RevDate: 2025-12-09
CmpDate: 2025-12-09

Miao X, Luo K, Li Y, et al (2025)

A Novel Palmitoylation-Related Molecular Signature for Predicting and Therapeutically Targeting Alzheimer's Disease.

Molecular neurobiology, 63(1):276.

Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by amyloid-beta (Aβ) plaques and hyperphosphorylated tau pathology. Although palmitoylation has been implicated in AD, its specific mechanisms remain poorly defined. To investigate this, seven transcriptomic datasets were obtained from the GEO database. Differential expression and Gene Set Enrichment Analysis (GSEA) were performed across five training sets (GSE5281, GSE29378, GSE36980, GSE122063, and GSE132903). By intersecting differentially expressed genes (DEGs) with palmitoylation-related genes from GeneCards, 65 AD-associated palmitoylation-related genes (AD-PRGs) were identified. Functional enrichment analyses (KEGG and GO) were performed on these genes. Furthermore, seven key AD-PRGs (CALM1, VAMP2, SYT1, MET, BAG3, TJP1, NOTCH1) were prioritized using protein-protein interaction (PPI) networks and three machine learning algorithms (LASSO, SVM-RFE, and Random Forest). A diagnostic model constructed from these seven genes exhibited strong predictive performance, with AUC values of 0.834 in the training set and 0.907/0.865 in two external validation sets (GSE33000, GSE44770). Single-gene GSEA indicated associations with synaptic function and oxidative phosphorylation pathways. Protein docking analyses using GRAMM (Global RAnge Molecular Matching) and PISA (Proteins, Interfaces, Surfaces, and Assemblies) further suggested interactions between these key genes and Aβ/tau, supporting their involvement in AD pathogenesis. Additionally, regulatory network analysis identified 23 miRNAs, 33 transcription factors, and 14 potential therapeutic agents targeting these key genes. Our findings underscore the importance of palmitoylation in synaptic dysfunction-notably VAMP2 and SYT1 roles in vesicle recycling and neurotransmitter release-and offer promising targets for novel therapeutic strategies in AD.

RevDate: 2025-12-09

Gao Y, Lin S, Jiang M, et al (2025)

The association between individualized functional connectivity disruption and metabolic abnormality in alzheimer's disease and mild cognitive impairment: insights from multimodal neuroimaging.

Neuroradiology [Epub ahead of print].

PURPOSE: The aim of this study was to leverage fluorodeoxyglucose-positron emission tomography (FDG-PET) and blood oxygen level dependent-functional magnetic resonance imaging (BOLD-fMRI) to perform a comprehensive multi-modal analysis of metabolic alteration and individualized functional connectivity in Alzheimer's Disease (AD) and mild cognitive impairment (MCI) and characterize the relationship of these alterations with neurocognitive scores.

METHODS: We analyzed data from 71 subjects, including those with AD, MCI and Health Control (HC), using FDG-PET and BOLD-fMRI acquired from Alzheimer's Disease Neuroimaging Initiative (ADNI). We examined network functional connectivities (FC) base on Independent Component Analysis (ICA), analyzed regional standardized uptake value ratios (SUVR) and their relationships with neurocognitive scores.

RESULTS: Both AD and MCI showed metabolic and functional connectivity abnormalities in Default Mode Network (DMN) region. We also found abnormalities in the somatomotor system in AD, which may be an early predictive indicator of AD. In MCI, both metabolic and functional connectivity abnormalities appear in precuneus, and these two modes were closely related, indicating that the precuneus may be a core region in the transition of healthy individuals to MCI.

CONCLUSION: This study demonstrated that the individual brain network technology based on ICA, combined with the metabolic characteristics of FDG-PET, facilitates the development of personalized early diagnosis for AD/MCI, enhances our understanding of the underlying neuropathological mechanisms, and also promotes the development of interdisciplinary technologies.

RevDate: 2025-12-09

Asnacios S, Staneva G, Thon G, et al (2025)

Alzheimer's disease amyloid-β affects membrane structure and mechanical properties of human neural progenitors.

Journal of Alzheimer's disease : JAD [Epub ahead of print].

BackgroundIn Alzheimer's disease (AD), neurogenesis and neuroplasticity are severely affected but there is not yet a consensus about the underlying mechanisms. The amyloid cascade hypothesis is associated with overproduction of the amyloid-β (Aβ) peptide in the brain and points out the soluble Aβ oligomers to be the primary toxic species.ObjectiveAs the ability of neuronal cells to deform is involved in neurogenesis and neuroplasticity processes, we investigated how an exposure to Aβ oligomers could affect the mechanical properties of the neural progenitor cells.MethodsHuman neural progenitor cells (h-NPCs) were derived from human embryonic pluripotent stem cells (h-ESCs). The effect of Aβ42 oligomers on the mechanical viscoelastic moduli of h-NPCs was determined using a custom-made microplate rheometer and the frequency analysis method. Fluorescence confocal microscopy of Di-4-ANEPPDHQ-stained cells was performed to assess the lipid order of h-NPC membranes. Aβ42 aggregation in the cell culture medium was thoroughly characterized by combining Thioflavin T fluorescence, dynamic light scattering, and transmission electron microscopy as complementary techniques.ResultsWe present here the first measurement of the visco-elastic moduli of a relevant model of h-NPC having the potential to differentiate in neuronal and glial subtypes. h-NPC exhibit a predominant elastic behavior, with low elastic modulus values of ∼200 Pa, in the range of those reported for the Young's modulus of glial cells and neurons in previous studies. Aβ42 oligomers induced 3-fold increase of both elastic and viscous h-NPC moduli, revealing a significant stiffening effect. This Aβ42-induced cell stiffening correlates with an increase in plasma membrane lipid order.ConclusionsOur findings raise questions about whether and how such Aβ42-induced effects on h-NPC deformability and membrane structure might have an impact on the differentiation of h-NPC which is at the root of neurogenesis, and could thus be involved in AD.

RevDate: 2025-12-09

Fang H, Tang A, Tang C, et al (2025)

Multimodal PET/MR Imaging in Early-onset Alzheimer's Disease With Parkinsonism due to a Novel Presenilin-1 (M233I) Mutation.

Clinical nuclear medicine pii:00003072-990000000-02009 [Epub ahead of print].

We report the multimodal PET/MR imaging findings in a 31-year-old woman with a novel presenilin 1 (PSEN1) missense mutation (c.699G>A, p.M233I) who developed progressive cognitive decline and parkinsonian features. Multimodal imaging, including glucose metabolism, dopamine transporter function, amyloid-β pathology, and tau protein PET imaging, combined with structural MRI, revealed widespread abnormalities concordant with her clinical manifestations. Findings included glucose hypometabolism, dopaminergic dysfunction, amyloid and tau deposition, and cerebellar atrophy. This case highlights the diagnostic value of multiprobe PET/MR imaging in characterizing complex neurodegenerative phenotypes and expands the genotypic and phenotypic spectrum of PSEN1-associated early-onset Alzheimer's disease (EOAD) with parkinsonism.

RevDate: 2025-12-09

Lu Z, Zhou H, Tang H, et al (2025)

Neural stem cell transplantation attenuates cognitive decline and neuroinflammation in a mouse model of Alzheimer's disease with chronic cerebral hypoperfusion.

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism [Epub ahead of print].

Alzheimer's disease (AD) and chronic cerebral hypoperfusion (CCH) frequently coexist in aging populations, synergistically aggravating neurodegeneration. To assess the therapeutic potential of stem cell interventions, an AD + CCH mouse model was generated by combining APP/PS1 mice with bilateral common carotid artery stenosis. Neural stem cells (NSCs) or induced pluripotent stem cells (iPSCs) were transplanted into the lateral ventricles at 5 months of age. Behavioral testing, Nissl staining, Western blotting, and immunofluorescence were conducted at 9 and 12 months to evaluate cognition, neuronal survival, cell death pathways (LC3-II, cleaved caspase-3, NLRP3), glial polarization, and neurotrophic/synaptic markers (BDNF, VEGF, VAChT, PSD95). CCH exacerbated AD-related cognitive deficits, neuronal loss, and activation of autophagic, apoptotic, and pyroptotic pathways, accompanied by enhanced M1 microglial polarization, astrogliosis, and downregulation of BDNF and VAChT. NSCs transplantation significantly improved cognitive performance, preserved neuronal integrity, attenuated glial activation, and restored neurotrophic and synaptic protein expression, characterized by increased BDNF, VEGF, and PSD95 levels and partial recovery of VAChT. In contrast, iPSCs transplantation failed to exert comparable effects. These findings demonstrate that NSCs, but not iPSCs, mitigate AD + CCH-induced neuropathology by re-establishing the balance between inflammatory, neurotrophic, and synaptic signaling, supporting NSCs as a promising therapeutic approach for AD with vascular comorbidity.

RevDate: 2025-12-09
CmpDate: 2025-12-09

Wang W, Wang L, Zhong X, et al (2025)

cGAS-STING Signaling in Central Nervous System Diseases: Neuroinflammatory Mechanisms and Immune Regulation.

Cell biochemistry and function, 43(12):e70146.

The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway has emerged as a critical cytosolic DNA-sensing mechanism that orchestrates innate immune activation in response to cellular stress. In the central nervous system (CNS), this pathway demonstrates highly context-specific and cell-type-dependent functions, ranging from promoting neuroinflammation in neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD), to modulating immune surveillance and therapeutic responsiveness in glioma. This review systematically delineates the molecular mechanisms, activation patterns, and regulatory networks of cGAS-STING signaling in the CNS. We highlight its dualistic roles in both inflammatory exacerbation and antitumor immunity, and further discuss recent advances in therapeutic strategies, including pharmacological modulators, blood-brain barrier (BBB)-penetrating delivery platforms, and nanotechnology-based precision interventions. Finally, we propose future directions focused on decoding tissue-specific immunodynamics and developing spatiotemporally controlled, multiorgan immunoregulatory frameworks. Together, this review underscores cGAS-STING as a promising therapeutic axis in the evolving landscape of neuroimmunology.

RevDate: 2025-12-09

Schmitz M, Thüne K, Fischer AL, et al (2025)

Evidence for different seeding activities of misfolded tau in classical and rapidly progressive Alzheimer's disease.

Brain pathology (Zurich, Switzerland) [Epub ahead of print].

Alzheimer's disease (AD) may display various clinical phenotypes with different disease progressions, such as rapidly progressive Alzheimer's disease (rpAD) type. The reason for clinical heterogeneity is still unknown and not predictable. Here, we subjected frontal cortex-derived tau seeds from classical AD, rpAD patients and controls to tau real-time quaking-induced conversion (RT-QuIC) assay analysis and examined biochemical properties, toxicity, and the morphology of tau fibrils generated during the RT-QuIC applying a cell-based assay and transmission electron microscopy (TEM). We observed seeding activity of misfolded tau protein in AD patients, which was significantly higher than in control cases. Additionally, the RT-QuIC signal response revealed differences between AD cases with a classical clinical phenotype and those with a rapidly progressive course of the disease (rpAD). The RT-QuIC reaction seeded with brain from rpAD exhibited a shorter lag phase, higher area under the curve and a higher seeding end point dilution compared to classical AD, independent from the Braak stage. The cellular toxicity of thioflavin T-positive RT-QuIC products from rpAD-seeded reactions was higher compared to those seeded by classical AD and controls. Morphological characterization of brain tissue-seeded RT-QuIC end-products via TEM showed that tau fibrils derived from rpAD seeded reactions revealed subtly different morphologies compared to classical AD. The study provides evidence for the existence of different tau assemblies in AD with different progression rates. As an alternative explanation, differences in the amounts of misfolded seed or the presence of other co-factors might influence the seeding activity of tau in AD and rpAD patients.

RevDate: 2025-12-09
CmpDate: 2025-12-09

Ahmadi S, Khaledi S, Ahmadi K, et al (2025)

Amyloid Beta in Alzheimer's Disease: Mechanisms, Biomarker Potential, and Therapeutic Targets.

CNS neuroscience & therapeutics, 31(12):e70688.

MAIN PROBLEMS: The accumulation of amyloid beta (Aβ) plaques and neurofibrillary tangles (NFTs) composed of Tau protein is two characteristic brain pathologies in Alzheimer's disease (AD). However, the Aβ hypothesis has recently faced challenges due to the limited clinical efficacy of anti-Aβ antibodies, such as aducanumab and lecanemab.

METHODS: This comprehensive review highlights recent advances and debates regarding the pathophysiology of Aβ peptides and plaques in AD, as well as their use as biomarkers and drug targets.

RESULTS: Aβ aggregation is primarily driven by an imbalance between its generation from amyloid precursor protein (APP) and its clearance from the brain, processes influenced by various risk factors. The toxicity of amyloid plaques is affected by the accumulation of different Aβ species with varying lengths and post-translational modifications of Aβ. Additionally, pathways including neuroinflammation, blood-brain barrier deterioration, autophagy and mitochondrial dysfunction, lipid raft changes, and oxidative stress have pivotal roles in AD. Therefore, a clear map of Aβ's upstream regulators and downstream effectors is crucial for developing effective diagnostics and treatments for AD.

CONCLUSIONS: Incorporating new research findings and ongoing debates surrounding the Aβ cascade hypothesis is crucial for improving early diagnosis and for guiding the development of effective treatments for AD.

RevDate: 2025-12-09
CmpDate: 2025-12-09

Burd SG, Bogolepova AN, Lebedeva AV, et al (2025)

[Epileptic seizures in patients with Alzheimer's disease].

Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova, 125(11):36-43.

Neurodegenerative diseases are one of the leading causes of epileptic seizures with onset in later life. Particular attention is paid to Alzheimer's disease (AD), as a disease that accounts for up to 70% of cases of all types of dementia, and, according to the literature, shares genetic and pathophysiological mechanisms with epilepsy. This paper reviews the literature on the prevalence of epilepsy in AD patients. The reasons for the widely varying data (ranging from 0.5 to 64%) depending on the selected population, the reliability of the established diagnosis, the form and genetic characteristics of the disease, as well as the examination methods used, are considered. The main risk factors for the development of AD and epilepsy, semiotics and features of seizures in patients with AD, as well as approaches to the treatment of such patients, are also covered.

RevDate: 2025-12-09
CmpDate: 2025-12-09

Xu Q, Soto C, Shahnawaz M, et al (2025)

Multi agent large language models for biomedical hypothesis generation in drug combination discovery.

iScience, 28(12):113984.

Recent advancements in large language models (LLMs) have demonstrated their potential in scientific reasoning, but their ability to open-ended hypotheses in data-scarce domains remains underexplored. Here, we introduce Combinatorial Alzheimer's Disease Therapeutic Efficacy Decision (Coated-LLM), an AI-driven framework that is inspired by scientific collaboration to predict efficacious combinatorial therapy when data-driven prediction is infeasible. Coated-LLM employs multiple specialized LLM agents-Researcher, Reviewer s, and Moderator-to systematically generate and evaluate hypotheses through several in-context learning techniques. Using Alzheimer's disease (AD) as a test case, Coated-LLM outperformed traditional knowledge-based methods (accuracy: 0.74 vs. 0.52), with external validation achieving an accuracy of 0.82. In addition, a drug combination predicted from Coated-LLM was experimentally validated to significantly reduce amyloid aggregation in vitro. These findings highlight the potential of our framework to augment human reasoning in complex scientific reasoning tasks, offering a scalable approach for hypothesis generation in biomedical research.

RevDate: 2025-12-09
CmpDate: 2025-12-09

Yu E, Zhang Y, Chen J, et al (2025)

Metabolic factors, gut microbiota, and cognitive performance: Mendelian randomization analysis.

Journal of Alzheimer's disease reports, 9:25424823251405877.

BACKGROUND: The associations between several metabolic factors, gut microbiota (GM), and cognitive performance have not been clearly identified. This study investigates their associations and GM's mediating effects.

OBJECTIVE: This study aimed to investigate the causal effects of key metabolic factors on cognitive performance and to determine whether gut microbiota mediate these associations.

METHODS: Genetic variants linked to four metabolic factors [body mass index (BMI), basal metabolic rate (BMR), systolic blood pressure (SBP), two-hour glucose], GM, and cognitive performance were selected from genome-wide association studies (GWAS). Univariable Mendelian randomization (MR) and mediation MR analyses were applied.

RESULTS: We found a protective effect of body metabolic rate (β = 0.061; 95% CI: 0.029, 0.093; p = 0.0002) and risk effect of body mass index (BMI, β = -0.047; 95% CI: -0.074, -0.019; p = 0.0009), systolic blood pressure (β = -0.049; 95% CI: -0.084, -0.014; p = 0.0063), and two-hour glucose (β = -0.043; 95% CI: -0.070, -0.016; p = 0.0017) on cognitive performance. In addition, the 2-step MR analysis further showed that the BMI-effect on cognitive performance was partially mediated by Rikenellaceae family, with a mediated proportion of 14.03% (95% CI: 0.99%, 27.06%; p < 0.05).

CONCLUSIONS: Our findings suggest that several metabolic factors influence cognitive performance, with gut microbiota potentially mediating these effects. These results provide insights into potential targets and useful biomarkers for understanding the pathogenesis and developing interventions for cognitive health.

RevDate: 2025-12-09
CmpDate: 2025-12-09

Campos-Peña V (2025)

Editorial: Unraveling the mysteries of aging and the brain: advancements in understanding neurodegenerative diseases and dementia.

Frontiers in genetics, 16:1745907 pii:1745907.

RevDate: 2025-12-09
CmpDate: 2025-12-09

Ikeda M, Ishibashi K, Amari M, et al (2025)

[18]F-MK-6240 uptake in cortical tau and hemorrhagic lesions in a case of Alzheimer's disease with possible crossed aphasia.

eNeurologicalSci, 41:100596.

We report neuroimaging findings from a 74-year-old right-handed male with Alzheimer's disease (AD) and lesions of cerebral amyloid angiopathy (CAA), utilizing [11]C-PiB-PET, [18]F-THK5351-PET, and [18]F-MK-6240-PET. [11]C-PiB-PET showed positive findings consistent with AD. [18]F-THK5351 accumulated in regions of astrogliosis due to tau pathology, subcortical hemorrhage, cortical superficial siderosis (cSS), and monoamine oxidase-B rich areas. [18]F-MK-6240 accumulated in regions with tau pathology, subcortical hemorrhage, and cSS, but not notably in CAA-related microbleeds (CMBs). [99m]Tc-ECD SPECT, conducted 9 years post-diagnosis, revealed reduced cerebral blood flow in the bilateral lower temporal lobes and the right posterior temporo-parietal lobes, overlapping the subcortical hemorrhage and cSS. The patient exhibited progression of global cognitive decline and persistent word fluency deficits (name listing) on neuropsychological examination from the early stage of the disease, irrespective of the right hemorrhagic lesions in the non-dominant hemisphere, suggesting possible crossed aphasia. This is the first report of [18]F-MK-6240 binding to a subcortical hemorrhage and cSS lesions, highlighting its binding differences compared to smaller vascular leakages, such as CMBs due to CAA. These results may help refine PET imaging interpretation and diagnostic accuracy for AD with concurrent CAA.

RevDate: 2025-12-09

Jafari EA, Alshahawey M, Zaman MA, et al (2025)

Characterizing Alzheimer's Disease and Related Dementia in a Hypertension Population Within the State of Florida Using Electronic Health Record-Based Data.

Clinical pharmacology and therapeutics [Epub ahead of print].

Hypertension is a known modifiable risk factor for Alzheimer's disease and related dementia (ADRD). However, it is unknown how variance in hypertension control, antihypertensive medications, and social determinants of health, such as social deprivation index (SDI), influence the risk of developing ADRD. Validated hypertension computable phenotype algorithms were applied to electronic health record data from the OneFlorida Data Trust (1/1/2013-12/31/2016), to identify apparent treatment-resistant hypertension (aTRH), and hypertension-control levels (well-controlled hypertension, intermediate-controlled hypertension, uncontrolled hypertension). The primary outcome was a new ADRD diagnosis using validated ICD-9/10 codes. Multiple adjusted stepwise logistic regression models were used to identify factors associated with ADRD development. ADRD cumulative hazard incidence per hypertension control levels was assessed using the Nelson-Aalen estimator and log-rank test. A total of 57,273 hypertension patients with 6401 (11%) incident ADRD cases were included in the analysis. The average age was 67 years, with 57% females and 32% identifying as Black or African American. aTRH was a significant ADRD predictor (OR: 1.327, 95% CI: 1.234-1.427), compared to other hypertension phenotypes. aTRH was also significantly associated with a higher incidence of ADRD over time (P < 0.0001). Patients prescribed thiazide diuretics (OR: 0.894, 95% CI: 0.837-0.956) and fixed-dose combination medications (OR: 0.804, 95% CI: 0.732-0.882) had a lower risk of ADRD. A linear relationship between SDI quartiles and ADRD risk was found. aTRH was significantly associated with the development of ADRD. Our study also highlights the importance of comprehensive hypertension control and socioeconomic interventions in preventing or reducing ADRD risk in hypertension patients.

RevDate: 2025-12-09

Wang Y, Lv M, Zhu W, et al (2025)

Study of the Aggregation Behavior of Proteins Related to Neurodegenerative Diseases Based on the Photoluminescence of Perovskite Nanocrystals.

Analytical chemistry [Epub ahead of print].

Neurodegenerative diseases (NDs) are closely associated with abnormal protein aggregation. In this study, SiO2-coated CsPbBr3 nanocrystals (CPB NCs) were exploited as label-free photoluminescence (PL) probes to investigate the aggregation behavior of amyloid β (Aβ), a key protein in Alzheimer's disease. The PL intensity of the CPB NCs in both aqueous dispersion and thin-film states decreased with increasing degree of Aβ aggregation. The relative PL intensity could quantitatively distinguish the aggregation states of Aβ, and the sensitivity of the thin-film system was twice that of the aqueous dispersion. This approach innovatively enabled the preliminary monitoring of protein aggregates without interfering with the aggregation process while avoiding the effects of reactive oxygen species generated during the aggregation and metal ions themselves on PL signals. Through threshold segmentation, the relative fluorescence intensity was further used to distinguish small-molecule drugs with disaggregation effects (ratio > 0.5) from those without (ratio ≈ 0). Based on a series of experiments, the photoinduced electron transfer mechanism was proposed to explain the change in the PL signal. Due to the electrostatic interaction between CPB NCs and proteins, this probe had potential for studying the aggregation states of other proteins (such as α-synuclein) related to NDs. Overall, this work offered new insights into the application of metal halide perovskites in biosensing as well as for the diagnosis and drug screening of NDs.

RevDate: 2025-12-09

Arnold M, Cui L, Stemmler M, et al (2025)

The Chinese version of the Short Cognitive Performance Test (SKT) - psychometric criteria and cross-validation.

Journal of clinical and experimental neuropsychology [Epub ahead of print].

The new Chinese version of the SKT (Syndrom-Kurz-Test) Short Cognitive Performance Test aims to detect early cognitive impairment and is a promising addition to neuropsychological test batteries in China and suitable for Chinese speaking patients. This study has three aims: 1. to assess whether the SKT's diagnostic accuracy is comparable to established cognitive impairment tests (e.g. Addenbrooke´s cognitive examination-III (ACE-III) and Montreal Cognitive Assessment-Basic (MoCA-B)); 2. to examine whether the three tests show intra-individual differences according to different types of mild cognitive impairment (single-domain amnestic MCI, semantic MCI and multiple-domain amnestic MCI); 3. to determine whether these tests distinguish between individuals with no cognitive impairment and those with subjective cognitive decline (SCD). The validation sample included 1038 older adults (mean age = 70.04, SD = 6.05) from the Chinese Preclinical Alzheimer's Disease Study (C-PAS). Participants underwent cognitive testing and received consensus diagnoses of normal cognition, MCI, or dementia. Sensitivity and specificity were calculated for each test. ANOVAs examined differences between MCI subtypes, and t-tests assessed group differences between normal cognition and SCD. Results: The SKT showed the highest discrimination between normal cognition and cognitive impairment (MCI or dementia), with a sensitivity of 85.4% and specificity of 69.8%. All three tests demonstrated significant score differences across MCI subtypes. Additionally, all tests significantly distinguished individuals with SCD from those without cognitive impairment (p < 0.01). Conclusions: The new Chinese produced weaker results than the established tests. However, given its strengths, it could be a useful tool for identifying cognitive impairment in certain situations.

RevDate: 2025-12-09

Takahashi M, Kitaura H, Nakahara A, et al (2025)

Dual Regulatory Roles of USP10 in Tau Pathology and Neuronal Fate During Alzheimer's Disease Progression.

Molecular and cellular biology [Epub ahead of print].

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by neuronal cell death, brain atrophy, and cognitive decline. Aggregation of Tau protein in neurons is a critical factor in the pathogenesis of AD. Tau aggregates increase as the disease progresses and contribute to neuronal cell death. This study investigated the role of ubiquitin-specific protease 10 (USP10) in Tau pathology and neuronal viability in AD. We found that the expression of USP10 was reduced in the brains of late-stage AD patients with severe Tau aggregate accumulation, which correlated with increased neuronal apoptosis. Mechanistically, our results suggest that USP10 downregulation in late-stage AD may be due to its degradation by the accumulation of p62, an inducer of selective autophagy. Brain-specific Usp10 knockout mice show increased neuronal apoptosis during embryonic development and postnatal brain atrophy. In the P301S-Tau transgenic mice, heterozygous Usp10 knockout lowered Tau levels and slightly improved early survival, suggesting USP10 has stage-dependent effects: its reduction lessens Tau burden early but worsens neuronal loss in late stage. This study identifies USP10 as a key regulator of Tau pathology and neuronal survival in AD.

RevDate: 2025-12-08

Yan G, Wu S, Qian Q, et al (2025)

Early diagnosis of Alzheimer's disease using machine learning and blood biomarkers.

BMC medical informatics and decision making pii:10.1186/s12911-025-03296-x [Epub ahead of print].

RevDate: 2025-12-09
CmpDate: 2025-12-09

Zebardast F, Riethmüller MPS, K Nowick (2025)

Integrative gene co-expression network analysis reveals protein-coding and LncRNA genes associated with Alzheimer's disease pathology.

Scientific reports, 15(1):43395.

Alzheimer's disease (AD) is a complex neurodegenerative disorder marked by widespread molecular changes, many of which remain poorly understood. While AD pathology progresses through specific brain regions, it is unclear whether these regions are affected similarly. Long non-coding RNAs (lncRNAs), emerging as key cellular regulators, remain largely uncharacterized in AD. Understanding how lncRNAs interact with protein-coding genes across brain regions could shed light on AD mechanisms and progression. To investigate this, we performed consensus weighted gene co-expression network analysis on 396 postmortem brain RNA-seq samples using a meta-analytic approach. Our analysis revealed substantial network rewiring in AD, particularly in the temporal cortex compared to the frontal cortex. The temporal cortex exhibited adaptive changes in gene interactions, while the frontal cortex showed a breakdown of healthy correlations-possibly reflecting regional differences in disease progression. We identified 46 protein-coding genes and 27 lncRNAs as key components in the AD network of the temporal cortex. Using known functions of protein-coding genes as reference points, we inferred potential functions for over 100 lncRNAs across both regions. These findings highlight novel lncRNA candidates potentially involved in AD and provide insights into their roles in both healthy and diseased brain states.

RevDate: 2025-12-08

Li G, Li P, Huang L, et al (2025)

[Protective effects of quercetin, the key component of Zuo Gui Wan, against Alzheimer's disease via the PI3K/AKT pathway: insights from network pharmacology, molecular docking, and cell experiments].

Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences [Epub ahead of print].

OBJECTIVES: To investigate the protective mechanism of quercetin, the core component of Zuo Gui Wan, against Alzheimer's disease through the PI3K/AKT signaling pathway, based on network pharmacology, molecular docking, and cell experi-ments.

METHODS: The active components of Zuo Gui Wan were identified by searching TCMSP, PubChem, Swiss Target Prediction, and BATMAN-TCM databases, and their potential targets were predicted. The target information was standardized using Uniprot, and Alzheimer's disease-related target genes were obtained from Drugbank, GeneCards, and OMIM. The intersection of these datasets was used to identify the potential targets of Zuo Gui Wan for treating Alzheimer's disease. Gene Ontology (GO) functional enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed. The protein-protein interaction (PPI) network of potential targets was visualized using Cytoscape 3.10.1 software and the STRING database. The key active compounds and core potential targets for treating Alzheimer's disease with Zuo Gui Wan were identified through calculation. Based on the enrichment analysis results and literature, quercetin and the PI3K/AKT pathway were selected for verification. Molecular docking and binding ability prediction between quercetin and the core target AKT were performed using CB-Dock2, and visualization was conducted with AutoDock and PyMOL software. Finally, Aβ1-42-induced HT-22 mouse hippocampal neuronal cells were used to construct an Alzheimer's disease cell model. Quercetin, the PI3K inhibitor LY294002, and the activator EGF were used as interventions. The groups were divided as follows: Control, Aβ1-42, Aβ1-42+Quercetin 2.5 μM, Aβ1-42+Quercetin 5 μM, Aβ1-42+Quercetin 10 μM, Aβ1-42+EGF, and the PI3K/AKT modulation group: Control, LY294002, LY294002+Quercetin 10 μM, LY294002+EGF. CCK-8 assays were performed to detect cell viability, while JC-1, Calcein AM-PI, and Hoechst staining were used to assess cell apoptosis. Western blotting was employed to detect the expression of relevant target proteins.

RESULTS: Network pharmacology and cell experiments collectively demonstrate that the key active ingredient of Zuo Gui Wan, quercetin, targets core proteins such as AKT1 and GSK3β through a network-based approach, significantly enriching the PI3K/AKT pathway. Molecular docking results indicate that quercetin has a strong binding affinity with AKT. Experimental validation in the Aβ1-42 oligomer-induced HT-22 model reveals that quercetin significantly activates the PI3K/AKT signaling pathway, which is inhibited by Aβ1-42 oligomers, as well as Bcl-2 protein expression. It also suppresses the expression of Cleaved Caspase 3/Caspase 3, BAX, and Cytochrome C proteins. JC-1, Hoechst 33342, and Calcein AM-PI staining results further show that quercetin can significantly alleviate apoptosis induced by Aβ1-42 oligomers in HT-22 cells. Treatment with the PI3K inhibitor LY294002 in HT-22 cells leads to reduced cell viability and decreased expression of p-AKT/AKT and Bcl-2 proteins, while increasing the expression of Cleaved Caspase 3/Caspase 3, BAX, and Cytochrome C proteins. Additionally, apoptosis levels increase as observed in JC-1, Hoechst 33342, and Calcein AM-PI staining, all of which can be reversed by quercetin and the PI3K agonist EGF.

CONCLUSIONS: Quercetin, the key active ingredient of Zuo Gui Wan, exerts its protective effects against Alzheimer's disease by regulating the PI3K/AKT signaling pathway, inhibiting neuronal cell damage and apoptosis.

RevDate: 2025-12-08
CmpDate: 2025-12-08

Menczel Schrire Z, Mitchell HF, Low LF, et al (2025)

NeuroMusic: protocol for a randomised-controlled trial of keyboard and singing music training programmes for older adults with mild cognitive impairment.

BMJ open, 15(12):e104158 pii:bmjopen-2025-104158.

INTRODUCTION: Music-based training programmes, such as learning how to play an instrument or sing in a choir, have been suggested as potential interventions for promoting healthy brain ageing in older adults at risk of cognitive decline because of their ability to enhance cognitive functions and potentially promote neuroplasticity. However, there is limited empirical evidence in older adults at risk of dementia, especially that evaluates both piano and singing interventions and their effects on cognition and neuroplasticity. In this protocol, we outline a study to assess the efficacy of keyboard and singing music training programmes on reducing cognitive decline and other outcomes in older adults with Mild Cognitive Impairment (MCI).

METHODS AND ANALYSIS: This randomised, single-blind, controlled, parallel-group trial aims to enrol 432 individuals with MCI from the community in Sydney, Australia. Participants are randomly allocated to participate in either keyboard lessons, singing lessons or a film discussion control group once a week for 3 months. The primary objective is to assess the effectiveness of two music training programmes (keyboard and choral singing) for enhancing verbal memory after 3 months compared with control. Additionally, we will examine how these music-based interventions affect other aspects of cognition, mood, sleep, overall well-being, markers of brain plasticity and blood biomarkers of Alzheimer's disease and neurodegeneration. Tertiary objectives are to identify factors that impact the success of the interventions, such as participation rates, engagement levels and key demographic and clinical features. Outcomes are collected at baseline and at 3 and 9 months. The primary endpoint analysis will include all randomised participants to estimate the treatment effect using intention-to-treat principles. Primary and secondary outcomes will be analysed using linear mixed models and effect size measures will be calculated.This study will be the first robust, randomised controlled trial to assess the potential and relative value of music engagement for cognitive decline in high-risk MCI individuals, as well as broader effects on other markers of mental health, well-being and neurodegeneration. Co-designed with implementation in mind, the music interventions can potentially be delivered within memory clinic or community settings.

ETHICS AND DISSEMINATION: The Sydney University Human Research Ethics Committee (2023-026) has approved this protocol. The trial findings will be shared through conferences, publications and media.

TRIAL REGISTRATION NUMBER: Australian and New Zealand Clinical Trials Registry (ACTRN12623000407695), Registered 21/04/2023 https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=385552 PROTOCOL VERSION: 2.02 29/11/2024.

RevDate: 2025-12-09

Singh R, Mishra A, Kumar V, et al (2025)

FTIR spectroscopy of plasma exosomes reveals distinct lipidomic and proteomic signatures for early Alzheimer's disease detection.

Clinica chimica acta; international journal of clinical chemistry, 581:120761 pii:S0009-8981(25)00640-0 [Epub ahead of print].

Alzheimer's disease (AD), the most common neurodegenerative disorder, is pathologically defined by amyloid-β plaques and tau tangles. Current diagnostic tools like CSF analysis and PET imaging are invasive or costly, limiting routine use. This study proposes a novel, label-free approach using Fourier-transform infrared (FTIR) spectroscopy to identify disease-specific biochemical signatures in plasma-derived small extracellular vesicles (sEVs) from 30 AD patients and 20 age-matched controls. sEVs were validated by ultracentrifugation, TEM, nanoparticle tracking (mean size: 98.7 ± 12.4 nm in AD vs. 102.3 ± 14.1 nm in controls), and Western blot for CD9, CD81, and TSG101. FTIR analysis revealed significant alterations in AD sEVs: consistent increase in lipid peroxidation (based on 3015 cm[-1], 1745 cm[-1] bands), 19.8 % change in β-sheet content, and 22.4 % enhancement in phosphate vibrations (1072 cm[-1]). Key spectral ratios showed excellent diagnostic accuracy, with the lipid peroxidation index (AUC = 0.998) and protein disorder index (AUC = 0.978). This rapid, cost-effective, and non-invasive method enables simultaneous assessment of lipid, protein, and glycan changes in AD. With broader validation, FTIR-based profiling of plasma sEVs could offer a transformative tool for early AD diagnosis and monitoring.

RevDate: 2025-12-08

Zhao D, Wang J, Zhang F, et al (2025)

Cerebral glymphatic system: structure, regulation, ageing, and mechanisms of encephalopathy.

Ageing research reviews pii:S1568-1637(25)00332-0 [Epub ahead of print].

The glymphatic system was initially considered as a perivascular channel, responsible for the clearance of substances within the brain. With the deepening comprehension of the functions of the extracellular space (ECS) and the discovery of meningeal lymphatic vessels and subarachnoid lymphatic-like membrane, it is proposed that the glymphatic system should be a complex system encompassing the perivascular space, ECS, and lymphatic-like structures, and it plays crucial roles in the delivery of substances, waste clearance, and neuroimmune functions within the brain. Recent studies have revealed that brain ECS essentially regulates these fundamental functions, including sleep, memory, and sensory processing. Here, in this review, we delineate advances in the roles of glymphatic system in structure, functions, ageing and brain diseases. The imaging technologies have facilitated a more nuanced understanding of the glymphatic system's architecture, particularly the pericellular space. The compartmentalized system, characterized by myelin sheath separation, serves as the conduit for cerebrospinal fluid (CSF) and interstitial fluid (ISF) exchange and plays a predominant role in modulating the ISF within the deep brain region. Furthermore, we discuss the pathophysiological implications of excessive formaldehyde (FA) accumulation in the aging brain. Especially, ageing-associated FA can cross-link Aβ, tau, α-synuclein, hemoglobin and extracellular matrix in the ECS and/or endochylema, which leads to the disorder of ISF-CSF exchanges and encephalopathy onset, such as: Alzheimer's disease, Parkinson's disease, multiple sclerosis, gliomas and sleep disorders. Hence, glymphatic system including ECS may be a promising therapeutic target for brain diseases.

RevDate: 2025-12-08

Fujita Y, Yabe T, Yamada Y, et al (2025)

MEGF10 knockout promotes cortical and hippocampal amyloid deposition in AD mouse model.

Neuroscience letters pii:S0304-3940(25)00376-3 [Epub ahead of print].

Multiple epidermal growth factor (EGF)-like domains 10 (MEGF10) is a single-pass transmembrane protein expressed in neurons and astrocytes, functioning as a phagocytic receptor for apoptotic cells and mediating homotypic adhesion in the mammalian brain. We previously demonstrated that MEGF10 facilitates the uptake of toxic amyloid-β (Aβ) species Aβ42 and Aβ43 by neurons and astrocytes in vitro. However, whether MEGF10 also serves as a phagocytic receptor for Aβ in the brain in vivo, particularly under neurodegenerative conditions such as Alzheimer's disease (AD), remains unclear. To address this question, we generated MEGF10 knockout mice on an AD model background and analyzed brain Aβ deposition and Aβ42 levels. We observed a significant increase in Aβ deposition and Aβ42 levels in the hippocampus and cortex of MEGF10-deficient AD mice compared with AD model controls. To assess cognitive function, we performed the Y-maze test. MEGF10 knockout AD mice exhibited impaired spatial memory relative to wild-type controls; however, no significant difference was found between MEGF10 knockout AD mice and AD model controls. These findings suggest that MEGF10 contributes to Aβ clearance in the brain and support its role as a phagocytic receptor for Aβ in vivo, potentially helping to maintain brain homeostasis in the context of Alzheimer's pathology.

RevDate: 2025-12-08

Pan L, Song X, Su G, et al (2025)

N-Sulfated Heparan Sulfate Promotes Reelin Signaling as a Co-receptor.

Journal of the American Chemical Society [Epub ahead of print].

Heparan sulfate (HS) plays a central role in signal transduction, while Reelin is an essential signaling protein in both the developing and adult brain. A Reelin COLBOS variant was recently discovered with enhanced HS binding and resilience against autosomal dominant Alzheimer's disease (ADAD), underscoring the importance of Reelin-HS interactions. However, the glycan determinants of Reelin-HS interactions have not been well-characterized, which we systematically investigated here. Surface plasmon resonance (SPR) showed that full length Reelin binds HS with high affinity (KD = 17 ± 5 nM), which is enhanced by the COLBOS variant (KD = 10 ± 2 nM). Competition SPR and glycan array studies further revealed that HS N-sulfation is critical for Reelin-HS binding, consistent with Haddock modeling. In cell surface binding assays, heparinase treatment, which degrades HS, or the knockout of a key HS N-sulfation enzyme (NDST1) significantly reduced Reelin attachment. Functionally, a cellular split-luciferase assay showed that heparinase treatment or adding heparin in culture medium reduces Reelin-induced ApoER2 dimerization, demonstrating that HS is a coreceptor for Reelin receptor activation. In contrast, N-desulfated heparin does not inhibit Reelin receptor dimerization. Our work establishes HS as a coreceptor for Reelin signaling and N-sulfation as a key glycan determinant of Reelin-HS recognition. Our work provides mechanistic insights into diverse neurodevelopmental and neurodegenerative diseases associated with Reelin signaling and suggests novel therapeutic strategies targeting HS sulfation.

RevDate: 2025-12-08

Banerjee S, Chandu PM, Sarkar M, et al (2025)

Engineering brain organoids and organ-on-chip systems for modeling neurodevelopmental and neurodegenerative pathophysiology.

Neurological research [Epub ahead of print].

OBJECTIVES: Neurodevelopmental and neurodegenerative disorders arise from complex disruptions in brain structure and function, many originating during early development. However, conventional in vitro and animal models often fail to capture the cellular diversity, temporal dynamics, and architectural complexity of the human brain. This review aims to synthesize recent advances in stem-cell-derived in vitro platforms, specifically brain organoids, assembloids, and organ-on-chip technologies, and evaluate how these systems are reshaping research on Alzheimer's and Parkinson's diseases by enabling more human-relevant modeling.

METHODS: We surveyed recent literature focusing on region-specific and vascularized organoids, integrated neuronal subtype models, and microfluidic organ-on-chip systems. Particular attention was given to studies demonstrating increased physiological relevance, enhanced modeling of disease-specific phenotypes, and expanding utility in translational research, therapeutic screening, and drug discovery pipelines.

RESULTS: Innovations in organoid engineering have enabled more faithful recapitulation of human brain development and degeneration. These platforms have advanced understanding of amyloid aggregation, neuroinflammatory processes, dopaminergic neuron vulnerability, and gut-brain axis contributions. The incorporation of vascular structures, improved microfluidic control, and assembly of multi-region neuronal circuits have strengthened functional readouts and boosted mechanistic insight. Collectively, these developments are accelerating preclinical therapeutic testing and enabling more predictive disease modeling.

DISCUSSION: Compared to prior reviews, this article uniquely integrates developmental and degenerative perspectives while evaluating emerging strategies that increase reproducibility and translational accuracy. Persistent limitations, including incomplete vascularization, cellular stress responses, and batch-to-batch variability, underscore the need for improved standardization and incorporation of immune components. Future directions that merge vascular, immune, and circuit-level complexity promise to advance organoid-based neuroscience toward personalized modeling and therapeutic application.

RevDate: 2025-12-08

Garcia MA, C García (2025)

Cognitive Difficulties among Middle-Aged and Older Latino Adults: Within-Group Variation Across U.S. States.

The journals of gerontology. Series B, Psychological sciences and social sciences pii:8374214 [Epub ahead of print].

OBJECTIVE: This study examined how cognitive difficulties, an early marker of memory impairment and a potential precursor to Alzheimer's disease and related dementias, vary across U.S. states among Latinos aged 45 and older.

METHODS: Using data from the 2008-2019 American Community Survey, we estimated logistic regression models to examine state-level differences in cognitive difficulties among Latinos aged 45 and older. We analyzed patterns within the pan-ethnic Latino population, stratified by nativity, Latino heritage, and country or region of origin.

RESULTS: We observed substantial heterogeneity in the prevalence of cognitive difficulties among Latino populations across states and subgroups. Pan-ethnic Latino populations in Pennsylvania, Massachusetts, Michigan, Ohio, and New Mexico exhibited notably higher rates of cognitive difficulties. When disaggregated by nativity, U.S.-born Latino populations consistently reported higher levels of cognitive difficulties compared to their foreign-born counterparts. Among these, Puerto Ricans, Dominicans, and Cubans showed the highest prevalence in several states. Our findings also highlight that the intersection of nativity, heritage, and state-level context shapes distinct cognitive risk profiles within the Latino population.

DISCUSSION: This study contributes to gerontological research by illuminating how structural, cultural, and geographic factors intersect to shape cognitive aging among diverse Latino populations. These findings underscore the importance of moving beyond pan-ethnic categorizations to understand cognitive health disparities within the Latino population. They also highlight the role of state-level sociopolitical environments in shaping cognitive health outcomes. Public health strategies should prioritize culturally and geographically tailored interventions, particularly in high-risk states, to improve access to cognitive screening and early diagnosis.

RevDate: 2025-12-08

Lv Y, Zhao X, Li D, et al (2025)

Spatiotemporal Ca2+ nanodomain remodeling at MERCS regulates mitochondrial proteostasis.

Protein & cell pii:8374226 [Epub ahead of print].

Mitochondrial calcium fluxes serve as pivotal regulators of optimal organellar function and cellular viability, yet the spatiotemporal regulation of nanodomain Ca2+ transients at mitochondria-ER contact sites (MERCS) and their integration into adaptive mitochondrial stress signaling remain unresolved. In this study, we employed custom-built high temporal-spatial resolution GI/3D-SIM imaging techniques to achieve nanoscale resolution of calcium transients. We identify that MERCS-localized calcium oscillations gate retrograde stress signaling. Mechanistically, we demonstrate that augmented mitochondria-associated ER membrane (MAMs) connectivity unexpectedly attenuated global mitochondrial Ca2+ efflux, which triggering ATF5 shuttling-mediated transcriptional licensing and calcium-sensitive epigenetic reprogramming that synergistically activating stress-resilience programs. Quantitative protein expression and transcriptome analyses confirm that CsA-mediated calcium retention mimics MAMs induction preserves mitochondrial integrity and protecting cells from apoptosis in Aβ1-42-challenged neurons through synchronized UPRmt activation. Our findings reveal a novel mechanism by which MERCS decode proteotoxic stress into transcriptional and epigenetic adaptations, offering therapeutic potential for neurodegenerative diseases.

RevDate: 2025-12-08
CmpDate: 2025-12-08

Cantoni V, Casula EP, Tarantino B, et al (2025)

Home-Based Gamma Transcranial Alternating Current Stimulation in Patients With Alzheimer Disease: A Randomized Clinical Trial.

JAMA network open, 8(12):e2546556 pii:2842460.

IMPORTANCE: Alzheimer disease (AD) is characterized by dysregulated gamma brain oscillations. Transcranial alternating current stimulation (tACS) is a novel, noninvasive brain stimulation technique capable of entraining cerebral oscillations at targeted frequencies.

OBJECTIVE: To assess the safety, feasibility, and efficacy of home-based gamma tACS applied over the precuneus in patients with prodromal and mild AD.

This double-blind, randomized, sham-controlled clinical trial with an open-label extension phase was conducted at a tertiary AD research clinic in Italy from December 10, 2022, to October 15, 2024. Patients with a diagnosis of AD were eligible to participate.

INTERVENTION: Participants were randomized to receive either home-based gamma tACS (5 sessions/wk, 60 minutes each) or sham stimulation for 8 weeks (double-blind phase). All participants subsequently received gamma tACS for an additional 8 weeks (open-label phase) and an 8-week follow-up.

MAIN OUTCOMES AND MEASURES: The primary end points were safety, feasibility, and clinical efficacy. Secondary end points included measures of biological efficacy, including gamma band power via electroencephalography, cholinergic neurotransmission, AD plasma biomarker levels, and brain connectivity as assessed via magnetic resonance imaging.

RESULTS: Sixty consecutive patients with prodromal or mild AD were screened; 50 were randomized to gamma or sham tACS (mean [SD] age, 67.3 [7.8] years; 25 [50.0%] female and 25 [50.0%] male). Home-based gamma tACS was safe and well-tolerated. A significant enhancement in global cognitive functions, activities of daily living, and associative memory performances was observed. Marginal mean differences between the sham vs gamma tACS groups were significant for the Clinical Dementia Rating sum of boxes (0.35; 95% CI, 0.10-0.61; P = .007), Alzheimer Disease Assessment Scale-cognitive subscale (0.93; 95% CI, 0.50-1.36; P = .001), Alzheimer Disease Cooperative Study-Activities of Daily Living (-0.55; 95% CI, -0.89 to -0.21; P = .02), and Face-Name Association Test (-1.14; 95% CI, -1.66 to -0.61; P ≤ .001). During the open-label phase, a significant marginal mean difference was observed for Alzheimer Disease Assessment Scale-cognitive subscale (-0.59; 95% CI, -1.02 to -0.16; P = .007), Alzheimer Disease Cooperative Study-Activities of Daily Living (0.41; 95% CI, 0.04-0.08; P = .02), and Face-Name Association Test (1.04; 95% CI, 0.50-1.57; P = .003). Neurophysiological measures showed an increase in cholinergic transmission, coinciding with an increase in gamma power following gamma tACS, effects not seen with sham stimulation. No changes of plasma biomarkers were observed. No add-on effect was observed after 2 repeated treatments with gamma tACS, suggesting that 8 rather than 16 weeks of treatment represents the ideal duration.

CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, home-based gamma tACS was feasible and improved clinical outcomes in AD, with neurophysiological evidence of brain engagement. These findings support further investigation of gamma tACS as a potential therapeutic intervention for AD.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05643326.

RevDate: 2025-12-08

Gotlieb E, Joseph B, Blank L, et al (2025)

Barriers and Consequences of Prior Authorization for Neurologic Medications: A Scoping Review.

JAMA neurology pii:2842313 [Epub ahead of print].

IMPORTANCE: Prior authorization (PA) is widely used by insurers to control health care costs and promote high-value care, but it can create significant barriers to accessing medications. This is particularly concerning in neurology, where timely treatment is critical to avoid disease progression and optimize patient outcomes.

OBJECTIVE: To assess the consequences, barriers, and facilitators of PA policies affecting access to pharmacologic treatment in 6 common neurologic conditions-Alzheimer disease, Parkinson disease, multiple sclerosis, migraine, cerebrovascular disease, and epilepsy-with focus on impacts on patients, clinicians, and administrators.

EVIDENCE REVIEW: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guidelines for scoping reviews were followed, and the study protocol was registered on Open Science Framework. MEDLINE and Embase were searched up to November 1, 2024, using Ovid for studies that assessed the role of PA as a primary or secondary outcome for the 6 included neurologic conditions, or for neurology broadly if strongly applicable to the study aim, after the signage of the Affordable Care Act in March 2010. Abstract screening and full-text review were done in duplicate. Key information was charted in extraction, including study characteristics, demographics, methods, results, and implications for relevant stakeholders. The results were aggregated and thematically analyzed.

FINDINGS: A total of 364 studies were identified using our search strategy on Ovid, 278 records were screened, and 20 studies were included in this review. The most frequently identified consequences for patients were delays in care (60%) and increase in disease activity (25%). The most frequently identified consequence for clinicians (35%) and administrators (15%) was time burden. The most common facilitators were the use of clinical pharmacists or technicians (20%) and health system specialty pharmacies (15%).

CONCLUSIONS AND RELEVANCE: According to the results of this scoping review, PA can contribute to significant access barriers for people with neurological conditions and is associated with burden for all stakeholders involved. Reforms to PA can work towards more equitable access to medications for patients.

RevDate: 2025-12-08

Ke S, Chen Z, Qi Y, et al (2025)

Heyndrickxia coagulans as a next-generation probiotic: current evidence and future perspectives.

Food & function [Epub ahead of print].

Heyndrickxia coagulans, a spore-forming probiotic, has garnered significant attention due to its exceptional tolerance to gastric acid and heat, alongside its multifaceted therapeutic potential. This review systematically delineates the unique biological characteristics of this bacterium, which include high survivability mediated by its spore form (retaining 73% viability after microwave treatment at 260 °C), dual lactate fermentation pathways, and plasticity in ATP synthesis that depends on pH and growth rate. Clinical evidence supports its efficacy in managing metabolic disorders (e.g., type 2 diabetes and non-alcoholic fatty liver disease), gastrointestinal conditions (e.g., constipation and irritable bowel syndrome), and neuropsychiatric disorders (e.g., depression and Alzheimer's disease). The underlying mechanisms involve the production of short-chain fatty acids (SCFAs), modulation of the TLR4/MyD88/NF-κB signaling pathway, and suppression of oxidative stress. Notably, therapeutic effects are strain-specific: H. coagulans MTCC 5856 (2 × 10[10] CFU day[-1]) significantly reduces abdominal distension (P < 0.01), while the strain Unique IS-2 alleviates anxiety-like behaviors by upregulating hippocampal BDNF. Although toxicological assessments establish a no observed adverse effect level (NOAEL) of >1000 mg kg[-1] in rodent models, its limited capacity for intestinal colonization presents a clinical challenge. Future research should prioritize large-scale clinical trials, multi-omics mechanistic investigations, and the development of synbiotic formulations to fully realize its potential as a next-generation therapeutic agent.

RevDate: 2025-12-08

Zhang S, Wang T, Xue G, et al (2025)

Dysregulated mTOR signaling in Alzheimer's disease: Linking pathogenic mechanisms to emerging therapeutic strategies.

Journal of Alzheimer's disease : JAD [Epub ahead of print].

Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by progressive cognitive decline and multifaceted pathogenic mechanisms (including amyloid-β [Aβ] plaques, tau neurofibrillary tangles, synaptic dysfunction, and neuroinflammation). Importantly, no effective disease-modifying treatment is currently available for AD. Emerging evidence implicates dysregulated mammalian target of rapamycin (mTOR) signaling as a key contributor to AD pathogenesis. This review analyzes how aberrant mTOR signaling influences major aspects of AD pathology, including Aβ production and clearance, tau protein hyperphosphorylation, autophagy dysfunction, synaptic plasticity impairments, neuroinflammation, and oxidative stress. Notably, hyperactivated mTOR accelerates AD progression through multiple mechanisms. It promotes Aβ accumulation and tau pathology, suppresses autophagic clearance of toxic aggregates, and disrupts neuronal homeostasis, thereby exacerbating cognitive decline. Consequently, mTOR has gained attention as a therapeutic target. This review evaluates the therapeutic potential of various mTOR-targeted interventions, such as the mTORC1 inhibitor rapamycin and its analogues (rapalogs), second-generation ATP-competitive mTOR inhibitors, and certain natural compounds and traditional Chinese medicine approaches. These strategies have demonstrated promise in mitigating AD-related pathology by enhancing autophagy, reducing Aβ/tau burden, and preserving synaptic and cognitive function in preclinical studies. However, the clinical translation of mTOR-targeted therapies faces key challenges, including poor blood-brain barrier penetration of many mTOR inhibitors, potential systemic side effects, and limited clinical validation to date. Further research is needed to optimize brain delivery, dosing regimens, and target specificity to fully realize the therapeutic potential of mTOR modulation in AD.

RevDate: 2025-12-08

Kiani I, Mohseni G, Hassani T, et al (2025)

Posterior cingulate cortex atrophy across the Alzheimer's disease spectrum: A cross-sectional MRI study linking volumetrics to cognitive decline.

Journal of Alzheimer's disease : JAD [Epub ahead of print].

BackgroundThe posterior cingulate cortex (PCC) is a metabolic hub within the default-mode network and an early target of Alzheimer's disease (AD) pathology, yet its quantitative relationship with cognition across the normal aging-mild cognitive impairment (MCI)-AD continuum remains incompletely defined.ObjectiveIn this study we aimed to compare PCC volumes across AD, MCI, and controls, and assess their relationship with cognitive performance.MethodsIn this single-center cross-sectional study, 161 participants (NL = 30, MCI = 60, AD = 71) underwent structural MRI. PCC volumes were automatically segmented and summed. Linear regressions adjusted for age and sex were performed to examine associations between PCC volumes and cognitive measures. False discovery rate correction was applied to multiple comparisons. Additional subgroup analyses were conducted by gender and education level using Mann-Whitney U tests, and ordinary least squares regression models tested for group × education interactions.ResultsMean Post-cin-T volume declined step-wise from NL (6.05 ± 0.21cm[3]) to MCI (5.64 ± 0.63cm[3]) to AD (4.98 ± 1.01cm[3]; p < 0.001). Post-cin-R and Post-cin-L showed parallel gradients. Higher MoCA scores correlated with larger PCC volumes (e.g., total: β = 0.069, p < 0.001), whereas higher CDR scores were linked to smaller volumes (total: β = -0.705, p < 0.001). Subgroup analyses revealed that higher-education participants showed broader PCC-cognition associations. Interaction analyses indicated no significant moderating effect of education on group-volume relationships.ConclusionsQuantitative PCC atrophy differentiates NL, MCI and AD and correlates robustly with cognitive performance, particularly in educated individuals. PCC volumetry may serve as a non-invasive MRI biomarker for early diagnosis and disease staging in the AD spectrum.

RevDate: 2025-12-08

Kandeel M, M Mahmoud (2025)

Comparative efficacy and safety of different brexpiprazole doses for agitation in Alzheimer's disease: A systematic review and network meta-analysis.

Journal of Alzheimer's disease : JAD [Epub ahead of print].

BackgroundAgitation in Alzheimer's disease significantly impacts patient outcomes and caregiver burden. Brexpiprazole has emerged as a promising treatment option, but optimal dosing remains unclear.ObjectiveTo evaluate the comparative efficacy and safety of different brexpiprazole doses in treating agitation associated with Alzheimer's disease through a systematic review and network meta-analysis (NMA).MethodsFollowing PRISMA guidelines, we searched PubMed, Embase, Web of Science, and Scopus through January 2025. Four randomized controlled trials (N = 1451) comparing various brexpiprazole doses (0.5-3 mg/day) with placebo were included. Primary outcomes included changes in the Cohen-Mansfield Agitation Inventory (CMAI), the Clinical Global Impression-Severity Scale (CGI-S), and the Neuropsychiatric Inventory-Nursing Home Version (NPI-NH) scores, alongside safety measures.ResultsBrexpiprazole 2 mg demonstrated significant improvement in CMAI scores versus placebo (mean difference [MD]: -5.88; 95% CI: -8.13 to -3.63) and CGI-S scores (MD: -0.48; 95% CI: -0.95 to -0.01). Multiple doses showed significant NPI-NH improvements, with 2-3 mg showing the strongest effect (MD: -4.60; 95% CI: -7.54 to -1.66). Higher doses (2-3 mg) increased treatment-emergent adverse events (risk ratio [RR]: 1.20-1.33) but showed no significant difference in serious adverse events compared to placebo.ConclusionsBrexpiprazole 2 mg provides optimal therapeutic benefit while maintaining a favorable safety profile. The findings support initiating treatment at lower doses with careful titration to 2 mg based on individual response and tolerability. Future research should focus on long-term outcomes and real-world effectiveness.

RevDate: 2025-12-08

Seixas-Lima B, Rosa-Neto P, Phillips NA, et al (2025)

Peripheral inflammation in a Canadian cohort of neurodegenerative conditions: Occurrence, determinants, and impact.

Journal of Alzheimer's disease : JAD [Epub ahead of print].

Background"Inflammaging" describes chronic low-grade inflammation observed in aging individuals. It may play a major role in neurodegeneration.ObjectiveTo assess blood inflammatory markers in older adults. We hypothesized that elevated inflammation would be found in some cognitively normal older adults but would be more prevalent in individuals with cognitive impairment.MethodsInterleukin-6 (IL-6) and C-reactive protein (CRP) were assessed in 514 Canadian individuals in COMPASS-ND, a detailed study of cognitive impairment in the elderly. Cumulative link model (CLM) was used to investigate the relationship between inflammation status (low, medium, or high tertiles) and demographic and lifestyle factors along with cognitive function and cognitive diagnoses.ResultsWe found that 12% of cognitively normal older adults had IL-6 levels in the highest tertile, but this increased in cognitively impaired cohorts-36% in Alzheimer's disease, 55% mixed dementia, 30% mild cognitive impairment, and 39% vascular mild cognitive impairment. We found that 36% of cognitively unimpaired older individuals display "elevated" IL-6 (middle and high tertile values), while approximately 70% of those with cognitive impairment also do so. Inflammation markers increased most robustly in association with age, higher body mass index, and higher Fazekas (MRI white matter hyperintensity) score. There were also weaker associations with female sex, nutrition, number of comorbidities, and poor sleep.ConclusionsPeripheral low-grade inflammation was common, particularly in individuals with cognitive impairment; and obesity and age were the main drivers. It remains unclear whether treatment targeting such inflammation might have a therapeutic role in dementia prevention.

RevDate: 2025-12-08
CmpDate: 2025-12-08

Nashiro K, Cahn BR, Choi P, et al (2025)

A Randomized Clinical Trial Reveals Effects of Mindfulness and Slow Breathing on Plasma Amyloid Beta Levels.

Psychophysiology, 62(12):e70182.

Prior research suggests that meditation may slow brain aging and reduce the risk of Alzheimer's disease (AD). However, we lack research systematically examining what aspect(s) of meditation may drive such benefits. In particular, it is unknown how breathing patterns during meditation might influence health outcomes associated with AD. In this study, we examined whether two types of mindfulness meditation practice-one with slow breathing and one with normal breathing-differently affect plasma amyloid beta (Aβ) relative to a no-intervention control group. One week of daily mindfulness practice with slow breathing decreased plasma Aβ levels whereas one week of daily mindfulness practice with normal breathing increased plasma Aβ levels. The no-intervention control group showed no changes in plasma Aβ levels. Slow breathing appears to be a factor through which meditative practices can influence pathways relevant for AD.

RevDate: 2025-12-08

Xue D, Yu DS, Yue L, et al (2025)

Home-based, caregiver-assisted multimodal exercise and cognitive training via videoconferencing for older adults with mild dementia: A mixed-methods pilot study.

Journal of Alzheimer's disease : JAD [Epub ahead of print].

BackgroundEvidence on the effects of caregiver-assisted combined exercise and cognitive interventions for persons with dementia (PwD) is inconsistent.ObjectiveThis study aimed to evaluate the feasibility and preliminary effects of a home-based Caregiver-Assisted Multimodal Exercise and Cognitive Training (CA-MECT) intervention via videoconferencing for persons with mild dementia in comparison with exercise or cognitive training alone and the control condition.MethodsThirty-three participants were randomized into a combined intervention, exercise, cognitive training, or control group. The combined intervention was a 12-week caregiver-assisted home-based sequentially combined multimodal exercise and cognitive training via videoconferencing. The exercise and cognitive training groups received a 12-week home-based Caregiver-Assisted Multimodal Exercise (CA-ME) and Caregiver-Assisted Cognitive Training (CA-CT), respectively, while the control group received health education. Validated instruments were used to evaluate cognitive, psychological, functional, and health-related quality of life (HRQoL) outcomes.ResultsCA-MECT was feasible, safe, and highly acceptable for PwD and their caregivers. Exploratory analyses suggested that compared with the control group, the CA-MECT participants showed potential improvements in global cognition, immediate recall, attention, number and severity of neuropsychiatric symptoms (NPS), and caregivers' distress, though no clear benefits were observed in functional ability or HRQoL. When compared with single-component interventions, CA-MECT appeared to yield more favorable outcomes for immediate recall (versus CA-CT) and NPS severity (versus CA-ME), whereas its effects on processing speed were less favorable than both comparators.ConclusionsCA-MECT is feasible and shows promise in improving cognition and NPS among PwD. Future studies are warranted to fully explore its efficacy and sustainability.

RevDate: 2025-12-08

Luo R (2025)

Chaperone-mediated autophagy as a sex-specific modulator of synaptic proteostasis and neural function.

Autophagy [Epub ahead of print].

Chaperone-mediated autophagy (CMA), once considered a secondary or auxiliary degradation pathway, is now recognized as a central regulator of synaptic proteostasis. A recent study by Khawaja et al. (2025) in Nature Cell Biology provides compelling evidence that CMA actively remodels the synaptic proteome in a sex-specific manner. Using a conditional knockout strategy based on Lamp2a-floxed mice crossed with a Camk2a-Cre driver line to achieve excitatory neuron-specific deletion of Lamp2a in adult mice, the authors revealed sexually divergent synaptic phenotypes: females exhibit enhanced presynaptic neurotransmitter release and GRIN/NMDAR-mediated plasticity, while males show increased postsynaptic GRIA/AMPAR activity due to impaired receptor endocytosis. These changes are driven by sex-specific degradation of synaptic proteins such as SYN1 (synapsin I) in females and AP2A/α-Adaptin in males. Importantly, reactivation of CMA - either genetically or pharmacologically - rescues synaptic dysfunction, seizure susceptibility, and memory deficits in aged mice and Alzheimer disease models. This commentary contextualizes these findings within the broader framework of activity-dependent proteostasis, sex-specific autophagy modulation, and therapeutic potential of CMA in brain aging and neurodegeneration.

RevDate: 2025-12-08

Lv L, Aly A, McKay C, et al (2025)

Real-world analysis of medication adherence and cost of care for comorbid conditions in patients with early Alzheimer's disease in the U.S.

Neurodegenerative disease management [Epub ahead of print].

AIM: To understand medication adherence and associated healthcare costs of patients with early Alzheimer's disease (AD).

METHODS: This retrospective cohort study used the Axon Registry® linked with claims data to examine medication adherence of U.S. patients with early AD (mild cognitive impairment [MCI] and mild dementia due to AD) from 2015 to 2022. Medication adherence was quantified by the proportion of days covered (PDC) over a one-year follow-up, and adherence rate was defined at a PDC ≥ 80%. Patient comorbidities and healthcare costs were described.

RESULTS: Of 333 patients included, 213 (64%) were female with a median (IQR) age 79 (72-83) years. Patients had a mean (SD) of 2.3 (2.1) comorbidities and took a mean (SD) of 3.0 (1.5) medications. Weighted-average PDC across medications was 74.4% with 7 out of 10 medication classes having a medication adherence rate lower than 60%. DPP-4 inhibitors had the highest medication adherence rate (66.67% of patients), and memantine had the lowest (39.13% of patients). Annual median (IQR) medical and pharmacy costs per-patient were $5,268 ($1,808-$14,651) and $658 ($187-$2,736), respectively.

CONCLUSION: Patients with early AD had multiple comorbidities and took multiple medications. Suboptimal medication adherence and high healthcare costs were observed.

RevDate: 2025-12-08
CmpDate: 2025-12-08

Lohman T, Kapoor A, Engstrom AC, et al (2025)

Low frequency BOLD oscillations, APOE4, and plasma pTau217.

medRxiv : the preprint server for health sciences pii:2025.11.25.25340991.

BACKGROUND: Intrinsic low frequency oscillations in BOLD signal (BOLD LFOs) are generally considered nuisance signal in connectivity analysis and discarded. However, recent evidence suggests BOLD LFOs may shed light on cerebrovascular dysfunction and early Alzheimers disease pathophysiology, but the mechanisms remain unclear. No investigations to date have assessed the relationship between BOLD LFOs and plasma pTau217, or how this relationship differs in apolipoprotein e4 (APOE4) carriers who are vulnerable to cerebrovascular dysfunction and genetically predisposed to AD pathophysiology.

METHODS: Independently living older adults (N=118) without major neurological or psychiatric disorder were recruited from the community. Participants underwent resting-state brain functional MRI and venipuncture. Total BOLD LFOs were quantified as signal power within the 0.01 to 0.10 Hz frequency range. Plasma level of pTau217 was assessed and linear regression was used to quantify the interactive effect of APOE4 carrier status and BOLD LFOs on plasma pTau217. 2x2 ANCOVA was used to compare BOLD LFOs across APOE4 carrier and amyloid positivity statuses based on previously reported pTau217 cutoffs.

RESULTS: The interactive effect of APOE4 carrier status and BOLD LFO power was significantly associated with plasma pTau217 (β=-.65, p=.004). This relationship was driven by an inverse relationship between BOLD LFOs and plasma pTau217 in APOE4 carriers (β=-.49, p=.003). Amyloidβ positive APOE4 carriers displayed lower BOLD LFOs than amyloidβ negative APOE4 carriers (p=.02) and amyloid-β positive APOE4 non carriers (p=.04). All models were adjusted for age and sex.

CONCLUSION: Present study findings suggests that BOLD LFOs are implicated early in AD pathophysiology in an APOE4 dependent manner, adding support for the continued study of BOLD LFOs in the context of cerebrovascular contributions to AD genetic risk.

RevDate: 2025-12-08
CmpDate: 2025-12-08

Li R, Feng R, Liu A, et al (2025)

Neuroimaging-derived brain endophenotypes link molecular mechanisms to Alzheimer's disease and aging.

medRxiv : the preprint server for health sciences pii:2025.11.25.25340884.

Alzheimer's disease (AD) genome-wide association studies (GWAS), typically based on clinical phenotypes, have identified numerous risk loci, yet linking these variants to brain changes and molecular processes remains challenging. We developed a DNE-xQTL framework integrating deep learning-derived dimensional neuroimaging endophenotypes (DNEs) with comprehensive brain molecular quantitative trait loci (xQTL) to dissect genetic pathways underlying AD- and aging-related brain variation. By performing GWAS on seven DNEs and applying integrative computational analyses, we biologically annotated each DNE and prioritized xQTL-supported gene targets. This approach both enhanced interpretation of established AD loci through DNE-mediated annotations and revealed underexplored regulatory pathways, organizing 209 candidate genes into evidence-based tiers. We highlight three regulatory clusters: glutamate-receptor and mitochondrial pathways implicating excitatory-neuron vulnerability, SREBP2-associated cholesterol homeostasis linked to vascular dysfunction, and primary-cilia-associated transport implicated in aging. By connecting pre-symptomatic brain alterations to molecular targets and relevant cell types, this framework may inform earlier risk stratification before clinical neurodegeneration occurs.

RevDate: 2025-12-09
CmpDate: 2025-12-09

Liu GH, Huang YH, Yuan TC, et al (2025)

Associations of Wearable-Measured Sleep and Physical Activity With Memory Performance in Older Adults: Cross-Sectional Study With Actigraphy and MRI.

JMIR aging, 8:e80584 pii:v8i1e80584.

BACKGROUND: Cognitive decline is a common aspect of aging, and identifying modifiable lifestyle factors, such as physical activity and sleep, is crucial for promoting healthy brain aging. While both are individually linked to cognition, few studies have simultaneously assessed their independent and combined effects using objective wearable-based data, particularly in older Asian populations.

OBJECTIVE: This study aimed to examine the independent and interactive effects of wearable-assessed sleep and physical activity parameters on memory performance in healthy older adults. We also explored whether age and hippocampal volume moderated these associations.

METHODS: This prospective cross-sectional analysis included 88 cognitively healthy community-dwelling adults (≥60 years of age) from the Integrating Systematic Data of Geriatric Medicine to Explore the Solution for Healthy Aging cohort in Taiwan. Participants underwent 12-day wrist-worn actigraphy, brain magnetic resonance imaging, and neuropsychological assessments. Light-intensity physical activity (LPA) and wake after sleep onset (WASO) were selected based on age-adjusted partial correlations with Consortium to Establish a Registry for Alzheimer's Disease Neuropsychological Battery memory scores. Multivariate regressions, age-stratified models (cutoff=72 years), and PROCESS moderation and mediation analyses were conducted, adjusting for age, education, daytime sleepiness, and hippocampal volume.

RESULTS: Partial correlation analyses adjusting for age showed that higher LPA (r=0.260; P=.02) and lower WASO (r=-0.251; P=.02) were significantly associated with better memory scores. Age significantly moderated both effects: LPA was beneficial beyond 73.8 years of age, and WASO was detrimental beyond 71.1 years of age. Multivariate regression models confirmed that both WASO (β=-.044; P=.04) and LPA (β=.042; P=.01) were significant predictors of memory. In subgroup analyses (age ≥72 years), both LPA (β=.054; P=.04) and WASO (β=-.111; P=.01) remained significant predictors. Moderated mediation analyses showed that WASO was associated with reduced LPA (β=-.325; P=.03), but the indirect effect on memory via LPA was not significant. Instead, WASO exerted a direct and age-moderated effect on memory performance. Hippocampal volume moderated both associations, supporting the brain reserve hypothesis.

CONCLUSIONS: Our findings highlight WASO and LPA, as measured by wearable devices, as modifiable behavioral factors linked to memory function in older adults. The impact of these factors intensifies with advancing age and may be influenced by hippocampal reserve. Promoting daily light physical activity and maintaining sleep continuity may serve as accessible, age-tailored strategies for preserving cognitive health in aging populations.

TRIAL REGISTRATION: ClinicalTrials.gov NCT04207502; https://classic.clinicaltrials.gov/ct2/show/NCT04207502.

RevDate: 2025-12-09

Anonymous (2025)

Erratum.

Neuro-degenerative diseases, 25(4):228.