@article {pmid41297218,
year = {2025},
author = {Mondragon, JD and Marcolini, S and Giacobbo, BL and Elsinga, PH and Dierckx, RAJO and Tollenaere, M and van Dam, D and De Deyn, PP},
title = {Integrating [[11]C]methylreboxetine PET and MRI to map in vivo norepinephrine transporter distribution: A proof-of-concept study of noradrenergic vulnerability in neurodegeneration.},
journal = {Nuclear medicine and biology},
volume = {152-153},
number = {},
pages = {109581},
doi = {10.1016/j.nucmedbio.2025.109581},
pmid = {41297218},
issn = {1872-9614},
abstract = {BACKGROUND: The locus coeruleus (LC) and its noradrenergic projections are among the earliest sites displaying pathology in Alzheimer's disease (AD) and Parkinson's disease (PD). In vivo measures of norepinephrine transporter (NET) availability with [[11]C]methylreboxetine ([[11]C]MRB) positron emission tomography (PET) and structural magnetic resonance imaging (MRI) indices of LC integrity provide complementary, but rarely integrated biomarkers.

METHODS: 13 Healthy controls (HC), individuals with 12 AD or amnestic mild cognitive impairment due to AD (AD/aMCI), and 5 patients with PD underwent [[11]C]MRB PET and high-resolution T1-weighted MRI. NET availability was quantified using [[11]C]MRB PET SUV-ratio-based binding potential (SUVr-BP) in the LC and projection regions (hippocampus, amygdala, thalamus, and prefrontal cortex). LC structural integrity was indexed by LC MRI contrast-to-noise ratio (CNR), and projection region volumes were extracted with FreeSurfer. Group differences were assessed with Kruskal-Wallis tests, and PET-MRI associations were examined using Pearson correlations with Yeo-Johnson transformation to reduce outlier influence.

RESULTS: No significant group-level differences in [[11]C]MRB PET SUVr-BP or MRI measures were observed across HC, AD/aMCI, and PD. However, LC [[11]C]MRB PET SUVr-BP correlated with LC MRI-CNR (r = 0.429, 95 % CI [0.082-0.684], p = 0.018). In contrast, PET-MRI associations in projection regions were weak and non-significant. Exploratory analyses confirmed expected differences in cognition, neuropsychiatric symptoms, and functional measures, most pronounced in AD/aMCI participants.

CONCLUSIONS: This proof-of-concept study demonstrates convergent multimodal assessment of LC integrity using [[11]C]MRB PET and LC MRI-CNR, whereas projection regions showed divergent or absent associations. These findings highlight the potential of the LC as a target for multimodal biomarker development and support further investigation of these imaging strategies in larger, longitudinal cohorts to delineate their role in detecting noradrenergic vulnerability in neurodegeneration.

SIGNIFICANCE STATEMENT: This study integrates [[11]C]MRB PET and MRI to examine noradrenergic integrity in Alzheimer's and Parkinson's disease. Results demonstrate strong PET-MRI convergence in the locus coeruleus, but not in projection regions, highlighting the locus coeruleus as a sensitive biomarker target and supporting multimodal imaging approaches for early detection of neurodegenerative vulnerability.},
}

@article {pmid41296938,
year = {2025},
author = {Molinero, N and Montero-Atalaya, M and Méndez, L and Roldán, M and Cortés, IP and Ruhland, S and Bartolomé, B and Medina, I and Moreno-Arribas, MV},
title = {The Multinutrient Fortasyn Connect Influences Gut Microbiota and Intestinal Function in Early Alzheimer's Disease.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2025.1176},
pmid = {41296938},
issn = {2152-5250},
abstract = {Nutritional supplementation is emerging as a promising strategy to support clinical management of early Alzheimer's disease (AD), partly through modulation of the intestinal microbiome via the microbiota-gut-brain axis. This study investigated the impact of Fortasyn Connect (Souvenaid[®]), a multinutrient formulation, on gut microbiota using a dual approach: i) a dynamic gastrointestinal simulator (simgi[®]) inoculated with feces from AD patients, and ii) an observational study involving early-stage AD patients (n = 22) receiving or not the supplement. The in vitro model provided a direct, host-independent assessment of microbiota responses, showing increased Bifidobacterium and Lactobacillus levels, alongside enhanced short-chain fatty acid (SCFA) production. In patients, supplementation was associated with higher fecal abundance of Bifidobacterium and Christensenellaceae, reduced inflammatory markers (calprotectin and myeloperoxidase), and increased butyrate levels. Fecal lipidomic and proteomic analyses indicated improved lipid digestion, increased secretory IgA, and modulation of host proteins linked to gut-brain homeostasis. Systemically, elevated levels of iron, folate, and vitamin B12 were also observed. For the first time, this study shows that supplements such as Fortasyn Connect can beneficially modulate the gut ecosystem and related immune-metabolic pathways in early AD, thereby targeting disease-relevant mechanisms through the gut-brain axis, in the context of aging.},
}

@article {pmid41296937,
year = {2025},
author = {Sun, L and Chen, C},
title = {Senescence in Aging and Alzheimer's Disease.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2025.1201},
pmid = {41296937},
issn = {2152-5250},
abstract = {Cellular senescence, once considered a protective mechanism against oncogenesis, is now recognized as a key driver of aging and age-related diseases, including Alzheimer's disease (AD). In the central nervous system (CNS), senescence-like states emerge in both proliferative and post-mitotic cells-astrocytes, microglia, oligodendrocyte lineage cells, endothelial cells, pericytes, and even neurons-contributing to chronic dysfunction. Canonical pathways, such as p16[INK4a]-pRB and p53-p21, enforced by persistent DNA damage responses, lead to irreversible cell-cycle arrest. The senescence-associated secretory phenotype (SASP) links intracellular stress to extracellular inflammation, tissue remodeling, and bystander senescence. CNS senescence is triggered by diverse insults, including amyloid-β and tau pathology, oxidative stress, mitochondrial dysfunction, NF-κB and cGAS-STING signaling, impaired proteostasis and autophagy, telomere attrition, and genomic instability. Senescence markers in the CNS are heterogeneous, ranging from p16/p21 expression and lamin B1 loss to lipofuscin accumulation and cell type-specific SASP profiles, highlighting the need for multiplexed detection strategies. Targeting senescence has emerged as a promising therapeutic avenue in AD. Senolytics selectively eliminate senescent cells and improve cognition in preclinical models, while senomorphics aim to suppress harmful phenotypes without inducing cell loss. Early clinical trials suggest feasibility, but challenges remain, including biomarker development, blood-brain barrier penetration, long-term safety, and optimal timing of intervention. This review summarizes recent advances in understanding CNS senescence in aging and AD, explores emerging therapeutic strategies, and outlines future directions emphasizing precision medicine through multi-omic biomarkers, advanced imaging, and stage-specific interventions. Targeting CNS senescence holds potential to delay or alter the course of AD.},
}

@article {pmid41296930,
year = {2025},
author = {Winslow, W and Judd, JM and Tallino, S and Serrano, GE and Beach, TG and Roust, LR and De Filippis, E and Brown, B and Katsanos, C and Velazquez, R},
title = {Reduced Blood Choline in Obesity Is Associated with Metabolic and Alzheimer's Biomarkers.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2025.1207},
pmid = {41296930},
issn = {2152-5250},
abstract = {Rising obesity rates pose significant concerns for aging and brain health. Insulin resistance (IR), prevalent in both obesity and Alzheimer's disease (AD), accelerates neurodegeneration. Adequate choline intake may help reduce obesity risk and IR, yet many individuals consume less than recommended-a deficiency associated with increased AD risk. Here, we examined circulating blood choline, metabolic dysfunction markers, inflammatory cytokines, and neurofilament light (NfL), a protein that is used as a prognostic marker for neuronal damage, in young-adult participants (mean age 33.6 years) with obesity (BMI > 30) versus healthy BMI (18.5-24.9) controls using a cross-sectional design. We also validated whether circulating choline levels correlate with NfL in a cohort of patients with mild cognitive impairment (MCI) with presence of either sparse or high neuritic plaque density and Braak stage and a second cohort with either moderate AD (moderate to frequent neuritic plaques, Braak stage = IV) or severe AD (frequent neuritic plaques, Braak stage = VI), compared to age-matched controls. We found that obese participants showed reduced circulating choline, correlating with higher %Body Fat, liver dysfunction markers, increased IR, and elevated inflammatory cytokines. NfL levels were elevated in obese participants and negatively correlated with circulating choline levels, findings consistent with that observed in MCI and AD cases. These findings reveal correlations between obesity, low choline, IR, systemic inflammation and NfL-key AD risk markers. Monitoring such markers in early adulthood may be useful for assessing future AD risk in individuals prone to obesity.},
}

@article {pmid41296806,
year = {2025},
author = {Magalhães, AD and Emmenegger, M and De Cecco, E and Carta, M and Frontzek, K and Chincisan, A and Guo, J and Hornemann, S and Aguzzi, A},
title = {Large-scale seroepidemiology uncovers nephro-urological pathologies in people with tau autoimmunity.},
journal = {PLoS biology},
volume = {23},
number = {11},
pages = {e3003488},
doi = {10.1371/journal.pbio.3003488},
pmid = {41296806},
issn = {1545-7885},
abstract = {Intraneuronal aggregates of the microtubule-associated protein tau play a pivotal role in Alzheimer's disease and several other neurodegenerative syndromes. Anti-tau antibodies can reduce pathology in mouse models of neurodegeneration and are currently being tested in humans. Here, we performed a large-scale seroepidemiological search for anti-tau IgG autoantibodies (ατ) on 40,497 human plasma samples. High-titer ατ+ individuals were surprisingly prevalent, with hospital patients being three times more likely to be ατ+ (EC50 ≥ 26; a nominal dilution of >1/64) than healthy blood donors (4.8% versus 1.6%). The prevalence increased with age over 70 years-old (RR 1.26, 95% CI 1.11-1.43, P < 0.001) and was higher for women (RR 1.20, 95% CI 1.07-1.39, P = 0.002). The autoantibodies bound selectively to tau, inhibited tau aggregation in vitro, and interfered with tau detection in plasma samples. No association was found between ατ autoantibodies and neurological disorders. Instead, tau autoreactivity showed a significant association with kidney and urinary disorders (adjusted RR 1.27, 95% CI 1.10-1.45, P = 0.001 and 1.40, 95% CI 1.20-1.63, P < 0.001, respectively). These results suggest a previously unrecognized association between ατ autoimmunity and extraneural diseases.},
}

@article {pmid41296690,
year = {2025},
author = {O'Connor, S and Riglea, T and Lavigne-Robichaud, M and Lapierre, L},
title = {Mapping social determinants of cognitive health in Canada: a scoping review.},
journal = {Health promotion and chronic disease prevention in Canada : research, policy and practice},
volume = {45},
number = {11-12},
pages = {431-444},
doi = {10.24095/hpcdp.45.11/12.01},
pmid = {41296690},
issn = {2368-738X},
mesh = {Humans ; *Social Determinants of Health/statistics & numerical data ; Canada/epidemiology ; *Cognition ; Social Support ; Socioeconomic Factors ; Adult ; },
abstract = {INTRODUCTION: We sought to map the literature assessing the associations between the social determinants of health (SDoH) and the cognitive health of adults in Canada.

METHODS: We searched the Embase, CENTRAL, Global Health and MEDLINE databases through Ovid, from inception to 20 February 2024, for studies examining associations between SDoH and cognitive health among Canadian adults, irrespective of health or cognitive status.

RESULTS: We identified 159 publications covering 93 studies; 27% (n = 25) had nationwide coverage and 48% (n = 45) were from Ontario or Quebec. Of the 410 associations between SDoH and cognition, 20 were from 6 qualitative studies and 390 from 87 quantitative studies. Education was the most frequently evaluated (46%) of the 29 identified SDoH categories, then social support (24%), household/individual income (19%), marital status (17%), occupation (16%), rural or urban area of residence (16%), living arrangement/household composition (12%) and environmental factors (13%). Two-thirds (67%) of the studies examined various cognitive health constructs, while 41% evaluated dementia (all types). Most of the SDoH were from the settings with which individuals directly interact. SDoH related to environmental exposure or pollution, societal norms, beliefs, values and practices were less frequently evaluated.

CONCLUSION: This scoping review provides a detailed map of the literature on SDoH and cognitive health in Canada. It highlights the importance of considering a comprehensive range of SDoH and of using diverse data sources and data collection approaches. The results also highlight SDoH that remain largely unexamined and should be prioritized in future research.},
}

Humans
*Social Determinants of Health/statistics & numerical data
Canada/epidemiology
*Cognition
Social Support
Socioeconomic Factors
Adult

@article {pmid41296471,
year = {2025},
author = {Du, Y and Xia, XY and Ni, Z and Fan, SS and He, J and He, Y and Meng, XY and Wang, X and Xu, X},
title = {Genetic Evidence Prioritizes Neurocognitive Decline as a Causal Driver of Sleep Disturbances: A Multi-Omics Analysis Identifying Causal Genes and Therapeutic Targets.},
journal = {Current issues in molecular biology},
volume = {47},
number = {11},
pages = {},
doi = {10.3390/cimb47110967},
pmid = {41296471},
issn = {1467-3045},
support = {2508085QC099//Natural Science Foundation of Anhui Province of China/ ; 0801059201//the Research Fund for the Doctoral Program of Anhui Medical University/ ; 2022AH030079//Excellent Youth Project of Natural Science Research of Anhui Education Department/ ; 2023xkjT001//Research Enhancement Program Funded Projects from Anhui Medical University/ ; 32371364//National Natural Science Foundation of China/ ; 82303057//National Natural Science Foundation of China/ ; },
abstract = {To resolve the ambiguous causal relationship between sleep disturbances and neurodegenerative diseases such as Alzheimer's disease (AD), we conducted a multi-stage genetic and multi-omics investigation. Our large-scale bidirectional Mendelian randomization analysis identified a robust, asymmetrical pattern of genetic association, providing strong genetic evidence suggesting that liability for neurocognitive decline and AD is associated with sleep disturbances, with substantially weaker evidence for the reverse direction. To identify the underlying molecular drivers, a multi-omics Summary-data-based MR (SMR) analysis prioritized high-confidence causal genes, including YWHAZ, NT5C2, COX6B1, and CDK10. The predictive power of this gene signature was confirmed using machine learning models (ROC-AUC > 0.8), while functional validation through bulk and single-cell transcriptomics uncovered profound, cell-type-specific dysregulation in the AD brain, most notably opposing expression patterns between neurons and glial cells (e.g., YWHAZ was upregulated in excitatory neurons but downregulated in glia). Functional enrichment and network analyses implicated two core pathways-nucleotide metabolism centered on NT5C2 and synaptic function involving YWHAZ-and our investigation culminated in the identification of a promising therapeutic interaction, with molecular docking validating high-affinity binding between Ecdysterone and COX6B1 (docking score = -5.73 kcal/mol). Collectively, our findings strengthen the evidence that sleep disruption as a likely consequence of neurodegenerative processes and prioritize a set of validated, cell-type-specific gene targets within critical pathways, offering promising new avenues for therapeutic development.},
}

@article {pmid41296463,
year = {2025},
author = {Caldarelli, M and Rio, P and Gasbarrini, A and Gambassi, G and Cianci, R},
title = {Environmental Stressors and Neuroinflammation: Linking Climate Change to Alzheimer's Disease.},
journal = {Current issues in molecular biology},
volume = {47},
number = {11},
pages = {},
doi = {10.3390/cimb47110959},
pmid = {41296463},
issn = {1467-3045},
support = {PNRR-MAD-2022-12376383, CIMA, G.G., R.C.//Italian Ministry of Health within the PNRR Mission 6 initiative on Health/ ; },
abstract = {Environmental exposures are widely recognized as major risk factors for human health. According to projections by the World Health Organization, climate change is expected to cause a significant increase in mortality within the next few decades. Environmental factors, including diet, weather, occupational exposures, and pollutants play a key role in human diseases affecting different systems, such as cardiovascular, pulmonary, gastrointestinal, and neurological. This narrative review explores the relationship between environmental stressors and neuropathological mechanisms, such as microglial and astrocytic activation, oxidative stress, and neuronal injury, involved in neuroinflammation and the associated neurodegeneration. The pathogenesis and progression of Alzheimer's disease is discussed in detail, establishing a link between environmental stressors and neuroinflammation. A deeper understanding of these neuropathological mechanisms may guide the development of preventive and therapeutic strategies to safeguard brain health in the context of global environmental change.},
}

@article {pmid41296223,
year = {2025},
author = {Bharath, HC and Pradeep, N and Shashidhar, R and Nanjappa, Y},
title = {Synergistic medical genetic evolutionary optimization and deep convolutional generative augmentation with SHAP-driven interpretability for precise Alzheimer's disease severity grading.},
journal = {Brain informatics},
volume = {12},
number = {1},
pages = {31},
pmid = {41296223},
issn = {2198-4018},
abstract = {Alzheimer's disease (AD) diagnosis at an early yet accurate stage is critical to support effective treatment or intervention. Still it is not very feasible due to the presence of image data class imbalance, low interpretability of models, and a high computational cost. This research proposes a novel, end-to-end diagnostic framework that considers a Medical Genetic Algorithm (MedGA)-optimized Convolutional Neural Network (CNN) with a Deep Convolutional Generative Adversarial Network (DCGAN) to generate synthetic MRIs and SHapley Additive Explanations (SHAP) to analyse and interpret the model. The given methodology is trained and tested on the Open Access Series of Imaging Studies (OASIS) dataset. The DCGAN component introduces 700 structurally coherent synthetic images (SSIM = 0.92) into the underrepresented Moderate Dementia class, improving the overall recall by 10% and balancing the dataset. MedGA succeeds in optimizing CNN hyperparameters and resulting in complexity reduction (20%) in networks without loss of testing accuracy (97%) at the four demonstrated stages of AD: Non-Demented, Very Mild Demented, Mild Demented, and Moderate Demented. SHAP analysis emphasises the role of key brain areas, the hippocampus and the amygdala in the results of classification accuracy, leading to 25% greater interpretability and clinician confidence. Comparative evaluation shows that the current framework is exceptionally better in terms of predictive performance and explainability than current state-of-the-art approaches. This combined method provides a powerful and adaptable device to categorize AD at an early age, with promising outcomes in precise diagnosis in health facilities.},
}

@article {pmid41296218,
year = {2025},
author = {Vaz, M and Soares Martins, T and Trigo, D and da Cruz E Silva, OAB and Amado, F and Vitorino, R and Henriques, AG},
title = {Aβ Modulates Extracellular Vesicles Proteomic Profile Impacting Phosphorylation Mediators.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {179},
pmid = {41296218},
issn = {1559-1182},
mesh = {*Extracellular Vesicles/metabolism/drug effects ; *Amyloid beta-Peptides/pharmacology ; Phosphorylation/drug effects ; *Proteomics/methods ; Animals ; Mice ; *Proteome/metabolism ; Glycogen Synthase Kinase 3 beta/metabolism ; Cell Line, Tumor ; Alzheimer Disease/metabolism ; Humans ; Protein Interaction Maps/drug effects ; },
abstract = {Alzheimer's disease (AD) is characterized by the formation of senile plaques and neurofibrillary tangles, mainly composed of amyloid-β (Aβ) peptide aggregates and hyperphosphorylated tau protein, respectively. AD pathophysiology is highly complex, involving multiple abnormal cellular pathways linked to disease progression. Recently, extracellular vesicles (EVs) have emerged as potential contributors to disease development. Thus, this study explored the proteome of neuronal EVs under conditions that mimic Alzheimer's disease by employing mass spectrometry in EVs isolated from N2a cells treated with Aβ. Bioinformatic analysis revealed proteins involved in signal transduction, post-translational protein modification, translation, and proteolysis. Furthermore, Aβ treatment led to either an enrichment or scarcity of proteins related to cytoskeletal and mitochondrial dynamics, calcium-dependent signalling, phosphorylation, as well as proteins involved in Aβ production and aggregation. Overlap between EVs' proteome upon Aβ treatment and key AD-related proteins identified glycogen synthase kinase 3β (GSK3β) as a central node in the resulting protein interaction network. Additionally, the GSK3β interactome, derived from the EVs' proteome, highlighted protein phosphatases as relevant EVs' cargo under Alzheimer's disease mimicking conditions. The activity of GSK3β and protein phosphatases in EVs was monitored, revealing significant differences between control and Aβ-treated conditions. These findings support not only that EVs carry key proteins involved in phosphorylation dynamics but also that Aβ treatment alters EVs' proteomic profile, potentially impacting AD development. Proteomic changes in EVs may provide valuable insights into the mechanisms underlying AD and also contribute to the identification of novel potential therapeutic targets.},
}

*Extracellular Vesicles/metabolism/drug effects
*Amyloid beta-Peptides/pharmacology
Phosphorylation/drug effects
*Proteomics/methods
Animals
Mice
*Proteome/metabolism
Glycogen Synthase Kinase 3 beta/metabolism
Cell Line, Tumor
Alzheimer Disease/metabolism
Humans
Protein Interaction Maps/drug effects

@article {pmid41296090,
year = {2025},
author = {Wang, M and Zeng, Y and Jin, Y and Wu, J and Li, J},
title = {Progress and Perspectives on the Estrogen-Microbiota-Brain Axis in Alzheimer's Disease.},
journal = {Neurochemical research},
volume = {51},
number = {1},
pages = {3},
pmid = {41296090},
issn = {1573-6903},
support = {No. QKHJC-ZK[2022]-260//Guizhou Provincial Science and Technology Projects/ ; NO.gzwjrs2023-005//Guizhou Provincial High level Innovative Talent Fund/ ; },
mesh = {Humans ; *Alzheimer Disease/metabolism/microbiology ; *Estrogens/metabolism ; *Gastrointestinal Microbiome/physiology ; *Brain/metabolism/drug effects ; Animals ; Dysbiosis/metabolism ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder shaped by genetic, metabolic, environmental, and sex-specific factors. Emerging evidence highlights the estrogen-gut microbiota-brain (EGMB) axis as a critical framework linking endocrine regulation, microbial activity, and cognitive outcomes. Estrogen exerts neuroprotective effects by modulating synaptic plasticity, oxidative stress, amyloid and tau pathology, and neuroinflammation, while its decline during menopause increases AD vulnerability. Parallel to this, gut dysbiosis and altered microbial metabolites, particularly short-chain fatty acids (SCFAs) and secondary bile acids (sBAs), contribute to barrier dysfunction, chronic inflammation, and synaptic impairment. Importantly, estrogen remodels microbial composition and metabolite profiles, whereas microbial β-glucuronidase (β-GUS) activity sustains estrogen bioavailability, establishing a reciprocal regulatory loop. Preclinical studies demonstrate that depletion of gut microbiota diminishes estrogen's protective effects, underscoring the central role of microbial metabolites as signaling bridges.Therapeutically, these insights support the integration of hormone replacement therapy with microbiota-targeted interventions such as probiotics, prebiotics, and fecal microbiota transplantation. Such combined strategies may synergistically enhance neuroprotection, though their efficacy depends on timing, dosage, and individual variability. Future precision approaches integrating multi-omics profiling and sex-specific stratification hold promise for identifying predictive biomarkers and optimizing treatment windows. In summary, the EGMB axis offers a mechanistic foundation for understanding sex differences in AD and a translational framework for developing individualized, multidimensional strategies for early diagnosis, prevention, and therapy.},
}

Humans
*Alzheimer Disease/metabolism/microbiology
*Estrogens/metabolism
*Gastrointestinal Microbiome/physiology
*Brain/metabolism/drug effects
Animals
Dysbiosis/metabolism

@article {pmid41295894,
year = {2025},
author = {Chacón, T and Hernández-Hincapié, H},
title = {Relationship periodontitis and Alzheimer's disease: Relevant aspects from an epigenetic view.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251397406},
doi = {10.1177/13872877251397406},
pmid = {41295894},
issn = {1875-8908},
abstract = {Periodontitis and Alzheimer's disease (AD) are chronic disorders that share an underlying inflammatory component and emerging epigenetic mechanisms influencing disease progression. Alterations in DNA methylation are increasingly recognized as critical in modulating immune responses and neurodegenerative processes. This review examines the evidence linking periodontal inflammation to AD pathogenesis and evaluates the potential of blood-based epigenetic biomarkers for early diagnosis and risk stratification. A narrative review was conducted by integrating findings from both preclinical and clinical studies that investigated the relationship between periodontitis and AD. Emphasis was placed on research assessing DNA methylation profiles, gene expression alterations, and the impact of proinflammatory mediators on the central nervous system. Particular attention was given to studies examining the role of the immune and complement systems in mediating the effects of chronic oral inflammation. The evidence indicates that chronic periodontal inflammation can trigger systemic responses that compromise the integrity of the blood-brain barrier, thereby facilitating the accumulation of amyloid-β plaques and hyperphosphorylated tau proteins in the brain. Aberrant methylation patterns in genes related to immune regulation and protein processing suggest converging molecular pathways between periodontitis and AD. Moreover, emerging data reveal that epigenetic alterations detectable in peripheral blood closely mirror cerebral changes, opening new avenues for early detection. As a narrative review, our synthesis is hypothesis-generating and does not establish causality; the proposed epigenetic link between periodontitis and AD remains provisional pending longitudinal and interventional confirmation.},
}

@article {pmid41295893,
year = {2025},
author = {Aguado, C and Alfaro-Ruiz, R and Martín-Belmonte, A and Puertas-Avendaño, R and Fernández, M and Martínez-Poyato, ML and Portero-Campillo, E and Pozuelo-Montero, M and Moreno-Martínez, AE and Alonso-Gómez, P and Kulik, A and Luján, R},
title = {Disruption of CaV2.3 channels in the brain of the 5xFAD mice.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251396963},
doi = {10.1177/13872877251396963},
pmid = {41295893},
issn = {1875-8908},
abstract = {BackgroundCaV2.3 (R-type) channels mediate calcium signals involved in neuronal excitability, synaptic plasticity, and neurotransmitter release in the hippocampus. However, there is currently no information about their potential changes in Alzheimer's disease (AD).ObjectiveThis study aims to analyze the protein levels, expression, and subcellular localization of CaV2.3 channels in the hippocampus of 5xFAD mice.MethodsWe employed histoblot, western blot, qRT-PCR, and immunoelectron microscopy techniques.ResultsUsing the histoblot technique, we observed that the protein content of CaV2.3 in female 5xFAD mice was downregulated in the hippocampus and caudate putamen at 5 months, with more pronounced downregulation at 10 months that also affected the septum. The hippocampus was the most affected region, where CaV2.3 immunodetection was significantly decreased in a few dendritic layers at 5 months, but this reduction extended to all layers and subregions by 10 months, demonstrating age- and laminar-dependent changes. The pattern in females differed from that seen in males and remained unchanged in APP/PS1 and P301S mice. Immunoelectron microscopy of the hippocampus showed CaV2.3 in apical and oblique dendrites of CA1 pyramidal cells, with a significantly higher presence in dendritic spines. Quantification revealed a significant decrease in the density of CaV2.3 in oblique dendrites and dendritic spines of CA1 pyramidal cells, whereas apical dendrites and presynaptic compartments were unaffected in 5xFAD mice.ConclusionsOverall, this downregulation in postsynaptic CaV2.3 channels could impact neural circuit activity and contribute to the cognitive deficits observed in 5xFAD mice.},
}

@article {pmid41295447,
year = {2025},
author = {Polte, S and Klingmann, L and Seßmann, A and Schwichtenberg, S and Herrmann, CS and Witt, K and Roheger, M},
title = {Neuromodulatory Effects of Transcranial Pulse Stimulation (TPS) in Neurological and Psychiatric Disorders-A Systematic Review and Meta-Analysis.},
journal = {Neurology international},
volume = {17},
number = {11},
pages = {},
doi = {10.3390/neurolint17110188},
pmid = {41295447},
issn = {2035-8385},
support = {456732630//Deutsche Forschungsgemeinschaft/ ; },
abstract = {BACKGROUND: Transcranial pulse stimulation (TPS) is an innovative non-invasive brain stimulation technique using ultrasonic waves. Despite its application in first clinical trials, so far, no systematic overview of its effects across different patient populations has been conducted.

OBJECTIVES: This systematic review and meta-analysis examines the effects of TPS on cognitive, motor, and mental health outcomes as well as on patient safety in neurological and psychiatric disorders.

METHODS: We conducted a literature search in MEDLINE, PsycINFO & PsycArticles, CENTRAL, Web of Science, and Google Scholar, covering the period from January 2013 to December 2024. Two independent reviewers conducted the study selection, data extraction, and quality assessment. To evaluate the risk of bias, the RoB2 tool was used for randomized studies and the ROBINS-I tool for non-randomized studies.

RESULTS: A total of fifteen studies (five randomized controlled trials and ten non-blinded, single-arm trials) including both adolescent and adult and elderly patient populations (Alzheimer's disease, mild cognitive impairment, Parkinson's disease, major depressive disorder, autism spectrum disorder, attention-deficit hyperactivity disorder) were included. Positive effects of TPS intervention on cognitive, motor, and mental health outcomes, as well as a high safety profile, were demonstrated in a majority of the studies and outcome parameters. However, limitations of the included studies persist due to small sample sizes, lack of control groups, retrospective analyses, and heterogeneity of study protocols and measurements.

CONCLUSIONS: TPS is a safe and promising method for treating neurological and psychiatric disorders. To better assess the potential of this innovative technique, standardized protocol procedures and larger, sham-controlled trials are needed.},
}

@article {pmid41295439,
year = {2025},
author = {Zachara, R and Gendosz de Carrillo, D and Wlaszczuk, A and Gorzkowska, A and Mazur, W and Jedrzejowska-Szypulka, H},
title = {The Cognitive Changes Among Patients over 65 Years of Age in a Rural Area-The Preliminary Report of Protective and Predisposing Factors.},
journal = {Neurology international},
volume = {17},
number = {11},
pages = {},
doi = {10.3390/neurolint17110180},
pmid = {41295439},
issn = {2035-8385},
support = {PCN-2-042/N/2/I//Medical University of Silesia/ ; },
abstract = {Background: Aβ1-42 and APOE concentrations, as well as Aβ42/40 ratio, may be considered as a link between hypertension (HTN) or diabetes mellitus (DM), brain amyloidosis, and dementia. HTN and DM are associated with cognitive impairment and may contribute to the development of Alzheimer's disease (AD). This preliminary study aimed to evaluate the impact of vascular risk factors on the concentration of biochemical AD markers and cognitive state. As it is a cross-sectional study in nature, causal relationships cannot be established. Methods: The study was conducted in the south of Poland among a rural population over 65 years of age. A total of 58 patients qualified into the study were divided into groups according to the presence of HTN (n = 18) or HTN coexisting with DM (n = 40). A healthy control group was also formed (n = 20), resulting in 78 study participants. The study population was also divided based on M-ACE results, forming a normal cognition group (NC) and a deteriorated cognition group (DC). Biochemical tests, neurological scales assessments, and ultrasound examinations were conducted. Results: Patients who scored in the normal range on the M-ACE had higher Aβ1-42 (median 38.52 vs. 27.35 pg/mL, p = 0.02) and apoE concentrations (median 125.0 vs. 65.73 μg/mL, p = 0.002), and a higher Aβ42/40 ratio (median 0.39 vs. 0.29 p < 0.000) compared to the DC group. Considering the study groups, the highest Aβ42/40 ratio was found among the HC group (median 0.47). The median score for the M-ACE scale was 3 points lower when HTN and DM coexisted, compared to the sole diagnosis of HTN (25 points and 28 points, respectively). A higher number of years of education correlated with better M-ACE results. Lipid and uric acid concentrations were not related to M-ACE or MMSE scores. An inverse relationship connected Aβ1-40 and Aβ1-42 to BMI, the duration of HTN treatment, and glycated hemoglobin. Conclusions: Aβ1-42, APOE, and Aβ42/40 are not only correlated with cognition but also related to patient's disease profile. The coexistence of DM and HTN was associated with the most significant decline in cognitive functioning. However, a higher number of years of education may protect against the development of dementia in old age. The roles of cholesterol and uric acid in cognitive decline are still inconclusive.},
}

@article {pmid41295414,
year = {2025},
author = {Favari, E and Parolini, C},
title = {Marine Bioactive Components and Chronic Neuroinflammation: Focus on Neurodegenerative Disease.},
journal = {Marine drugs},
volume = {23},
number = {11},
pages = {},
doi = {10.3390/md23110446},
pmid = {41295414},
issn = {1660-3397},
support = {NA//MUR Progetto Eccellenza/ ; },
mesh = {Humans ; *Neurodegenerative Diseases/drug therapy ; Animals ; *Neuroinflammatory Diseases/drug therapy ; *Aquatic Organisms/chemistry ; Oxidative Stress/drug effects ; Inflammation/drug therapy ; },
abstract = {Advances in neuroscience, immunology, and neuroimmunology have revealed that the nervous and immune systems form a bidirectional integrated network, ranging from regulating inflammation to directing stress responses, pivotal for the maintenance of the brain-body physiology. Like peripheral inflammation, neuroinflammation is a conserved process aimed at activating innate/adaptive immune and non-immune cells to effectively deal with bacteria, viruses, toxins, and injuries, and eventually at removing the microbial pathogens and supporting tissue repair and recovery. A failure of this process or the permanent release of pro-inflammatory mediators causes a condition called "chronic low-grade neuroinflammation" resulting in tissue damage and an increased risk of developing neurodegenerative diseases (NDD), such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS). Marine-derived bioactive components are able to modulate lipid and glucose metabolism as well as inflammation and oxidative stress. In this review, we describe the neuroinflammatory process and its involvement in the pathogenesis and progression of AD, PD, MS, and ALS. Then, we discuss the potential therapeutic efficacy of select marine-derived bioactive components.},
}

Humans
*Neurodegenerative Diseases/drug therapy
Animals
*Neuroinflammatory Diseases/drug therapy
*Aquatic Organisms/chemistry
Oxidative Stress/drug effects
Inflammation/drug therapy

@article {pmid41295407,
year = {2025},
author = {Dimitrova, D and Kehayova, G and Dimitrova, S and Dragomanova, S},
title = {Marine-Derived Natural Substances with Anticholinesterase Activity.},
journal = {Marine drugs},
volume = {23},
number = {11},
pages = {},
doi = {10.3390/md23110439},
pmid = {41295407},
issn = {1660-3397},
mesh = {*Cholinesterase Inhibitors/pharmacology/chemistry/isolation & purification ; *Biological Products/pharmacology/chemistry/isolation & purification/therapeutic use ; Humans ; *Aquatic Organisms/chemistry ; Animals ; Alzheimer Disease/drug therapy ; Butyrylcholinesterase/metabolism ; Neuroprotective Agents/pharmacology/chemistry/isolation & purification ; Acetylcholinesterase/metabolism ; },
abstract = {Alzheimer's disease continues to be one of the most urgent neurodegenerative conditions, with acetylcholinesterase (AChE) inhibitors serving as a fundamental component of contemporary treatment approaches. Growing evidence underscores that marine ecosystems are a rich source of structurally varied and biologically active natural products exhibiting anticholinesterase properties. This review presents a thorough synthesis of marine-derived metabolites-including those sourced from bacteria, fungi, sponges, algae, and other marine life-that demonstrate inhibitory effects against AChE and butyrylcholinesterase (BuChE). Numerous compounds, such as meroterpenoids, alkaloids, peptides, and phlorotannins, not only show nanomolar to micromolar inhibitory activity but also reveal additional neuroprotective characteristics, including antioxidant effects, anti-amyloid properties, and modulation of neuronal survival pathways. Despite these encouraging findings, the transition to clinical applications is hindered by a lack of comprehensive pharmacokinetic, toxicity, and long-term efficacy studies. The structural variety of marine metabolites provides valuable frameworks for the development of next-generation cholinesterase inhibitors. Further interdisciplinary research is essential to enhance their therapeutic potential and facilitate their incorporation into strategies for addressing Alzheimer's disease and related conditions.},
}

*Cholinesterase Inhibitors/pharmacology/chemistry/isolation & purification
*Biological Products/pharmacology/chemistry/isolation & purification/therapeutic use
Humans
*Aquatic Organisms/chemistry
Animals
Alzheimer Disease/drug therapy
Butyrylcholinesterase/metabolism
Neuroprotective Agents/pharmacology/chemistry/isolation & purification
Acetylcholinesterase/metabolism

@article {pmid41295276,
year = {2025},
author = {Gayger-Dias, V and Da Silva, VF and Sobottka, TM and Leite, MC and Vizuete, AFK and Gonçalves, CA},
title = {Methylglyoxal, a Knot to Be Untied in Brain Glucose Hypometabolism.},
journal = {Metabolites},
volume = {15},
number = {11},
pages = {},
doi = {10.3390/metabo15110690},
pmid = {41295276},
issn = {2218-1989},
support = {Not applicable//Coordenação de Aperfeicoamento de Pessoal de Nível Superior/ ; Not applicable//National Council for Scientific and Technological Development/ ; Not applicable//Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul/ ; 465671/2014-4//Institutos Nacionais de Ciência e Tecnologia/ ; },
abstract = {Background: Advanced glycation end products (AGEs) and receptors for AGEs (RAGE) have been extensively implicated in metabolic and neurodegenerative disorders due to their capacity to alter protein structure and function through non-enzymatic glycation. More recently, methylglyoxal (MG), a highly reactive glycolytic byproduct, has gained attention as a critical mediator of AGE formation and an independent contributor to cellular distress, particularly in the context of diabetes mellitus and Alzheimer's disease. Objectives: This review synthesizes evidence from experimental and clinical studies addressing MG generation and metabolism in brain tissue, emphasizing the glyoxalase system as the primary detoxification mechanism, the functional contribution of astrocytes, and the downstream consequences of MG accumulation. In addition, we examined the interplay between MG, RAGE signaling, unfolded protein response, and regulatory mechanisms involving the hexosamine biosynthesis pathway and O-GlcNAcylation of key proteins in glucose metabolism and insulin signaling. Results and Conclusions: Brain glucose hypometabolism is a consequence of insulin resistance and results in a metabolic rearrangement that expands the glycolytic pathway and generates more MG, which, in turn, can affect insulin signaling, further compromising the molecular basis of insulin resistance and creating a vicious cycle. Astrocytes are key cells in the generation and detoxification of MG in the brain, making them a therapeutic target.},
}

@article {pmid41295163,
year = {2025},
author = {Balenzano, G and Spagnoletta, A and Lentini, G and Brunetti, G and De Mastro, F and Rullo, M and Pisani, L and Cirlincione, F and Gargano, ML and Cavalluzzi, MM},
title = {Microwave-Assisted Extraction of Pleurotus Mushrooms Cultivated on 'Nero di Troia' Grape Pomace and Evaluation of the Antioxidant and Antiacetylcholinesterase Activities.},
journal = {Journal of fungi (Basel, Switzerland)},
volume = {11},
number = {11},
pages = {},
doi = {10.3390/jof11110783},
pmid = {41295163},
issn = {2309-608X},
support = {H91I22000210007//National Recovery and Resilience Plan NRRP - M4C1 Investment 3.4 and 4.1 - PhD in "Sustainable Land Management" (XXXVIII Cycle) of the University of Bari Aldo Moro-Department of Soil, Plant and Food Sciences (DiSSPA) - CUP H91I22000210007/ ; },
abstract = {The sustainable management of winery residues could represent a cornerstone for promoting environmental and economic sustainability from a circular economy perspective. In this context, our study aimed to evaluate Vitis vinifera L. 'Nero di Troia' cultivar grape pomace as a valuable waste product for the cultivation of Pleurotus mushroom, in comparison with traditional wheat straw-based cultivation. Mushroom extracts were prepared through the eco-friendly microwave-assisted extraction technique, using green solvents with different polarity degrees. Total protein content, total polyphenol content, and antioxidant activity (FRAP and DPPH assays) were assessed for the water and EtOH hydrophilic extracts. Grape pomace often gave higher values than wheat straw, especially for the P. eryngii var. eryngii water extract protein content, which was 3.5-fold higher (0.68 ± 0.14 mg BSA/mL and 0.192 ± 0.025 mg BSA/mL, respectively). The ethyl acetate extracts of both mushroom species gave biologically relevant results in terms of inhibiting activity against acetylcholinesterase, an enzyme involved in the pathogenesis of Alzheimer's disease (50% inhibitory activity at concentrations ≤ 1.5 mg/mL), thus paving the way for more in-depth investigation. The extract's metabolic profile was investigated through GC-MS analysis. The results show that incorporating grape pomace into mushroom production represents a concrete step toward more sustainable biotechnological processes.},
}

@article {pmid41294911,
year = {2025},
author = {Abreu, MM and Hosseine-Farid, M and Silverman, DG},
title = {Total Reversal of ALS Confirmed by EMG Normalization, Structural Reconstitution, and Neuromuscular-Molecular Restoration Achieved Through Computerized Brain-Guided Reengineering of the 1927 Nobel Prize Fever Therapy: A Case Report.},
journal = {Diseases (Basel, Switzerland)},
volume = {13},
number = {11},
pages = {},
doi = {10.3390/diseases13110371},
pmid = {41294911},
issn = {2079-9721},
abstract = {BACKGROUND: Neurological disorders are the leading cause of disability, affecting over three billion people worldwide. Amyotrophic lateral sclerosis (ALS) is among the most feared and uniformly fatal neurodegenerative diseases, with no therapy capable of restoring lost function.

METHODS: We report the first application of therapeutic fever to ALS using Computerized Brain-Guided Intelligent Thermofebrile Therapy (CBIT[2]). This fully noninvasive treatment, delivered through an FDA-approved computerized platform, digitally reengineers the 1927 Nobel Prize-recognized malarial fever therapy into a modern treatment guided by the Brain-Eyelid Thermoregulatory Tunnel. CBIT[2] induces therapeutic fever through synchronized hypothalamic feedback, activating heat shock proteins, which are known to restore proteostasis and neuronal function.

CASE PRESENTATION: A 56-year-old woman was diagnosed with progressive ALS at the Mayo Clinic, with electromyography (EMG) demonstrating fibrillation and fasciculation indicative of denervation corroborated by neurological and MRI findings; the patient was informed that she had an expected survival of three to five years. A neurologist from Northwestern University confirmed the diagnosis and thus maintained the patient on FDA-approved ALS drugs (riluzole and edaravone). Her condition rapidly worsened despite pharmacological treatment, and she underwent CBIT[2], resulting in (i) electrophysiological reversal with complete disappearance of denervation; (ii) biomarker correction, including reductions in neurofilament and homocysteine, IL-10 normalization (previously linked to mortality), and robust HSP70 induction; (iii) restoration of gait, swallowing, respiration, speech, and cognition; (iv) reconstitution of tongue structure; and (v) return to complex motor tasks, including golf, pickleball, and swimming.

DISCUSSION: This case provides the first documented evidence that ALS can be reversed through digitally reengineered fever therapy aligned with thermoregulation, which induces heat shock response and upregulates heat shock proteins, resulting in the patient no longer meeting diagnostic criteria for ALS and discontinuation of ALS-specific medications. Beyond ALS, shared protein-misfolding pathology suggests that CBIT[2] may extend to Alzheimer's, Parkinson's, and related disorders. By modernizing this Nobel Prize-recognized therapeutic principle with computerized precision, CBIT[2] establishes a framework for large-scale clinical trials. A century after fever therapy restored lost brain function and so decisively reversed dementia paralytica such that it earned the 1927 Nobel Prize in Medicine, CBIT[2] now safely harnesses the therapeutic power of fever through noninvasive, intelligent, brain-guided thermal modulation. Amid a global brain health crisis, fever-based therapies may offer a path to preserve thought, memory, movement, and independence for the more than one-third of humanity currently affected by neurological disorders.},
}

@article {pmid41294899,
year = {2025},
author = {Chapple, B and Bayliss, E and Woodfin, S and Smith, M and Winter, J and Moore, W},
title = {Type 3 Diabetes: Linking Insulin Resistance to Cognitive Decline.},
journal = {Diseases (Basel, Switzerland)},
volume = {13},
number = {11},
pages = {},
doi = {10.3390/diseases13110359},
pmid = {41294899},
issn = {2079-9721},
abstract = {Type 3 diabetes (T3D) is characterized by chronic insulin resistance and insulin deficiency in the brain, leading to neuronal death, inflammation, oxidative stress, apoptosis, and synaptic dysfunction. These pathological processes contribute to cognitive decline and neurodegenerative disorders such as Alzheimer's disease. However, despite increasing evidence that links insulin resistance to cognitive impairment, the precise mechanisms that underly T3D remain largely unknown. This highlights a critical gap in research and potential therapeutic strategies. Given the significant impact of diet on metabolic health, investigating the correlation between the gut-brain axis may offer novel insights into the prevention and management of T3D. This review aims to elucidate the potential connections between insulin resistance and cognitive decline while also proposing interventions to slow aging and reduce the risk of early cognitive decline. At the same time, we acknowledge that the classification of type 3 diabetes is debatable and there is uncertainty as to whether insulin resistance is a primary driver or secondary manifestation of neurodegeneration.},
}

@article {pmid41294873,
year = {2025},
author = {Wang, S and Feng, Z and Wu, H and Wang, S and Qin, S and Wang, X and Zhou, F and Zheng, K and Huang, X and Liu, X},
title = {The m[6]A Modification in Neurodegenerative Disease: A Cellular Perspective.},
journal = {Cells},
volume = {14},
number = {22},
pages = {},
doi = {10.3390/cells14221820},
pmid = {41294873},
issn = {2073-4409},
support = {BK20231347//Natural Science Foundation of Jiangsu Province/ ; 81971179//National Natural Science Foundation of China/ ; Z2019035//Jiangsu Commission of Health/ ; 20KJA320004//Jiangsu Provincial Department of Education/ ; KC23242//Technology Innovation Foundation of Xuzhou City/ ; JBGS202202//Open Competition Grant of Xuzhou Medical University/ ; },
mesh = {Humans ; *Neurodegenerative Diseases/genetics/metabolism/pathology ; *Adenosine/analogs & derivatives/metabolism/genetics ; Animals ; Neurons/metabolism ; },
abstract = {N6-methyladenosine (m[6]A) is the most abundant internal RNA modification in eukaryotes and plays a critical role in gene expression regulation by influencing RNA stability, splicing, nuclear export, and translation. Emerging evidence suggests that dysregulation of m[6]A contributes to neuroinflammation, neurotoxicity, and synaptic dysfunction-key features of neurodegenerative diseases. This review aims to examine the role of m6A modification in neurodegenerative diseases from a cell-type-specific perspective. We systematically reviewed recent studies investigating m[6]A modifications in neurons and glial cells. Data from transcriptomic, epitranscriptomic, and functional studies were analyzed to understand how m[6]A dynamics influence disease-related processes. Findings indicate that m[6]A modifications regulate neuroinflammation and immune responses in microglia, modulate astrocytic support functions, affect myelination through oligodendrocytes, and alter m[6]A patterns in neurons, impacting synaptic plasticity, stress responses, and neuronal survival. These cell-type-specific roles of m[6]A contribute to the progression of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and Amyotrophic lateral sclerosis (ALS). Understanding m[6]A-modulated mechanisms in specific neural cell types may facilitate the development of targeted interventions for neurodegenerative diseases.},
}

Humans
*Neurodegenerative Diseases/genetics/metabolism/pathology
*Adenosine/analogs & derivatives/metabolism/genetics
Animals
Neurons/metabolism

@article {pmid41294871,
year = {2025},
author = {Chen, W and Beheshtian, C and Kim, S and Kim, R and Kim, S and Park, NH},
title = {GV1001, an hTERT-Derived Peptide, Prevents Cisplatin-Induced Nephrotoxicity by Preserving Mitochondrial Function.},
journal = {Cells},
volume = {14},
number = {22},
pages = {},
doi = {10.3390/cells14221818},
pmid = {41294871},
issn = {2073-4409},
support = {441902-19900//UCLA/ ; 441930-54065//Various Donors Fund/ ; 1R21DE031074-01/NH/NIH HHS/United States ; },
mesh = {*Cisplatin/adverse effects ; *Mitochondria/drug effects/metabolism ; Animals ; Humans ; Mice ; *Kidney/drug effects/pathology/metabolism ; Apoptosis/drug effects ; Reactive Oxygen Species/metabolism ; Membrane Potential, Mitochondrial/drug effects ; Male ; Mice, Inbred C57BL ; Epithelial Cells/drug effects/metabolism ; *Peptide Fragments/pharmacology ; *Kidney Diseases/chemically induced/prevention & control/pathology ; Cell Line ; },
abstract = {GV1001, a multifunctional peptide, has shown numerous biomedical activities, including antioxidant, anti-inflammatory, anti-Alzheimer's, and anti-atherosclerotic effects, and protects mitochondria from cytotoxic agents. Cisplatin is a widely used chemotherapeutic agent against cancers, but its clinical utility is limited by nephrotoxicity driven by mitochondrial dysfunction in renal epithelial cells. Here, we investigated whether GV1001 protected against cisplatin-induced nephrotoxicity (CIN) in vivo and preserved mitochondrial integrity in human renal epithelial cells in vitro. In mice, GV1001 substantially mitigated CIN by significantly reducing histological damage, kidney injury marker expression, macrophage infiltration, endothelial-to-mesenchymal transition, inflammation, and apoptosis. In cultured renal epithelial cells, GV1001 maintained mitochondrial membrane potential, preserved ATP production, and prevented mitochondrial membrane peroxidation possibly by binding to cardiolipin. GV1001 also reduced the level of reactive oxygen species (ROS), suppressed cytochrome c release into the cytosol, and inhibited activation of apoptosis-related pathways elicited by cisplatin. Collectively, these findings demonstrated that GV1001 might protect kidney from cisplatin through maintaining mitochondrial structure and function and suppressing downstream injury cascades in renal epithelial cells. By directly targeting the mitochondrial mechanisms underlying cisplatin toxicity, GV1001 represents as a promising therapeutic strategy to mitigate CIN and improve the safety of cisplatin-based chemotherapy.},
}

*Cisplatin/adverse effects
*Mitochondria/drug effects/metabolism
Animals
Humans
Mice
*Kidney/drug effects/pathology/metabolism
Apoptosis/drug effects
Reactive Oxygen Species/metabolism
Membrane Potential, Mitochondrial/drug effects
Male
Mice, Inbred C57BL
Epithelial Cells/drug effects/metabolism
*Peptide Fragments/pharmacology
*Kidney Diseases/chemically induced/prevention & control/pathology
Cell Line

@article {pmid41294869,
year = {2025},
author = {Storlino, G and Posa, F and Dell'Endice, TS and Piccolo, F and Colaianni, G and Cassano, T and Grano, M and Mori, G},
title = {Cortical Bone Loss and Fragility in a 2-Month Triple Transgenic Mouse Model of Alzheimer's Disease.},
journal = {Cells},
volume = {14},
number = {22},
pages = {},
doi = {10.3390/cells14221816},
pmid = {41294869},
issn = {2073-4409},
support = {PNRR - M4C2-I1.3 Project PE_00000019//Ministero dell'università e della ricerca/ ; },
mesh = {Animals ; *Alzheimer Disease/pathology/complications/genetics ; Mice, Transgenic ; Disease Models, Animal ; Mice ; Male ; *Cortical Bone/pathology/diagnostic imaging/physiopathology ; X-Ray Microtomography ; Presenilin-1/genetics/metabolism ; Humans ; Amyloid beta-Protein Precursor/genetics/metabolism ; Osteoporosis/pathology ; },
abstract = {Alzheimer's disease (AD) and osteoporosis frequently co-occur in the elderly; however, the pathophysiological link between these two diseases remains unclear. This study investigates skeletal alterations in a triple transgenic 3xTg-AD mouse model of AD (3xTg-AD), which harbors mutations in β-amyloid precursor protein (βAPPSwe), presenilin-1 (PS1M146V), and tauP301L, and recapitulates key aspects of AD pathology, including age-dependent β-amyloid plaque accumulation and cognitive decline. To assess early skeletal changes, we analyzed femurs and tibiae of 2-month-old male non-Tg and 3xTg-AD mice (n = 9/group) using micro-CT. Despite the absence of β-amyloid plaques at this stage, 3xTg-AD mice showed significant cortical bone loss, with reduced bone surface, periosteal and endosteal perimeters, total and cortical cross-sectional area, and polar moment of inertia. The 3-point-bending test confirmed compromised mechanical properties, including reduced maximum load-to-fracture and stiffness. Histological analyses highlighted an increased number of Empty Osteocyte Lacunae, reduced TRAP[+] osteocytes, and an elevated number of osteoclasts; such evidence indicates impaired osteocyte function and increased bone resorption. These findings indicate that cortical bone loss and compromised mechanical properties occur before detectable neuropathological hallmarks in this AD model.},
}

Animals
*Alzheimer Disease/pathology/complications/genetics
Mice, Transgenic
Disease Models, Animal
Mice
Male
*Cortical Bone/pathology/diagnostic imaging/physiopathology
X-Ray Microtomography
Presenilin-1/genetics/metabolism
Humans
Amyloid beta-Protein Precursor/genetics/metabolism
Osteoporosis/pathology

@article {pmid41294858,
year = {2025},
author = {Thiyagarajan, S and Leclerc, E and Vetter, SW},
title = {The Receptor for Advanced Glycation End-Products (RAGE) Regulates Cell Adhesion Through Upregulation of ITGA8.},
journal = {Cells},
volume = {14},
number = {22},
pages = {},
doi = {10.3390/cells14221805},
pmid = {41294858},
issn = {2073-4409},
support = {1U54GM128729-20/NH/NIH HHS/United States ; },
mesh = {Humans ; *Cell Adhesion ; *Receptor for Advanced Glycation End Products/metabolism/chemistry/genetics ; *Up-Regulation ; },
abstract = {The Receptor for Advanced Glycation End-Products (RAGE) is a cell surface receptor of the immunoglobulin-like receptor superfamily. RAGE is a pattern-recognition, multi-ligand receptor that binds glycated proteins, specific non-glycated proteins, and nucleic acids. RAGE ligands are typically part of the group of damage-associated molecular patterns (DAMPs) or alarmins. As such, RAGE is a receptor for molecular products of cellular stress, abnormal metabolism, and inflammation. Activation of RAGE by its ligands leads to pro-inflammatory signaling, often resulting in persistent RAGE activation in various disease states. Consequently, RAGE has been investigated as a potential drug target in the treatment of diabetic complications, vascular disease, Alzheimer's disease, and multiple types of cancer. An underexplored aspect of RAGE is its role in cell adhesion. Structural comparison of the extracellular domain of RAGE has revealed structural similarity to the activated leukocyte cell adhesion molecule (ALCAM). The present study reveals the role and mechanism of RAGE in regulating cell adhesion. We investigated the role of individual RAGE domains in cell adhesion to extracellular matrix proteins and the changes in protein expression resulting from RAGE upregulation. Key findings include that RAGE displays substrate-specific adhesion to extracellular matrix proteins, that the intracellular domain of RAGE is required for modulating cell spreading, and that regulation of ITGA8 depends on the cytoplasmic domain of RAGE.},
}

Humans
*Cell Adhesion
*Receptor for Advanced Glycation End Products/metabolism/chemistry/genetics
*Up-Regulation

@article {pmid41294851,
year = {2025},
author = {Shen, W},
title = {Retinal Neurovascular Coupling: From Mechanisms to a Diagnostic Window into Brain Disorders.},
journal = {Cells},
volume = {14},
number = {22},
pages = {},
doi = {10.3390/cells14221798},
pmid = {41294851},
issn = {2073-4409},
support = {IOS2126141//NSF/ ; },
mesh = {Humans ; *Neurovascular Coupling/physiology ; *Retina/physiopathology/diagnostic imaging/pathology ; Animals ; *Brain Diseases/diagnosis/physiopathology ; Tomography, Optical Coherence ; },
abstract = {Retinal neurovascular coupling reflects the precise coordination between neuronal activity, glial support, and vascular responses, mirroring key neurovascular mechanisms in the brain. This review emphasizes the cellular and molecular processes underlying retinal neurovascular coupling and positions the retina as a sensitive and accessible model for investigating neurovascular function in the brain. It highlights how parallel neurovascular degeneration in the brain and retina provides critical insights into the pathophysiology of neurodegenerative and vascular disorders. Advances in retinal imaging, including functional optical coherence tomography (fOCT), OCT angiography (OCTA), and functional electrophysiology, offer unprecedented opportunities to detect early neuronal and vascular dysfunction, establishing the retina as a non-invasive biomarker for early detection, disease monitoring, and therapeutic evaluation in Alzheimer's, Parkinson's and Huntington's disease, and stroke. By integrating structural, functional, and mechanistic approaches, the review emphasizes the retina's potential as a translational platform bridging basic science and clinical applications in neurovascular research.},
}

Humans
*Neurovascular Coupling/physiology
*Retina/physiopathology/diagnostic imaging/pathology
Animals
*Brain Diseases/diagnosis/physiopathology
Tomography, Optical Coherence

@article {pmid41294837,
year = {2025},
author = {Subasinghe, K and Hall, C and Rowe, M and Zhou, Z and Barber, R and Phillips, N},
title = {Neuronal Enriched Extracellular Vesicle miR-122-5p as a Potential Biomarker for Alzheimer's Disease.},
journal = {Cells},
volume = {14},
number = {22},
pages = {},
doi = {10.3390/cells14221784},
pmid = {41294837},
issn = {2073-4409},
support = {2T32AG020494-25/NH/NIH HHS/United States ; N/A//Texas Alzheimer's Research and Care Consortium under the direction of the Texas Council on AD and Related Disorder/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics/blood ; *MicroRNAs/genetics/metabolism/blood ; *Extracellular Vesicles/metabolism/genetics ; Biomarkers/blood/metabolism ; Male ; Female ; Aged ; *Neurons/metabolism ; Cognitive Dysfunction/genetics/blood ; Aged, 80 and over ; Case-Control Studies ; },
abstract = {Alzheimer's disease (AD) is the leading cause of dementia and is often prefaced by mild cognitive impairment (MCI). Detection of AD-related changes via blood-based biomarkers would enable critical therapeutic interventions early in disease progression. Neuronal enriched extracellular vesicle (NEEV) miRNAs regulate peripheral genes as a response to early AD brain changes and hence may have biomarker potential. Plasma NEEVs were captured from plasma samples of Mexican Americans (MAs) and Non-Hispanic Whites (NHWs) using an antibody against the neuronal surface marker CD171. miRNAs isolated from NEEVs were sequenced and analyzed using miRDeep2/DEseq2 and QIAGEN RNA-seq portal for differential expression between cognitively impaired (CI) and cognitively unimpaired controls. hsa-miR-122-5p was significantly underrepresented in the CI group in both MAs and NHWs compared to the healthy control. Other population-specific miRNAs (MAs: hsa-miR-26a-5p, hsa-let-7f-5p, and hsa-miR-139-5p, NHWs: hsa-miR-133a-3p, hsa-miR-125b-5p, and hsa-miR-100-5p) identified may have biomarker potential in AD precision medicine. Some of these differentially expressed miRNAs were associated with key AD-related comorbidities such as APOE genotype, age, and metabolic burden and were predicted to target genes within NF-κB -regulated inflammatory pathways. Together, these findings suggest that dysregulated miRNA networks may serve as a mechanistic link between comorbidity burden and AD-related neuroinflammation and neurodegeneration.},
}

Humans
*Alzheimer Disease/genetics/blood
*MicroRNAs/genetics/metabolism/blood
*Extracellular Vesicles/metabolism/genetics
Biomarkers/blood/metabolism
Male
Female
Aged
*Neurons/metabolism
Cognitive Dysfunction/genetics/blood
Aged, 80 and over
Case-Control Studies

@article {pmid41294836,
year = {2025},
author = {Stephens, IO and Johnson, LA},
title = {Knockout of Perilipin-2 in Microglia Alters Lipid Droplet Accumulation and Response to Alzheimer's Disease Stimuli.},
journal = {Cells},
volume = {14},
number = {22},
pages = {},
doi = {10.3390/cells14221783},
pmid = {41294836},
issn = {2073-4409},
support = {R01AG081421/AG/NIA NIH HHS/United States ; R01AG080589/AG/NIA NIH HHS/United States ; P20 GM148326/GM/NIGMS NIH HHS/United States ; ABA-22-972169/ALZ/Alzheimer's Association/United States ; },
mesh = {*Perilipin-2/metabolism/genetics/deficiency ; *Microglia/metabolism ; Animals ; *Lipid Droplets/metabolism ; *Alzheimer Disease/metabolism/pathology/genetics ; Mice ; Phagocytosis ; Amyloid beta-Peptides/metabolism ; Mice, Knockout ; Energy Metabolism ; Mitochondria/metabolism ; Gene Knockout Techniques ; Cell Line ; Glycolysis ; Lipid Metabolism ; },
abstract = {Lipid droplets (LDs) are emerging as key regulators of metabolism and inflammation, with their buildup in microglia linked to aging and neurodegeneration. Perilipin-2 (Plin2) is a ubiquitously expressed LD-associated protein that stabilizes lipid stores; in peripheral tissues, its upregulation promotes lipid retention, inflammation, and metabolic dysfunction. Yet, its role in microglia remains unclear. Using CRISPR-engineered Plin2 knockout (KO) BV2 microglia, we examined how Plin2 contributes to lipid accumulation, bioenergetics, and immune function. Compared to wild-type (WT) cells, Plin2 KO microglia showed markedly reduced LD burden under basal and oleic acid-loaded conditions. Functionally, this was linked to enhanced phagocytosis of zymosan particles, even after lipid loading, indicating improved clearance capacity. Transcriptomics revealed genotype-specific responses to amyloid-β (Aβ), especially in mitochondrial metabolism pathways. Seahorse assays confirmed a distinct bioenergetic profile in KO cells, with reduced basal respiration and glycolysis but preserved mitochondrial capacity, increased spare reserve, and a blunted glycolytic response to Aβ. Together, these findings establish Plin2 as a regulator of microglial lipid storage and metabolic state, with its loss reducing lipid buildup, enhancing phagocytosis, and altering Aβ-induced metabolic reprogramming. Targeting Plin2 may represent a strategy to reprogram microglial metabolism and function in aging and neurodegeneration.},
}

*Perilipin-2/metabolism/genetics/deficiency
*Microglia/metabolism
Animals
*Lipid Droplets/metabolism
*Alzheimer Disease/metabolism/pathology/genetics
Mice
Phagocytosis
Amyloid beta-Peptides/metabolism
Mice, Knockout
Energy Metabolism
Mitochondria/metabolism
Gene Knockout Techniques
Cell Line
Glycolysis
Lipid Metabolism

@article {pmid41294807,
year = {2025},
author = {Shim, G and Hall, R and Zhang, Z and Shokry, IM and To, A and Cruz, L and Adam, MC and Prentice, H and Wu, JY and Su, H and Tao, R and For The Alzheimer's Disease Neuroimaging Initiative, },
title = {Three-Dimensional PET Imaging Reveals Canal-like Networks for Amyloid Beta Clearance to the Peripheral Lymphatic System.},
journal = {Cells},
volume = {14},
number = {22},
pages = {},
doi = {10.3390/cells14221754},
pmid = {41294807},
issn = {2073-4409},
support = {Seed grant//Ross University School of Veterinary Medicine/ ; },
mesh = {Humans ; *Amyloid beta-Peptides/metabolism ; *Positron-Emission Tomography/methods ; *Imaging, Three-Dimensional/methods ; Male ; Female ; Aged ; Alzheimer Disease/diagnostic imaging/metabolism ; *Lymphatic System/diagnostic imaging/metabolism ; Brain/diagnostic imaging/metabolism ; Aged, 80 and over ; Middle Aged ; Aniline Compounds ; Ethylene Glycols ; },
abstract = {[18]F-Florbetapir PET imaging is widely used to assess amyloid-β (Aβ) burden in the brain, particularly in the context of Alzheimer's disease (AD). Conventional assessments typically rely on selected individual slices, which may limit spatial accuracy and are prone to image blurring. In the present study, we introduce novel techniques to enhance the spatial resolution and clarity of Aβ signal visualization in individuals pretreated with [18]F-florbetapir. PET scans were retrospectively obtained from the Imaging and Data Archive for twelve individuals, including six cognitively unimpaired subjects and six diagnosed with AD. Each dataset consisted of 346 raw images, comprising 90 axial, 128 coronal, and 128 sagittal slices. Images were reconstructed into a single 3D volume using the 3D Slicer platform. Crucially, we applied artificial intelligence or AI-driven signal enhancement techniques to suppress background noise and amplify Aβ signals. This AI-enhanced processing improved image clarity and enabled visualization of subtle and spatially organized signal patterns. To verify anatomical location, Aβ PET signals were registered with MRI. This integrated workflow allowed us to visualize Aβ signals across regions of interest, including the brain parenchyma, skull, and cervical tissues. Our analytical approaches revealed that Aβ signals are highly concentrated and confined within non-CNS fluid compartments, forming canal-like networks that extend from the brain parenchyma toward the skull base, particularly the occipital clivus, and connect to the cervical lymph nodes. Additional Aβ signals were observed along the internal carotid plexus. These findings suggest that, when reconstruction in 3D and enhanced with AI, [18]F-florbetapir PET imaging may not only reflect Aβ plaque burden in the brain but also visualize soluble Aβ species concentrated within anatomical clearance pathways leading to the peripheral lymphatic system. This approach offers a new dimension to PET signal interpretation and highlights the potential of AI-enhanced 3D in advancing neuroimaging analysis.},
}

Humans
*Amyloid beta-Peptides/metabolism
*Positron-Emission Tomography/methods
*Imaging, Three-Dimensional/methods
Male
Female
Aged
Alzheimer Disease/diagnostic imaging/metabolism
*Lymphatic System/diagnostic imaging/metabolism
Brain/diagnostic imaging/metabolism
Aged, 80 and over
Middle Aged
Aniline Compounds
Ethylene Glycols

@article {pmid41294748,
year = {2025},
author = {Ki, MR and Kim, DH and Abdelhamid, MAA and Pack, SP},
title = {Cancer and Aging Biomarkers: Classification, Early Detection Technologies and Emerging Research Trends.},
journal = {Biosensors},
volume = {15},
number = {11},
pages = {},
doi = {10.3390/bios15110737},
pmid = {41294748},
issn = {2079-6374},
support = {RS2021NR060107//the National Research Foundation of Korea/ ; the National Research Foundation of Korea//the National Research Foundation of Korea/ ; },
mesh = {Humans ; *Neoplasms/diagnosis ; *Biomarkers, Tumor ; *Aging ; *Early Detection of Cancer ; Biomarkers ; Biosensing Techniques ; Artificial Intelligence ; },
abstract = {Cancer and aging are two distinct biological processes with shared cellular pathways, such as cellular senescence, DNA damage repair, and metabolic reprogramming. However, the outcomes of these processes differ in terms of proliferation. Understanding biomarkers related to aging and cancer opens a pathway for therapeutic interventions and more effective prevention, detection, and treatment strategies. Biomarkers, ranging from molecular to phenotypic indicators, play an important role in early detection, risk assessment, and prognosis in this endeavor. This review comprehensively examines key biomarkers associated with cancer and aging, highlighting their importance in early diagnostic strategies. The review discusses recent advances in biomarker-based diagnostic technologies, such as liquid biopsy, multi-omics integration, and artificial intelligence, and emphasizes their novel potential for early detection, accurate risk assessment, and personalized therapeutic interventions in cancer and aging science. We also explore the current state of biosensor development and clinical application cases. Finally, we discuss the limitations of current early diagnostic methods and propose future research directions to enhance biomarker-based diagnostic technologies.},
}

Humans
*Neoplasms/diagnosis
*Biomarkers, Tumor
*Aging
*Early Detection of Cancer
Biomarkers
Biosensing Techniques
Artificial Intelligence

@article {pmid41294740,
year = {2025},
author = {Nchouwat Ndumgouo, IM and Chowdhury, MZU and Andreescu, S and Schuckers, S},
title = {Integrating AI with Biosensors and Voltammetry for Neurotransmitter Detection and Quantification: A Systematic Review.},
journal = {Biosensors},
volume = {15},
number = {11},
pages = {},
doi = {10.3390/bios15110729},
pmid = {41294740},
issn = {2079-6374},
mesh = {*Biosensing Techniques ; *Neurotransmitter Agents/analysis ; Humans ; *Artificial Intelligence ; Machine Learning ; Electrochemical Techniques ; },
abstract = {BACKGROUND: The accurate and timely diagnosis of neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, and major depressive disorder critically depends on real-time monitoring and precise interpretation of authentic neurotransmitter (NT) signal dynamics in complex biological fluids (CBFs), including cerebrospinal fluid. These NT dynamics are governed by both the type and concentration of NTs present in the CBFs. However, current biosensors face significant limitations in sensitivity and selectivity, thereby hindering reliable estimation (detection and quantification) of NTs. Though nanomaterials and bioenzymes have been utilized to modify sensor interfaces for enhanced performance, issues like signal convolution, electrode fouling, and inter-NT crosstalk persist.

OBJECTIVES: This review aims to evaluate and synthesize current research on the use of artificial intelligence (AI), particularly machine learning (ML), pattern recognition (PR), and deep learning (DL), to improve the automated detection and quantification of neurotransmitters from complex biological fluids.

DESIGN: A systematic review of 33 peer-reviewed studies was conducted, focusing on the integration of AI methods in neurotransmitter estimation. The review includes an analysis of commonly studied NTs, the methodologies for their detection, data acquisition techniques, and the AI algorithms applied for signal processing and interpretation.

RESULTS: The studies reviewed demonstrate that AI-based approaches have shown considerable potential in overcoming traditional biosensor limitations by effectively deconvoluting complex, multiplexed NT signals. These techniques allow for more accurate NT estimation in real-time monitoring scenarios. The review categorizes AI methodologies by their application and performance in NT signal analysis.

CONCLUSIONS: AI-enhanced NT monitoring represents a promising direction for advancing diagnostic and therapeutic capabilities in neurodegenerative diseases. Despite current challenges, such as sensor stability and NT interaction complexity, AI integration, particularly in applications like closed-loop deep brain stimulation (CLDBS), offers significant potential for more effective and personalized treatments.},
}

*Biosensing Techniques
*Neurotransmitter Agents/analysis
Humans
*Artificial Intelligence
Machine Learning
Electrochemical Techniques

@article {pmid41294531,
year = {2025},
author = {Ding, F and Hou, R and Han, B and Fang, X},
title = {Cell Membrane- and Vesicle-Based Bionic Nanodrugs: Applications in Central Nervous System Diseases and Exploration of Nasal-Cerebral Delivery.},
journal = {Gels (Basel, Switzerland)},
volume = {11},
number = {11},
pages = {},
doi = {10.3390/gels11110846},
pmid = {41294531},
issn = {2310-2861},
abstract = {Central nervous system (CNS) diseases exhibit high incidence rates, and the blood-brain barrier (BBB) poses a major obstacle to drug delivery. Conventional drug delivery methods not only show limited therapeutic efficacy but also cause significant side effects. Intranasal administration offers a new strategy for CNS therapy by bypassing the BBB through the unique nasal-brain pathway, while nanodrug delivery systems (NDDSs) can improve drug delivery efficiency. On this basis, biomimetic drug delivery systems (BDDSs) based on cell membrane structure have been developed. The combination of nanoparticles modified by cell membranes or cell membrane-derived vesicles with carriers such as hydrogels creates a drug delivery system that utilizes a unique transnasal-to-brain pathway, opening new avenues for treating CNS disorders. This paper systematically reviews the classification, characteristics, and preparation strategies of BDDSs, while analyzing the anatomical pathways and physiological mechanisms of nasal-cerebral delivery. Furthermore, it delves into the biogenesis mechanisms of extracellular vesicles (EVs) and bacterial extracellular vesicles (BEVs). For CNS disorders, including glioblastoma multiforme (GBM), ischemic stroke (IS), Alzheimer's disease (AD), and Parkinson's disease (PD), this paper presents diverse applications and challenges of BDDSs in nasal-cerebral delivery.},
}

@article {pmid41294271,
year = {2025},
author = {Gupta, R and Lin, S and DiStefano, MJ and Woo, HYJ and Mao, E and Wilson, R and Amjad, H and Drabo, EF and Segal, JB},
title = {Patient Preferences for Dementia Interventions: A Scoping Review With a Systematic Review of Medications and Choice-Based Methods.},
journal = {Journal of the American Geriatrics Society},
volume = {},
number = {},
pages = {},
doi = {10.1111/jgs.70209},
pmid = {41294271},
issn = {1532-5415},
support = {1R61AG088961-01/AG/NIA NIH HHS/United States ; K23AG064036/AG/NIA NIH HHS/United States ; },
abstract = {BACKGROUND: Despite emerging treatment options for Alzheimer's disease and related dementias (ADRD), patient preferences for treatment and care remain poorly understood.

METHODS: We searched PubMed, PsycINFO, CINAHL, and EMBASE through November 12, 2024 for studies reporting stated preferences for dementia treatment- and care-related interventions. We synthesized key findings from studies using choice-based preference elicitation methods and those addressing medication preferences.

RESULTS: We screened 8300 abstracts and 82 studies published between 1996 and 2024 were included. Most evaluated preferences for non-pharmacological interventions. Studies were experimental (37; 45.1%), observational (36; 43.9%), and qualitative (21; 25.6%). Six studies used choice-based preference elicitation methods and five assessed preferences for medications. Patients valued memory improvement and emotional or social support, despite highly heterogeneous data.

CONCLUSIONS: This review highlights significant gaps in the literature on treatment preferences-particularly for medications-among older adults with cognitive impairment, underscoring the need for further research, development of validated clinical tools, and appropriate methods to elicit preferences to better align interventions with patient values.},
}

@article {pmid41293984,
year = {2025},
author = {Huang, C and Wu, Q and Wang, J and Cai, J and Wang, Z and You, L and Zhu, Z and Ding, Y},
title = {Regulation of sterol metabolism by gut microbiota and its relevance to disease.},
journal = {Gut microbes},
volume = {17},
number = {1},
pages = {2589493},
doi = {10.1080/19490976.2025.2589493},
pmid = {41293984},
issn = {1949-0984},
mesh = {*Gastrointestinal Microbiome/physiology ; Humans ; *Sterols/metabolism ; Animals ; Phytosterols/metabolism ; Alzheimer Disease/metabolism/microbiology ; Neoplasms/metabolism/microbiology ; Homeostasis ; Bacteria/metabolism/classification/genetics ; },
abstract = {Sterols play an indispensable role in maintaining cell membrane stability, regulating hormone synthesis, and preserving physiological homeostasis. Recently, the function of the gut microbiota in modulating host sterol metabolism has become the focus of extensive research. Nonetheless, the specific functions carried out by the gut microbiota in sterol metabolism and their health implications remain unclear due to a lack of comprehensive synthesis and analysis. This review aims to consolidate current perspectives regarding the sources and metabolic mechanisms of sterols, with an emphasis on the involvement of gut microbiota in the biotransformation of zoosterols, phytosterols, and mycosterols. Additionally, it explores the pathological implications of sterol metabolism disorders in diseases such as Alzheimer's disease and cancer. Finally, the review highlights the potential of dietary interventions to reshape gut microbiota composition and restore sterol metabolic homeostasis, presenting novel strategies for disease prevention and therapy through targeted modulation of sterol metabolism.},
}

*Gastrointestinal Microbiome/physiology
Humans
*Sterols/metabolism
Animals
Phytosterols/metabolism
Alzheimer Disease/metabolism/microbiology
Neoplasms/metabolism/microbiology
Homeostasis
Bacteria/metabolism/classification/genetics

@article {pmid41293951,
year = {2025},
author = {Katbe, A and Hanna, R and Flamier, A and Serhani, D and Hamam, R and Barabino, A and Tavares, E and Héon, É and Bernier, G},
title = {Epigenomic alterations and neural development anomalies in induced pluripotent stem cells from sporadic Alzheimer's disease.},
journal = {Development (Cambridge, England)},
volume = {},
number = {},
pages = {},
doi = {10.1242/dev.204910},
pmid = {41293951},
issn = {1477-9129},
support = {RGPIN-2023-04490//NSERC/ ; },
abstract = {Reprogramming of adult somatic cells into induced pluripotent stem cells (iPSCs) resets the aging clock. However, primed iPSCs can retain cell-of-origin epigenomic marks, especially those linked to heterochromatin. Here we show that iPSCs produced from fibroblasts of late-onset sporadic Alzheimer's disease (AD) cases retain epigenomic alterations that correlate with developmental anomalies and neurodegeneration. When compared to controls, AD iPSCs show reduced BMI1 expression and H3K9me3 levels and an altered DNA methylome. Gene Ontology analysis of differentially methylated DNA regions (DMRs) reveals terms linked to cell-cell adhesion and synapse, with MEF2C binding sites being the most enriched at DMRs. Upon noggin exposure, AD iPSCs show lesser efficient neural induction and forebrain specification, together with elevated WNT signaling. Mature AD neurons present a mixed cell lineage identity phenotype and reduced MEF2C expression. AD glial cells express neuronal, cell proliferation, and stem cell-related genes. Despite these anomalies, AD iPSCs generate cortical neurons in normal proportion and readily form cerebral organoids showing AD-related pathologies. These findings implicate reprogramming resistant epigenomic alterations or genetic variants working in trans on the epigenome in AD pathophysiology.},
}

@article {pmid41293752,
year = {2025},
author = {Kanetkar, S and Morrill, VN and Egle, MT and Walker, KA and Wong, DF and Gottesman, RF},
title = {The association of late-life depressive symptoms with brain amyloid-β deposition: the ARIC-PET study.},
journal = {Aging brain},
volume = {8},
number = {},
pages = {100152},
pmid = {41293752},
issn = {2589-9589},
abstract = {Late-life depression is associated with an increased risk of developing dementia related to Alzheimer's disease, yet the mechanism underlying this relationship remains poorly understood. This study investigated the association of late-life depressive symptoms (LLDS) with brain amyloid deposition by PET. 334 dementia-free individuals from the Atherosclerosis Risk in Communities Study had Florbetapir-PET scans in late-life (ages 67-89). Elevated global and regional brain amyloid deposition was defined as a Florbetapir standardized uptake value ratio (SUVR) > 1.2. LLDS was assessed using the 11-item Center for Epidemiological Studies Depression Scale (CES-D) and defined as late-life CES-D ≥ 9. Several secondary depression measures (e.g., antidepressant use) were also explored. Stratified analyses across race, sex, and cognitive status groups were conducted. Participants (median age 76 years; 57.2 % female; 42.5 % Black; 26.9 % mild cognitive impairment) showed no association of LLDS with global amyloid deposition. Although antidepressant use was not associated with global amyloid overall, antidepressant use was associated with elevated global amyloid in individuals with normal cognition but not mild cognitive impairment. There was no effect modification by race and sex. Overall, our findings suggest that LLDS are generally not associated with global amyloid deposition, but further investigation of this relationship in larger sample sizes is warranted.},
}

@article {pmid41293671,
year = {2025},
author = {Jin, L and Xie, Q and Fang, R and Xiao, M and Kueckelhaus, M},
title = {Cervical Lymphatic Bypass for Alzheimer Disease: Toward Standardized Monitoring in a New Frontier of Supermicrosurgery.},
journal = {Plastic and reconstructive surgery. Global open},
volume = {13},
number = {11},
pages = {e7320},
pmid = {41293671},
issn = {2169-7574},
}

@article {pmid41293543,
year = {2025},
author = {Spoto, F and Zanobetti, A and Delaney, SW and Gill, TM and Bell, ML and Dominici, F and Braun, D and Mork, D},
title = {Combined and synergistic effects of heat and fine particulate matter on hospitalization among patients with Alzheimer's disease and related dementias.},
journal = {Environmental epidemiology (Philadelphia, Pa.)},
volume = {9},
number = {6},
pages = {e440},
pmid = {41293543},
issn = {2474-7882},
abstract = {BACKGROUND: Patients with Alzheimer's disease and related dementias (ADRD) are vulnerable to environmental stressors such as extreme heat and air pollution, yet their combined health effects remain poorly understood.

METHODS: We assessed the joint impact of extreme heat and fine particulate matter exposure (PM2.5) on the risk of all-cause hospitalization among an ADRD cohort of Medicare beneficiaries aged ≥65 years. Using a time-stratified case-crossover design, we analyzed data from beneficiaries with prior ADRD-related hospitalizations across the contiguous US in 2000-2016. Daily heat index and PM2.5 concentrations were linked to residential ZIP codes, and conditional logistic regression models were applied to estimate same-day associations during the warm season (May-September), including interaction terms to explore potential synergistic effects.

RESULTS: We found a linear association between heat and hospitalization, with an odds ratio (OR) of 1.017 (95% confidence interval [CI] = 1.004, 1.031) on extreme heat days (99th percentile) versus median. The PM2.5-hospitalization relationship was nonlinear, with stronger effects at lower concentrations (10 vs. 5 µg/m[3] OR = 1.010; 95% CI = 1.005, 1.015). When accounting for changes in PM2.5, the OR on extreme heat days versus the median was 1.016 (95% CI = 1.001, 1.032).

CONCLUSION: These findings underscore the need to consider both environmental stressors when assessing health risks in ADRD populations.},
}

@article {pmid41293533,
year = {2025},
author = {Li, C and Mao, Y and Liu, X and Hao, W},
title = {Data-driven spatiotemporal modeling reveals personalized trajectories of cortical atrophy in Alzheimer's disease.},
journal = {ArXiv},
volume = {},
number = {},
pages = {},
pmid = {41293533},
issn = {2331-8422},
abstract = {Alzheimer's disease (AD) is characterized by the progressive spread of pathology across brain networks, yet forecasting this cascade at the individual level remains challenging. We present a personalized graph-based dynamical model that captures the spatiotemporal evolution of cortical atrophy from longitudinal MRI and PET data. The approach constructs individualized brain graphs and learns the dynamics driving regional neurodegeneration. Applied to 1,891 participants from the Alzheimer's Disease Neuroimaging Initiative, the model accurately predicts key AD biomarkers -- including amyloid-beta, tau, neurodegeneration, and cognition -- outperforming clinical and neuroimaging benchmarks. Patient-specific parameters reveal distinct progression subtypes and anticipate future cognitive decline more effectively than standard biomarkers. Sensitivity analysis highlights regional drivers of disease spread, reproducing known temporolimbic and frontal vulnerability patterns. This network-based digital twin framework offers a quantitative, personalized paradigm for AD trajectory prediction, with implications for patient stratification, clinical trial design, and targeted therapeutic development.},
}

@article {pmid41293531,
year = {2025},
author = {Jacobson, A and Dan, T and Styner, M and Wu, G and Kovalsky, S and Moosmueller, C},
title = {De-Individualizing fMRI Signals via Mahalanobis Whitening and Bures Geometry.},
journal = {ArXiv},
volume = {},
number = {},
pages = {},
pmid = {41293531},
issn = {2331-8422},
abstract = {Functional connectivity has been widely investigated to understand brain disease in clinical studies and imaging-based neuroscience, and analyzing changes in functional connectivity has proven to be valuable for understanding and computationally evaluating the effects on brain function caused by diseases or experimental stimuli. By using Mahalanobis data whitening prior to the use of dimensionality reduction algorithms, we are able to distill meaningful information from fMRI signals about subjects and the experimental stimuli used to prompt them. Furthermore, we offer an interpretation of Mahalanobis whitening as a two-stage de-individualization of data which is motivated by similarity as captured by the Bures distance, which is connected to quantum mechanics. These methods have potential to aid discoveries about the mechanisms that link brain function with cognition and behavior and may improve the accuracy and consistency of Alzheimer's diagnosis, especially in the preclinical stage of disease progression.},
}

@article {pmid41293481,
year = {2025},
author = {Cankaya, S and Akturk, A and Karakus, A and Hanoğlu, L and Mardinoglu, A and Yulug, B},
title = {Targeting the parietal memory network with tDCS in MCI: study protocol for a randomized controlled trial.},
journal = {Frontiers in human neuroscience},
volume = {19},
number = {},
pages = {1661790},
pmid = {41293481},
issn = {1662-5161},
abstract = {BACKGROUND: Mild cognitive impairment (MCI) is a critical transitional stage in dementia related disorders. In that context, dorsolateral prefrontal cortex (DLPFC), and lateral parietal cortex (LPC) are subjected to neuropathological changes in MCI. Furthermore, alterations in parietal memory network (PMN) integrity and default mode network (DMN) also occur in MCI. Transcranial direct current stimulation (tDCS) is a promising neuroprotective tool that might interfere with cognitive decline in Alzheimer's disease-MCI (aMCI) and Parkinson's disease-MCI (PD-MCI) when applied to DLPFC or LPC separately.

METHODS: This is a randomized and controlled study evaluating the effectiveness of tDCS in 120 patients (60 aMCI and 60 PD-MCI). Firstly, all patients will be randomly (1:1) divided into two groups: DLPFC (30 aMCI; 30 PD-MCI) and LPC (30 aMCI, 30 PD-MCI) for tDCS stimulation. Secondly, they will classify randomly (2:1) real and sham groups for tDCS applied to once a day for 10 days over 2 weeks. The stimulation will be delivered with a 2-mA current frequency and will last 20 min. The primary outcome assessment for this study will be the change in score from baseline to the end of (14-days and 90 days follow-up) the tDCS application for the neurocognitive tests. Potential outcome parameters will be discussed in the light of current literature to contribute to the new area of personalized non-invasive brain stimulation research in neurodegenerative diseases at early stages. The results of this study are expected to shed light on the neural underpinnings and pro-cognitive outcomes of tDCS. Potential outcome parameters will be discussed in the light of current literature to contribute to the new area of personalized non-invasive brain stimulation research in neurodegenerative diseases at early stages.},
}

@article {pmid41293417,
year = {2025},
author = {Lang, J and Xiong, Z},
title = {Reduced levels of nitrated α-synuclein in the protective effect of harpagoside on rotenone-induced cellular models of Parkinson's disease.},
journal = {Frontiers in cell and developmental biology},
volume = {13},
number = {},
pages = {1624315},
pmid = {41293417},
issn = {2296-634X},
abstract = {INTRODUCTION: Parkinson's disease (PD), ranking as the second most common neurodegenerative disorders following Alzheimer's disease, involves the progressive accumulation of misfolded proteins in affected neural tissues. This pathological process appears linked to overproduction of reactive oxygen species (ROS) and reactive nitrogen species (RNS). Significantly, more than 30% of proteins aggregated in Lewy bodies exhibit post-translational modifications, particularly RNS-mediated nitration and S-nitrosylation. Experimental evidence suggests that α-synuclein nitration promotes its misfolding and neurotoxic effects in PD models.

METHODS: To model PD pathology, rotenone was applied to induce cellular damage in Neuro-2A (N2A) cells and BV-2 microglial cells. Three iridoid constituents from Scrophularia ningpoensis Hemsl, harpagoside, acetylharpagide, and haragide, were investigated for their neuroprotective potential against rotenone-induced cytotoxicity, with catalpol serving as reference compound. Cell viability was assessed using the CCK-8 assay, nitric oxide (NO) levels were measured via the nitroso assay, nitric oxide synthase (NOS) activity was determined by enzyme-linked immunosorbent assay (ELISA), and nitrated α-synuclein expression was evaluated through immunocytochemistry.

RESULTS: Our studies revealed that both acetylharpagide and harpagoside demonstrated substantial cytoprotective effects on rotenone-treated N2A cells. Further investigation focusing on harpagoside showed its ability to suppress NO generation and inhibit α-synuclein nitration.

DISCUSSION: Detailed pathway analysis indicated that harpagoside's protective actions involved regulation of the nuclear factor-κB (NF-κB)/NOS/NO/α-synuclein nitration signaling cascade.},
}

@article {pmid41293234,
year = {2025},
author = {Diachenko, M and Krivoshein, G and van den Maagdenberg, AMJM and Mansvelder, HD and van Kesteren, RE and Tolner, EA and Linkenkaer-Hansen, K},
title = {Hippocampal and cortical activities reflect early hyperexcitability in an Alzheimer's mouse model.},
journal = {Brain communications},
volume = {7},
number = {6},
pages = {fcaf443},
pmid = {41293234},
issn = {2632-1297},
abstract = {Early stages of Alzheimer's disease are marked by brain hyperexcitability, evidenced by subclinical epileptiform features suggesting an excitation-inhibition imbalance. Clinically translatable biomarkers for early detection of excitation-inhibition changes at the network level, however, are lacking. We investigated the functional excitation-inhibition ratio, theta-gamma phase-amplitude coupling and epileptiform features in hippocampal and cortical local field potentials recorded weekly in freely behaving male APPswe/PS1dE9 (APP/PS1) mice (n = 10) and wild-type controls (n = 10) between 3 and up to and including 11 months of age. APP/PS1 mice exhibited a shift towards increased excitation, reflected in the elevated functional excitation-inhibition ratio emerging most prominently in the hippocampus at 6 months. Additionally, elevated population spiking activity and age-related impairments in theta-gamma phase-amplitude coupling were observed in the local field potentials of APP/PS1 mice in both the hippocampus and the cortex. Importantly, the functional excitation-inhibition ratio correlated positively with elevated population spiking activity in both brain regions in APP/PS1 mice. Our findings highlight the functional excitation-inhibition ratio as a promising biomarker of hippocampal and cortical network disinhibition and hyperexcitability in APP/PS1 mice, with potential value as an early disease marker in Alzheimer's disease.},
}

@article {pmid41293233,
year = {2025},
author = {Futamura, A and Kinno, R and Hanazuka, Y and Ochi, R and Midorikawa, A and Kitazawa, S and Ono, K and Kawamura, M},
title = {The precuneus and posterior cingulate gyrus support temporal orientation in Alzheimer's disease.},
journal = {Brain communications},
volume = {7},
number = {6},
pages = {fcaf424},
pmid = {41293233},
issn = {2632-1297},
abstract = {Although the classifications of 'past,' 'present,' and 'future' are considered abstract concepts, we naturally understand them. Those classifications were named 'A-series' time by McTaggart in 1908. Alzheimer's disease (AD) is the most common type of dementia, with initial symptoms generally including temporal disorientation. This study aims to (1) elucidate the impairment process of temporal cognition in AD by administering A-series temporal tasks to individuals with AD, mild cognitive impairment (MCI), and healthy controls, and (2) clarify the relationship between temporal cognition at each stage of impairment and cerebral blood flow (CBF). A diagnosis of AD (n = 37), MCI (n = 10), and no dementia (ND) (n = 10) took part. The 'A-series' task consisted of eleven short sentences that were grammatically correct using seven-time qualifiers (last week, yesterday, today, now, tomorrow, this week, or next week). The participants were required to respond when the events in the sentences happened or would happen in nine stages. We compared the pattern of their responses, the scores of the Japanese version of the Mini-Mental State Examination (MMSE-J), and the regional CBFs performed by [99m]Tc-ethyl cysteinate dimer Single Photon Emission Computed Tomography. We found that ND was intact in the ability to distinguish between the past, present, and future, on the other hand, AD and MCI showed a diminished ability in temporal orientation when we sorted the 11 sentences in the ascending order of the mean response scores among the ND participants, they were generally ordered according to the time represented by adverbs of time. We also found that the participants could be best classified into three clusters. All ND participants (10/10) and half of the MCI participants (5/10) belonged to Cluster 1, whereas only 19% of the AD participants belonged to the cluster (7/37). Cluster 2 was contributed by three MCI participants (3/10) and 30% of the AD participants (11/37). Finally, most of the AD participants (51%) belonged to cluster 3 (19/37) with a few MCI participants (2/10). We compared CBFs across the three clusters and found the CBF in the pairs of the left and the right pericallosal region could predict whether a participant belonged to either cluster at the largest hit rate of 75%. Our findings suggest that the bilateral pericallosal region, including the posterior cingulate gyrus and precuneus cortex, is associated with temporal orientation.},
}

@article {pmid41293128,
year = {2025},
author = {Khera, N and Raju, RM and Lipton, SA},
title = {The transcriptional and cellular landscape of cognitive resilience to Alzheimer's disease.},
journal = {Frontiers in molecular neuroscience},
volume = {18},
number = {},
pages = {1665802},
pmid = {41293128},
issn = {1662-5099},
abstract = {It is estimated that 5%-40% of patients with pathological features of Alzheimer's disease (AD) maintain normal cognitive health throughout their lifetimes, a phenomenon known as cognitive resilience. Studies have identified many factors that contribute to a patient's capacity for resilience, with those that modulate gene expression being the most dynamic, adaptable, and potentially addressable as targets for future drug development. In patients cognitively resilient to AD and AD-related dementias (ADRD), transcriptional changes within specific cell types serve to preserve the processes most critical to cognitive function within each cell, exerting protective effects on other cell types as well via non-cell autonomous effects. Key themes in preserved cognitive function include maintenance of synaptic stability and function, dampening neuronal hyperexcitability, reducing misfolded protein accumulation, increasing myelination, and countering neuroinflammation. With future research on the most upstream and impactful transcriptional drivers, there lies immense potential for both therapeutics to address AD and a greater fundamental understanding of AD and the brain.},
}

@article {pmid41293017,
year = {2025},
author = {Qi, Y and Goldberg, TE and Kim, H and Devanand, DP and Lee, S},
title = {Neuropathological Correlates of Apathy Progression in Alzheimer's Disease and Related Dementias: A Longitudinal NACC Cohort Study.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.11.06.686966},
pmid = {41293017},
issn = {2692-8205},
abstract = {OBJECTIVE: Apathy is a prevalent and disabling symptom in Alzheimer's disease and related dementias, yet its progression across neuropathological subtypes remains incompletely understood. This cohort study investigates longitudinal changes in apathy and their associations with major neuropathologies using data from the National Alzheimer's Coordinating Center.

METHODS: We analyzed 1,488 participants with autopsy-confirmed neuropathology and at least two caregiver-reported NPI-Q assessments. Generalized linear mixed models were used to assess associations between apathy and six neuropathologies-Alzheimer's disease (AD), Lewy body disease (LBD), frontotemporal lobar degeneration (FTLD), hippocampal sclerosis (HS), cerebrovascular disease (CVD), and cerebral amyloid angiopathy (CAA). with time modeled as years to death and including interaction terms. Sex-stratified analyses were also conducted. All models were adjusted for age at death, sex, and NPI-Q total score excluding apathy.

RESULTS: Apathy prevalence increased over time across all pathology groups. FTLD (OR = 2.11, 95% CI: 1.32-3.39) and HS (OR = 2.23, 95% CI: 1.38-3.60) were consistently associated with higher odds of apathy throughout the disease course. No significant interaction effect was observed in any of the neuropathologies. In sex-stratified analyses, FTLD (OR=2.58, 95% CI 1.40-4.77), HS (OR=2.48, 95% CI 1.29-4.77), and LBD (OR=1.64, 95% CI 1.03-2.61) were significantly associated with apathy in males, while only HS (OR=2.18, 95% CI 1.06-4.47) remained significant in females.

INTERPRETATION: Apathy severity varied by neuropathologies but progressed similarly over time. The elevated burden in FTLD and HS, particularly among males, underscores the importance of stratified approaches to early detection and intervention targeting apathy in ADRDs.},
}

@article {pmid41293014,
year = {2025},
author = {Marriott, AE and Schroeder, JP and Korukonda, A and Pate, BS and McCann, KE and Weinshenker, D and Kelberman, MA},
title = {Impact of early locus coeruleus lesions in the TgF344 Alzheimer's disease rat model.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.11.09.687363},
pmid = {41293014},
issn = {2692-8205},
abstract = {INTRODUCTION: In murine models of Alzheimer's disease (AD), lesioning the locus coeruleus-norepinephrine (LC-NE) system with DSP-4 exacerbates AD-like neuropathology and cognitive impairment. However, the impact of LC lesions during prodromal stages is poorly characterized.

METHODS: TgF344-AD and wild-type rats received monthly injections of DSP-4 or saline from 1-5 months of age, a time point preceding forebrain plaque or tangle deposition in TgF344-AD rats, after which behavior and pathology were assessed.

RESULTS: DSP-4 compromised LC cell bodies, fibers, and NE content. LC lesion and the AD transgene each affected several affective behaviors and/or cognition individually, but few interactions were found and DSP-4 failed to exacerbate behavioral phenotypes or neuropathology in TgF344-AD rats.

DISCUSSION: Combined with previous literature, our data suggest that LC lesions exacerbate pre-existing AD-like pathology and behavioral impairments, rather than accelerate their onset. Further characterization of LC lesions in TgF344-AD rats at different ages is warranted.

RESEARCH-IN-CONTEXT: Systemic review: The authors reviewed existing literature using traditional sources, including PubMed. Previous studies investigated the impact of locus coeruleus (LC) lesions on Alzheimer's disease (AD)-like neuropathology and behavior in murine models of AD. However, the impact of LC degeneration in an animal model that expresses both amyloid and endogenous tau pathology at a time point before the emergence of significant forebrain pathology is underexplored.Interpretation: We expanded the behavioral and molecular characterization of TgF344-AD rats in response to N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP-4)-induced LC lesions during the pre-pathology stages of disease. Unexpectedly, we found that TgF344-AD genotype and DSP-4 rarely interacted to exacerbate AD-related symptoms or pathology.Future Directions: Our results indicate LC lesions do not accelerate onset of AD-like neuropathology or behavioral impairment in this model. Future studies in older TgF344-AD animals and using different DSP-4 treatment regimens would help clarify the relationship between LC integrity and AD progression.

HIGHLIGHTS: Locus coeruleus damage causes apathy-like behavior and changes in arousalTgF344-AD genotype induces social recognition deficits and anxiety-like behaviorLocus coeruleus damage and TgF344-AD genotype rarely interact to worsen deficitsInteractions that exacerbate Alzheimer's disease neuropathology were also scarce.},
}

@article {pmid41292999,
year = {2025},
author = {Deasy, S and Amontree, M and Colon, Z and Thorland, E and Modi, K and Hummel, K and Blanco, I and Greco, G and Maguire-Zeiss, K and Conant, K},
title = {Increased levels of HAPLN2, which anchors dense extracellular matrix, in the hippocampus of APOE4 targeted replacement mice.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.11.09.687435},
pmid = {41292999},
issn = {2692-8205},
abstract = {Hyaluronan and proteoglycan link protein 2 (HAPLN2) / Brain link protein-1 (Bral1) is important for the binding of chondroitin sulfate proteoglycans (CSPGs) to hyaluronan and thus for the formation of specific types of brain extracellular matrix (ECM). It is also significantly increased with aging. Moreover, machine learning has identified it as a brain-derived protein most predictive of Alzheimer's disease (AD). HAPLN2 binds to CSPGs that may sequester aggregation-prone proteins and also restrict neuronal plasticity. Because the apolipoprotein 4 (APOE4) allele increases AD risk, in the present study we have examined hippocampal lysates from APOE3 and APOE4 targeted replacement (TR) mice using unbiased proteomics, Western blot and hippocampal immunostaining. With proteomics, we observe that HAPLN2 is among the most significantly upregulated proteins in APOE4 mice. Prior work suggests HAPLN2 is particularly important to the assembly of perinodal matrix, and herein we show that it also co-localizes with Wisteria floribunda agglutinin (WFA) positive perineuronal nets (PNNs). PNNs represent a dense form of ECM that can increase GABAergic neurotransmission to alter overall excitatory/inhibitory (E/I) balance and neuronal oscillations important to mood and memory. Proteomics also detected elevated levels of high temperature requirement peptidase-1 (HTRA1), which accumulates in cerebral blood vessels harboring amyloid, in APOE4 mice. In Western blot studies, lysates from APOE4 mice also showed significantly reduced levels chondroitin-6 sulfated proteoglycans, which makes PNNs more susceptible to proteolysis and less inhibitory. In addition, immunostaining studies showed that levels of the PNN component aggrecan were increased in the hippocampus of APOE4 animals. Overall, these findings contribute to an emerging body of literature suggesting that brain extracellular matrix may be altered with aging and other risk factors for AD, and suggest that future studies should assess PNNs, peri-nodal structure and axonal conduction in the background of APOE4.},
}

@article {pmid41292987,
year = {2025},
author = {Gogola, JV and Wee, SWS and Garcia, AJ},
title = {Repeat Opioid Use Modulates Microglia Activity and Amyloid Beta Clearance in a Mouse Model of Alzheimer's Disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.11.14.688256},
pmid = {41292987},
issn = {2692-8205},
abstract = {In addition to driving dependency and overdose, illicit use of opioids, such as fentanyl, is linked to the risk for cognitive decline and dementia. Growing evidence also indicates that opioid use is associated with pathological features, paralleled early in Alzheimer's disease (AD), which raises the possibility of the involvement of mechanistic interactions between opioid use and AD progression. Here, we investigate how chronic fentanyl use (i.e., 20 days) influences the neuroimmune state, microglial activity, and amyloid burden in wildtype and APPPS1-21 mice, a transgenic model of AD. In wild-type mice, fentanyl use promoted a pro-inflammatory state without increasing the incidence of disease-associated microglia. In APPPS1-21 mice, chronic fentanyl use led to a shift favoring an anti-inflammatory state, which was associated with increased microglia clustering and activation at Aβ plaques, increased Aβ internalization in plaque-associated activated microglia, decreased soluble Aβ, and decreased plaque burden. Our findings indicate that chronic fentanyl use fundamentally changes the trajectory of neuroimmune activity and features characteristic of early AD by enabling microglia to enhance Aβ clearance. The interactions demonstrate how substance use can reshape the neuroimmune landscape in neurodegenerative disease, emphasizing the importance of tailored treatment strategies.},
}

@article {pmid41292981,
year = {2025},
author = {de Leeuw, SM and Nuriel, T},
title = {Investigating the Effects of APOE Genotype on Intracellular Cholesterol and the Endolysosomal System in the Aging Mouse Brain.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.11.11.687891},
pmid = {41292981},
issn = {2692-8205},
abstract = {Individuals who possess the ε4 allele of apolipoprotein E (APOE) are at a significantly increased risk for developing Alzheimer's disease (AD). However, the precise reason for this association is not fully understood. Beyond its effects on amyloid and tau, APOE also influences fundamental cellular processes in the brain, including cholesterol trafficking between cells and within the endolysosomal system, which may be a critical component of the APOE4 -associated vulnerability to AD. Here, we examined how APOE genotype, sex, and aging alter intracellular cholesterol processing and the endolysosomal system in the mouse brain. Using the novel cholesterol-binding probe D4H*-mCherry, we quantified intracellular cholesterol levels, the levels of early endosomes (Rab5), late endosomes (CD63), and lysosomes (LAMP1), and the colocalization of cholesterol with these endolysosomal compartments. This analysis was performed in the cortex, hippocampus, and entorhinal cortex of young, middle-aged, and old APOE2 , APOE3 , and APOE4 mice. Our analysis revealed region-specific changes in intracellular cholesterol and the endolysosomal system in response to aging, sex, and APOE genotype. Notably, young APOE4 mice showed reduced cholesterol within early and late endosomes, but increased lysosomal abundance, suggesting impaired cholesterol processing. These APOE4-specific effects were less apparent in older animals. These effects were strongly modified by sex, with female APOE4 mice exhibiting elevated lysosomal cholesterol in the hippocampus and entorhinal cortex at old age, indicating sex-dependent susceptibility. Together, these results reveal that APOE genotype, age, and sex interact to influence endolysosomal cholesterol homeostasis, with female APOE4 mice showing the greatest dysregulation. These findings suggest that early and region-specific endolysosomal defects may contribute to the heightened AD risk associated with APOE4 , particularly in females.},
}

@article {pmid41292944,
year = {2025},
author = {Volkmer, G and Hjerling-Leffler, J and Bast, L},
title = {Cell Type Specific Inference of Perturbations in Synaptic Communication with MultiNeuronChat.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.11.11.687822},
pmid = {41292944},
issn = {2692-8205},
abstract = {Inference of differential neuron-neuron and neuron-glia communication from single nucleus RNA sequencing data is a powerful technique to uncover altered communication pathways when comparing groups, such as disease and control, developmental stages, or age groups, or different treatments. Yet, the communication changes are typically not identified on the cell type pair level, limiting its resolution in terms of answering biological and medical questions. Here we present MultiNeuronChat, a highly resolved framework that utilizes gene expression measurements of single cells from case-control single-cell/nucleus RNA-seq data sets together with an existing comprehensive database comprising cell adhesion molecules, gap junctions and synaptic transmission for the differential analysis of neuron-neuron and neuronglia communication. In an in silico study, we show our method accurately and efficiently predicts known cell type-specific perturbations without summarizing communication scores across donor samples. Using a published single-nucleus RNA sequencing dataset, we highlight the sensitivity of our method by showcasing that MultiNeuronChat identifies both known and novel communication pathways in several cell type pairs in Alzheimer's disease. Lastly, we highlight that MultiNeuronChat's donor-specific communication score calculation can be utilized to inform patient stratification.},
}

@article {pmid41292940,
year = {2025},
author = {Mayeri, Z and Woods, G and Rane, A and Kifle, A and Chamoli, M and Shukla, S and Walton, CC and Andersen, JK},
title = {A Compound Enhancing Lysosomal Function Reduces Tau Pathology, Microglial Reactivity and Rescues Working Memory in 3xTg AD Mice.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.11.09.687389},
pmid = {41292940},
issn = {2692-8205},
abstract = {BACKGROUND: Recent advancements in Alzheimer's disease (AD) therapeutics have validated the use of amyloid beta (Aβ)-clearing antibodies, which reduce Aβ pathology but leave other disease hallmarks largely unaddressed. Since AD involves multiple pathological processes, additional strategies are needed to target complementary mechanisms. One such target is autophagy, a lysosomal mediated degradation pathway essential for cellular homeostasis that removes toxic protein aggregates and damaged organelles. This process is implicated in AD, as impaired lysosomal function promotes Aβ and tau accumulation. Our laboratory recently identified a novel natural mitophagy-inducing compound (MIC) that may serve as a therapeutic intervention for AD.

METHODS: We evaluated the effects of MIC in aged 3xTgAD mice, a transgenic model displaying both Aβ and tau pathology. Mice received either standard diet or diet containing MIC beginning at age 4 months until 20 months on alternating weeks. Age-matched non-transgenic (NonTg) controls were included under standard and MIC-supplemented diets to assess compound effects during normal aging. Neuropathological changes were assessed using immunohistochemistry (IHC) for Aβ, phosphorylated tau (pTau), and microglial reactivity. Cognitive performance was evaluated using the Morris Water Maze (MWM) to assess spatial learning and memory and the Y-maze to measure working memory.

RESULTS: At 20 months of age, our neuropathological assessment showed that 3xTgAD mice fed an MIC-supplemented diet had a significant reduction in pTau accumulation and microglial reactivity, although Aβ burden remained unchanged. At 15 months, MIC diet also improved spatial learning and memory in aged NonTg controls but not in 3xTgAD mice. However, in younger 8-month-old 3xTgAD mice, MIC restored working memory performance to NonTg levels, indicating an age-dependent therapeutic response.

CONCLUSION: MIC emerges as a potential modulator of tau pathology and neuroinflammation. As a naturally derived compound, MIC offers potential for combination therapy with FDA-approved Aβ-clearing antibodies, enabling a multimodal approach to AD treatment that addresses amyloid, tau, and microglia-related pathology.},
}

@article {pmid41292906,
year = {2025},
author = {Honma, PS and Bangera, SC and Thomas, R and Kaliss, N and Xia, D and Palop, JJ},
title = {Decoding hidden goal-directed navigational states and their neuronal representations using a novel labyrinth paradigm and probabilistic modeling framework.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.11.13.688348},
pmid = {41292906},
issn = {2692-8205},
abstract = {Goal-directed navigation involves a sequence of planned actions aimed at achieving long-term goals through reinforcement, but detecting hidden states that support this process and their neuronal substrates remains a fundamental challenge. To address this, we developed a complex labyrinth test that mimics naturalistic foraging and implemented a novel hierarchical probabilistic modeling framework, Cognitive Mapping of Planned Actions with State Spaces (CoMPASS). This framework infers a nested state structure, comprising short-term surveillance-ambulation states (Level 1) and long-term goal-oriented navigational states (Level 2). Using CoMPASS, we show that successful navigation in wild-type mice is marked by increased recruitment of both surveillance and goal-oriented states specifically at decision nodes, revealing how sequential behavioral decisions culminate in long-term goals. In contrast, the humanized App [SAA] mouse model of Alzheimer's disease (AD) exhibited navigational impairments marked by diminished surveillance during decisions, reduced goal-directed states, and increased navigation stochasticity. Importantly, we show that gamma oscillations in the posterior parietal cortex (PPC), a region involved in spatial navigation planning, encode these CoMPASS behavioral states and their dynamic operating modes linking spatial locations to long-term goals. Our findings provide a novel paradigm for assessing hidden goal-directed navigational states and identify gamma oscillations in the PPC as their neural substrates.},
}

@article {pmid41292900,
year = {2025},
author = {Feng, Y and Villalón-Reina, JE and Gari, IB and Alibrando, JD and Nir, TM and Jahanshad, N and Chandio, BQ and Thompson, PM},
title = {Evaluating Sample-Size Efficiency and Sensitivity of Tractometry in Alzheimer's Disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.11.11.687878},
pmid = {41292900},
issn = {2692-8205},
abstract = {Tractometry allows quantitative analysis of white matter microstructure along the brain's fiber tracts, but the impact of study design parameters-such as sample size and along-tract resolution-on sensitivity and specificity is not well understood. In this study, we conducted tractometry bootstrap analysis using linear-mixed models across four diffusion tensor imaging (DTI) metrics to systematically evaluate how these factors affect the detection of dementia- and amyloidrelated effects. While coarser along-tract segments yield greater sensitivity and higher mean effect sizes, finer segments tend to produce higher peak effect sizes, revealing more spatially localized effects. Dementia-related effects were more widespread and detectable with fewer subjects, whereas amyloid-related effects were more subtle and localized, requiring larger cohorts to detect them. These findings highlight that tractometry offers improved spatial specificity and can reliably detect small, fine-scale effects, but study design should be tailored to specific research questions, considering the expected spatial extent and magnitude of effects, to optimize sample size efficiency and interpretability.},
}

@article {pmid41292865,
year = {2025},
author = {Shuai, Y and Feng, Y and Villalon-Reina, JE and Nir, TM and Thomopoulos, SI and Thompson, PM and Chandio, BQ},
title = {ASSESSING THE INFLUENCE OF TRACTOGRAPHY METHODS ON WHITE MATTER MICROSTRUCTURE AND TRACTOMETRY ANALYSIS IN ALZHEIMERS DISEASE.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.11.11.687747},
pmid = {41292865},
issn = {2692-8205},
abstract = {Tractometry enables detailed mapping of white matter microstructure along individual tracts and is widely used to study disease effects such as those seen in Alzheimer's disease (AD). However, how different tractography algorithms influence tractometry outcomes remains unclear. Here, we compared whole-brain deterministic and probabilistic tractography using the BUndle ANalytics (BUAN) framework in the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset, including 118 AD and 728 cognitively normal (CN) participants. Both approaches revealed the expected pattern of lower fractional anisotropy (FA) and higher mean, radial, and axial diffusivity (MD, RD, AxD) in AD, consistent with white matter degeneration. Despite broadly similar global trends, substantial bundle-level differences emerged between the two tractography methods. Probabilistic tracking produced stronger and more spatially extended effects in the fornix, a small and highly curved limbic pathway vulnerable to AD-related degeneration, whereas deterministic tracking showed greater sensitivity in the posterior segments of the right superior longitudinal fasciculus (SLF R). These discrepancies highlight that the choice of tractography algorithm can alter detecting disease effects, emphasizing the need for cross-method validation to ensure the robustness and interpretability of along-tract measures.},
}

@article {pmid41292846,
year = {2025},
author = {Shin, J and Brady, E and Chen, C and Lauderdale, K and Agrawal, A and Zhang, Y and Jiang, X and Nambiar, P and Herbert, J and Mallen, DD and Ly, KK and Honma, PS and Guo, Z and Sant, C and Thomas, R and Miller, SR and Cobos, I and Palop, JJ},
title = {APOE4-Aβ synergy drives brain network dysfunction and neuronal lysosomal-ER proteostasis dysregulation a preclinical Alzheimer's disease model.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.11.11.687887},
pmid = {41292846},
issn = {2692-8205},
abstract = {UNLABELLED: Amyloid-β (Aβ) and APOE4 represent two of the strongest pathological and genetic risk factors for Alzheimer's disease (AD), but how these co-pathogens interact during preclinical stages remains undefined. We addressed this question by developing a humanized knock-in model expressing physiological, endogenously regulated human Aβ and APOE4. Aged App [NLF] :APOE4 mice displayed incipient amyloidosis with subtle memory-related changes, consistent with preclinical AD. We found largely distinct, non-overlapping APOE4- and Aβ-driven functional synaptic, sleep, and behavioral alterations. However, at the transcriptomic level, APOE4xAβ had a pronounced detrimental interaction in neuronal populations, whereas glial populations were primarily affected by either genotype. We found APOE4xAβ molecular interactions in neuronal populations, including excitatory and inhibitory cells, converged on a core lysosomal-ER proteostasis axis. We propose that APOE4xAβ interaction produces an early neuronal pathogenic signature, involving the lysosomal-ER proteostasis axis, preceding functional decline and driving disease progression. APOE4xAβ-KI models provide a physiologically relevant platform to study early pathogenesis.

HIGHLIGHTS: Early synergistic APOE4xAβ interaction emerges predominantly at the transcriptomic level in neurons, but not in glial cells.APOE4 and Aβ drive largely non-overlapping physiological changes in preclinical stages of disease, but converge at the level of network hyperexcitability.APOE4xAβ neuronal synergy converges on a conserved lysosomal-ER proteostasis axis.Humanized APOE4xAβ KI mice provide a physiologically relevant model to dissect early AD pathogenesis in preclinical stages.},
}

@article {pmid41292809,
year = {2025},
author = {Steigmeyer, AD and Battison, AS and Liebman, IR and van Dyck, CH and Slusher, BS and Arnsten, AFT and Malaker, SA and Datta, D},
title = {Region-specific proteomic analysis of aging rhesus macaques following chronic glutamate-carboxypeptidase-II (GCPII) inhibition elucidates potential treatment strategies for sporadic Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.11.07.687004},
pmid = {41292809},
issn = {2692-8205},
abstract = {Sporadic Alzheimer's disease (sAD) lacks effective preventive therapies, underscoring the need to target pathogenic drivers. Aberrant calcium signaling is an established early event in sAD pathogenesis that is closely linked to neuroinflammation. Aged rhesus macaques are predominantly APOE-ε4 homozygotes and naturally exhibit cognitive decline, calcium dysregulation, amyloid deposition, and tau pathology, which allows for a translationally relevant animal model. We previously identified an evolutionarily expanded role for postsynaptic type 3 metabotropic glutamate receptors (mGluR3) in dorsolateral prefrontal and entorhinal cortex, where they regulate cAMP- calcium opening of K[+] channels to sustain neuronal firing and working memory. mGluR3 signaling is driven by N-acetylaspartylglutamate (NAAG) and constrained by glutamate carboxypeptidase II (GCPII), whose expression rises with age and inflammation. In prior work, chronic inhibition of GCPII with the orally bioavailable inhibitor 2-(3-mercaptopropyl) pentanedioic acid (2-MPPA) improved neuronal firing, working memory, and reduced pT217Tau pathology in aged macaques. Here, we employed liquid chromatography-tandem mass spectrometry (LC-MS/MS) to define the proteomic consequences of chronic 2-MPPA treatment in vulnerable (entorhinal cortex, dorsolateral prefrontal cortex) versus resilient (primary visual cortex) regions. We identified >2,400 proteins across experimental conditions, and label-free quantification revealed region-specific differential expression patterns paralleling known vulnerability gradients in sAD. Gene ontology enrichment of vulnerable regions implicated pathways governing protein deneddylation, amyloid and tau-associated processes, synaptic plasticity, mitochondrial homeostasis, and oxidative stress, revealing putative targets for therapeutic intervention in sAD. These findings demonstrate that GCPII inhibition engages distinct, region-selective molecular programs in the aging primate cortex, consistent with the protection of circuits most vulnerable to sAD. By mapping the proteomic shifts that occur with treatment, we reveal molecular signatures that not only serve as candidate biomarkers but also highlight novel mechanistic pathways contributing to calcium-driven degeneration in sAD. As such, more focused investigations into these pathways of therapeutic interest are warranted, in addition to the analysis of key post-translational modifications and their potential roles in sAD.},
}

@article {pmid41292796,
year = {2025},
author = {D'Anniballe, VM and Kim, S and Finlay, JB and Wang, M and Ko, T and Luo, S and Whitson, HE and Johnson, KG and Goldstein, BJ},
title = {Olfactory biopsy analysis of Alzheimer's pathobiology across disease stages.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.11.11.687356},
pmid = {41292796},
issn = {2692-8205},
abstract = {Alzheimer's Disease (AD) is a neurodegenerative condition affecting millions worldwide. Defining early pathobiological events remains challenging, in part due to inaccessibility of neural tissue. Because olfactory neurons are accessible, and olfactory loss is prevalent in AD, we evaluated olfactory brush biopsies from controls, individuals with cerebrospinal fluid (CSF) biomarker-confirmed AD, and cognitively typical individuals whose positive biomarkers signal a pre-clinical AD stage. We define via single cell RNA-sequencing (n=22 subjects) conserved neuroinflammatory T cell, myeloid, and olfactory neuron changes detectable even in pre-clinical AD subjects. Activated memory T cell states were a hallmark of pre-clinical AD, paralleling CSF T cell phenotypes seen in advanced disease, accompanied by both microglia-like inflammatory programs and olfactory neuron inflammatory injury. Together, our findings establish a novel platform permitting analysis of neural tissue in AD at its earliest stages.},
}

@article {pmid41292786,
year = {2025},
author = {Dong, Y and Watson, DJ},
title = {Thyrotropin-releasing hormone protects hippocampal neurons against glutamate toxicity via phosphatidylinositol 3-kinase/AKT pathway and new protein synthesis.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.11.11.687668},
pmid = {41292786},
issn = {2692-8205},
abstract = {UNLABELLED: Thyrotropin-releasing hormone is best known as a neuropeptide that stimulates the release of thyroid-stimulating hormone and prolactin in hypothalamic-pituitary-thyroid (HPT) axis. Independent from its activity in the HPT axis, TRH also exerts strong neuroprotective activity against neurodegenerative diseases such as Alzheimer's disease, epilepsy and traumatic brain injury. Although multiple factors have been linked to its neuroprotective action, the cellular mechanism of TRH neuroprotection is still not clear. Here we show that TRH protects hippocampal neurons against glutamate toxicity via phosphatidylinositol 3-kinase (PI3K)/AKT pathway and new protein synthesis. Both adeno-associated virus (AAV) mediated TRH transduction and TRH peptide given exogenously over 24 hours period of time inhibit glutamate-induced lactate dehydrogenase (LDH) release. This effect is not mediated by the decreased intracellular calcium response as TRH treatment (24 hours) has no effect on glutamate-induced increase in intracellular calcium nor the calpain activity. While TRH treatment (10 minutes) significantly inhibits glutamate-induced increase in intracellular calcium, no protective effect is observed when TRH is applied 30 minutes before or after glutamate stimulation. Instead, PI3K inhibitor LY294002 but not mitogen-activated protein kinase (MAPK)/Extracellular signal-regulated kinase (ERK)1/2 inhibitor U0126 completely inhibits the protective effect of TRH. LY294002 also blocks TRH induced AKT activation. In addition, protein synthesis inhibitor cycloheximide inhibits the protective effect of TRH. Taken together, these results suggest PI3K/AKT signaling pathway and new protein synthesis are involved in the protective effect of TRH against glutamate toxicity, thereby providing mechanistic support for its action in neurodegenerative diseases.

HIGHLIGHTS: TRH has strong neuroprotective activity against neurodegenerative diseases such as traumatic brain injury and Alzheimer's disease. Understanding the cellular mechanism for TRH neuroprotection might aid developing novel treatment strategy. In the present study we demonstrate that TRH neuroprotection is mediated via PI3K/AKT signaling pathway and new protein synthesis. This finding provides mechanistic support for the action of TRH in traumatic brain injury and other neurodegenerative diseases.},
}

@article {pmid41292743,
year = {2025},
author = {Tsay, K and Equbal, A and Li, Y and Tsui, T and Han, S and Fichou, Y},
title = {DEER of Singly Labelled Proteins to Evaluate Supramolecular Packing of Amyloid Fibrils.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.11.10.687719},
pmid = {41292743},
issn = {2692-8205},
abstract = {The formation of protein amyloid fibrils in the brain is a hallmark of various neurodegenerative diseases, including Alzheimer diseases and Parkinson diseases. Amyloid fibrils are highly ordered aggregates in which proteins folded in two-dimensional layers stack along one axis to form elongated linear assemblies. The specific conformations adopted by the proteins within each layer of the amyloid correlates with the pathology. Furthermore, their spreading and templating competency relies on strict in register packing of the folded proteins along the fibril growing axis. There is a need for tools to characterize not only the protein fold across the fibril cross section but also the spatial ordering of the proteins stacked along the amyloid fibril axis. We present an approach based on double electron electron resonance spectroscopy (DEER) using singly labelled tau protein assembled in amyloid fibrils that can deliver an apparent dimensionality of the supramolecular organization of tau fibrils. The parameters of the DEER background function can be used to assess the amyloid core location and packing order, and track time-resolved formation of aggregation intermediates. Showcasing the method on tau, we demonstrate that heparin-induced tau fibrils are mispacked while seeded aggregation can template amyloid fibrils with a higher packing order. This study benchmarks a new method that will provide critical structural insights into amyloid assemblies.},
}

@article {pmid41292721,
year = {2025},
author = {Buchholz, HE and Martin, SA and Dorweiler, JE and Prosser, DC and Sontag, EM and Manogaran, AL},
title = {Stress granules and protein aggregates reveal intracellular resource competition.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.11.08.687377},
pmid = {41292721},
issn = {2692-8205},
abstract = {Stress granules are biomolecular condensates that form in response to environmental stress and disassemble once normal conditions are restored. However, when disassembly fails, stress granules can persist and solidify. While stress granule solidification has been well documented, the cellular mechanisms underlying the transition from reversible to persistent stress granules remain unclear. Persistent stress granules can seed the formation of pathological aggregates, such as TDP-43 in amyotrophic lateral sclerosis [1, 2] . Although amyloid and tau aggregates are hallmarks of Alzheimer's disease, a subset of patients also develop TDP-43 deposits, suggesting a possible role for stress granule solidification in Alzheimer's disease progression [3-5] . Despite theoretical models explaining why persistence and ensuing solidification occurs, strong in vivo evidence is lacking [6] . Here we show that competition for limited chaperone resources drive stress granule persistence. In the presence of TDP-43 aggregates or yeast amyloid proteins called prions, stress granule disassembly is slowed or halted disassembly. Using yeast prions as a model, we show that the addition of chaperones, specifically the AAA+ ATPase molecular chaperone, Hsp104, resulted in resumption of stress granule disassembly. Our results demonstrate that the competition for shared resources, such as molecular chaperones, can limit stress granule disassembly. We suspect that the presence of pathological aggregates results in resource competition within the aging brain, contributing to the persistence of stress granules and their subsequent solidification and aggregation.},
}

@article {pmid41292666,
year = {2025},
author = {Vakli, P and Weiss, B and Keresztes, A and Hermann, P and , and Cole, JH and Vidnyánszky, Z},
title = {Regional brain aging patterns reveal disease-specific pathways of neurodegeneration.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.11.12.25339989},
pmid = {41292666},
abstract = {The heterogeneity of brain aging is a hallmark of neurological and psychiatric disorders, yet machine-learning tools used to characterize this process, including the 'brain age' paradigm, have largely relied on global metrics that lack the specificity to map these complex patterns. Here, we introduce BrainAgeMap, an interpretable deep learning framework that generates fine-grained, voxel-wise maps of brain-predicted age difference (brain-PAD) from T1-weighted magnetic resonance imaging scans. We provide converging lines of evidence for the framework's clinical, prognostic, and neurobiological utility. Disorder-specific topographies of accelerated aging were identified in Alzheimer's disease (AD), frontotemporal dementia, and schizophrenia. Longitudinal analysis of the hippocampus revealed accelerated aging in individuals with progressive versus stable mild cognitive impairment (MCI), demonstrating prognostic value. Regional brain-PAD in the temporal lobe correlated strongly with in vivo tau pathology measured by positron emission tomography in AD, linking the maps to underlying molecular pathology. Furthermore, regional brain aging in MCI and AD was linked to individual differences in episodic memory function. BrainAgeMap provides a robust tool to delineate disease-specific pathways of neurodegeneration, offering new opportunities for early diagnosis, patient stratification, and monitoring therapeutic interventions.},
}

@article {pmid41292647,
year = {2025},
author = {Taneja, SB and Boyce, RD and Malec, SA and Albert, SM and Shaaban, CE and Levine, AS and Munro, P and Bian, J and Xu, J and Maraganore, D and Schliep, K and Silverstein, JC and Kienholz, M and Karim, HT},
title = {Predicting Alzheimer's Disease Diagnosis, a Decade or more Years before Onset using the Electronic Health Record and Random Forest Machine Learning Models.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.11.04.25338396},
pmid = {41292647},
abstract = {INTRODUCTION: There is need to detect and intervene in pre-clinical phases of Alzheimer's disease (AD). Electronic health records (EHRs) may help predict AD using machine learning methods.

METHODS: We identified EHRs for 19,473 cases with AD and 111,922 controls. Records spanned 10 or more years prior to AD diagnosis. We trained a random forest model (employing 5-fold cross-validation with 2,499 features) to predict AD 10 years prior to its onset using a 75/25% train/test split and then computed permuted feature importance.

RESULTS: We achieved an area under the ROC curve of 0.80. Feature importance identified factors associated with AD, including age, sex, race, ethnicity, BMI, cardiovascular diseases, inflammation, pain, sleep and mood disorders, trauma, other neurodegenerative disorders, diuretics, colon-related disorders and procedures, seizures, and vitamin B12.

DISCUSSION: This is the first EHR-based model to predict AD 10 years prior to onset, which could help predict AD and inform prevention/early intervention.},
}

@article {pmid41292642,
year = {2025},
author = {Jiang, C and Krivinko, J and Yu, Z and Sweet, RA and Zeng, L and Wang, H and Ding, Y and Zeng, Z and Kofler, J and Wang, L},
title = {Comparative Mortality Risk of Aripiprazole, Olanzapine, Quetiapine and Risperidone in Alzheimer's Disease: A Real□World Cohort Study with Treatment Effect Heterogeneity Analysis.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.11.13.25340096},
pmid = {41292642},
abstract = {BACKGROUND: Second-generation antipsychotics (SGAs) are frequently used off-label to manage behavioral symptoms in Alzheimer's disease (AD), despite ongoing concerns about their safety. Comparative evidence on mortality risk across specific SGAs remains limited.

OBJECTIVE: To compare all-cause mortality among AD patients treated with commonly prescribed SGAs and to explore treatment effect heterogeneity using causal machine learning.

METHODS: We conducted a retrospective cohort study using de-identified electronic health records from the Truveta platform (2018-2024). Patients with incident AD initiating treatment with aripiprazole, risperidone, quetiapine, or olanzapine were identified using an active-comparator, new-user design. Drug exposure was modeled as a time-varying covariate in Cox proportional hazards models, with propensity score matching applied to control for confounding. Causal tree and targeted maximum likelihood estimation (TMLE) were used to identify subgroups with heterogeneous treatment effects.

RESULTS: Among 17,004 AD patients, aripiprazole was associated with significantly lower mortality than olanzapine (HR = 0.667, 95% CI: 0.472-0.941) and quetiapine (HR = 0.677, 95% CI: 0.462-0.990). Quetiapine was also associated with lower mortality than olanzapine (HR = 0.833, 95% CI: 0.702-0.990) and risperidone (HR = 0.830, 95% CI: 0.705-0.978). Causal tree analysis revealed treatment effect heterogeneity by clinical characteristics, particularly among patients using type 2 diabetes (T2DM) medications. In subgroup analyses, aripiprazole remained protective in T2DM users (HR = 0.604 vs. quetiapine and risperidone, p = 0.002).

CONCLUSIONS: Mortality risks vary substantially across SGAs in AD patients. Aripiprazole and quetiapine were associated with lower mortality compared to olanzapine and risperidone. Treatment effect heterogeneity suggests the need for individualized prescribing based on patient characteristics such as comorbid T2DM.},
}

@article {pmid41292640,
year = {2025},
author = {Rathore, S and Dammer, EB and Shantaraman, A and Wu, F and Duong, DM and Fox, EJ and Johnson, ECB and Lah, JJ and , and Seyfried, NT and Levey, AI},
title = {CSF Proteomics and Machine Learning Reveal Distinct Stages Across the Alzheimer's Disease Continuum.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.11.05.25339138},
pmid = {41292640},
abstract = {UNLABELLED: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by heterogeneous pathophysiological changes that begin years before symptoms emerge. Existing biomarkers like Aβ and pTau capture only fragments of this complexity, limiting diagnosis and therapeutic development. Leveraging high-resolution cerebrospinal fluid (CSF) proteomics, quantifying 2,492 proteins using tandem-mass-tag mass spectrometry (TMT-MS), in 1,104 ADNI participants, we identified pathways reflecting AD pathogenesis and stage-specific molecular events in-vivo . In biomarker-positive MCI (due-to-AD) and AD Dementia, beyond well-established metabolic and mitochondrial dysfunction, we observed upregulated neuropeptide signaling, G-protein-coupled receptors activity, and synaptic remodeling, highlighting underrecognized synaptic and signaling alterations. Asymptomatic AD showed significant alterations in mitoschondrial metabolism, RNA processing, and extracellular matrix pathways. Across the continuum from asymptomatic AD to MCI (due-to-AD) and AD Dementia, 92 proteins were differentially abundant, revealing a stage-specific progression, with early disruptions in neurodevelopmental and extracellular vesicle-related pathways in asymptomatic and MCI (due-to-AD) participants, transitioning to impairments in intracellular signaling, synaptic architecture, and cytoskeletal integrity in AD Dementia. This progressive dysregulation supports a continuum model where early compensatory mechanisms gradually give way to widespread neuronal degeneration. Using machine learning, we derived CSF proteomic panels capable of accurately distinguishing disease stages (asymptomatic AD vs. MCI (due-to-AD): AUC=0.92; MCI (due-to-AD) vs. AD Dementia: AUC=0.87). In parallel, we developed machine learning models to estimate pathological burden (Aβ-PET, tau-PET), which substantially outperformed conventional biomarkers. These findings uncover protein signatures that reflect underlying AD biology and provide a foundation for stage-specific biomarkers and therapeutic targeting, with important implications for patient stratification and personalized intervention strategies.

ONE SENTENCE SUMMARY: Comprehensive CSF proteomics across 1,104 ADNI participants delineated molecular signatures of Alzheimer's disease pathogenesis and progression, enabling robust machine learning models for diagnosis, staging, and estimation of pathology.},
}

@article {pmid41292628,
year = {2025},
author = {Dou, J and Cockell, S and Wang, H and Hemenway, N and Ryan, L and Zawistowski, M and Ware, EB and Bakulski, KM},
title = {DNA methylation-wide association study of prevalent and incident dementia in the US Health and Retirement Study.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.11.10.25339919},
pmid = {41292628},
abstract = {BACKGROUND: Peripheral blood DNA methylation may have utility as an early dementia risk biomarker.

METHODS: We analyzed DNA methylation (blood collected 2016) and cognitive impairment in the Health and Retirement Study, a longitudinal study representative of US adults over age 50 (3,921 individuals and 585,356 CpG sites). We analyzed methylation associations with cognitive status both cross-sectionally and prospectively among participants with normal cognition at baseline with four years follow-up.

RESULTS: Cross-sectionally, 5,322 CpGs were associated (p-value<0.01) with cognitive impairment non-dementia, and 14,366 (166 genome-wide FDR<0.05) with dementia. Prospectively, 4,898 CpGs were associated with any-impairment. Enriched biologic pathways include ion transport, ligand-gated channel, and neuron differentiation. Nine CpGs overlapped all analyses including cg02583484 (HNRNPA1), cg15266133 (LOC102724084), cg24287460 (CCDC48), cg17124509 (C17orf57), and cg02553054 (SMARCD1).

DISCUSSION: CpGs identified were enriched in pathways related to Alzheimer's disease pathology and provide promising grounds for non-invasive blood biomarkers. Future studies for replication and with longer follow-up are needed.},
}

@article {pmid41292618,
year = {2025},
author = {Thakur, LS and Bharj, G and Nguyen, DT and Saroya, M and Malik, B},
title = {Integrating Infection Burden and Multimodal Biomarkers for Early Detection of Alzheimers Disease: A Sheaf-ML Framework.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.11.10.25339915},
pmid = {41292618},
abstract = {Alzheimers disease (AD) remains a major global health challenge, with growing evidence linking chronic infections, immune aging, and neurodegeneration. Grounded in the Antimicrobial Protection Hypothesis , this study introduces a sheaf-theoretic machine learning framework, Sheaf-ML , for integrating multimodal health data and assessing infection-related cognitive risk. Sheaf-ML constructs a unified patient-level representation that coherently combines diverse data streamsincluding serological infection markers, cognitive assessments, cardiovascular and metabolic measures, nutritional and behavioral evaluationswhile preserving the intrinsic structure and relationships of each modality. Applying this framework to the Harmonized LASI-DAD dataset (N = 6168), we modeled six clinically motivated domains (Infection, Cognition, Mental Health, Cardiovascular, Nutrition, and Demographics) and integrated them into a topologically consistent representation using learnable cross-domain mappings and consistency constraints. The sheaf-integrated embeddings revealed clinically meaningful interactions: infection burden was linked with cardio-vascular, nutritional, and cognitive outcomes, highlighting system-level coordination across modalities. Using these embeddings, Sheaf-ML produced interpretable patient-level predictions and identified the most influential features both globally and individually. We further derived an Infection Burden Index (IBI) , which quantified patient-level infection-related risk. Patients exceeding the 80 [th] percentile were flagged as early-warning cases, corresponding to approximately 20% of the cohort, demonstrating actionable stratification for clinical monitoring. This study provides the first empirical evidence that sheaf-based architectures can integrate multimodal health data in a clinically interpretable manner, uncover biologically meaningful interactions, and support patient-specific risk prediction. By linking population-level patterns with individualized insights, Sheaf-ML establishes a foundation for scalable, interpretable, and equitable precision models of infection-related cognitive decline in Alzheimers disease.},
}

@article {pmid41292499,
year = {2025},
author = {Spoto, F and Tian, J and Hügel, J and Ortega, DT and Ritchie, CS and Blacker, D and Dominici, F and Patel, CJ and Mork, D and Estiri, H},
title = {Quantifying diagnostic signal decay in dementia: a national study of Medicare hospitalization data.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70945},
doi = {10.1002/alz.70945},
pmid = {41292499},
issn = {1552-5279},
support = {R01AI165535//National Institute of Allergy and Infectious Diseases/ ; R01AG074372/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; United States ; *Medicare/statistics & numerical data ; *Dementia/diagnosis/epidemiology ; *Hospitalization/statistics & numerical data ; Cohort Studies ; Male ; Female ; Aged ; International Classification of Diseases ; *Artificial Intelligence ; },
abstract = {INTRODUCTION: Artificial intelligence (AI) models in healthcare require accurate diagnostic data. In dementia, diagnostic ambiguity and inconsistent coding may distort data quality.

METHODS: This cohort study analyzed 2016 to 2018 Medicare Part A hospitalization claims across 3000+ U.S. counties. Seventeen International Classification of Diseases, 10th Revision dementia codes were grouped into five categories. Temporal patterns were modeled using the transitive sequential pattern mining (tSPM+) algorithm; matrix similarity and multivariable regression assessed geographic and demographic variation.

RESULTS: Non-specific codes were most common. Alzheimer's and vascular dementia codes showed high regional variability. Frequent transitions from specific to non-specific codes indicated diagnostic signal decay. Counties with more rural, Medicaid-eligible, and Black or Hispanic patients had lower alignment with national patterns.

DISCUSSION: Dementia documentation varies widely and systematically across the United States. Much of this reflects inconsistent diagnostic practices, not true disease differences. Signal decay introduces bias into claims-based research and AI. Linking claims to validated cohorts may improve data quality and model fairness.

HIGHLIGHTS: Non-specific dementia codes dominate Medicare hospitalization data. Temporal analysis shows diagnostic signal decay over time. Geographic variation is linked to rurality and racial demographics. Signal decay poses bias risks for AI and claims-based research. Model explains 38% of variation in diagnostic pattern similarity.},
}

Humans
United States
*Medicare/statistics & numerical data
*Dementia/diagnosis/epidemiology
*Hospitalization/statistics & numerical data
Cohort Studies
Male
Female
Aged
International Classification of Diseases
*Artificial Intelligence

@article {pmid41292493,
year = {2025},
author = {Li, Y and Liu, W and Wang, X and Qin, W and Liu, Z and Lyu, D and Li, Y and Li, B and Xu, L and Cao, S and , and Chong, JRF and Lai, MKP and Chen, CLH and Jia, J},
title = {Effect of SSRIs on clinical progression in amnestic mild cognitive impairment stratified by Alzheimer's disease pathology.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70946},
doi = {10.1002/alz.70946},
pmid = {41292493},
issn = {1552-5279},
support = {2021ZD0201802//STI2030-Major Projects/ ; Z201100005520016//Beijing Municipal Science & Technology Commission/ ; Z201100005520017//Beijing Municipal Science & Technology Commission/ ; CX23YZ15//Chinese Institutes for Medical Research/ ; 31627803//National Key Scientific Instrument and Equipment Development Project/ ; U20A20354//Key Project of the National Natural Science Foundation of China/ ; 81530036//Key Project of the National Natural Science Foundation of China/ ; NMRC/CG/NUHS/2010//National Medical Research Council/ ; NMRC/CG/013/2013//National Medical Research Council/ ; NMRC/CIRG/1485/2018//National Medical Research Council/ ; CG21APR2010//National Medical Research Council/ ; MOH-000707//National Medical Research Council/ ; 2024KCJY0104//Key Project of the Science and Technology Innovation Elite Program/ ; GZC20240164//Postdoctoral Fellowship Program (Grade C) of China Postdoctoral Science Foundation/ ; 2024M750266//China Postdoctoral Science Foundation/ ; },
mesh = {Humans ; *Cognitive Dysfunction/pathology/drug therapy/diagnostic imaging ; *Selective Serotonin Reuptake Inhibitors/therapeutic use ; *Alzheimer Disease/pathology/drug therapy ; Male ; Female ; Disease Progression ; Aged ; Positron-Emission Tomography ; Amyloid beta-Peptides/metabolism ; *Amnesia/pathology ; Aged, 80 and over ; tau Proteins/metabolism ; Longitudinal Studies ; },
abstract = {INTRODUCTION: This study examined whether selective serotonin reuptake inhibitors (SSRIs) treatment influenced cognitive trajectory and progression to Alzheimer's disease (AD) dementia in amnestic mild cognitive impairment (MCI) patients, stratified by AD pathology.

METHODS: Four hundred fifty-seven amnestic MCI participants in the ADNI database were analyzed. AD pathology was determined by baseline amyloid beta (Aβ) and tau positron emission tomography. Kaplan-Meier survival analysis and Cox proportional hazards models evaluated MCI-to-AD progression. Linear mixed models analyzed longitudinal cognitive trajectories, amyloid accumulation, and cortical thickness.

RESULTS: SSRI treatment showed no significant effect on AD dementia progression (hazard ratio = 1.64, 95% confidence interval: 0.61 to 4.38) or cognitive trajectories, regardless of AD pathology. No significant differences in Aβ accumulation or cortical thickness were observed between SSRI users and non-users. External validation confirmed no significant SSRI effect on AD progression or cognitive decline.

DISCUSSION: SSRI treatment was not associated with long-term cognitive effects in amnestic MCI, irrespective of underlying AD pathology.

HIGHLIGHTS: SSRI treatment was not associated with long-term AD dementia risk in MCI. SSRI treatment had no impact on long-term cognitive performance changes in MCI. SSRI treatment did not affect Aβ accumulation or cortical thickness in MCI. SSRIs had no effect on MCI progression, regardless of underlying AD pathology.},
}

Humans
*Cognitive Dysfunction/pathology/drug therapy/diagnostic imaging
*Selective Serotonin Reuptake Inhibitors/therapeutic use
*Alzheimer Disease/pathology/drug therapy
Male
Female
Disease Progression
Aged
Positron-Emission Tomography
Amyloid beta-Peptides/metabolism
*Amnesia/pathology
Aged, 80 and over
tau Proteins/metabolism
Longitudinal Studies

@article {pmid41292426,
year = {2025},
author = {Menta, BW and Schueddig, E and Ranjan, A and Li, Y and Andrews, SJ and Wilkins, HM and Pei, D and Swerdlow, RH},
title = {MtDNA-depleted neuronal cell transcriptomes reveal Alzheimer's disease-related changes.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70929},
doi = {10.1002/alz.70929},
pmid = {41292426},
issn = {1552-5279},
support = {P30AG072973//The University of Kansas Alzheimer's Disease Research Center/ ; P30 GM122731/GM/NIGMS NIH HHS/United States ; S10OD021743//An NIH S10 High End Instrumentation award/ ; UL1TR002366//The KUMC Frontiers CTSA/ ; P30 CA168524/CA/NCI NIH HHS/United States ; P20 GM130423/GM/NIGMS NIH HHS/United States ; //The KUMC Neurological & Rehabilitation Sciences Training Program: NIHCHD T32HD057850/ ; //The Institute for Neurological Discoveries Mabel A. Woodyard Memorial Fellowship Fund/ ; //The KU Institute for Neurologic Discoveries/ ; //The Clune Family Foundation/ ; //The Ruble Family Foundation/ ; //The Snyder Family Foundation/ ; //The Stop Alzheimer's Now Foundation/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics/metabolism ; *DNA, Mitochondrial/genetics ; *Transcriptome/genetics ; *Neurons/metabolism ; Sequence Analysis, RNA ; Cell Line, Tumor ; },
abstract = {INTRODUCTION: We determined whether mitochondrial DNA (mtDNA) depletion induced Alzheimer's disease (AD)-relevant transcription changes.

METHODS: Following RNA sequencing (RNA-seq), we identified differentially expressed genes (DEGs) between SH-SY5Y or NT2 mtDNA-depleted (ρ0) and intact (ρ+) cell lines and quantified concordant DEG changes. Gene set enrichment analysis and over-representation analysis were used to determine the impact on the Kyoto Encyclopedia of Genes and Genomes (KEGG) AD and other neurodegenerative disease pathways, ascertain pathway and term enrichment in the Reactome and Gene Ontology databases, and generate Ingenuity Pathway Analysis z-scores.

RESULTS: Relative to their ρ+ comparators, ρ0 lines differentially expressed >75% of their genes. The KEGG AD pathway was significantly enriched, and equivalently altered genes ranked the AD, Parkinson's disease, ALS, and Huntington's disease KEGG pathways among the most enriched gene sets. AD-related enriched pathways and terms reflected lipid, insulin signaling, synapse, inflammation/immune response, endosome/endocytosis, RNA, and proteostasis biology.

CONCLUSION: MtDNA depletion alters gene expression in ways that recapitulate or predictably promote AD molecular phenomena.

HIGHLIGHTS: MtDNA-depleted neuronal cell lines reshuffle nuclear gene expression. The KEGG AD pathway is enriched with DEGs. Transcription-defined pathways and terms relating to AD biology broadly change.},
}

Humans
*Alzheimer Disease/genetics/metabolism
*DNA, Mitochondrial/genetics
*Transcriptome/genetics
*Neurons/metabolism
Sequence Analysis, RNA
Cell Line, Tumor

@article {pmid41292421,
year = {2025},
author = {Sideman, AB and Merrilees, J and Dulaney, S and Allawala, M and Barclay, M and Rosenbloom, M and Hanson, LR and Ward, KT and Hess, M and Olney, NT and Lum, HD and Sawyer, RJ and Possin, KL},
title = {Facilitators and challenges in the implementation of the Care Ecosystem at six clinical sites in the United States: A qualitative study.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70917},
doi = {10.1002/alz.70917},
pmid = {41292421},
issn = {1552-5279},
support = {R01AG056715//the National Institute on Aging/ ; R01AG074710//the National Institute on Aging/ ; R01AG087166//the National Institute on Aging/ ; K01AG059840//the National Institute on Aging/ ; //the Alzheimer's Association/ ; //the Merck Foundation/ ; #24-10129//the California Department of Public Health Alzheimer's Disease Program/ ; //the Global Brain Health Institute/ ; },
mesh = {Humans ; United States ; *Dementia/therapy ; Qualitative Research ; *Patient Care Team ; *Patient Navigation ; },
abstract = {INTRODUCTION: Collaborative care models with care navigation bridge medical and social needs in dementia care. These models, including the Care Ecosystem (CE), are being implemented at health systems and community-based programs across the United States.

METHODS: Interdisciplinary team members from six early adopter CE programs were interviewed about the facilitators and challenges they faced implementing the CE. Interviews were analyzed thematically.

RESULTS: Implementation facilitators included the presence of a champion or visionary, a clinical team with expertise in dementia, easy access to CE care protocols and consultative support, and flexibility in being able to modify the program to meet site-specific needs. Challenges centered on program launch, personnel turnover, reaching people from historically marginalized communities or those facing structural barriers to care, and program sustainability.

DISCUSSION: This study provides practical information to guide successful implementation of effective dementia care from research to practice.

HIGHLIGHTS: Collaborative care models with care navigation bridge medical and social needs in dementia care. Implementation facilitators included a champion, an expert clinical team, and flexibility. Challenges included program launch, personnel turnover, and program sustainability. Findings can guide implementation of effective dementia care from research to practice.},
}

Humans
United States
*Dementia/therapy
Qualitative Research
*Patient Care Team
*Patient Navigation

@article {pmid41292400,
year = {2025},
author = {Kang, X and Bergman, D and Sun, J and Wirdefeldt, K and Ludvigsson, JF},
title = {Microscopic colitis is associated with an increased risk of dementia in a Swedish population.},
journal = {Journal of internal medicine},
volume = {},
number = {},
pages = {},
doi = {10.1111/joim.70046},
pmid = {41292400},
issn = {1365-2796},
support = {//Region Stockholm/ ; //Svenska Sällskapet för Medicinsk Forskning/ ; //European Crohn's and Colitis Organization/ ; //Loo och Hans Ostermans Stiftelse för Medicinsk Forskning/ ; //Parkinsonfonden/ ; //Stockholms Läns Landsting/ ; 2022-00164//Vetenskapsrådet/ ; //Karolinska Institutet/ ; },
abstract = {BACKGROUND: The microbiota-gut-brain axis has been implicated in dementia. Yet whether dementia is associated with microscopic colitis (MC), an age-related inflammatory colonic disease involving gut dysbiosis, remains unknown.

METHODS: Using the nationwide ESPRESSO cohort in Sweden, we compared MC patients histologically diagnosed 1990-2017 and aged ≥30 years to their population-based comparators and siblings, separately. MC association with incident and prevalent dementia diagnosis, respectively, was investigated in a matched cohort and a matched case-control design.

FINDINGS: Following 13,037 MC patients and 61,710 population comparators for a median of ∼10 years, we observed 4674 incident dementia cases (46% were Alzheimer's disease [AD]). During the first 5 years since biopsy, MC was associated with a 19% higher dementia risk (adjusted hazard ratio [aHR]: 1.19; 95% confidence interval [CI]: 1.07-1.32). This short-term association applied to both AD and vascular dementia and appeared stronger as compared to siblings (aHR: 1.55; 95% CI: 1.22-1.97). After 5 years, it attenuated to null in both comparisons, regardless of dementia subtype. Prior dementia was less prevalent in MC (adjusted odds ratio [aOR]: 0.73; 95% CI: 0.65-0.82). This inverse association was independent from medications commonly prescribed in MC but was not supported by sibling findings (aOR: 1.11; 95% CI: 0.81-1.51).

CONCLUSIONS: MC patients may be more vulnerable to dementia diagnosis in early disease course. The intriguing inverse association between MC and preexisting dementia implies a possible underdiagnosis of MC in demented population and warrants further investigation.},
}

@article {pmid41292253,
year = {2025},
author = {Pérez-Ramírez, R and Cuchillo-Ibáñez, I and Sánchez-Romero, R and Beltrán-Sanahuja, A and Escamilla, S and Molina-Gasset, R and Zetterberg, H and Blennow, K and Sáez-Valero, J and Todolí-Torró, JL},
title = {Development and Validation of an ICP-MS/MS Method for the Multielemental Analysis of Cerebrospinal Fluid, Examination of Alzheimer's Disease Samples.},
journal = {Journal of neurochemistry},
volume = {169},
number = {11},
pages = {e70307},
doi = {10.1111/jnc.70307},
pmid = {41292253},
issn = {1471-4159},
support = {101053962//European Union's Horizon Europe/ ; #ALFGBG-71320//Swedish State Support for Clinical Research/ ; PI22/01329//Fondo de Investigaciones Sanitarias/ ; #2023-00356 #2022-01018 #2019-02397//Swedish Research Council/ ; AEI/10.13039/501100011033//Agencia Estatal de Investigación/ ; PID2021-127566NB-I00//Agencia Estatal de Investigación/ ; //Instituto de Salud Carlos III/ ; },
mesh = {Humans ; *Alzheimer Disease/cerebrospinal fluid/diagnosis ; Male ; Female ; Aged ; Biomarkers/cerebrospinal fluid ; *Tandem Mass Spectrometry/methods ; Middle Aged ; Aged, 80 and over ; Amyloid beta-Peptides/cerebrospinal fluid ; Peptide Fragments/cerebrospinal fluid ; tau Proteins/cerebrospinal fluid ; },
abstract = {Multielemental analysis of cerebrospinal fluid (CSF) yields critical insights into the pathophysiology of neurological disorders and holds potential as a diagnostic and predictive tool for Alzheimer's disease (AD). The present work presents the development and validation of an inductively coupled plasma tandem mass spectrometry (ICP-MS/MS) based method for multielemental determination in CSF, including metals and metalloids as analytes. As a proof of concept, the importance of the CSF element determination was evaluated in a cohort of patients with AD (n = 20) and non-AD controls (n = 19) who displayed typical levels of core CSF biomarkers (Aβ42, P-tau, and total-tau). Discrete sample introduction ICP-MS/MS procedure was effective for accurate and precise CSF analysis. The methodology provided better sensitivities and limits of detection than a conventional one based on sample dilution and analysis in continuous sample introduction mode, while only requiring a 20 μL CSF sample volume. A total of 24 elements were encountered and quantified in CSF, with reduced levels of Mn, Cr, Se, Fe, and Zn in the CSF from AD patients and increased levels of Ag and Bi, compared with non-AD patients. Particularly, Mn fully discriminated AD from non-AD subjects, with binary regression analysis indicating that Mn was the most effective element to distinguish between AD and non-AD groups. Furthermore, distinctive correlation profiles were found between AD and non-AD controls for elements with AD core biomarkers and the alternative amyloidogenic sAPPβ fragment. Quantitative determination of metals, metalloids and non-metals displays differences associated with pathological status, serving as additional biomarkers for neurological diseases.},
}

Humans
*Alzheimer Disease/cerebrospinal fluid/diagnosis
Male
Female
Aged
Biomarkers/cerebrospinal fluid
*Tandem Mass Spectrometry/methods
Middle Aged
Aged, 80 and over
Amyloid beta-Peptides/cerebrospinal fluid
Peptide Fragments/cerebrospinal fluid
tau Proteins/cerebrospinal fluid

@article {pmid41292222,
year = {2025},
author = {Paraiso, HC and Yen, JJ and Scofield, BA and Kuo, PC and Chang, FL and Yu, II},
title = {Microglial Nrf2 Functions as a Cell-Autonomous Regulator of Neuroinflammation and Trained Immunity in the Aging Brain.},
journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology},
volume = {39},
number = {22},
pages = {e71244},
doi = {10.1096/fj.202501457RR},
pmid = {41292222},
issn = {1530-6860},
support = {1R21AG070971 01A1//HHS | NIH | National Institute on Aging (NIA)/ ; 1R01NS102449 01A1//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; },
mesh = {Animals ; *NF-E2-Related Factor 2/metabolism/genetics ; *Microglia/metabolism/immunology/pathology ; Mice ; *Aging/immunology/metabolism ; *Brain/immunology/metabolism/pathology ; Mice, Knockout ; *Neuroinflammatory Diseases/metabolism/immunology/pathology ; Mice, Inbred C57BL ; Male ; Inflammation/metabolism ; Trained Immunity ; },
abstract = {Aging is the primary risk factor for Alzheimer's disease (AD) and related dementias, with chronic neuroinflammation contributing to disease progression. Microglia, the brain's resident immune cells, undergo age-associated changes that disrupt neuroimmune homeostasis and exacerbate neuroinflammation. The transcription factor Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2), a master regulator of cellular stress responses, has an undefined role in microglial aging. We demonstrate that Nrf2 mRNA expression and protein decline in aged microglia, coinciding with increased neuroinflammation and antigen presentation. Global Nrf2-deficient (Nrf2[-/-]) mice exhibit amplified microglial activation, elevated MHC class II-related CD74 expression, and enhanced infiltration of peripheral CD4[+] T cells into the brain. Nrf2[-/-] microglia adopt a disease-associated microglia (DAM)-like phenotype, characterized by upregulated activation markers and transcriptional reprogramming. Functionally, Nrf2 loss impairs motor learning and cognitive performance in middle-aged mice. To dissect the role of microglial Nrf2, we generated microglia-specific Nrf2 knockout (MG-Nrf2-KO) mice using a Cx3cr1-CreERT2 system. MG-Nrf2-KO mice exhibit exaggerated microglial immune training characterized by elevated brain TNFα and IL-1β production upon secondary LPS challenge, despite preserved peripheral immune tolerance. The heightened training response is accompanied by reduced IL-10 expression in MG-Nrf2-KO brains, indicating impaired anti-inflammatory counter-regulation. Ex vivo restimulation confirms that Nrf2-deficient microglia intrinsically produce elevated pro-IL-1β protein upon rechallenge, establishing Nrf2 as a cell-autonomous regulator of microglial immune memory. These findings identify Nrf2 as an intrinsic regulator of microglial immune memory and neuroinflammatory restraint. Modulating Nrf2 signaling in microglia may offer a therapeutic strategy to mitigate chronic neuroinflammation and cognitive decline in aging and neurodegeneration.},
}

Animals
*NF-E2-Related Factor 2/metabolism/genetics
*Microglia/metabolism/immunology/pathology
Mice
*Aging/immunology/metabolism
*Brain/immunology/metabolism/pathology
Mice, Knockout
*Neuroinflammatory Diseases/metabolism/immunology/pathology
Mice, Inbred C57BL
Male
Inflammation/metabolism
Trained Immunity

@article {pmid41291954,
year = {2025},
author = {Xiao, L and Sharma, P and Yang, X and Abebe, D and Loh, YP},
title = {Neurotrophic factor-α1/carboxypeptidase E regulates critical protein networks to rescue neurodegeneration, defective synaptogenesis and impaired autophagy in Alzheimer's disease mice.},
journal = {Translational neurodegeneration},
volume = {14},
number = {1},
pages = {59},
pmid = {41291954},
issn = {2047-9158},
support = {Intramural research grant//National Institute of Child Health and Human Development/ ; },
mesh = {Animals ; *Alzheimer Disease/metabolism/pathology/genetics/therapy ; Mice ; *Autophagy/physiology ; *Synapses/metabolism/pathology ; Male ; Mice, Transgenic ; *Carboxypeptidase H/genetics/metabolism ; Hippocampus/metabolism/pathology ; Humans ; Disease Models, Animal ; Genetic Therapy/methods ; Proteomics ; Mice, Inbred C57BL ; },
abstract = {BACKGROUND: The global aging population is increasingly inflicted with Alzheimer's disease (AD), but a cure is still unavailable. Neurotrophic factor-α1/carboxypeptidase E (NF-α1/CPE) gene therapy has been shown to prevent and reverse memory loss and pathology in AD mouse models. However, the mechanisms of action of NF-α1/CPE are not fully understood. We investigated if a non-enzymatic form of NF-α1/CPE-E342Q is efficient in reversing AD pathology and carried out a proteomic study to uncover the mechanisms of action of NF-α1/CPE in AD mice.

METHODS: AAV-human NF-α1/CPE or a non-enzymatic form, NF-α1/CPE-E342Q, was delivered into the hippocampus of 3 × Tg-AD male mice. The effects on cognitive function, neurodegeneration, synaptogenesis and autophagy were investigated. A quantitative proteomic analysis of the hippocampus was carried out.

RESULTS: Hippocampal delivery of AAV-NF-α1/CPE-E342Q prevented memory loss, neurodegeneration and microglial activation in 3 × Tg-AD mice, indicating that the action is independent of its enzymatic activity. Quantitative proteomic analysis of the hippocampus of 3 × Tg-AD mice revealed differential expression of > 2000 proteins involving many metabolic pathways after NF-α1/CPE gene therapy. Of these, two new proteins, Snx4 and Trim28, which increase Aβ production and tau levels, respectively, were down-regulated by NF-α1/CPE. Western blot analysis verified their reduction in AAV-NF-α1/CPE-treated 3 × Tg-AD mice compared to untreated mice. Our proteomic analysis indicated synaptic organization as the top signaling pathway altered in response to CPE expression. Synaptic markers PSD95 and Synapsin1 were decreased in 3 × Tg-AD mice and were restored with AAV-NF-α1/CPE treatment. Proteomic analysis hypothesized involvement of autophagic signaling pathway. Indeed, multiple protein markers of autophagy were down-regulated in 3 × Tg-AD mice, accounting for impaired autophagy. NF-α1/CPE gene therapy upregulated the levels of these proteins in 3 × Tg-AD mice, thereby reversing autophagic impairment.

CONCLUSIONS: This study uncovered vast actions of NF-α1/CPE in restoring expression of networks of critical proteins including those necessary for maintaining neuronal survival, synaptogenesis and autophagy, while down-regulating many proteins that promote tau and Aβ accumulation to reverse memory loss and AD pathology in 3 × Tg-AD mice. AAV-NF-α1/CPE gene therapy uniquely targets many metabolic levels, offering a promising holistic approach for AD treatment (Graphical Abstract).},
}

Animals
*Alzheimer Disease/metabolism/pathology/genetics/therapy
Mice
*Autophagy/physiology
*Synapses/metabolism/pathology
Male
Mice, Transgenic
*Carboxypeptidase H/genetics/metabolism
Hippocampus/metabolism/pathology
Humans
Disease Models, Animal
Genetic Therapy/methods
Proteomics
Mice, Inbred C57BL

@article {pmid41291905,
year = {2025},
author = {Maschio, CA and Moreno, O and Wang, J and Maheshwari, U and Keller, A and Konietzko, U and Razansky, D and Nordberg, A and Rominger, A and Hock, C and Llop, J and Nitsch, RM and Ni, R},
title = {Increased levels of GFAP and purinergic P2X7 receptor in Alzheimer's disease brain are associated with Aβ, tau pathologies and synaptic loss.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-025-01916-2},
pmid = {41291905},
issn = {1758-9193},
support = {PRE2019-089068//MCIN/AEI/ 10.13039/501100011033/ ; PID2023-148642OB-I00 and PID2020-117656RB-I00//MCIN/AEI/ 10.13039/501100011033/ ; 31ND30_213444//Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung/ ; },
}

@article {pmid41291841,
year = {2025},
author = {Li, L and Xu, F and Duan, H and Qi, J and Zhang, J and Ma, K},
title = {Identification and validation of PANoptosis-related biomarkers in Alzheimer's disease via single-cell RNA sequencing and machine learning.},
journal = {European journal of medical research},
volume = {30},
number = {1},
pages = {1170},
pmid = {41291841},
issn = {2047-783X},
support = {QNYJ2023001//Henan Academy of Medical Sciences/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics/pathology ; *Machine Learning ; Biomarkers/metabolism ; *Single-Cell Analysis/methods ; Sequence Analysis, RNA/methods ; Gene Regulatory Networks ; Gene Expression Profiling ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with complex underlying mechanisms. PANoptosis, a newly defined form of programmed cell death that integrates pyroptosis, apoptosis, and necroptosis, may play a crucial role in AD pathogenesis. However, the involvement of PANoptosis-related genes in AD remains unclear.

METHODS: We analyzed single-cell RNA-seq data (GSE181279) to identify differentially expressed genes (scDEGs) between AD patients and normal controls. PANoptosis-associated genes (PAGs), curated from published studies, were intersected with differentially expressed genes (DEGs) from GSE85426 to identify differentially expressed PAGs (DE-PAGs). Weighted gene co-expression network analysis was performed to identify key gene modules. Candidate genes were identified by overlapping scDEGs, DEGs, and module genes. Hub genes were screened via three machine learning algorithms: least absolute shrinkage and selection operator (LASSO), support vector machine (SVM), and random forest (RF). Genes with consistent expression across GSE85426 and GSE48350 were considered potential biomarkers. These were evaluated by receiver operating characteristic analysis and incorporated into a nomogram. Gene set enrichment analysis was used to explore associated pathways. Immune infiltration analysis was used to assess the biomarkers' roles in the immune microenvironment and identify potential therapeutic targets. Finally, qRT-PCR was performed to validate biomarker expression in clinical samples.

RESULTS: Overlapping 987 scDEGs, 991 DEGs, and 5327 module genes yielded 27 candidate genes. LASSO, SVM, and RF analyses identified eight hub genes, among which five (BACH2, CKAP4, DDIT4, GGNBP2, and ZFP36L2) were ultimately validated as biomarkers. A nomogram based on these genes showed good predictive performance (area under the curve (AUC) = 0.779). Seven immune cell types differed significantly between the AD and control groups, with T follicular helper cells strongly correlated with most biomarkers except CKAP4 (cor > 0.36, p < 0.001). Several Aβ- and tau-related genes and immune factors also showed significant associations (|cor|> 0.3, p < 0.05). These biomarkers were further linked to AD and other functional pathways. qRT-PCR was used to validate the transcriptomic findings, with the exception of BACH2.

CONCLUSIONS: This study identified five novel PANoptosis-related biomarkers with diagnostic and therapeutic potential in AD. These findings provide a theoretical basis for future clinical research and may contribute to improved AD diagnosis and treatment strategies.},
}

Humans
*Alzheimer Disease/genetics/pathology
*Machine Learning
Biomarkers/metabolism
*Single-Cell Analysis/methods
Sequence Analysis, RNA/methods
Gene Regulatory Networks
Gene Expression Profiling

@article {pmid41291825,
year = {2025},
author = {Tian, G and Zheng, D and Zhang, N and Deng, W and Xu, J and Huang, C and Chen, Q and Hu, S and Xin, L and Wang, H and Wang, B and Li, K and Xu, D},
title = {Association of blood-based DNA methylation of lncRNAs with Alzheimer's disease diagnosis.},
journal = {Clinical epigenetics},
volume = {17},
number = {1},
pages = {200},
pmid = {41291825},
issn = {1868-7083},
support = {Qhys2023-489, Qhys2023-447, Qhys2024-477, Qhys2024-473//Innovative research project for Graduate students in Hainan Province/ ; Qhys2023-489, Qhys2023-447, Qhys2024-477, Qhys2024-473//Innovative research project for Graduate students in Hainan Province/ ; Qhys2023-489, Qhys2023-447, Qhys2024-477, Qhys2024-473//Innovative research project for Graduate students in Hainan Province/ ; Qhys2023-489, Qhys2023-447, Qhys2024-477, Qhys2024-473//Innovative research project for Graduate students in Hainan Province/ ; ZDYF2022SHFZ040, ZDYF2021SHFZ247//Hainan Province Science and Technology special fund/ ; ZDKJ2021040//Major Science and Technology Program of Hainan Province/ ; 32160152, 32460161//National Natural Science Foundation of China/ ; 825QN315//Hainan Provincial Natural Science Foundation of China/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics/diagnosis/blood ; *DNA Methylation/genetics ; *RNA, Long Noncoding/genetics/blood ; Male ; Female ; Aged ; Biomarkers/blood ; Epigenesis, Genetic ; Machine Learning ; Aged, 80 and over ; },
abstract = {BACKGROUND: DNA methylation has shown great potential in Alzheimer's disease (AD) blood diagnosis. However, the ability of long non-coding RNAs (lncRNAs), which can be modified by DNA methylation, to serve as noninvasive biomarkers for AD diagnosis remains unclear.

METHODS: We performed logistic regression analysis of DNA methylation data from the blood of patients with AD compared and normal controls to identify epigenetically regulated (ER) lncRNAs. Through five machine learning algorithms, we prioritized ER lncRNAs associated with AD diagnosis. An AD blood diagnosis model was constructed based on lncRNA methylation in Australian Imaging, Biomarkers, and Lifestyle (AIBL) subject and verified in two large blood-based studies, the European collaboration for the discovery of novel biomarkers for Alzheimer's disease (AddNeuroMed) and the Alzheimer's Disease Neuroimaging Initiative (ADNI). In addition, the potential biological functions and clinical associations of lncRNAs were explored, and their neuropathological roles in AD brain tissue were estimated via cross-tissue analysis.

RESULTS: We characterized the ER lncRNA landscape in AD blood, which is strongly related to AD occurrence and process. Fifteen ER lncRNAs were prioritized to construct an AD blood diagnostic and nomogram model. The receiver operating characteristic (ROC) curve and the decision and calibration curves show that the model has good prediction performance. We found that the targets and lncRNAs were correlated with AD clinical features. Moreover, cross-tissue analysis revealed that the lncRNA ENSG0000029584 plays both diagnostic and neuropathological roles in AD.

CONCLUSION: Our results demonstrate the diagnostic capacity of lncRNA methylation in AD blood, providing novel insights into the development of noninvasive biomarkers of AD.},
}

Humans
*Alzheimer Disease/genetics/diagnosis/blood
*DNA Methylation/genetics
*RNA, Long Noncoding/genetics/blood
Male
Female
Aged
Biomarkers/blood
Epigenesis, Genetic
Machine Learning
Aged, 80 and over

@article {pmid41291701,
year = {2025},
author = {Liu, XG and Zhang, L and Lu, S and Liu, DQ and Huang, YR and Zhu, J and Zhou, WW and Yu, XL and Liu, RT},
title = {Retraction Note: Superparamagnetic iron oxide nanoparticles conjugated with Aβ oligomer-specific ScFv antibody and class A scavenger receptor activator show therapeutic potentials for alzheimer's disease.},
journal = {Journal of nanobiotechnology},
volume = {23},
number = {1},
pages = {739},
doi = {10.1186/s12951-025-03880-3},
pmid = {41291701},
issn = {1477-3155},
}

@article {pmid41291536,
year = {2025},
author = {Barr, PJ and Martinez-Pereira, A and O'Malley, J and Carpenter-Song, E and Bruce, ML and Jacobson, N and Morgan, B and Lee, YS and Fernandez, G and Onsando, WM and Khaleghzadegan, S and Flaherty, E and Ganoe, C and Hernandez, D and Mistler, L and Oh, L and Tarczewski, S and Chodosh, J},
title = {Evaluating the role of visit audio recordings in triadic dementia care: study protocol.},
journal = {BMC geriatrics},
volume = {25},
number = {1},
pages = {956},
pmid = {41291536},
issn = {1471-2318},
support = {R01AG077113/AG/NIA NIH HHS/United States ; R01AG077113/AG/NIA NIH HHS/United States ; R01AG077113/AG/NIA NIH HHS/United States ; R01AG077113/AG/NIA NIH HHS/United States ; R01AG077113/AG/NIA NIH HHS/United States ; R01AG077113/AG/NIA NIH HHS/United States ; R01AG077113/AG/NIA NIH HHS/United States ; R01AG077113/AG/NIA NIH HHS/United States ; R01AG077113/AG/NIA NIH HHS/United States ; R01AG077113/AG/NIA NIH HHS/United States ; R01AG077113/AG/NIA NIH HHS/United States ; R01AG077113/AG/NIA NIH HHS/United States ; R01AG077113/AG/NIA NIH HHS/United States ; R01AG077113/AG/NIA NIH HHS/United States ; R01AG077113/AG/NIA NIH HHS/United States ; R01AG077113/AG/NIA NIH HHS/United States ; R01AG077113/AG/NIA NIH HHS/United States ; R01AG077113/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Dementia/therapy/psychology/diagnosis ; *Communication ; *Interpersonal Relations ; Female ; Male ; Aged ; },
abstract = {BACKGROUND: Effective interpersonal communication is associated with improved health-related outcomes, yet it is unclear to what extent this occurs in triadic clinic visits for persons living with dementia (PLWD) and few tools exist to characterize triadic interpersonal communication and assess its effectiveness. The objective of this project is to characterize the interpersonal communication that occurs during triadic visits for PLWD, examine how interpersonal communication is related to health outcomes and use this understanding to adapt an innovative clinic visit audio recording intervention, HealthPAL (Personal Audio Library) for use in this setting.

METHODS: Following the NIH Stage Model, we will redesign a visit recording platform, HealthPAL, which leverages natural language processing to structure visit information. In Aim 1, we will use an explanatory sequential mixed methods design. Informed by the Behavior Change Wheel, targets for behavior change will be identified using quantitative assessment of interpersonal communication during triadic visits (200 dyads, 3 visits annually; ∼600 visits), supplemented by semi-structured interviews with a purposive sample of triads (n = 42); In Aim 2, we will use participatory design methods (n = 60) to redesign HealthPAL using findings from Aim 1; and in Aim 3, we will use an open label, single-arm, multi-site pilot trial (n = 30) to determine usability, feasibility and acceptability of HealthPAL and gather preliminary data on its impact on interpersonal communication in triadic AD/ADRD visits. We hypothesize: (1) Constructs from models of interpersonal communication will be associated with health-related outcomes; (2) HealthPAL will surpass usability, feasibility, and acceptability metrics for dyads and clinicians.

DISCUSSION: This work is a necessary first step to improving PLWD triadic care by identifying behaviors that impact triadic interpersonal communication and their associations with health-related outcomes. The novel intervention that we will develop--the use of visit recordings--and the diverse and extensive data we will collect will serve as a unique resource that can be leveraged to address other gaps in clinical knowledge related to the care of PLWD.},
}

Humans
*Dementia/therapy/psychology/diagnosis
*Communication
*Interpersonal Relations
Female
Male
Aged

@article {pmid41291280,
year = {2025},
author = {Manso, Y and Carrasco, J and Comes, G and Adlard, PA and Bush, AI and Hidalgo, J},
title = {Correction: Characterization of the role of the antioxidant proteins metallothioneins 1 and 2 in an animal model of Alzheimer's disease.},
journal = {Cellular and molecular life sciences : CMLS},
volume = {82},
number = {1},
pages = {429},
doi = {10.1007/s00018-025-05953-w},
pmid = {41291280},
issn = {1420-9071},
}

@article {pmid41291238,
year = {2025},
author = {Li, H and Yu, C and Markovic, T and Nestler, EJ and Dong, Y},
title = {Chemical strategies for brain delivery of genomic therapy.},
journal = {Nature reviews. Chemistry},
volume = {},
number = {},
pages = {},
pmid = {41291238},
issn = {2397-3358},
abstract = {Genomic therapy has emerged as a transformative strategy for the prevention, diagnosis and treatment of a wide array of diseases, including Alzheimer's disease, amyotrophic lateral sclerosis and other CNS-related diseases. Recent developments in chemical strategies and delivery platforms have enhanced the potential of genomic therapies for brain disorders. In this Review, we summarize such strategies, focusing on advances in delivery platforms such as lipid nanoparticles, polymers and oligonucleotide conjugates to facilitate the brain delivery of DNA-based or RNA-based therapeutics into the CNS. We present an overview of the chemical structures and functional moieties of lipids, polymers and oligonucleotides used in these platforms. Lastly, we provide an outlook on future chemical directions to further improve the delivery of genomic medicines to the brain.},
}

@article {pmid41291173,
year = {2025},
author = {Mutee, AF and Shareef, A and Kaur, I and Malathi, H and Maharana, L and Kumar, S and Purohit, B and Buzrukzoda, J and Sameer, HN and Yaseen, A and Athab, ZH and Adil, M and , },
title = {Elevated plasma sex hormone-binding globulin (SHBG) is associated with reduced temporal lobe volume and cognitive impairment in individuals with mild cognitive impairment.},
journal = {European geriatric medicine},
volume = {},
number = {},
pages = {},
pmid = {41291173},
issn = {1878-7649},
abstract = {PURPOSE: Sex hormone-binding globulin (SHBG), which regulates androgen and estrogen bioavailability, has been linked to cognitive decline, but its relationship with temporal lobe changes-an area vulnerable in early Alzheimer's disease (AD)-remains unclear. This study aimed to investigate whether plasma SHBG levels are associated with temporal lobe volume and cognitive performance across the cognitive spectrum from normal aging to AD.

METHODS: Participants included individuals with AD (n = 85), mild cognitive impairment (MCI; n = 304), and cognitively normal controls (CN; n = 50). Cognitive performance was assessed using the ADAS-Cog 11, MMSE, and CDR-SB. Temporal lobe volumes were derived from MRI scans using tensor-based morphometry (TBM), and plasma SHBG levels were measured using a validated immunoassay. Multiple regression analyses adjusted for age, sex, education, handedness, and APOE ε4 status were conducted, followed by mediation analysis to test indirect effects through temporal lobe volume.

RESULTS: After covariate adjustment, elevated plasma SHBG levels were significantly associated with reduced temporal lobe volume in the MCI group. Across both MCI and AD participants, greater temporal lobe volume correlated with better cognitive performance on all tests. Mediation analysis indicated that in MCI, the relationship between higher plasma SHBG and poorer cognitive outcomes was significantly mediated by reduced temporal lobe volume.

CONCLUSION: These findings suggest that elevated SHBG may contribute to early cognitive impairment in MCI through its impact on temporal lobe integrity, highlighting SHBG as a potential target in the prodromal stages of AD.},
}

@article {pmid41290974,
year = {2025},
author = {Salmani, M and Anoush, M and Kalantari-Hesari, A and Jahani-Maleki, A and Nouri, F and Hosseini, MJ and Mohammadi, M},
title = {Protective role of fucoidan against cognitive deficits and redox imbalance in a scopolamine-induced Alzheimer's disease model in rats.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {41813},
pmid = {41290974},
issn = {2045-2322},
mesh = {Animals ; *Polysaccharides/pharmacology ; *Scopolamine/toxicity/adverse effects ; *Alzheimer Disease/chemically induced/drug therapy/metabolism ; Male ; Rats ; Disease Models, Animal ; Oxidative Stress/drug effects ; Rats, Wistar ; *Cognitive Dysfunction/drug therapy/chemically induced/metabolism ; *Neuroprotective Agents/pharmacology ; Hippocampus/drug effects/metabolism ; Oxidation-Reduction/drug effects ; Donepezil/pharmacology ; Prefrontal Cortex/drug effects/metabolism ; Maze Learning/drug effects ; Antioxidants ; },
abstract = {This study examined the neuroprotective impacts of fucoidan on behavioral performance and oxidative damage in an animal model with scopolamine-induced cognitive deficits. Male Wistar rats, aged 8 weeks, were administered scopolamine (2 mg/kg) for 10 days. Fucoidan (15-60 mg/kg) or donepezil (1 mg/kg) was administered prior to behavioral tests over three consecutive weeks. To assess memory and learning, all rats underwent the Morris water maze (MWM) task and the Novel Object Recognition (NOR) test. Following the tests, the hippocampi and prefrontal cortex (PFC) of the rats were collected to evaluate oxidative stress parameters across all treatment groups. A significant decrease in the mean Q2 time was observed during the probe trial in the water maze task after scopolamine injection on the test day. Administration of fucoidan (15-60 mg/kg) or donepezil (1 mg/kg) notably improved cognitive dysfunction (p < 0.001). Biochemical analysis demonstrated a decline in protein carbonyl and malondialdehyde levels, along with an elevation in reduced glutathione and total antioxidant capacity in the fucoidan-treated rats (15-60 mg/kg). It is supposed that cholinergic dysfunction and oxidative stress are key contributors to cognitive deficits, and fucoidan may protect the hippocampus and prefrontal cortex by mitigating oxidative damage biomarkers.},
}

Animals
*Polysaccharides/pharmacology
*Scopolamine/toxicity/adverse effects
*Alzheimer Disease/chemically induced/drug therapy/metabolism
Male
Rats
Disease Models, Animal
Oxidative Stress/drug effects
Rats, Wistar
*Cognitive Dysfunction/drug therapy/chemically induced/metabolism
*Neuroprotective Agents/pharmacology
Hippocampus/drug effects/metabolism
Oxidation-Reduction/drug effects
Donepezil/pharmacology
Prefrontal Cortex/drug effects/metabolism
Maze Learning/drug effects
Antioxidants

@article {pmid41290970,
year = {2025},
author = {Zareen, W and Rafique, M and Ahmed, N and Khan, MA and Tahir, M and Mali, SN and Sadeghian, N and Taslimi, P and Ismail, MA and Chaudhari, SY and Khan, A and Şenol, H and Shafiq, Z},
title = {Design, synthesis, and computational insights into 3-acetyl-8-methoxy coumarin hybrids as potential anti-alzheimer's agents.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {41752},
pmid = {41290970},
issn = {2045-2322},
mesh = {*Coumarins/chemistry/pharmacology/chemical synthesis ; *Cholinesterase Inhibitors/pharmacology/chemistry/chemical synthesis ; *Alzheimer Disease/drug therapy ; Humans ; Molecular Docking Simulation ; Acetylcholinesterase/metabolism/chemistry ; Butyrylcholinesterase/metabolism/chemistry ; *Drug Design ; Monoamine Oxidase/metabolism/chemistry ; Monoamine Oxidase Inhibitors/pharmacology/chemistry/chemical synthesis ; Structure-Activity Relationship ; },
abstract = {The most prevalent degenerative brain disease, Alzheimer's disease (AD), is characterized by cognitive function impairment. The ability to code new memories is lost in AD patients, and their lives are very challenging. Inhibitors of cholinesterase (ChE) and monoamine oxidase (MAO) have drawn interest as potential therapies for AD. To combat Alzheimer's disease (AD), a new class of Coumarin-hydrazone hybrids has been synthesized 3(a-m). Compounds 3a, 3e, and 3l exhibited significant acetylcholinesterase (AChE) inhibitory activity with low IC50 values of 7.40 ± 0.14 µM, 8.01 ± 0.70 µM, and 8.54 ± 1.01 µM, respectively. Additionally, these compounds, along with 3k, demonstrated potent butyrylcholinesterase (BChE) inhibition, with IC50 values from 65.41 ± 4.55 µM to 74.98 ± 5.30 µM, highlighting their dual cholinesterase inhibitory potential. Compound like 3a (1.44 ± 0.03 µM), 3e (1.51 ± 0.13 µM), and 3l (1.65 ± 0.03 µM) display robust MAO-A inhibition, suggesting high potency. To see how the most potent inhibitor chemicals affected the substrate-enzyme relationship, enzyme kinetic tests were conducted in addition to enzyme inhibition investigations. Compound 3e may function as a dual binding site AChE inhibitor, according to docking studies in addition to in vitro testing.},
}

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

@article {pmid41290916,
year = {2025},
author = {Osama, L and ElShebiney, S and Beherei, HH and Elzayat, EM and Mabrouk, M},
title = {Modulation of experimental Alzheimer's disease in rats through donepezil-loaded CSF implant.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {42017},
pmid = {41290916},
issn = {2045-2322},
mesh = {Animals ; *Donepezil/administration & dosage/pharmacology ; *Alzheimer Disease/drug therapy/cerebrospinal fluid/pathology ; Rats ; Rats, Wistar ; Disease Models, Animal ; Male ; Brain-Derived Neurotrophic Factor/metabolism ; Drug Liberation ; Polymethyl Methacrylate/chemistry ; Drug Delivery Systems ; Streptozocin ; Amyloid beta-Peptides/metabolism ; },
abstract = {Alzheimer's disease (AD) is a growing challenge worldwide, with current treatments largely symptomatic and limited. The current study aimed to introduce coated nanoporous membranes for localized drug delivery of donepezil, combining both antifouling activity and sustained drug release, unlike traditional Alzheimer's treatments that rely on systemic administration. Nanoporous membranes were prepared by electrochemical anodization, coated with Polymethyl methacrylate (PMMA) or a PMMA/polyurethane (PU) mixture to mitigate biofouling. The fabricated nanoporous membranes before and after coating were characterized using SEM/EDX, FTIR, BET, and contact angle measurements. In vitro drug release and release kinetics were studied in artificial cerebrospinal fluid (ACSF). Coated and donepezil loaded membranes were implanted on the dura surface in Wistar rats AD model via intracerebral streptozotocin (STZ) injection. The activity was evaluated on behavioral, biochemical and histological levels. PMMA enhanced membrane hydrophobicity (contact angle increased from 62.8° to 79°) and sustained drug release over 7 days, making it the preferred coating. The PMMA membrane demonstrated a reduction in beta-amyloid levels without being loaded with donepezil, while the donepezil-loaded membrane showed cognitive function improvement in Morris water maze and Y-maze. Acetylcholinesterase activity was elevated after STZ-induction of AD and got ameliorated by the membranes implantation. Brain-Derived Neurotrophic Factor (BDNF) was lowered by STZ, while increased in treated animals. Histological examination revealed the neuronal regeneration after donepezil-loaded PMMA coated membrane. These findings suggest that coated nanoporous membranes are promising systems for localized active donepezil drug delivery for AD-like symptoms modulation in STZ-induced AD model, warranting further validation in other AD paradigms.},
}

Animals
*Donepezil/administration & dosage/pharmacology
*Alzheimer Disease/drug therapy/cerebrospinal fluid/pathology
Rats
Rats, Wistar
Disease Models, Animal
Male
Brain-Derived Neurotrophic Factor/metabolism
Drug Liberation
Polymethyl Methacrylate/chemistry
Drug Delivery Systems
Streptozocin
Amyloid beta-Peptides/metabolism

@article {pmid41290819,
year = {2025},
author = {Arastoo, M and Penny, LK and Lofthouse, R and Hitchcock, A and Moelders, A and Szalma, S and Porter, A and Palliyil, S and Harrington, CR and Wischik, CM},
title = {Quantification of plasma tau species containing the proline-rich region as a biomarker in Alzheimer's disease.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {41881},
pmid = {41290819},
issn = {2045-2322},
mesh = {*Alzheimer Disease/blood/diagnosis ; *tau Proteins/blood/chemistry/immunology ; Humans ; *Biomarkers/blood ; Animals ; Aged ; Male ; Female ; *Proline ; Sheep ; Aged, 80 and over ; },
abstract = {Tau-based blood biomarkers are increasingly recognised as important for the diagnosis of Alzheimer's disease (AD). More than 60 proteolytic cleavage sites of tau have been identified, and current assays may miss critical information from some of the smaller protein fragments. By capturing a broader range of tau species, a polyclonal approach may offer greater interrogation of this complex "tauosome" and deliver valuable insights into the onset or progression of AD. A sheep was hyper-immunised with 2N4R tau113-251 peptide, encompassing the proline-rich region. An affinity-purified proline region polyclonal antibody (P.pAb) was derived from sheep serum, after four rounds of immunisation. Following characterisation of P.pAb, utility as a plasma biomarker/diagnostic agent for AD was assessed using a single molecular array (Simoa) assay in a selected cohort consisting of clinically diagnosed AD patients and age-matched cognitively unimpaired (CU) individuals. Two assays were considered for this assessment including pairing the P.pAb with itself (P.pAb-P.pAb) to capture and detect multiple tau fragments in plasma, and pairing pTau217 capture mAb with P.pAb (pTau217-P.pAb). The P.pAb showed high affinity towards full-length tau and 113-251 peptide immunogen and bound smaller 13-amino acid (aa) fragments throughout the proline rich region. The selected patient cohort was initially assessed by commercial neurofilament light (NfL) and pTau217 assays, the results of which were consistent with AD-related neurodegeneration in the AD sample and not in the CU group. The P.pAb-P.pAb and the pTau217-P.pAb assays were each able to distinguish between CU and AD groups; values were greater in AD (1.4-fold, p < 0.0001 and 2.8-fold, p < 0.001, respectively). By contrast, a commercial total-tau (T-tau) assay did not distinguish between the two groups. We demonstrate the feasibility of an immunodiagnostic approach based on the detection of tau species containing the proline-rich region. The development of an affinity-purified proline region-specific pAb, capable of detecting multiple tau species in plasma, provides the foundation for a novel approach with potential applications in AD diagnosis and monitoring of disease progression.},
}

*Alzheimer Disease/blood/diagnosis
*tau Proteins/blood/chemistry/immunology
Humans
*Biomarkers/blood
Animals
Aged
Male
Female
*Proline
Sheep
Aged, 80 and over

@article {pmid41290806,
year = {2025},
author = {Nasiri, H and Khosravi, F and Saberian, P and Kavian, M and Mozafar, M and Torabi, P and Malekzadeh, T and Hadavi, SM and Rezaee, A and Ghorbanalinejad, M and Heidari, Z and Zangene, D and Abdi, M and Houshyar, M and Habibzadeh, A and Bemanalizadeh, M},
title = {White matter hyperintensity burden predicts domain-specific cognitive decline across the Alzheimer's disease continuum.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {41780},
pmid = {41290806},
issn = {2045-2322},
mesh = {Humans ; *Alzheimer Disease/pathology/diagnostic imaging ; *White Matter/pathology/diagnostic imaging ; Male ; Female ; *Cognitive Dysfunction/pathology/diagnostic imaging ; Aged ; Magnetic Resonance Imaging ; Cross-Sectional Studies ; Aged, 80 and over ; Executive Function ; Neuropsychological Tests ; Neuroimaging ; Cognition ; },
abstract = {White matter hyperintensity (WMH), indicative of cerebral small vessel disease, has emerged as a potential biomarker for cognitive decline in Alzheimer's disease (AD). However, their predictive role across specific cognitive domains within the AD spectrum remains unclear. This study investigates the relationship between WMH volume and cognitive performance in memory, executive function, and language across the AD continuum. A cross-sectional analysis was conducted using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), comprising 557 participants categorized into cognitively normal (CN; n = 158), mild cognitive impairment (MCI; n = 334), and Alzheimer's dementia (AD; n = 65) groups. Cognitive function was assessed using composite scores for memory (ADNI-MEM), executive function (ADNI-EF), and language (ADNI-LAN). WMH volume was quantified through validated Bayesian segmentation of MRI data. Associations between cognitive scores and WMH volume, adjusted for age, gender, APOE ε4 status, and vascular risk factors, were evaluated via multiple linear regression analyses. WMH volume showed numerically progressive increases from CN to MCI and AD groups; however, between-group differences did not reach statistical significance. Within the MCI group, significant negative associations emerged between WMH volume and memory (β=-0.13, adjusted p = 0.045) and language scores (β=-0.12, adjusted p = 0.045). Conversely, these relationships were absent in both the CN and AD groups. WMH volume relates specifically to declines in memory and language abilities, particularly in individuals with MCI. These results support using WMH measurements as early markers to identify cognitive decline in AD, potentially helping to guide earlier diagnosis and treatment decisions.},
}

Humans
*Alzheimer Disease/pathology/diagnostic imaging
*White Matter/pathology/diagnostic imaging
Male
Female
*Cognitive Dysfunction/pathology/diagnostic imaging
Aged
Magnetic Resonance Imaging
Cross-Sectional Studies
Aged, 80 and over
Executive Function
Neuropsychological Tests
Neuroimaging
Cognition

@article {pmid41290768,
year = {2025},
author = {Shafiee, L and Pishva, MS and Hosseinzadegsn, R and Bahadori, Z and Baziyar, P and Mehboodi, M and Khademee, S and Akbari, M and Motamed, M and Nadimi, E},
title = {Hesperetin reduces neuronal death in an SHSY5Y Alzheimer's model by inhibiting inflammation and apoptosis and pyroptosis cell death pathways.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {41901},
pmid = {41290768},
issn = {2045-2322},
mesh = {Humans ; *Hesperidin/pharmacology ; *Pyroptosis/drug effects ; *Alzheimer Disease/metabolism/drug therapy/pathology ; *Apoptosis/drug effects ; Amyloid beta-Peptides/metabolism ; Cell Line, Tumor ; *Inflammation/drug therapy/metabolism/pathology ; *Neurons/drug effects/metabolism/pathology ; Peptide Fragments/metabolism ; Lipopolysaccharides ; Cytokines/metabolism ; },
abstract = {Alzheimer's disease (AD) features amyloid-β (Aβ)1-42 plaques, neuroinflammation, and neuronal loss. Apoptosis and pyroptosis contribute to AD, with inflammatory cytokines involved. Flavonoids like Hesperetin may reduce Aβ1-42 deposition through anti-inflammatory effects. This study introduces a novel method combining LPS and Aβ1-42 to investigate Hesperetin's mechanism for potential AD treatments. Using computational and experimental methods, we evaluated the physicochemical properties and their correlation with protein aggregation at the molecular level. Human neuroblastoma SH-SY5Y cells were induced to differentiate and then exposed to Hesperetin (1 µM and 10 µM), LPS (1 µg/mL), and Aβ1-42 (20 µM) for 24 h. The expression levels of pro- (Bak, Bax, and Caspase-3) and anti-apoptotic genes (Bcl-2), pyroptosis-related genes (Caspase-1, Caspase-4, Caspase-5, NLRP3, and GSDMD), and pro-inflammatory cytokines genes (interleukins 6 and 1β, and TNF-α) were analyzed via qRT-PCR. The obtained simulation of our result clearly showed that Hesperetin led to the disintegration of the cross-linked structure of organized Aβ1-42 fibrils. Increased RMSD, Rg, and SASA values might lead to destabilization of Aβ1-42 fibrils in the presence of Hesperetin. Our experimental study also demonstrated that Hesperetin increased cell viability in SH-SY5Y cells induced by LPS and Aβ1-42. Hesperetin effectively reverses the enhanced apoptosis caused by LPS and Aβ1-42. Our findings indicated that Hesperetin significantly reduced the elevated expression levels of pro-inflammatory cytokines in the SH-SY5Y cells induced by LPS and Aβ1-42. Treatment with Hesperetin led to a notable downregulation of the enhanced expression of pyroptotic-related genes in LPS and Aβ1-42 induced cells. The details of the molecular level along with the investigation of the physicochemical properties of Hesperetin regarding the mechanism of destabilization of Aβ1-42 fibrils introduce it as a promising therapeutic agent for AD management. Our experimental findings also indicate that Hesperetin is a compound that prevents neuronal death by reducing inflammation and inhibiting apoptosis and pyroptosis.},
}

Humans
*Hesperidin/pharmacology
*Pyroptosis/drug effects
*Alzheimer Disease/metabolism/drug therapy/pathology
*Apoptosis/drug effects
Amyloid beta-Peptides/metabolism
Cell Line, Tumor
*Inflammation/drug therapy/metabolism/pathology
*Neurons/drug effects/metabolism/pathology
Peptide Fragments/metabolism
Lipopolysaccharides
Cytokines/metabolism

@article {pmid41290365,
year = {2025},
author = {Chiotis, K and Wang, Y and La Joie, R and Rabinovici, GD},
title = {The Role of Amyloid-β and Tau PET in the New Era of Alzheimer Disease Therapies.},
journal = {Journal of nuclear medicine : official publication, Society of Nuclear Medicine},
volume = {},
number = {},
pages = {},
doi = {10.2967/jnumed.124.268339},
pmid = {41290365},
issn = {1535-5667},
abstract = {The advent of amyloid-β (Aβ) and tau PET imaging has revolutionized Alzheimer disease (AD) research, enabling in vivo detection of hallmark pathologies and transforming both diagnosis and therapeutic development. These imaging modalities have played a central role in the clinical trials that led to the recent approval of Aβ-targeting therapies, with Aβ PET used for participant selection and treatment monitoring and tau PET increasingly integrated to assess disease staging and prognosis. This continuing-education article reviews the current clinical validation of Aβ and tau PET imaging in AD, outlines the available evidence for the recently approved anti-Aβ therapies, and examines how PET imaging was operationalized in the trials for these novel therapeutic agents. We explore the potential for translating trial-based imaging protocols into clinical practice-particularly how PET quantification beyond binary visual reads can support nuanced decisions regarding patient eligibility, risk stratification, therapeutic monitoring, and duration of treatment. In addition, we discuss the emerging landscape of tau-targeting therapies and the anticipated central role of tau PET in their clinical evaluation. Finally, we identify key knowledge gaps and unmet needs that must be addressed to facilitate broader clinical adoption of PET imaging, including standardization efforts, accessibility and reimbursement, and evidence-based guidelines for interpretation and use.},
}

@article {pmid41289941,
year = {2025},
author = {Xu, X and Zhao, Y and Ma, H and Hu, Y and Yu, L and Su, Y and Song, J and Xie, Z and Zhang, Z and Wang, P},
title = {Mechanism of Atractylodis Rhizoma in improving cognitive dysfunction in Alzheimer's disease by regulating the cAMP/CREB/BDNF pathway.},
journal = {International immunopharmacology},
volume = {168},
number = {Pt 2},
pages = {115923},
doi = {10.1016/j.intimp.2025.115923},
pmid = {41289941},
issn = {1878-1705},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive, debilitating condition with substantially limited therapeutic options. Atractylodis Rhizoma, a spleen-invigorating herb in Traditional Chinese Medicine (TCM), shows promise for AD, but its mechanisms are unknown.

METHODS: Chemical constituents of the ethanol extract of Atractylodis Rhizoma (EEAR) were identified via UHPLC-HRMS and followed by network pharmacology integrated with molecular docking to predict putative therapeutic targets. An AD rat model was established by bilateral intracerebral stereotaxic injection of Aβ₂₅-₃₅. Cognitive function and neuronal damage were evaluated using behavioral tests and Nissl staining. Levels of key pathway components were measured by ELISA, RT-qPCR, and Western blotting, and inflammatory factors were measured by ELISA. RNA sequencing (RNA-Seq) and in vitro experiments were conducted to validate EEAR's regulatory effects on the key signaling pathway.

RESULTS: EEAR administration ameliorated cognitive deficits and attenuated hippocampal neuronal damage in AD rats. Notably, EEAR markedly reduced the concentrations of IL-6, IL-1β, and TNF-α in the rat hippocampus, concomitant with upregulation of the cAMP/CREB/BDNF signaling pathway. RNA-seq analysis confirmed significant enrichment of DEGs in the cAMP signaling pathway in the EEAR-H. In vitro, EEAR protected HT22 cells against Aβ₂₅-₃₅-induced injury, and the CREB-specific inhibitor KG-501 effectively blocked EEAR-induced activation of the cAMP/CREB/BDNF pathway.

CONCLUSION: EEAR mitigates AD pathogenesis by directly targeting hippocampal neuroinflammation and potently activating cAMP signaling, establishing its potential as a multi-target therapeutic candidate and providing a scientific basis for traditional medicine-derived AD interventions.},
}

@article {pmid41289912,
year = {2025},
author = {Verma, A and Waiker, DK and Gupta, PS and Shrivastava, SK},
title = {Recent advances in bioisosteric modifications for targeting Alzheimer's disease pathways.},
journal = {Bioorganic chemistry},
volume = {167},
number = {},
pages = {109248},
doi = {10.1016/j.bioorg.2025.109248},
pmid = {41289912},
issn = {1090-2120},
abstract = {The drug development process is highly challenging due to high cost, ethical consideration and takes a long time to reach in to the market for the ultimate benefit of the patients. Considering the global health issues, brain disorders such as Parkinsons disease (PD) and Alzheimer's disease (AD) are major concerns and are difficult to treat because of the complex nature of the disease. The complexity of these diseases, poor efficacy of the current drugs, and their low ability to cross blood brain barrier (BBB) limits the overall biological effectiveness of the treatment. These challenges must be addressed urgently to reduce the burden of these diseases and to improve the quality and expectancy of life. In a drug molecule its molecular properties are the key attributes in determining selectivity, stability, pharmacokinetics and BBB permeability. Any unfavorable changes in these molecular properties may compromise, whereas favorable modification can enhance the overall biological effectiveness of the drug molecule. Bioisosterism is a powerful chemical tool that offers replacement of undesired functional group on the drug molecule with more suitable group resulting in improved pharmacokinetics, minimizing side effects and toxicity, and could tailored it to complex environments such as brain. In this review we present recent bioisosteric replacement approaches which have been employed to optimize the existing molecular properties of the compound to improve their biological effectiveness particularly focusing on AD.},
}

@article {pmid41289380,
year = {2025},
author = {Ye, S and Wang, B and Li, Z and Zhu, L and Yin Sun, C and Mukamel, S and Jiang, J},
title = {A machine learning protocol for predicting structural distributions of amyloid-forming proteins from 2D IR spectra.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {122},
number = {48},
pages = {e2522772122},
doi = {10.1073/pnas.2522772122},
pmid = {41289380},
issn = {1091-6490},
support = {22203001//National Natural Science Foundation of China/ ; 22025304 22033007//National Natural Science Foundation of China/ ; GXXT-2022-062//University Synergy Innovation Program of Anhui Province/ ; 2208085Y04//| Natural Science Foundation of Anhui Province ()/ ; open research fund//Key Laboratory of Precision and Intelligent Chemistry/ ; CHE-2246379//NSF (NSF)/ ; },
mesh = {*Machine Learning ; Humans ; alpha-Synuclein/chemistry ; Amyloid beta-Peptides/chemistry ; Islet Amyloid Polypeptide/chemistry ; Spectrophotometry, Infrared/methods ; *Amyloidogenic Proteins/chemistry ; Prealbumin/chemistry ; Protein Conformation ; Protein Folding ; },
abstract = {Protein misfolding plays a central role in diseases such as Alzheimer's disease, Parkinson's disease, type 2 diabetes, and transthyretin amyloidosis (ATTR), often driven by specific aggregation-prone segments such as Aβ17-23 and Aβ37-42 of amyloid-β42 (Aβ42), α-Syn66-74 and α-Syn71-82 of α-synuclein (α-syn), hIAPP22-27 of human islet amyloid polypeptide (hIAPP), and TTR105-115 of transthyretin (TTR). Capturing the atomic-level structural features of these transient and dynamically fluctuating regions remains challenging. Two-dimensional infrared (2DIR) spectroscopy provides rich vibrational fingerprints that are highly sensitive to protein conformational dynamics, but extracting atomic-resolution structural information from these complex signals is nontrivial. In this study, we present a machine learning framework that integrates 2DIR spectra with deep structural modeling to reconstruct the three-dimensional atomic structures of monomeric intrinsically disordered aggregation-prone segments of amyloidogenic proteins. Using this model, we were able to predict the conformational ensembles of aggregation-prone segments from amyloid-β42, α-synuclein, human islet amyloid polypeptide, and transthyretin, as well as the structural evolution of Aβ42 bound to a small-molecule inhibitor, directly from computationally derived 2DIR spectra. An attention module highlights the most informative spectral features associated with local structural variations, providing interpretable links between spectra and structure. This generalizable strategy paves the way for interpreting time-resolved spectroscopic studies and offers a promising computational framework for probing misfolding-related structural dynamics and therapeutic mechanisms.},
}

*Machine Learning
Humans
alpha-Synuclein/chemistry
Amyloid beta-Peptides/chemistry
Islet Amyloid Polypeptide/chemistry
Spectrophotometry, Infrared/methods
*Amyloidogenic Proteins/chemistry
Prealbumin/chemistry
Protein Conformation
Protein Folding

@article {pmid41289288,
year = {2025},
author = {Angelvy, P and Badin, M and Pelletier-Visa, M and Givron, P and Pereira, B and Coudeyre, E},
title = {Musical intervention to reduce stress during botulinum toxin injection for spasticity: Protocol for a randomized controlled trial (MUSIBOT).},
journal = {PloS one},
volume = {20},
number = {11},
pages = {e0327259},
pmid = {41289288},
issn = {1932-6203},
mesh = {Humans ; *Music Therapy/methods ; *Muscle Spasticity/drug therapy/psychology ; *Stress, Psychological/therapy/prevention & control/etiology ; *Botulinum Toxins/administration & dosage/adverse effects/therapeutic use ; Adult ; Male ; Female ; Randomized Controlled Trials as Topic ; Prospective Studies ; Heart Rate ; Middle Aged ; Injections, Intramuscular ; },
abstract = {INTRODUCTION: Botulinum toxin injections are a common treatment for managing spasticity resulting from central nervous system damage, including stroke, multiple sclerosis, and traumatic brain injury. However, the injections are associated with perceived pain, and many patients experience significant anticipatory stress regarding future sessions. The intensity of this stress varies among individuals. Music therapy, particularly receptive musical interventions structured around a U-shaped sequence, promotes progressive relaxation through distinct musical phases. This method has demonstrated efficacy in reducing pain and anxiety across various clinical contexts, including chronic and acute pain, Alzheimer's disease, fibromyalgia, and neurologically mediated pain. Given the painful nature of botulinum toxin injections, this study proposes the use of receptive music therapy to improve patient tolerance of the procedure. We hypothesize that receptive musical intervention can reduce injection-induced stress in adults undergoing botulinum toxin treatment. To our knowledge, no studies have specifically investigated the effect of music therapy on stress related to botulinum toxin injections. We aim to conduct a prospective randomized (1:1) controlled trial to evaluate the impact of receptive music intervention on stress levels, measured via heart rate variability (HRV), during botulinum toxin injection sessions. The primary objective is to assess the effect of receptive musical intervention during botulinum toxin injections on injection-induced stress, measured by HRV. Secondary objectives include evaluating the intervention's effects on pain intensity and anxiety levels.

METHODS AND ANALYSIS: Patient satisfaction following the music-assisted injection session will also be assessed. Additionally, the physician's evaluation of the procedure and the patient's perception of time during the session will be recorded.

ETHICS AND DISSEMINATION: All participants will provide written informed consent prior to enrollment. The study has received approval from the relevant institutional ethics committee (Comité de Protection des Personnes - ID: 25.00156.000468, Sud-Méditerranée IV, approved on 3 April 2025). Findings will be disseminated through peer-reviewed publications and presentations at scientific conferences.

TRIAL REGISTRATION: ClinicalTrials.gov NCT06920524.},
}

Humans
*Music Therapy/methods
*Muscle Spasticity/drug therapy/psychology
*Stress, Psychological/therapy/prevention & control/etiology
*Botulinum Toxins/administration & dosage/adverse effects/therapeutic use
Adult
Male
Female
Randomized Controlled Trials as Topic
Prospective Studies
Heart Rate
Middle Aged
Injections, Intramuscular

@article {pmid41289189,
year = {2025},
author = {Teng, E and Li, Y and Blendstrup, M and Lansdall, CJ},
title = {Formal and informal care utilization in MCI and mild dementia due to AD: Cross-sectional and longitudinal analyses of RUD-Lite data from the Tauriel study.},
journal = {Dementia and geriatric cognitive disorders},
volume = {},
number = {},
pages = {1-18},
doi = {10.1159/000549652},
pmid = {41289189},
issn = {1421-9824},
abstract = {INTRODUCTION: Evaluating formal and informal care utilization in Alzheimer's disease (AD) is crucial for assessing the economic impact of novel disease-modifying treatments. The Resource Utilization in Dementia-Lite (RUD-Lite) scale is widely used to measure care utilization in dementia; however, RUD-Lite data is limited for mild cognitive impairment (MCI) and mostly from observational studies. We analyzed RUD-Lite data from a study of semorinemab (NCT03289143) in MCI (i.e., prodromal AD) and mild AD dementia (i.e., mild AD) to explore potential differences in care utilization between observational and interventional studies.

METHODS: We analyzed cross-sectional and longitudinal RUD-Lite indices in prodromal (pAD: n=160) and mild (mAD: n=288) AD groups, examining formal care usage and informal caregiver time. Unadjusted and adjusted analyses were performed on longitudinal data. North American and European cohorts were compared to explore potential regional differences.

RESULTS: More informal caregiving assistance was required for mAD versus pAD participants at baseline and the mAD group demonstrated significant greater increases over 18 months. Cross-sectional data indicated more caregiver assistance for instrumental activities of daily living in North America versus Europe, with comparable longitudinal increases in caregiver assistance across regions.

CONCLUSIONS: Longitudinal RUD-Lite changes in interventional early AD studies are detectable but smaller than in observational studies, possibly due to differences in cohort characteristics. These factors, along with subtle regional differences in care utilization, should be considered when using observational data to guide interventional trials.},
}

@article {pmid41288829,
year = {2025},
author = {Shokr, MM},
title = {"Rewiring brain immunity: targeting microglial metabolism for neuroprotection in neurodegenerative disorders".},
journal = {Metabolic brain disease},
volume = {40},
number = {8},
pages = {326},
pmid = {41288829},
issn = {1573-7365},
mesh = {Humans ; *Microglia/metabolism/immunology ; *Neurodegenerative Diseases/metabolism/immunology ; Animals ; *Neuroprotection/physiology ; *Brain/metabolism/immunology ; Neuroprotective Agents/therapeutic use/pharmacology ; Neuroinflammatory Diseases/metabolism ; },
abstract = {Neuroinflammation, a pervasive hallmark in many neurological and neuropsychiatric diseases, is largely dictated by the functional phenotypic dynamics of microglia, the immune system of the brain. Recent data illustrate that these phenotypic changes, from neuroprotective scavenging to neurotoxic pro-inflammatory effects, are intrinsically regulated by microglial metabolic repolarization. This review synthesizes understanding of discrete microglial metabolic phenotypes like the glycolytic reliance of pro-inflammatory (M1-like) microglia and the oxidative phosphorylation/fatty acid oxidation bias of anti-inflammatory/resolving (M2-like) microglia. We discuss how central metabolic sensors like AMPK, mTOR, and HIF-1α oversee these metabolic shifts in response to disease-targeted pathologies in Alzheimer's, Parkinson's, Multiple Sclerosis, ischemic stroke, and traumatic brain injury. Moreover, we review innovative therapeutic strategies directed toward microglial metabolism, involving pharmacological modulators (e.g., metformin, rapamycin, and ketone bodies), nutritional interventions (e.g., ketogenic diets), and modulation of gut microbiota. By tightly specific re-tuning of microglial cells' bioenergetics, these approaches enable unprecedented opportunities to counteract neuroinflammation, enhance pathological clearance, and induce neuroprotection, paving the way for a new generation of disease-modifying therapies of neurodegenerative disorders.},
}

Humans
*Microglia/metabolism/immunology
*Neurodegenerative Diseases/metabolism/immunology
Animals
*Neuroprotection/physiology
*Brain/metabolism/immunology
Neuroprotective Agents/therapeutic use/pharmacology
Neuroinflammatory Diseases/metabolism

@article {pmid41288748,
year = {2025},
author = {Manso, Y and Carrasco, J and Comes, G and Adlard, PA and Bush, AI and Hidalgo, J},
title = {Correction: Characterization of the role of the antioxidant proteins Metallothioneins 1 and 2 in an animal model of alzheimer's disease.},
journal = {Cellular and molecular life sciences : CMLS},
volume = {82},
number = {1},
pages = {416},
doi = {10.1007/s00018-025-05965-6},
pmid = {41288748},
issn = {1420-9071},
}

@article {pmid41288695,
year = {2025},
author = {Hirjak, D and Volkmer, S and Peretzke, R and Meyer-Lindenberg, A and Maier-Hein, KH and Neher, P},
title = {Delineating white matter phenotypes of sensori-/psychomotor functioning in large-scale cohorts of healthy individuals and patients with mental disorders across the lifespan (whiteSPAN): rationale and methods of an interdisciplinary bicentric project.},
journal = {European archives of psychiatry and clinical neuroscience},
volume = {},
number = {},
pages = {},
pmid = {41288695},
issn = {1433-8491},
support = {1928/14-1//Deutsche Forschungsgemeinschaft/ ; },
abstract = {Aberrant sensori-/psychomotor functioning-including muscular hand weakness, sedentary behavior, psychomotor agitation, slowing, agitation, apathy, and anxiety-is increasingly recognized as a transdiagnostic feature across mental and neurodegenerative disorders. Objectively measured sensori-/psychomotor abnormalities serve as rapid, noninvasive indicators of cognitive and affective dysfunction, yet large-scale neuroimaging studies examining their white matter (WM) correlates remain limited. This bi-centric research project aims to investigate associations between sensori-/psychomotor functioning and WM microstructure across anxiety disorders (AD), major depressive disorder (MDD), schizophrenia spectrum disorders (SSD), mild cognitive impairment (MCI), and Alzheimer's disease (AD). We will analyze diffusion MRI data from over 2,400 healthy individuals and 1,600 patients, combining publicly available datasets (e.g., Human Connectome Project, Alzheimer's Disease Neuroimaging Initiative) with in-house cohorts comprising >400 deeply-phenotyped SSD and MDD patients. A major strength of the project lies in the harmonization of psychopathological rating scales and sensori-/psychomotor assessments across these populations. Using advanced computational tools-including tractometry, tractomics, normative modeling, and deep learning-we aim to map a WM phenotype of sensori-/psychomotor dysfunction across the lifespan. Multivariate taxometric approaches will help identify biologically informed sensori-/psychomotor biotypes that cut across traditional diagnostic boundaries. By distinguishing disorder-specific WM changes from normative developmental and aging processes, this project seeks to inform precision medicine approaches and guide biomarker-driven interventions for mental and neurodegenerative disorders.},
}

@article {pmid41288387,
year = {2025},
author = {Kim, B and Yuk, M and Park, M and Ryu, H and Park, J and Yu, H and Park, S and Hong, JT and Lim, KH and Han, SB and Song, N and Park, H},
title = {CRISPR editing of miR-33 restores ApoE lipidation and amyloid-β metabolism in ApoE4 sporadic Alzheimer's disease.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awaf244},
pmid = {41288387},
issn = {1460-2156},
support = {//National Research Foundation of Korea/ ; 2021R1C1C1006551//Korean government/ ; //Bio & Medical Technology Development Program/ ; //National Research Foundation/ ; RS-2024-00440787//Korean government/ ; },
abstract = {Sporadic Alzheimer's disease (sAD) is marked by dysregulated lipid metabolism, prominently involving apolipoprotein E (ApoE). MicroRNA-33 (miR-33) has emerged as a key regulator of lipid homeostasis, yet its role in sAD remains unclear. This study investigated miR-33 dysregulation in APOE ε4 allele (ApoE4)-associated sAD and explored its therapeutic potential using clustered regulatory interspaced short palindromic repeats (CRISPR)-mediated gene editing. Elevated miR-33 expression was observed in both AD patients, particularly those with ApoE4-associated sAD, and in the ApoE4 mouse model, implicating its role in AD pathology. Using CRISPR/Cas9, we modulated miR-33 expression in astrocytes to regulate ApoE lipidation and ameliorate AD-related pathology. Our results show that targeted miR-33 regulation in astrocytes via CRISPR/Cas9 restores ApoE lipidation and mitigates AD pathology in both in vitro and in vivo AD mice. Additionally, applying this gene therapy approach in ApoE4 sAD patient cell lines highlights its translational potential for therapeutic intervention. In conclusion, our findings elucidate miR-33's role in AD pathogenesis and underscore the therapeutic promise of CRISPR-mediated miR-33 targeting for restoring lipid homeostasis and ameliorating AD pathology. This study provides valuable insights into developing miRNA-based gene therapy strategies for treating sAD.},
}

@article {pmid41288291,
year = {2025},
author = {Liu, H and Liu, Y and Feng, R and Qian, M and Li, Y and Zhai, S and Song, J and Qiu, X},
title = {Homogeneous Femtomolar Detection of P-tau181 via Proximity Extension and CRISPR/Cas Technique.},
journal = {Analytical chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.analchem.5c04856},
pmid = {41288291},
issn = {1520-6882},
abstract = {Accurate quantification of site-specific tau phosphorylation in plasma holds great promise for the noninvasive early diagnosis of Alzheimer's disease (AD). Here, we integrated the proximity extension assay (PEA) with nucleic acid amplification techniques-polymerase chain reaction (PCR) and recombinase polymerase amplification (RPA)-and coupled them with CRISPR/Cas12a-mediated fluorescence detection to enable quantitative and homogeneous measurement of threonine-181-phosphorylated tau (p-tau181), a key biomarker of AD. Binding of two PEA probes to a single p-tau181 molecule induces proximity-mediated probe hybridization and extension, thereby converting the protein signal into an amplifiable nucleic acid signal. The resulting double-stranded DNA is subsequently amplified by PCR or RPA and detected through Cas12a trans-cleavage activity. The limits of detection (LODs) for the PEA-PCR-CRISPR/Cas and PEA-RPA-CRISPR/Cas assays were 149.0 fM (6.8 pg·mL[-1]) and 45.4 fM (2.1 pg·mL[-1]), respectively. In fetal bovine serum, LODs of 231.4 fM (10.6 pg·mL[-1]) and 139.2 fM (6.3 pg·mL[-1]) were achieved, demonstrating excellent antimatrix performance. The accuracy of the PEA-RPA-CRISPR/Cas assay in human serum was further validated using a commercial enzyme-linked immunosorbent assay (ELISA) kit. This homogeneous, wash-free approach combines operational simplicity with ultrahigh sensitivity, showing great potential for routine clinical detection and early stage monitoring of AD biomarkers.},
}