gbadero, JO and Ajao, DI and Olorunsesan, MD and Oyesiji, AI and Ayilara, GO and Ogunsina, MK and Justus, BS and Ademola, FM and Adetunji, EA and Okodio, PS and Amedu, NO},
title = {The Amino Acid-Neurodegeneration Axis: Excitotoxicity and Oxidative Stress as Context-Dependent Amplifiers of Metabolic Dysfunction.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42576087},
issn = {1559-1182},
mesh = {*Oxidative Stress/physiology ; Humans ; Animals ; *Amino Acids/metabolism ; *Neurodegenerative Diseases/metabolism/pathology ; *Nerve Degeneration/metabolism/pathology ; Mitochondria/metabolism ; },
abstract = {Homeostasis of amino acids is essential for the integrity of the CNS, and is maintained by a tightly regulated transport and metabolic circuit that ensures efficient neurotransmission, mitochondrial bioenergetics and redox homeostasis. Disruption of this equilibrium is associated with the pathogenesis of the major neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease and Amyotrophic lateral sclerosis. Excessive glutamatergic stimulation and impaired glycine or homocysteine metabolism result in pathological Ca[2][+] influx, loss of mitochondrial membrane potential and production of reactive oxygen species, which are hallmarks of these disorders. It also limits cysteine availability and causes glutathione depletion, which affects antioxidant defence, and disrupts tryptophan-kynurenine metabolism, further affecting neurotoxic and neuroprotective signalling. Though there are disease-specific molecular triggers, the convergent pathogenesis of metabolic disruption makes neurons susceptible to disease. The convergent pathways link amino acid dysregulation to the reinforcement of each other's mechanisms of excitotoxicity, oxidative stress, mitochondrial dysfunction, and protein aggregation. Correcting the amino acid balance has clear translational potential for developing new therapies, such as glutathione augmentation, modulation of NMDA receptors, targeting of transporters, and regulation of metabolic enzymes. In addition, the use of metabolic biomarkers alongside neuroprotective endpoints in clinical trials could improve detection rates, patient stratification, and therapeutic precision. The concept of amino acid metabolism as a mechanism of neurodegeneration, therefore, provides a systems-level perspective and targets potential areas for continued neuroprotection and disease modification.},
}

*Oxidative Stress/physiology
Humans
Animals
*Amino Acids/metabolism
*Neurodegenerative Diseases/metabolism/pathology
*Nerve Degeneration/metabolism/pathology
Mitochondria/metabolism

@article {pmid42576162,
year = {2026},
author = {Park, JH and Kim, B and Al-Amin, MM and Tate, MD and Sharify, AD and John, SK and Karahan, H and Lu, HC and Dabin, LC and Kim, J},
title = {Unique transcriptomic alterations in 5XFAD;PS19 mouse model identify glial lipid dysregulation and coordinated microglial-oligodendrocyte responses.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71742},
doi = {10.1002/alz.71742},
pmid = {42576162},
issn = {1552-5279},
support = {R01NS086794/NH/NIH HHS/United States ; R01AG077829/NH/NIH HHS/United States ; RF1AG074543/NH/NIH HHS/United States ; U01AG076804/NH/NIH HHS/United States ; },
mesh = {Animals ; Mice ; *Microglia/metabolism/pathology ; *Transcriptome ; Disease Models, Animal ; *Alzheimer Disease/genetics/metabolism/pathology ; *Oligodendroglia/metabolism/pathology ; *Lipid Metabolism/genetics ; Mice, Transgenic ; Humans ; Brain/metabolism/pathology ; Female ; *Neuroglia/metabolism ; },
abstract = {INTRODUCTION: Alzheimer's disease (AD) features amyloid beta (Aβ) plaques and tau tangles, yet how their coexistence reshapes brain transcriptomic programs remains unclear.

METHODS: We performed high-quality, sex-balanced single-nucleus RNA sequencing of 5XFAD (Aβ), PS19 (tau), and combined 5XFAD;PS19 mice.

RESULTS: We identified transcriptional programs that emerged most prominently under combined pathology. These programs included disruption of glial lipid metabolism and immune pathways at the network level, alongside immune and synaptic alterations coordinated between microglia and oligodendrocytes. Cross-species analyses further revealed that the pathway-level alterations under combined pathology, particularly in immune, lipid, and cell cycle programs, exhibited the strongest concordance with human AD datasets, underscoring their translational relevance.

DISCUSSION: Beyond benchmarking mouse models, this study provides a high-quality transcriptomic resource to dissect multicellular disease mechanisms in AD and to prioritize therapeutic targets for a network-level systems pharmacology approach.},
}

Animals
Mice
*Microglia/metabolism/pathology
*Transcriptome
Disease Models, Animal
*Alzheimer Disease/genetics/metabolism/pathology
*Oligodendroglia/metabolism/pathology
*Lipid Metabolism/genetics
Mice, Transgenic
Humans
Brain/metabolism/pathology
Female
*Neuroglia/metabolism

@article {pmid42576167,
year = {2026},
author = {Uruk, G and Gatto, RG and Hossain, N and Whitwell, JL and Reichard, RR and Josephs, KA},
title = {Structural Heterogeneity of TDP-43 Fragments in Alzheimer's Disease and Primary Age-Related Tauopathy by Artificial Intelligence (AI)-Based 3D Segmentation.},
journal = {Neuropathology and applied neurobiology},
volume = {52},
number = {4},
pages = {e70096},
doi = {10.1111/nan.70096},
pmid = {42576167},
issn = {1365-2990},
support = {R01-AG37491/NH/NIH HHS/United States ; },
mesh = {Humans ; *DNA-Binding Proteins/metabolism ; *Alzheimer Disease/pathology/metabolism ; *Tauopathies/pathology/metabolism ; Female ; Male ; Aged ; *Artificial Intelligence ; Aged, 80 and over ; *Brain/pathology/metabolism ; Imaging, Three-Dimensional/methods ; },
abstract = {TAR DNA-binding protein 43 (TDP-43) inclusions are defining pathological features of frontotemporal lobar degeneration (FTLD) but are also often observed in Alzheimer's disease (AD) and primary age-related tauopathy (PART). TDP-43 in AD is either associated with cognitive impairment or a protective-life prolonging impact, and yet the localization, cellular and fragment characteristics of TDP-43 need to be determined. We investigated the relationships between TDP-43 volumetric inclusion burden in low likelihood AD (lAD) and definite PART by immunostaining against phosphorylated TDP-43 (pTDP-43), TDP-43 C terminal (TDP-C) and TDP-43 N-terminal (TDP-N) fragments combined with 3D confocal imaging taken from eight regions: amygdala (basolateral [amygdala-BL] and centromedial amygdala [amygdala-CM]), the hippocampus (Cornu Ammonis [CA]-1, CA2/3, CA4, dentate gyrus [DG] and subiculum [SUB]) and entorhinal cortex (ERC) and artificial intelligence (AI)-based segmentation via object recognition, reconstruction and quantification. We found amygdala-CM in lAD and PART to have the overall greatest burden of pTDP-43 whereas TDP-N burden in amygdala-BL of PART cases was greater than other TDP-43 fragments. There was no difference in TDP-43 burden in hippocampal subfields in PART. However, CA2/3 region showed greater pTDP-43 burden while TDP-N stood out in DG and SUB. Multiple comparisons among the groups revealed that TDP-C was the only fragment showing differences among PART and lAD in CA2/3, DG and SUB regions. Overall, unbiased AI-based volumetric burden analysis pipeline demonstrated unique fragment aggregation patterns in the neurodegenerative processes of PART and AD.},
}

Humans
*DNA-Binding Proteins/metabolism
*Alzheimer Disease/pathology/metabolism
*Tauopathies/pathology/metabolism
Female
Male
Aged
*Artificial Intelligence
Aged, 80 and over
*Brain/pathology/metabolism
Imaging, Three-Dimensional/methods

@article {pmid42576170,
year = {2026},
author = {Wan, L and Kang, C and Harrison, R and Solis-Urra, P and Sewell, KR and Oberlin, LE and Jain, S and Huang, H and Grove, G and Kamboh, MI and Sutton, BP and Snitz, BE and Kramer, AF and McAuley, E and Burns, JM and Hillman, CH and Vidoni, ED and Marsland, AL and Karikari, TK and Morris, J and Erickson, KI},
title = {Neurobiological markers across joint profiles of subjective cognitive decline and objective cognitive function in older adults.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71743},
doi = {10.1002/alz.71743},
pmid = {42576170},
issn = {1552-5279},
support = {R01 AG053952/NH/NIH HHS/United States ; R35 AG072307/NH/NIH HHS/United States ; },
mesh = {Humans ; Aged ; Male ; Female ; Biomarkers/blood ; Neurofilament Proteins/blood ; Magnetic Resonance Imaging ; *Cognitive Dysfunction/blood/diagnostic imaging/psychology ; Glial Fibrillary Acidic Protein/blood ; *Cognition/physiology ; tau Proteins/blood ; Brain/pathology/diagnostic imaging ; Neuropsychological Tests ; Aging ; Aged, 80 and over ; },
abstract = {INTRODUCTION: Subjective cognitive concerns frequently diverge from objective cognitive performance in cognitively unimpaired (CU) older adults, yet the neurobiological basis of this mismatch remains unclear.

METHODS: In 648 participants from the Investigating Gains in Neurocognition in an Intervention Trial of Exercise (IGNITE), we defined four profiles by integrating subjective and objective cognitive status. We examined associations with plasma neurofilament light chain (NfL), phosphorylated tau 217 (p-tau217), glial fibrillary acidic protein (GFAP), a magnetic resonance imaging-based volumetric Alzheimer's disease (AD) signature reflecting atrophy, and brain-predicted age difference (brain-PAD).

RESULTS: Joint profiles were differentially associated with NfL (P = 0.0427) and brain-PAD (P = 0.0296). Follow-up contrasts further indicated higher NfL and lower volumetric AD signature in the concordant lower functioning profile, and higher brain-PAD in discordant profiles. p-tau217 and GFAP did not differ across profiles.

DISCUSSION: Joint subjective-objective cognitive profiles may capture biologically meaningful heterogeneity relevant to neurodegeneration and brain aging in older adults.

TRIAL REGISTRATION: ClinicalTrials.gov: NCT02875301.},
}

Humans
Aged
Male
Female
Biomarkers/blood
Neurofilament Proteins/blood
Magnetic Resonance Imaging
*Cognitive Dysfunction/blood/diagnostic imaging/psychology
Glial Fibrillary Acidic Protein/blood
*Cognition/physiology
tau Proteins/blood
Brain/pathology/diagnostic imaging
Neuropsychological Tests
Aging
Aged, 80 and over

@article {pmid42576193,
year = {2026},
author = {Saifullah, K and Ridwan, AR and Evia, AM and Leurgans, SE and Wagner, M and Bennett, DA and Schneider, JA and Arfanakis, K},
title = {Brain morphometry patterns in the presence of Alzheimer's disease and/or LATE neuropathologic changes.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71719},
doi = {10.1002/alz.71719},
pmid = {42576193},
issn = {1552-5279},
support = {R01AG064233/AG/NIA NIH HHS/United States ; R01AG067482/AG/NIA NIH HHS/United States ; R01AG017917/AG/NIA NIH HHS/United States ; R01AG015819/AG/NIA NIH HHS/United States ; RF1AG022018/AG/NIA NIH HHS/United States ; R01AG056405/AG/NIA NIH HHS/United States ; R01AG052200/AG/NIA NIH HHS/United States ; P30AG010161/AG/NIA NIH HHS/United States ; P30AG072975/AG/NIA NIH HHS/United States ; UH2-UH3NS100599//Institute of Neurological Disorders and Stroke (NINDS)/ ; U01NS100599//Institute of Neurological Disorders and Stroke (NINDS)/ ; },
mesh = {Humans ; *Alzheimer Disease/pathology/diagnostic imaging ; Magnetic Resonance Imaging ; *Brain/pathology/diagnostic imaging ; Aged ; Female ; Male ; Aged, 80 and over ; Image Processing, Computer-Assisted ; },
abstract = {INTRODUCTION: Alzheimer's disease neuropathologic change (ADNC) and limbic-predominant age-related transactive response DNA-binding protein 43 kDa (TDP-43) encephalopathy neuropathologic change (LATENC) are common in older adults, yet differences in brain morphometry patterns when one or both pathologies are present remain unclear.

METHODS: We used deformation-based morphometry on ex-vivo MRI from 912 community-based older adults to compare groups with or without ADNC and/or LATENC.

RESULTS: AD+LATE- and AD-LATE+ groups showed less tissue in the medial temporal lobe than AD-LATE-. The AD+LATE+ group had less tissue in temporal, frontal, and parietal lobes. The AD-LATE+ group exhibited smaller anterior hippocampi than the AD+LATE- group. These findings were less pronounced in individuals without dementia. Increments in LATENC stages were associated with smaller hippocampi than increments in ADNC severity, independent of the severity of comorbid ADNC or LATENC, respectively.

DISCUSSION: These findings reveal distinct and overlapping brain morphometry patterns associated with ADNC and/or LATENC, with possible implications for diagnosis in older adults.},
}

Humans
*Alzheimer Disease/pathology/diagnostic imaging
Magnetic Resonance Imaging
*Brain/pathology/diagnostic imaging
Aged
Female
Male
Aged, 80 and over
Image Processing, Computer-Assisted

@article {pmid42576197,
year = {2026},
author = {Um, YJ and Cho, IY and Koo, HY and Park, YM and Kim, KM and Lee, CE and Han, K},
title = {Intellectual disabilities and risk of dementia: A Korean population-based cohort study.},
journal = {Journal of intellectual disabilities : JOID},
volume = {},
number = {},
pages = {17446295261476476},
doi = {10.1177/17446295261476476},
pmid = {42576197},
issn = {1744-6309},
abstract = {This retrospective cohort study assessed the risk of all-cause dementia, Alzheimer's disease (AD), and vascular dementia (VaD) in individuals with intellectual disabilities compared to those without. Using data from the Korean National Disability Registry and National Health Insurance Service, individuals over 40 who underwent health examinations in 2009 were followed until 2020. Cox proportional hazards models estimated hazard ratios (HRs) for dementia outcomes, adjusting for confounders. Over a mean 8-year follow-up, 161 dementia, 111 AD, and 22 VaD cases occurred among individuals with intellectual disabilities. Adjusted HRs for all-cause dementia, AD, and VaD were 5.75, 5.23, and 4.66, respectively, compared to those without intellectual disabilities. The risk was especially elevated among those aged 40-64 years (P for interaction <0.01). In conclusion, individuals with intellectual disabilities have a significantly higher risk of dementia, particularly at younger ages, highlighting the need for increased awareness and targeted healthcare strategies.},
}

@article {pmid42576199,
year = {2026},
author = {Zheng, F and Guan, R and Yu, X and Yang, J and Zhao, H and Yang, F},
title = {ADAR-mediated RNA editing in CNS disorders: from pathogenic mechanisms to therapeutic opportunities.},
journal = {Cellular & molecular biology letters},
volume = {31},
number = {1},
pages = {},
pmid = {42576199},
issn = {1689-1392},
mesh = {Humans ; *RNA Editing/genetics ; *Adenosine Deaminase/metabolism/genetics ; *Central Nervous System Diseases/genetics/therapy/pathology/metabolism ; Animals ; *RNA-Binding Proteins/metabolism/genetics ; },
abstract = {The adenosine deaminases acting on RNA (ADAR) family of enzymes (ADAR1 and ADAR2) catalyze adenosine-to-inosine (A-to-I) RNA editing. This post-transcriptional change is remarkably prevalent in the central nervous system (CNS). ADAR-mediated editing is critical for proper brain development, synaptic plasticity, and immunological homeostasis in the central nervous system (CNS) via recoding neurotransmitter receptors and ion channels. Conversely, a wide range of CNS disorders, such as neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis), neuropsychiatric conditions (schizophrenia, bipolar disorder, and major depression), cerebrovascular diseases, and gliomas, are now linked to dysregulation of ADAR activity, whether through loss-of-function mutations, altered expression, or mislocalization. To address the main question of whether altered RNA editing is a fundamental driver of pathogenesis, a compensatory response, or a context-dependent modulator, this review critically synthesizes existing evidence. The basic processes of ADAR enzymes and their regulation throughout neurodevelopment are first described. Next, we thoroughly assess the unique molecular fingerprints of ADAR dysregulation across several CNS disorders, emphasizing recurring themes such as Alu RNA hypo-editing, induction of innate immunity, and GRIA2 editing, which can cause excitotoxicity. Lastly, we examine new treatment approaches that use or reinstate ADAR activity, such as small-molecule modulators and site-directed RNA editing tools (leveraging endogenous ADAR for programmable editing of RNA [LEAPER], clustered ADAR-recruiting guide RNAs (gRNAs) for effective RNA editing [CLUSTER], and mimicking inverted repeats to recruit ADARs using engineered oligoribonucleotides [MIRROR]). We summarize by reviewing key obstacles to clinical translation, including crossing the blood-brain barrier, the risks of off-target editing, and the challenges of achieving spatiotemporal accuracy. We also list important open topics for further investigation.},
}

Humans
*RNA Editing/genetics
*Adenosine Deaminase/metabolism/genetics
*Central Nervous System Diseases/genetics/therapy/pathology/metabolism
Animals
*RNA-Binding Proteins/metabolism/genetics

@article {pmid42576501,
year = {2026},
author = {Li, D and Li, Y and Yang, X and Wang, Y and Qu, Y},
title = {[Association between 473 gut microbiota and Alzheimer's disease: a Mendelian randomization mediation analysis of 233 circulating metabolites].},
journal = {Nan fang yi ke da xue xue bao = Journal of Southern Medical University},
volume = {46},
number = {8},
pages = {1926-1935},
doi = {10.12122/j.issn.1673-4254.2026.08.20},
pmid = {42576501},
issn = {1673-4254},
mesh = {*Alzheimer Disease/microbiology/genetics ; *Mendelian Randomization Analysis ; Humans ; *Gastrointestinal Microbiome ; Genome-Wide Association Study ; },
abstract = {OBJECTIVES: To investigate the causal associations between gut microbiota (GM) and Alzheimer's disease (AD) and the mediating role of circulating metabolites using Mendelian randomization (MR) analysis.

METHODS: A two-sample MR analysis was conducted based on genome-wide association study (GWAS) summary data. Valid instrumental variables for 473 GM taxa and 233 circulating metabolites were selected, and the inverse-variance weighted (IVW) method was used as the primary analytical approach, with MR-Egger regression and weighted median method as the complementary analyses. Multiple sensitivity analyses were conducted to assess the robustness of the results, and reverse MR analyses were used to verify the direction of causality. Mediation MR analyses were performed to determine the mediating effects of the circulating metabolites.

RESULTS: A positive causal association was identified between the abundance of Negativibacillus massiliensis and the risk of AD (OR=1.204, 95% CI: 1.020-1.421,P=0.028), and the results were stable and reliable as confirmed by sensitivity analyses (P>0.05). Reverse MR analysis revealed no significant causal effect of AD on the abundance of Negativibacillus massiliensis (P=0.678). Mediation MR analysis showed that the indirect effect mediated by free cholesterol to total lipid ratio in very small very-low-density lipoprotein (v-VLDL FC/TL) accounted for 6.63% of the total effect of Negativibacillus massiliensis on AD.

CONCLUSIONS: From a genetic causal inference perspective, Negativibacillus massiliensis is likely associated with an increased risk of AD, and v-VLDL FC/TL may partially mediate this association, suggesting their potential as targets for AD prevention and treatment.},
}

*Alzheimer Disease/microbiology/genetics
*Mendelian Randomization Analysis
Humans
*Gastrointestinal Microbiome
Genome-Wide Association Study

@article {pmid42576518,
year = {2026},
author = {Shakya, M and Patel, SK and Singh, M and Rao, H and Moorthy, NHN and Tiwari, A},
title = {An Overview of 1,2,4-Triazole-5-Thiol and 3-Thione Derivatives as Promising Scaffolds for Anti-Neuroinflammatory Drug Discovery.},
journal = {Mini reviews in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113895575433269260710072055},
pmid = {42576518},
issn = {1875-5607},
abstract = {Neuroinflammation is a major complex reaction that causes Neurodegenerative Diseases (ND) and cognitive behavioural disorders such as Alzheimer's Disease (AD), Parkinson's disease, multiple sclerosis, and traumatic brain injury. Neuroinflammation can be regulated by different types of enzymes and proteins, including acetyl- and butyrylcholinesterases, cyclooxygenases, kinases, and the accumulation of Amyloid-beta (Aβ) plaques and hyperphosphorylated tau protein. Due to the complex physiology of enzymes and proteins, ND cannot be cured permanently yet. Therefore, we need to design and synthesise novel small molecules with high selectivity and inhibitory properties against enzymes and proteins associated with neuroinflammation. In recent decades, researchers have examined a range of different heterocyclic scaffolds for their ability to fight neuroinflammation. The 1,2,4-triazole scaffold, especially its 5-thiol and 3-thione derivatives, is a chemically flexible heterocyclic scaffold that has attracted significant attention due to its wide range of biological activities and promising drug-like properties. As a review methodology, comprehensive literature searches of the PubMed, Scopus, Web of Science (WoS), ScienceDirect, and DOAJ databases were conducted using keywords to gather information on synthesis, in vitro (IC50 values), in vivo biology, and in silico approaches related to the 1,2,4-triazole-targeted scaffold. This literature review highlights 1,2,4-triazole scaffold 5-thiol and 3-thione derivatives, potent compounds from the synthesised derivatives, presenting synthetic schemes, biological activity data, and in silico studies. Molecular docking, in silico predictions, and preclinical experiments are summarised in detail to show how they can be used in medicinal drug discovery. The goal of this review is to provide a source of information that will help with future efforts to design new neuroprotective agents based on the 1,2,4-triazole scaffold.},
}

@article {pmid42576561,
year = {2026},
author = {Kara, S and Özandaç, S and Sencar, L and Akillioglu, K and Polat, S},
title = {Transforming Growth Factor Beta-1 Alleviates Neurodegeneration by Regulating Aβ42 and VDAC1 Expression in the Temporal Lobe and Cerebellum in an Alzheimer's Disease-Like Model.},
journal = {Current molecular medicine},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115665240501722260724103809},
pmid = {42576561},
issn = {1875-5666},
abstract = {BACKGROUND: Alzheimer's Disease (AD) has a critical pathology that causes neurodegeneration and mitochondrial dysfunctions via the amyloid deposition. The temporal lobe plays a role in converting sensory input into derived meanings for appropriate processing of visual memory, language comprehension, and emotional association. The cerebellum plays a critical role in the control of motor systems, cognitive, and emotional functions. Aβ42 accumulates between nerve cells in the brain, disrupting synaptic functions and negatively affecting memory and other cognitive functions. VDAC1 is a protein located in the cell membrane that facilitates energy transport to the mitochondria. TGF-β1 is a cytokine that plays a role in many biological functions, including cell growth, differentiation, and tissue repair.

OBJECTIVE: The aim of the study was to investigate the effect of TGF-β1 on scopolamine-induced neurodegeneration of the temporal lobe and cerebellum in experimental AD.

METHODS AND RESULTS: The evaluation showed that, according to light and electron microscopic results, edema areas, cytoplasmic vacuolization, and cellular damage were increased in the scopolamine group, while these changes were significantly reduced in the treatment group. According to immunohistochemical findings, the expression levels of Aβ42 and VDAC1 were significantly higher in the scopolamine group than in the control and TGF-β1 groups, while in the treatment group, a low expression was observed compared to the scopolamine group.

CONCLUSION: When all these results are considered together, it has been concluded that TGF-β1 application may regulate the expression of Aβ42 and VDAC1 in critical control centers such as the temporal lobe and cerebellum in a Scopolamin-induced neurodegeneration model, potentially alleviating cellular damage.

DISCUSSION: Previous studies have reported that TGF-β1 exerts both antineurodegenerative and neuroprotective effects. In our study, evaluation of the effects of TGF-β1 demonstrated beneficial effects on both mitochondrial damage and amyloid accumulation. Nevertheless, further detailed investigations of these effects may provide valuable insights for future studies.},
}

@article {pmid42576562,
year = {2026},
author = {Kumar, D and Ashesh, AM and Gupta, S and Kumar, A and Lohidasan, S and Tosaramandani, TJ},
title = {WNT Signaling in Alzheimer's Disease: Mechanisms, Pathological Implications, and Therapeutic Potential.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273455895260722103746},
pmid = {42576562},
issn = {1996-3181},
abstract = {The WNT signaling pathway plays a significant role in various biological processes during embryonic development, childhood, and adulthood. It is involved in neurogenesis, synapse formation, and such cognitive processes as learning and memory in the CNS. Dysregulated WNT signaling is associated with cognitive decline, synaptic dysfunction, neuronal loss, and has been associated with diseases like leukemia and colorectal cancer. The studies show that WNT/β-catenin signaling affects the cellular, molecular, and metabolic mechanisms that promote disease progression. The WNT pathway is a potential therapeutic target because it helps maintain neuronal survival, supports the growth of new nerve cells, and enhances synaptic plasticity. WNT signaling is important for stem cell selfrenewal and differentiation. Research is being conducted on therapeutic methods targeting WNT signaling to treat neurological diseases and cancer. This review explores the connection between WNT signaling and the pathology of Alzheimer's disease. This review explores the role of WNT signaling in AD pathogenesis, with a focus on the Wnt/β-catenin pathway as a therapeutic target. It summarizes existing findings to demonstrate that WNT signaling is a context-dependent regulatory network in which a shift from protective canonical activity to dysregulated non-canonical and inflammatory pathways contributes to disease progression.},
}

@article {pmid42576583,
year = {2026},
author = {Ahmed, A and Fu, X and Khan, H and Li, P},
title = {A Narrative Review: Suvorexant's Role in Sleep Deprivation and Neurodegenerative Disease.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X468876260722063322},
pmid = {42576583},
issn = {1875-6190},
abstract = {Sleep loss is a major risk factor for neurodegenerative diseases like Alzheimer's disease (AD) and Parkinson's disease (PD), accelerating cognitive impairment with neuropathology. Cumulative sleep loss impairs the glymphatic system, reduces amyloid-β clearance, and enhances the neuroinflammatory response, all of which contribute to the development of neurodegeneration. Given the orexin system's essential role in modulating sleep-wake rhythms, orexin receptor antagonists such as Suvorexant are potent candidates for treating sleep disturbances and cognitive decline associated with neurodegenerative conditions. Suvorexant promotes sustained sleep without the side effects commonly associated with sleep-inducing drugs, such as drowsiness and cognitive impairment, potentially offering a neuroprotective approach by selectively antagonizing orexin receptors. By inhibiting excessive orexin signaling in the brain, Suvorexant may benefit other neurodegenerative diseases. Preclinical studies support the idea that improving sleep quality, as seen with Suvorexant, can normalize sleep architecture, leading to reduced tau phosphorylation and amyloid plaque deposition, both of which are pathological hallmarks of AD. Furthermore, enhanced sleep quality may bolster synaptic plasticity and aid in memory consolidation, potentially counteracting cognitive deterioration. Although most research has been conducted in AD, the putative applications of Suvorexant in PD and other tauopathies are worth exploring, especially given the common involvement of sleep disturbances in these diseases. Animal studies show that Suvorexant not only promotes sleep but also prevents neuronal damage, suggesting its dual therapeutic potential. Long-term clinical trials are necessary, however, to prove its effectiveness in humans, especially in populations at risk for sleep disorders and early neurodegenerative alterations. Suvorexant could be a novel approach to slow cognitive decline and improve quality of life in patients with AD, PD, and related diseases, highlighting the vital interplay between sleep and brain health.},
}

@article {pmid42576592,
year = {2026},
author = {Jeeru, TR and Palathoti, N and Swaminathan, G},
title = {The Multifaceted Role of the P2X7 Receptor in Alzheimer's Disease: A Unifying Pathological Link.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273460900260724035926},
pmid = {42576592},
issn = {1996-3181},
abstract = {Alzheimer's Disease (AD) is a neurodegenerative disorder that characterizes depletion of memory, cognition, and a change in behavioural patterns. There is no standard treatment that completely cures this prevalent disease. This review delves into the existing pathologies of AD, which include the Aβ plaques accumulation, neurofibrillary tangles and Lewy bodies formation, and the influence of the P2X7 receptor on cellular mechanisms of neuronal cells like microglial cells, astrocytes and oligodendrocytes and also its influence on pathways such as JAK2/STAT3, NGF signalling, (Transactive response DNA binding protein) TDP-43 Proteinopathy, Wnt/β-Catenin signalling, and FGF7/FGFR2/PI3K/Akt causing AD. It discusses the unifying role of the P2X7 receptor mediating these pathways that link to the occurrence and progression of AD. The role of the Purinergic receptor (P2X7 receptor), a ligand-gated ion channel activated by extracellular ATP, was examined across existing cellular mechanisms and possible pathways involved in AD, as well as the co-pathologies encompassed and their hypothetical relationship with the P2X7 receptor. Additionally, the current P2X7 receptor antagonists treating neurotoxicity are discussed along with existing pre-clinical and clinical data. This may further advance drug development by targeting the P2X7 receptor to mitigate AD across multiple mechanisms.},
}

@article {pmid42576595,
year = {2026},
author = {Maghsoudlou, F and Esteki, A},
title = {Audio‒Visual Gamma Stimulation for Alzheimer's Disease: Current Evidence and Future Directions.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050478693260720114427},
pmid = {42576595},
issn = {1875-5828},
abstract = {INTRODUCTION/OBJECTIVE: Alzheimer's Disease (AD) is characterized by progressive cognitive decline and disrupted neural oscillations. Recently, 40 Hz gamma stimulation has emerged as a potential non-invasive therapy. This review evaluates the safety, tolerability, and clinical outcomes of this intervention based on evidence from the past decade.

METHODS: A literature search was conducted across PubMed, Web of Science, Google Scholar, and ClinicalTrials.gov for studies published during the last ten years. Registered and ongoing studies were also identified through ClinicalTrials.gov. Extracted data included stimulation modality, stimulation parameters, safety and tolerability outcomes, and reported effects on functional connectivity, brain atrophy, cognitive performance, and sleep-related measures.

RESULTS: Thirty studies were identified, comprising eight sensory-based 40-Hz gamma stimulation approaches, 12 40-Hz transcranial Alternating Current Stimulation (tACS) protocols, and 10 ongoing clinical trials. Among the 20 completed studies, 40-Hz gamma stimulation was reported to be safe and well-tolerated. The synthesized evidence from these completed trials suggests potential beneficial effects on functional connectivity, brain atrophy progression, cognitive outcomes, and sleep-related measures.

DISCUSSION: Gamma stimulation may represent a promising approach for modulating neural network activity and cognitive function in AD. Nevertheless, current evidence remains limited by small sample sizes, methodological heterogeneity, differences in stimulation protocols, and short follow-up periods. These factors limit the ability to draw definitive conclusions regarding therapeutic efficacy.

CONCLUSION: 40-Hz gamma stimulation is a feasible and generally well-tolerated non-invasive intervention with potential relevance for AD treatment. Further large-scale, randomized, and controlled studies are required to establish standardized stimulation protocols, determine long-term efficacy, and clarify its clinical utility.},
}

@article {pmid42576606,
year = {2026},
author = {Ioakeimidis, V and Palombo, M and Casella, C and Layland, L and McNabb, C and Schubert, R and Pallmann, P and Busse, M and Drew, C and Alusi, S and Harrower, T and Davies, J and Rosser, A and Metzler-Baddeley, C},
title = {In vivo mapping of striatal neurodegeneration in Huntington's disease with Soma and Neurite Density Imaging.},
journal = {eLife},
volume = {14},
number = {},
pages = {},
doi = {10.7554/eLife.107661},
pmid = {42576606},
issn = {2050-084X},
support = {NIHR-FS(A)-2022/HCRW_/HCRW_/United Kingdom ; MR/T020296/2//UKRI/ ; 10.35802/204005/WT_/Wellcome Trust/United Kingdom ; 10.35802/104943/WT_/Wellcome Trust/United Kingdom ; },
mesh = {Humans ; *Huntington Disease/pathology/diagnostic imaging/physiopathology ; Female ; Male ; *Neurites/pathology ; Middle Aged ; *Corpus Striatum/pathology/diagnostic imaging ; Adult ; Diffusion Magnetic Resonance Imaging/methods ; Basal Ganglia/pathology/diagnostic imaging ; Aged ; },
abstract = {Huntington's disease (HD) is an inherited neurodegenerative disorder characterised by progressive cognitive and motor decline driven by basal ganglia (BG) atrophy. Clinical trials of novel disease-modifying therapies are ongoing, creating a need for sensitive non-invasive imaging biomarkers. Soma and Neurite Density Imaging (SANDI) is a multi-shell diffusion MRI model that estimates intracellular signal fractions from sphere-shaped soma and shows promise as a marker of neurodegeneration. The objectives of this study were to characterise HD-related microstructural abnormalities in the BG using SANDI and to examine relationships between SANDI and volumetric measurements and motor performance. T1- and diffusion-weighted images (b-values 200-6000 s/mm[2]) were acquired on a 3T Siemens Connectom scanner (300 mT/m) in 56 individuals with HD and 57 age- and sex-matched controls. HD participants completed Quantitative Motor (Q-Motor) tasks, summarised using principal component analysis. SANDI estimated apparent soma and neurite density, apparent soma size, and extracellular signal fraction. Microstructural and volumetric indices were extracted from bilateral caudate, putamen, pallidum and thalamus regions, compared between groups, and correlated with Q-Motor performance. HD was associated with reduced apparent soma density and increased apparent soma size and extracellular signal fraction in the BG but not the thalami. No group differences were present for apparent neurite density. SANDI metrics correlated with Q-Motor performance and explained up to 63% of striatal atrophy in HD. SANDI indices detected HD-related striatal neurodegeneration, explained atrophy, and correlated with motor impairments, demonstrating its potential as an in vivo biomarker and surrogate clinical outcome measure for HD and other neurodegenerative diseases.},
}

Humans
*Huntington Disease/pathology/diagnostic imaging/physiopathology
Female
Male
*Neurites/pathology
Middle Aged
*Corpus Striatum/pathology/diagnostic imaging
Adult
Diffusion Magnetic Resonance Imaging/methods
Basal Ganglia/pathology/diagnostic imaging
Aged

@article {pmid42576610,
year = {2026},
author = {Yang, Y and Yang, Y and Tang, Y and Yang, W},
title = {Myokines, Microbiota, and Neuroinflammation: Physical Activity Modulates the Gut-Brain Axis.},
journal = {Immunological investigations},
volume = {},
number = {},
pages = {1-28},
doi = {10.1080/08820139.2026.2689670},
pmid = {42576610},
issn = {1532-4311},
abstract = {BACKGROUND: Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis are increasingly recognized as disorders influenced not only by intrinsic neural pathology but also by systemic physiological networks, including the gut-brain axis. Emerging evidence highlights physical activity as a potent modulator of this bidirectional communication system, with muscle-derived signals particularly myokines, metabolites, and extracellular vesicles playing a central role.

METHODS: This narrative review synthesizes current knowledge on how exercise-induced molecular mediators influence gut microbiota composition, intestinal barrier integrity, immune signaling, and neuroinflammatory pathways. Findings were integrated across the disciplines of neuroscience, microbiology, and exercise physiology to evaluate mechanistic links between muscle-secreted factors and gut-mediated responses.

RESULTS: Mechanistic links exist between muscle-secreted factors such as irisin, cathepsin B, BDNF-inducing pathways, and lactate with microbial metabolites including short-chain fatty acids. These interacting pathways demonstrate a combined impact on neuroprotection, synaptic plasticity, and the modulation of disease progression in neurodegenerative conditions.

CONCLUSION: Physical activity represents a promising non-pharmacological strategy for modulating the gut-brain axis in neurodegenerative conditions. Understanding the interplay between muscle-derived signals and gut-mediated pathways may open new avenues for targeted interventions aimed at slowing or preventing neurodegenerative decline.},
}

@article {pmid42576612,
year = {2026},
author = {Carrier, T and Rouleau, I and St-Georges, MA and Afrooz, P and Montembeault, M},
title = {Deficits in the knowledge of social norms and their correlates in Alzheimer's disease.},
journal = {The Clinical neuropsychologist},
volume = {},
number = {},
pages = {1-18},
doi = {10.1080/13854046.2026.2712921},
pmid = {42576612},
issn = {1744-4144},
abstract = {Objective: Compared to other components of social cognition, knowledge of social norms has received less attention in the scientific literature. While social cognitive and semantic memory deficits appear early in the course of Alzheimer's disease (AD), no study has examined knowledge of social norms at earlier stages of the disease. In addition, it is unclear whether the knowledge of social norms in AD is associated with socioemotional deficits, as may be seen in the behavioral variant of frontotemporal dementia (bvFTD). Method: This study included 136 participants with amnestic mild cognitive impairment (aMCI), 134 with AD, most of whom were younger than 65 years, 280 with bvFTD, and 361 older healthy controls (HC). All participants were selected from the National Alzheimer's Coordinating Center (NACC). They completed the Social Norms Questionnaire (SNQ), which assesses the tendency to break or overadhere to social norms. They also completed tests assessing executive, semantic, and socioemotional functions. Results: Between-group comparisons showed that individuals with AD and aMCI made significantly more Break and Overadhere errors than HC, while they demonstrated better social norms knowledge than individuals with bvFTD. In aMCI and AD, social norms overadherence errors were most consistently associated with executive functioning. In bvFTD, semantic memory was the most consistent correlate across all SNQ variables. Conclusions: These findings may help clinicians and researchers better understand social cognitive changes in patients, support the inclusion of social norms knowledge assessment within broader neuropsychological evaluations, and provide complementary insight into the cognitive correlates of social knowledge loss in major neurocognitive disorders.},
}

@article {pmid42576814,
year = {2026},
author = {Singh, N and Guha, L and Kumari, A},
title = {Exosome-based nanomedicine for neurological disorders: mechanisms, engineering, and therapeutic potential.},
journal = {Therapeutic delivery},
volume = {},
number = {},
pages = {1-40},
doi = {10.1080/20415990.2026.2715878},
pmid = {42576814},
issn = {2041-6008},
abstract = {Exosomes are naturally occurring extracellular vesicles that have emerged as promising bio-inspired nanocarriers for the treatment of neurological disorders owing to their intrinsic biocompatibility, low immunogenicity, and ability to cross the blood-brain barrier. This review highlights recent advances in exosome biology, cargo-sorting mechanisms, and engineering strategies designed to enhance therapeutic delivery and targeting within the central nervous system. Particular emphasis is placed on the application of engineered exosomes in neurodegenerative diseases, stroke, spinal cord injury, neuropathic pain, and neuroinflammatory disorders. In addition, we discuss how exosomes compare with conventional delivery platforms and critically examine the major barriers limiting their clinical translation, including heterogeneity, scalability, reproducibility, purity, and regulatory standardization. By integrating mechanistic insights with translational perspectives, this review provides a framework for the rational design and future clinical implementation of exosome-based nanomedicines for neurological disorders. Relevant literature was identified through searches of PubMed, Scopus, Web of Science, and Google Scholar. Publications available from database inception through [Month Year] were screened using combinations of keywords including "exosomes," "extracellular vesicles," "neurological disorders," "brain-targeted delivery," "exosome engineering," "drug delivery," and "clinical trials." Additional relevant articles were identified through manual searches of reference lists from selected studies and recent reviews.},
}

@article {pmid42577088,
year = {2026},
author = {Zheng, K and Tsitsos, FN and Konofagou, EE and Leong, KW},
title = {Focused ultrasound-mediated lipid nanoparticle delivery for brain gene editing.},
journal = {Molecular therapy. Nucleic acids},
volume = {37},
number = {3},
pages = {103012},
pmid = {42577088},
issn = {2162-2531},
abstract = {Efficient brain gene editing remains constrained by the lack of delivery platforms that combine efficacy, spatial precision, and translational potential. Compared with viral vectors, lipid nanoparticles (LNPs) offer larger cargo capacity and lower immunogenicity for repeat dosing. However, their brain delivery is restricted by the blood-brain barrier (BBB). Here, we show that focused ultrasound (FUS)-mediated BBB opening enables systemic delivery of CRISPR-encoding plasmid DNA (pDNA)-LNPs for brain gene editing. Using a pDNA construct containing astrocyte-targeting GfaABC1D promoter and dual guide RNAs targeting apolipoprotein E4 (APOE4), the strongest genetic risk factor for Alzheimer's disease, we achieved efficient APOE4 knockdown, with reduced APOE4 mRNA and apoE4 protein expression, and attenuated astrocytes and microglial activation. These results establish FUS-mediated pDNA-LNP delivery as a non-invasive, non-viral strategy for brain gene editing that provides spatial control and cell-type-specific expression, while accommodating large genetic payload and enabling repeatable dosing.},
}

@article {pmid42577096,
year = {2026},
author = {Gaborit, M and Arabi, A and Mariotti, L},
title = {The emerging role of astrocytes in spatial cognition, action and Alzheimer's disease.},
journal = {Frontiers in cellular neuroscience},
volume = {20},
number = {},
pages = {1811370},
pmid = {42577096},
issn = {1662-5102},
abstract = {Astrocytes sense synaptic activity, neuromodulation, and metabolic signals, and respond by modulating neurotransmission, excitability, and plasticity in neural networks. Increasing evidence demonstrates that these processes contribute to information processing and encoding across brain areas, thereby influencing perception, memory, cognition, and goal-directed behaviours. Notably, impairments in these functions represent some of the earliest hallmarks of ageing and neurodegenerative disorders such as Alzheimer's disease. Here we review molecular, cellular, and computational insights into astrocyte-neuron interactions, framing their importance at the system and behavioural level; then, we discuss the role of these interactions in spatial cognition, goal-directed behaviour, and their impairment in Alzheimer's disease, and review the mouse models used to investigate spatial deficits and associated astrocyte activity. Finally, we highlight major open questions in the field, outline future research directions, and discuss emerging strategies to address astrocyte role in cognitive function in health and disease.},
}

@article {pmid42577185,
year = {2026},
author = {Highet, B and Singh-Bains, M and Eszes, M and Parker, R and McShane, E and Webb-Robinson, C and Hubbard, K and Biggins, F and Sharma, S and Bell, P and Burnett, O and Lehnert, K and Jacobsen, JC and Ryan, B and Hu, M and Turner, C and Faull, RLM and Curtis, MA},
title = {Operational, molecular, and cultural perspectives at the Neurological Foundation Human Brain Bank, New Zealand.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1900088},
pmid = {42577185},
issn = {1664-2295},
abstract = {Post-mortem human brain tissue is an irreplaceable resource for advancing understanding of the brain and neurological disease. Brain banks that collect, preserve, and distribute this tissue underpin discoveries across neuropathology, genomics, and emerging molecular disciplines. Yet brain banking is a resource-intensive enterprise that faces distinct operational, cultural, and scientific challenges depending on the national context in which it operates. Here, we present the perspective of the Neurological Foundation Human Brain Bank (NFHuBB) - New Zealand's sole post-mortem human brain bank, based at The University of Auckland. Operating as the only such facility in the country, the NFHuBB confronts a unique convergence of challenges: the logistical complexity of coordinating donation across a dispersed population, the scientific imperative to preserve tissue for molecular-era multi-omics technologies, and a multi-cultural population that needs culturally informed consent practices. We describe the growth of the bank's donor registry and collection over 45 years with specific emphasis on donations in the last five calendar years (2021-2025), outline recent advances in tissue processing, including the development of formalin-fixed paraffin-embedded (FFPE) RNA preservation protocols and integration of whole-genome sequencing from un-fixed cerebellar tissue. Finally, we discuss the community engagement strategies that have supported increasing donation rates in New Zealand.},
}

@article {pmid42577242,
year = {2026},
author = {Meera, B and Hiatt, M and Hays, A and Punshon, S and Christensen, JR and Fields, B},
title = {Implementation of Riding in the Moment™: the crucial role of implementer preparedness and satisfaction in an adaptive horseback riding program for older adults with dementia.},
journal = {Frontiers in health services},
volume = {6},
number = {},
pages = {1799552},
pmid = {42577242},
issn = {2813-0146},
abstract = {INTRODUCTION: Riding in the Moment™ (RM) is a community-based, standardized, evidence-informed equine-assisted service program designed to support individuals with Alzheimer's disease and related dementias and their caregivers through social connection, physical activity, and meaningful engagement. Delivered by trained non-clinical personnel, RM's long-term success depends on effective implementation and sustainability in real-world settings. This project explored implementation strategies used to deliver RM, focusing on staff and volunteer preparedness and satisfaction.

METHODS: A repeated measures survey design that included closed-ended items and open-ended questions, guided by the RE-AIM framework, was used to explore implementation strategies. Pre-and post-implementation surveys assessed training satisfaction, perceived preparedness, and delivery experience among RM staff and volunteers. Quantitative data were analyzed using descriptive statistics, while qualitative feedback was organized into key categories. Implementation and fidelity checklists were also completed.

RESULTS: Majority of the participants (95%; n = 21) reported overall satisfaction with training and felt prepared to deliver RM. All fidelity checklist items were met, indicating strong adherence to program protocols. Post-implementation, majority of the participants (74%; n = 11) were extremely satisfied with RM, and 100% (n = 15) stated they would recommend the program. Qualitative feedback emphasized the emotional impact of the experience, value of structured training, and opportunities to improve volunteer engagement and communication.

DISCUSSION: This program evaluation project contributes to understanding early-stage implementation considerations for community-based dementia-specific programs in real-world settings. Continued evaluation is needed to determine how these factors influence long-term implementation, program sustainability, and scalability across broader settings.},
}

@article {pmid42577281,
year = {2026},
author = {Dhapola, R and Sharma, P and Kumari, S and Vellingiri, B and HariKrishnaReddy, D},
title = {Neuroprotective effect of normal and modified mesenchymal stem cell-derived exosomes by mitigating Alzheimer's-related oxidative and inflammatory damage via Nrf2/HO-1 in SH-SY5Y cells.},
journal = {Ibrain},
volume = {},
number = {},
pages = {},
pmid = {42577281},
issn = {2769-2795},
abstract = {Exosome therapy is emerging as a promising neuroprotective strategy for Alzheimer's disease (AD). We evaluated and compared whether normal exosomes (NE) and modified exosomes (ME) derived from AD rat brain extract-treated rat bone marrow mesenchymal stem cells possess the potential to protect SH-SY5Y cells against streptozotocin (STZ) induced toxicity. The effect of exosomes on oxidative stress, inflammation and neuronal survival was evaluated. Further, antioxidant mechanism of exosomes by nuclear factor erythroid 2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) signaling was explored. Cells were exposed to 5 mM STZ and treated with NE and ME at an equivalent concentration of 50 µg/mL. Exosomes were characterized by specific exosomal markers, CD63 and CD9. Cell viability was assessed using the MTT assay. Neuronal growth and survival were evaluated by measuring brain-derived neurotrophic factor (BDNF) using ELISA and neuronal nuclei (NeuN) expression using immunocytochemistry. Intracellular reactive oxygen species (ROS) levels were determined using H2DCFDA, while inflammatory mediators, including interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were quantified by ELISA. Expression levels of Nrf2 and HO-1 were also determined. Exosome treatment improved cell viability, reduced ROS, and lowered IL-6 and TNF-α levels. Immunocytochemistry quantification showed increased nuclear Nrf2 and HO-1 expression in exosome-treated cells. Moreover, our data indicate that ME derived from AD rat brain extract-treated rat bone marrow mesenchymal stem cells are more potent in protecting SH-SY5Y cells from STZ-induced oxidative stress and inflammation, possibly via Nrf2/HO-1 signaling, as compared to NE. These in vitro results support further preclinical evaluation of exosome-based strategies for AD.},
}

@article {pmid42577341,
year = {2026},
author = {Chattopadhyay, T and Kush, R and Ankarath, RH and Senthilkumar, P and Gleave, EJ and Patterson, C and Owens-Walton, C and Thomopoulos, SI and Johnson, SC and Mormino, EC and Tosun, D and Hohman, TJ and Thompson, PM},
title = {Multi-modal deep learning and explainable AI for predicting multiple dementia-related neuropathologies from brain MRI, clinical, and genetic data.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1839071},
pmid = {42577341},
issn = {1664-2295},
abstract = {Alzheimer's disease and related dementias (ADRD) typically involve multiple, overlapping pathologies-such as amyloid-β (Aβ), tau, cerebral amyloid angiopathy (CAA), TDP-43, hippocampal sclerosis, and alpha-synuclein-that complicate diagnosis and treatment. While PET and CSF biomarkers can detect abnormal levels of Aβ and tau, they are invasive, expensive, and not widely available. By contrast, structural magnetic resonance imaging (MRI) offers a non-invasive and scalable alternative, one that is now showing promise for neuropathological prediction when combined with artificial intelligence methods. Prior efforts have largely focused on inferring single pathologies such as abnormal Aβ; however, there is a pressing need for models that can jointly predict multiple co-occurring pathologies. In this work, we develop and evaluate a hybrid deep learning framework that integrates 3D T1-weighted brain MRI with demographic, clinical, and genetic covariates to make inferences, in living individuals, regarding the presence of six ADRD pathologies. The models are trained and tested using autopsy-confirmed neuropathology from individuals who were scanned while they were alive. Based on their strong performance on related tasks, we evaluate two machine learning models: (1) a deep learning algorithm based on a 3D convolutional neural network, a widely used model in computer vision applications, and (2) AutoGluon, an automated machine learning framework that automatically selects an approach for the problem. Each method can use both imaging and non-imaging covariates as inputs. To improve model transparency, we incorporate explainable AI methods-including occlusion sensitivity analysis (OSA), Grad-CAM, and Integrated Gradients (IG)-to interpret the spatial contribution of brain regions to model predictions. Finally, we compare the resulting feature importance maps ('salience maps') with traditional voxel-based morphometry (VBM) analyses to assess their biological plausibility. Our findings show the promise of multimodal, interpretable AI approaches for comprehensive, non-invasive profiling of dementia-related pathologies.},
}

@article {pmid42577349,
year = {2026},
author = {Xu, Z and Li, H and Liu, W and Li, H},
title = {ScaleSpecter: a frequency-aware multi-scale patch framework for robust physiological classification under non-stationarity.},
journal = {Frontiers in human neuroscience},
volume = {20},
number = {},
pages = {1856803},
pmid = {42577349},
issn = {1662-5161},
abstract = {INTRODUCTION: Early detection and intervention for cognitive impairment associated with neurodegenerative diseases are important for slowing disease progression and improving quality of life. Electroencephalography provides high temporal resolution and sensitivity to neural oscillations, making it a promising tool for early disease identification. However, weak and transient pathological abnormalities are often obscured by diffuse, non-stationary low-frequency background rhythms, making robust feature extraction challenging.

METHODS: We propose ScaleSpecter, a frequency-aware multiscale patch framework for neurodegenerative disease-related EEG classification. ScaleSpecter first constructs temporal representations at multiple scales to jointly capture transient local abnormalities and long-term rhythmic variations. A lightweight cross-scale attention mechanism then enables interaction between fine-grained temporal tokens and coarse scale-level summaries. Finally, an amplitude-phase-aware spectral modulation module uses learnable complex-valued weights to recalibrate spectral responses and provide frequency-domain guidance for temporal feature aggregation.

RESULTS: Extensive experiments were conducted on three public EEG datasets: the Alzheimer's Disease and Frontotemporal Dementia (ADFTD) dataset, the Alzheimer's Patients' Relatives Association of Valladolid (APAVA) dataset, and the Two Decades-Brainclinics Research Archive for Insights in Neurophysiology (TDBRAIN) database. These datasets cover classification tasks related to Alzheimer's disease, frontotemporal dementia, and Parkinson's disease. ScaleSpecter achieved competitive and generally favorable performance on most key evaluation metrics. The ablation and visualization results further demonstrated the complementary contributions of multiscale temporal modeling, cross-scale interaction, and spectral modulation.

DISCUSSION: The results suggest that integrating frequency-domain guidance with multiscale temporal representations can improve the discriminative capability and robustness of EEG classification under non-stationary conditions. ScaleSpecter provides a potentially generalizable framework for neurodegenerative disease-related physiological signal analysis.},
}

@article {pmid42577352,
year = {2026},
author = {Lu, LC and Lan, SH and Lan, SJ and Hsieh, YP},
title = {Effectiveness of noninvasive brain stimulation techniques on cognitive function in individuals with Alzheimer's disease and MCI: a systematic review and meta-analysis.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1782521},
pmid = {42577352},
issn = {1663-4365},
abstract = {BACKGROUND: Noninvasive brain stimulation (NIBS) may alleviate cognitive impairments in individuals with Alzheimer's disease (AD). However, clinical findings remain inconsistent, highlighting the need for a systematic review and meta-analysis to clarify the efficacy of NIBS.

OBJECTIVE: To compare the effects of NIBS and sham stimulation on global cognition in individuals with AD.

METHODS: Randomized controlled trials were identified from PubMed, Web of Science, Scopus, and the Cochrane Central Register of Controlled Trials by using relevant search terms. Cognitive outcomes were assessed using objective scales, and pooled standardized mean differences with 95% confidence intervals (CIs) were calculated using a random-effects model.

RESULTS: NIBS was associated with significant improvements in global cognition in individuals with AD, as measured using the Mini-Mental State Examination (MMSE; standardized mean difference = 0.58, 95% CI = 0.32 to 0.84, p < 0.001) and Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog; standardized mean difference = -0.40, 95% CI = -0.68 to -0.13, p = 0.004). The subgroup analysis revealed that treatment is efficacious when patients are stable medication users for 3 months or less (MMSE scores), intervention is delivered for 6 weeks, and NIBS is administered singularly. Longer duration of pharmacological treatment was associated with reduced NIBS efficacy on MMSE scores in both the meta-regression and subgroup analyses. Cognitive gains based on MMSE outcomes were maintained at 4 and 8 weeks after treatment.

CONCLUSION: This meta-analysis provides evidence for the effects of NIBS on common cognitive outcomes in AD and explores potential moderators related to sample and intervention characteristics.

https://www.crd.york.ac.uk/PROSPERO/view/CRD420251065634.},
}

@article {pmid42577392,
year = {2026},
author = {Tan, NIYZ and Welton, T and Tan, YJ and Saffari, SE and Morgenroth, E and Foo, SJY and Kwok, ZR and Lim, YC and Chiew, HJ and Ng, KP and Ting, SKS and Kumar, S and Keong, N and Ng, ASL},
title = {Choroid plexus enlargement is negatively associated with cognitive performance in a DTI-ALPS-dependent manner.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1883244},
pmid = {42577392},
issn = {1663-4365},
abstract = {BACKGROUND: Disturbances in brain fluid homeostasis are increasingly implicated in neurodegeneration. Imaging measures of structural alterations of the choroid plexus (CP) and impaired glymphatic transport have each been associated with cognitive decline, yet their potential interaction in humans remains poorly understood.

METHODS: We investigated the relationship between CP volume, glymphatic diffusion, and cognitive performance in 100 memory clinic patients. Diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) was used as an imaging proxy of glymphatic diffusion, and CP volume and WMH volume were derived from structural MRI using FastSurfer segmentation. Multivariable linear regression models examined associations between CP volume, ALPS index, and global cognitive performance measured by the Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE). Models were adjusted for age, sex, education, APOE ε4 status, WMH burden and plasma phosphorylated tau (pTau217). Interaction terms tested whether CP structure and glymphatic diffusion jointly influenced cognition.

RESULTS: Larger CP volume was associated with lower ALPS index after adjustment for demographic and molecular covariates (β = -282.19, p = 0.015). CP volume and ALPS index were not independently associated with MoCA scores; however, a significant interaction between CP volume and ALPS index was observed (β = -13,299.09, p = 0.036). The association between CP volume and cognitive performance depended on DTI-ALPS, such that larger CP volumes were associated with poorer MoCA scores at higher ALPS values, whereas CP volume showed little association with cognition at lower ALPS values. This interaction improved model fit compared with main-effects models (R[2]  = 0.31). The findings remained significant after adjusting for CSF volume and were replicated using MMSE as the outcome. Plasma pTau217 levels were strongly associated with worse cognition but did not significantly modify the CP-ALPS interaction.

CONCLUSION: CP enlargement is associated with glymphatic diffusion, and its relationship with cognitive performance varies across DTI-ALPS index values. These findings suggest that interactions between CSF regulatory systems may correlate with cognitive performance in a state-dependent manner. Notably, higher ALPS values in individuals with enlarged CP may reflect compensatory or altered perivascular fluid dynamics rather than preserved glymphatic function, highlighting the complexity of interpreting diffusion-based markers of brain clearance.},
}

@article {pmid42577438,
year = {2026},
author = {Harris, GA and Barnhard, L and Brummet, J and Diaz, K},
title = {From clinical phenotypes to molecular precision: multimodal biomarkers for progressive supranuclear palsy.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1893149},
pmid = {42577438},
issn = {1662-4548},
abstract = {Progressive Supranuclear Palsy (PSP) is the most prevalent primary 4R-tauopathy, characterized by the pathogenic accumulation of misfolded tau protein within neurons and glial cells. Historically, clinical diagnosis relied upon the identification of Richardson's Syndrome, however, the recognition of diverse clinical phenotypes that overlap with Parkinson's disease, corticobasal syndrome, and frontotemporal dementia has complicated the diagnostic landscape and hindered the success of developing therapeutic interventions. As the field transitions toward a precision medicine paradigm, there is a growing need for validated biomarkers that can provide molecular specificity, facilitate early diagnosis, and accurately track disease progression. This paper reviews the recent advancements in neuroimaging and fluid-based biomarkers, assessing their potential to delineate PSP from similar neurodegenerative conditions and unlock the 4R-tau therapeutic pipeline. In the domain of neuroimaging, while structural magnetic resonance imaging (MRI) and the Magnetic Resonance Parkinsonism Index (MRPI) continue to provide measures of subcortical atrophy, the emergence of second-generation tau-selective positron emission tomography (PET) radioligands represents a transformative shift. New tau PET tracers offer the ability to visualize tau pathology in vivo, providing a more direct assessment of the underlying proteinopathy than traditional volumetric measures. These advancements are complemented by significant progress in fluid biomarkers. Plasma phosphorylated tau at residue 217 (p-tau217) has gained prominence as a robust marker for Alzheimer's disease, and its primary utility in PSP research currently serves as a critical negative signature to exclude amyloid-associated co-pathology. In contrast, novel assays targeting microtubule-binding region tau fragments show burgeoning potential for the specific identification of 4R-tau isoforms. Furthermore, neurofilament light chain (NfL) has been firmly established as a sensitive, albeit non-specific, indicator of neuroaxonal injury and clinical severity. Additional advancements with digital health approaches and electrophysiological assessments add to the opportunities for improved objective measures. This review concludes that the shift from clinical-only diagnostic criteria to a biomarker-enabled molecular framework is the necessary catalyst for developing effective disease-modifying therapies for PSP and related 4R-tauopathies. The synthesis of these multimodal biomarkers into a unified framework will be essential to improve participant stratification, enable the use of adaptive trial models, and provide supportive evidence of target engagement for future clinical trials.},
}

@article {pmid42577455,
year = {2026},
author = {Sabari Vasan, S and Jayalakshmi, P},
title = {TriFusion-ADFormer: a deep learning framework for early Alzheimer's disease detection using MRI and cognitive metrics.},
journal = {Frontiers in artificial intelligence},
volume = {9},
number = {},
pages = {1849315},
pmid = {42577455},
issn = {2624-8212},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with the gradual loss of cognitive functions and neuronal degeneration. Early and accurate diagnosis is essential for timely therapeutic intervention and improved patient management. However, effectively integrating complementary multimodal information for reliable AD classification remains a significant challenge.

METHODS: This study proposes TriFusion-ADFormer, a multimodal deep learning framework for multiclass classification of Alzheimer's disease (AD), mild cognitive impairment (MCI), and cognitively normal (CN) subjects. The framework extracts structural MRI features and MRI-derived clinical text summary based on volumetric measurements and cognitive assessment features such as MMSE, GDS, Global CDR, FAQ, and NPI-Q, then fuses them to classify the disease.

RESULTS: The proposed TriFusion-ADFormer achieved an overall classification accuracy of 86.0%, a Macro AUC of 0.93, and an F1-score of 86.0% for multiclass AD classification. Moreover, the MRI-based clinical summaries were also consistently consistent with structural abnormalities typically associated with AD, such as diffuse brain atrophy, which further supports the interpretability of the proposed framework.

DISCUSSION: The results show that the combination of multimodal information from structural MRI, semantic clinical summary generated from the MRI, and cognitive assessment scores enhances the accuracy and interpretability of Alzheimer's diagnosis. The results highlight the potential of incorporating complementary imaging, semantic, and cognitive features for better multiclass classification of AD, MCI, and CN in a transformer framework.},
}

@article {pmid42577511,
year = {2026},
author = {Tulupova, TV and Vedunova, MV and Mitroshina, EV},
title = {The prognostic potential of circulating BDNF levels and its polymorphisms in age-related cognitive impairment and neurodegeneration.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1901527},
pmid = {42577511},
issn = {1663-4365},
abstract = {Brain-derived neurotrophic factor (BDNF) is essential for neuronal survival, synaptic plasticity, and cognitive function. Age-related decline in BDNF signaling has been implicated in the pathogenesis of Alzheimer's disease, Parkinson's disease, and mild cognitive impairment. However, the prognostic value of circulating BDNF and its genetic variants remains controversial due to inconsistent findings across studies. This review synthesizes current evidence on peripheral BDNF levels and the Val66Met polymorphism as potential biomarkers of age-related cognitive decline and neurodegeneration. We critically analyze biological mechanisms linking BDNF to neurodegeneration, including its interaction with amyloid-beta and tau pathology. We further examine factors underlying discrepant results: demographic characteristics, comorbidities, lifestyle factors, pharmacological interventions, and methodological variability. Despite these challenges, BDNF remains a promising diagnostic factor. Nevertheless, standardizing preanalytical protocols and accounting for patient heterogeneity are essential to unlock its diagnostic potential.},
}

@article {pmid42577545,
year = {2026},
author = {Senapati, SG},
title = {Insulin resistance, aging biology, and non- communicable chronic diseases: a narrative review of bidirectional mechanisms and translational implications.},
journal = {Frontiers in endocrinology},
volume = {17},
number = {},
pages = {1891078},
pmid = {42577545},
issn = {1664-2392},
mesh = {Humans ; *Insulin Resistance/physiology ; *Aging/metabolism/physiology ; Animals ; *Noncommunicable Diseases/epidemiology ; Hyperinsulinism/metabolism ; Chronic Disease ; },
abstract = {BACKGROUND: Insulin resistance has been considered a metabolic disorder related to obesity, metabolic syndrome, and type 2 diabetes mellitus. Growing evidence points to possible interactions between insulin resistance and hyperinsulinemia and the biological aging process and age-related non-communicable diseases, like cardiovascular disease, neurodegenerative disorders, sarcopenia, frailty, adipose tissue dysfunction, chronic kidney disease, and liver disease. Most published associations lack causality, and some biological aging mechanisms may also independently increase the risk for both insulin resistance and chronic disease.

AIM: In this narrative review, we summarize bidirectional connections between insulin resistance, compensatory hyperinsulinemia, aging biology, and age-related non-communicable diseases and the quality of existing data.

METHODS: We performed a structured narrative literature review for mechanistic, translational, omics, epidemiologic, and intervention studies on the connection between insulin resistance and biological mechanisms of aging and chronic disease.

RESULTS: Mechanisms of age-related disease that may be affected by insulin resistance include insulin/IGF-1 signaling disruption, hyperinsulinemia, mitochondria dysfunction, oxidative stress, endothelial dysfunction, adipokine imbalance, chronic low-grade inflammation, cell senescence, ectopic lipids accumulation, AGE-RAGE signaling, and autophagy impairment. Aging mechanisms, such as cell senescence, mitochondria dysfunction, inflammaging, altered nutrient sensing, impaired proteostasis, adipose tissue remodeling, and physical inactivity may contribute to insulin resistance. Quality of evidence differs from strong to associative and exploratory depending on disease domain.

CONCLUSION: It is important to understand insulin resistance as an important mediator in reciprocal network of connections between metabolism, biological aging, and age-related chronic diseases, rather than one of the causes of aging.},
}

Humans
*Insulin Resistance/physiology
*Aging/metabolism/physiology
Animals
*Noncommunicable Diseases/epidemiology
Hyperinsulinism/metabolism
Chronic Disease

@article {pmid42577708,
year = {2026},
author = {Gelman, A and Nielsen, LK and Hansen, C},
title = {A Novel Plate Reader-Based Protocol for Measurement of DNAJB6 Dimerization Activity.},
journal = {Bio-protocol},
volume = {16},
number = {15},
pages = {e5776},
pmid = {42577708},
issn = {2331-8325},
abstract = {Progressive neurodegeneration linked to the accumulation of misfolded proteins is a hallmark of several neurodegenerative disorders, including Parkinson's disease, Huntington's disease, and Alzheimer's disease. Dysfunction in the protein homeostasis machinery correlates with pathology. The chaperone protein DNAJB6 is expressed in neurons and oligodendrocytes and has been shown to play a key role in preventing amyloid aggregation by binding to amyloidogenic proteins and facilitating their refolding or degradation, in cooperation with other chaperones. Here, we describe a simple and feasible assay that enables high-throughput screening for DNAJB6 activity in a plate reader format. We use genetically engineered HEK293 cells that stably express DNAJB6 fused to either CFP or YFP. These cells can be plated into multi-well plates, and the fluorescence resonance energy transfer (FRET) signal can be measured for analysis of DNAJB6 dimerization, which is linked to DNAJB6 activity. The protocol can be used for drug screening and to identify compounds that increase DNAJB6 dimerization, and can serve as a starting point for finding new medicines that act through modulating DNAJB6 activity. Key features • The protocol requires a plate reader capable of FRET analysis and bandwidth adjustment for CFP/YFP separation. It was developed using a CLARIOstar plate reader. • The protocol requires access to the authors' FRET DNAJB6 cell line or equivalent cells with stable expression of CFP/YFP-DNAJB6. • The assay measures DNAJB6 dimerization and can potentially be adapted to other proteins whose functional state is linked to dimerization activity. • The protocol is useful for compound screening purposes and requires pre-existing knowledge of basic cell culture.},
}

@article {pmid42578020,
year = {2026},
author = {Riccardi, C and Napolitano, E and Platella, C and Conte, A and Paladino, S and Musumeci, D and Montesarchio, D},
title = {Lipid-conjugated Ru(iii) complexes as inhibitors of pathological peptide aggregation in neurodegenerative disorders.},
journal = {RSC medicinal chemistry},
volume = {},
number = {},
pages = {},
pmid = {42578020},
issn = {2632-8682},
abstract = {Neurodegenerative diseases (NDs), characterized by the progressive loss of neuronal homeostasis and function, represent an increasing global health burden. Their severity and profound impact on quality of life highlight the urgent need for effective and targeted therapeutic strategies. Recent studies have drawn attention to the potential of certain Ru(iii) complexes, including NAMI-A and KP1019, as promising therapeutic candidates for NDs. Originally developed as anticancer agents, these compounds have demonstrated remarkable activity in inhibiting the aggregation of model misfolded proteins, which represent a common pathological feature of various neurological disorders. Herein, searching for Ru(iii) complexes which could be effective as anti-neurodegenerative agents, we selected AziRu - a NAMI-A-like compound - and some of its lipid-conjugated derivatives, previously explored as anticancer drug candidates, and tested them for their ability to interfere with the self-aggregation of selected model peptides involved in the pathogenesis of NDs, such as Alzheimer's disease (AD), Parkinson's disease (PD) and prion diseases. Among them, the Ru(iii) complexes we named MyriPyRu and PalmiPyRu, bearing myristic and palmitic acid-based tails, respectively, emerged as promising candidates. These complexes effectively modulated and inhibited the aggregation of amyloid peptides linked to AD pathogenesis with IC50 values in the low micromolar range (ca. 5 μM for both compounds). More detailed studies on their interaction with AD peptides revealed their capacity to be coordinated by histidine residues in the N-terminal region. Biological investigations on human neuroblastoma-derived cells indicated no relevant cytotoxicity at concentrations comparable to those that caused anti-aggregation effects. Overall, these findings are highly promising, as MyriPyRu or PalmiPyRu could be the starting compounds to evolve further modified derivatives functionalized with specific targeting moieties for amyloid peptides, potentially paving the way to a new generation of Ru(iii)-based anti-amyloid agents for the treatment of Alzheimer's disease.},
}

@article {pmid42578069,
year = {2026},
author = {Chen, HW},
title = {Active Craniospinal Tensioning (ACT) for Posture Correction and Spinal Decompression: Biomechanical Rationale for Glymphatic Clearance and Cerebral Venous Preconditioning (CVPC).},
journal = {Cureus},
volume = {18},
number = {7},
pages = {e112433},
pmid = {42578069},
issn = {2168-8184},
abstract = {For approximately two-thirds of each 24-hour period, the upright human spine bears a continuous gravitational load; yet no common movement or exercise naturally produces meaningful axial decompression of the entire spine. Active craniospinal tensioning (ACT) addresses this unmet need through a brief, self-administered squat maneuver against an overhead anchor, intended to generate reproducible axial spinal decompression without specialized equipment. This report, which extends a previously published series on axial spinal traction, presents ACT as a postural correction and spinal decompression intervention. Building on those findings, a second distinct hypothesis is advanced: that two transient physiological events occurring simultaneously during the maneuver may together acutely accelerate glymphatic clearance. The first is a cerebrospinal fluid (CSF) pressure gradient generated during traction and rapidly reversed upon release, as detailed in the previous technical reports; the second is suboccipital venous occlusion during the tensioning phase, followed by a rebound upon release. The second mechanism, suboccipital venous occlusion-rebound, is further proposed as a novel venous-side modality for cerebral venous preconditioning (CVPC), distinct from existing arterial-based ischemic preconditioning approaches, whether local or remote (e.g., remote ischemic preconditioning (RIPC)). Diffusion tensor image analysis along the perivascular space (DTI-ALPS) is proposed as the primary falsifiable endpoint for the glymphatic clearance hypothesis, which does not itself test the separately proposed CVPC effect of suboccipital venous occlusion-rebound. If confirmed, this endpoint would support glymphatic clearance as an additional mechanism of ACT, positioning ACT, alongside its proposed roles in posture correction, spinal decompression, and cerebral venous preconditioning (CVPC), as a brief, self-administered maneuver addressing multiple physiological targets through daily applications totaling less than one minute, without specialized equipment or clinical access.},
}

@article {pmid42578101,
year = {2026},
author = {Chandra, G and Rangasamy, SB and Pahan, K},
title = {Corrected Version: Neutralization of RANTES and Eotaxin Prevents the Loss of Dopaminergic Neurons in a Mouse Model of Parkinson's Disease.},
journal = {Journal of clinical & experimental immunology},
volume = {11},
number = {3},
pages = {},
pmid = {42578101},
abstract = {Parkinson's disease (PD) is second only to Alzheimer's disease as the most common human neurodegenerative disorder. Despite intense investigation, no interdictive therapy is available for PD. Recent studies indicate that both innate and adaptive immune processes are active in PD. Accordingly, we found rapid increase in RANTES (regulated on activation, normal T cell expressed and secreted) and eotaxin, chemokines that are involved in T cell trafficking, in vivo in the substantia nigra pars compacta (SNpc) and the serum of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxicated mice. RANTES and eotaxin were also upregulated in the SNpc of postmortem PD brains as compared to age-matched controls. Therefore, we investigated whether neutralization of RANTES and eotaxin could protect against nigrostriatal degeneration in MPTP-intoxicated mice. Interestingly, after peripheral administration, functional blocking antibodies against RANTES and eotaxin reduced the infiltration of CD4+ and CD8+ T cells into the nigra, attenuated nigral expression of proinflammatory molecules, and suppressed nigral activation of glial cells. These findings paralleled dopaminergic neuronal protection, normalized striatal neurotransmitters, and improved motor functions in MPTP-intoxicated mice. Therefore, we conclude that attenuation of chemokine-dependent adaptive immune response may be of therapeutic benefit for PD patients.},
}

@article {pmid42578165,
year = {2026},
author = {Kachhadia, MP and Puri, P and Topiwala, U and Shaikh, JD and Gill, G and Gupta, S and Byrus, M and Sanghvi, HA},
title = {Retinal Artery Occlusion and Incident Dementia in the All of Us Research Program: Detection Bias Calibration with Prespecified Negative-Control Outcomes.},
journal = {Journal of clinical medicine research},
volume = {18},
number = {7},
pages = {489-495},
pmid = {42578165},
issn = {1918-3003},
abstract = {BACKGROUND: Retinal artery occlusion (RAO) shares vascular pathophysiology with cerebrovascular disease, and its relationship to incident dementia remains unsettled. Reported associations may reflect shared vascular pathology, differential ascertainment along the intensive workup pathways that RAO patients enter, or both. No prior study has calibrated RAO-dementia estimates against prespecified negative-control outcomes spanning distinct ascertainment pathways.

METHODS: Among 129,279 All of Us participants aged 50 years or older and free of prevalent dementia (controlled-tier release R2024Q3R9, OMOP common data model), strict RAO was defined by seven verified SNOMED concept identifiers (n = 339). Incident dementia required two or more codes at least 30 days apart (Wilkinson algorithm), with prespecified vascular and Alzheimer subtypes. Cox models used age as timescale with left truncation and time-varying exposure; 1:5 propensity-score matching was the primary confounder-adjusted analysis. Cataract, benign paroxysmal positional vertigo (BPPV), and inguinal hernia were prespecified negative controls for ophthalmology, neurology, and general-contact pathways.

RESULTS: There were 1,506 incident dementia events. RAO was not associated with all-cause dementia (unmatched hazard ratio (HR) 0.81, 95% confidence interval (CI) 0.40-1.64; matched HR 1.33, 95% CI 0.72-2.47; 10 exposed events). The vascular dementia estimate remained elevated but imprecise (unmatched HR 1.93, 95% CI 1.02-3.66; matched HR 1.81, 95% CI 0.66-4.94; 3 exposed events). Cataract was elevated (HR 1.87, 95% CI 1.45-2.42), whereas BPPV (HR 1.27, 95% CI 0.90-1.79) and hernia (HR 1.10, 95% CI 0.68-1.78) were not.

CONCLUSIONS: We found no evidence that RAO is independently associated with incident dementia, replicating a large European null finding in a diverse United States cohort. The cohort was underpowered to exclude clinically meaningful effects, particularly for vascular dementia. Detection bias in this dataset was demonstrably pathway-specific, but same-pathway calibration accounts for only part of the residual vascular dementia estimate.},
}

@article {pmid42578315,
year = {2026},
author = {Chib, S and Shukla, S and Sharma, K and Singh, R},
title = {Luteolin and neurodegenerative disease modulation: linking molecular mechanisms, neurotransmission, and pharmacokinetics.},
journal = {Nutritional neuroscience},
volume = {},
number = {},
pages = {1-18},
doi = {10.1080/1028415X.2026.2700760},
pmid = {42578315},
issn = {1476-8305},
abstract = {Neurodegenerative disorders arise from the convergence of oxidative stress, neuroinflammation, synaptic dysfunction, mitochondrial failure, and dysregulated cell death, highlighting the need for therapeutic agents capable of coordinated, multi-target modulation. Luteolin (3',4',5,7-tetrahydroxyflavone), a dietary flavonoid widely present in edible and medicinal plants, has emerged as a promising neuroactive compound with pleiotropic biological actions. Rather than focusing on isolated outcomes, this review presents an integrated summary of how luteolin orchestrates interconnected signaling networks, with receptor-level neuromodulation and neuroimmune regulation to preserve neuronal integrity. Particular emphasis is placed on pathway convergence, cross-talk, and system-level neuroprotection across models of Alzheimer's disease, Parkinson's disease, and related disorders. In parallel, pharmacokinetic behavior, metabolite activity, and emerging delivery strategies are examined in relation to mechanistic efficacy. By linking molecular signaling, neurotransmission and therapeutic feasibility within a unified framework, this review offers a refined perspective on role of luteolin in neurodegenerative disease modulation.},
}

@article {pmid42578516,
year = {2026},
author = {Seo, SH and Lee, JE and Cho, EJ and Shin, EH},
title = {Attenuation of Tau Hyperphosphorylation by Chronic Toxoplasma gondii Infection in a Mouse Model of Alzheimer's Disease.},
journal = {Parasite immunology},
volume = {48},
number = {8},
pages = {e70096},
doi = {10.1111/pim.70096},
pmid = {42578516},
issn = {1365-3024},
support = {RS-2025-00516274//NKorea Government (MSIT)/ ; RS-2025-00559259//NKorea Government (MSIT)/ ; },
mesh = {Animals ; *tau Proteins/metabolism/genetics ; *Alzheimer Disease/pathology/parasitology/metabolism ; Disease Models, Animal ; Phosphorylation ; Mice ; Brain/pathology/parasitology/metabolism ; Amyloid beta-Peptides/metabolism ; *Toxoplasma/immunology ; *Toxoplasmosis/metabolism ; Female ; Chronic Disease ; Mice, Transgenic ; },
abstract = {Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) peptide accumulation and tau protein-mediated neurodegeneration, and neuroinflammation is increasingly recognized as a major process associated with tau pathology. Chronic Toxoplasma gondii infection reduces amyloid accumulation in AD models through immune modulation, but its stage-specific associations with tau-related pathology remain unclear. Here, we investigated how chronic T. gondii infection is associated with tau-related molecular and neuropathological changes in the 5XFAD AD mouse model. At 40 weeks post-infection, we profiled transcriptomic changes and evaluated Aβ-associated (21 genes), Aβ/tau-shared (22 genes), and tau-associated (21 genes) pathological programs together with p-tau immunoreactivity in brain sections. Chronic infection was associated with selective modulation of molecular networks linked to neuroimmune signalling and tau-related pathways rather than broad suppression of AD-related gene expression. Among tau-related pathological stages, the neuroinflammation-related amplification module linking Aβ and tau exhibited the most prominent transcriptomic change in T. gondii-infected AD mice, whereas upstream kinase-related initiation pathways and downstream toxin conversion or accumulation-related processes changed relatively minimally. These transcriptomic changes were accompanied by a marked reduction in phosphorylated tau load at the tissue level. Collectively, these findings suggest that chronic T. gondii infection is associated with selective modulation of tau-related pathogenic programs and reduced p-tau burden in the 5XFAD brain.},
}

Animals
*tau Proteins/metabolism/genetics
*Alzheimer Disease/pathology/parasitology/metabolism
Disease Models, Animal
Phosphorylation
Mice
Brain/pathology/parasitology/metabolism
Amyloid beta-Peptides/metabolism
*Toxoplasma/immunology
*Toxoplasmosis/metabolism
Female
Chronic Disease
Mice, Transgenic

@article {pmid42578598,
year = {2026},
author = {Gameiro, GR and Hoover, A and Schor, P and Jiang, H and Wang, J},
title = {Reduced Retinal Perfusion With Preserved Microvascular Network Density in Early Alzheimer's Disease: A Multimodal Imaging Study.},
journal = {Translational vision science & technology},
volume = {15},
number = {8},
pages = {7},
doi = {10.1167/tvst.15.8.7},
pmid = {42578598},
issn = {2164-2591},
mesh = {Humans ; *Alzheimer Disease/physiopathology/diagnostic imaging ; Female ; *Retinal Vessels/physiopathology/diagnostic imaging ; Male ; Tomography, Optical Coherence/methods ; Aged ; *Multimodal Imaging/methods ; Regional Blood Flow/physiology ; Cognitive Dysfunction/physiopathology/diagnostic imaging ; *Microvessels/diagnostic imaging ; *Microvascular Density/physiology ; Aged, 80 and over ; *Retina/diagnostic imaging/physiopathology ; },
abstract = {PURPOSE: To characterize retinal neurovascular alterations in Alzheimer's disease (AD) and mild cognitive impairment (MCI) and examine structure-function relationships.

METHODS: Eighty-two participants (28 with AD, 21 with MCI, and 33 cognitively normal controls) underwent retinal imaging. Retinal blood flow (RBF) was measured using a function imager. Retinal vessel density (RVD), retinal vessel length density (RVLD), vessel width, and capillary perfusion density (CPD) were quantified with optical coherence tomography (OCT) angiography and retinal tissue volume (RTV) with ultra-high-resolution OCT. Derived metrics included retinal tissue perfusion (RTP), retinal capillary flow index (RCF), and volumetric vessel density. Group comparisons and age-adjusted correlations were performed.

RESULTS: Compared with controls, the combined AD + MCI group had significantly lower RBF (3.18 ± 1.02 vs. 4.22 ± 0.79 nL/s; P < 0.001), RCF (0.21 ± 0.07 vs. 0.26 ± 0.04 nL/s/mm; P < 0.001), and RTP (2.89 ± 0.94 vs. 3.86 ± 0.77 nL/s/mm3; P < 0.001). Morphometric indices of the perfused capillary network and retinal tissue volume (RVD, RVLD, CPD, vessel width, RTV) did not differ (all P > 0.05). In AD + MCI, RBF was not associated with structural or morphometric microvascular metrics, whereas controls exhibited age-adjusted correlations between RBF and vessel density and length density.

CONCLUSIONS: AD and MCI are characterized by reduced retinal perfusion and capillary flow index despite preserved network density and retinal tissue volume, suggesting altered retinal hemodynamic-morphometric relationships.

TRANSLATIONAL RELEVANCE: Hemodynamic retinal imaging detects early perfusion impairment in AD and MCI before changes in microvascular network density or retinal tissue volume, offering a noninvasive biomarker for detection and therapeutic monitoring.},
}

Humans
*Alzheimer Disease/physiopathology/diagnostic imaging
Female
*Retinal Vessels/physiopathology/diagnostic imaging
Male
Tomography, Optical Coherence/methods
Aged
*Multimodal Imaging/methods
Regional Blood Flow/physiology
Cognitive Dysfunction/physiopathology/diagnostic imaging
*Microvessels/diagnostic imaging
*Microvascular Density/physiology
Aged, 80 and over
*Retina/diagnostic imaging/physiopathology

@article {pmid42578810,
year = {2026},
author = {Welty, S and Bagnell, M and Ma, F and Herrup, K and Levine, AS},
title = {Effects of damaged astrocytes on DNA damage and repair in human neurons: Implications for Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261476036},
doi = {10.1177/13872877261476036},
pmid = {42578810},
issn = {1875-8908},
abstract = {BackgroundStudies suggest a strong association between astrocytes, neuronal DNA damage, elevated amyloid-β, and brain degeneration in Alzheimer's disease (AD).ObjectiveThis study aimed to show whether astrocytes with damaged DNA affect human neuronal progenitor cells (NPCs) or differentiated neurons in close proximity, dependent on astrocytic APOE allele expression.MethodsImmortalized human astrocytes (hTERT) expressing APOE were treated with etoposide to induce DNA damage and co-cultured in a transwell system with human NPCs or differentiated neurons. We used western blotting and immunostaining to evaluate the DNA damage response of the NPCs and neurons.ResultsUndamaged NPCs showed increased DNA damage when co-cultured with damaged astrocytes. The astrocytic APOE genotype had little to no effect on the transcellular damage response. NPCs overexpressing the amyloid-β protein precursor responded more robustly when co-cultured with damaged astrocytes. Differentiated neurons showed no significant changes in their DNA damage response to damaged astrocytes.ConclusionsThis study is the first to demonstrate that astrocytic DNA damage may contribute to early stages of neuronal pathology in AD by inducing a DNA damage response in vulnerable neuronal populations.},
}

@article {pmid42578825,
year = {2026},
author = {Wang, R and Yamasaki, T and Mitsudo, T and Matsuda, Y and Goto, S and Sugi, T},
title = {Individual alpha peak frequency tracks Alzheimer's disease progression: A longitudinal pilot study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261476331},
doi = {10.1177/13872877261476331},
pmid = {42578825},
issn = {1875-8908},
abstract = {BackgroundEarly and accurate tracking of Alzheimer's disease (AD) progression is critical for timely intervention. However, electrophysiological biomarkers capable of capturing long-term neurodegenerative changes remain largely underexplored.ObjectiveWe investigated whether individual alpha peak frequency (IAPF), an electroencephalography (EEG)-derived measure of dominant neural oscillatory activity, could serve as a longitudinal biomarker of AD progression.MethodsTwenty-seven patients with AD aged 63-91 years underwent annual EEG and cognitive assessments over 2-7 years. IAPF was extracted from eyes-closed resting-state EEG. Longitudinal associations among IAPF, Mini-Mental State Examination (MMSE) scores, age, and follow-up time were evaluated using repeated-measures correlation and linear mixed-effects models. Annual IAPF changes were compared with those of healthy controls (HC) aged 20-70 years, stratified by decade-based age subgroups. Longitudinal changes in relative spectral power were also analyzed.ResultsPatients with AD showed significant longitudinal declines in both IAPF and MMSE scores, with a positive longitudinal association between the two measures. Mixed-effects models indicated that these declines were better explained by follow-up time after accounting for baseline age than by age at assessment alone. Compared with all healthy-control age subgroups, patients with AD exhibited a significantly steeper annual IAPF decline. Relative theta power increased and alpha/beta power decreased over follow-up, consistent with spectral slowing. However, annualized spectral-power changes showed limited disease specificity, with significant AD-HC differences only for delta and alpha power relative to the oldest HC subgroup.ConclusionsThese findings support IAPF as a non-invasive, temporally sensitive, and clinically accessible biomarker for monitoring AD progression.},
}

@article {pmid42579090,
year = {2026},
author = {Filippi, L and Nuvoli, S and Spanu, A and Palumbo, B},
title = {Mapping the Synaptome in Neurodegeneration: Emerging Clinical Applications of SV2A PET Imaging.},
journal = {Molecular diagnosis & therapy},
volume = {},
number = {},
pages = {},
pmid = {42579090},
issn = {1179-2000},
support = {Ricerca Corrente//Ministero della Salute/ ; },
abstract = {Synaptic loss is a core pathological feature of neurodegenerative disorders and closely relates to cognitive and functional decline. Positron emission tomography (PET) targeting synaptic vesicle glycoprotein 2A (SV2A) has recently emerged as a promising tool for the indirect assessment of presynaptic alterations in the living human brain. This leading article discusses the evolving clinical landscape of SV2A PET across the neurodegenerative spectrum, emphasizing its translational trajectory and emerging applications. Current evidence spans Alzheimer's disease (AD), other dementias, movement disorders, Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). The literature is currently dominated by PET with [[11]C]UCB-J, while [[18]F]-labeled tracers, particularly [[18]F]SynVesT-1, are expanding clinical feasibility through longer half-life and broader distribution potential. Across disorders, PET consistently detected SV2A reductions that frequently correlated with cognition, disease severity, and complementary biomarkers, including amyloid, tau, glucose metabolism, and dopaminergic imaging. Although the field remains limited by small cohorts, heterogeneous quantification strategies, and incomplete longitudinal validation, SV2A PET is rapidly evolving into a promising translational tool for studying synaptopathies and monitoring disease progression.},
}

@article {pmid42571023,
year = {2026},
author = {Frings, L and Brumberg, J and Meyer, PT},
title = {Semantic fluency predicts survival of memory clinic patients.},
journal = {Alzheimer's research & therapy},
volume = {18},
number = {1},
pages = {},
pmid = {42571023},
issn = {1758-9193},
mesh = {Humans ; Female ; Male ; Aged ; Positron-Emission Tomography ; Neuropsychological Tests ; *Alzheimer Disease/mortality/diagnostic imaging ; Fluorodeoxyglucose F18 ; Aged, 80 and over ; *Semantics ; Predictive Value of Tests ; Registries ; Brain/diagnostic imaging/metabolism ; *Memory Disorders/mortality/diagnostic imaging ; },
abstract = {BACKGROUND: Semantic fluency is commonly assessed in the diagnostic work-up of individuals with suspected cognitive impairment due to neurodegenerative disease. Semantic fluency has a predictive value for survival in clinical AD and in healthy elderly individuals, but it is unknown if this also applies to biomarker-confirmed AD and non-AD memory clinic patients. Potential associations with and added value of imaging biomarkers of amyloid pathology and neurodegeneration have yet to be explored.

METHODS: From our clinical registry, we included patients who were assessed at a memory clinic with the neuropsychological assessment battery of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD-NAB) and whose vital status could be retrieved in 07/2024. We tested the association of semantic fluency performance at first assessment and over time (and, for comparison, further CERAD-NAB subtest scores) with mortality risk using age-adjusted single-predictor Cox proportional hazard models. Amyloid status (positive vs negative on clinical PET reads) and global cognitive impairment (MMSE) were included as covariates. In addition, we explored associations between semantic fluency performance and both regional cortical glucose metabolism (FDG PET) and global amyloid load (centiloids; PiB PET). Finally, the predictive value of global amyloid load and glucose metabolism in comparison to and in combination with semantic fluency performance was assessed.

RESULTS: 583 patients were included (age 68.9 ± 8.7, 45% female). 280 patients (48%) had died and 303 (52%) were alive after a median of 8.0 years [95% C.I. 7.7-8.4]. Better semantic fluency (age-, sex- and education adjusted Z score, based on normative data) was significantly associated with lower mortality risk (HR = 0.71 [0.63 - 0.80], Bonferroni-corrected p < 0.001). Its predictive value was higher than that of all other CERAD-NAB subscores (e.g., memory, visuospatial abilities). Semantic fluency remained a significant predictor when amyloid status and global cognitive impairment were accounted for (HR = 0.75 [0.61 - 0.91], p = 0.0035). In patients with more than one assessment (N = 163), longitudinal change of semantic fluency (derived from a linear mixed effects model) was also a significant predictor (HR = 0.66 [0.53-0.83], p < 0.001). In 218/583 patients who had received amyloid and FDG PET, worse semantic fluency was associated with decreased FDG uptake of left inferior and middle temporal, dorsolateral frontal, and posterior parietal cortical regions (Bonferroni-corrected p < 0.05), but not with amyloid load. FDG uptake of the left IFG (pars opercularis) was itself a predictor of survival (HR = 0.68 [0.55 - 0.84], Bonferroni-corrected p < 0.05), but to a lesser degree than semantic fluency (and MMSE, naming and figure drawing). Predictive accuracy of semantic fluency was further improved by including FDG uptake of the right anterior cingulate (Bonferroni-corrected p = 0.078). Global amyloid load was not associated with survival.

CONCLUSIONS: Survival of memory clinic patients can be predicted by semantic fluency, independently from amyloid status and global cognitive impairment. Anterior cortical glucose metabolism is itself a significant predictor of survival and slightly improves prediction by semantic fluency.},
}

Humans
Female
Male
Aged
Positron-Emission Tomography
Neuropsychological Tests
*Alzheimer Disease/mortality/diagnostic imaging
Fluorodeoxyglucose F18
Aged, 80 and over
*Semantics
Predictive Value of Tests
Registries
Brain/diagnostic imaging/metabolism
*Memory Disorders/mortality/diagnostic imaging

@article {pmid42571045,
year = {2026},
author = {Marvanova, M},
title = {Comment on "Review of Donanemab and Lecanemab in Mild Dementia Stage of Alzheimer's Disease: Progress and Challenges".},
journal = {The Senior care pharmacist},
volume = {41},
number = {5},
pages = {157-158},
doi = {10.4140/TCP.n.2026.157},
pmid = {42571045},
issn = {2639-9636},
}

@article {pmid42571047,
year = {2026},
author = {Qudoos, MA and Elliott, DP},
title = {Response to Comment on "Review of Donanemab and Lecanemab in Mild Dementia Stage of Alzheimer's Disease: Progress and Challenges".},
journal = {The Senior care pharmacist},
volume = {41},
number = {5},
pages = {159-160},
doi = {10.4140/TCP.n.2026.159},
pmid = {42571047},
issn = {2639-9636},
}

@article {pmid42571168,
year = {2026},
author = {Oxenkrug, G and Comai, S},
title = {Up-Regulation of Anthranilic Acid Formation and Pro-Cognitive Effect of Indoleamine 2,3-Dioxygenase Inhibition.},
journal = {International journal of tryptophan research : IJTR},
volume = {19},
number = {},
pages = {11786469261472317},
pmid = {42571168},
issn = {1178-6469},
abstract = {Inhibition of indoleamine 2,3-dioxygenase (IDO) is a promising therapeutic strategy for cognitive impairment in Alzheimer's disease (AD). The pro-cognitive effect is often attributed to restoring glycolysis by preventing tryptophan (Trp) conversion to kynurenine (Kyn). However, this overlooks the metabolic fate of Trp when IDO is blocked. Since IDO and tryptophan 2,3-dioxygenase (TDO) compete for the same substrate, inhibiting IDO may shunt Trp toward TDO, potentially increasing Kyn and its downstream catabolites. This commentary explores the hypothesis that the upregulation of anthranilic acid (AA), a Kyn catabolite, contributes to the cognitive benefits of IDO inhibition. Recent evidence shows elevated AA in animal models of AD and individuals with mild cognitive impairment and preclinical AD, where it may serve as an early biomarker. Notably, these elevations and the pro-cognitive effects of AA-modulating compounds like sodium benzoate exhibit sex-specificity, being more prominent in females. The mechanism may involve AA's dual action on G-protein coupled receptors: antagonism of GPR17 promotes myelination, while agonism of GPR109A may protect myelin from degradation. Preserving myelin integrity is critical, as demyelination is an early event in AD pathogenesis. We propose that AA upregulation is not merely a biomarker but part of a compensatory defense mechanism. Therefore, the pro-cognitive effect of IDO inhibition may be partly mediated by the subsequent shunting of Trp toward TDO and production of the myelin-preserving metabolite, AA. This reframes the therapeutic goal from reducing neurotoxic kynurenines to leveraging the protective potential of the entire pathway.},
}

@article {pmid42571320,
year = {2026},
author = {Pinnelli, SP and T, SB and Ca, J and Pinnelli, VB and Harikrishna, GV and Mudamanchu, VK and Sam, KT and Ms, D and Bhupathiraju, P and Sucharitha, AS and Kandi, V},
title = {Artificial Intelligence for the Diagnosis and Management of Neurodegenerative Diseases: A Comprehensive Review With an Emphasis on Parkinson's and Alzheimer's Diseases.},
journal = {Cureus},
volume = {18},
number = {7},
pages = {e112325},
pmid = {42571320},
issn = {2168-8184},
abstract = {Artificial intelligence (AI) is rapidly transforming research in neurodegenerative diseases, yet its clinical translation remains limited. We conducted a structured literature search across Google Scholar, PubMed, Scopus, and Web of Science, screening studies published between 2015 and April 2026 that applied machine learning (ML), deep learning (DL), and multimodal data integration to neuroimaging, biomarkers, and digital phenotyping. Our analysis revealed that AI models demonstrate strong potential for differentiating disease subtypes, predicting progression, and enhancing diagnostic accuracy, with notable advances in neuroimaging interpretation, fluid biomarker analysis, and wearable sensor data. In Parkinson's disease (PD), digital phenotyping through gait, speech, and handwriting analysis has enabled sensitive monitoring, while in Alzheimer's disease (AD), AI applied to imaging and plasma biomarkers has improved risk stratification. Despite these advances, barriers such as dataset heterogeneity, label noise, lack of external validation, and ethical concerns regarding bias, transparency, and patient trust persist. We conclude that while AI holds promise to revolutionize the care of PD and AD, real-world adoption requires multicenter validation, standardized reporting frameworks, regulatory guidance, and interdisciplinary collaboration, alongside prospective trials that embed AI tools into clinical workflows to ensure safety, equity, and effectiveness.},
}

@article {pmid42571323,
year = {2026},
author = {Jiménez-Mausbach, M and Tijms, BM and Paterson, C and Refsgaard, JC},
title = {Semaglutide attenuates a proteomics-based dementia risk signature in older adults with overweight or obesity and cardiovascular disease without diabetes: A post hoc analysis of the SELECT phase 3 trial.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70432},
pmid = {42571323},
issn = {2352-8729},
abstract = {INTRODUCTION: Plasma proteomics detect multi-pathway biological changes preceding dementia onset. The Dementia SomaSignal Test (dSST) is a validated 25-protein score predicting 5- and 20-year all-cause dementia risk. Preclinical and clinical data suggest glucagon-like peptide-1 receptor agonists may have neuroprotective effects.

METHODS: In a post hoc analysis of the Semaglutide Effects on Heart Disease and Stroke in Patients With Overweight or Obesity (SELECT) trial, adults ≥ 65 years with overweight/obesity and cardiovascular disease without diabetes (n = 2970) were randomized to semaglutide 2.4 mg or placebo. Non-fasted serum samples at baseline and week 104 were analyzed using the dSST.

RESULTS: Semaglutide reduced increases in predicted dementia risk versus placebo: 2.5-fold less increase in 5-year risk (26.0% lower predicted event rate; odds ratio [OR] 0.74, 95% confidence interval [CI] 0.65-0.85) and 1.67-fold less increase in 20-year risk (8.8% lower; OR 0.91, 95% CI 0.88-0.94). It also reduced odds of higher dementia risk classification by 36% (β -0.44; P < 0.001).

DISCUSSION: Semaglutide slowed progression of a validated proteomics-based dementia risk signature.},
}

@article {pmid42571406,
year = {2026},
author = {Urso, D and Nichols, E and Giannoni-Luza, S and Brayne, C and Ray, N and Logroscino, G},
title = {Burden of Dementia in Europe, 1990-2023: a systematic analysis from the Global Burden of Disease Study 2023.},
journal = {The Lancet regional health. Europe},
volume = {68},
number = {},
pages = {101796},
pmid = {42571406},
issn = {2666-7762},
abstract = {BACKGROUND: Dementia is a leading cause of disability and mortality in Europe, yet no recent harmonised assessment has described its impact across the European Union (EU-27) and the WHO European Region.

METHODS: We used data from the Global Burden of Disease Study 2023 (GBD 2023) to estimate prevalence, mortality, and disability-adjusted life years (DALYs) for dementia from 1990 to 2023. Estimates were produced for the EU-27 and the WHO European Region, by age and sex. Non-fatal outcomes were modelled using DisMod-MR 2.1, and dementia-attributable mortality was estimated using an excess-mortality framework. We also quantified DALYs attributable to six modifiable risk factors.

FINDINGS: In 2023, 7.76 million people (95% UI 6.69-8.72) were living with dementia in the EU-27 and 12.28 million (10.44-13.90) in the WHO European Region, representing ∼90% increases since 1990 despite modest declines in age-standardised prevalence. Prevalence was nearly twice as high in women as in men. Dementia rose from the eighth to the third leading cause of death in the EU-27. Dementia accounted for 5.49 million DALYs (2.44-11.41) in the EU-27. An estimated 41% (24.4-57.4) of dementia DALYs in the EU-27 were attributable to modifiable risk factors, particularly ambient particulate matter pollution, high fasting plasma glucose, and high body-mass index, which are disproportionately concentrated in socioeconomically disadvantaged populations.

INTERPRETATION: Despite modest declines in age-standardised rates, the absolute burden of dementia in Europe continues to rise, driven by population ageing. The substantial contribution of modifiable risk factors highlights major opportunities for prevention. Robust, country-specific estimates are essential to guide integrated strategies combining prevention and care planning.

FUNDING: Regione Puglia and CNR for Tecnopolo per la Medicina di Precisione; Regione Puglia for the national "Fund for Alzheimer's and Dementia 2021-2023" (Piano Regionale Demenze 2021/2023).},
}

@article {pmid42571433,
year = {2026},
author = {Kloosterman, M and Vongpromek, R and Friesema, ECH and Bramer, W and Verhoeven, AJM and Mulder, MT},
title = {LR11/SorLA and its role in cardiovascular disease.},
journal = {International journal of cardiology. Heart & vasculature},
volume = {66},
number = {},
pages = {101982},
pmid = {42571433},
issn = {2352-9067},
abstract = {Cardiovascular diseases account for the highest morbidity worldwide. LR11 (also called SorLA), an LDL receptor family member characterized as a sorting receptor, was initially identified in the brain and has a causative role in the development of Alzheimer's disease. However, LR11, and its circulating shed isoform, sLR11, are also associated to cardiovascular diseases and risk factors for atherosclerosis, such as obesity and diabetes. In the current narrative review, we discuss that elevation of plasma sLR11 levels can result from different forms of vascular injury, but also plays a role in subsequent vascular remodeling. We provide an overview of the mechanisms whereby LR11 promotes vascular remodeling and thereby atherosclerosis and how it could be involved in obesity and diabetes. Furthermore, we discuss the possibilities of (s)LR11 as a biomarker and therapeutic target for cardiovascular diseases.},
}

@article {pmid42571539,
year = {2026},
author = {Nguyen, HD and Siddiqui, S and Bohannon, DG and Blair, RV and Deng, HW and Prat, A and Kim, WK},
title = {Single-cell transcriptomic analysis reveals age-related remodeling of brain endothelial cells.},
journal = {Aging brain},
volume = {10},
number = {},
pages = {100164},
pmid = {42571539},
issn = {2589-9589},
abstract = {Blood-brain barrier (BBB) integrity naturally declines with age. Brain endothelial cells (ECs) and pericytes (PCs) form the BBB, and aging impairs tight junctions, likely via altered PC-to-EC signaling. However, the molecular mechanisms underlying this impairment remain unclear. Using single-cell RNA sequencing, we profiled 68,316 brain ECs expressing 15,564 genes from young and old mice. Unsupervised clustering and annotation revealed five distinct EC subtypes-Capillary EC1, Capillary EC2, Arterial EC, Venous EC1, and Venous EC2-defined by marker genes Mfsd2a, Plvap, Bmx, Nr2f2, and Vcam1, respectively. Aging shifted EC subtype distribution, with reduced Capillary EC1 (45% vs. 57%) and increased Arterial (33% vs. 16%) and Venous ECs (12% vs. 2%) compared with young mice. Mio analysis further showed that Capillary EC1 and Venous EC2 neighborhoods were less abundant in aged brains. Biotin metabolism was decreased in old vs. young mice, particularly within Capillary EC1, Capillary EC2, and Arterial EC. Although widespread gene downregulation was observed across EC subsets, overall expression trends were largely consistent among clusters. Key genes-Ramp2, Hbb-bs, Ly6c1, Calm1-were less abundant, whereas Rasgrf2 was uniquely enriched in aged mice. Immunohistochemistry confirmed reduced LY6C and RAMP2 and elevated RASGRF2 in aged mouse and human brains. Cell-cell interaction analyses revealed age-associated remodeling of ligand-receptor signaling. Enrichment analyses implicated pathways involved in neurovascular integrity, inflammation, amyloid processing, and vascular remodeling. Collectively, these findings show that aging reprograms EC subtype composition, gene expression, and metabolism, thereby contributing to BBB disruption and neurovascular dysfunction.},
}

@article {pmid42571702,
year = {2026},
author = {Dávila-Cervantes, CA and Agudelo-Botero, M},
title = {Uneven progress in Alzheimer's disease and other dementias across Mexico, 1990-2023: updated estimates from the Global Burden of Disease Study.},
journal = {Aging & mental health},
volume = {},
number = {},
pages = {1-14},
doi = {10.1080/13607863.2026.2710256},
pmid = {42571702},
issn = {1364-6915},
abstract = {OBJECTIVES: To quantify the magnitude and trends the national and subnational burden of Alzheimer's disease and other dementias (ADOD) in Mexico from 1990 to 2023, analyzing patterns by sex and age and exploring their association with the Socio-Demographic Index (SDI) and the Healthcare Access and Quality Index (HAQI).

METHOD: A secondary ecological study was conducted using updated estimates from the Global Burden of Disease and Risk Factors Study (GBD) 2023. Prevalence, incidence, mortality, and disability-adjusted life years (DALYs) were examined. Temporal trends were assessed using joinpoint regression. Pearson correlation and linear regression were used to evaluate associations between DALYs rates and SDI and HAQI.

RESULTS: Between 1990 and 2023, ADOD prevalence and incidence increased, despite significant declines in age-standardized prevalence and incidence rates. Females consistently experienced higher mortality and disability, with age-standardized DALYs rates 1.28 times those of males. The ADOD burden increased sharply with age, peaking among those aged 85 years and older, with premature mortality accounting for 63.0% of total DALYs. A significant increase in DALYs rates occurred during 2020-2023 after previous periods of gradual decline. DALYs rates were negatively correlated with both SDI and HAQI.

CONCLUSION: ADOD disproportionately affect women, while higher modeled burden was observed in several states with lower socioeconomic development and weaker health system performance. The post-2020 increase represents an epidemiological signal warranting further investigation into excess mortality among people with dementia, healthcare disruption, social isolation, and changes in long-term care during the COVID-19 period. Strengthening early diagnosis, long-term care, and management of modifiable risk factors is essential to reduce the future burden and persistent regional and sex-based inequalities in ageing populations.},
}

@article {pmid42571730,
year = {2026},
author = {Li, Q and Li, M and Huang, X and Cao, C and Hu, Y},
title = {Integrative multi-omics analysis identifies AIF1 as an immune-associated factor linked to monocyte-centered inflammatory networks in Alzheimer's disease.},
journal = {Immunobiology},
volume = {231},
number = {5},
pages = {153229},
doi = {10.1016/j.imbio.2026.153229},
pmid = {42571730},
issn = {1878-3279},
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder in which immune dysregulation has emerged as an important component of disease pathogenesis; however, the contribution of circulating proteins and their cellular context remains incompletely understood. Here, we performed an integrative multi-omics analysis combining Mendelian randomization (MR), bulk transcriptomics, single-cell RNA sequencing, and peripheral blood validation to systematically identify plasma proteins associated with AD. Proteome-wide MR analysis identified multiple circulating proteins associated with AD risk. Integration with transcriptomic data identified AIF1 (allograft inflammatory factor 1) as a shared candidate supported by both genetic prioritization and differential expression analysis. Although bulk transcriptomic data showed reduced AIF1 expression in AD, single-cell analysis revealed distinct cell type-specific expression patterns, with predominant enrichment in monocytes and other innate immune populations. PBMC-based qPCR further confirmed an overall reduction in AIF1 expression in AD. Further analyses suggested that AIF1-associated immune alterations were linked to changes in inflammatory signaling pathways, including STAT, IRF, and NF-κB-related activity, as well as differences in intercellular communication involving MIF, GALECTIN, ANNEXIN, and CypA-related signaling. Peripheral immune cell composition analysis indicated differences between AD and control samples, characterized by relative changes in innate immune cell proportions. Collectively, these findings identify AIF1 as an immune-associated factor linked to genetic and transcriptional alterations in AD and suggest its association with monocyte-related immune states and altered immune signaling patterns. This study provides a multi-layered framework for investigating peripheral immune involvement in AD and highlights potential directions for understanding immune-related alterations and biomarker discovery.},
}

@article {pmid42571753,
year = {2026},
author = {Rani, S and Mahesh, KV and Sandhir, R and Prabhakar, N},
title = {AuNP decorated-Ni-MOF nanosheet based cDNA sensor for detection of miRNA-128 in Alzheimer's disease.},
journal = {Talanta},
volume = {312},
number = {Pt A},
pages = {130405},
doi = {10.1016/j.talanta.2026.130405},
pmid = {42571753},
issn = {1873-3573},
abstract = {A cDNA sensor based on gold nanoparticles (Au) supported on nickel metal-organic framework nanosheets (MOF-NS) modified fluorine-tin oxide (FTO) glass electrode for the ultrasensitive and selective detection of miRNA-128 biomarker associated with the progression of Alzheimer's disease (AD) has been reported. The MOF-NS and Au nanoparticles were electrodeposited onto FTO electrode using chronoamperometry to immobilize 5'-biotinylated DNA (btn-cDNA) complementary to miRNA-128 by streptavidin-biotin interaction, generating the modified electrode (btn-cDNA/SV/Au/MOF-NS/FTO). The fabricated electrode was characterized using various surface characterization techniques, including FESEM, XPS, FTIR, and electrochemical methods. The fabricated electrode was then utilized for the selective detection of miRNA-128 using electrochemical impedance spectroscopy. The results indicated a linear response range of 1.0 × 10[-1] fM-1.0 × 10[2] nM with limit of detection of 0.017 fM, and sensitivity of 180.11 Ω fM[-1]cm[-2]. Moreover, the cDNA sensor showed satisfactory performance with real serum samples from AD patients and healthy individuals, as validated by real time-PCR technique with area under curve of 0.93 and a sensitivity of 90%, respectively, demonstrating the potential of present cDNA sensing approach in the biomedical field.},
}

@article {pmid42571787,
year = {2026},
author = {Bhakta-Guha, D and Guha, G},
title = {Alzheimer's disease as a disorder of time-gated clearance: Circadian regulation of Glymphatic function in neurodegeneration.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115959},
doi = {10.1016/j.expneurol.2026.115959},
pmid = {42571787},
issn = {1090-2430},
abstract = {Alzheimer's disease (AD) is traditionally defined by amyloid-β (Aβ) accumulation, tau pathology, synaptic dysfunction, and progressive neurodegeneration. However, increasing evidence suggests that impaired brain waste clearance represents an additional and clinically relevant dimension of disease pathogenesis. The glymphatic system, a perivascular cerebrospinal fluid-interstitial fluid exchange network, facilitates removal of soluble metabolites including Aβ and tau, and functions most efficiently during sleep. Recent studies indicate that glymphatic influx, meningeal lymphatic drainage, and blood-brain barrier (BBB) efflux transport are temporally regulated by circadian mechanisms, creating time-restricted windows of maximal clearance capacity. In AD, sleep fragmentation, suprachiasmatic nucleus degeneration, clock gene disruption, vascular stiffening, BBB tight junction failure, aquaporin-4 depolarization, and neuroinflammation may converge to impair this coordinated clearance network. We propose a time-gated clearance framework in which temporally misaligned or insufficient waste removal contributes to protein accumulation and disease progression. We also evaluate major controversies, including relative roles of advection and diffusion in parenchymal transport, predominance of rodent-derived data, and current limitations of human imaging biomarkers. Finally, we discuss therapeutic implications of circadian re-entrainment, sleep optimization, BBB restoration, vascular protection, and enhancement of glymphatic-lymphatic flow. This systems-level perspective complements established amyloid/tau models and identifies potentially modifiable targets for AD intervention.},
}

@article {pmid42571855,
year = {2026},
author = {Guo, X and Wu, S and Sun, Z and Jia, T and Ouyang, Y and Zhang, M and Kou, C and Bai, W},
title = {Peripheral GDF15 as an early biomarker for brain disorders: A large prospective cohort study.},
journal = {Progress in neuro-psychopharmacology & biological psychiatry},
volume = {},
number = {},
pages = {111886},
doi = {10.1016/j.pnpbp.2026.111886},
pmid = {42571855},
issn = {1878-4216},
abstract = {BACKGROUND: Growth differentiation factor 15 (GDF15) is a stress-responsive cytokine involved in metabolic and inflammatory pathways. We examined the associations of plasma GDF15 with incident brain disorders and explored potential mediating pathways and causality.

METHODS: UK Biobank participants were followed for a median of 14 years. Plasma GDF15 was measured at baseline. Cox proportional hazards models assessed associations with incident brain disorders, including all-cause dementia (ACD), Alzheimer's disease (AD), Parkinson's disease (PD), anxiety, depression, sleep disorders, stroke, and epilepsy. Mediation analyses evaluated biochemical and hematological pathways, and one-sample Mendelian randomization (MR) was used to assess potential causal effects.

RESULTS: Higher GDF15 levels were associated with increased risks of overall brain disorders and all examined subtypes. In continuous analyses (per 1-unit increase in log2-transformed GDF15), hazard ratios (95% CIs) were 1.54 (1.48-1.60) for overall brain disorders, 1.98 (1.80-2.17) for ACD, 1.84 (1.60-2.10) for AD, 1.37 (1.18-1.59) for PD, 1.26 (1.16-1.37) for anxiety, 1.38 (1.29-1.49) for depression, 1.40 (1.26-1.55) for sleep disorders, 1.92 (1.81-2.05) for stroke, and 1.71 (1.46-2.01) for epilepsy (all P < 0.001). Lipid- and inflammation-related markers appeared to partially mediate these associations. High-density lipoprotein cholesterol (HDL-C) accounted for an estimated 7.51% of the association with depression and 11.47% with sleep disorders, while neutrophil count showed relatively larger mediation estimates across multiple outcomes. MR analyses did not support a direct causal effect of GDF15.

CONCLUSION: Plasma GDF15 is associated with a broad range of incident brain disorders and may act partly through lipid- and inflammation-related pathways, particularly HDL-C and neutrophil count.},
}

@article {pmid42571862,
year = {2026},
author = {Ding, F and Yang, L and Qiao, S and Lam, TKY and Su, Z and He, Y and Chen, Z and Cui, X and Chan, Y and Zhang, W and Xu, J and Cai, Z and Lyu, A and Li, F},
title = {Targeting transthyretin tetramer with a novel blood-brain barrier-penetrating small-molecule stabilizer for the treatment of Alzheimer's disease.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {153998},
doi = {10.1016/j.ijbiomac.2026.153998},
pmid = {42571862},
issn = {1879-0003},
abstract = {The stability of the transthyretin (TTR) tetramer is critical for regulating cerebral amyloid-β (Aβ) homeostasis in Alzheimer's disease (AD). Stable TTR tetramer can directly bind Aβ and promote its clearance from the brain. However, current TTR tetramer stabilizers lack blood-brain barrier (BBB) penetration, limiting their clinical translation. Therefore, to fully realize the therapeutic potential of TTR in AD, novel TTR tetramer stabilizers with superior BBB penetration must be discovered. Here, we aim to identify TTR tetramer stabilizers with BBB penetration via a multidimensional virtual screening workflow, and perform preliminary validation of their biological activities. Finally, Z1097086893 was identified as the lead compound. In vitro, the compound exhibited significant BBB penetration and robust TTR tetramer stabilization activity. In vivo, Z1097086893 also crossed the BBB. MSI showed localization to the choroid plexus within the ventricular system, the principal site of TTR synthesis and secretion in the brain. In the 5xFAD mouse model, the compound significantly reduced hippocampal Aβ plaque burden, alleviated neuronal injury, and rescued spatial learning and recognition memory deficits. Safety assessments confirmed that Z1097086893 was well tolerated at therapeutic doses, with no detectable drug-induced organ toxicity or abnormalities in liver and kidney function. Our findings validate cerebral TTR tetramer stabilization as a promising therapeutic strategy for AD, and provide a lead compound for further clinical translation. Furthermore, the BBB-first screening workflow established in this work offers a generalizable technical framework for the development of brain-targeted therapeutics for AD.},
}

@article {pmid42571934,
year = {2026},
author = {Lee, SH and Kim, K and Bae, J and Choi, K and Jung, DH and Park, EJ and Ju, HC and Kang, WS and Moon, C},
title = {A Novel Methodology for Temporal Analysis of Consumer Wearable Sleep Data: Feasibility and Application to Early Cognitive Impairment.},
journal = {Experimental neurobiology},
volume = {},
number = {},
pages = {},
doi = {10.5607/en26014},
pmid = {42571934},
issn = {1226-2560},
abstract = {While sleep disturbances are recognized as early markers of Alzheimer's disease (AD), the practical application of gold-standard polysomnography (PSG) for long-term monitoring is limited. This study aims to establish a novel methodological framework for the time-series analysis of sleep data collected via consumer-grade wearables and to explore whether this approach can detect differentiated signals across various stages of cognitive impairment. Daily sleep patterns of thirteen participants (5 healthy controls, 4 with aMCI, and 4 with mild AD) were monitored over three months using the Fitbit Charge 2. Rather than relying on aggregate nightly averages, we implemented a time-resolved analysis across 10-minute intervals to examine the temporal dynamics of sleep architecture. The proposed analysis revealed distinct, group-dependent temporal signatures. Specifically, the aMCI and AD groups exhibited shorter deep sleep during the early phase of the night, reduced REM sleep approximately three hours after sleep onset, and consistently elevated levels of light sleep and wake after sleep onset (WASO). These findings demonstrate that time-series analysis of wearable sleep data presents the potential to identify candidate digital phenotypes associated with cognitive decline. This study supports the feasibility of using longitudinal, dynamic sleep monitoring as an exploratory analytical framework warranting further validation for the detection of pathophysiological changes in older adults, shifting the focus from simple detection to the identification of candidate temporal sleep features. All reported findings are exploratory in nature and require replication in larger, independent cohorts.},
}

@article {pmid42572052,
year = {2026},
author = {Pradhan, S},
title = {Letter to the Editor "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 = {e70784},
doi = {10.1111/ggi.70784},
pmid = {42572052},
issn = {1447-0594},
}

@article {pmid42572115,
year = {2026},
author = {Rodrigues, JFR and Rodrigues, LP and Teshima, T and Yang, S and Wu, Y and Hu, X and Abarca, GIF and da Cruz, KCT and Rodriguez, MFS and Rubatino, FVM and Yamakawa, M and de Godoy, MF and de Araújo Filho, GM},
title = {Replay Letter to: 'Loneliness as an Interface Between Alzheimer's Disease and Suicidal Behaviour: A Methodological Concern'.},
journal = {Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society},
volume = {26},
number = {5},
pages = {e70203},
doi = {10.1111/psyg.70203},
pmid = {42572115},
issn = {1479-8301},
}

@article {pmid42572118,
year = {2026},
author = {Indumathi, J and Arulappan, A and Ramasamy, S},
title = {Comment on "Executive and General Cognitive Domain as a Relevant Factor of Specific Neuropsychiatric Symptoms in Alzheimer's Disease".},
journal = {Geriatrics & gerontology international},
volume = {26},
number = {8},
pages = {e70763},
doi = {10.1111/ggi.70763},
pmid = {42572118},
issn = {1447-0594},
}

@article {pmid42572565,
year = {2026},
author = {Song, Z and Xie, Y and Zhu, H and Li, J and Yang, C and Guo, Y and Nong, X and Zhu, Z and Chen, Z and Wang, Z},
title = {Evaluating the cognitive efficacy of marine-derived drugs in Alzheimer's disease: A systematic review and Bayesian network meta-analysis.},
journal = {Therapeutic advances in neurological disorders},
volume = {19},
number = {},
pages = {17562864261476868},
pmid = {42572565},
issn = {1756-2856},
abstract = {BACKGROUND: In recent years, marine-derived drugs for Alzheimer's disease (AD) have attracted growing attention, but their comparative cognitive efficacy and safety remain uncertain because of inconsistent findings across studies.

OBJECTIVES: To compare the efficacy and safety of marine-derived interventions for Alzheimer's disease.

DESIGN: Systematic review and Bayesian network meta-analysis of randomized controlled trials conducted in accordance with PRISMA 2020.

DATA SOURCES AND METHODS: We systematically searched PubMed and the Cochrane Library for randomized controlled trials (RCT) of marine-derived drugs in patients with AD. Continuous outcomes were synthesized as mean differences (MD) in change-from-baseline, and dichotomous outcomes were synthesized as odds ratios (OR), each with 95% credible intervals (CI).

RESULTS: A total of 16 eligible RCTs involving 4,158 patients were included. For the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), GV-971 (vs placebo; MD -1.85, 95% CI -2.89 to -0.82) and tramiprosate (vs placebo; MD -0.83, 95% CI -1.63 to -0.02) significantly improved cognitive function. For the Mini-Mental State Examination (MMSE), rifampicin (vs placebo; MD 1.90, 95% CI 0.25 to 3.56) was associated with greater improvement in MMSE scores, whereas tramiprosate (vs placebo; MD -2.40, 95% CI -4.67 to -0.09) was associated with poorer cognitive performance. No statistically significant differences among drugs were observed for the Clinical Dementia Rating-Sum of Boxes (CDR-SB) or for the incidence of adverse events. Overall, treatment effects were outcome-dependent, with significant benefits observed mainly in ADAS-Cog and MMSE, whereas no intervention demonstrated consistent superiority across all cognitive outcomes.

CONCLUSION: Marine-derived drugs showed generally acceptable safety and potential cognitive benefits in selected outcomes. GV-971 and tramiprosate improved ADAS-Cog scores, while rifampicin therapy showed a possible MMSE benefit. However, no intervention was consistently superior across cognitive outcomes, and the antibiotic finding was based on a single small trial. Current evidence is therefore insufficient to identify the optimal marine-derived therapy for AD, highlighting the need for larger, adequately powered RCTs.},
}

@article {pmid42573021,
year = {2026},
author = {Alsfouk, AA and El-Shiekh, RA and Kariuki, BM and Sabry, E and Abouelenein, MG and Saleh, A and Saleh, MGA and Srour, AM},
title = {Design, Synthesis, X-Ray Crystallographic Characterization, Anticholinesterase and Antioxidant Evaluation, and Molecular Modeling of Novel Dispiroindene-Pyrrolidine Derivatives as Multifunctional Anti-Alzheimer Agents.},
journal = {Drug development research},
volume = {87},
number = {5},
pages = {e70361},
doi = {10.1002/ddr.70361},
pmid = {42573021},
issn = {1098-2299},
support = {PNURSP2026R116//Princess Nourah Bint Abdulrahman University/ ; NBU-FFR-2026-145-02//Northern Border University/ ; },
mesh = {*Cholinesterase Inhibitors/chemistry/pharmacology/chemical synthesis ; *Antioxidants/pharmacology/chemistry/chemical synthesis ; *Pyrrolidines/chemistry/pharmacology/chemical synthesis ; Drug Design ; Crystallography, X-Ray ; Acetylcholinesterase/metabolism/chemistry ; Butyrylcholinesterase/metabolism/chemistry ; *Alzheimer Disease/drug therapy ; Animals ; Models, Molecular ; Structure-Activity Relationship ; Humans ; Molecular Docking Simulation ; },
abstract = {A novel series of 5-chloro-N-alkyl-1',1″-dimethyl-4'-aryldispiro[indene-2,3'-pyrrolidine-2',3″-indoline]-1,2″(3H)-diones (4a-r) was rationally designed and synthesized via a one-pot multicomponent reaction of N-alkylated 5-chloroisatin derivatives, 2-(arylmethylidene)-2,3-dihydro-1H-inden-1-ones (2a-i), and sarcosine (3). To assess their potential therapeutic efficacy, the entire library of synthesized compounds was screened for its inhibitory profiles against both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), where most derivatives exhibited moderate to potent cholinesterase inhibitory activity. Notably, derivatives 4b, 4f, and 4o emerged as the most effective dual inhibitors, displaying strong potent activity against AChE (IC50 = 0.91 ± 0.02, 0.89 ± 0.01, and 0.74 ± 0.01 µM, respectively; donepezil IC50 = 0.68 ± 0.005 µM) alongside significant BChE inhibition (IC50 = 10.19 ± 0.16, 9.59 ± 0.08, and 9.11 ± 0.01 µM, respectively; donepezil IC50 = 2.97 ± 0.01 µM). The structure of the most active derivatives (4b, 4f, and 4o) was further confirmed by X-ray crystallographic analysis. In addition, antioxidant evaluation of compounds 4b, 4f, and 4o demonstrated that derivative 4f possessed the most superior radical scavenging profile (IC50 = 23.18 ± 0.33 µM), representing approximately a 5.5-fold enhancement in potency relative to ascorbic acid (IC50 = 128.20 ± 0.82 µM). Molecular docking studies revealed favorable binding interactions of the lead derivatives within the catalytic binding pockets of both AChE and BChE, with docking scores comparable to those of the standard inhibitor. Furthermore, in silico ADME profiling demonstrated promising pharmacokinetic behavior, characterized by robust gastrointestinal absorption and excellent predicted blood-brain barrier penetration, supporting the potential of these derivatives as promising multifunctional candidates for the development of anti-Alzheimer agents.},
}

*Cholinesterase Inhibitors/chemistry/pharmacology/chemical synthesis
*Antioxidants/pharmacology/chemistry/chemical synthesis
*Pyrrolidines/chemistry/pharmacology/chemical synthesis
Drug Design
Crystallography, X-Ray
Acetylcholinesterase/metabolism/chemistry
Butyrylcholinesterase/metabolism/chemistry
*Alzheimer Disease/drug therapy
Animals
Models, Molecular
Structure-Activity Relationship
Humans
Molecular Docking Simulation

@article {pmid42573081,
year = {2026},
author = {Saffour, S and Gul, TS and Gul, HI},
title = {Rational drug design for Alzheimer's disease: from approved therapies to next-generation clinical candidates and AI-guided innovation.},
journal = {Future medicinal chemistry},
volume = {},
number = {},
pages = {1-19},
doi = {10.1080/17568919.2026.2714022},
pmid = {42573081},
issn = {1756-8927},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by multifactorial pathology, including amyloid-β (Aβ) aggregation, tau hyperphosphorylation, oxidative stress, neuroinflammation, and synaptic dysfunction. Despite extensive research, currently approved treatment provides only symptomatic relief, while recently approved disease-modifying monoclonal antibodies have shown limited benefits. Ongoing clinical investigations have shifted toward multi-target directed ligands (MTDLs), RNA-based therapies, immunotherapies, and vaccines. Some approved drugs that have established safety profiles are being repurposed to address the disease's neuropsychiatric symptoms or modulate AD pathological changes. Integrating diverse pharmacophores, such as curcumin, resveratrol, chromone, and indole, within a single skeleton is anticipated to exert multi-modal modifying properties. In parallel, optimization of ADME properties, particularly blood-brain barrier (BBB) permeation and efflux modulation, remains a major obstacle in AD drug design. The incorporation of artificial intelligence (AI) and machine learning (ML) is expected to enhance the prediction of pharmacokinetic, pharmacodynamic, and toxicity parameters.},
}

@article {pmid42573117,
year = {2026},
author = {Abul, MS and Parvizi, J and Skowronek, P and Erdogan, F and Tuncay, İ and Hirschmann, MT and Kayaalp, ME},
title = {Osteoarthritis management through medical reversal: Glucosamine, Alzheimer's disease risk, and long-term outcomes after arthroscopic partial meniscectomy.},
journal = {Knee surgery, sports traumatology, arthroscopy : official journal of the ESSKA},
volume = {},
number = {},
pages = {},
doi = {10.1002/ksa.70578},
pmid = {42573117},
issn = {1433-7347},
abstract = {The adoption of interventions in osteoarthritis and musculoskeletal care frequently precedes the availability of robust long-term evidence, creating the conditions for subsequent medical reversal. Recent findings raising concern about possible adverse neurocognitive associations with glucosamine use challenge the assumption that widely used supplements are necessarily biologically inert, although their causal significance and direct relevance to routine osteoarthritis management remain uncertain. In contrast, 10-year follow-up evidence after arthroscopic partial meniscectomy for degenerative meniscal tears provides a more established example of medical reversal, demonstrating no sustained clinical benefit over sham surgery and raising concern regarding structural harm. Evidence concerning repeated intra-articular corticosteroid injections similarly illustrates the limitations of relying on biological plausibility or short-term symptomatic outcomes. These examples, while differing in evidentiary maturity, support a common principle: orthopaedic interventions should be evaluated according to rigorous comparative evidence and durable patient-centred outcomes. Clinicians should communicate uncertainty, avoid treating structural abnormalities or mechanistic rationale as sufficient indications for intervention, and remain willing to revise established practices when stronger evidence emerges.},
}

@article {pmid42573418,
year = {2026},
author = {Norevik, CS and Huuha, AM and Kobro-Flatmoen, A and Lydersen, S and Røsbjørgen, RN and Bækkerud, FH and Scrimgeour, N and Tari, AR},
title = {Effects of Intravenously Administered Plasma from Exercise-Trained Donors on Mitochondrial Respiration in a Rat Model of Alzheimer's Disease.},
journal = {Medicine and science in sports and exercise},
volume = {58},
number = {9},
pages = {1901-1913},
doi = {10.1249/MSS.0000000000004018},
pmid = {42573418},
issn = {1530-0315},
mesh = {Animals ; *Alzheimer Disease/therapy/metabolism ; Male ; *Mitochondria/metabolism ; Disease Models, Animal ; *Physical Conditioning, Animal/physiology ; Oxidative Phosphorylation ; Rats ; Hippocampus/metabolism ; Rats, Transgenic ; *Plasma ; Proteomics ; Blood Donation ; Cell Respiration ; },
abstract = {PURPOSE: Dysfunction of mitochondria is observed early in Alzheimer's disease (AD), possibly driving the pathogenesis of the disease. This study aims to assess whether plasma from exercise-trained donors can enhance mitochondrial function in a transgenic AD model and to gain insight into the proteomic profile of the donor plasma.

METHODS: Male McGill-R-Thy1-APP rats (n = 3 per treatment group) were treated at either an early preplaque stage (2.2 months) or a later stage (5.2 months) with plasma from exercise-trained donors (ExPlas), sedentary donors (SedPlas), or saline. The rats received 14 transfusions over 6 wk. Mitochondrial respiration was assessed in cornu ammonis (CA), dentate gyrus (DG), gastrocnemius, and left ventricle using high-resolution respirometry. Proteomic analyses were performed in donor blood using mass spectrometry.

RESULTS: In early-stage AD rats, ExPlas improved hippocampal mitochondrial respiration. Compared with saline, CA oxidative phosphorylation (OXPHOS) capacity for complex I increased by +30.8 pmol O2·s-1·mg-1 (P < 0.001) and CI+II by +37.8 pmol O2·s-1·mg-1 (P < 0.001). Compared with SedPlas, CA OXPHOS for CI increased by +16.9 pmol O2·s-1·mg-1 (P = 0.01) and CI+II by +23.8 pmol O2·s-1·mg-1 (P = 0.007). In DG, similar improvements were only seen compared with saline. In CA, but not DG, of later-stage rats, ExPlas produced smaller but significant increases in CI and CI+II OXPHOS compared with saline, but no significant differences compared with SedPlas. No changes were observed in muscle or heart. Proteomics revealed enrichment of complement and platelet-related pathways in ExPlas.

CONCLUSIONS: This proof-of-concept study shows that exercise-trained donor plasma enhances hippocampal mitochondrial respiration in early-stage AD rats and, to a lesser extent, in later-stage AD rats. The proteomic profile of the exercise-trained donor plasma indicates a role of altered complement and platelet functions.},
}

Animals
*Alzheimer Disease/therapy/metabolism
Male
*Mitochondria/metabolism
Disease Models, Animal
*Physical Conditioning, Animal/physiology
Oxidative Phosphorylation
Rats
Hippocampus/metabolism
Rats, Transgenic
*Plasma
Proteomics
Blood Donation
Cell Respiration

@article {pmid42573479,
year = {2026},
author = {Kang, S and Goodridge, HS},
title = {Metabolic Reprogramming of Brain Microglia: Implications for Aging and Aging-Associated Neurodegenerative Diseases.},
journal = {Aging cell},
volume = {25},
number = {8},
pages = {e70660},
doi = {10.1111/acel.70660},
pmid = {42573479},
issn = {1474-9726},
support = {ABA-25-1372697/ALZ/Alzheimer's Association/United States ; },
mesh = {Humans ; *Microglia/metabolism ; *Aging/metabolism ; *Neurodegenerative Diseases/metabolism/pathology ; *Brain/metabolism/pathology ; Animals ; Metabolic Reprogramming ; },
abstract = {Microglia, the resident macrophages of the central nervous system (CNS), are key players in maintaining brain and spinal cord homeostasis and protecting the CNS from damage and disease. During aging, the brain undergoes profound changes-including chronic low-grade inflammation, synaptic dysfunction, and increased vulnerability to neurodegenerative diseases-all of which are closely related to alterations in microglial function. One emerging theme is that microglial metabolism is a crucial determinant of their immune and homeostatic activity. In this mini-review, we explore how metabolic programs shape brain microglial behavior and how these processes change during aging and in neurodegenerative diseases. We first highlight the link between specific metabolic pathways and key microglial functions, including phagocytosis, cytokine production, and the oxidative stress response. We then discuss how microglial metabolism is reprogrammed during healthy aging and in Alzheimer's disease and Parkinson's disease, including sex-specific differences. Finally, we examine regulators that influence microglial metabolic states and discuss how these pathways contribute to disease susceptibility and progression. Collectively, recent findings highlight the central role of metabolic reprogramming in shaping microglial responses during aging and in neurodegenerative diseases. We emphasize the need for integrative studies that consider microglial subsets, sex differences, disease context, and upstream molecular regulators to better understand how microglial metabolism contributes to brain health and pathology. A deeper understanding of these pathways may offer new opportunities for therapeutic strategies aimed at restoring microglial homeostasis and mitigating harmful neuroinflammatory processes.},
}

Humans
*Microglia/metabolism
*Aging/metabolism
*Neurodegenerative Diseases/metabolism/pathology
*Brain/metabolism/pathology
Animals
Metabolic Reprogramming

@article {pmid42573507,
year = {2026},
author = {Zhu, X and Wang, L and Tang, R and Huang, ZA and Huang, YA and Tan, F and Hu, L and You, Z and Hu, P},
title = {Spatial-Spectral Fusion Enables Drug Repositioning by Capturing Indirect and Long-Range Associations in Biological Networks.},
journal = {Bioinformatics (Oxford, England)},
volume = {},
number = {},
pages = {},
doi = {10.1093/bioinformatics/btag553},
pmid = {42573507},
issn = {1367-4811},
abstract = {MOTIVATION: Drug repositioning accelerates clinical translation by identifying new therapeutic indications for approved drugs. However, therapeutic associations in biomolecular networks often exist indirectly, through transitive chains and long-range mechanisms, rather than as directly observed links. Shallow methods are confined to direct similarity and miss such indirect associations, whereas deep graph neural networks suffer from over-smoothing and lose discriminative power in highly connected networks.

RESULTS: We propose a spatial-spectral collaborative framework. In the spatial domain, a wave-evolution process propagates similarity from local to global, capturing multi-hop transitive associations while preserving discriminative representations. In the spectral domain, network-specific spectral transforms model global connectivity for long-range dependencies over homogeneous similarity and heterogeneous drug-protein-disease networks, with the two views aligned by contrastive learning. On three benchmarks the method outperforms state-of-the-art baselines on most evaluation metrics; case studies on Alzheimer's and Parkinson's disease and molecular docking confirm its ability to recover non-explicit therapeutic associations.

AVAILABILITY: The source code and data are available at https://github.com/Juniper-cola/BIO_SSF.

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

@article {pmid42573665,
year = {2026},
author = {Mukim, RD and Xu, Y and Evola, V and Parmar, MS},
title = {Semaglutide as a potential neuroprotective agent for neurological and neurodegenerative disorders: Mechanisms, preclinical evidence, and translational challenges and opportunities.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42573665},
issn = {1573-4978},
mesh = {Semaglutide ; Humans ; *Glucagon-Like Peptides/pharmacology/therapeutic use/metabolism ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Neurodegenerative Diseases/drug therapy/metabolism ; Animals ; Biomarkers/metabolism ; Oxidative Stress/drug effects ; *Nervous System Diseases/drug therapy/metabolism ; },
abstract = {Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are established treatments for metabolic disease, with growing evidence suggesting neuroprotective potential in central nervous system (CNS) disorders. In preclinical models of Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and stroke, semaglutide has been reported to reduce neuroinflammatory and oxidative stress markers and improve selected pathological or behavioral outcomes, although the specific effects vary by model and indication. However, significant translational challenges remain. The Phase 3 EVOKE and EVOKE+ trials in early symptomatic AD failed to meet primary cognitive endpoints, although biological target engagement was reported, with improvements in selected AD-related biomarkers including p-tau181, p-tau217, neurogranin, YKL-40, and plasma hsCRP. This dissociation between biomarker changes and clinical benefit may reflect treatment timing, advanced neurodegeneration, limited CNS exposure, endpoint sensitivity, or other factors. In contrast, observational studies suggest an association between semaglutide or GLP-1 RA exposure and lower dementia-related risk in at-risk populations, although preservation of cognitive reserve has not been directly demonstrated and causality has not been established. This review evaluates the current mechanistic, preclinical, and emerging clinical evidence for semaglutide across neurodegenerative and neuroinflammatory disorders, with emphasis on distinguishing semaglutide-specific findings from broader GLP-1 RA class effects and identifying key translational limitations. Collectively, current evidence supports continued investigation of semaglutide as a potential neuroprotective strategy, while highlighting the need for earlier intervention studies, improved understanding of CNS target engagement, and further clinical validation.},
}

Semaglutide
Humans
*Glucagon-Like Peptides/pharmacology/therapeutic use/metabolism
*Neuroprotective Agents/pharmacology/therapeutic use
*Neurodegenerative Diseases/drug therapy/metabolism
Animals
Biomarkers/metabolism
Oxidative Stress/drug effects
*Nervous System Diseases/drug therapy/metabolism

@article {pmid42573807,
year = {2026},
author = {Maman, D and Steinfield, Y and Berkovich, Y},
title = {Factors associated with selection of total hip arthroplasty versus hemiarthroplasty for femoral neck fracture in older adults: a nationwide analysis of 99,084 cases.},
journal = {Archives of orthopaedic and trauma surgery},
volume = {146},
number = {1},
pages = {},
pmid = {42573807},
issn = {1434-3916},
mesh = {Humans ; *Femoral Neck Fractures/surgery ; *Hemiarthroplasty/statistics & numerical data ; *Arthroplasty, Replacement, Hip/statistics & numerical data ; Aged ; Male ; Female ; Retrospective Studies ; Aged, 80 and over ; United States ; *Patient Selection ; Comorbidity ; Proximal Femoral Fractures ; },
abstract = {BACKGROUND: Surgical management of displaced femoral neck fractures in older adults typically involves hemiarthroplasty or total hip arthroplasty (THA). Although clinical guidelines suggest that THA may be considered in selected healthier and cognitively intact patients, real-world procedure selection varies widely. This study evaluated patient factors associated with selection of THA versus hemiarthroplasty in a contemporary U.S.

METHODS: A retrospective cohort study was conducted using the 2022 Nationwide Readmissions Database (NRD). Patients ≥ 65 years hospitalized with femoral neck fracture were identified using ICD-10-CM codes. Those treated with internal fixation or non-arthroplasty procedures were excluded. Weighted analyses characterized demographics, comorbidities, and hospital utilization between THA and hemiarthroplasty groups. A multivariable logistic regression model identified factors independently associated with receiving THA. All analyses accounted for NRD survey design.

RESULTS: Among 142,013 operative cases, 99,084 met inclusion criteria (81.8% hemiarthroplasty; 18.2% THA). Patients receiving THA were younger (76.6 vs. 81.9 years), had shorter length of stay (6.06 vs. 7.24 days), and were more frequently discharged home (17.5% vs. 6.2%). Metabolic conditions were associated with increased odds of THA, including obesity (OR 1.17) and sleep apnea (OR 1.12). Frailty-related conditions were associated with markedly reduced THA likelihood, including Alzheimer's disease (OR 0.48), Parkinson disease (OR 0.55), chronic kidney disease (OR 0.78), chronic lung disease (OR 0.72), and congestive heart failure (OR 0.77). Each additional year of age decreased the odds of THA by approximately 9%.

CONCLUSION: In this nationwide cohort, selection of THA rather than hemiarthroplasty was associated with younger age and lower prevalence of frailty- and cognition-related comorbidities, while several metabolic comorbidities showed modest positive associations with THA use. These findings describe contemporary national selection patterns but do not establish treatment appropriateness, clinical benefit, or guideline concordance, as key factors such as pre-fracture mobility, functional independence, and living situation were not available in the dataset.

LEVEL OF EVIDENCE: Level III.},
}

Humans
*Femoral Neck Fractures/surgery
*Hemiarthroplasty/statistics & numerical data
*Arthroplasty, Replacement, Hip/statistics & numerical data
Aged
Male
Female
Retrospective Studies
Aged, 80 and over
United States
*Patient Selection
Comorbidity
Proximal Femoral Fractures

@article {pmid42573852,
year = {2026},
author = {Nguyen, HM and Nguyen, LDT},
title = {Towards Structural Restoration: Epigenetic Reprogramming and Direct Astrocyte-to-Neuron Lineage Conversion as Next-Generation Regenerative Neurotherapeutics.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42573852},
issn = {1559-1182},
mesh = {Humans ; *Astrocytes/metabolism/cytology ; Animals ; *Neurons/metabolism/cytology ; *Epigenesis, Genetic ; *Cellular Reprogramming/genetics ; *Cell Lineage ; *Nerve Regeneration ; },
abstract = {While the recent clinical approval of amyloid-targeting monoclonal antibodies represents a landmark in Alzheimer's disease (AD) management, these immunotherapies fundamentally function as agents of mitigation rather than restoration, failing to reconstitute decimated neural circuitry. Direct in situ astrocyte-to-neuron reprogramming offers a compelling regenerative alternative by leveraging the abundant endogenous glial reservoir. However, translating this cellular plasticity in vivo is severely bottlenecked by the hostile pathological microenvironment and the deeply entrenched epigenetic memory of reactive astrocytes. In this review, we delineate a tripartite neuroregenerative framework. First, we evaluate the prerequisite use of senotherapeutics to engineer a permissive parenchymal niche for nascent neuronal survival. Second, we explore epigenomic editing strategies-including CRISPR-dCas9 platforms and targeted pharmacological modulators-required to dismantle repressive heterochromatin and unlock sequestered neurogenic loci. Third, we dissect the molecular execution of reprogramming via pioneer transcription factors (TFs), emphasizing the obligatory metabolic rewiring from astrocytic glycolysis to neuronal oxidative phosphorylation (OXPHOS). Finally, to overcome formidable translational hurdles, we highlight the convergence of AI-optimized lipid nanoparticles (LNPs) for non-viral blood-brain barrier (BBB) transcytosis alongside Neurological Digital Twins (NDTs) to computationally predict the optimal presymptomatic intervention window. By harmonizing microenvironmental conditioning, epigenetic rejuvenation, and precision delivery, this systems-level blueprint provides a promising rationale for transitioning AD therapeutics from passive deceleration to active structural restoration.},
}

Humans
*Astrocytes/metabolism/cytology
Animals
*Neurons/metabolism/cytology
*Epigenesis, Genetic
*Cellular Reprogramming/genetics
*Cell Lineage
*Nerve Regeneration

@article {pmid42573994,
year = {2026},
author = {Di Molfetta, G and Brum, WS and Pola, I and Tan, K and Benedet, AL and Sauer, M and Montoliu-Gaya, L and Janelidze, S and Mattsson-Carlgren, N and Rahmouni, N and Chan, T and Denkinger, MN and Proitsi, P and Zetterberg, H and Hansson, O and Rosa-Neto, P and Ashton, NJ},
title = {Plasma Biomarkers for Neocortical Tau Burden.},
journal = {JAMA neurology},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamaneurol.2026.2650},
pmid = {42573994},
issn = {2168-6157},
abstract = {IMPORTANCE: Phosphorylated tau-217 (p-tau217) is now an established plasma biomarker for assessing amyloid-β pathology in individuals at risk of Alzheimer disease. However, its performance in identifying advanced neocortical neurofibrillary tangle burden remains suboptimal. Precise assessment of tau pathology is increasingly critical for the rational implementation of anti-amyloid therapies and developing anti-tau interventions. Improved biofluid biomarker-based tau staging could enhance patient stratification and optimize participant selection for clinical care and therapeutic trials.

OBJECTIVE: To develop and validate a multiprotein plasma panel to improve identification of neocortical tau pathology beyond p-tau217 alone.

This multicenter cohort study included 2 independent observational cohorts, Swedish BioFINDER study and Translational Biomarkers in Aging and Dementia (TRIAD). Cross-sectional clinical data and blood samples were collected between 2017 and 2024. Participants included 560 individuals spanning the clinical spectrum from cognitively unimpaired to dementia. These data were analyzed from January 2025 to May 2026.

EXPOSURES: Plasma concentrations of 125 proteins measured using Nucleic Linked Immuno-Sandwich Assay central nervous system panel.

MAIN OUTCOME AND MEASURE: Advanced tau pathology defined as tau positron emission tomography (PET) uptake within Braak stage V and VI regions. Predictive performance of biomarker models was evaluated using area under the receiver operating characteristic curve (AUC).

RESULTS: The study included 560 amyloid-positive participants (BioFINDER: n = 431; mean [SD] age, 73.6 [7.0] years; 212 female [49.2%] and 219 male [51.8%]; TRIAD: n = 129; mean [SD] age, 70.4 [8.3] years; 76 female [58.9%] and 53 male [41.1%]). Using multivariable logistic regression approaches, a 7-protein panel was found in BioFINDER to identify tau PET uptake within Braak stage V and VI regions. When compared with p-tau217 (AUC, 0.86-0.88; 95% CI, 0.82-0.94), this multiprotein panel was associated with improved identification in both discovery and validation cohorts (AUC, 0.92-0.94; 95% CI, 0.89-0.98; DeLong P < .001). This reduced the proportion of individuals classified within the intermediate-risk range (between paired sensitivity and specificity thresholds) in the validation cohort by 14.7% to 21.0%.

CONCLUSIONS AND RELEVANCE: This multicohort study demonstrated how including additional plasma proteins significantly enhanced the performance of p-tau217 in predicting advanced tau pathology among amyloid-positive individuals. This suggests a multiprotein approach may offer a viable and scalable alternative to tau PET staging in clinical or research settings.},
}

@article {pmid42574041,
year = {2026},
author = {Sarathkumar, E and Sasi, R and Menon, RN and Jayasree, RS},
title = {Electrochemical profiling of plasma pTau-181 levels associated with mild cognitive impairment and Alzheimer's disease using an MXene-gold nanorod interface.},
journal = {Journal of materials chemistry. B},
volume = {},
number = {},
pages = {},
doi = {10.1039/d6tb00880a},
pmid = {42574041},
issn = {2050-7518},
abstract = {Early diagnosis of Alzheimer's disease (AD) remains a major clinical challenge, particularly during the mild cognitive impairment (MCI) stage, where subtle cognitive changes overlap with normal ageing and reliable diagnostic indicators are limited. Plasma phosphorylated tau at threonine-181 (pTau-181) has emerged as a disease-specific biomarker associated with tau pathology and early neurodegenerative progression, with increasing evidence supporting its relevance for identifying individuals at risk of AD during the prodromal phase. However, accurate quantification of plasma pTau-181 is hindered by its extremely low concentration and the complex biochemical environment of blood. In this study, a label-free electrochemical impedance biosensor was developed for sensitive detection of plasma pTau-181 using a self-assembled two-dimensional MXene-gold nanorod (MXene-GNR) hybrid interface. Modification of a glassy carbon electrode with the MXene-GNR nanocomposite enhanced interfacial charge-transfer behaviour and increased the electroactive surface area by approximately 37%, enabling improved anti-pTau-181 immobilization and signal transduction. The biosensor exhibited a concentration-dependent impedance response toward pTau-181 over a wide dynamic range and achieved an ultrasensitive limit of detection of 12.561 fg mL[-1] in 10% plasma spiked samples while maintaining high analytical selectivity. Clinical plasma analysis demonstrated statistically significant differentiation of AD and MCI groups from healthy controls (p < 0.001), supporting the relevance of plasma pTau-181 measurement for assessing disease-associated cognitive impairment. These findings demonstrate the potential of the MXene-GNR electrochemical platform as a minimally invasive approach for plasma biomarker evaluation toward early AD diagnosis and monitoring.},
}

@article {pmid42574303,
year = {2026},
author = {Mena, D and Vincze, A and Shultz, A and Rauch, JN},
title = {A Split-Luciferase Complementation Assay for Temporally Resolved Measurement of Tau Clearance in Microglia.},
journal = {Journal of visualized experiments : JoVE},
volume = {},
number = {233},
pages = {},
doi = {10.3791/71870},
pmid = {42574303},
issn = {1940-087X},
mesh = {*tau Proteins/metabolism/analysis ; *Microglia/metabolism/cytology/chemistry ; Humans ; Induced Pluripotent Stem Cells/metabolism/cytology ; *Luciferases/chemistry/metabolism/genetics ; *Luminescent Measurements/methods ; },
abstract = {As the resident immune cells of the central nervous system, microglia are central regulators of brain homeostasis and key mediators of neurodegenerative disease. These cells continuously survey the neural environment and play a critical role in the recognition, internalization, and degradation of extracellular substrates, including misfolded and aggregated proteins such as pathological tau. Despite growing evidence implicating microglia in tau clearance, existing approaches to measure tau uptake and degradation lack the temporal resolution and sensitivity needed to fully capture these dynamic processes. Here, we developed a luminescence-based assay to quantitatively monitor tau clearance in human induced pluripotent stem cell (iPSC)-derived microglia. This platform leverages a split-luciferase-based complementation system to enable highly sensitive, real-time detection of tau in live cells, allowing for precise tracking of its intracellular processing. This assay is scalable and adaptable across multiple cell types, providing a versatile tool to interrogate endolysosomal pathways and cellular mechanisms governing tau handling in neurodegenerative diseases, including Alzheimer's disease.},
}

*tau Proteins/metabolism/analysis
*Microglia/metabolism/cytology/chemistry
Humans
Induced Pluripotent Stem Cells/metabolism/cytology
*Luciferases/chemistry/metabolism/genetics
*Luminescent Measurements/methods

@article {pmid42574385,
year = {2026},
author = {Flores, R and Musenda, K and Barbosa, DB and Cheng, KH and Sikazwe, D},
title = {Bis-hydrophobic 5-(1,2-dithiolan-3-yl)pentanamide budding leads targeting brain sigma-1 receptors.},
journal = {PloS one},
volume = {21},
number = {8},
pages = {e0352906},
doi = {10.1371/journal.pone.0352906},
pmid = {42574385},
issn = {1932-6203},
mesh = {*Receptors, sigma/metabolism/antagonists & inhibitors/chemistry ; Sigma-1 Receptor ; Hydrophobic and Hydrophilic Interactions ; *Amides/chemistry/pharmacology/chemical synthesis ; *Brain/metabolism/drug effects ; Animals ; Ligands ; Humans ; Thioctic Acid/chemistry ; Molecular Docking Simulation ; Pharmacophore ; Protein Binding ; },
abstract = {Multi-mechanistic sigma-1 (σ1) receptors are implicated in several neurodegenerative pathologies including Alzheimer's disease (AD). As part of an ongoing effort to create a collection of diverse, readily synthesizable, σ1 acting small molecules for anti-neurodegenerative applications, we opted to try lipoic acid (LA) derived amides. These amides are designated as "5-(1,2 dithiolan-3-yl)pentanamides" throughout this publication. Our design approach was σ1 pharmacophore based - that is, ligands possessing three key functionalities (a hydrophobic dithiolane group, a flexible amide H-bonding linker, a hydrophobic alkyl/aryl group). Twenty-one dithiolane pentanamides were therefore designed, docked, synthesized, and pharmacologically assessed for σ1/σ2 binding affinities. Compounds 2, 6, 17 possessed promising selective σ1 binding affinities (with respective Ki values of 256, 133 and 32 nM) versus the standard ligand PD144418 (Ki = 0.08 nM). The three compounds will be used as leads in follow-up structure activity optimizations.},
}

*Receptors, sigma/metabolism/antagonists & inhibitors/chemistry
Sigma-1 Receptor
Hydrophobic and Hydrophilic Interactions
*Amides/chemistry/pharmacology/chemical synthesis
*Brain/metabolism/drug effects
Animals
Ligands
Humans
Thioctic Acid/chemistry
Molecular Docking Simulation
Pharmacophore
Protein Binding

@article {pmid42574716,
year = {2026},
author = {Watry, RA and Hadidi, NN and Kreitzer, MJ and Bhimani, R and Yu, F and Salisbury, DL},
title = {Exercise Impact on Affective/Cognitive Symptoms and QoL in Subjective Cognitive Decline: An RCT.},
journal = {American journal of Alzheimer's disease and other dementias},
volume = {41},
number = {},
pages = {15333175261476974},
doi = {10.1177/15333175261476974},
pmid = {42574716},
issn = {1938-2731},
mesh = {Humans ; Female ; Aged ; *Quality of Life/psychology ; *Cognitive Dysfunction/therapy/psychology ; *Anxiety/therapy/psychology ; Male ; *Depression/therapy/psychology ; *Exercise Therapy/methods ; Aged, 80 and over ; *Exercise/psychology ; COVID-19 ; },
abstract = {IntroductionThe purpose of this secondary data analysis of an RCT, was to examine the preliminary efficacy of moderate-intensity cycling exercise versus control on cognitive and affective symptoms (i.e., depressive and anxiety), and quality of life (QoL) in older adults with subjective cognitive decline (SCD).MethodsCommunity-dwelling older adults with SCD (N=38) were randomized to 12 weeks/36 sessions. For this secondary data analysis, between-group change was evaluated by analysis of covariance, adjusting for baseline values.ResultsThe participants' mean age was 74.6(7.4) years, and 69% female. There were no significant between-group changes in all outcomes (p-values ranged from .06-.70. Large and moderate between-group effect sizes were seen in favor of the control group for anxiety symptoms (between-group change=-5.36 [4.74], ηp[2]=0.11.DiscussionAttention and social interaction received by this secluded population of older adults and COVID-19 losses likely impacted results. Further mixed-methods research with larger groups that does not span a pandemic, is necessary.Clinical Trial RegistryConcurrent Aerobic Exercise and Cognitive Training to Prevent Alzheimer's in At-risk Older Adults (Exergames): NCT04311736.},
}

Humans
Female
Aged
*Quality of Life/psychology
*Cognitive Dysfunction/therapy/psychology
*Anxiety/therapy/psychology
Male
*Depression/therapy/psychology
*Exercise Therapy/methods
Aged, 80 and over
*Exercise/psychology
COVID-19

@article {pmid42574828,
year = {2026},
author = {Lin, X and Wei, Z and Dong, X and Sun, Y},
title = {A sequential photodynamic-antioxidation therapy against Alzheimer's β-amyloid enabled by a dual‑carbon dots nanomotor.},
journal = {Journal of colloid and interface science},
volume = {724},
number = {Pt 3},
pages = {141317},
doi = {10.1016/j.jcis.2026.141317},
pmid = {42574828},
issn = {1095-7103},
abstract = {Abnormal accumulation of β-amyloid protein (Aβ) in the brain is considered as the primary hallmark of Alzheimer's disease (AD). Beyond inducing neuronal metabolic disorders and apoptosis, Aβ activates oxidative stress pathways, thereby exacerbating reactive oxygen species (ROS) toxicity. Therefore, the design of effective multi-target synergistic therapeutics targeting Aβ and excessive ROS has emerged as a critical strategy for AD prevention and treatment. Herein, we propose a "Sequential Photodynamic-Antioxidation Therapy (SPAT)" against Alzheimer's Aβ, and the SPAT strategy is enabled by the design of a sub-10nm dual‑carbon dots Janus composite (SeRCD) composed of a newly designed and synthesized selenium-doped high-efficiency antioxidant carbon dot (SeCD) and a previously reported near-infrared (NIR) carbon dot (RCD) possessing both thermogenic and photodynamic functionalities. The thermogenic property of RCD in SeRCD endows the Janus composite with photo-propelled autonomous motion powered by "self-thermophoretic force" under NIR irradiation. Thus, SeRCD shows potent inhibition of Aβ fibrillization at low concentrations (0.5 to 5 μg/mL) via photooxygenation and the nanomotor effect under NIR irradiation for only 10 min. Under the subsequent NIR-off condition, SeCD in SeRCD effectively mitigates the oxidative damage to cells by scavenging ROS. Thus, the lifespan of AD nematodes is prolonged by the SPAT strategy from 12 to 19 d at 2 μg/mL. The results collectively demonstrate the effectiveness of the dual-CDs composite design and great potential of the SPAT strategy for application in fighting against AD.},
}

@article {pmid42570085,
year = {2026},
author = {Bu, Y and Fan, Z and Li, L},
title = {Bacterial outer membrane vesicles in oral diseases: from pathogenic mediators to theranostic platforms.},
journal = {Critical reviews in microbiology},
volume = {},
number = {},
pages = {1-19},
doi = {10.1080/1040841X.2026.2713518},
pmid = {42570085},
issn = {1549-7828},
abstract = {Bacterial outer membrane vesicles (bOMVs) are nanoscale structures derived from Gram-negative (G[-]) bacteria that play an important role in oral diseases. As key mediators of host-microbe interactions, bOMVs contribute to the pathogenesis of periodontitis, oral squamous cell carcinoma (OSCC), and oral lichen planus (OLP) by disrupting immune homeostasis and promoting tissue destruction. Beyond the oral cavity, bOMVs serve as critical vectors in the oral-systemic axis, disseminating virulence factors to distant organs and contributing to atherosclerotic cardiovascular diseases (ACVDs), Alzheimer's disease (AD), and gastrointestinal (GI) disorders. Concurrently, their inherent properties, including cargo-loading capacity, immunogenicity, and biofilm penetration, position them as promising platforms for noninvasive diagnostics and targeted therapeutics. This review systematically integrates current knowledge on bOMVs biogenesis, pathogenic mechanisms in oral and systemic diseases, and emerging applications in diagnosis and treatment. We also highlight key challenges and future directions for translating bOMVs-based strategies into clinical practice, emphasizing their potential as next-generation theranostic tools (combining therapeutic and diagnostic functions) for oral diseases.},
}

@article {pmid42570239,
year = {2026},
author = {Cruz-Sese, J and Mirón-Alcala, M and Alfonso-Triguero, M and Olalde, J and Ruiz, L and Galbis-Gramage, N and Cortes, L and Escobar, L and Preman, P and Snellinx, A and Saito, T and Saido, TC and Saiz-Aúz, L and Rábano-Gutiérrez, A and Aransay, AM and Diez, I and Tcw, J and Goate, A and De Strooper, B and Alberdi, E and Arranz, AM},
title = {APOE3 and APOE4 human astrocytes differentially modulate Alzheimer's disease pathology and microglial responses in chimeric mice.},
journal = {Cell reports},
volume = {45},
number = {8},
pages = {117803},
doi = {10.1016/j.celrep.2026.117803},
pmid = {42570239},
issn = {2211-1247},
abstract = {Astrocytes and APOE are strongly implicated in Alzheimer's disease (AD), yet the impact of astrocytes carrying different APOE variants on AD hallmarks remains incompletely understood. Here, we generate a chimeric model of AD by transplanting isogenic APOE3 or APOE4 human induced pluripotent stem cell-derived astrocyte progenitors into neonatal AD mice. Donor cells differentiate into human astrocytes that integrate into the cortex and display morphologies consistent with interlaminar-like astrocytes. APOE3 and APOE4 astrocytes differ in expression of APOE, which associates differentially with Aβ plaques. Notably, APOE3 astrocytes are associated with reduced Aβ burden, Tau pathology, and neuritic dystrophy, whereas APOE4 astrocytes exacerbate these processes. They also induce distinct microglial responses: APOE4 astrocytes enhance microglial clustering around Aβ plaques and promote a disease-associated microglia-like state, whereas APOE3 astrocytes reduce clustering and support a more homeostatic profile. These findings highlight a role for human astrocytes and APOE-dependent astrocyte functions in modulating AD-related pathology.},
}

@article {pmid42570244,
year = {2026},
author = {Sun, GG and Wang, C and Mazzarino, RC and Perez-Corredor, PA and Davtyan, H and Blurton-Jones, M and Lopera, F and Arboleda-Velasquez, JF and Shi, Y},
title = {Microglial APOE3 Christchurch protects neurons from Tau pathology in a human iPSC-based model of Alzheimer's disease.},
journal = {Cell reports},
volume = {45},
number = {8},
pages = {117853},
doi = {10.1016/j.celrep.2026.117853},
pmid = {42570244},
issn = {2211-1247},
}

@article {pmid42570275,
year = {2026},
author = {Van Houwelingen, AS and Vernooij, MW and Vermeiren, MR and Ossenkoppele, R and Van De Giessen, E and Seelaar, H and Neitzel, J},
title = {Concordance between plasma biomarkers of phosphorylated tau and tau-PET: A narrative review.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261468708},
doi = {10.1177/13872877261468708},
pmid = {42570275},
issn = {1875-8908},
abstract = {Plasma phosphorylated tau (p-tau) and tau positron emission tomography (PET) are key biomarkers for detecting tau pathology in Alzheimer's disease (AD), offering both diagnostic and prognostic value. However, the concordance between plasma p-tau (p-tau217/p-tau181/p-tau231) positivity and tau-PET positivity remains incompletely understood. In this narrative review, we show that concordance varies by clinical disease stage, the plasma p-tau biomarker assessed, the definition of tau-PET positivity, and the presence of comorbidities and other risk factors. We also present evidence for a temporal sequence of plasma p-tau changes, with plasma p-tau231 positivity preceding p-tau181 positivity, followed by plasma p-tau217 reflecting more advanced stages of tau pathology. We highlight the relevance of these temporal dynamics for the potential development of a stage-specific trajectory framework for plasma p-tau and discuss how such a framework may support improved integration of plasma p-tau and tau-PET, thereby enhancing screening efficiency. Finally, we outline methodological challenges, highlight current efforts such as the development of tau-PET harmonization strategies, and identify priorities for future research. Taken together, this review provides a comprehensive overview of the factors influencing concordance between plasma p-tau positivity and tau-PET positivity. Careful consideration of these factors will be essential for the optimal integration of these biomarkers across the AD spectrum, with the potential to improve both diagnostic and therapeutic strategies.},
}

@article {pmid42570276,
year = {2026},
author = {Kurniadi, NE and Steele, JS and Mattek, N and Guevara, JE and Duff, K},
title = {Predicting progression from mild cognitive impairment to dementia with baseline neuropsychological test scores.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261469182},
doi = {10.1177/13872877261469182},
pmid = {42570276},
issn = {1875-8908},
abstract = {BackgroundAlthough neuropsychological scores have predicted progression from mild cognitive impairment (MCI) to dementia, past work has limitations, including small samples, limited batteries, and research cohorts.ObjectiveThis study sought to identify which baseline cognitive scores predicted progression in clinical patients with MCI followed over 1.5 years.Methods243 individuals clinically diagnosed with MCI at a baseline visit completed neuropsychological testing at baseline and were followed approximately 1.5 years later. Using follow-up diagnoses from neurologists, they were grouped as "MCI-Stable" (i.e., MCI at baseline and follow-up, n = 131) or "MCI-Progressors" (i.e., MCI at baseline but dementia at follow-up, n = 112). Stepwise logistic regression examined follow-up group status predicted from demographics, baseline cognitive scores, and self-reported depressive symptoms.ResultsNeither baseline demographic variables nor depressive symptoms significantly predicted group status at follow-up. Conversely, worse baseline performance on tests of visuospatial construction and semantic fluency were significant predictors of progression from MCI to dementia. Longer follow-up interval also significantly predicted conversion.ConclusionsAlthough many individuals progress from MCI to dementia, there is considerable variability in the timing and cognitive performance among those who convert to dementia versus those who remain stable over time. The current findings identified multiple baseline neuropsychological test scores that predicted that progression over approximately 1.5 years. Such results have implications for clinical care (e.g., providing more services and closer monitoring of at-risk individuals) and research (e.g., enriching clinical trials with those more likely to progress).},
}

@article {pmid42570281,
year = {2026},
author = {Amemiya, S and Takao, H and Matsumoto, S and Umeda-Kameyama, Y and Niimi, Y and Kakumoto, T and Satake, W and Mitsui, J and Ogawa, S and Abe, O},
title = {Subthreshold early white-matter hyperintensity increase predicts accelerated hippocampal and whole-brain atrophy in anti-amyloid-β immunotherapy.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261475336},
doi = {10.1177/13872877261475336},
pmid = {42570281},
issn = {1875-8908},
abstract = {BackgroundAnti-amyloid-β (anti-Aβ) therapy slows cognitive decline but paradoxically accelerates whole-brain gray matter atrophy, complicating outcome prediction.ObjectiveTo identify early imaging markers that predict long-term prognoses.MethodsThis longitudinal cohort study prospectively enrolled participants with early Alzheimer's disease, initiating anti-Aβ therapy. We performed automated T1-weighted MRI volumetric analysis of the whole-brain gray matter, hippocampus, and white matter hyperintensities (WMH). Temporal dynamics were characterized using piecewise linear regression, and predictive utility was assessed using multivariate linear regression analyses.ResultsTwenty-two participants (74 ± 11 years; 14 women) were followed for 376 ± 146 days. Significant volume changes occurred in all regions (p < 0.01). No overt amyloid-related edema was detected, and hemorrhagic events were mild to moderate. Piecewise regression revealed an initial WMH surge that decelerated after 60 days (β=-0.19 [95%CI: -0.33, -0.042], p = 0.01), whereas gray matter regions showed linear volume decline. Early subthreshold WMH expansion predicted long-term atrophy independent of baseline covariates (age, sex, amyloid burden, mini-mental state examination score, drug, and hemorrhagic events) in the hippocampus (β=-0.058 [95%CI: -0.092, -0.025], p = 0.003), and whole-brain gray matter (β=-0.033 [95%CI: -0.065, -0.002], p = 0.04). Early whole-brain gray matter atrophy correlated with the WMH surge (β=-0.53 [95%CI: -0.69, -0.38], p < 0.001) and predicted long-term hippocampal atrophy (β=0.098 [95%CI: 0.038, 0.16], p = 0.004).ConclusionsA transient WMH surge within the first 60 days of therapy mirrors the known time course of amyloid-related imaging abnormalities. Along with concurrent early whole-brain volume loss, this surge independently predicts accelerated long-term hippocampal and whole-brain atrophy, highlighting its potential as an early prognostic imaging marker.},
}

@article {pmid42570282,
year = {2026},
author = {Fatima, SUK and Jabber, A and Khanam, MH and Khan, J and Talukder, MM and Hasnat, MA},
title = {Integrative machine learning reveals telomere-associated gene modules reflecting neuronal dysregulation in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261476085},
doi = {10.1177/13872877261476085},
pmid = {42570282},
issn = {1875-8908},
abstract = {BackgroundTelomere dysfunction contributes to cellular aging and genome instability, but telomere-associated transcription in Alzheimer's disease (AD) is poorly characterized. Telomere genes are commonly tested gene by gene, leaving it uncertain whether they organize into reproducible, disease-linked co-expression programs across cohorts.ObjectiveTo identify AD linked telomere gene modules and evaluate their diagnostic and biological relevance.MethodsWe curated 157 telomere maintenance genes and analyzed two GPL570-platform GEO Series datasets: GSE5281 (n = 161; AD = 87, control = 74) and GSE48350 (n = 253; AD = 80, control = 173). In GSE5281 hippocampus, RMA + age-adjusted limma identified 38 AD-associated telomere genes (FDR<0.05). Ward clustering (silhouette) defined two modules, summarized as eigengenes (module PC1). Eigengenes were evaluated across seven classifiers with nested stratified 5 × 5 cross-validation; Youden's J thresholds from out-of-fold predictions were fixed and applied to GSE48350 using frozen z-scoring (GSE5281 μ/σ) and fixed cutoffs. Robustness used 500-bootstrap stability; hub genes from the dominant module were interpreted with BRETIGEA and Reactome/GO enrichment.ResultsPCA and t-SNE showed AD-associated structure in telomere-gene expression. With only two module features, models achieved ROC-AUC 0.722-0.780 internally and 0.689-0.695 externally. Bootstrap resampling converged on one dominant axis: Cluster 2 was consistently the strongest feature and was reduced in AD (Cohen's d = -1.07; Welch p = 8.13 × 10[-10]). Hub genes (TSPYL5, TUBB3, PLCL2, NHP2) were downregulated, tracked neuronal signatures positively, varied inversely with microglial/astrocytic signatures, and mapped to telomere/chromosome maintenance, DNA repair, and cell-cycle regulation.ConclusionsAD features a reproducible, resampling-stable telomere genome-maintenance module that provides an interpretable systems-level disease axis for mechanistic follow-up and integrative biomarker development.},
}

@article {pmid42570289,
year = {2026},
author = {Tian, Y and Qing, H and Quan, Z},
title = {A working feedback-based framework for goal-directed spatial memory deficits in Alzheimer's disease: Feedforward and feedback interactions along the RSC-MEC-CA1-RSC axis.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261473933},
doi = {10.1177/13872877261473933},
pmid = {42570289},
issn = {1875-8908},
abstract = {Spatial navigation deficits are among the earliest and most clinically significant cognitive impairments in Alzheimer's disease (AD), particularly when navigation depends on goal-directed spatial memory. This review defines goal-directed spatial memory as a task-oriented construct and proposes a network-level framework for interpreting early AD navigation deficits. We synthesize anatomical, physiological, behavioral, and disease-related evidence concerning the retrosplenial cortex (RSC), medial entorhinal cortex (MEC), hippocampal CA1, and CA1-RSC feedback interactions. We propose the RSC-MEC-CA1-RSC axis as a testable working framework based on coordinated feedforward and feedback interactions. Within this system, the RSC integrates behaviorally relevant external cues and supports reference-frame transformation. The MEC contributes to path integration and self-goal relational coding, and CA1 consolidates these signals into functional goal-location representations. These representations can be retrieved, stabilized, and then transmitted back to cortical networks to guide continuous behavioral updating. Notably, we define the CA1-RSC pathway as a functional feedback route that supports iterative information updating, route correction and strategic adjustment. We argue that AD navigation deficits stem from the progressive breakdown of feedforward and feedback interactions across this axis, rather than from isolated dysfunction of single brain regions. The RSC-MEC-CA1-RSC framework offers a circuit-level mechanistic account for spatial disorientation in early AD. As a working model instead of a fully validated canonical circuit, it puts forward a series of testable hypotheses for future research, including cross-regional electrophysiological recordings, projection-specific circuit manipulation, imaging assessments, and differentiated navigation paradigms to examine cue use, path integration, goal retrieval and feedback-dependent updating.},
}