@article {pmid41237536,
year = {2025},
author = {Platero, C and Bengoa, J},
title = {Benchmarking parametric models of disease progression for early detection of cognitive decline.},
journal = {Computer methods and programs in biomedicine},
volume = {274},
number = {},
pages = {109162},
doi = {10.1016/j.cmpb.2025.109162},
pmid = {41237536},
issn = {1872-7565},
abstract = {BACKGROUND AND OBJECTIVE: Disease progression models (DPMs) are valuable tools for characterizing early cognitive decline in Alzheimer's Disease (AD) and supporting clinical decision-making. This study aimed to (1) evaluate the diagnostic and prognostic performance of parametric DPMs, (2) identify optimal subsets of neuropsychological markers for DPM construction, and (3) benchmark three parametric DPM frameworks in early detection tasks.

METHODS: We analyzed longitudinal neuropsychological data from 1163 participants classified as cognitively unimpaired (CU) or with mild cognitive impairment (MCI). Three DPM approaches (Leaspy, RPDPM, and GRACE) were trained on selected marker subsets and evaluated using metrics related to diagnostic accuracy, time to conversion estimation, and robustness to missing data. Model performance was assessed via detection rates, area under the curve (AUC), mean absolute error (MAE), and Pearson correlation between estimated/observed onset ages.

RESULTS: Leaspy achieved the highest diagnostic accuracy with an AUC of 0.96 and strong correlation with observed conversion time (r = 0.78). RPDPM showed superior robustness to missing data and maintained accurate predictions even with up to 40% data loss. GRACE offered the best trajectory fit (lowest error) but lower sensitivity to clinical transitions. A compact combination of neuropsychological tests, particularly CDRSB, ADAS13, and MMSE, was sufficient for reliable model training. Prognostic evaluation demonstrated that Leaspy provided the most consistent identification of individuals who converted to mild cognitive impairment within five years.

CONCLUSIONS: Parametric DPMs based solely on neuropsychological measures can effectively support early detection and prognosis of cognitive decline. Leaspy showed the best overall performance, while RPDPM proved more resilient to missing data. These models enable individualized disease timelines and can inform clinical decision-making and patient stratification. All code and data used are publicly available, facilitating reproducibility and clinical translation.},
}

@article {pmid41237466,
year = {2025},
author = {Peng, TR and Lin, HH and Tseng, TL and Wu, TW},
title = {Effectiveness of probiotic supplements on cognitive function in mild cognitive impairment and Alzheimer's disease: A meta-analysis of randomized controlled trials.},
journal = {General hospital psychiatry},
volume = {97},
number = {},
pages = {284-293},
doi = {10.1016/j.genhosppsych.2025.11.004},
pmid = {41237466},
issn = {1873-7714},
abstract = {BACKGROUND: Cognitive impairment, encompassing mild cognitive impairment (MCI) and Alzheimer's disease (AD), poses a significant public health challenge worldwide. Emerging evidences suggest that probiotics, through modulation of the gut-brain axis, may improve cognitive function. However, their efficacy in individuals with cognitive impairment remains unclear.

METHODS: This meta-analysis adhered to PRISMA guidelines, systematically reviewing randomized controlled trials (RCTs) investigating the effects of probiotics for individuals with cognitive impairment. Data were extracted from the PubMed, Embase, and Cochrane databases. Subgroup analyses were conducted based on different measurement scales (MMSE, MoCA, and RBANS), population types (cognitive impairment vs. no cognitive impairment), multiple or single strain and intervention duration. Effect sizes were expressed as standardized mean differences (SMDs) using random-effects models.

RESULTS: Fifteen RCTs involving 994 participants were included. Probiotic supplementation significantly improved cognitive function compared to placebo (SMD = 0.57; 95 % CI, 0.19-0.94; P = 0.003). Subgroup analyses revealed that both single-strain and multi-strain probiotics were effective; however, multi-strain probiotics demonstrated greater heterogeneity and variability in efficacy. Cognitive improvements were most pronounced with supplementation durations of at least 12 weeks (SMD = 0.73; 95 % CI, 0.30-1.16; P = 0.0009) and higher probiotic doses (>1 × 10[9] CFU/g; SMD = 0.93; 95 % CI, 0.36-1.49; P < 0.01).

CONCLUSION: Probiotic supplementations significantly enhance cognitive function in individuals with cognitive impairment, particularly with single-strain formulations, higher doses, and a minimum duration of 12 weeks.},
}

@article {pmid41237463,
year = {2025},
author = {Cho, E and Yi, JH and Jeon, SJ and Kim, DH and Kwon, H and Jeon, J and Kwon, KJ and Jang, DP and Moon, M and Shin, CY and Kim, DH},
title = {Increases in brain catecholamine levels counteract memory deficits and reduces Aβ deposition in 5XFAD male mice.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {193},
number = {},
pages = {118764},
doi = {10.1016/j.biopha.2025.118764},
pmid = {41237463},
issn = {1950-6007},
abstract = {Alzheimer's disease (AD) is a degenerative brain disease that presents with neurological symptoms and memory loss, with no clear treatment. Catecholamines, including dopamine, epinephrine, and norepinephrine, can inhibit or degrade the abnormal aggregation of proteins that cause diseases; however, developing these catecholamines as medication is difficult. This study aimed to demonstrate that increasing the levels of catecholamines in the brain may help improve symptoms of AD. We tested whether an increase in catecholamines by bupropion, a dopamine and norepinephrine re-uptake inhibitor, improves the symptoms of AD. Dopamine and norepinephrine showed similar effects in inhibiting amyloid β (Aβ) aggregation and the decomposition of Aβ aggregates as curcumin, a positive control. Dopamine and norepinephrine blocked Aβ aggregates-induced abnormal hippocampal long-term potentiation. The intraperitoneal administration of bupropion increased the concentrations of dopamine and norepinephrine in the hippocampus from 1 to 6 h after administration. In the Aβ-induced memory decline model, bupropion showed a dose-dependent improvement in learning and memory. In 5XFAD mice administered bupropion for 2 months, significant improvements in memory and Aβ deposition were also found compared to vehicle-treated 5XFAD mice. These results suggest that the symptoms of AD can be improved or delayed by increasing the amount of dopamine and norepinephrine using bupropion.},
}

@article {pmid41237410,
year = {2025},
author = {Wenzheng, H and Agyemang, EF and Srivastav, S and Shaffer, J and Kakraba, S},
title = {AI-Enhanced Multi-Algorithm R Shiny App for Predictive Modeling and Analytics: A Case study of Alzheimer's Disease Diagnostics.},
journal = {JMIR aging},
volume = {},
number = {},
pages = {},
doi = {10.2196/70272},
pmid = {41237410},
issn = {2561-7605},
abstract = {BACKGROUND: AI has demonstrated superior diagnostic accuracy compared to medical practitioners, highlighting its growing importance in healthcare. SMART-Pred (Shiny Multi-Algorithm R Tool for Predictive Modeling) is an innovative AI-based application for Alzheimer's disease (AD) prediction using handwriting analysis.

OBJECTIVE: To develop and evaluate a non-invasive, cost-effective AI tool for early AD detection, addressing the need for accessible and accurate screening methods.

METHODS: The study employed Principal Component Analysis (PCA) for dimensionality reduction of handwriting data, followed by training and evaluation of ten diverse AI models, including logistic regression, Naïve Bayes, random forest, AdaBoost, Support Vector Machine (SVM), and neural network. Model performance was assessed using accuracy, sensitivity, specificity, F1-score, and ROC-AUC metrics. The DARWIN dataset, comprising handwriting samples from 174 participants (89 AD patients, 85 healthy controls) was used for validation.

RESULTS: The Neural Network classifier achieved an accuracy of 91% with a 95% CI ranging from 0.79-0.97 and an AUC of 94%, on the test set after identifying the most significant features for AD prediction. These results surpass current clinical diagnostic tools, which typically achieve around 81% accuracy. SMART-Pred's performance aligns with recent AI advancements in AD prediction, such as the Cambridge scientists' AI tool achieving 82% accuracy in identifying AD progression within three years using cognitive tests and MRI scans. The variables "air_time" and "paper_time" consistently emerged as critical predictors for AD across all ten AI models, highlighting their potential importance in early detection and risk assessment. To augment transparency and interpretability, we incorporated the principles of explainable AI, specifically using SHapley Additive exPlanations (SHAP) values, a state-of-the-art method to emphasize the features responsible for our model's efficacy.

CONCLUSIONS: SMART-Pred offers non-invasive, cost-effective, and efficient AD prediction, demonstrating the transformative potential of AI in healthcare. While clinical validation is necessary to confirm the practical applicability of the identified key variables, this study contributes to the growing body of research on AI-assisted AD diagnosis and may lead to improved patient outcomes through early detection and intervention.},
}

@article {pmid41237058,
year = {2025},
author = {Xu, F and Wang, J and Gao, P and Li, D and Liu, X},
title = {Neuroprotective Effects of Triterpenoids From Rosa laevigata Root: Identification, Molecular Docking, and In Vitro Evaluation for Alzheimer's Disease Treatment.},
journal = {Chemistry & biodiversity},
volume = {},
number = {},
pages = {e02742},
doi = {10.1002/cbdv.202502742},
pmid = {41237058},
issn = {1612-1880},
abstract = {This study investigates the neuroprotective effects of triterpenoid compounds from Rosa laevigata Michx. roots against Alzheimer's disease (AD). A total of 62 compounds were identified using ultra-performance liquid chromatography-Orbitrap-tandem mass spectrometry analysis, which included 55 triterpenoids and seven flavonoids. Among 15 isolated compounds, compound 13 demonstrated the strongest acetylcholinesterase (AChE) inhibitory activity, with an IC50 of 3.38 µmol/L, and a maximum inhibition rate of 87.20%. Compound 13 exhibited favorable and stable binding with AChE in molecular docking studies, whilst demonstrating mixed-type inhibition in enzyme kinetics. In the H2O2-induced SH-SY5Y cell model, compound 13 exhibited 84.45% viability at 25 µmol/L, surpassing Trolox's 74.16%. Research indicates that R. laevigata Michx. root triterpenes exert neuroprotective effects through AChE inhibition and antioxidant activity, with compound 13 potentially serving as a multi-target lead compound for treating AD.},
}

@article {pmid41236865,
year = {2025},
author = {Hanyu, H and Koyama, Y and Momose, T and Watanabe, S},
title = {Patient With Mild Alzheimer's Disease Homozygous for ApoE ε4 Showing Improved Cognition, No Brain Volume Loss, and Complete Amyloid Clearance After Lecanemab Treatment.},
journal = {Geriatrics & gerontology international},
volume = {},
number = {},
pages = {},
doi = {10.1111/ggi.70251},
pmid = {41236865},
issn = {1447-0594},
}

@article {pmid41236724,
year = {2025},
author = {Eissman, JM and Qiao, M and Kalia, V and Zerlin-Esteves, M and Reyes-Dumeyer, D and Piriz, A and Dubey, S and Nandakumar, R and Lee, AJ and Lantigua, RA and Medrano, M and Mejia, DR and Honig, LS and Dalgard, CL and Miller, GW and Mayeux, R and Vardarajan, BN},
title = {Genetic regulation of the metabolome differs by sex, Alzheimer's disease stage, and plasma biomarker status.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70898},
doi = {10.1002/alz.70898},
pmid = {41236724},
issn = {1552-5279},
support = {R56AG063908/AG/NIA NIH HHS/United States ; R01AG067501/AG/NIA NIH HHS/United States ; RF1AG015473/AG/NIA NIH HHS/United States ; 5UL1TR001873/AG/NIA NIH HHS/United States ; /TR/NCATS NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/genetics/blood/metabolism ; Male ; Female ; Biomarkers/blood ; *Metabolome/genetics ; Quantitative Trait Loci/genetics ; Aged ; Polymorphism, Single Nucleotide/genetics ; Sex Factors ; Aged, 80 and over ; },
abstract = {INTRODUCTION: We investigated genetic regulators of circulating plasma metabolites to identify pathways underlying biochemical changes in clinical and biomarker-supported Alzheimer's disease (AD).

METHODS: We computed metabolite quantitative trait loci (QTL) with whole-genome sequencing (WGS) and small molecule plasma metabolites from 229 older adults with clinical AD and 322 age-matched healthy controls. Unbiased associations between 6881 metabolites and 332,772 common genetic variants were tested, adjusted for age, sex, and both metabolomic and genomic principal components.

RESULTS: We identified 72 SNP-metabolite associations spanning 66 genes and 12 metabolite classes, including PYROXD2/N6-methyllysine, FAAH/myristoylglycine, and FADS2/arachidonic acid. Additionally, we found differences in genetic regulation of metabolites among individuals with clinically-defined AD compared to biomarker-defined AD based on a published plasma P-tau181 cutoff. We also found more SNP-metabolite associations among males compared to females.

DISCUSSION: In summary, we identified sex- and disease-specific genetic regulators of plasma metabolites, revealing unique biological mechanisms of genetic perturbations in AD.

HIGHLIGHTS: Genetic regulators of the metabolome spanned 66 genes and 12 metabolite classes. Clinically versus biomarker-defined Alzheimer's disease (AD) affects genetic regulators of the metabolome. Most metabolite quantitative trait loci (QTLs) are not shared between males and females.},
}

Humans
*Alzheimer Disease/genetics/blood/metabolism
Male
Female
Biomarkers/blood
*Metabolome/genetics
Quantitative Trait Loci/genetics
Aged
Polymorphism, Single Nucleotide/genetics
Sex Factors
Aged, 80 and over

@article {pmid41236559,
year = {2025},
author = {Liu, X and Valencak, TG and Guo, B and Ren, D},
title = {Effects of Osteopontin Combined with Milk Fat Globule Membrane Proteins on Scopolamine-Induced Learning and Memory Impairment in Mice.},
journal = {Neurochemical research},
volume = {50},
number = {6},
pages = {359},
pmid = {41236559},
issn = {1573-6903},
support = {2024AC38038//Guangxi Science and Technology Base and Talent Program/ ; 2024AC38038//Guangxi Science and Technology Base and Talent Program/ ; },
mesh = {Animals ; *Scopolamine/toxicity ; *Osteopontin/therapeutic use/pharmacology/administration & dosage ; Mice ; *Memory Disorders/chemically induced/drug therapy/metabolism ; Male ; Hippocampus/drug effects/metabolism ; *Glycoproteins/therapeutic use/pharmacology/administration & dosage ; *Glycolipids/therapeutic use/pharmacology/administration & dosage ; Lipid Droplets ; Maze Learning/drug effects ; Acetylcholinesterase/metabolism ; Superoxide Dismutase/metabolism ; Malondialdehyde/metabolism ; },
abstract = {This study investigated the effects of osteopontin (OPN) combined with milk fat globule membrane (MFGM) proteins on scopolamine-induced learning and memory impairment in mice. A dementia model was established through intraperitoneal injection of scopolamine, followed by random allocation into seven experimental groups: blank control, model control, OPN alone, MFGM alone, and three combination groups (low-, intermediate-, and high-dosage OPN + MFGM). Cognitive performance was evaluated using the Morris water maze test, accompanied by quantification of hippocampal acetylcholinesterase (AChE) activity, antioxidant enzyme activities (superoxide dismutase [SOD], glutathione peroxidase [GSH-Px]), malondialdehyde (MDA)) from both hippocampal tissue and serum. We found significant cognitive improvements in the intermediate- and high-dosage combination group to the model group, which had reduced escape latency, increased platform crossings, and prolonged target quadrant duration in the water maze test. Biochemical results suggest that these combination treatments significantly suppressed AChE activity in hippocampal tissue while they enhanced antioxidant capacity through elevated SOD and GSH-Px activities, accompanied by reduced MDA levels in both brain and serum. Our study demonstrates that the combination of OPN and MFGM administration improved learning and memory in mice with scopolamine-induced dementia through dose-dependent effects on the central cholinergic nervous and antioxidant system.},
}

Animals
*Scopolamine/toxicity
*Osteopontin/therapeutic use/pharmacology/administration & dosage
Mice
*Memory Disorders/chemically induced/drug therapy/metabolism
Male
Hippocampus/drug effects/metabolism
*Glycoproteins/therapeutic use/pharmacology/administration & dosage
*Glycolipids/therapeutic use/pharmacology/administration & dosage
Lipid Droplets
Maze Learning/drug effects
Acetylcholinesterase/metabolism
Superoxide Dismutase/metabolism
Malondialdehyde/metabolism

@article {pmid41236362,
year = {2025},
author = {Zide, BS and Barker, MS and Silverman, HE and Manoochehri, M and Fremont, R and Stein, C and Kunicki, ZJ and Lee, S and Devanand, DP and Huey, ED},
title = {Feasibility and tolerability of low-dose lithium for the treatment of agitation and abnormal motor behaviors in Frontotemporal Dementia.},
journal = {International review of psychiatry (Abingdon, England)},
volume = {},
number = {},
pages = {1-11},
doi = {10.1080/09540261.2025.2572365},
pmid = {41236362},
issn = {1369-1627},
abstract = {Agitation and abnormal motor behaviors are common, distressing symptoms of Frontotemporal Dementia (FTD). While these symptoms currently lack efficacious and safe pharmacological treatments, case reports in FTD and a clinical trial in Alzheimer's disease suggest that patients may benefit from lithium treatment. We designed a randomized, double-blind, placebo-controlled, 12-week clinical trial to evaluate low-dose lithium for the treatment of agitation and abnormal motor behaviors in FTD. However, the trial did not meet its recruitment target (n = 60). This report assesses the trial's feasibility and tolerability using recruitment, study completion, and safety metrics. Sixteen adults with FTD (median age 59.5 years; 69% female) were enrolled from 2017 to 2021. Fourteen participants (88%) completed the trial. The majority of participants on lithium were taking the maximum daily dose by Week 12 (600 mg), had median (interquartile range) final serum lithium levels of 0.42 (0.37-0.57), and reported minimal side effects, including drowsiness, diarrhea, constipation and insomnia. Preliminary data from intended efficacy outcomes showed no median pre-post changes between treatment groups. Low-dose lithium is feasible and well-tolerated in an FTD population. Further systematic study of lithium and its efficacy to treat agitation and abnormal motor behaviors in FTD is warranted.},
}

@article {pmid41236360,
year = {2025},
author = {Zhang, Y and Wang, Y and Zhao, Y and Xin, Y and Zhang, L and Shan, P and Zhu, Y},
title = {Associations Between Malignant Tumors and Alzheimer's Disease: A Cross-Sectional Study.},
journal = {Brain and behavior},
volume = {15},
number = {11},
pages = {e71066},
doi = {10.1002/brb3.71066},
pmid = {41236360},
issn = {2162-3279},
support = {QDFYQN2023226//Youth Research Fund of Qingdao University/ ; 202418000774//Shandong Provincial Medical and Health Science and Technology Guidance Project/ ; },
mesh = {Humans ; Male ; Female ; Cross-Sectional Studies ; *Alzheimer Disease/epidemiology ; Middle Aged ; Aged ; *Neoplasms/epidemiology ; Nutrition Surveys ; Adult ; Neurofilament Proteins ; Risk Factors ; United States/epidemiology ; COVID-19/epidemiology ; },
abstract = {INTRODUCTION: Although there is potential overlap in the pathological and physiological mechanisms underlying malignant tumors and Alzheimer's disease (AD), a significant gap remains in the epidemiological evidence supporting their association. We used data from the National Health and Nutrition Examination Survey (NHANES) to elucidate the epidemiological relationship between malignant tumors and AD.

METHODS: We analyzed data from NHANES from 2013 to March 2020, prior to the COVID-19 pandemic, including 9274 participants aged ≥ 20 years. Multivariate logistic regression was used to explore the link among malignant tumors, tumor types, and AD risk. Sensitivity analyses were performed to evaluate the robustness of the association with neurofilament light chain levels, composite cognitive function scores, and different analytic populations. Additionally, subgroup analyses were performed to explore the association between malignancy and AD risk in specific subpopulations.

RESULTS: Among the 9274 participants included in the study, 1432 were identified as having malignant tumors. There was a significant association between malignant tumors and AD [adjusted odds ratio (aOR): 1.55; 95% confidence interval (CI): 1.27-1.89; p < 0.001]. The risk of AD was higher in patients with colorectal and prostate cancer compared to those with other malignancies. Sensitivity analysis of neurofilament light chain levels suggested that malignant tumors may contribute to the development of mild cognitive impairment (aOR: 1.52; 95% CI: 1.01-2.27; p = 0.044). Subgroup analysis revealed that AD risk following a malignant tumor diagnosis was higher in people < 65 years old and those with medium-high incomes.

CONCLUSIONS: Malignant tumors may be significantly associated with increased AD risk, particularly in patients with colorectal and prostate cancer. Moreover, individuals < 65 years old and those with middle-high income had increased risk of developing AD following a malignancy. These findings underscore the significance of early AD detection and prevention in patients with a history of malignant tumors.},
}

Humans
Male
Female
Cross-Sectional Studies
*Alzheimer Disease/epidemiology
Middle Aged
Aged
*Neoplasms/epidemiology
Nutrition Surveys
Adult
Neurofilament Proteins
Risk Factors
United States/epidemiology
COVID-19/epidemiology

@article {pmid41236085,
year = {2025},
author = {Zhu, H and Yi, X and He, M and Wu, S and Li, M and Gao, S},
title = {Childhood Obesity and Age-Related Diseases: A Systematic Review and Meta-Analysis of Mendelian Randomization Evidence.},
journal = {Pediatric obesity},
volume = {},
number = {},
pages = {e70071},
doi = {10.1111/ijpo.70071},
pmid = {41236085},
issn = {2047-6310},
support = {82270924//National Natural Science Foundation of China/ ; 81970732//National Natural Science Foundation of China/ ; 2021-I2M-1-016//the CAMS Innovation Fund for Medical Sciences (CIFMS)/ ; 2022-PUMCH-C-014//the National High Level Hospital Clinical Research Funding/ ; 2025-PUMCH-C-041//the National High Level Hospital Clinical Research Funding/ ; },
abstract = {BACKGROUND: Childhood obesity poses a global health threat, with emerging evidence suggesting distinct adipocyte senescence patterns compared to adult-onset obesity. We systematically explored whether childhood obesity may be causally associated with age-related diseases through a meta-analysis of Mendelian randomization (MR) evidence.

METHODS: We screened six databases (MEDLINE, PubMed, EMBASE, Web of Science, Cochrane Library and CNKI) and identified 45 MR articles examining paediatric adiposity and major age-related diseases. For each disease, we performed a meta-analysis using results from published MR studies and conducted de novo analyses based on genetic data from UK Biobank (n = 453 169), FinnGen (n > 200 000) and other large consortiums.

RESULTS: The meta-analysis examined 44 diseases across 9 systems, revealing suggestive associations between genetically determined childhood obesity and increased risk of 16 age-related diseases, including hypertension, atrial fibrillation, coronary artery disease, stroke and myocardial infarction; colorectal, endometrial and pancreatic cancers; nonalcoholic fatty liver disease, type 2 diabetes, diabetic nephropathy; multiple sclerosis and gout; Alzheimer's disease; depression and asthma. Three of these associations were marginal (p = 0.03-0.05). Paradoxical inverse associations emerged for breast cancer and ulcerative colitis.

CONCLUSION: The findings from this meta-analysis underscore associations between childhood adiposity and multisystem age-related pathologies, underscoring the imperative for early obesity prevention.},
}

@article {pmid41236074,
year = {2025},
author = {Wu, J and Ge, YH and Zhang, XZ and Li, Y and Luo, MQ and Fang, X and Zhang, W and Wang, YK and Ding, XP and Zhu, YC and Gao, F and Shen, Y and Zhang, W},
title = {Association of plasma p-tau217 levels with cerebral small vessel disease burden: Cross-sectional insights from the Hefei Aging Study.},
journal = {Brain research bulletin},
volume = {232},
number = {},
pages = {111602},
doi = {10.1016/j.brainresbull.2025.111602},
pmid = {41236074},
issn = {1873-2747},
mesh = {Humans ; *Cerebral Small Vessel Diseases/blood/pathology/diagnostic imaging ; *tau Proteins/blood ; Female ; Cross-Sectional Studies ; Male ; Aged ; Aged, 80 and over ; Magnetic Resonance Imaging ; *Aging/blood/pathology ; Biomarkers/blood ; Phosphorylation ; },
abstract = {BACKGROUND: Phosphorylated tau (p-tau217) is a well-established and recognized biomarker for Alzheimer's disease (AD), however, its relationship with cerebral small vessel disease (CSVD) remains inadequately explored. This study examines the association between plasma p-tau217 levels and CSVD burden within a community-based cohort.

METHODS: We conducted a cross-sectional analysis of data from 515 participants aged years and older enrolled in the Hefei Aging Study (HAS). CSVD burden was quantified using magnetic resonance imaging (MRI) markers, including white matter hyperintensities (WMH), lacunar infarcts, cerebral microbleeds (CMBs), and enlarged perivascular spaces (EPVS). Associations were evaluated using logistic regression and generalized linear models, adjusting for relevant covariates.

RESULTS: Individuals with CSVD (score ≥1, n = 145) had significantly higher median p-tau217 levels compared to those without CSVD (0.245 vs. 0.227 pg/mL, p = 0.010). Elevated p-tau217 was independently associated with WMH (odds ratio [OR] =1.462, p = 0.006) and CMBs (OR =1.290, p = 0.033) after adjusting for covariates. Stratified analyses indicated stronger associations in APOE ε4-negative individuals (OR=1.244, p = 0.027). A linear relationship was observed between log-transformed p-tau217 and CSVD burden (β =0.113, p < 0.001), although the effect sizes were modest (adjusted R² =0.025).

CONCLUSION: Plasma p-tau217 levels are associated with CSVD burden, particularly WMH and CMBs, suggesting a role for tau pathology in vascular injury. The APOE ε4 genotype appears to modulate this relationship, highlighting distinct pathways in amyloid- and tau-mediated vascular damage.},
}

Humans
*Cerebral Small Vessel Diseases/blood/pathology/diagnostic imaging
*tau Proteins/blood
Female
Cross-Sectional Studies
Male
Aged
Aged, 80 and over
Magnetic Resonance Imaging
*Aging/blood/pathology
Biomarkers/blood
Phosphorylation

@article {pmid41235867,
year = {2025},
author = {Ladurner, G and Harper, DJ and May, L and Worm, S and Patel, Y and Varaka, M and Prokesch, M and Garhöfer, G and Merkle, C and Baumann, B},
title = {Comparative Investigation of the Retinal Phenotype of Three Mouse Models of Alzheimer's Disease With Optical Coherence Tomography.},
journal = {Investigative ophthalmology & visual science},
volume = {66},
number = {14},
pages = {35},
doi = {10.1167/iovs.66.14.35},
pmid = {41235867},
issn = {1552-5783},
mesh = {Animals ; *Tomography, Optical Coherence/methods ; *Alzheimer Disease/pathology ; Disease Models, Animal ; Mice ; Mice, Transgenic ; *Retina/pathology ; Phenotype ; Mice, Inbred C57BL ; Male ; Amyloid beta-Protein Precursor/genetics ; },
abstract = {PURPOSE: Mouse models of Alzheimer's disease (AD) are designed to replicate a multitude of pathologies. However, a direct comparison between models is virtually impossible due to vastly differing data acquisition and image processing protocols. Based on the hypothesis that a well-defined experimental framework is key to determining subtle differences in their retinal phenotype, we use a standardized anesthesia protocol, the same optical coherence tomography (OCT) system and image processing pipeline to compare commercially available AD mouse models.

METHODS: Two models of amyloidosis (5xFAD and APP/PS1) and one of tau pathology (PS19) were investigated (age = 42.5 ± 6.5 weeks). A high-resolution OCT prototype was used to image the retina of animals under isoflurane anesthesia. Retinal OCT parameters were mapped and compared.

RESULTS: Total retinal thickness was comparable for the amyloidosis models (transgenic [tg] and non-transgenic [ntg] APP/PS1 = 209.3 µm and 210.7 µm, and tg and ntg 5xFAD = 212.1 µm and 211.2 µm), but, on average, approximately 17% thicker for the tg and ntg PS19 mice (256.4 µm and 236.8 µm). APP/PS1 mice had approximately 10 µm thicker outer retinal layers (ORL) in tg and ntg models and 10 µm thinner inner retinal layers (IRL) in comparison to 5xFAD mice. PS19 mice had between 10 and 20 µm thicker IRL and ORL than the amyloidosis models. The vascular density in superficial vascular, intermediate, and deep capillary plexuses differed significantly for 5xFAD mice.

CONCLUSIONS: Despite standardized conditions, the retinal parameters were not constant across different mouse models of AD, indicating fundamental phenotypical differences.},
}

Animals
*Tomography, Optical Coherence/methods
*Alzheimer Disease/pathology
Disease Models, Animal
Mice
Mice, Transgenic
*Retina/pathology
Phenotype
Mice, Inbred C57BL
Male
Amyloid beta-Protein Precursor/genetics

@article {pmid41235769,
year = {2025},
author = {Wang, J and Li, Y and Yang, Y and Liang, Z and Xie, P and Li, X and Guo, Y and Li, S and Chen, X},
title = {Lateralization Disruption and Dynamic Balance Alterations in Alzheimer's Disease: Impacts on Hemispheric Interaction and Cognitive Performance.},
journal = {Human brain mapping},
volume = {46},
number = {16},
pages = {e70411},
doi = {10.1002/hbm.70411},
pmid = {41235769},
issn = {1097-0193},
support = {F2022203081//Natural Science Foundation of Hebei Province/ ; 62103354//National Natural Science Foundation of China/ ; 62271341//National Natural Science Foundation of China/ ; 62371416//National Natural Science Foundation of China/ ; 62471428//National Natural Science Foundation of China/ ; C20220337//Funding Project for the Introduced Overseas Students of Hebei Province/ ; 22567619H//Hebei Innovation Capability Improvement Plan Project/ ; },
mesh = {Humans ; *Alzheimer Disease/physiopathology/diagnostic imaging/complications ; Male ; Female ; *Functional Laterality/physiology ; Aged ; Magnetic Resonance Imaging ; Middle Aged ; *Nerve Net/diagnostic imaging/physiopathology ; *Default Mode Network/diagnostic imaging/physiopathology ; *Cognitive Dysfunction/physiopathology/diagnostic imaging/etiology ; *Cerebral Cortex/diagnostic imaging/physiopathology ; },
abstract = {Brain lateralization is considered evolutionarily adaptive. Impaired functional specialization is thought to cause abnormal lateralization in neurological disorders. However, the dynamic changes in brain laterality in Alzheimer's disease (AD) remain unclear. In this study, resting-state fMRI data and neuropsychological assessments from 109 participants (49 AD patients and 60 healthy controls [HC]) were used. Dynamic laterality time series were constructed by extracting the dynamic laterality index (DLI) within each sliding window. We assessed two key features: laterality reversal (LR), reflecting intra-hemispheric processing efficiency, and laterality fluctuation (LF), indicating inter-hemispheric communication. Group differences in dynamic laterality characteristics were analyzed using statistically rigorous methods, regressing out gender, age, years of education, and head movements. Spearman correlation analyses examined the relationship between laterality characteristics and cognitive performance. Our results showed that AD patients exhibited a more pronounced loss of left lateralization as well as stronger right lateralization, especially in the somatomotor network (SMN) and default mode network (DMN). Additionally, we observed decreased LR as well as increased LF with global trends in AD. These divergent changes disrupted the dynamical balance between intra- and inter-hemispheric information interaction. Notably, this imbalance depended on the degree of lateralization, and the higher order cognitive networks with high-level lateralization were more vulnerable. Importantly, the observed abnormal lateralization metrics were associated with worse cognitive impairment. Our study highlights a disruption of dynamic lateralization balance in higher order cortical networks in AD patients and reveals its potential role in the disease's pathophysiology.},
}

Humans
*Alzheimer Disease/physiopathology/diagnostic imaging/complications
Male
Female
*Functional Laterality/physiology
Aged
Magnetic Resonance Imaging
Middle Aged
*Nerve Net/diagnostic imaging/physiopathology
*Default Mode Network/diagnostic imaging/physiopathology
*Cognitive Dysfunction/physiopathology/diagnostic imaging/etiology
*Cerebral Cortex/diagnostic imaging/physiopathology

@article {pmid41235755,
year = {2025},
author = {Ramirez, P and Sun, W and Dehkordi, SK and Zare, H and Pascarella, G and Carninci, P and Fongang, B and Bieniek, KF and Frost, B},
title = {Long-read sequencing reveals genomic and epigenomic variation in the dark genome of human Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70852},
doi = {10.1002/alz.70852},
pmid = {41235755},
issn = {1552-5279},
support = {//BrightFocus Foundation/ ; R25 GM095480/GM/NIGMS NIH HHS/United States ; RF1 NS112391/NS/NINDS NIH HHS/United States ; R01AG078964/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/genetics/pathology ; DNA Methylation/genetics ; Aged ; Male ; Female ; Epigenomics ; Brain/metabolism/pathology ; *Epigenesis, Genetic/genetics ; Aged, 80 and over ; Genome, Human ; Retroelements/genetics ; Genomics ; Genetic Variation ; },
abstract = {INTRODUCTION: Faulty DNA repair and epigenetic regulation contribute to neurodegeneration in Alzheimer's disease. Long-read sequencing enables analysis of "dark regions" that are difficult to study via traditional sequencing methodologies.

METHODS: Using nanopore whole-genome DNA sequencing of post mortem brain from early- and late- stage Alzheimer's disease cases and controls, we analyzed retrotransposition, non-allelic homologous recombination (NAHR), structural variation, and DNA methylation within repetitive regions.

RESULTS: Retrotransposon insertions and NAHR were enriched in centromeric/pericentromeric and ribosomal DNA (rDNA) in the aged brain. Putatively somatic AluY retrotransposon insertions trended upward in late-stage disease. Enrichment of NAHR between repetitive regions and DNA demethylation were detected in early disease. Differential methylation of dark regions within specific Alzheimer's disease risk genes and repetitive elements occurred across disease stage.

DISCUSSION: This study provides the first long-read analysis of repetitive elements in the aged human brain and identifies these regions as hotspots for genomic variation in Alzheimer's disease.

HIGHLIGHTS: Long-read sequencing enables analysis of "dark" regions Alzheimer's disease brains Somatic AluY retrotransposon insertions may be elevated in late-stage disease Retrotransposon-associated non-allelic homologous recombination (NAHR) is enriched in repetitive regions in early disease DNA demethylation within the centro/pericentromere and ribosomal DNA (rDNA) occur across disease stage Dark regions of risk genes are differentially methylated across disease stage.},
}

Humans
*Alzheimer Disease/genetics/pathology
DNA Methylation/genetics
Aged
Male
Female
Epigenomics
Brain/metabolism/pathology
*Epigenesis, Genetic/genetics
Aged, 80 and over
Genome, Human
Retroelements/genetics
Genomics
Genetic Variation

@article {pmid41235368,
year = {2025},
author = {Arellano, A and Palma-Florez, S and Cabrera, P and Cortés-Adasme, E and Bolaños, K and Celis, F and Araya-Vergara, AJ and Pérez, M and Crespo, A and Matus, MH and Araya, E and Aldunate, R and Kogan, MJ and Samitier, J and Lagunas, A and Mir, M and Hassan, N},
title = {Attenuation of blood-brain barrier dysfunction by functionalized gold nanoparticles against amyloid-β peptide in an Alzheimer's disease-on-a-chip model.},
journal = {Materials today. Bio},
volume = {35},
number = {},
pages = {102453},
pmid = {41235368},
issn = {2590-0064},
abstract = {Gold nanoparticles (GNP) are highly valuable in nanotechnology due to their biocompatibility and unique physicochemical properties, which make them attractive as nanocarriers for targeted drug delivery. In the context of neurodegenerative diseases (NDDs) such as Alzheimer's disease (AD), GNP hold promise for reducing the toxicity of Amyloid-β peptide (Aβ) aggregates. However, a major challenge in developing new therapies for NDDs lies in the limited reliance on animal models and the difficulty of crossing the blood-brain barrier (BBB). This study investigates the effects of GNP on Aβ toxicity using a human-based BBB-organ-on-a-chip model (BBB-oC), mimicking the 3D cellular architecture of the BBB under both normal and pathological conditions. We rationally designed a novel nanosystem functionalized with the peptide D3, which functions both as a selective Aβ toxicity inhibitor and a BBB-targeting agent. The results show that GNP can cross the BBB, reduce the Aβ-induced cytotoxicity, and promote the maintenance of the BBB integrity. Moreover, controlling the shape of GNP further enhanced their protective effect. Overall, this work highlights the feasibility of rationally designed GNP as a promising therapeutic strategy for AD, evaluated through a more reliable and predictive human-relevant model.},
}

@article {pmid41235285,
year = {2025},
author = {Manzoor, H},
title = {A Neuroimaging Audit of Patients Referred to an Old-Age Community Mental Health Team From Memory Assessment Service: Compliance With the Royal College of Radiologists Guidance.},
journal = {Cureus},
volume = {17},
number = {11},
pages = {e96682},
pmid = {41235285},
issn = {2168-8184},
abstract = {Background Neuroimaging is a crucial component in the assessment of patients with suspected dementia, aiding in diagnostic confirmation, subtype differentiation, and the exclusion of reversible causes. The Royal College of Radiologists (RCR) provides standards to guide the structured and comprehensive reporting of imaging scans, aiding in diagnostic accuracy and clinical decision-making. Local compliance with RCR standards may vary, which could influence the clinical utility of the scans. This audit was undertaken to evaluate local compliance with RCR reporting standards and identify areas for improvement. Methodology A total of 50 referrals from the Memory Assessment Service to the Old Age Community Mental Health Team (April 2024-September 2025) were reviewed. Radiology reports were analyzed for compliance with RCR standards, focusing on documentation of atrophy pattern, vascular pathology, reversible causes, use of rating scales, and inclusion of diagnostic conclusions. Data were also organized by imaging modality and indication to assess reporting consistency and completeness. Results Of the 50 referrals, nine (18%) patients were diagnosed with dementia without neuroimaging, consistent with clinical guidelines. Among 41 imaged patients, 33 had CT and four had MRI scans. Cerebral atrophy was described in 85% of reports, increasing to 100% for cognitive impairment cases; however, standardized scoring systems were infrequently used (Medial Temporal Atrophy score 7/22). Vascular pathology was mentioned in most reports with severity markers, but Fazekas scoring was used in 3/22 scans. Reversible causes were more comprehensively covered in scans done for indications other than cognitive impairment. Overall, 15/22 (68%) cognitive impairment reports included a diagnostic conclusion. Conclusions Local neuroimaging reports for dementia patients showed comprehensive recognition of atrophy and vascular changes but inconsistent use of standardized scoring, documentation of reversible causes, and diagnostic conclusions. Structured reporting templates and multidisciplinary feedback could improve adherence to RCR standards and enhance clinical utility.},
}

@article {pmid41235150,
year = {2025},
author = {Nigdelioglu Dolanbay, S},
title = {Monoterpene-rich essential oil from Artemisia santonicum L. exerts neuroprotective effects in Aβ-induced SH-SY5Y cells: Modulation of tau pathology, neuroinflammation, oxidative stress, and synaptic-metabolic pathways.},
journal = {Toxicology research},
volume = {14},
number = {6},
pages = {tfaf155},
pmid = {41235150},
issn = {2045-452X},
abstract = {Understanding the complex biological mechanisms of ad requires innovative treatment approaches for this disease. In this context, natural compounds, especially monoterpenes, attract attention with their potential for biological activity. In this study, the therapeutic potential of monoterpene rich essential oil obtained from Artemisia santonicum L. for the treatment of ad was comprehensively evaluated. GC-MS analysis showed that the major monoterpenes were limonene, camphor, pinene, terpineol, and carvone in essential oil obtained from A. santonicum L. Possible common targets of monoterpenes with ad were predicted and their PPI networks were analyzed. Furthermore, gene set enrichment analysis was applied to understand the functional roles of these possible common targets and their relationships with biological pathways. Molecular docking studies revealed the binding affinities and interaction abilities of monoterpenes with the predicted possible common targets. The monoterpene rich essential oil obtained from A. santonicum L. used in our study provides a neuroprotective effect by targeting the pathological mechanisms of ad. We designed in vitro experiments to elucidate the mechanism of the mentioned neuroprotective effect. Within the scope of the study, neuroprotective effect analyses were performed to evaluate cell viability rates and in vitro AChE enzyme activity, while the ELISA method was used to determine phosphorylated tau levels and to assess neuroinflammatory responses. In addition, apoptosis levels, MMP changes and intracellular ROS accumulation were examined by flow cytometry analyses. These comprehensive analyses aimed to reveal the molecular mechanisms of the neuroprotective effect of monoterpene rich essential oil obtained from A. santonicum L. and to shed light on its potential therapeutic applications in ad.},
}

@article {pmid41235132,
year = {2025},
author = {Chatterjee, A and Cavaillès, C and Davies, NM and Yaffe, K and Andrews, SJ},
title = {Disentangling the Causal Effects of Education and Participation Bias on Alzheimer Disease Using Mendelian Randomization.},
journal = {Neurology. Genetics},
volume = {11},
number = {6},
pages = {e200307},
pmid = {41235132},
issn = {2376-7839},
abstract = {BACKGROUND AND OBJECTIVES: People with university degrees have a lower incidence of Alzheimer disease (AD). However, the relationship between education and AD could be due to selection, collider, or ascertainment biases, such as lower familiarity with cognitive testing or the fact that those with degrees are more likely to participate in research. In this study, we use 2-sample Mendelian randomization (MR) to investigate the causal relationships between education, participation, and AD.

METHODS: We used genome-wide association study summary statistics for educational attainment, 3 measures of participation, AD (clinically diagnosed AD), and AD/ADRD (AD and related dementia; includes clinical diagnosis and family history). Independent genome-wide significant single-nucleotide variations (SNVs) were extracted from the exposure data sets and harmonized with the outcome SNPs. Fixed-effects inverse variance-weighted meta-analysis was the primary MR method; Cochran Q statistic and MR Egger intercept were used to test for heterogeneity and pleiotropy, and radial MR was used to identify outliers. Sensitivity analyses included MR Egger, weighted median, and mode. Bidirectional analyses were used to test whether AD pathology affects participation, and multivariable MR (MVMR) assessed independent exposure-outcome effects.

RESULTS: Educational attainment reduced the risk of AD (ORIVW 95% CI 0.70 [0.63-0.79], p = 8e-10), and the results were robust based on sensitivity analyses. However, education increased the risk of AD/ADRD, although the results were not robust in sensitivity analyses (ORIVW 95% CI 1.09 [1.02-1.15], p = 0.006). Participation in the mental health questionnaire reduced the odds of AD (ORIVW 95% CI 0.325 [0.128-0.326], p = 0.01). When adjusting for participation in MVMR, education remained associated with a reduced risk of AD (ORIVW 95% CI 0.76 [0.62-0.92], p = 0.006).

DISCUSSION: Univariable MR analyses indicated that education and participation reduced the risk of AD. However, MR also suggested that education increased the risk of AD/ADRD, highlighting the inconsistencies between clinical and proxy diagnoses of AD, as proxy-AD may be affected by selection, collider, or ascertainment bias. MVMR suggested that education remained associated with reduced AD risk after adjusting for participation and the protective effect of education may be due to other biological mechanisms, such as cognitive reserve.},
}

@article {pmid41235113,
year = {2025},
author = {Zampieri, TT and Higa, GSV and Borges, FS and Viana, FJC and Cruvinel, E and Bentivoglio, LE and Lugao, AB and Ulrich, H and Britto, LR and Katti, KV and Chesne, AM and de Pasquale, R},
title = {Exposure to β-hydroxybutyrate reduces the operating set point and increases excitability in hippocampal circuitry of healthy mice.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1557612},
pmid = {41235113},
issn = {1663-9812},
abstract = {The ketogenic diet is a therapeutic strategy applied to reduce brain hyperexcitability in conditions such as epilepsy, Parkinson's and Alzheimer's disease, migraines, and autism. This diet reduces circulating glucose levels and increases ketone bodies, with β-hydroxybutyrate (BHB) being one of the leading promoters of the beneficial effects. BHB was previously reported as a mediator of cognitive restoration and memory formation. Herein, we investigate the effect of exogenous BHB on hippocampal neuronal excitability and synaptic plasticity mechanisms, regardless of the pathological or neurodegenerative conditions. Electrophysiological experiments were conducted to explore both passive and active neuronal properties, including action potential firing and spontaneous and evoked postsynaptic responses. Electrical stimulation along the CA3-CA1 pathway enabled the assessment of both short- and long-term synaptic plasticity, as well as the mechanisms mediated by AMPA and NMDA receptors. Experiments were conducted in hippocampal slices treated with 3-β-hydroxybutyrate glycerides (DHB) and niacin (HCAR2 agonist). Although DHB incubation did not alter passive membrane properties, it significantly increased neuronal excitability, reflected in an elevated firing rate upon depolarizing stimulation and enhanced spontaneous excitatory postsynaptic currents in CA1 pyramidal neurons, which were dependent on synaptic inputs. DHB treatment led to a reduction in long-term potentiation (LTP) in CA1 neurons, suggesting a metaplastic effect independent of NMDA receptor activation. Importantly, these DHB-induced neuronal alterations were found to be independent of HCAR2 receptor activation, supporting the involvement of distinct intracellular pathways and long-term modulatory mechanisms. Our findings indicate that DHB exerts a modulatory effect on hippocampal neural activity by enhancing excitability and concurrently promoting a compensatory reduction in LTP, suggesting a homeostatic balancing mechanism.},
}

@article {pmid41235101,
year = {2025},
author = {Chen, XQ},
title = {APP Gene-based Strategies to Combat Alzheimer's Disease in Down Syndrome.},
journal = {Current genomics},
volume = {26},
number = {4},
pages = {245-248},
pmid = {41235101},
issn = {1389-2029},
}

@article {pmid41235013,
year = {2025},
author = {Nenezic, N and Dragicevic Jeremic, J and Rancic, N and Dejanovic, B and Kostic, D and Nenezic, D and Safiye, T and Alexopoulos, C and Kostic, S},
title = {The Link Between Serum Levels of Dehydroepiandrosterone and Alzheimer's Disease: A Pilot Study in the Serbian Population.},
journal = {Cureus},
volume = {17},
number = {10},
pages = {e94489},
pmid = {41235013},
issn = {2168-8184},
abstract = {Background and aim Alzheimer's disease (AD) is the most prevalent type of dementia and a major health concern among the elderly population. Considering the role of neurosteroids in neurodegenerative processes, this pilot study aimed to investigate the association between serum dehydroepiandrosterone sulfate (DHEA-S) and cortisol concentrations, as well as their ratio, in patients with AD compared with cognitively intact individuals. Methods An observational case-control study was conducted involving 45 patients with clinically probable AD, diagnosed according to the 2011 National Institute on Aging-Alzheimer's Association criteria, and 40 healthy control participants matched for age and sex. Fasting morning serum concentrations of DHEA-S and cortisol were measured after a 12-hour overnight fast in all participants, and the cortisol/DHEA-S ratio was calculated. Cognitive status was assessed using the Montreal Cognitive Assessment and Clinical Dementia Rating scales. Results No statistically significant difference in serum DHEA-S concentrations was found between patients with AD and controls. However, patients with AD had significantly higher cortisol levels (398.85 vs. 337.40 nmol/L; p = 0.026) and a higher cortisol/DHEA-S ratio, showing a trend toward statistical significance (p = 0.078). Among participants aged 65-75 years, the cortisol/DHEA-S ratio was significantly higher in patients with AD than in controls (p = 0.031). In the control group, males had significantly higher DHEA-S levels than females (p = 0.020), whereas no sex difference was observed in the AD group. Conclusions The findings of this pilot study suggest that elevated cortisol levels and an imbalance in the cortisol/DHEA-S ratio may contribute to AD pathophysiology. DHEA-S alone did not show a significant association with disease presence, but the observed age- and sex-related differences indicate that this neurosteroid may play a differential role in the development and progression of AD.},
}

@article {pmid41234939,
year = {2025},
author = {Wang, R and Peng, S and Zhu, J and Xu, Y and Wang, M and Zhang, L and Qiu, Y and Hou, D and Wang, Q and Liu, R},
title = {Innovations in Alzheimer's disease diagnostic technologies: clinical prospects of novel biomarkers, multimodal integration, and non-invasive detection.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1651708},
pmid = {41234939},
issn = {1664-2295},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the deposition of β-amyloid (Aβ) plaques and the formation of neurofibrillary tangles composed of hyperphosphorylated tau protein, ultimately leading to cognitive decline and neuronal loss. Current diagnostic methods, including clinical evaluations, neuroimaging examinations, and cerebrospinal fluid biomarker testing, face challenges such as insufficient sensitivity and specificity, as well as operational complexity. In recent years, significant advancements have been made in diagnostic technologies, with the emergence of new biomarkers and detection methods, including blood-based Aβ and tau protein detection, ocular biomarker testing, and non-invasive screening through urine or breath analysis. These innovative developments, combined with multimodal diagnostic technologies that integrate imaging, genomics, and proteomics, have opened new possibilities for the early diagnosis and precise staging of Alzheimer's disease. Furthermore, advancements in microfluidic chips and biosensor technologies have enhanced the capability for rapid, efficient, and cost-effective diagnosis. As research continues to evolve, the gradual application of these advanced technologies in clinical practice is expected to revolutionize the management of Alzheimer's disease, facilitating early intervention and the formulation of individualized treatment strategies.},
}

@article {pmid41234527,
year = {2025},
author = {Akbarian, B and Hett, K and Phan, T and Lee, JJ and Eaton, J and Donahue, MJ and Darby, RR},
title = {Microstructural grey matter alterations in patients with behavioural variant frontotemporal dementia.},
journal = {Brain communications},
volume = {7},
number = {6},
pages = {fcaf427},
pmid = {41234527},
issn = {2632-1297},
abstract = {Behavioural variant frontotemporal dementia is characterized by progressive changes to personality and behaviour, yet early detection and disease staging remain challenging. Current clinical neuroimaging relies on visual assessment of atrophy patterns, which may overlook subtle structural changes. While volumetric analysis has improved the ability to detect neurodegeneration and track disease progression, it may lack the sensitivity to identify microstructural alterations that precede frank atrophy. Texture analysis, a quantitative approach that evaluates the spatial regularity of grey matter density, has demonstrated promise in detecting early microstructural changes in Alzheimer's disease and distinguishing frontotemporal dementia subtypes. However, its potential as a biomarker for early behavioural variant frontotemporal dementia detection and disease staging remain unexplored. This study evaluates the potential of autocorrelation-based texture features as biomarkers for detecting early-stage behavioural variant frontotemporal dementia and tracking disease progression, comparing their sensitivity and specificity to regional brain volume. We analysed structural MRI scans from behavioural variant frontotemporal dementia patients with mild (n = 21, 61.5 ± 8.5 years, 4.7% female) and moderate dementia (n = 11, 64.4 ± 9.3, 18.1% female) alongside healthy controls (n = 33, 63.1 ± 7.9 years; 36.3% female). Texture and volumetric measures were extracted from frontotemporal regions implicated in behavioural variant frontotemporal dementia pathology. First, we compared these features between healthy controls and patients with mild dementia to identify regions relevant for early diagnosis. Second, we compared patients with mild versus moderate dementia to identify regions linked to disease stage. Analyses were performed both within a composite frontotemporal region of interest and within 160 frontotemporal subregions. We applied false discovery rate correction for multiple comparisons. Microstructural abnormalities captured by texture analysis and volumetric reductions were significantly lower in patients with mild dementia compared to healthy controls within the composite frontotemporal and many subregions (PFDR < 0.05). In moderate dementia, texture features detected alterations in composite frontotemporal (PFDR < 0.05) and subregions, including the anterior cingulate, insula and orbitofrontal cortices (PFDR < 0.05) even when volumetric differences were absent. This study demonstrates that texture-based MRI metrics provide a sensitive measure of microstructural alterations in behavioural variant frontotemporal dementia, detecting some disease-related changes even in regions without detectable volumetric reductions. While volumetric measures are effective for identifying individuals with early-stage disease, texture analysis may offer increased sensitivity for tracking disease progression. Longitudinal studies are needed to validate the predictive value of texture features for clinical decline in behavioural variant frontotemporal dementia.},
}

@article {pmid41234424,
year = {2025},
author = {Hosseini, AA and Shao, B and Lee, AR and Dhillon, P and Junaid, K and Gran, B and Sellars, P and Sargisson, H and Jung, J and Mukaetova-Ladinska, EB},
title = {The Cognitive and Neuroimaging for Neurodegenerative Disorders Study (CogNID): design and initial findings from real-world clinical practice.},
journal = {Frontiers in psychiatry},
volume = {16},
number = {},
pages = {1630082},
pmid = {41234424},
issn = {1664-0640},
abstract = {INTRODUCTION: Dementia presents with significant heterogeneity across age groups, particularly in early-onset cognitive decline (EOCD), which poses diagnostic and management challenges. The Cognitive and Neuroimaging for Neurodegenerative Disorders (CogNID) study aims to characterise clinical, cognitive, neuroimaging, and biomarker features across a diverse cohort of individuals with cognitive impairment, with a focus on diagnostic complexity, biomarker utility, and mortality.

METHODS: Out of 680 study participants within this prospective cohort enrolled from the real-world clinics within the National Health Service, who consented to take part in the study, we analysed data from 429. Individuals were recruited between December 2018 and November 2024 from the Memory Clinics, including the early-onset dementia service and associated services. Participants underwent structured cognitive assessments, neuroimaging (MRI/CT), and Cerebrospinal fluid (CSF) biomarker evaluation, where available. Diagnoses were made by multidisciplinary consensus. Group comparisons were conducted between early-onset (EOCD, <65 years) and late-onset cognitive decline (LOCD, ≥65 years).

RESULTS: Of the 429 participants, 349 (81.4%) had EOCD and 80 (18.6%) had LOCD. The mean age was 60.05 years, with no significant difference in sex or ethnicity across groups. Depression and anxiety were common (29.6%), as were cardiovascular risk factors. Lumbar punctures were more frequently performed in EOCD (p = 0.03), with 36.4% of tested participants demonstrating biomarker profiles consistent with Alzheimer's disease (A+T+). Functional cognitive disorder (FCD) was more common in EOCD (22.3% vs. 5.0%, p < 0.001). Subgroup analysis revealed significantly lower ACE-III scores and higher pathological CSF findings in Alzheimer's disease versus FCD. Mortality was higher in the LOCD group (11.3% vs. 4.6%, p = 0.03).

CONCLUSION: The CogNID study highlights the clinical and diagnostic heterogeneity of individuals with cognitive impairment, particularly in younger adults. Incorporating neuroimaging and CSF biomarkers into routine clinical pathways enhances diagnostic precision and reveals distinct phenotypic profiles between EOCD and LOCD. These findings underscore the need for harmonised diagnostic protocols, broader biomarker accessibility, and inclusive recruitment strategies in dementia research and clinical services.},
}

@article {pmid41234238,
year = {2025},
author = {Song, K and Choi, J and Jeong, D and Shin, D and Ah, YM and Lee, KY and Choi, KH},
title = {Comparative effects of SGLT2 inhibitors and incretin-based therapies on dementia risk in type 2 diabetes: a systematic review and meta-analysis.},
journal = {Frontiers in endocrinology},
volume = {16},
number = {},
pages = {1695075},
pmid = {41234238},
issn = {1664-2392},
mesh = {Humans ; *Diabetes Mellitus, Type 2/drug therapy/complications ; *Sodium-Glucose Transporter 2 Inhibitors/therapeutic use ; *Incretins/therapeutic use ; *Dementia/prevention & control/epidemiology/etiology ; *Hypoglycemic Agents/therapeutic use ; Dipeptidyl-Peptidase IV Inhibitors/therapeutic use ; },
abstract = {BACKGROUND: Antidiabetic drugs lower blood glucose levels and may also have neuroprotective and vascular protection effects. In particular, sodium-glucose cotransporter 2 inhibitors (SGLT2is) and incretin mimetics have demonstrated dementia-reducing effects. We evaluated whether SGLT2is reduce dementia risk compared with incretin mimetics in patients with type 2 diabetes (T2D).

METHODS: Systematic review and meta-analysis were performed by searching the PubMed, Embase, and Cochrane Library databases through February 2025. Both randomized trials and cohort studies were identified and qualitatively assessed, but only cohort studies were included in the quantitative meta-analysis. We also compared the effects of SGLT2is with those of dipeptidyl peptidase-4 inhibitors (DPP-4i) or glucagon-like peptide-1 receptor agonists (GLP-1RA) on dementia incidence.

RESULTS: Nine studies were identified for analysis. Compared with incretin mimetics, SGLT2is significantly reduced the overall dementia risk [hazard ratio (HR) 0.82, 95% CI: 0.73-0.91], and SGLT2is had stronger effects than DPP-4i (HR 0.67, 95% CI: 0.59-0.77) and GLP-1RA (HR 0.93, 95% CI: 0.86-1.00). SGLT2i also reduced the risks of vascular dementia and Alzheimer's disease (HR 0.49, 95% CI: 0.35-0.70 vs. HR 0.68, 95% CI: 0.52-0.88, respectively). The results of subgroup analyses revealed increased benefits for patients aged older than 65 years. Empagliflozin was the most consistently protective among the SGLT2i agents.

CONCLUSION: SGLT2is may provide neuroprotective benefits beyond glycemic control in patients with T2D, particularly in older populations at higher risk of cognitive decline. These findings support consideration of SGLT2is as a preferred therapeutic option for patients with T2D at increased risk of dementia, although randomized controlled trials would further strengthen this evidence base.

https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024567890 identifier PROSPERO (CRD420251037959).},
}

Humans
*Diabetes Mellitus, Type 2/drug therapy/complications
*Sodium-Glucose Transporter 2 Inhibitors/therapeutic use
*Incretins/therapeutic use
*Dementia/prevention & control/epidemiology/etiology
*Hypoglycemic Agents/therapeutic use
Dipeptidyl-Peptidase IV Inhibitors/therapeutic use

@article {pmid41234220,
year = {2025},
author = {Fujishiro, H and Kawakami, I and Oshima, K and Torii, Y and Arafuka, S and Iritani, S and Ikeda, K},
title = {Systematized delusions in a patient with covert hepatic encephalopathy: A clinicopathological insight into prodromal dementia with Lewy bodies.},
journal = {PCN reports : psychiatry and clinical neurosciences},
volume = {4},
number = {4},
pages = {e70247},
pmid = {41234220},
issn = {2769-2558},
abstract = {BACKGROUND: Late-onset psychosis is an early clinical manifestation of psychiatric-onset prodromal dementia with Lewy bodies (DLB); however, its underlying neuropathology remains poorly understood. Clinicopathological correlations are often limited by the gap between symptom onset and the autopsy.

CASE PRESENTATION: A 66-year-old man with autopsy-confirmed DLB presented with persistent systematized delusions. After treatment for liver cirrhosis during hospitalization, the patient's physical symptoms improved; however, persecutory delusions developed. The patient was clinically diagnosed with covert hepatic encephalopathy (HE). The delusions were atypical for covert HE, suspecting delusional disorder. His systematized delusions persisted for 3 months until his death, without the development of cognitive decline or Parkinsonism during his lifetime. An autopsy revealed an early transitional type of Lewy body disease with minimal Alzheimer's type II astrocytes indicative of HE. Severe neuronal loss was observed in the locus coeruleus (LC), while the substantia nigra (SN) and nucleus basalis of Meynert (nbM) were preserved. Abundant alpha-synuclein-positive structures were identified in the LC, periaqueductal gray matter, nbM, amygdala, and thalamus, with sparse involvement of the SN, neocortex, peripheral autonomic nervous system, including the heart and gastrointestinal tract.

CONCLUSION: Selective Lewy body involvement, sparing the SN and neocortex, may explain the isolated psychiatric symptoms in the absence of Parkinsonism or dementia. Systemic conditions such as covert HE may have contributed to the emergence of persistent delusions. This case highlights the need for multidisciplinary approaches that integrate psychosomatic assessments with neuropathological investigations to evaluate late-onset psychosis.},
}

@article {pmid41234138,
year = {2025},
author = {},
title = {Correction to: Polygenic Risk Scores for Alzheimer's Disease and General Cognitive Function Are Associated With Measures of Cognition in Older South Asians.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {80},
number = {12},
pages = {},
doi = {10.1093/gerona/glaf220},
pmid = {41234138},
issn = {1758-535X},
}

@article {pmid41234025,
year = {2025},
author = {Oomens, JE and Vos, SJ and Maserejian, NN and Boada, M and Didic, M and Engelborghs, S and Fladby, T and van der Flier, WM and Frisoni, GB and Fröhlich, L and Gill, KD and Grimmer, T and Hort, J and Itoh, Y and Iwatsubo, T and Klimkowicz-Mrowiec, A and Landau, SM and Lee, DY and Lleó, A and Martinez-Lage, P and de Mendonça, A and Meyer, PT and Parchi, P and Pardini, M and Parnetti, L and Popp, J and Rami, L and Reiman, EM and Rinne, JO and Rodrigue, KM and Sánchez-Juan, P and Santana, I and Scarmeas, N and Scheltens, P and Skoog, I and Sperling, RA and Stern, Y and Villeneuve, S and Waldemar, G and Wiltfang, J and Zetterberg, H and Alcolea, D and Allegri, RF and Altomare, D and Bateman, RJ and Baiardi, S and Baldeiras, I and Blennow, K and Braber, AD and van Buchem, MA and Byun, MS and Cerman, J and Chen, K and Chipi, E and Day, GS and Drzezga, A and Ekblad, LL and Förster, S and Fortea, J and Freund-Levi, Y and Frings, L and Guedj, E and Habeck, CG and Handels, R and Hausner, L and Hellwig, S and Jiménez-Bonilla, JF and Juaristi, AI and Kandimalla, R and Kern, S and Bordewick Kirsebom, BS and Kornhuber, J and Legdeur, N and Levin, J and Maier, W and Marquié, M and Minatani, S and Morbelli, SD and Mroczko, B and Ntanasi, E and de Oliveira, CR and Orellana, A and Peters, O and Prabhakar, S and Ramakers, IH and Rodríguez-Rodriguez, E and Ruiz, A and Rüther, E and Sakhardande, J and Selnes, P and Silva, D and Soininen, H and Spiru, L and Takeda, A and Teunissen, CE and Tijms, BM and Vermunt, L and Wallin, ÅK and Wiels, W and Yannakoulia, M and Yi, D and Zettergren, A and , and , and , and , and , and , and Ossenkoppele, R and Verhey, FR and Visser, PJ and Jansen, WJ},
title = {Associations of lifestyle factors with amyloid pathology in persons without dementia.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251379083},
doi = {10.1177/13872877251379083},
pmid = {41234025},
issn = {1875-8908},
abstract = {BackgroundThe association between lifestyle factors and Alzheimer's disease (AD) pathophysiology remains incompletely understood.ObjectiveThe aim of this study was to assess the association of alcohol consumption, smoking behavior, sleep quality and physical, cognitive, and social activity with cerebral amyloid pathology.MethodsFor this cross-sectional study, we selected participants from the Amyloid Biomarker Study data pooling initiative. We used generalized estimating equations to assess associations of dichotomized lifestyle measures with amyloid pathology.ResultsWe included 9171 participants with normal cognition (NC) and 2555 participants with mild cognitive impairment (MCI) from the Amyloid Biomarker Study. Of participants with NC, 58% were women, 34% were APOE ε4 carrier, and 27% had amyloid pathology. Of participants with MCI, 48% were women, 47% were APOE ε4 carrier, and 57% had amyloid pathology. In NC, cognitively active participants were less likely to have amyloid pathology (OR = 0.77, 95%CI 0.66-0.89, p < 0.001). In MCI, participants who had ever smoked or had sleep problems were less likely to have amyloid pathology (OR = 0.85, 95%CI 0.73-0.99, p = 0.029; OR = 0.62, 95%CI 0.45-0.86, p = 0.004).ConclusionsIn NC, cognitive activity was associated with a lower frequency of amyloid pathology. In MCI, favorable lifestyle behaviors were not associated with a lower frequency of amyloid pathology. The results of the current study contribute to the broader evidence base on lifestyle and AD by further characterizing the role of lifestyle behaviors in AD pathology across different clinical stages.},
}

@article {pmid41233906,
year = {2025},
author = {Kaloss, AM and Browning, JL and Li, J and Pan, Y and Watsen, S and Sontheimer, H and Theus, MH and Olsen, ML},
title = {Meningeal vascular Aβ deposition associates with cerebral hypoperfusion and compensatory collateral remodeling.},
journal = {Alzheimer's research & therapy},
volume = {17},
number = {1},
pages = {245},
pmid = {41233906},
issn = {1758-9193},
support = {R01 AG065836/AG/NIA NIH HHS/United States ; R01 AG065836/AG/NIA NIH HHS/United States ; },
mesh = {Animals ; Male ; Female ; *Cerebrovascular Circulation/physiology ; *Amyloid beta-Peptides/metabolism ; Mice ; *Alzheimer Disease/pathology/metabolism ; *Meninges/metabolism/blood supply/pathology ; Mice, Transgenic ; Disease Models, Animal ; *Cerebral Amyloid Angiopathy/pathology/metabolism ; *Collateral Circulation/physiology ; },
abstract = {BACKGROUND: Global reductions in cerebral blood flow (CBF) are among the earliest and most consistent abnormalities observed in Alzheimer's disease (AD), preceding both cortical plaque formation and cognitive decline. While the pial arterial network-a critical supplier of intracortical perfusion-has been overlooked in this context, it may play a pivotal role in early vascular pathology. Here, we report extensive cerebral amyloid angiopathy (CAA) within the pial artery and arteriole network in the J20 (PDGF-APPSw, Ind) mouse model of AD.

METHODS: Using premortem delivery of Methoxy-XO4 to label Aβ, and arterial vascular labeling, we assessed Aβ burden on the pial artery/arteriole network and cerebral blood flow in aged male and female WT and J20 AD mice.

RESULTS: We show that 12-month-old J20 mice exhibit significant Aβ deposition across major leptomeningeal arteries (ACA, MCA) and pial collaterals, with ~ 40% vessel coverage in males and ~ 20% in females-substantially exceeding Aβ levels in cortical or hippocampal vessels. This vascular Aβ burden was accompanied by compensatory enlargement and increased tortuosity of pial collateral vessels. Yet, despite this apparent remodeling, CBF was reduced by ~ 15% in J20 mice, and this decline was significantly associated with leptomeningeal CAA burden.

CONCLUSIONS: This is the first study to comprehensively characterize meningeal arterial Aβ accumulation in a preclinical model of vascular AD, mirroring recent observations in early-stage human disease. Our findings implicate meningeal CAA as a potential driver of early CBF disruption and suggest that pial collateral remodeling may reflect a compensatory response to vascular insufficiency. Moreover, we identify robust sex differences in CAA burden, paralleling sex-specific patterns of parenchymal Aβ pathology in humans. These results highlight the leptomeningeal vasculature as a novel and understudied locus for early AD pathology and a potential therapeutic target to preserve cerebrovascular integrity.},
}

Animals
Male
Female
*Cerebrovascular Circulation/physiology
*Amyloid beta-Peptides/metabolism
Mice
*Alzheimer Disease/pathology/metabolism
*Meninges/metabolism/blood supply/pathology
Mice, Transgenic
Disease Models, Animal
*Cerebral Amyloid Angiopathy/pathology/metabolism
*Collateral Circulation/physiology

@article {pmid41233833,
year = {2025},
author = {Yu, C and Li, M and Shen, F and Gao, S and Wang, J and He, C and Wang, L and Wu, Y and Du, Y},
title = {Electroacupuncture alleviates cognitive impairments in APP/PS1 mice via gastric vagal afferent-mediated activation of the nucleus tractus solitarius‒locus coeruleus noradrenergic circuit.},
journal = {Chinese medicine},
volume = {20},
number = {1},
pages = {188},
pmid = {41233833},
issn = {1749-8546},
support = {No. 82205271//National Natural Science Foundation of China/ ; No. 82505777//National Natural Science Foundation of China/ ; No. 82074566//National Natural Science Foundation of China/ ; No. ZY2025L183//Chinese Medicine Research Project supported by the Hubei Administration of Traditional Chinese Medicine, China/ ; No. ZY2025Q034//Chinese Medicine Research Project supported by the Hubei Administration of Traditional Chinese Medicine, China/ ; 2023AFD113//Key Chinese Medicine Project supported by Hubei Provincial Natural Science Foundation/ ; },
abstract = {OBJECTIVE: Neuroinflammatory cascades mediated by the locus coeruleus-norepinephrine (LC-NE) system emerge as critical pathophysiological determinants governing the etiology and advancement of neurodegenerative disorders, including Alzheimer's disease (AD). Therapeutic modulation of neuroinflammatory processes may mitigate AD-associated cognitive decline. Electroacupuncture (EA) targeting the Foot Yangming of Stomach Meridian acupoints demonstrates efficacy in ameliorating AD-related cognitive dysfunction through dual peripheral and central anti-inflammatory actions, though the precise neural circuitry linking peripheral interventions to central effects remains undefined.

METHODS: In this study, APP/PS1 transgenic mice were administrated with EA stimulation at ST36 and ST37. Cognitive function was assessed via the Morris water maze and novel object recognition tests. Spatial learning capacities and episodic memory retention were quantified through Morris water maze paradigm and object novelty discrimination assays, respectively. Retrograde neural tracing was employed to validate the nucleus tractus solitarius (NTS)-LC noradrenergic projection. Multimodal approaches integrating chemogenetic manipulation, immunofluorescence microscopy, Western blotting, Golgi-Cox neuronal morphology analysis, and Nissl histochemistry elucidated the gastrointestinal vagal afferent fiber (GVAF)-NTS-LC circuit's role in EA-mediated neuroinflammatory regulation. Circuit-specific functional validation was conducted through selective GVAF blockade.

RESULTS: EA at ST36 and ST37 attenuated hippocampal synaptic ultrastructural degeneration via NTS-LC noradrenergic circuit activation. This intervention suppressed proinflammatory cytokines expression (IL-6, IL-1β, TNF-α) and microglial hyperactivation through ADRB2/PKA/CREB pathway modulation, effectively rescuing cognitive deficits in AD models. GVAF ablation reversed EA-induced neuroinflammatory suppression, confirming the circuit dependence.

CONCLUSIONS: EA at ST36/ST37 alleviates AD-related cognitive impairment through sequential GVAF-NTS-LC circuit activation and downstream ADRB2/PKA/CREB-mediated neuroinflammatory resolution. This work identifies a previously unrecognized peripheral-central neural circuit mechanism underlying EA's therapeutic efficacy in AD pathogenesis.},
}

@article {pmid41233412,
year = {2025},
author = {Christova, P and James, LM and Georgopoulos, AP},
title = {Brain volumes discriminate clinical dementia rating scale categories.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {39852},
pmid = {41233412},
issn = {2045-2322},
mesh = {Humans ; Male ; Female ; Aged ; *Dementia/pathology/diagnosis/diagnostic imaging ; *Brain/pathology/diagnostic imaging ; Magnetic Resonance Imaging ; Organ Size ; Gray Matter/pathology ; Aged, 80 and over ; Middle Aged ; Severity of Illness Index ; Atrophy ; Alzheimer Disease/pathology ; },
abstract = {Brain atrophy is well documented in various kinds of dementia, particularly in Alzheimer's disease. Here, we evaluated gray matter volume of 87 cortical and subcortical areas in 460 individuals characterized according to the Clinical Dementia Rating (CDR) as cognitively unimpaired (n = 352), undetermined (n = 72), or mild dementia (n = 36). We found a highly significant correspondence between increased dementia severity and reduced brain volume, particularly for the amygdala and temporal cortical areas, including the hippocampus, middle temporal gyrus, and inferior temporal gyrus. The negative correlation between brain volumes and dementia severity was significantly stronger in men than women, and in apolipoprotein E4 carriers than non-carriers. Brain volumes discriminated between cognitively unimpaired and mild dementia cases with high accuracy; application of those classification functions to the undetermined group resulted in two distinct groups, one resembling the cognitively unimpaired Control group and another resembling the Dementia group. These findings highlight the correspondence between clinical dementia stages and objective brain volume measures, and point to the potential clinical utility of adjunctive structural brain measures to identify individuals with memory complaints who may be at risk of dementia.},
}

Humans
Male
Female
Aged
*Dementia/pathology/diagnosis/diagnostic imaging
*Brain/pathology/diagnostic imaging
Magnetic Resonance Imaging
Organ Size
Gray Matter/pathology
Aged, 80 and over
Middle Aged
Severity of Illness Index
Atrophy
Alzheimer Disease/pathology

@article {pmid41233409,
year = {2025},
author = {Lai, Y and Zhao, H},
title = {Therapeutic efficacy of rehmannioside A on 5×FAD mice in Alzheimer's disease.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {39825},
pmid = {41233409},
issn = {2045-2322},
mesh = {Animals ; *Alzheimer Disease/drug therapy/pathology/metabolism ; Mice ; Oxidative Stress/drug effects ; Disease Models, Animal ; *Neuroprotective Agents/pharmacology/therapeutic use ; Hippocampus/drug effects/metabolism/pathology ; Male ; *Saponins/pharmacology/therapeutic use ; Amyloid beta-Peptides/metabolism ; Memory/drug effects ; Mice, Transgenic ; Plaque, Amyloid/drug therapy/pathology ; Drugs, Chinese Herbal ; },
abstract = {Alzheimer's disease (AD), characterized by Aβ plaques and cognitive decline, remains a significant therapeutic challenge due to limited efficacy of current pharmacotherapies, while Rehmannioside A (ReA) has shown promising neuroprotective effects against neurodegenerative diseases. This research focuses on investigating the therapeutic effects of ReA on 5×FAD mice, emphasizing its potential application in AD treatment. The 5×FAD mice were divided into experimental groups and treated with ReA at varied dosages or donepezil for a twelve-week continuous treatment period. A series of evaluation methods, including behavioral tests, histopathological analysis, Western blotting, and measurement of oxidative and inflammatory markers, were implemented. The findings demonstrated that optimal ReA doses significantly improved learning, memory, and cognitive functions in 5×FAD mice, reduced Aβ plaque accumulation in the hippocampus, decreased microglial cell counts, increased PSD 95 and synapsin-1 protein expression, mitigated oxidative stress and inflammation, and showed no harmful effects on liver or kidney function. ReA's diverse biological activities suggest its potential in reducing neural damage. More extensive studies are needed to fully understand its molecular mechanisms in AD, which could lead to the development of innovative and effective treatments for this severe neurodegenerative condition.},
}

Animals
*Alzheimer Disease/drug therapy/pathology/metabolism
Mice
Oxidative Stress/drug effects
Disease Models, Animal
*Neuroprotective Agents/pharmacology/therapeutic use
Hippocampus/drug effects/metabolism/pathology
Male
*Saponins/pharmacology/therapeutic use
Amyloid beta-Peptides/metabolism
Memory/drug effects
Mice, Transgenic
Plaque, Amyloid/drug therapy/pathology
Drugs, Chinese Herbal

@article {pmid41233403,
year = {2025},
author = {Kovač, V and Huntosova, V and Fedorova, V and Georgiou, N and Lai, JZ and Chien, FC and Chen, SJ and Dolenec, F and Siposova, K},
title = {Unraveling the structure-activity relationships of organometallic ferrocene-pyrazole and ferrocene-pyrimidine curcumin analogues in amyloid-β aggregation and glioblastoma treatment.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {39867},
pmid = {41233403},
issn = {2045-2322},
support = {HRZZ-IP-2020-02-9162//Hrvatska Zaklada za Znanost/ ; No. 09-I02-03-V01-00021//NextGenerationEU/ ; SAS-NSTC-JRP-2024-03_SUPRA-SIGHT//Slovenská Akadémia Vied/ ; 2/0034/22//Vedecká Grantová Agentúra MŠVVaŠ SR a SAV/ ; No.101007642; PhytoApp//European Union's Horizon 2020 Research and Innovation programme/ ; },
mesh = {Humans ; *Ferrous Compounds/chemistry/pharmacology ; *Glioblastoma/drug therapy/metabolism/pathology ; *Metallocenes/chemistry/pharmacology ; *Curcumin/pharmacology/chemistry/analogs & derivatives ; *Amyloid beta-Peptides/metabolism/chemistry ; *Pyrazoles/chemistry/pharmacology ; *Pyrimidines/chemistry/pharmacology ; Structure-Activity Relationship ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Apoptosis/drug effects ; Protein Aggregates/drug effects ; Cell Survival/drug effects ; *Protein Aggregation, Pathological/drug therapy/metabolism ; },
abstract = {Neurodegenerative and oncological disorders, such as Alzheimer's disease (AD) and glioblastoma (GBM), are major global health challenges. Recent evidence indicates shared molecular mechanisms between these diseases, including dysregulated oxidative stress, mitochondrial dysfunction, and protein aggregation. We hypothesized that ferrocene-containing curcumin derivatives could exert dual-functional effects by simultaneously modulating amyloid-β (Aβ) aggregation and inhibiting glioblastoma cell proliferation. This study explores organometallic ferrocene compounds linked to four pyrazole and two pyrimidine analogues of curcumin with different substituents for their effects on amyloid-β-peptide (Aβ) aggregation and glioblastoma. To test this, pyrazole (FcPy-Cur-H, FcPy-Cur-COPh, FcPy-Cur-COFc, FcPy-Cur-Me) and pyrimidine (FcPyn-Cur-O, FcPyn-Cur-S) analogues were synthesized and evaluated. Thioflavin T fluorescence, atomic force microscopy, and single-molecule localization microscopy revealed structure-dependent inhibition of Aβ fibrillogenesis, with FcPyn-Cur-O, FcPyn-Cur-S, and FcPy-Cur-H showing the strongest anti-amyloidogenic activity. Concurrently, these derivatives reduced U87MG glioblastoma cell viability in a dose-dependent manner, inducing apoptotic features, mitochondrial disruption, and α-tubulin destabilization. Our results demonstrate that specific structural modifications of ferrocene-curcumin analogues enhance their dual anti-amyloidogenic and anticancer activities, highlighting the therapeutic potential of multifunctional compounds. This study provides a conceptual advance by combining neurodegenerative and oncological targets within a single chemical framework, offering a promising strategy for the development of multitargeted therapeutics for complex brain disorders.},
}

Humans
*Ferrous Compounds/chemistry/pharmacology
*Glioblastoma/drug therapy/metabolism/pathology
*Metallocenes/chemistry/pharmacology
*Curcumin/pharmacology/chemistry/analogs & derivatives
*Amyloid beta-Peptides/metabolism/chemistry
*Pyrazoles/chemistry/pharmacology
*Pyrimidines/chemistry/pharmacology
Structure-Activity Relationship
Cell Line, Tumor
Cell Proliferation/drug effects
Apoptosis/drug effects
Protein Aggregates/drug effects
Cell Survival/drug effects
*Protein Aggregation, Pathological/drug therapy/metabolism

@article {pmid41233387,
year = {2025},
author = {Park, JS and Kim, S and Jeong, D and Choi, JP and Jeong, H and Park, AJ and Kim, YS and Lee, J and Kim, SH},
title = {Dementia in older adults with schizophrenia: a 12-year analysis of prevalence, incidence, and treatment patterns in South Korea.},
journal = {Schizophrenia (Heidelberg, Germany)},
volume = {11},
number = {1},
pages = {134},
pmid = {41233387},
issn = {2754-6993},
abstract = {Older adults with schizophrenia face a significantly elevated risk of dementia. However, recent trends remain unclear within South Korea's rapidly aging schizophrenia population. This study aimed to quantify the burden of dementia in older schizophrenia patients by examining prevalence, incidence, dementia subtypes, pharmacologic treatment, and healthcare utilization. Using nationwide Health Insurance Review and Assessment (HIRA) data from 2010 to 2021, we identified 220,378 individuals aged ≥50 with schizophrenia. Dementia was diagnosed in 14.6% of patients, with 20.7% of cases occurring before age 60. Patients with dementia were more likely to be female and to have a higher comorbidity burden. Age-standardized all-cause dementia prevalence rose from 11.8% (2010) to 15.8% (2021) in those aged ≥50, and from 24.2% to 32.8% in those aged ≥65-exceeding estimates in the general population. In contrast, incidence declined from 3.4% to 1.7% over the same period. Alzheimer's disease (AD) was the most prevalent subtype (12.2%), followed by vascular dementia (VD, 2.4%), and frontotemporal dementia (0.5%). A lower AD/VD prevalence ratio in schizophrenia (5.3 vs. 8.6 in the general population) suggests a relatively higher burden of vascular pathology. Cognitive enhancer prescriptions increased from 62% to 77% in patients with dementia, compared to 4% to 10% in those without dementia. In 2021, those with dementia were more likely to live in nursing homes (68% vs. 56%) and had greater annual increases in psychiatric hospitalization duration (+2.30 vs. +1.11 days/year). These findings underscore growing care demands and need for integrated treatment strategies for aging schizophrenia patients with dementia.},
}

@article {pmid41233270,
year = {2025},
author = {Li, D and He, J and Liu, B and Zhu, L and Yang, Y and Peng, Y and Wang, R},
title = {Iron Dysregulation and Neuronal Volume Loss in Alzheimer's Disease: Insights from Hippocampal Subregional Analysis.},
journal = {Academic radiology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.acra.2025.10.038},
pmid = {41233270},
issn = {1878-4046},
abstract = {RATIONALE AND OBJECTIVES: Disruption of iron homeostasis and ferroptosis has been implicated in Alzheimer's disease (AD), yet their effects on brain volume across hippocampal subregions remain unclear. This study aimed to examine the relationship between iron deposition and brain atrophy across hippocampal subregions, and to identify potential imaging biomarkers for early diagnosis and disease monitoring.

MATERIALS AND METHODS: Fifty-four AD patients and 48 age- and gender-matched cognitively normal controls underwent quantitative susceptibility mapping (QSM) and 3D T1-weighted MRI to assess magnetic susceptibility and volume across 24 hippocampal subregions. Associations among imaging metrics, demographic data, and cognitive scores were analyzed. An AD prediction model was established through multivariate logistic regression of QSM indicators.

RESULTS: Several subregions exhibited significant alterations in both QSM and volume in AD (p < 0.05), with iron deposition and atrophy in specific regions correlating with cognitive impairment. Notably, five AD-specific subregions (left CA4, GC_ML_DG, Fimbria; right CA4, Fimbria) showed significant inverse correlations between susceptibility values and neuronal volume (p < 0.05). A multivariate diagnostic model incorporating QSM features demonstrated strong discriminatory power (AUC = 0.914, 95% CI: 0.861-0.967).

CONCLUSION: Alzheimer's disease exhibits spatially heterogeneous iron accumulation and atrophy, whose interconnections underscore the disease's complex pathology. Subregional QSM indicators exhibit early diagnostic potential, warranting further validation as a prospective biomarker.},
}

@article {pmid41233182,
year = {2025},
author = {Nakayama, H},
title = {[Brain Pathology of Cognitive Dysfunction in Aged Non-human Animals].},
journal = {Brain and nerve = Shinkei kenkyu no shinpo},
volume = {77},
number = {11},
pages = {1241-1247},
doi = {10.11477/mf.188160960770111241},
pmid = {41233182},
issn = {1881-6096},
mesh = {Animals ; *Cognitive Dysfunction/pathology ; *Brain/pathology/metabolism ; *Aging/pathology ; Humans ; Alzheimer Disease/pathology ; Cats ; Amyloid beta-Peptides/metabolism ; },
abstract = {Cognitive dysfunction, characterized by the deposition of amyloid β (Aβ), such as senile plaque (SP) and cerebral amyloid angiopathy (CAA), and phosphorylated tau are observed in several animal species, including primates, dogs, and cats, suggesting that these disorders are universal age-related phenomena in vertebrates. Additionally, argyrophilic neurofibrillary tangles positive for phosphorylated tau have been observed in primates, marine mammals, and felines. Recent findings regarding the pathology of cognitive dysfunction in aged non-human animals provide valuable information from a comparative perspective for advancing research on the pathogenesis, diagnosis, and treatment of Alzheimer's disease.},
}

Animals
*Cognitive Dysfunction/pathology
*Brain/pathology/metabolism
*Aging/pathology
Humans
Alzheimer Disease/pathology
Cats
Amyloid beta-Peptides/metabolism

@article {pmid41233181,
year = {2025},
author = {Yoshiyama, K},
title = {[Agitation].},
journal = {Brain and nerve = Shinkei kenkyu no shinpo},
volume = {77},
number = {11},
pages = {1231-1240},
doi = {10.11477/mf.188160960770111231},
pmid = {41233181},
issn = {1881-6096},
mesh = {Humans ; *Dementia/therapy/complications ; *Psychomotor Agitation/therapy/etiology ; },
abstract = {Agitation is a behavioral and psychological symptom of dementia (BPSD); however, until recently, there has been no consensus-based definition. When initiating therapeutic interventions, the type of dementia that is the cause of the BPSD must be considered and treatment must be tailored accordingly. As with other types of BPSD, non-pharmacological interventions are considered the first-line treatment for agitation, unless the symptoms present an exceptional level of urgency. Person-centered care is effective as a non-pharmacological intervention for agitation. Other examples include music therapy, animal-assisted therapy, and aromatherapy; however, these are not very effective for agitation. Useful information on non-pharmacological interventions for agitation can be obtained from the website "Ninchisho Chienowa-net," which is a web-based system that collects information on the coping strategies of caregivers for BPSD. If non-pharmacological interventions are ineffective or the symptoms are urgent, pharmacological treatment should be considered. Brexpiprazole has been approved as effective for agitation in Alzheimer's disease. For the treatment of agitation, medications other than brexpiprazole are frequently used in clinical settings and may offer some degree of efficacy.},
}

Humans
*Dementia/therapy/complications
*Psychomotor Agitation/therapy/etiology

@article {pmid41232837,
year = {2025},
author = {Čater, M and Šimon, M and Morton, NM and Kunej, T and Horvat, S},
title = {PLA2G4E in health and disease: Insights from omics and functional analyses.},
journal = {Progress in lipid research},
volume = {},
number = {},
pages = {101359},
doi = {10.1016/j.plipres.2025.101359},
pmid = {41232837},
issn = {1873-2194},
abstract = {The phospholipase A2 (PLA2) enzyme superfamily has been extensively studied, but comprehensive reviews on cytosolic phospholipase A2 group IVE (PLA2G4E) remain scarce, limiting our understanding of its role in lipid metabolism and disease. Our review synthesizes current findings on the human PLA2G4E gene and its murine ortholog Pla2g4e, drawing from multi-omics analyses and a range of functional studies. Pla2g4e exhibits distinct expression patterns across tissues, suggesting potential tissue-specific roles. In addition to its phospholipase activity, PLA2G4E exhibits N-acyltransferase activity and responds to calcium influx. Emerging evidence suggests possible involvement in metabolic disorders such as obesity and diabetes, particularly through effects on glucose uptake and insulin sensitivity. PLA2G4E has been implicated in the synthesis of N-acylethanolamines with potential effects on energy homeostasis, stress adaptation, neuronal signaling, pain perception, cognition, and motor coordination. Genomic and preliminary functional evidence further point to possible roles in immune regulation and neurobiology, with some associations reported in neurodegenerative diseases such as Alzheimer's disease. Comprehensive insights into the biological roles of PLA2G4E are essential for clarifying its enzymatic functions and potential involvement in disease mechanisms; however, further experimental and clinical studies are needed to substantiate these emerging associations and assess its therapeutic potential.},
}

@article {pmid41232786,
year = {2025},
author = {Shen, B and Zhang, Y and Travison, TG and Shardell, M and McCoy, RG and Saegusa, T and Falvey, J and Chen, C},
title = {A joint learning framework for analyzing data from national geriatric centralized networks: A new toolbox deciphering real-world complexity.},
journal = {Journal of biomedical informatics},
volume = {},
number = {},
pages = {104954},
doi = {10.1016/j.jbi.2025.104954},
pmid = {41232786},
issn = {1532-0480},
abstract = {OBJECTIVE: We propose JLNet, along with a companion R software package, as a systematic joint learning framework for analyzing data from national geriatric centralized networks, such as Medicare Claims. JLNet addresses key challenges in real-world, large-scale healthcare datasets, including hospital-level clustering and heterogeneity, patient-level variability from high-dimensional covariates, and losses to follow-up, while promoting easy implementation to ultimately support decision-making.

METHODS: JLNet proceeds in three steps: (1) fit a dynamic propensity score model to handle patient loss to follow-up; (2) fit a projection-based regularized regression to identify predictive patient-level features while adjusting for hospital-level confounding; and (3) perform hospital-level clustering using transformed residuals, enabling downstream analyses without sharing raw data. We applied JLNet to Medicare claims data to study post-fracture recovery among older adults with Alzheimer's disease and related dementias (ADRD) following a hip fracture (2010-2018), and evaluated its performance via numerical experiments.

RESULTS: JLNet identified clinically meaningful patient-level variables (e.g., age, weight loss, peripheral vascular disease, etc.) and distinct hospital clusters associated with variation in post-discharge recovery, measured by days at home, among patients with ADRD. Numerical experiments showed that JLNet outperformed existing approaches in variable selection and hospital clustering in the setting involving high-dimensional covariates and unmeasured hospital-level confounding.

DISCUSSION AND CONCLUSION: JLNet is a scalable, interpretable framework for analyzing centralized health data. It enhances identification of high-risk subcohorts and hospital clusters, supporting more precise resource allocation and personalized care strategies for high-risk older adults. Findings also inform the design of tailored interventions in real-world settings.},
}

@article {pmid41232727,
year = {2025},
author = {Zhang, Q and Long, S and Zhang, N and Sun, G and Zhao, L and Zhong, R},
title = {Shared and divergent neurotoxic mechanisms of Bisphenol A and Di(2-ethylhexyl) phthalate with implication for Alzheimer's disease: Insights from network toxicology and in vitro validation.},
journal = {Toxicology and applied pharmacology},
volume = {506},
number = {},
pages = {117637},
doi = {10.1016/j.taap.2025.117637},
pmid = {41232727},
issn = {1096-0333},
abstract = {Bisphenol A (BPA) and di(2-ethylhexyl) phthalate (DEHP) are widely recognized environmental neurotoxicants implicated in Alzheimer's disease (AD). However, the shared and divergent mechanisms by which BPA and DEHP induce neurotoxicity in AD remain largely unexplored. In this study, we conducted the first systematic comparative analysis of overlapping and distinct neurotoxic pathways of BPA and DEHP by integrating network toxicology and in vitro experimental validation. Five shared core targets (MMP9, PPARG, MAPK14, BCL2, and BCL2L1) were identified from multiple databases. Experimental validation confirmed that BPA and DEHP significantly upregulated MMP9, PPARG, and phosphorylated MAPK14, while downregulating BCL2 and BCL2L1 at both transcriptional and protein levels. KEGG pathway enrichment revealed both shared and divergent pathways, with the lipid and atherosclerosis pathway emerging as a common AD-relevant pathway, whereas BPA and DEHP showed compound-specific involvement in PI3K-Akt, MAPK, and other signaling cascades. Molecular docking analysis further demonstrated favorable binding of both BPA and DEHP to the shared core targets. Collectively, this study provides novel mechanistic insights into both overlapping and distinct neurotoxic effects of BPA and DEHP in AD, offering a theoretical basis for future mechanistic research and environmental risk assessment.},
}

@article {pmid41232717,
year = {2025},
author = {Castellano Candalija, A and Díez Porres, L and Notario Leo, H and Roca Martiartu, A and Mayoral Canalejas, N and Alonso Babarro, A},
title = {Prevalence and decision-making in advanced dementia.},
journal = {Revista clinica espanola},
volume = {},
number = {},
pages = {502388},
doi = {10.1016/j.rceng.2025.502388},
pmid = {41232717},
issn = {2254-8874},
abstract = {INTRODUCTION: Dementia is a chronic neurodegenerative disease with a high prevalence and economic cost. Our objective was to evaluate the prevalence of advanced dementia (AD) in patients hospitalized in the Internal Medicine service; to analyze the therapeutic and diagnostic measures implemented, the degree of adequacy of the therapeutic effort and the information of the family.

METHODOLOGY: Descriptive study that included a retrospective analysis of medical records and a telephone interview with family. Patients with GDS 6-7 dementia admitted to Internal Medicine were included, for 3 weeks in 3 different months.

RESULTS: 194 (22%) patients with dementia were included. The prevalence of admissions with AD was 11%. The median age was 87.5 years (QR 81.75-93), 65% women. 45% came from residence for the elderly. The most frequent etiology was Alzheimer's (48%). The most frequent cause of admission was infection (72%). 37% died. Regarding the measures implemented: 100% were treatment intravenous; 89% received anticoagulation; 26% received artificial nutrition; 81% received pharmacological restraint and 63% physical restraint; and 48% underwent invasive diagnostic tests. Regarding adequacy: lipid-lowering treatment was withdrawn in 19%, antidementia drugs in 23%, anticoagulation in 21%; cardiopulmonary resuscitation was not performed in 30%, adequacy of care in 34%, and 13% were assessed by Palliative Care. A telephone interview was conducted with 55 patients. 42% were not aware of any complications. Care planning was carried out in 2 patients.

CONCLUSIONS: The prevalence of admission to AD is high, and almost half of the patients come from residence for the elderly. Associated mortality is high and therapeutic adequacy and planning are very scarce.},
}

@article {pmid41232709,
year = {2025},
author = {Zhou, W and Qu, R and Luo, W and Zhang, H and Gong, L and , },
title = {Identification of cognitive brain diseases using a dual-branch siamese network on structural magnetic resonance imaging data.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2025.11.011},
pmid = {41232709},
issn = {1873-7544},
abstract = {Early diagnosis of Alzheimer's Disease is crucial for optimizing treatment efficacy, as delayed detection often limits therapeutic outcomes. Traditional diagnostic approaches, such as cognitive assessments, PET scans, and lumbar punctures, are often invasive, costly, and less accessible. To address these limitations, we propose a Dual-Branch Siamese Network aimed at enhancing the classification accuracy of Alzheimer's Disease, Mild Cognitive Impairment, and Cognitively Normal individuals using structural MRI data. Our model integrates neuroimaging features from both Subcortical Segmentation and Cortical Parcellation, leveraging their complementary strengths to improve diagnostic precision. Experimental evaluations demonstrate that our model achieves a classification accuracy of 93% on the original dataset. To further validate the model's generalizability, we tested the trained model on a separate independent test set from the new ADNI4 database (N=191). On this independent cohort, the model achieved a robust classification accuracy of 88.48%, demonstrating its potential for real-world application. Additionally, by implementing network pruning, we reduced the model's complexity by 60% without sacrificing accuracy, thereby enhancing its feasibility for clinical use. Compared to other methods, such as convolutional neural networks and ensemble learning systems, our model demonstrates superior accuracy in multi-class classification and remains competitive in binary classification tasks. Notably, our pruned model balances accuracy with efficiency, outperforming other models in terms of computational feasibility without compromising diagnostic precision. These findings highlight the potential of our approach to facilitate early diagnosis and intervention for neurodegenerative diseases like Alzheimer's Disease.},
}

@article {pmid41232530,
year = {2025},
author = {Wang, D and Gazzara, MR and Jewell, S and Wales-McGrath, BD and Yang, K and Brown, CD and Choi, PS and Barash, Y},
title = {A deep dive into statistical modeling of RNA splicing QTLs reveals variants that explain neurodegenerative disease.},
journal = {American journal of human genetics},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.ajhg.2025.10.012},
pmid = {41232530},
issn = {1537-6605},
abstract = {Genome-wide association studies (GWASs) have identified thousands of putative disease-causing variants with unknown regulatory effects. Efforts to connect these variants with splicing quantitative trait loci (sQTLs) have provided functional insights, yet sQTLs reported by existing methods cannot explain many GWAS signals. We show that current sQTL modeling approaches can be improved by considering alternative splicing representation, model calibration, and covariate integration. We then introduce MAJIQTL, a pipeline for sQTL discovery. MAJIQTL includes two statistical methods: a weighted multiple-testing approach for sGene discovery and a model for sQTL effect-size inference to improve variant prioritization. By applying MAJIQTL to GTEx, we find significantly more sGenes harboring sQTLs with functional significance. Notably, our analysis implicates the variant rs528823 in Alzheimer disease. Using antisense oligonucleotides, we test this variant's effect by blocking the implicated YBX3 binding site, leading to exon skipping in MS4A3.},
}

@article {pmid41232397,
year = {2025},
author = {Zuo, Y and Ding, X and Sun, Y and Wang, L and Song, Y and Zhao, Z and Liu, C},
title = {Critical nodes in precision diagnosis and treatment of Alzheimer's disease: exploration of multidimensional biomarkers and prospects for targeted intervention.},
journal = {Journal of the neurological sciences},
volume = {479},
number = {},
pages = {123734},
doi = {10.1016/j.jns.2025.123734},
pmid = {41232397},
issn = {1878-5883},
abstract = {Alzheimer' s disease (AD), characterized by cognitive decline and progressive neurodegeneration, remains a major clinical and scientific challenge due to its complex pathophysiology and marked heterogeneity. Important signs of the disease, like the buildup of β-amyloid, changes in Tau proteins, inflammation in the brain, and problems with mitochondria, form the basis for developing targeted treatments. This review summarizes recent advances in the identification of therapeutic targets and multi-dimensional biomarkers, such as liquid, imaging, and multi-omics-based markers. These biomarkers hold potential for early diagnosis, disease subtyping, and therapeutic response monitoring. We suggest that combining biomarkers and treatment targets could be a key approach to improving personalized care for AD.},
}

@article {pmid41232357,
year = {2025},
author = {Castillo-Moral, Á and Tchoumtchoua, J and Leonard, K and Del Bas, JM and Ortega, N and Escoté, X and Teichenné, J},
title = {Neuroprotective effects of polyphenol-rich extracts obtained from agricultural by-products in an induced cognitive decline model of zebrafish larvae and in human neurons.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {193},
number = {},
pages = {118776},
doi = {10.1016/j.biopha.2025.118776},
pmid = {41232357},
issn = {1950-6007},
abstract = {Neurodegenerative diseases are closely associated with chronic neuroinflammation and oxidative stress, which contribute to progressive neuronal dysfunction and cell death. Due to their antioxidant and anti-inflammatory properties, polyphenols have gained attention as potential neuroprotective agents. Agricultural by-products represent a promising and sustainable source of polyphenols, yet their neuroprotective value remains underexplored. In this study, we evaluated four polyphenol-rich extracts derived from red onion peels (ROPE), olive pruning (OPE), vineyard pruning (VPE) and chicory leaves (CLE), obtained by subcritical water extraction. Their effects were tested in two complementary models of neurodegeneration: in vitro human neurons (SH-SY5Y cells) exposed to D-galactose and a basic cognitive decline model of zebrafish larvae exposed to aluminium chloride (AlCl3). All extracts exhibited anti-inflammatory effects in vitro, significantly reducing IL-1β and IL-8 mRNA expression, at doses ranging 12.5-50 μg/mL in cell medium. In the zebrafish model, treatment with 100 μg/mL ROPE or VPE in medium restored the normal sensorimotor pattern in the Dark-Light-Dark test, while ROPE treatment additionally rescued basal startle responses and enhanced habituation indexes, even surpassing healthy control larvae. Overall, these results highlight the potential of polyphenol-rich agri-food extracts, particularly ROPE, as neuroprotective and cognitive-enhancing compounds and support their further investigation as natural and sustainable interventions to slow or prevent neurodegenerative processes.},
}

@article {pmid41232325,
year = {2025},
author = {Guo, X and Tang, P and He, J and Li, R},
title = {Dissecting the effect of blood colony-stimulating factors and receptors on Alzheimer's disease: the role of myeloid traits and inflammation.},
journal = {Cytokine},
volume = {197},
number = {},
pages = {157072},
doi = {10.1016/j.cyto.2025.157072},
pmid = {41232325},
issn = {1096-0023},
abstract = {BACKGROUND: Research has suggested a potential link between colony-stimulating factors (CSFs) and Alzheimer's disease (AD), but the findings have been inconsistent, and the causal relationship remains uncertain.

METHODS: We performed a Mendelian Randomization (MR) analysis to explore the association between blood levels of CSFs and their receptors with AD and its biomarkers. The study utilized summary-level data on blood levels of granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor, macrophage colony-stimulating factor, and their receptors from deCODE. Data on AD were sourced from the International Genomics of Alzheimer's Project (IGAP), UK Biobank (UKB), and FinnGen, while cerebrospinal fluid p-Tau and β-amyloid levels were from the largest GWAS currently available. Additional summary-level data on amyloid PET imaging and AD progression from ADNI and the Knight-ADRC were also included.

RESULTS: Genetically predicted one standard deviation increase in blood G-CSF was associated with a higher risk of AD across three datasets (IGAP: OR = 1.35, 95 %CI = 1.15-1.57, P < 0.001; IGAP+UKB: OR = 1.27, 95 %CI = 1.12-1.43, P < 0.001; FinnGen: OR = 1.43, 95 %CI = 1.26-1.61, P < 0.001), but not AD progression. Elevated blood G-CSF levels were inversely related to β-amyloid levels (β = -0.14, 95 %CI = -0.19 to -0.09, P < 0.001) and positively associated with p-Tau levels (β = 0.08, 95 %CI = 0.03 to 0.14, P = 0.001) in cerebrospinal fluid. Furthermore, genetically predicted blood G-CSF levels were positively associated with amyloid PET imaging in the brain (β = 0.10, 95 % CI: 0.06 to 0.14, P < 0.001). However, no significant associations were found between blood levels of other CSFs, and their receptors and AD risk. In contrast, there was little evidence supporting the impact of AD on CSFs levels. The multivariable MR analysis showed that the association between G-CSF and AD, along with its biomarkers, disappeared after adjusting for C-reactive protein levels, but not for neutrophil count.

CONCLUSION: These findings indicate a harmful role of G-CSF in the development of AD, primarily driven by inflammatory responses rather than neutrophil counts. Therefore, interventions targeting AD through CSFs, especially G-CSF, should be cautiously approached.},
}

@article {pmid41231963,
year = {2025},
author = {Zhang, T and Zhu, H},
title = {Library size-stabilized metacells construction enhances co-expression network analysis in single-cell data.},
journal = {PLoS computational biology},
volume = {21},
number = {11},
pages = {e1013697},
doi = {10.1371/journal.pcbi.1013697},
pmid = {41231963},
issn = {1553-7358},
abstract = {Single-cell RNA sequencing (scRNA-seq) deciphers cell type-specific co-expression networks to resolve biological functions but remains constrained by data sparsity and compositional biases. Conventional metacells construction strategies mitigate sparsity by aggregating transcriptionally similar cells but often neglect systematic biases introduced by compositional data. This problem leads to spurious co-expression correlations and obscuring biologically meaningful interactions. Through mathematical modeling and simulations, we demonstrate that uncontrolled library size variance in traditional metacells inflates false-positive correlations and distorts co-expression networks. Here, we present LSMetacell (Library Size-stabilized Metacells), a computational framework that explicitly stabilizes library sizes across metacells to reduce compositional noise while preserving cellular heterogeneity. LSMetacell addresses this by stabilizing library sizes during metacells aggregation, thereby enhancing the accuracy of downstream analyses such as Weighted Gene Co-expression Network Analysis (WGCNA). Applied to a postmortem Alzheimer's disease brain scRNA-seq dataset, LSMetacell revealed robust, cell type-specific co-expression modules enriched for disease-relevant pathways, outperforming the conventional metacells approach. Our work establishes a principled strategy for resolving compositional biases in scRNA-seq data, advancing the reliability of co-expression network inference in studying complex biological systems. This framework provides a generalizable solution for improving transcriptional analyses in single-cell studies.},
}

@article {pmid41231728,
year = {2025},
author = {Luan, Y and Huang, Q and Wang, J and Guan, Y and Li, B and Franzmeier, N and Xie, F and Ewers, M},
title = {Synaptic density and tau pathology in Alzheimer's disease: a dual role in susceptibility and degeneration.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awaf425},
pmid = {41231728},
issn = {1460-2156},
abstract = {Fibrillar tau is a defining hallmark of Alzheimer's disease, gradually accumulating and spreading throughout the brain. The synapse plays a key role in this process-both by facilitating the spread of tau between neurons and by serving as a direct target of tau-induced neurotoxicity. However, few studies in humans have explored synaptic density both as a facilitating factor and as a target of tau pathology. In this dual PET tracer study, we used 18F-SynVesT-1 synaptic vesicle glycoprotein 2A (SV2A) PET to assess synaptic density and 18F-MK6240 tau-PET to assess fibrillar tau in 59 amyloid-PET-positive patients and 25 amyloid-PET-negative cognitively normal individuals from the Chinese Preclinical Alzheimer's Disease Study (CPAS). Spatial correlation analyses revealed that brain regions with higher SV2A tracer uptake in cognitively normal individuals exhibited higher 18F-MK6240 uptake in Alzheimer's disease. These findings were independently replicated in the Alzheimer's Disease Neuroimaging Initiative (ADNI), where normal SV2A-PET maps from CPAS were correlated with tau-PET data from 372 Aβ+ participants, including longitudinal follow-up in 204 cases. In both cohorts, regions with higher normal synaptic density showed greater tau burden, and in ADNI, higher synaptic density in normal brain also predicted faster tau accumulation over time. Gene-set enrichment analyses of transcriptomic data mapped onto regional tau-PET uptake further showed that areas of high 18F-MK6240 uptake were enriched in genes encoding synapse-related proteins. Together, these findings suggest that synapse-rich regions are especially prone to tau accumulation. We also investigated the downstream impact of tau on synaptic integrity. Notably, regions with higher 18F-MK6240 uptake showed reduced SV2A tracer uptake, indicating synaptic loss, not only in the same regions but also in areas connected to those with high tau. Stronger loss of SV2A tracer uptake was observed in the regions with stronger resting-state functional connectivity to epicenters of high 18F-MK6240 uptake in the Alzheimer's disease group. The connectivity-dependent synaptic loss could not be fully explained by tau levels in the connected target regions but was found to be partially mediated by them. These findings suggest that tau pathology contributes to synaptic loss both locally and in distant, connected brain regions. Overall, our results highlight the central importance of the synapse in Alzheimer's disease: synapses appear to both facilitate fibrillar tau accumulation and become impaired through its toxic effects. Understanding the synapse's role in tau pathology may open new avenues for therapeutic interventions aimed at slowing down tau progression and neurodegeneration.},
}

@article {pmid41231717,
year = {2025},
author = {Al-Nasser, M and Al-Nasser, A},
title = {The second victim's satisfaction index model.},
journal = {International journal of health care quality assurance},
volume = {},
number = {},
pages = {1-17},
doi = {10.1108/IJHCQA-05-2025-0071},
pmid = {41231717},
issn = {1758-6542},
abstract = {PURPOSE: This article proposes a new customer satisfaction model. The purpose of the proposed model is to identify the key factors that influence the second victim's (SV's) satisfaction level. In a medical context, the SV refers to caregivers who provide all kinds of daily support to a close relative who is living with chronic and irreversible conditions, such as Alzheimer's patients.

DESIGN/METHODOLOGY/APPROACH: The model is simulated from the American customer satisfaction model, but with different latent variables. Based on literature and theoretical considerations, four predictors of caregiver satisfaction were identified: knowledge, empathy, memory and lifestyle. To evaluate the research model, this study employed the partial least squares structural equation modeling technique.

FINDINGS: Data were collected from a sample of 154 Alzheimer's caregivers over a period of three months using convenience and network sampling techniques. The analysis revealed several key findings. Both knowledge and memory had a significant and positive influence on caregivers' satisfaction, indicating the importance of cognitive resources and caregiving competence. In addition, memory and lifestyle influence empathy, suggesting that both personal reflection and healthy routines may enhance emotional attunement toward care recipients.

The main limitation we faced in this study is the difficulty in collecting a large sample size; the study relies on a sample of 154 caregivers.

PRACTICAL IMPLICATIONS: This study offers valuable models that shape SV's satisfaction. By identifying and validating the roles of knowledge, memory, empathy and lifestyle, the model offers a robust framework for developing targeted interventions to support and empower caregivers.

SOCIAL IMPLICATIONS: The insights gained from this research can contribute to greater family caregivers' awareness, especially on caregiver knowledge and memory to improve the lifestyle and increase their satisfaction level when they are dealing with Alzheimer's patients.

ORIGINALITY/VALUE: The originality of this study lies in its optimal model results, which show the main significant factors of the SVs, which advances understanding and opens new avenues for future research.},
}

@article {pmid41231696,
year = {2025},
author = {Zheng, C and El-Sappagh, S and Abuhmed, T},
title = {4DfCF: 4D fMRI CrossFormer Vision Transformer.},
journal = {IEEE journal of biomedical and health informatics},
volume = {PP},
number = {},
pages = {},
doi = {10.1109/JBHI.2025.3631655},
pmid = {41231696},
issn = {2168-2208},
abstract = {Investigating the spatiotemporal dynamics of the human brain is a complex challenge due to the intricate nature of brain networks, and the limitations of current analytical methods. Herein, we introduce the 4D functional Magnetic Resonance Imaging (fMRI) CrossFormer (4DfCF), a novel vision transformer architecture designed to process high-dimensional 4D fMRI data. This model integrates temporal and spatial dimensions to effectively learn and predict cognitive and clinical outcomes. We further evaluated the 4DfCF on three benchmark datasets: Attention Deficit Hyperactivity Disorder-200 (ADHD-200), Alzheimer's Disease Neuroimaging Initiative (ADNI), and Autism Brain Imaging Data Exchange (ABIDE). The results showed that our model consistently outperforms state-of-the-art baseline models, achieving an accuracy improvement of 5-10%, a precision increase of 4-8%, a recall enhancement of 6-9%, and an F1-score boost of 7-11%. Additionally, the 4D fMRI CrossFormer-Tiny variant demonstrated greater efficiency than existing methods, using 20% fewer computational resources and achieving 30% faster training times. Pre-training experiments further reveal that models pre-trained on one dataset and fine-tuned on another achieved faster convergence and higher accuracy, with the Autism Brain Imaging Data Exchange (ABIDE) pre-trained models showing the best performance. Additionally, we employed an explainable AI method to identify the brain regions associated with disease diagnosis. Overall, our findings highlight the potential of the 4DfCF to advance precision neuroscience through efficient and scalable analysis of complex fMRI data.},
}

@article {pmid41225397,
year = {2025},
author = {Melendo-Azuela, EM and Lladó, A and Vela, E and Mariscal, S and Cleries, M and Piñol-Ripoll, G and Santaeugènia, SJ},
title = {Epidemiological evolution and healthcare services utilization in elderly dementia patients of Catalonia.},
journal = {BMC public health},
volume = {25},
number = {1},
pages = {3919},
pmid = {41225397},
issn = {1471-2458},
support = {SLT008/18/00061//PERIS 2019/ ; SLT008/18/00050//PERIS 2019/ ; },
abstract = {BACKGROUND: Assessing the dynamics and burden of dementia is necessary to improve healthcare plans. This study aimed to describe the epidemiology and characteristics of dementia diagnoses in Catalonia (North-East of Spain) and evaluate healthcare services utilization and associated expenditures in people with dementia compared with people without.

METHODS: Retrospective study including all the dementia population (2013–2020) using data from an administrative database, the Catalan Health Surveillance System, covering a 7.5–7.7-million population. Data included demographic, clinical, healthcare services utilization, and morbidity-associated risk variables, and was analyzed according to dementia type, including Alzheimer’s disease (AD), vascular dementia (VD), frontotemporal dementia (FTD), dementia with Lewy bodies (LBD), and unspecified dementia (UD). We compared comorbidities and morbidity-associated risk, healthcare services utilization and associated expenditures, and mortality rates between people with dementia and the population without dementia adjusted for age, sex, and income level.

RESULTS: During the study period, dementia prevalence remained stable, and incidence modestly decreased. AD and VD incidence rates decreased, whereas UD modestly increased, being the highest in 2019. Patients with dementia had a higher prevalence of comorbidities, morbidity-associated risk, healthcare services utilization, specially admissions in nursing homes and intermediate care, healthcare-associated expenditures, and mortality than people without dementia adjusted by age, sex, and income level in 2019. An expenditure €1311.7 per person per year was attributable to dementia, representing an increase of 44.1% of total healthcare costs. Compared to other dementia types, AD and VD had increased admissions, and VD had the highest expenditures. The use of antidepressants and benzodiazepines progressively decreased.

CONCLUSIONS: Using a population dataset, this study showed that dementia is associated with a high burden and healthcare needs, providing useful information to design improved healthcare plans.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12889-025-24341-4.},
}

@article {pmid41231544,
year = {2025},
author = {Benedet, AL and Arslan, B and Tan, K and Huber, H and Pola, I and Di Molfetta, G and Kvartsberg, H and Dolado, AO and Janelidze, S and Blennow, K and Zetterberg, H and Hansson, O and Rosa-Neto, P and Ashton, NJ},
title = {Diagnostic Value of Serum p-tau217 in Alzheimer Disease: Equal to Plasma in Levels and Clinical Utility?.},
journal = {Clinical chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1093/clinchem/hvaf162},
pmid = {41231544},
issn = {1530-8561},
support = {//University of Gothenburg/ ; //Weston Brain Institute/ ; MOP-11-51-31/CAPMC/CIHR/Canada ; RFN 152985/CAPMC/CIHR/Canada ; 159815/CAPMC/CIHR/Canada ; 162303/CAPMC/CIHR/Canada ; MOP-11-51-31//Canadian Consortium of Neurodegeneration and Aging/ ; NIRG-12-92090/ALZ/Alzheimer's Association/United States ; NIRP-12-259245/ALZ/Alzheimer's Association/United States ; //Brain Canada Foundation/ ; 2020-VICO-279314//Fonds de Recherche du Québec-Santé/ ; 2024-VICO-356138//Fonds de Recherche du Québec-Santé/ ; AF-940262//Swedish Alzheimer Foundation/ ; //Stiftelsen för Gamla Tjänarinnor/ ; AARFD-22-974564//Alzheimer's Association Research Fellowship/ ; 2023-00356//Swedish Research Council/ ; 2022-01018//Swedish Research Council/ ; 2019-02397//Swedish Research Council/ ; 101053962//European Union's Horizon Europe/ ; ALFGBG-71320//Swedish State Support for Clinical Research/ ; 201809-2016862//Alzheimer Drug Discovery Foundation/ ; ADSF-21-831376-C//AD Strategic Fund/ ; ADSF-21-831381-C//AD Strategic Fund/ ; ADSF-21-831377-C//AD Strategic Fund/ ; ADSF-24-1284328-C//AD Strategic Fund/ ; 22HLT07//AD Strategic Fund/ ; //Bluefield Project/ ; //Cure Alzheimer's Fund/ ; //Olav Thon Foundation/ ; //Erling-Persson Family Foundation/ ; //Familjen Rönströms Stiftelse/ ; FO2022-0270//Hjärnfonden, Sweden/ ; //Marie Skłodowska-Curie grant/ ; JPND2021-00694//European Union Joint Programme-Neurodegenerative Disease Research/ ; //National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre/ ; UKDRI-1003//UK Dementia Research Institute/ ; 2017-00915//UK Dementia Research Institute/ ; 2022-00732//UK Dementia Research Institute/ ; AF-930351//UK Dementia Research Institute/ ; AF-939721//UK Dementia Research Institute/ ; AF-968270//UK Dementia Research Institute/ ; FO2017-0243//UK Dementia Research Institute/ ; ALZ2022-0006//UK Dementia Research Institute/ ; ALFGBG-715986//UK Dementia Research Institute/ ; ALFGBG-965240//UK Dementia Research Institute/ ; JPND2019-466-236//UK Dementia Research Institute/ ; SG-23-1038904//UK Dementia Research Institute/ ; ZEN24-1069572//UK Dementia Research Institute/ ; SG-23-1061717//UK Dementia Research Institute/ ; 2022-00775//GHR Foundation/ ; 2022-0231//Knut and Alice Wallenberg Foundation/ ; AF-980907//Lund University/ ; FO2021-0293//Swedish Brain Foundation/ ; 1412/22//Parkinson Foundation of Sweden/ ; //Rönström Family Foundation/ ; //Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse/ ; 2020-O000028//Skåne University Hospital Foundation/ ; 2022-1259//Regionalt Forskningsstöd/ ; 2022-Projekt0080//Swedish Federal Government/ ; },
abstract = {BACKGROUND: Phosphorylated tau 217 (p-tau217) has emerged as a leading blood-based biomarker for Alzheimer disease (AD). While typically measured in plasma, serum is a widely used matrix in clinical laboratories, yet few p-tau217 assays have been validated for serum. Evaluating serum p-tau217 performance is essential for expanding its use in clinical and research settings, particularly for cohorts with only serum samples available.

METHODS: We quantified p-tau217 in plasma and serum from individuals within the AD continuum (n = 100; mean age 72.5 ± 5.0 years; 54% female) using 6 assays across 4 platforms. Spearman correlation, Passing-Bablok regression, and receiver operating characteristics analysis were used to assess intermatrix agreement and diagnostic performance. Specific validation parameters (e.g., precision, parallelism, dilution linearity, stability) were evaluated in both matrices.

RESULTS: High correlations between plasma and serum were observed for most assays (ρ > 0.8), though plasma often yielded higher concentrations. Notably, the Lumipulse assay showed near-perfect correlation (ρ = 0.98) and minimal bias. Fold changes in p-tau217 levels across the AD continuum were comparable between matrices, though cutoffs for detecting AD pathology differed. Applying plasma-derived cutoffs to serum resulted in misclassification rates ranging from 16% to 47%, except for Lumipulse (10% in serum vs 5% in plasma). Not all assays performed equally in serum, as reflected in validation metrics.

CONCLUSIONS: Serum p-tau217, across multiple platforms, shows strong correlations with plasma p-tau217 and reflected comparable patterns across the AD continuum. However, absolute concentrations differed for most assays, thus requiring differing disease specific cutoffs. Most of the evaluated platforms demonstrated reliable quantification of p-tau217 in serum, yielding satisfactory validation performance. These findings support serum as a viable alternative to plasma for p-tau217 quantification in both research and clinical settings, provided matrix-specific validation is ensured.},
}

@article {pmid41231438,
year = {2025},
author = {Constantino, NJ and Ashley, CC and Macauley, SL},
title = {The Energetic Collapse of the Alzheimer's Brain: Metabolic Inflexibility Across Cells and Networks.},
journal = {Journal of neurochemistry},
volume = {169},
number = {11},
pages = {e70294},
doi = {10.1111/jnc.70294},
pmid = {41231438},
issn = {1471-4159},
support = {//Coins for Alzheimer's Research Trust/ ; A20201775S//BrightFocus Foundation/ ; P20GM148326/GM/NIGMS NIH HHS/United States ; P30AG072946/AG/NIA NIH HHS/United States ; R01AG068330/AG/NIA NIH HHS/United States ; R01AG093847/AG/NIA NIH HHS/United States ; T32NS115704/NS/NINDS NIH HHS/United States ; },
mesh = {*Alzheimer Disease/metabolism/pathology ; Humans ; *Energy Metabolism/physiology ; *Brain/metabolism/pathology ; Animals ; *Neurons/metabolism/pathology ; *Nerve Net/metabolism ; },
abstract = {Alzheimer's disease (AD) is more than just amyloid and tau. While often described as a disease of metabolic dysfunction, AD can more accurately be described as a disorder of metabolic inflexibility that leads to bioenergetic failure. In the healthy brain, neurons, glia, and vascular cells dynamically share and switch between different fuel sources (e.g., glucose, lactate, ketones, and fatty acids) to match functional demand. In AD, this adaptability is progressively lost because cellular metabolism is actively reprogrammed to support neuroinflammatory and disease-associated processes at the cost of neuronal function. Microglia, in particular, upregulate glycolytic metabolism, alter lipid handling, and prioritize immune functions, which actively depletes the brain's energy supply. These adaptations are initially compensatory but ultimately trap the brain in a rigid metabolic program that deprioritizes neuronal support. This metabolic shift unfolds along a biphasic trajectory: early, glia-driven hypermetabolism aligned with inflammation, followed by late-stage brain hypometabolism and energy collapse that leads to neuronal dysfunction. System-level consequences include altered excitability, decreased network connectivity, sleep disruption, and cognitive decline. Critically, these changes feed forward to accelerate AD pathogenesis: glycolytically biased microglia and stressed neurons promote amyloid-β production, tau release, and protein aggregation, adding to metabolic rigidity. Evidence from human neuroimaging studies, brain/cerebral spinal fluid (CSF) multi-omic studies, and preclinical studies demonstrate that shifts in glycolytic flux, tricarboxylic acid cycle (TCA) intermediates, and lipid metabolism parallel amyloid and tau pathology and cognition decline. We hypothesize that these metabolic programs, while initially protective, are chronically maladaptive yet reversible. We propose that restoring metabolic flexibility can mitigate amyloid and tau pathology, neuronal loss, and functional decline. Ongoing preclinical studies and clinical trials are actively exploring metabolism as a therapeutic target in AD. Collectively, these findings define AD as a disorder of metabolic inflexibility, where adaptive shifts in cellular metabolism become pathologically rigid and drive disease progression, while offering a promising target for therapeutic intervention in AD.},
}

*Alzheimer Disease/metabolism/pathology
Humans
*Energy Metabolism/physiology
*Brain/metabolism/pathology
Animals
*Neurons/metabolism/pathology
*Nerve Net/metabolism

@article {pmid41231363,
year = {2025},
author = {Prufer Q C Araujo, I and Ellingson, T and Schwartz, NU and Dietz, CD and Tammewar, G and Deniz, K and Eslami-Amirabadi, M and Breithaupt, AG and Rosenberg, M and Bui, NM and Gonzalez, Y and La Joie, R and Ljubenkov, PA and Possin, KL and Rojas, JC and Soleimani-Meigooni, DN and Wang, Y and Staffaroni, AM and Stephens, ML and Tsoy, E and Windon, CC and Boxer, AL and Rabinovici, GD and Miller, BL and VandeVrede, L},
title = {Blood-based Alzheimer's disease biomarkers in a behavioral neurology clinic: Real-world implementation, clinical utility, and diagnostic performance.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70891},
doi = {10.1002/alz.70891},
pmid = {41231363},
issn = {1552-5279},
support = {K23AG073514/NH/NIH HHS/United States ; P30AG062422/NH/NIH HHS/United States ; P01AG038791/NH/NIH HHS/United States ; R01AG019724/NH/NIH HHS/United States ; /ALZ/Alzheimer's Association/United States ; //Shenandoah Foundation/ ; },
mesh = {Humans ; *Alzheimer Disease/diagnosis/blood ; *Biomarkers/blood ; *tau Proteins/blood ; Retrospective Studies ; Female ; Male ; Aged ; Aged, 80 and over ; Middle Aged ; },
abstract = {INTRODUCTION: Blood-based biomarkers (BBMs) for Alzheimer's disease (AD), including plasma phosphorylated tau (p-tau), are increasingly used in clinical practice, but "real-world" implementation patterns, context-of-use (COU), clinical utility, and diagnostic performance are incompletely understood.

METHODS: A retrospective analysis of the first year of BBM use in a tertiary level cognitive neurology subspecialty clinic was conducted, including review of COU, impact on diagnostic certainty, prescription of AD-related medications, and additional AD-biomarker testing.

RESULTS: P-tau181 was ordered frequently to detect AD in a diverse cohort, across a wide spectrum of COU, including typical, early-onset, and atypical AD presentations; mixed etiology; AD co-pathology; and borderline symptoms. P-tau181 impacted diagnostic confidence, AD-related medication prescription, and follow-on testing. Renal impairment was a common confounder.

CONCLUSIONS: Implementation of BBMs was feasible and impactful in a memory clinic, especially in a diagnostically complex and diverse patient population, underscoring the need for additional data from real-world settings.

HIGHLIGHTS: Blood-based biomarkers (BBMs) were quickly adopted and accelerated precision diagnosis in a large memory clinic. BBM use cases were diverse and included all stages/types of AD and non-AD syndromes. Plasma p-tau has the potential to impact diagnostic certainty and clinical decision making. Diagnostic performance of p-tau is reasonable, though renal function impacts overall accuracy.},
}

Humans
*Alzheimer Disease/diagnosis/blood
*Biomarkers/blood
*tau Proteins/blood
Retrospective Studies
Female
Male
Aged
Aged, 80 and over
Middle Aged

@article {pmid41231278,
year = {2025},
author = {Kechko, OI and Mukhina, KA and Yanvarev, DV and Eremina, SY and Katkova-Zhukotskaya, OA and Chaprov, KD and Drutskaya, MS and Kozin, SA and Makarov, AA and Mitkevich, VA},
title = {Therapeutic Potential of HAEEPGP Peptide Against β-Amyloid Induced Neuropathology.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {36},
pmid = {41231278},
issn = {1559-1182},
support = {19-74-30007//Russian Science Foundation/ ; },
mesh = {Animals ; *Amyloid beta-Peptides/toxicity/metabolism ; Mice, Transgenic ; Humans ; Caenorhabditis elegans/metabolism ; *Alzheimer Disease/drug therapy/pathology/metabolism ; Mice ; *Oligopeptides/pharmacology/pharmacokinetics/therapeutic use ; Brain/pathology/metabolism/drug effects ; Microglia/drug effects/metabolism/pathology ; Mice, Inbred C57BL ; Astrocytes/drug effects/metabolism/pathology ; },
abstract = {The development of effective therapies for Alzheimer's disease remains a critical challenge in modern medicine. While monoclonal antibodies targeting beta-amyloid (Aβ) have shown the most significant clinical efficacy, their use is limited by poor blood-brain barrier permeability and side effects, which are occasionally severe. We previously devised ion-complementary to Aβ tetrapeptide HAEE, that was able to suppress amyloidogenesis in vivo. In this study, we modified HAEE by adding PGP amino acid residues to its C-terminus to improve its pharmacological properties. Pharmacokinetic analysis revealed that the [125]I-HAEEPGP half-life in mouse plasma was twice that of [125]I-HAEE and C-terminus modification of HAEE significantly increased its brain tissue penetration. Isothermal titration calorimetry experiments revealed that HAEEPGP formed a stable complex with Aβ and, besides, exhibited higher affinity for pathogenic isomerized Aβ than for the native peptide. [125]I-HAEEPGP showed enhanced accumulation in the brain of 5xFAD transgenic mice compared to wild-type controls. Furthermore, using western blotting, ELISA, and flow cytometry, we demonstrated that HAEEPGP considerably reduced Aβ-induced astrocyte and microglia activation, prevented synaptic degeneration in 5xFAD mice, and restored lifespan of Caenorhabditis elegans overexpressing human Aβ. These features of HAEEPGP have positioned it as a promising therapeutic candidate for Aβ-related neuropathology.},
}

Animals
*Amyloid beta-Peptides/toxicity/metabolism
Mice, Transgenic
Humans
Caenorhabditis elegans/metabolism
*Alzheimer Disease/drug therapy/pathology/metabolism
Mice
*Oligopeptides/pharmacology/pharmacokinetics/therapeutic use
Brain/pathology/metabolism/drug effects
Microglia/drug effects/metabolism/pathology
Mice, Inbred C57BL
Astrocytes/drug effects/metabolism/pathology

@article {pmid41231253,
year = {2025},
author = {Yu, Y and Sun, Y and Zhao, T},
title = {The roles of glycerophospholipids in the aging retina and age-related macular degeneration.},
journal = {Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie},
volume = {},
number = {},
pages = {},
pmid = {41231253},
issn = {1435-702X},
support = {No. 2023SK2032//Key Research and Development Program of Hunan Province of China/ ; No. kq2502054//the Changsha Municipal Natural Science Foundation/ ; No. 2025JGB161//Project Program of central south university graduate education teaching reform/ ; },
abstract = {Glycerophospholipids (GPs) are integral constituents of cellular membranes, and play a crucial role in the regulation of lipid metabolism homeostasis and physiological conditions. However, pathological alterations associated with aging, such as variations in plasma GP concentrations, disruptions in intercellular GP transport, and local accumulation of excessive GPs, have been observed. These changes induce irreversible cellular degeneration, ultimately leading to tissue damage in organs such as the brain and retina. A growing body of evidences has demonstrated that GPs play significant roles in neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD). Similarly, GPs have been implicated in the pathogenesis and progression of age-related macular degeneration (AMD), a degenerative condition affecting the choroid and retinal layers of the eye. Understanding the homeostasis of GP metabolism in the aging retina and in AMD is essential for elucidating the pathogenic processes involved in AMD. In this review, we present a comprehensive overview of the mechanisms of GPs in the aging retina and their correlation with degenerative processes associated with AMD. KEY MESSAGES: What is known Metabolic dysregulation of glycerophospholipids (GPs) plays vital roles in age-related macular degeneration (AMD) and neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD). Patients with age-related neurological disorders exhibit a significantly higher risk of developing AMD compared to healthy individuals, potentially due to shared pathological mechanisms, including mitochondrial metabolic disturbance, chronic inflammation and autophagy dysfunction. What is new The interconnection between multiple GP species and their metabolites has been established to delineate complex pathogenic mechanisms underlying the aging retina and AMD, including cell senescence, autophagy and apoptosis, oxidative stress, inflammation, vascular abnormalities. GPs may serve as potential therapeutic targets to prevent or delay the progression of AMD.},
}

@article {pmid41231230,
year = {2025},
author = {Venkatesh, R and Cardone, KM and Bradford, Y and Moore, AK and Kumar, R and Moore, JH and Shen, L and Kim, D and Ritchie, MD},
title = {Integrative multi-omics approaches identify molecular pathways and improve Alzheimer's disease risk prediction.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70886},
doi = {10.1002/alz.70886},
pmid = {41231230},
issn = {1552-5279},
support = {R01HL169458,U01AG066833,P30AG073105//the National Institutes of Health/ ; T32HG000046/HG/NHGRI NIH HHS/United States ; U19 AG074879/AG/NIA NIH HHS/United States ; P30AG073105/AG/NIA NIH HHS/United States ; HL-169458//NHLBI Division of extramural Research/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics ; Genome-Wide Association Study ; Male ; Female ; Multifactorial Inheritance/genetics ; Transcriptome/genetics ; Aged ; Genetic Predisposition to Disease ; Risk Assessment ; Risk Factors ; Multiomics ; },
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a complex neurodegenerative disorder with heterogeneous genetic and molecular underpinnings. Polygenic scores (PGS) capture little of this complexity.

METHODS: We conducted genome-, transcriptome-, and proteome-wide association studies (G/T/PWAS) on 15,480 individuals from the Alzheimer's Disease Sequencing Project R4 (ADSP) to identify AD-associated signals, followed by pathway enrichment analysis. Integrative risk models (IRMs) were developed using genetically regulated components of gene and protein expression and clinical covariates. Elastic-net logistic regression and random forest classifiers were evaluated using standard metrics and compared against baseline PGS.

RESULTS: Known and novel signals were identified via G/T/PWAS. Enrichment analyses highlighted cholesterol and immune signaling pathways. The best-performing IRM, random forest with transcriptomic and covariate features, achieved area under the receiver operating characteristic (AUROC) of 0.703 and area under the precision-recall curve (AUPRC) of 0.622, significantly outperforming PGS and baseline models.

DISCUSSION: Integrating univariate discovery approaches with multivariate modeling enhances AD risk prediction and offers novel insights into underlying biological processes.

HIGHLIGHTS: Identified novel contributions to Alzheimer's disease (AD) from a multi-omics perspective. Integrated genome-wide association studies (GWAS), transcriptome-wide association studies (TWAS), and proteome-wide association studies (PWAS) in a unified association study framework. Developed a method for predicting heritable risk of late-onset AD. Demonstrated that ancestry-aware modeling improves AD risk prediction accuracy.},
}

Humans
*Alzheimer Disease/genetics
Genome-Wide Association Study
Male
Female
Multifactorial Inheritance/genetics
Transcriptome/genetics
Aged
Genetic Predisposition to Disease
Risk Assessment
Risk Factors
Multiomics

@article {pmid41231229,
year = {2025},
author = {Rousset, RZ and Dolan, CV and Wilson, DH and In 't Veld, L and Ligthart, L and Teunissen, CE and de Geus, EJC and den Braber, A},
title = {Genetic and environmental contributions to variation in plasma phosphorylated tau 217.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70906},
doi = {10.1002/alz.70906},
pmid = {41231229},
issn = {1552-5279},
support = {904-61-090//Netherlands Organization for Scientific Research (NWO)/ ; 985-10-002//Netherlands Organization for Scientific Research (NWO)/ ; 904-61-193//Netherlands Organization for Scientific Research (NWO)/ ; 480-04-004//Netherlands Organization for Scientific Research (NWO)/ ; 400-05-717//Netherlands Organization for Scientific Research (NWO)/ ; Addiction-31160008//Netherlands Organization for Scientific Research (NWO)/ ; 016-115-035//Netherlands Organization for Scientific Research (NWO)/ ; 400-07-080//Netherlands Organization for Scientific Research (NWO)/ ; NWO-Groot 480-15-001/674//Netherlands Organization for Scientific Research (NWO)/ ; Middelgroot-911-09-032//Netherlands Organisation for Health Research and Development (ZonMW)/ ; 73305095007//Netherlands Organisation for Health Research and Development (ZonMW)/ ; 10510032120003//Netherlands Organisation for Health Research and Development (ZonMW)/ ; 01254 (GenomEUtwin)//European Commission/ ; 01413 (ENGAGE)//European Commission/ ; 860197 (MIRIADE)//European Commission/ ; 381434 (Horizon 2020)//European Commission/ ; 101034344 (EPND)//European Commission/ ; //Alzheimer Drug Discovery Foundation/ ; //National Multiple Sclerosis Society/ ; /ALZ/Alzheimer's Association/United States ; LSHM20106//Health Holland, Topsector Life Sciences & Health/ ; //The Selfridges Group Foundation/ ; //Alzheimer Netherlands/ ; },
mesh = {Humans ; *tau Proteins/blood/genetics ; Male ; Female ; Phosphorylation ; Amyloid beta-Peptides/blood ; Aged ; Biomarkers/blood ; Neurofilament Proteins/blood ; Middle Aged ; Alzheimer Disease/genetics/blood ; Glial Fibrillary Acidic Protein/blood ; Peptide Fragments/blood ; Aged, 80 and over ; *Gene-Environment Interaction ; },
abstract = {INTRODUCTION: Plasma phosphorylated tau 217 (p-au217) is a promising Alzheimer's disease (AD) biomarker. Little is known about the causes of variance in p-tau217 concentrations in cognitively unimpaired populations.

METHODS: The present sample included cognitively healthy twins and their family members (n = 6495). Biometric twin models were used to determine relative genetic and environmental contributions to variance in p-tau217, and genetic and environmental correlations between p-tau217 and neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), and amyloid beta 42/40 (Aβ42/40).

RESULTS: Genetic contributions accounted for 42% (males) and 41% (females) of variance in p-tau217. Half of the genetic effects were sex specific. Genetic and environmental contributions to p-tau217 were partially shared with NfL, GFAP, and Aβ42/40, but different patterns were found in males and females.

DISCUSSION: P-tau217 concentrations are moderately heritable. Sex-specific genetic influences are found to act on p-tau217. In cognitively unimpaired participants, p-tau217 and Aβ42/40 reflect different biological processes.

HIGHLIGHTS: Phosphorylated tau (p-tau)217 concentrations are substantially heritable (> 41%). Genetic contributions to variation in plasma p-tau217 were found to be sex specific. Genetic and environmental correlations were found between p-tau217 and Alzheimer's disease biomarkers. P-tau217 reflects different processes in cognitively unimpaired males and females.},
}

Humans
*tau Proteins/blood/genetics
Male
Female
Phosphorylation
Amyloid beta-Peptides/blood
Aged
Biomarkers/blood
Neurofilament Proteins/blood
Middle Aged
Alzheimer Disease/genetics/blood
Glial Fibrillary Acidic Protein/blood
Peptide Fragments/blood
Aged, 80 and over
*Gene-Environment Interaction

@article {pmid41230990,
year = {2025},
author = {Chakraborty, N and Long, Q and Kundu, S},
title = {Bayesian scalar-on-image regression with spatial interactions for modeling Alzheimer's disease.},
journal = {Biometrics},
volume = {81},
number = {4},
pages = {},
doi = {10.1093/biomtc/ujaf144},
pmid = {41230990},
issn = {1541-0420},
support = {RF1 AG063481/NH/NIH HHS/United States ; R01 AG071174/NH/NIH HHS/United States ; R01 MH120299/NH/NIH HHS/United States ; },
mesh = {*Alzheimer Disease/diagnostic imaging/pathology ; Humans ; Bayes Theorem ; Neuroimaging/methods/statistics & numerical data ; Computer Simulation ; Monte Carlo Method ; Algorithms ; Markov Chains ; Magnetic Resonance Imaging ; Risk Factors ; Models, Statistical ; Brain/pathology ; Regression Analysis ; },
abstract = {There has been substantial progress in predictive modeling for cognitive impairment in neurodegenerative disorders such as Alzheimer's disease (AD), based on neuroimaging biomarkers. However, existing approaches typically do not incorporate heterogeneity that may potentially arise due to interactions between the spatially varying imaging features and supplementary demographic, clinical and genetic risk factors in AD. Unfortunately, ignoring such heterogeneity may potentially result in poor prediction and biased estimation. Building on existing scalar-on-image regression framework, we address this issue by incorporating spatially varying interactions between brain image and supplementary risk factors to model cognitive impairment in AD. The proposed Bayesian method tackles spatial interactions via hierarchical representation for the functional regression coefficients depending on supplementary risk factors, which is embedded in a scalar-on-function framework involving a multi-resolution wavelet decomposition. To address the curse of dimensionality, we induce simultaneous sparsity and clustering via a spike and slab mixture prior, where the slab component is characterized by a latent class distribution. We develop an efficient Markov chain Monte Carlo algorithm for posterior computation. Extensive simulations and application to the longitudinal Alzheimer's Disease Neuroimaging Initiative study illustrate significantly improved prediction of cognitive impairment in AD across multiple visits by our model in comparison with alternate approaches. The proposed approach also identifies key brain regions in AD that exhibit significant association with cognitive abilities, either directly or through interactions with risk factors.},
}

*Alzheimer Disease/diagnostic imaging/pathology
Humans
Bayes Theorem
Neuroimaging/methods/statistics & numerical data
Computer Simulation
Monte Carlo Method
Algorithms
Markov Chains
Magnetic Resonance Imaging
Risk Factors
Models, Statistical
Brain/pathology
Regression Analysis

@article {pmid41230868,
year = {2025},
author = {Cavagnero, PS and Sánchez, Y and Fell, B and Ramírez Molina, O and Gavilán, J and Polo, EA and Fuentealba, J and Gutierrez, M and Jiménez, CA and López, JJ},
title = {Neuroprotective Activity of 3-((6-(Phenylethynyl)pyridin-3-yl)oxy)quinuclidine: A Potential Ligand for the Treatment of Alzheimer's Disease.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00527},
pmid = {41230868},
issn = {1948-7193},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder marked by the accumulation of β-amyloid (Aβ) peptides, which disrupt neuronal homeostasis through their neurotoxic effects. Aβ aggregates interfere with synaptic function by interacting with nicotinic acetylcholine receptors (nAChRs), particularly the α7 subtype, thereby impairing cholinergic signaling, which is crucial for cognition and memory. Pharmacological advancements have identified Positive Allosteric Modulators (PAMs) as promising therapeutic agents to counteract Aβ neurotoxicity. PAMs enhance nAChR activity by binding to allosteric sites, thereby reducing Aβ-induced neurotoxicity without competing with acetylcholine. This study evaluates 3-((6-(phenylethynyl)pyridine-3-yl)oxy)quinuclidine (EQ-04), a novel PAM with high selectivity for the α7 nAChR subtype, demonstrating neuroprotective potential. In vitro analyses using PC-12 cells evaluated the cytotoxic and neuroprotective properties of EQ-04. Cytotoxicity assays confirmed EQ-04's safety, showing no adverse effects on cell viability across concentrations. EQ-04 significantly enhanced cell viability by 37% at 1 nM against Aβ toxicity and inhibited Aβ aggregation. These findings highlight the potential of EQ-04 as a neuroprotective agent for Alzheimer's disease (AD) therapy, warranting further investigation into its pharmacokinetics and in vivo efficacy.},
}

@article {pmid41230793,
year = {2025},
author = {George, GC and Keller, SA and Abner, E and Adar, S and Alosco, ML and Apostolova, LG and Bakulski, K and Barnes, LL and Bateman, JR and Batterman, S and Beach, TG and Bendlin, BB and Bennett, DA and Betthauser, TJ and Brewer, J and Buckingham, W and Carrión, CI and Chodosh, J and Craft, S and Croff, R and Fabio, A and Farias, ST and Feldman, EL and Goldstein, F and Goutman, SA and Green-Harris, G and Henderson, V and Karikari, TK and Kofler, J and Kucharska-Newton, A and Lamar, M and Lanata, S and Lepping, RJ and Lingler, J and Lockhart, S and Mahnken, J and Marsh, K and Mathew, J and Mecca, AP and Meyer, O and Miller, B and Morris, J and Neugroschl, J and O'Connor, MK and Paulson, H and Perrin, RJ and Pettigrew, C and Pierce, A and Powell, WR and Pyarajan, S and Raji, CA and Reiman, E and Risacher, S and Rissman, R and Espivnosa, PR and Sano, M and Saykin, AJ and Serrano, GE and Singh, V and Soldan, A and Sultzer, D and van Dyck, CH and Whitmer, R and Wisniewski, T and Woltjer, R and Yu, M and Zhu, CW and Kind, AJH},
title = {The Neighborhoods Study: Examining the social exposome in Alzheimer's disease and related dementias.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70810},
doi = {10.1002/alz.70810},
pmid = {41230793},
issn = {1552-5279},
support = {U24 AG072122/AG/NIA NIH HHS/United States ; P30 AG062429/AG/NIA NIH HHS/United States ; P30 AG066468/AG/NIA NIH HHS/United States ; P30 AG062421/AG/NIA NIH HHS/United States ; P30 AG066509/AG/NIA NIH HHS/United States ; P30 AG066514/AG/NIA NIH HHS/United States ; P30 AG066530/AG/NIA NIH HHS/United States ; P30 AG066507/AG/NIA NIH HHS/United States ; P30 AG066444/AG/NIA NIH HHS/United States ; P30 AG066518/AG/NIA NIH HHS/United States ; P30 AG066512/AG/NIA NIH HHS/United States ; P30 AG066462/AG/NIA NIH HHS/United States ; P30 AG072979/AG/NIA NIH HHS/United States ; P30 AG072972/AG/NIA NIH HHS/United States ; P30 AG072976/AG/NIA NIH HHS/United States ; P30 AG072975/AG/NIA NIH HHS/United States ; P30 AG072978/AG/NIA NIH HHS/United States ; P30 AG072977/AG/NIA NIH HHS/United States ; P30 AG066519/AG/NIA NIH HHS/United States ; P30 AG062677/AG/NIA NIH HHS/United States ; P30 AG079280//NIA/NIH/ ; P30 AG062422/AG/NIA NIH HHS/United States ; P30 AG066511/AG/NIA NIH HHS/United States ; P30 AG072946/AG/NIA NIH HHS/United States ; P30 AG062715/AG/NIA NIH HHS/United States ; P30 AG072973/AG/NIA NIH HHS/United States ; P30 AG066506/AG/NIA NIH HHS/United States ; P30 AG066508/AG/NIA NIH HHS/United States ; P30 AG066515/AG/NIA NIH HHS/United States ; P30 AG072947/AG/NIA NIH HHS/United States ; P30 AG072931/AG/NIA NIH HHS/United States ; P30 AG066546/AG/NIA NIH HHS/United States ; P30 AG086401/AG/NIA NIH HHS/United States ; P30 AG086404/AG/NIA NIH HHS/United States ; P20 AG068082/AG/NIA NIH HHS/United States ; P30 AG072958/AG/NIA NIH HHS/United States ; P30 AG072959/AG/NIA NIH HHS/United States ; R01 AG070883/AG/NIA NIH HHS/United States ; P30 AG072959/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/epidemiology ; Male ; Female ; Aged ; *Dementia/epidemiology ; *Exposome ; *Neighborhood Characteristics ; *Residence Characteristics ; Biomarkers ; Brain/pathology ; Risk Factors ; Aged, 80 and over ; },
abstract = {INTRODUCTION: The Neighborhoods Study (TNS) is a novel investigation of adverse social exposome and brain health leveraging 22 Alzheimer's Disease Research Centers (ADRCs). TNS aims to understand if the adverse social exposures increase Alzheimer's disease and related dementias (ADRD) risk.

METHODS: TNS uses innovative methods to determine lifetime addresses of living (n = ≈ 3116) and brain bank cohorts (n = ≈ 8637). Addresses are linked to time-concordant adverse social exposome using the Area Deprivation Index (ADI) and summarized over time. Brain health measures are provided by the National Alzheimer's Coordinating Center.

RESULTS: We highlight a general overview and methodology of TNS. Data collection is ongoing; however, preliminary findings indicate that the adverse social exposome is related to ADRD biomarkers, neuropathology, and cognitive function.

DISCUSSION: TNS is the largest study of adverse social exposome and ADRD, using the ADRC network to build robust scientific consortia. Its findings will inform ADRD interventions, precision medicine, and policy.

HIGHLIGHTS: The Neighborhoods Study (TNS) investigates adverse social exposome and brain health. TNS is a collaboration among 22 Alzheimer's Disease Research Centers. TNS will give insight on environmental and exposomal factors which may be modifiable. Participant lifetime addresses are linked to temporal adverse social exposome metrics. This study's findings will inform precision approaches to mitigate dementia risk.},
}

Humans
*Alzheimer Disease/epidemiology
Male
Female
Aged
*Dementia/epidemiology
*Exposome
*Neighborhood Characteristics
*Residence Characteristics
Biomarkers
Brain/pathology
Risk Factors
Aged, 80 and over

@article {pmid41230551,
year = {2025},
author = {Wendt, S and Lee, C and Cai, W and Lin, AJ and Huang, J and Poon, V and Xiang, X and Hong, W and MacVicar, BA and Nygaard, HB},
title = {Generation of 3D Human iPSC-Derived Multi-Cell Type Neurospheres for Studying Neuron, Astrocyte, and Microglia Crosstalk.},
journal = {Bio-protocol},
volume = {15},
number = {21},
pages = {e5493},
pmid = {41230551},
issn = {2331-8325},
abstract = {Three-dimensional (3D) human brain tissue models derived from induced pluripotent stem cells (iPSCs) have transformed the study of neural development and disease in vitro. While cerebral organoids offer high structural complexity, their large size often leads to necrotic core formation, limiting reproducibility and challenging the integration of microglia. Here, we present a detailed, reproducible protocol for generating multi-cell type 3D neurospheres that incorporate neurons, astrocytes, and optionally microglia, all derived from the same iPSCs. While neurons and astrocytes differentiate spontaneously from neural precursor cells, generated by dual SMAD-inhibition (blocking BMP and TGF-b signaling), microglia are generated in parallel and can infiltrate the mature neurosphere tissue after plating neurospheres into 48-well plates. The system supports a range of downstream applications, including functional confocal live imaging of GCaMP6f after adeno-associated virus (AAV) transduction of neurospheres or immunofluorescence staining after fixation. Our approach has been successfully implemented across multiple laboratories, demonstrating its robustness and translational potential for studying neuron-glia interactions and modeling neurodegenerative processes. Key features • Reproducible human iPSC-derived 3D neurosphere multi-cell type tissue culture system. • Optional addition of microglia allows for studying neuron-microglia interaction in vitro in 3D. • Reliable spontaneous activity offers functional tissue culture readouts of neural firing. • System allows modeling of human brain diseases, such as Alzheimer's disease.},
}

@article {pmid41230516,
year = {2025},
author = {Chan, JC},
title = {Alzheimer's disease model explains Alzheimer's disease incidences.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251395616},
pmid = {41230516},
issn = {2542-4823},
abstract = {AD-MODEL RATIONALE: The contributing factors of Alzheimer's disease are cerebral vessel disease, insulin resistance, hypometabolism, oxidative stress, abnormal-protein aggregation, and inflammation. Brain insulin resistance is influenced by inflammation, glycemia, and stress, and glucose uptake into the central nervous system is mediated by brain glucose transporter. Glucose hypometabolism leads to oxidative stress. During protein synthesis, DNA is vulnerable to being insulted by reactive oxygen species. If repair fails, the neuron undergoes apoptosis. If the repair is imperfect, it may synthesize an abnormal protein, which could induce an immune response. The resulting inflammation may initiate brain insulin resistance, leading to glucose hypometabolism. Integrating all these major factors forms an AD model. One factor impacts more other factors. This process becomes a vicious cycle, creating a positive feedback loop.

AD-MODEL APPLICATION: The AD model should be able to explain the observable AD incidents. The amyloid-β (Aβ) is extracellular, which would induce an immune response. On the contrary, tau and α-synuclein are intracellular proteins, which only cause an immune response if they leak out of the neuron. This is the reason why 2/3 of dementia cases are AD. Besides living longer, women have more immune sensitivity compared to men, and postmenopausal women have higher insulin resistance and endothelial dysfunction due to a decline in estrogen production. This is the reason why women have twice the AD in comparison to men. Removing abnormal proteins or applying an anti-inflammatory agent could reduce inflammation; therefore, one-third of people remain cognitively normal despite the presence of Aβ buildup in the brain.},
}

@article {pmid41230515,
year = {2025},
author = {Mekulu, K and Aqlan, F and Yang, H},
title = {Reimagining dementia screening: A stakeholder-informed perspective on artificial intelligence, digital biomarkers, and real-world implementation.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251395310},
pmid = {41230515},
issn = {2542-4823},
abstract = {The approval of disease-modifying treatments for Alzheimer's disease demands a rethinking of cognitive screening. Drawing on over 180 stakeholder interviews from the NSF National I-Corps program, this perspective highlights barriers in current workflows, from time constraints in primary care to learning effects in long-term care, and presents innovation pathways centered on AI and digital biomarkers. Speech analysis, in particular, offers a scalable and cost-effective screening tool aligned with existing CPT codes. We outline implementation strategies and emphasize the urgent opportunity to align technological innovation with frontline clinical needs to ensure advances translate into meaningful patient and provider benefit.},
}

@article {pmid41230514,
year = {2025},
author = {Wang, X and Liu, Y and Fan, S and Zhao, H and Sun, C and Liu, L and Wang, X and Zou, L},
title = {Combined 64-channel EEG and PET evaluation of lecanemab efficacy: Two case reports.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251395615},
pmid = {41230514},
issn = {2542-4823},
abstract = {Lecanemab, an anti-amyloid-β (Aβ) monoclonal antibody, has shown potential in slowing Alzheimer's disease (AD) progression. We report divergent responses in two AD patients with similar backgrounds following lecanemab treatment. Subject 1 showed worsened daily functioning, increased Aβ/tau deposition, and elevated electroencephalogram (EEG) slow/fast wave ratios (>30%) in right fronto-occipital regions (Fp2/F8/O1). Subject 2 improved cognitively, with modest Aβ reduction, marked tau suppression, and mixed EEG frontal declines (F3/F7/O1/Pz) and parietal/occipital gains (P3/P4/T3/T6). EEG alterations corresponded with positron emission tomography findings, suggesting its potential for therapeutic monitoring. Multimodal analysis revealed region-specific lecanemab effects, supporting EEG's role in evaluating treatment efficacy.},
}

@article {pmid41230509,
year = {2025},
author = {Harrison, JR and Foley, SF and Simmonds, E and Bracher-Smith, M and Holmans, P and Stergiakouli, E and Caseras, X and Escott-Price, V and Jones, DK},
title = {White matter microstructure in mid- to late adulthood is influenced by pathway-stratified polygenic risk for Alzheimer's disease.},
journal = {Frontiers in neuroscience},
volume = {19},
number = {},
pages = {1638503},
pmid = {41230509},
issn = {1662-4548},
abstract = {INTRODUCTION: Alzheimer's disease involves progressive white matter microstructural degeneration that may precede clinical symptoms by decades. While polygenic risk scores (PRS) quantify cumulative genetic liability for AD, genome-wide PRS lack mechanistic specificity. We tested whether pathway-specific PRS, targeting areas of biology including tau binding, lipid metabolism, and immune response, are differentially associated with diffusion MRI measures across the lifespan.

METHODS: We analyzed two population-based cohorts: the Avon Longitudinal Study of Parents and Children (ALSPAC; mean age = 19.8 years, n = 517) and UK Biobank (mean age = 64.2 years, n = 18,172). Genome-wide and nine pathway-specific PRS for Alzheimer's disease were constructed using GWAS summary statistics and a clumping threshold of r[2] < 0.2 at p < 0.001. Diffusion MRI data were processed separately within each cohort: in ALSPAC, tract-based fractional anisotropy (FA) and mean diffusivity (MD) were extracted using probabilistic tractography from native-space regions of interest; in UK Biobank, diffusion metrics were derived from TBSS-aligned skeletons and standard atlas-based ROIs. Analyses focused on three tracts vulnerable to early AD pathology: the dorsal cingulum, parahippocampal cingulum, and fornix. Multiple linear regression models were used to assess PRS associations with FA and MD, adjusting for demographic, scanner, and genetic ancestry covariates. False discovery rate correction addressed multiple comparisons, and sensitivity analyses were performed excluding the APOE region.

RESULTS: In UK Biobank, higher PRS for protein-lipid complex assembly and tau protein binding were robustly associated with lower fractional anisotropy and higher mean diffusivity in both dorsal and parahippocampal cingulum segments (False discovery rate-corrected p < 0.05), explaining more variance than APOE alone; no significant effects emerged in the fornix. Genome-wide PRS showed weaker, non-significant associations. In ALSPAC, no PRS metric survived FDR correction, though nominal trends appeared in the dorsal cingulum. Sensitivity analyses confirmed that key cingulum associations in older adults persisted after omitting APOE.

CONCLUSION: Pathway-specific polygenic risk for Alzheimer's disease manifests in white matter microstructure by mid- to late adulthood but not in early adulthood, suggesting an age-dependent emergence of genetic effects. dMRI phenotypes may thus serve as intermediate biomarkers for dissecting mechanistic pathways of preclinical Alzheimer's disease vulnerability.},
}

@article {pmid41230384,
year = {2025},
author = {Chen, Y and Wang, Z and Wang, J and Yang, J and Ma, R and Men, K},
title = {L-Theanine Mitigates Aβ1-42-Induced Apoptosis in SH-SY5Y Cells.},
journal = {Food science & nutrition},
volume = {13},
number = {11},
pages = {e71180},
pmid = {41230384},
issn = {2048-7177},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder that significantly impacts the physical and mental health of elderly individuals. Previous research has demonstrated a close association between neurodegenerative diseases and neuronal apoptosis, with cognitive disorders such as AD often exhibiting pathological features, including neuronal apoptosis. In recent years, the application of natural plant molecules for the prevention of AD has emerged as a focal point in food nutrition research. L-theanine, a unique active compound found in tea, has been shown to possess neuroprotective properties, although its underlying mechanisms remain to be fully elucidated. This study established an in vitro model of AD using SH-SY5Y cells induced by Amyloid-beta (1-42) (Aβ1-42) to investigate whether L-theanine can interfere with Aβ1-42-induced apoptosis in these cells and to explore its potential mechanisms of action, thereby providing a theoretical foundation for the intervention and prevention of AD. L-theanine effectively inhibits Aβ1-42-induced apoptosis in SH-SY5Y cells, potentially through the suppression of oxidative stress and preservation of mitochondrial function.},
}

@article {pmid41230097,
year = {2025},
author = {Porcher, C and Rivera, C and Medina, I and Koric, L},
title = {Altered GABAergic signaling and chloride homeostasis in eye movement circuits during late neurodevelopment: implications for Alzheimer's disease therapy.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1675799},
pmid = {41230097},
issn = {1663-9812},
abstract = {Eye movement deficits, including abnormal saccades and impaired smooth pursuits, are among the earliest observable indicators of neurodegenerative diseases, particularly Alzheimer's disease (AD). These deficits arise from dysfunctions in neural circuits controlling oculomotor function, including the superior colliculus, parietal and frontal eye fields, cerebellum, and locus coeruleus (LC). Since these circuits rely on a delicate balance of excitation and inhibition (E/I), their impairment reflects broader neural dysregulation seen in neurodegenerative diseases. Notably, oculomotor abnormalities strongly correlate with cognitive decline and the progression of neuropathological hallmarks, highlighting their potential as sensitive, non-invasive clinical markers for early detection. GABAergic signaling, the principal mechanism of inhibitory neurotransmission, plays a central role in maintaining E/I balance and regulating neural network activity. In neurodegenerative diseases, GABAergic dysfunction is characterized by reduced GABA levels, altered GABAA receptor function, and compromised inhibitory control. These changes drive network hyperexcitability, synaptic instability, and cognitive impairments. Such disruptions are particularly impactful in oculomotor circuits, contributing directly to eye movement deficits. The potassium-chloride co-transporter 2 (KCC2), a key regulator of intracellular chloride homeostasis, is essential for maintaining GABAergic inhibition. In AD, KCC2 dysfunction exacerbates GABAergic dysregulation, amplifying E/I imbalance and impairing neural circuits. This review integrates current findings on GABAergic signaling, KCC2 dysfunction, and oculomotor deficits in AD, offering novel insights into the mechanisms linking KCC2 dysfunction and oculomotor impairments within the context of AD.},
}

@article {pmid41230033,
year = {2025},
author = {Oviedo, DC and Haughbrook, R and Culjat, C and Ramirez Surmeier, L and Tratner, AE and Carreira, MB and Villarreal, AE and Harmon, SL and Batista, OI and Meng, Z and Millender, E and Xavier Hall, CD and Britton, GB},
title = {Ethical disclosure of biomarkers for Alzheimer risk in Latin American participants.},
journal = {Frontiers in dementia},
volume = {4},
number = {},
pages = {1672075},
pmid = {41230033},
issn = {2813-3919},
abstract = {INTRODUCTION: In recent years, the disclosure of Alzheimer's disease (AD) biomarkers has become increasingly common, offering critical insights into disease risk and progression. However, in low-resource settings, where healthcare access, provider training, and patient support are often limited, disclosing AD biomarkers presents unique ethical, logistical, and psychological challenges.

OBJECTIVE: This perspective explores the implications of AD biomarker disclosure in these settings, highlighting the potential risks of patient distress, misinformation, and inadequate follow-up care. For this purpose, we conducted a review of available literature, peer-reviewed studies, regional reports, and policy documents addressing AD in Latin America. Our literature search prioritized diagnostic advances, biomarker disclosure, treatment access, and health system challenges, providing a focused evidence base to frame the discussion of regional gaps and opportunities.

DISCUSSION: We discuss strategies to support responsible disclosure practices, including culturally sensitive participant education, enhanced provider training, and policy adaptations to improve accessibility and support systems. Ultimately, we advocate for a careful, context-specific approach to AD biomarker disclosure that prioritizes patient well-being and equity in low-resource environments.},
}

@article {pmid41229731,
year = {2025},
author = {Nasir, AR and Delpirou Nouh, C},
title = {TDP-43-proteinopathy at the crossroads of tauopathy: on copathology and current and prospective biomarkers.},
journal = {Frontiers in cellular neuroscience},
volume = {19},
number = {},
pages = {1671419},
pmid = {41229731},
issn = {1662-5102},
abstract = {Though usually described as isolated models, neurodegenerative diseases exist in a significant proportion of cases as mixed pathologies, particularly in older adults. The presence of co-pathologies may influence phenotypes and progression, and the correct classification in vivo has proven to be challenging, particularly without proper biomarker panels. Recent breakthroughs in biomarkers, enabling earlier detection in Alzheimer's disease and, more recently, in synuclein-related diseases, are promising as a first step toward the wider detection of all other abnormal proteins involved in neurodegenerative diseases. Over the past decade, the growing body of research on TDP-43 pathology has led to considering TDP-43 as a potential major contributor to the neurodegenerative process. TDP-43's normal function is essential for neuronal survival and the regulation of RNA processing and cellular stress response; abnormal TDP-43 protein leads to altered cell function and survival. TDP-43 is notably the neuropathological hallmark of amyotrophic lateral sclerosis (ALS) as well as some form of frontotemporolobar degeneration (FTLD). Tauopathies, divided in primary or secondary tauopathies cover other forms of FTLD including Pick disease (PiD), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP) but also non-FTLD diseases like Alzheimer's disease (AD) which can be classified as secondary tauopathy. As the importance of copathology is more and more recognized, TDP-43 is also frequently observed in conjunction with other proteinopathies, possibly with a synergistic or additive effect, although the exact mechanism is still unclear. In Alzheimer's disease, the limbic predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) co-occurrence with Alzheimer's disease neuropathologic changes (ADNC) lead to a more rapid course. Although there are currently no approved and validated biomarkers for its early detection, several promising tools, including neuroimaging and biofluid biomarkers, are under development, offering hope for the earlier detection of TDP-43 pathology in vivo. Accurate identification of the underlying proteinopathies and pathological processes could lead to better diagnosis and classification, more precise selection of clinical trial candidates, and ultimately, disease-specific tailored treatments.},
}

@article {pmid41229615,
year = {2025},
author = {Tiwari, P and Gupta, A and Kaushik, M and Yadav, A and Anjali, A and Dwivedi, R and Mudgal, P and Kumar, Y and Tripathi, M and Dada, R},
title = {Comprehensive metabolomics profiling reveals novel biomarkers and pathways for early detection of Alzheimer's disease.},
journal = {Brain communications},
volume = {7},
number = {6},
pages = {fcaf410},
pmid = {41229615},
issn = {2632-1297},
abstract = {Alzheimer's disease is a multifactorial neurodegenerative disorder marked by cognitive decline, synaptic dysfunction, and metabolic alterations. This study investigated disease-associated profiles in the Indian population using integrated clinical, metabolomic, and plasma biomarker analyses. We enrolled 25 clinically diagnosed patients (mean age: 61.20 ± 7.76 years) and 25 cognitively healthy controls (mean age: 60.56 ± 7.48 years). Cognitive and neuropsychiatric assessments included Addenbrooke's Cognitive Examination-III, Clinical Dementia Rating-Global, and Patient Health Questionnaire-9 for patients, and Montreal Cognitive Assessment, Clinical Dementia Rating-Global, and Patient Health Questionnaire-9 for controls. Plasma metabolomics was performed using liquid chromatography-mass spectrometry, and targeted ELISA quantified amyloid beta 40, amyloid beta 42, phosphorylated tau181, phosphorylated tau217, neurofilament light chain, apolipoprotein E, APOE4, 8-hydroxy-2'-deoxyguanosine, C-reactive protein, brain-derived neurotrophic factor, and glutamate. Statistical analyses included principal component analysis, volcano plots, receiver operating characteristic curves, pathway enrichment, and correlation analyses. Patients showed reduced cognition (median Addenbrooke's Cognitive Examination-III: 26). Clinical Dementia Rating-Global scores (1.44 ± 0.65 versus 0.24 ± 0.25; P < 0.0001) and Patient Health Questionnaire-9 scores (4.88 ± 4.21 versus 0.20 ± 0.50; P < 0.0001) were higher than controls. Principal component analysis revealed distinct metabolic clustering with 75 altered metabolites. Volcano analysis identified six upregulated (leucine, ascorbic acid, guanine) and 14 downregulated metabolites (valine, nicotinamide, octadecanedicarboxylic acid). Receiver operating characteristic curves highlighted octadecanedicarboxylic acid (AUC = 0.917), prolinamide (AUC = 0.908), 2-phosphoglycerate (AUC = 0.858), nicotinamide (AUC = 0.848), leucine (AUC = 0.768), and ascorbic acid (AUC = 0.748). Pathway enrichment indicated disruptions in branched-chain amino acid metabolism, nicotinamide metabolism, the tricarboxylic acid cycle, and neurotransmitter pathways. Biomarker analysis revealed elevated amyloid beta 40, amyloid beta 42/40 ratio, phosphorylated tau181, phosphorylated tau217, phosphorylated tau217/amyloid beta 42 ratio, neurofilament light chain, APOE4, C-reactive protein, and 8-hydroxy-2'-deoxyguanosine, with reduced brain-derived neurotrophic factor (all P < 0.05). Significant correlations included eupatilin with phosphorylated tau217 and 8-hydroxy-2'-deoxyguanosine, glyceraldehyde with brain-derived neurotrophic factor, guanine with APOE4, and valine inversely with phosphorylated tau181. This study identifies distinct metabolic (octadecanedicarboxylic acid, prolinamide, leucine, ascorbic acid) and biomarker profiles (phosphorylated tau217, 8-hydroxy-2'-deoxyguanosine, brain-derived neurotrophic factor) in Alzheimer's disease. Disrupted pathways linked to neuroinflammation and oxidative stress support the potential for integrated early detection strategies. Despite the small cross-sectional cohort, findings highlight the need for longitudinal, multi-centric validation.},
}

@article {pmid41229208,
year = {2025},
author = {Bosire, EN and Kamau, LW and Kiio, C and Blackmon, K and Taylor, ON and Shah, J and Sokhi, D and Mbugua, S and Meier, I and Hooker, J and Narayan, V and Merali, Z and Udeh-Momoh, C},
title = {Community perceptions and willingness to donate biospecimen for Alzheimer's disease research in Nairobi, Kenya.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251389227},
doi = {10.1177/13872877251389227},
pmid = {41229208},
issn = {1875-8908},
abstract = {BackgroundBiomarkers play a critical role in understanding disease mechanisms and advancing diagnostic and treatment options for Alzheimer's disease and related dementias (AD/ADRD). However, in many African countries, biomarker research is limited by insufficient knowledge, infrastructure, funding, and trained personnel.ObjectiveThis study explored community perceptions and willingness to donate biospecimens for AD/ADRD research in Kenya.MethodsEight focus group discussions were conducted in the informal settlements of Mathare and Kibera in Nairobi, Kenya, stratified by age and gender (n = 81). Data were transcribed verbatim and thematically analyzed using QSR Nvivo 14.ResultsParticipants generally expressed a positive attitude toward brain health research and donating biospecimens. Willingness to participate was influenced by altruism, perceived benefits, and improved understanding of AD/ADRD. Non-invasive samples such as saliva, blood, and stool were widely accepted due to perceptions of safety and familiarity. However, several barriers were identified, including cultural beliefs (e.g., fear of witchcraft linked to donating hair), religious beliefs, fear of invasive procedures (spinal taps), and low awareness about biospecimen research. To address these barriers, participants recommended community sensitization, inclusive and transparent research processes, clear communication of benefits, involvement of family members in consenting, and assurance of safety measures for managing potential risks.ConclusionsCommunity willingness to donate biospecimens for AD/ADRD research in Kenya is shaped by a complex interplay of cultural, ethical, and practical considerations. Culturally sensitive, community-driven approaches are essential to enhance participation in AD/ADRD biomarker research in Kenya and similar low-resource settings.},
}

@article {pmid41229183,
year = {2025},
author = {Fatima, H and Schaffert, J and Carlew, AR and Thakkar, VJ and Lacritz, L and Rossetti, H and Cullum, CM},
title = {The utility of global versus domain-specific neuropsychological test score dispersion as markers of cognitive impairment.},
journal = {The Clinical neuropsychologist},
volume = {},
number = {},
pages = {1-25},
doi = {10.1080/13854046.2025.2577149},
pmid = {41229183},
issn = {1744-4144},
abstract = {OBJECTIVE: Cognitive dispersion (CD) or neuropsychological test score variability has been associated with more rapid cognitive decline, and the development of mild cognitive impairment (MCI) and Alzheimer's disease (AD). The predictive utility of global (cross-domain) versus domain-specific dispersion remains understudied. We examined whether baseline global versus domain-specific CD better predicted conversion to MCI or dementia over time.

METHODS: 1,595 participants (Mage = 71.41, SD = 7.73) from the National Alzheimer's Coordinating Center (NACC) dataset were followed for ≥4 visits. Baseline CD was calculated using standardized neuropsychological test scores, with global dispersion defined as the intraindividual standard deviation (ISD) across 10 NACC scores. Domain-specific dispersion was calculated by constructing composites with ISD across tests within three domains (Memory, Language, and Executive functioning/attention/processing speed [EFAS]). Multinomial logistic regression model fit statistics were compared across four dispersion models (global, EFAS, language, memory) in predicting progression to MCI and dementia in (1) the full non-dementia sample and (2) those cognitively normal at baseline only, controlling for demographics, APOE4 status, and MMSE. Model fit was evaluated using LRT and AIC. Follow-up hierarchical regressions assessed the incremental value of the most successful dispersion metric beyond mean EFAS and memory composite scores.

RESULTS: In the full sample, 25% were considered to have MCI at follow-up, and 20% developed dementia, whereas among those considered cognitively normal at baseline (n = 1166), 17.6% progressed to MCI, and 11% progressed to dementia in their follow-up. In the overall sample, global dispersion was the only significant predictor of dementia diagnosis (AIC = 2504.27, p < .001) with moderate classification accuracy: 62.6%. Adding global dispersion to a model with covariates + mean EFAS and memory composite performances did not improve prediction (Δχ[2] = 1.803, p = .179). Among cognitively normal at baseline, only EFAS dispersion predicted dementia conversion, and classification accuracy remained moderate, though it was increased (71.7%). Adding EFAS dispersion to a model with covariates and mean composite performance also did not improve prediction (Δχ[2] = .614, p = .433). None of the dispersion metrics predicted conversion to MCI.

CONCLUSIONS: Dispersion (global in a non-dementia sample or domain-specific [EFAS] among cognitively asymptomatic individuals) may show limited predictive value for dementia conversion, but it does not exceed traditional mean-based cognitive performance, highlighting its complementary, rather than superior, role in diagnostic prediction.},
}

@article {pmid41229078,
year = {2025},
author = {Zhang, N and Liu, Y and Guan, Y},
title = {Piceatannol ameliorates the memory ability and cognitive behavior in Alzheimer's disease mice.},
journal = {Neurological research},
volume = {},
number = {},
pages = {1-10},
doi = {10.1080/01616412.2025.2581245},
pmid = {41229078},
issn = {1743-1328},
abstract = {OBJECTIVE: To investigate the effects of different doses of Piceatannol (PIC) on oxidative stress and cognitive function in a mouse model of Alzheimer's disease (AD).

METHODS: Firstly, a mouse model was established by inducing 70 days with D-gal and AlCl3. Sixty male mice are randomly divided into a normal control group (Control), an AD group (AD Model), positive control group (treated with donepezil), an AD model+low-dose group (PIC-L) receiving low-dose piceatannol treatment, an AD model+medium-dose group (PIC-M) receiving medium-dose piceatannol treatment, and an AD model+high-dose group (PIC-H) receiving high-dose piceatannol treatment, with 10 mice in each group. After 35 days of establishing an AD mouse model, different doses of piceatannol are continuously applied for treatment.

RESULTS: After 2 days of treatment, the AD Model had a longer escape latency than the Control. The escape latency time of PIC-L, PIC-M, and PIC-H was below AD Model, (p < 0.05). After treatment for 4d and 5d, the escape latency time of PIC-L, PIC-M, and PIC-H was below the AD Model, and the PIC-H group was even lower, with statistical significance (p < 0.05). PIC-L, PIC-M, and PIC-H crossed the platform more frequently than the AD Model, (p < 0.05). The SOD and GSH-Px levels in AD Model were below the Control, (p < 0.05). The MDA of AD Model exceeded the Control, (p < 0.05). The SOD, and GSH-Px in PIC-L, PIC-M, PIC-H exceeded the AD Model, (p < 0.05).

CONCLUSION: PIC significantly improved memory and cognition in AD mice, elevated serum SOD and GSH-Px, lowered MDA, and attenuated oxidative tissue injury with minimal organ toxicity.},
}

@article {pmid41229039,
year = {2025},
author = {Jabeen, K and Naveed, M and Aziz, T and Saad, M and Binsaleh, AY and Al-Hoshani, N and Alwethaynani, MS and Alkhateeb, MA and Alhhazmi, AA and Mansouri, OA},
title = {Identification of the common pathogenesis of Alzheimer's and nonalcoholic fatty liver disease and exploration of their relationship with immune cells.},
journal = {Allergologia et immunopathologia},
volume = {53},
number = {6},
pages = {20-31},
pmid = {41229039},
issn = {1578-1267},
mesh = {Humans ; *Alzheimer Disease/immunology/genetics/diagnosis ; *Non-alcoholic Fatty Liver Disease/immunology/genetics/diagnosis ; Biomarkers/metabolism ; Gene Expression Profiling ; Chemokine CXCL9/genetics ; Databases, Genetic ; Transcriptome ; ROC Curve ; },
abstract = {Alzheimer's disease (AD) and nonalcoholic fatty liver disease (NAFLD) are both prominent public health concerns owing to their increasing prevalence and burden on healthcare systems. The interconnected genetic and immunological mechanisms that may cause both of these diseases are poorly understood. This study used broad gene expression datasets to identify similar molecular markers and immunological profiles in AD and NAFLD and evaluate their potential. Using the Gene Expression Omnibus (GEO) database, mRNA expression profiles from patients with AD and NAFLD were analyzed alongside control samples to identify differentially expressed genes (DEGs). Systems biology approaches, including LASSO regression and multivariate logistic regression models, were used to further refine the significance of DEGs. The diagnostic potential of the key genes was evaluated using receiver operating characteristic (ROC) curves, and the immune cell environment was quantified using the Immune Cell Abundance Identifier (ImmuCellAI). We identified 11,278 DEGs, with 3551 upregulated and 7857 downregulated genes. S100A8, CXCL9, and ST8SIA3 have emerged as significant biomarkers of both AD and NAFLD. ROC analysis substantiated the diagnostic value of these markers. Additionally, distinct patterns of immune cell populations have been observed in AD and NAFLD, highlighting potential targets for immunomodulatory therapy. This study elucidates shared molecular and immune mechanisms in AD and NAFLD, offering insights into the pathophysiological underpinnings that could inform the development of novel diagnostic and therapeutic strategies. S100A8, CXCL9, and ST8SIA3 are potential candidates for future clinical application. Further investigation into these genetic discoveries and their immune system effects may lead to a unified strategy for treating these complicated disorders.},
}

Humans
*Alzheimer Disease/immunology/genetics/diagnosis
*Non-alcoholic Fatty Liver Disease/immunology/genetics/diagnosis
Biomarkers/metabolism
Gene Expression Profiling
Chemokine CXCL9/genetics
Databases, Genetic
Transcriptome
ROC Curve

@article {pmid41228597,
year = {2025},
author = {Gomes, ACC and Almeida, A and Freire, CSR and Ferreira, BL},
title = {Chitosan (Nano)formulations as Therapeutic Tools for Neurodegenerative Diseases: A Comprehensive Review.},
journal = {Polymers},
volume = {17},
number = {21},
pages = {},
pmid = {41228597},
issn = {2073-4360},
support = {UIDB/50011/2020 (DOI 10.54499/UIDB/50011/2020)//FCT/MCTES (PIDDAC)/ ; UIDP/50011/2020 (DOI 10.54499/UIDP/50011/2020)//FCT/MCTES (PIDDAC)/ ; LA/P/0006/2020 (DOI 10.54499/LA/P/0006/2020)//FCT/MCTES (PIDDAC)/ ; (UIDP/50017/2020+UIDB/50017/2020+LA/P/0094/2020)//FCT/MCTES (PIDDAC)/ ; 2022.10449.BD (https://doi.org/10.54499/2022.10449.BD)//Fundação para a Ciência e Tecnologia/ ; DOI 10.54499/ND/00464/2017/CP1459/CT0033//Fundação para a Ciência e Tecnologia/ ; DOI: 10.54499/DL57/2016/CP1482/CT0019//National funds (OE), through FCT/ ; },
abstract = {According to the World Health Organization, Alzheimer's disease and other forms of dementia were the seventh leading cause of death in 2021. The prevalence of these disorders is predictable to increase with life expectancy, and their control is hampered by several factors, including late diagnosis due to the lack of specific biomarkers and the absence of disease-modifying treatments, as currently available therapies can only lighten some of the symptoms. Nanotechnology could be the key to overcoming some of the limitations associated with neurodegenerative diseases, as nanomaterials have excellent properties compared to their bulk counterparts and can be used as drug delivery systems, diagnostic tools and platforms for tissue regeneration. Chitosan is a biopolymer with numerous properties that impart it with great potential for biomedical applications, in particular its ability to cross the blood-brain barrier and its versatility in nanoscale design. In this context, the aim of this review is to provide an in-depth analysis of the latest developments and future opportunities for chitosan (nano)formulations for the treatment and management of neurodegenerative diseases.},
}

@article {pmid41228523,
year = {2025},
author = {Liu, Y and Dong, Y and Cao, Z and Ji, Y and Cheng, X and Zheng, X},
title = {The Multi-Dimensional Action Map of Resveratrol Against Alzheimer's Disease: Mechanism Integration and Treatment Strategy Optimization.},
journal = {Nutrients},
volume = {17},
number = {21},
pages = {},
doi = {10.3390/nu17213451},
pmid = {41228523},
issn = {2072-6643},
support = {//the Youth Talent Cultivation Fund Project of Dalian Medical University./ ; },
mesh = {*Resveratrol/pharmacology/therapeutic use ; *Alzheimer Disease/drug therapy/metabolism ; Humans ; Oxidative Stress/drug effects ; *Antioxidants/pharmacology/therapeutic use ; *Neuroprotective Agents/pharmacology/therapeutic use ; Animals ; Plaque, Amyloid/drug therapy ; Energy Metabolism/drug effects ; Mitochondria/drug effects/metabolism ; Neurofibrillary Tangles/drug effects/metabolism ; },
abstract = {Alzheimer's disease (AD) represents a prevalent neurodegenerative disorder marked by a gradual decline in cognitive and behavioral functions. Despite advancements in elucidating several potential mechanisms underlying the pathogenesis of AD, there remains a limitation in effective supplements or medications for its intervention. Resveratrol, a natural antioxidant, has emerged as a significant player in the treatment of AD. This article reviews the role of resveratrol in four key aspects: amyloid plaque deposition and neurofibrillary tangles, inflammatory response and oxidative stress, energy metabolism and mitochondrial homeostasis, and neuroprotection and regeneration. Furthermore, we also explore treatment strategies to enhance the therapeutic effect of resveratrol.},
}

*Resveratrol/pharmacology/therapeutic use
*Alzheimer Disease/drug therapy/metabolism
Humans
Oxidative Stress/drug effects
*Antioxidants/pharmacology/therapeutic use
*Neuroprotective Agents/pharmacology/therapeutic use
Animals
Plaque, Amyloid/drug therapy
Energy Metabolism/drug effects
Mitochondria/drug effects/metabolism
Neurofibrillary Tangles/drug effects/metabolism

@article {pmid41228437,
year = {2025},
author = {Kim, G and Lee, HG and Kwon, S},
title = {Current Utilization and Research Status of the Herbal Medicine Guibi-Tang and Its Variants for Cognitive Impairment: A Scoping Review.},
journal = {Nutrients},
volume = {17},
number = {21},
pages = {},
doi = {10.3390/nu17213365},
pmid = {41228437},
issn = {2072-6643},
support = {RS-2022-KH127675//Korea Health Industry Development Institute/Republic of Korea ; },
mesh = {Humans ; *Cognitive Dysfunction/drug therapy ; *Drugs, Chinese Herbal/therapeutic use/adverse effects ; Aged ; Cognition/drug effects ; Middle Aged ; },
abstract = {Background/Objectives: Guibi-tang (GBT) and its variant Kami-guibi-tang (KGBT) are traditional East Asian multi-herb formulas prescribed for memory loss, insomnia, and fatigue. Preclinical data suggest multimodal neuroprotective actions, including cholinergic signaling modulation and activation of the cAMP response element-binding protein (CREB)/extracellular signal-regulated kinase (ERK) pathway; however, clinical evidence for cognitive disorders remains scattered. This scoping review aimed to map the breadth, design characteristics, efficacy signals, and safety profile of GBT and KGBT across the full spectrum of cognitive impairment. Methods: Following the Arksey-O'Malley framework and PRISMA-ScR guidelines, seven databases were searched (MEDLINE, Embase, Cochrane Library, China National Knowledge Infrastructure, ScienceON, Scopus, Citation Information by the National Institute of Informatics) from inception to 31 January 2025, for human studies evaluating GBT or KGBT in subjective cognitive decline, mild cognitive impairment (MCI), dementia, or post-stroke cognitive impairment (PSCI). Two reviewers independently screened, extracted, and charted data on study design, participants, interventions, outcomes, and adverse events. Results: Fifteen studies met the inclusion criteria-nine randomized controlled trials, one crossover trial, and five observational reports-enrolling 555 participants (age range, 59-87 years). All were conducted in the Republic of Korea, Japan, or China. GBT or KGBT, given as monotherapy or adjunctive therapy for 4 weeks to 9 months, produced modest but consistent improvements in global cognition (Mini-Mental State Examination/Montreal Cognitive Assessment), memory domains, activities of daily living, and neuropsychiatric symptoms across MCI, Alzheimer's disease, and PSCI cohorts. Reported adverse event rates were comparable to or lower than those of placebo, usual care, or conventional drugs, and no serious treatment-related toxicity was identified. Conclusions: Current evidence-although limited by small sample sizes, heterogeneous formulations, short follow-up durations, and regional concentration-indicates that GBT and KGBT are well tolerated and confer clinically meaningful cognitive and functional benefits. Standardized, multicenter, placebo-controlled trials with biomarker end points are warranted to confirm long-term efficacy, clarify mechanisms, and guide integrative clinical use.},
}

Humans
*Cognitive Dysfunction/drug therapy
*Drugs, Chinese Herbal/therapeutic use/adverse effects
Aged
Cognition/drug effects
Middle Aged

@article {pmid41228412,
year = {2025},
author = {Kim, J and Wi, D and Han, SN and Park, CY},
title = {Effects of Dietary Vitamin D Levels on Markers Related to Amyloidogenesis and Neuroinflammation in db/db Mice.},
journal = {Nutrients},
volume = {17},
number = {21},
pages = {},
doi = {10.3390/nu17213339},
pmid = {41228412},
issn = {2072-6643},
support = {NRF-RS-2024-00455010//National Research Foundation of Korea/ ; NRF-RS-2024-00353119//National Research Foundation of Korea/ ; },
mesh = {Animals ; *Vitamin D/administration & dosage/pharmacology/blood ; Male ; Hippocampus/metabolism/pathology/drug effects ; Mice, Inbred C57BL ; Mice ; Biomarkers/metabolism ; *Alzheimer Disease/metabolism ; Amyloid beta-Peptides/metabolism ; *Neuroinflammatory Diseases/metabolism ; Aspartic Acid Endopeptidases/metabolism/genetics ; *Diet ; Neurons/pathology/metabolism ; Prefrontal Cortex/metabolism/drug effects ; Amyloid Precursor Protein Secretases/metabolism/genetics ; *Diabetes Mellitus, Experimental/metabolism ; Amyloid beta-Protein Precursor/metabolism/genetics ; },
abstract = {BACKGROUND/OBJECTIVES: Low vitamin D levels are associated with an elevated risk of Alzheimer's disease (AD). Given the rising prevalence of diabetes and its association with AD, this study investigated whether vitamin D modulates amyloidogenesis and inflammation in the brains of diabetic mice.

METHODS: Five-week-old male C57BLKS/J-m+/m+(con) and C57BLKS/J-db/db (db) mice received diets with low or high vitamin D (LVD or HVD) for 8 weeks. Hippocampal neuronal morphology was assessed using H&E and Nissl staining, and Aβ levels, along with the mRNA expression of genes related to amyloidogenesis, amyloid degradation, inflammation, antioxidation, and neurotrophic factors, were measured in the hippocampus and prefrontal cortex (PFC).

RESULTS: High dietary vitamin D levels attenuated neuronal necrosis in db/db mice. Hippocampal App and Bace1 expression levels were higher in db/db mice; however, amyloidogenic gene (App, Bace1, Ps1) expression levels in both the hippocampus and PFC were significantly lower in db_HVD group compared with those in db_LVD group (all p < 0.05). Among control mice, PFC App and Ps1 expression levels were lower in con_HVD group than in con_LVD group. Nonetheless, Aβ42 protein levels were not affected by either diabetes or dietary vitamin D levels. Furthermore, lower hippocampal Iκbα and PFC Mcp-1 expression levels in db_HVD group than those in db_LVD group were observed, both upregulated in diabetic mice. Amyloid degradation-related gene or Vdr expression was not altered by dietary vitamin D levels.

CONCLUSIONS: These findings suggest that vitamin D may exert neuroprotective effects on the hippocampus and PFC in diabetic mice by mitigating neuronal damage and suppressing amyloidogenic and inflammatory gene expression.},
}

Animals
*Vitamin D/administration & dosage/pharmacology/blood
Male
Hippocampus/metabolism/pathology/drug effects
Mice, Inbred C57BL
Mice
Biomarkers/metabolism
*Alzheimer Disease/metabolism
Amyloid beta-Peptides/metabolism
*Neuroinflammatory Diseases/metabolism
Aspartic Acid Endopeptidases/metabolism/genetics
*Diet
Neurons/pathology/metabolism
Prefrontal Cortex/metabolism/drug effects
Amyloid Precursor Protein Secretases/metabolism/genetics
*Diabetes Mellitus, Experimental/metabolism
Amyloid beta-Protein Precursor/metabolism/genetics

@article {pmid41227390,
year = {2025},
author = {Habib, SA and Kamal, MM and Aly, MH and Ghaiad, HR and Rizk, SM and Banks, WA and Erickson, MA},
title = {Streptozotocin Causes Blood-Brain Barrier and Astrocytic Dysfunction In Vitro.},
journal = {Cells},
volume = {14},
number = {21},
pages = {},
doi = {10.3390/cells14211745},
pmid = {41227390},
issn = {2073-4409},
support = {ACOS Research Fund//VA Puget Sound Health Care System/ ; Graduate Scholarship//United States Agency for International Development/ ; },
mesh = {*Blood-Brain Barrier/drug effects/pathology/metabolism ; *Astrocytes/drug effects/pathology/metabolism ; Humans ; *Streptozocin/pharmacology/toxicity ; Endothelial Cells/drug effects/metabolism/pathology ; Induced Pluripotent Stem Cells/drug effects/metabolism ; Glucose Transporter Type 1/metabolism ; Cells, Cultured ; },
abstract = {Streptozotocin (STZ) is an alkylating agent that has neurotoxic effects when injected into the cerebral ventricles (ICV) and also models many other features of Alzheimer's disease. However, the mechanisms of STZ neurotoxicity are not well understood. In this study, we hypothesized that some of the neurotoxic effects of STZ could be due to direct activities on brain endothelial cells and astrocytes, which are key in forming and supporting the functions of the blood-brain barrier (BBB), respectively. To test this hypothesis, we characterized the changes induced by STZ either in cultures of human-induced pluripotent stem cell (iPSC)-derived brain endothelial-like cells (iBECs), which form an in vitro BBB model, or in primary human astrocytes. We found that STZ at a dosage of 5 mM caused a delayed reduction in the transendothelial electrical resistance (TEER) of iBECs at 7-11 days post-treatment, indicating induction of BBB leakage. Additionally, we observed significant increases in albumin leakage across the monolayer, altered iBEC morphology, and reductions in tight junction proteins, suggesting that STZ causes BBB disruption. We further found that the BBB glucose transporter GLUT-1 was reduced in iBECs, as was the total number of iBECs. In astrocytes, the 5 mM dose of STZ reduced the GFAP signal and total number of cells, suggesting that STZ has anti-proliferative and/or toxic effects on astrocytes. Together, these data support that STZ's neurotoxic effects could be due, in part, to its direct toxic activities on brain endothelial cells and astrocytes.},
}

*Blood-Brain Barrier/drug effects/pathology/metabolism
*Astrocytes/drug effects/pathology/metabolism
Humans
*Streptozocin/pharmacology/toxicity
Endothelial Cells/drug effects/metabolism/pathology
Induced Pluripotent Stem Cells/drug effects/metabolism
Glucose Transporter Type 1/metabolism
Cells, Cultured

@article {pmid41227358,
year = {2025},
author = {Szabó, Á and Galla, Z and Spekker, E and Martos, D and Szűcs, M and Fejes-Szabó, A and Fehér, Á and Takeda, K and Ozaki, K and Inoue, H and Yamamoto, S and Monostori, P and Toldi, J and Ono, E and Vécsei, L and Tanaka, M},
title = {Behavioral Balance in Tryptophan Turmoil: Regional Metabolic Rewiring in Kynurenine Aminotransferase II Knockout Mice.},
journal = {Cells},
volume = {14},
number = {21},
pages = {},
doi = {10.3390/cells14211711},
pmid = {41227358},
issn = {2073-4409},
support = {NKFIH K138125//National Research, Development, and Innovation Office/ ; No:2022/5S729//SZTE SZAOK-KKA/ ; TKP-2021-EGA-32//Hungarian Research Network/ ; JPJSBP120203803//JSPS Joint Research Projects under Bilateral Programs/ ; 7571//University of Szeged Open Access Fund/ ; },
mesh = {Animals ; *Tryptophan/metabolism ; Mice, Knockout ; *Transaminases/metabolism/deficiency/genetics ; Mice ; *Behavior, Animal ; Male ; Kynurenine/metabolism/analogs & derivatives ; Mice, Inbred C57BL ; Brain/metabolism ; Kynurenic Acid/metabolism ; },
abstract = {BACKGROUND: Cognitive, emotional, and social impairments are pervasive across neuropsychiatric conditions, where alterations in the tryptophan (Trp)-kynurenine pathway and its product kynurenic acid (KYNA) from kynurenine aminotransferases (KATs) have been linked to Alzheimer's disease, Parkinson's disease, depression, and post-traumatic stress disorder. In novel CRISPR/Cas9-engineered KAT II knockout (aadat[-/-] also known as kat2[-/-]) mice, we observed despair-linked depression-like behavior with peripheral excitotoxicity and oxidative stress. KAT II's role and its crosstalk with serotonin, indole-pyruvate, and tyrosine-dopamine remain unclear. It is unknown whether deficits extend to cognitive, emotional, motor, and social domains or whether brain tissues mirror peripheral stress.

OBJECTIVES: Delineate domain-wide behaviors, brain oxidative/excitotoxic profiles, and pathway interactions attributable to KAT II.

RESULTS: Behavior was unchanged across strains. kat2[-/-] deletion remodeled Trp metabolic pathways: 3-hydroxykynurenine increased, xanthurenic acid decreased, KYNA fell in cortex and hippocampus but rose in striatum, quinaldic acid decreased in cerebellum and brainstem. These region-specific changes indicate metabolic stress across the brain and align with higher oxidative load and signs of excitotoxic pressure.

CONCLUSIONS: Here, we show that KAT II deletion reshapes regional Trp metabolism and amplifies oxidative and excitotoxic imbalance. Although domain-wide behavioral measures, spanning cognition, sociability, and motor coordination, remained largely unchanged, these neurochemical alterations signify a latent emotional bias rather than overt depressive-like behavior. This work, therefore, refines prior findings by delineating KAT II-linked biochemical vulnerability as a potential substrate for stress-reactive affective dysregulation.},
}

Animals
*Tryptophan/metabolism
Mice, Knockout
*Transaminases/metabolism/deficiency/genetics
Mice
*Behavior, Animal
Male
Kynurenine/metabolism/analogs & derivatives
Mice, Inbred C57BL
Brain/metabolism
Kynurenic Acid/metabolism

@article {pmid41227353,
year = {2025},
author = {Nowacka, A and Śniegocki, M and Ziółkowska, EA},
title = {Calcium Dynamics in Astrocyte-Neuron Communication from Intracellular to Extracellular Signaling.},
journal = {Cells},
volume = {14},
number = {21},
pages = {},
doi = {10.3390/cells14211709},
pmid = {41227353},
issn = {2073-4409},
mesh = {*Astrocytes/metabolism ; Humans ; *Neurons/metabolism ; Animals ; *Calcium Signaling ; *Cell Communication ; *Calcium/metabolism ; *Extracellular Space/metabolism ; },
abstract = {Astrocytic calcium signaling is a central mechanism of neuron-glia communication that operates across multiple spatial and temporal scales. Traditionally, research has focused on intracellular Ca[2+] oscillations that regulate gliotransmitter release, ion homeostasis, and metabolic support. Recent evidence, however, reveals that extracellular calcium ([Ca[2+]]o) is not a passive reservoir but a dynamic signaling mediator capable of influencing neuronal excitability within milliseconds. Through mechanisms such as calcium-sensing receptor (CaSR) activation, ion channel modulation, surface charge effects, and ephaptic coupling, astrocytes emerge as active partners in both slow and rapid modes of communication. This dual perspective reshapes our understanding of brain physiology and disease. Disrupted Ca[2+] signaling contributes to network instability in epilepsy, synaptic dysfunction in Alzheimer's and Parkinson's disease, and impaired maturation in neurodevelopmental disorders. Methodological advances, including Ca[2+]-selective microelectrodes, genetically encoded extracellular indicators, and computational modeling, are beginning to uncover the richness of extracellular Ca[2+] dynamics, though challenges remain in achieving sufficient spatial and temporal resolution. By integrating classical intracellular pathways with emerging insights into extracellular signaling, this review highlights astrocytes as central architects of the ionic landscape. Recognizing calcium as both an intracellular messenger and an extracellular signaling mediator provides a unifying framework for neuron-glia interactions and opens new avenues for therapeutic intervention.},
}

*Astrocytes/metabolism
Humans
*Neurons/metabolism
Animals
*Calcium Signaling
*Cell Communication
*Calcium/metabolism
*Extracellular Space/metabolism

@article {pmid41227148,
year = {2025},
author = {Bermejo-Pareja, F and Del Ser, T},
title = {Alzheimer Syndrome or Age-Related Dementia-History, Therapy and Prevention.},
journal = {Journal of clinical medicine},
volume = {14},
number = {21},
pages = {},
pmid = {41227148},
issn = {2077-0383},
abstract = {This narrative review of Alzheimer's disease (AD) history, therapy and prevention shows that its conceptualization has changed three times over 100 years. First, AD was a normative creation by Kraepelin in 1910 of a rare presenile dementia characterized by specific histological features. Second, during the 1970s, American neurologists, driven by sociological changes, merged presenile and senile dementias into an Alzheimer-type dementia with the universally accepted clinicopathological diagnostic criteria of McKhann. By the end of the 20th century, AD was divided into early-onset genetic (1%) and late-onset sporadic (99%) forms. In the 21st century, AD was redefined as a biological entity, using biological and neuroimaging markers of amyloid, tau and neurodegeneration, to better address research and clinical trials. This new nosology has been widely criticized, given the absence of curative therapy, the evidence of mixed pathology in most cases and the decline in the dementia/AD incidence in high-income countries. However, there are currently many drugs against AD in the pipeline; prevention appears as medical and social therapy. In summary, the ancient concept of age-related dementia has evolved into AD normative disorders over 100 years. Nowadays, AD requires a conceptual reassessment, although its medical paradigm remains. Awaiting pharmacological breakthroughs, dementia prevention seems the best practical approach.},
}

@article {pmid41226869,
year = {2025},
author = {Rafti, D and Uzun, AB and Bodeanu, L and Stanciu, LE and Popescu, MN and Iliescu, MG},
title = {The Potential of Focal Muscle Vibration Therapy in the Management of Parkinson's Disease: A Systematic Review.},
journal = {Journal of clinical medicine},
volume = {14},
number = {21},
pages = {},
pmid = {41226869},
issn = {2077-0383},
abstract = {Background and Objectives: Parkinson's disease is the second most common neurodegenerative disorder after Alzheimer's disease, and its incidence increases with age, being particularly high in people over 70 years of age. For patients with this condition, medical rehabilitation can have a profound impact, helping to improve mobility, preserve functional autonomy, and enhance quality of life. Focal vibration stimulation is a promising, well-tolerated, and easy-to-apply method with potential to facilitate motor activity and support the motor learning process, making it also useful in gait reeducation for patients with various neurological conditions. This systematic review aims to analyze the existing scientific evidence on the effectiveness of focal muscle vibration therapy in managing symptoms of Parkinson's disease. Materials and Methods: This systematic review of the literature was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, and the protocol was registered in PROSPERO under the protocol registration number CRD420251120737. Searches were conducted in five databases (PubMed, PEDro, ScienceDirect, Cochrane Library, Web of Science). The selection criteria targeted original clinical studies, published in English between 2010 and the present, that investigated focal muscle vibration therapy in patients with Parkinson's disease and were fully available, excluding review papers, meta-analyses, books, and articles inaccessible in full text. Version 2 of the Cochrane risk-of-bias tool for randomized trials (RoB 2) was used to assess the quality of the included studies. Results: The results of the studies were interpreted individually for each study, and the main information was synthesized in a comparative table to facilitate analysis. The final analysis included five studies that investigated the effects of focal muscle vibration in patients with Parkinson's disease. The results suggest that this form of stimulation may offer benefits for patients with gait disorders, improving balance and stability. Among the study's limitations are the small number of included articles (n = 5) and the restriction to English-language publications, which may limit the applicability of the results. Conclusions: Given the promising results, focal muscle vibration therapy could represent a useful option in the management of Parkinson's disease. Integrating this method into rehabilitation plans could bring significant functional benefits, but further studies are needed to confirm its long-term effectiveness and to establish standardized application protocols. No external funding was received for the conduct of this review.},
}

@article {pmid41226838,
year = {2025},
author = {Zhao, Y and Wang, Z and Xi, E and Yang, F and Gao, N},
title = {Hydrophobic Drug Delivery Platforms Based on Covalent Organic Frameworks for Combined Treatment of Alzheimer's Disease.},
journal = {International journal of molecular sciences},
volume = {26},
number = {21},
pages = {},
doi = {10.3390/ijms262110803},
pmid = {41226838},
issn = {1422-0067},
support = {2022YFB3805902//the National Key R&D Program of China/ ; 22077118//National Natural Science Foundation of China/ ; B18012//the "111" project/ ; 20210101353JC//the National Natural Science Foundation of Jilin Province/ ; },
mesh = {*Alzheimer Disease/drug therapy ; Animals ; *Curcumin/chemistry/administration & dosage/pharmacology/therapeutic use ; Hydrophobic and Hydrophilic Interactions ; Mice ; *Drug Delivery Systems/methods ; *Metal-Organic Frameworks/chemistry ; *Drug Carriers/chemistry ; Humans ; Disease Models, Animal ; },
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disease. The pathogenesis of AD remains incompletely understood. It is characterized by a variety of neuropathological changes, including neuroinflammation, neuronal loss and synaptic damage. Multiple pathological changes make achieving good therapeutic effects with a single drug treatment difficult, and using multiple drugs for combination therapy is currently the most effective method. Currently, the mainstay drugs used for AD treatment are hydrophobic drugs, such as curcumin, donepezil, and resveratrol. Because hydrophobic drugs cannot dissolve in bodily fluids and often aggregate or precipitate, their efficacy is greatly reduced. Therefore, there is an urgent need for a drug carrier that can effectively load and continuously release drugs. However, currently, there are few drug carriers that can achieve efficient co-loading of multiple hydrophobic drugs. Therefore, three of two-dimensional imine covalent organic frameworks (COFs) with different monomers were synthesized through rational design and screening. These three synthesized COFs are simultaneously loaded with curcumin (CUR) and benzofurazan (BZ) to achieve combined therapy. The results indicate that among this series of synthesized COFs, the COF synthesized from 4,4',4″-(1,3,5-Triazine-2,4,6-triyl) trianiline and benzene-1,3,5-tricarboxaldehyde (COF-TB) exhibits optimal hydrophobic drug-loading capacity, enabling effective co-loading of CUR and BZ (BC@COF-TB). After treatment with BC@COF-TB, the cognitive function of 5×FAD mice was significantly improved. The COF platform provides a new way to deliver hydrophobic drugs for AD treatment.},
}

*Alzheimer Disease/drug therapy
Animals
*Curcumin/chemistry/administration & dosage/pharmacology/therapeutic use
Hydrophobic and Hydrophilic Interactions
Mice
*Drug Delivery Systems/methods
*Metal-Organic Frameworks/chemistry
*Drug Carriers/chemistry
Humans
Disease Models, Animal

@article {pmid41226821,
year = {2025},
author = {Paszternák, A and Varga, K and Gyöngyössy, R and Tarnóczi, K and Sikur, N and Szökő, É and Tábi, T},
title = {Resveratrol Analogs Ameliorate Mitochondrial Impairment and Insulin Resistance in a Streptozotocin-Induced In Vitro Model of Alzheimer's Disease.},
journal = {International journal of molecular sciences},
volume = {26},
number = {21},
pages = {},
doi = {10.3390/ijms262110787},
pmid = {41226821},
issn = {1422-0067},
support = {2024-2.1.1-EKÖP-2024-0004 (203)//National Research, Development and Innovation Office/ ; EFOP-3.6.3.-VEKOP-16-2017-00009//National Research, Development and Innovation Office/ ; },
mesh = {*Resveratrol/pharmacology/analogs & derivatives ; *Insulin Resistance ; Humans ; *Alzheimer Disease/metabolism/drug therapy/chemically induced/pathology ; *Mitochondria/drug effects/metabolism/pathology ; Streptozocin/toxicity ; Cell Line, Tumor ; *Neuroprotective Agents/pharmacology/chemistry ; Autophagy/drug effects ; Oxidative Stress/drug effects ; Stilbenes/pharmacology/chemistry ; Antioxidants/pharmacology ; },
abstract = {Alzheimer's disease (AD) is characterized by mitochondrial dysfunction, oxidative stress, insulin resistance, and aberrant protein aggregation. Neurodegeneration model with neuronal insulin resistance was induced in SH-SY5Y human neuroblastoma cells by streptozotocin (STZ). We evaluated the neuroprotective effects of resveratrol (RZV) and three structural analogs: oxyresveratrol (OXI), monomethyl resveratrol (MONO), and trimethyl resveratrol (TRI). Mitochondrial function, plasma membrane integrity, oxidative stress) and autophagy were studied by fluorescent assays. Phosphorylated GSK3 levels were measured by ELISA as an indicator of insulin sensitivity. TRI exhibited significant mitochondrial protective effects and strongly induced autophagy. OXI demonstrated excellent antioxidant activity but showed no detectable mitochondrial protective or autophagy-inducing effects. RZV and MONO exhibited moderate antioxidant effects along with strong insulin-sensitizing and autophagy-inducing properties. Insulin sensitivity was most potently restored by RZV (IC50 = 54 pM) and MONO (IC50 = 50 pM), whereas TRI (IC50 = 160 pM) was less potent, and OXI (IC50 = 97 pM) showed moderate potency. Our findings suggest that the neuroprotective effects of resveratrol analogs significantly depend on their molecular structure and that they exert their beneficial effects through distinct mechanisms. This research may contribute to the development of novel, multi-target compounds for the treatment of neurodegenerative diseases.},
}

*Resveratrol/pharmacology/analogs & derivatives
*Insulin Resistance
Humans
*Alzheimer Disease/metabolism/drug therapy/chemically induced/pathology
*Mitochondria/drug effects/metabolism/pathology
Streptozocin/toxicity
Cell Line, Tumor
*Neuroprotective Agents/pharmacology/chemistry
Autophagy/drug effects
Oxidative Stress/drug effects
Stilbenes/pharmacology/chemistry
Antioxidants/pharmacology

@article {pmid41226802,
year = {2025},
author = {Nowacka, A and Śniegocki, M and Bożiłow, D and Ziółkowska, E},
title = {Circadian Regulation of Neuronal Membrane Capacitance-Mechanisms and Implications for Neural Computation and Behavior.},
journal = {International journal of molecular sciences},
volume = {26},
number = {21},
pages = {},
doi = {10.3390/ijms262110766},
pmid = {41226802},
issn = {1422-0067},
mesh = {Humans ; *Neurons/physiology/metabolism ; *Circadian Rhythm/physiology ; Animals ; *Cell Membrane/metabolism/physiology ; Electric Capacitance ; },
abstract = {Neuronal membrane capacitance (Cm) has traditionally been viewed as a static biophysical property determined solely by the geometric and dielectric characteristics of the lipid bilayer. Recent discoveries have fundamentally challenged this perspective, revealing that Cm exhibits robust circadian oscillations that profoundly influence neural computation and behavior. These rhythmic fluctuations in membrane capacitance are orchestrated by intrinsic cellular clocks through coordinated regulation of molecular processes including transcriptional control of membrane proteins, lipid metabolism, ion channel trafficking, and glial-mediated extracellular matrix remodeling. The dynamic modulation of Cm directly impacts the membrane time constant (τm = RmCm), thereby altering synaptic integration windows, action potential dynamics, and network synchronization across the 24 h cycle. At the computational level, circadian Cm oscillations enable neurons to shift between temporal summation and coincidence detection modes, optimizing information processing according to behavioral demands throughout the day-night cycle. These biophysical rhythms influence critical aspects of cognition including memory consolidation, attention, working memory, and sensory processing. Disruptions in normal Cm rhythmicity are increasingly implicated in neuropsychiatric and neurodegenerative disorders, including depression, schizophrenia, Alzheimer's disease, and epilepsy, where altered membrane dynamics compromise neural circuit stability and information transfer. The integration of circadian biophysics with chronomedicine offers promising therapeutic avenues, including chronotherapeutic strategies that target membrane properties, personalized interventions based on individual chronotypes, and environmental modifications that restore healthy biophysical rhythms. This review synthesizes evidence from molecular chronobiology, cellular electrophysiology, and systems neuroscience to establish circadian Cm regulation as a fundamental mechanism linking molecular timekeeping to neural computation and behavior.},
}

Humans
*Neurons/physiology/metabolism
*Circadian Rhythm/physiology
Animals
*Cell Membrane/metabolism/physiology
Electric Capacitance

@article {pmid41226793,
year = {2025},
author = {Machowska, M and Leszek, J and Rączy-Krzemianowska, M and Tomasiewicz, B and Hurkacz, M and Rąpała, M and Piechota, J and Głowacka, K and Wiela-Hojeńska, A},
title = {ABC Transporters, APOE, CYP46A1, and LRP1 Gene Polymorphisms as Markers of Dementia Development in Patients with Hyperlipidemia.},
journal = {International journal of molecular sciences},
volume = {26},
number = {21},
pages = {},
doi = {10.3390/ijms262110759},
pmid = {41226793},
issn = {1422-0067},
support = {RPDS.01.02.01-02-0002/20//Regional Operational Programme of the Lower Silesian Voivodeship 2014-2020, co-financed by the European Union, European Regional Development Fund/ ; },
mesh = {Humans ; *Hyperlipidemias/genetics/complications ; Male ; Female ; *Apolipoproteins E/genetics ; *Dementia/genetics/etiology ; Aged ; *Polymorphism, Single Nucleotide ; *ATP Binding Cassette Transporter 1/genetics ; Genetic Predisposition to Disease ; *Low Density Lipoprotein Receptor-Related Protein-1/genetics ; Genotype ; Middle Aged ; Alleles ; Gene Frequency ; Biomarkers ; Alzheimer Disease/genetics ; Aged, 80 and over ; *ATP-Binding Cassette Transporters/genetics ; Case-Control Studies ; },
abstract = {In an aging society, solving problems associated with the diagnosis and treatment of dementia-related diseases represents a serious challenge. The aim of the study was to evaluate the possibility of applying molecular biology methods to test polymorphisms recognized in the global literature as potentially useful in assessing the risk of developing dementia in a group of patients with hyperlipidemia. A sample of 203 patients: 109 diagnosed with both dementia and hyperlipidemia, 94 with hyperlipidemia, and 101 individuals as an allele frequency control group-were genotyped. Additional data about cognitive decline and neuropsychological assessment were collected. Among all the studied polymorphisms, the frequency of the ABCA1 rs2230806 polymorphism differed between the analyzed groups. The GG genotype (p = 0.0002, RR = 3.22, CI = 1.63 ÷ 6.37) and the G allele (p = 0.0007, RR = 1.53, CI = 1.19 ÷ 1.97) were more frequent in patients diagnosed with dementia, specifically in those with Alzheimer's disease. Furthermore, the GG genotype was more common in individuals with a shorter disease duration and lower scores on the Montreal Cognitive Assessment (MoCA) scale, and consequently, with greater cognitive function deficits during early stages of the diagnostic process. ABCA1 rs2230806 genotyping is a potential marker for the early identification of dementia risk in patients with hyperlipidemia, which supports the validity of exploring options for incorporating diagnostics based on molecular biology methods.},
}

Humans
*Hyperlipidemias/genetics/complications
Male
Female
*Apolipoproteins E/genetics
*Dementia/genetics/etiology
Aged
*Polymorphism, Single Nucleotide
*ATP Binding Cassette Transporter 1/genetics
Genetic Predisposition to Disease
*Low Density Lipoprotein Receptor-Related Protein-1/genetics
Genotype
Middle Aged
Alleles
Gene Frequency
Biomarkers
Alzheimer Disease/genetics
Aged, 80 and over
*ATP-Binding Cassette Transporters/genetics
Case-Control Studies

@article {pmid41226780,
year = {2025},
author = {Moaket, OS and Obaid, SE and Obaid, FE and Shakeeb, YA and Elsharief, SM and Tania, A and Darwish, R and Butler, AE and Moin, ASM},
title = {GLP-1 and the Degenerating Brain: Exploring Mechanistic Insights and Therapeutic Potential.},
journal = {International journal of molecular sciences},
volume = {26},
number = {21},
pages = {},
doi = {10.3390/ijms262110743},
pmid = {41226780},
issn = {1422-0067},
mesh = {Humans ; Animals ; *Glucagon-Like Peptide 1/metabolism ; *Neurodegenerative Diseases/metabolism/drug therapy/pathology ; *Brain/metabolism/pathology/drug effects ; *Neuroprotective Agents/therapeutic use/pharmacology ; Glucagon-Like Peptide-1 Receptor/metabolism ; Alzheimer Disease/drug therapy/metabolism ; Glucagon-Like Peptide-1 Receptor Agonists ; Signal Transduction/drug effects ; },
abstract = {Neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), stroke, and depression, are marked by progressive neuronal dysfunction and loss, yet current treatments remain largely symptomatic with limited disease-modifying efficacy. Glucagon-like peptide-1 (GLP-1), an incretin hormone traditionally associated with metabolic regulation, has emerged as a promising neuroprotective agent. Its receptor, GLP-1R, is expressed in key brain regions implicated in cognition, emotion, and motor control, including the hippocampus, frontal cortex, and substantia nigra. GLP-1R agonists (GLP-1RAs) activate multiple intracellular signaling cascades-cAMP/PKA, PI3K/Akt, and MAPK pathways-that collectively promote neuronal survival, enhance synaptic plasticity, reduce oxidative stress, inhibit apoptosis, and modulate neuroinflammation. These agents also regulate autophagy, promote remyelination, and reprogram microglial phenotypes toward anti-inflammatory states. Preclinical models have shown that GLP-1RAs reduce amyloid-β and tau pathology in AD, preserve dopaminergic neurons in PD, protect astrocytes and neural progenitors after ischemic stroke, and alleviate depressive behaviors. Notably, GLP-1RAs such as liraglutide, exenatide, and dulaglutide can cross the blood-brain barrier and have demonstrated safety and potential efficacy in early-phase clinical trials. These studies report attenuation of cortical atrophy, preservation of cerebral glucose metabolism, and improvements in quality of life, though changes in core AD biomarkers remain inconclusive. Ongoing large-scale trials (e.g., EVOKE, ELAD) are further exploring their therapeutic impact. This review consolidates the mechanistic basis and translational potential of GLP-1RAs in age-related neurodegenerative diseases, highlighting both their promise and the challenges that must be addressed in future clinical applications.},
}

Humans
Animals
*Glucagon-Like Peptide 1/metabolism
*Neurodegenerative Diseases/metabolism/drug therapy/pathology
*Brain/metabolism/pathology/drug effects
*Neuroprotective Agents/therapeutic use/pharmacology
Glucagon-Like Peptide-1 Receptor/metabolism
Alzheimer Disease/drug therapy/metabolism
Glucagon-Like Peptide-1 Receptor Agonists
Signal Transduction/drug effects

@article {pmid41226707,
year = {2025},
author = {Hale, HK and Elias, KM and Ho, S and Kwakye, GF},
title = {Methylene Blue Attenuates 3-Nitropropionic Acid-Induced Oxidative Stress and Mitochondrial Dysfunction in Striatal Cells: Therapeutic Implications in Huntington's Disease Neuropathology.},
journal = {International journal of molecular sciences},
volume = {26},
number = {21},
pages = {},
doi = {10.3390/ijms262110672},
pmid = {41226707},
issn = {1422-0067},
support = {Research and Professional Development Portfolio//Oberlin College Arts and Sciences Dean's Office (GFK)/ ; Endowed Professor Research Portfolio//Robert W. & Eleanor H. Biggs Endowed Professor of Neuroscience (GFK)/ ; },
mesh = {*Oxidative Stress/drug effects ; *Huntington Disease/drug therapy/metabolism/pathology ; *Nitro Compounds/toxicity ; *Propionates/toxicity ; *Methylene Blue/pharmacology ; *Mitochondria/drug effects/metabolism/pathology ; Animals ; *Corpus Striatum/drug effects/metabolism/pathology ; Humans ; Reactive Oxygen Species/metabolism ; *Neuroprotective Agents/pharmacology ; Huntingtin Protein/genetics/metabolism ; Cell Survival/drug effects ; Membrane Potential, Mitochondrial/drug effects ; Mice ; },
abstract = {There are no disease-modifying treatments available for Huntington's disease (HD), a neurodegenerative disease caused by a genetic mutation in the Huntingtin gene. Previous research suggests that disruptions in the bioenergetics of the mitochondria and increased oxidative stress are potential inducers of HD. Therapies that enhance antioxidant pathways intend to target and attenuate the overproduction of reactive oxygen species associated with mitochondrial dysfunction. We have investigated the effect of Methylene Blue (MB) as a potential therapy for HD. MB is a small molecule demonstrated to exhibit neuroprotective effects in other neurodegenerative disease models, including Parkinson's and Alzheimer's, by attenuating the oxidative stress pathways implicated in their pathophysiology. We used an established striatal cell model of HD expressing wild-type (STHdh[Q7/Q7]) or mutant (STHdh[Q111/Q111]) HTT and a chemical inducer of HD, 3-Nitropropionic acid (3-NPA), to determine the HD-specific mechanisms regulated by 3 h of MB pre-treatment. Upon 24 h of exposure to 3-NPA, mutant HD cells exhibited a significant concentration-dependent decrease in cell survival and a concomitant increase in cell death compared to wild-type, confirming that 3-NPA exacerbates mutant HTT neurotoxicity. Examination of mitochondrial membrane potential and mitochondrial function in the striatal cells by JC-1 and ATP assays, respectively, revealed MB mediated neuroprotection against 3-NPA-induced reduction in mitochondrial activity. Immunoblotting analysis revealed that MB restores baseline expression of oxidative-stress-related proteins, including HO1 and p62, in both wild-type and mutant cells exposed to 3-NPA. Our findings establish a novel neuroprotective role of MB in both genetic and pharmacological models of HD, suggesting that MB might be a promising therapeutic candidate for altering the underlying pathophysiology of HD by improving mitochondrial function.},
}

*Oxidative Stress/drug effects
*Huntington Disease/drug therapy/metabolism/pathology
*Nitro Compounds/toxicity
*Propionates/toxicity
*Methylene Blue/pharmacology
*Mitochondria/drug effects/metabolism/pathology
Animals
*Corpus Striatum/drug effects/metabolism/pathology
Humans
Reactive Oxygen Species/metabolism
*Neuroprotective Agents/pharmacology
Huntingtin Protein/genetics/metabolism
Cell Survival/drug effects
Membrane Potential, Mitochondrial/drug effects
Mice

@article {pmid41226670,
year = {2025},
author = {Bayo Jimenez, MT and Rivas-García, L and Sánchez-González, C and Grosso, G and Lipari, V and Vera-Ramírez, L and Battino, M and Giampieri, F and Quiles, JL and Forbes-Hernández, TY},
title = {Natural Products in Alzheimer's Disease: A Systematic Review of Clinical Trials and Underlying Molecular Mechanisms.},
journal = {International journal of molecular sciences},
volume = {26},
number = {21},
pages = {},
doi = {10.3390/ijms262110631},
pmid = {41226670},
issn = {1422-0067},
support = {PID2019-106778RB-I00//MCIN/AEI/10.13039/501100011033 FEDER "Una manera de hacer Europa/ ; Visiting Scholars 2022//Universidad de Granada/ ; },
mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; *Biological Products/therapeutic use/pharmacology ; Clinical Trials as Topic ; *Plant Extracts/therapeutic use/pharmacology ; Cognitive Dysfunction/drug therapy ; *Neuroprotective Agents/therapeutic use/pharmacology ; Aged ; },
abstract = {This systematic review included 31 clinical trial articles examining the effects of natural compounds on Alzheimer's disease (AD) and mild cognitive impairment (MCI), involving 3582 participants aged 50-90. Treatment durations ranged from 8 weeks to 2 years, with an average of 12.5 months. Notably, 11 studies focused on herbal extracts highlighting their prominence in current research. These extracts showed potential cognitive and neuroprotective benefits, although results varied across compounds and study designs. Other natural compounds-including flavonoids, polyphenols, omega-3 fatty acids, Aloe vera, Spirulina, and citrus phytochemicals-may provide cognitive and neuroprotective benefits, with ginseng and Ginkgo biloba combinations also showing promise. Curcumin and Melissa officinalis had limited effects, resveratrol showed mixed outcomes with some side effects, and matcha green tea may improve cognition and sleep quality. Despite generally favorable results, the studies varied considerably in design and quality; nonetheless, herbal extracts represent a prominent category of natural interventions in AD and MCI, underscoring the need for further large-scale, high-quality clinical trials to confirm their therapeutic potential.},
}

*Alzheimer Disease/drug therapy/metabolism
Humans
*Biological Products/therapeutic use/pharmacology
Clinical Trials as Topic
*Plant Extracts/therapeutic use/pharmacology
Cognitive Dysfunction/drug therapy
*Neuroprotective Agents/therapeutic use/pharmacology
Aged

@article {pmid41226605,
year = {2025},
author = {Oliveira, MVB and Garguerra, JA and Lamas, CB and Laurindo, LF and Rodrigues, VD and Sloan, KP and Sloan, LA and Chagas, EFB and Guiguer, EL and Detregiachi, CRP and Miglino, MA and Pereira, ESBM and Valenti, VE and Silva, LR and Barbalho, SM},
title = {Unraveling the Effects of Melissa officinalis L. on Cognition and Sleep Quality: A Narrative Review.},
journal = {International journal of molecular sciences},
volume = {26},
number = {21},
pages = {},
doi = {10.3390/ijms262110566},
pmid = {41226605},
issn = {1422-0067},
mesh = {*Melissa/chemistry ; Humans ; *Cognition/drug effects ; *Plant Extracts/pharmacology/chemistry/therapeutic use ; *Sleep Quality ; Cognitive Dysfunction/drug therapy ; Rosmarinic Acid ; *Sleep/drug effects ; Sleep Wake Disorders/drug therapy ; Quality of Life ; },
abstract = {The aging process is closely linked to cognitive decline, and numerous studies have demonstrated a decrease in both the quality and quantity of sleep in the general population. Melissa officinalis (lemon balm) is a plant rich in bioactive compounds, including flavonoids, phenolic acids, and essential oils, which are responsible for its neuroprotective and antidepressant properties. Its positive effects on the sleep quality are probably, at least in part, attributable to the presence of rosmarinic acid, which modulates γ-aminobutyric acid transaminase activity. This review aimed to investigate the effects of M. officinalis on cognition and sleep quality in human clinical trials. For cognition, studies have shown that the plant improved cognitive performance and mood. In elderly individuals with mild cognitive impairment or early Alzheimer's disease, extracts standardized in rosmarinic acid stabilized cognitive functions and reduced neuropsychiatric symptoms such as agitation. Regarding sleep, a combination of lemon balm and valerian significantly improved sleep quality in postmenopausal women. Isolated lemon balm extracts also reduced sleep disorders in cardiac patients. When compared to citalopram, lemon balm enhanced the quality of life, including sleep quality. It is concluded that lemon balm has the potential to improve cognition and sleep quality; however, robust evidence is needed, as more rigorous trials are required.},
}

*Melissa/chemistry
Humans
*Cognition/drug effects
*Plant Extracts/pharmacology/chemistry/therapeutic use
*Sleep Quality
Cognitive Dysfunction/drug therapy
Rosmarinic Acid
*Sleep/drug effects
Sleep Wake Disorders/drug therapy
Quality of Life

@article {pmid41226604,
year = {2025},
author = {Hu, C and Lin, M and Wang, C and Zhang, S},
title = {Current Understanding of Protein Aggregation in Neurodegenerative Diseases.},
journal = {International journal of molecular sciences},
volume = {26},
number = {21},
pages = {},
doi = {10.3390/ijms262110568},
pmid = {41226604},
issn = {1422-0067},
support = {32170784, 32170707//National Natural Science Foundation of China/ ; },
mesh = {Humans ; *Neurodegenerative Diseases/metabolism/therapy/pathology ; Animals ; *Protein Aggregates ; *Protein Aggregation, Pathological/metabolism ; Autophagy ; Protein Folding ; },
abstract = {Protein aggregates are central to the pathogenesis of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. This comprehensive review explores the mechanisms of protein misfolding and aggregation, their prion-like propagation, and the critical role of oligomeric species in neurotoxicity. It further examines cellular clearance pathways, including the ubiquitin-proteasome system and autophagy, alongside the regulatory functions of molecular chaperones. The review also covers advanced diagnostic imaging and biomarker techniques, as well as emerging therapeutic strategies such as pharmacological agents, gene therapy, and immunotherapy. Controversies regarding the toxicity of aggregates and future directions, including novel degradation technologies and targeted therapeutic approaches, are discussed. By integrating current knowledge, this review aims to provide a broad yet detailed overview of the field, highlighting both established concepts and promising avenues for research and treatment.},
}

Humans
*Neurodegenerative Diseases/metabolism/therapy/pathology
Animals
*Protein Aggregates
*Protein Aggregation, Pathological/metabolism
Autophagy
Protein Folding

@article {pmid41226584,
year = {2025},
author = {Costea, D and Dobrin, N and Tataru, CI and Toader, C and Șerban, M and Covache-Busuioc, RA and Munteanu, O and Diaconescu, IB},
title = {The Glymphatic-Venous Axis in Brain Clearance Failure: Aquaporin-4 Dysfunction, Biomarker Imaging, and Precision Therapeutic Frontiers.},
journal = {International journal of molecular sciences},
volume = {26},
number = {21},
pages = {},
doi = {10.3390/ijms262110546},
pmid = {41226584},
issn = {1422-0067},
mesh = {Humans ; *Glymphatic System/metabolism/diagnostic imaging ; *Aquaporin 4/metabolism ; Biomarkers/metabolism ; Animals ; *Brain/metabolism/diagnostic imaging/blood supply ; *Neurodegenerative Diseases/metabolism/therapy/diagnostic imaging ; Precision Medicine ; },
abstract = {The identification of brain clearance failure as a precursor to a large variety of neurodegenerative diseases has shifted fluid dynamics from a secondary to a tertiary target of brain health. The identification of the glymphatic system, detailing cerebrospinal fluid entry along perivascular spaces and exit via perivenous and meningeal lymphatic pathways, provided a challenge to previous diffusion models and established aquaporin-4-dependent astroglial polarity as a governing principle of solute transport. Multiple lines of evidence now support a coupled glymphatic-venous axis, wherein vasomotion, venous outflow, and lymphatic drainage are functionally interrelated. Failure of any axis will cascade and affect the entire axis, linking venous congestion, aquaporin-4 disassembly, and meningeal lymphatic failure to protein aggregation, neuroinflammation, edema, and intracranial hypertension. Specific lines of evidence from diffusion tensor imaging along vascular spaces, clearance MRI, and multi-omic biomarkers can provide a measure of transport. Therapeutic strategies are rapidly advancing from experimental strategies to translational approval, including behavioral optimization, closed-loop sleep stimulation, vascular and lymphatic therapies, focused ultrasound, pharmacological polarity recoupling, and regenerative bioengineering. Novel computational approaches, such as digital twin dynamic modeling and adaptive trial designs, suggest that clearance measures may serve as endpoints to be approved by the FDA. This review is intended to bridge relevant mechanistic and translational reviews, focusing on impaired clearance as an exploitable systems defect rather than an incapacitating secondary effect. Improving our understanding of the glymphatic-venous axis Injury may lead to future target strategies that advance cognitive resilience, alleviate disease burden, and improve quality of life. By clarifying the glymphatic-venous axis, we provide a mechanistic link between impaired interstitial clearance and the pathological accumulation of amyloid-β, tau, and α-synuclein in neurodegenerative diseases. The repair of aquaporin-4 polarity, venous compliance, and lymphatic drainage might therefore open new avenues for the diagnosis and treatment of Alzheimer's and Parkinson's disease, supplying both biomarkers of disease progression and new targets for early intervention. These translational implications not only locate clearance failure as an epiphenomenon of neurodegeneration but, more importantly, as a modifiable driver of the course of neurodegeneration.},
}

Humans
*Glymphatic System/metabolism/diagnostic imaging
*Aquaporin 4/metabolism
Biomarkers/metabolism
Animals
*Brain/metabolism/diagnostic imaging/blood supply
*Neurodegenerative Diseases/metabolism/therapy/diagnostic imaging
Precision Medicine

@article {pmid41226373,
year = {2025},
author = {Kim, KY and Shin, KY and Chang, KA},
title = {Blood-Based Tau as a Biomarker for Early Detection and Monitoring of Alzheimer's Disease: A Systematic Review and Meta-Analysis.},
journal = {International journal of molecular sciences},
volume = {26},
number = {21},
pages = {},
doi = {10.3390/ijms262110330},
pmid = {41226373},
issn = {1422-0067},
support = {RS-2022-NR069987//National Research Foundation of Korea/ ; RS-2024-00338662//Korea Dementia Research Center(KDRC)/ ; RS-2025-02292973//Korea Institute of Marine Science and Technology Promotion(KIMST)/ ; },
mesh = {*tau Proteins/blood ; *Alzheimer Disease/blood/diagnosis ; Humans ; *Biomarkers/blood ; Early Diagnosis ; Positron-Emission Tomography ; Cognitive Dysfunction/blood ; },
abstract = {Alzheimer's disease (AD), the most prevalent form of dementia, is a progressive neurodegenerative disorder characterized by cognitive decline and memory loss, ultimately leading to loss of independence and reduced quality of life. Since current treatments are most effective in early stages, the development of reliable and noninvasive biomarkers for early diagnosis and monitoring is crucial. Abnormal tau protein aggregation is a key pathological hallmark of AD, disrupting neuronal integrity, accelerating progression, and associating closely with cognitive decline and the transition to mild cognitive impairment, a prodromal stage of AD. Currently, tau pathology is evaluated mainly by cerebrospinal fluid analysis and tau positron emission tomography (tau PET), which are invasive or costly, limiting their clinical applicability. This systematic review and meta-analysis synthesized evidence on tau as a blood-based biomarker for dementia, with emphasis on its relationship to tau PET, the gold standard for in vivo tau assessment. Findings indicate that elevated plasma tau levels such as p-tau181, p-tau217 and p-tau231 consistently reflect brain tau pathology, supporting their role as surrogate markers. Large-scale longitudinal validation is warranted to establish blood-based tau as a practical, accessible tool for early detection and disease monitoring, thereby improving therapeutic outcomes in AD.},
}

*tau Proteins/blood
*Alzheimer Disease/blood/diagnosis
Humans
*Biomarkers/blood
Early Diagnosis
Positron-Emission Tomography
Cognitive Dysfunction/blood

@article {pmid41226363,
year = {2025},
author = {Thakur, B and Tarazi, S and Doležalová, L and Behbahani, H and Darreh-Shori, T},
title = {Comparative Analysis of Cholinergic Machinery in Carcinomas: Discovery of Membrane-Tethered ChAT as Evidence for Surface-Based ACh Synthesis in Neuroblastoma Cells.},
journal = {International journal of molecular sciences},
volume = {26},
number = {21},
pages = {},
doi = {10.3390/ijms262110311},
pmid = {41226363},
issn = {1422-0067},
support = {//Åhlén-Foundation/ ; //Frimurarna Foundation/ ; //Ulla-Carin Linquist Foundation for ALS research/ ; AARG-24-1310046//Alzheimer´s Association/ ; //Dementia Foundation (Demensfonden)/ ; //Foundation for Old Servants (Gamla Tjänarinnor)/ ; //Karolinska Institutet´s Research Foundations/ ; //Olle Engkvist Byggmästare Foundation/ ; //Magnus Bergvalls Foundation/ ; //Gun and Bertil Stohnes Foundation/ ; ALF Med N 20200330//grant from the Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement/ ; #CAN2021/1469, and # 24 3793//the Swedish Cancer Society/ ; #221212, #241282 and #221383//the Stockholm Cancer Society/ ; },
mesh = {Humans ; *Neuroblastoma/metabolism/pathology ; *Acetylcholine/biosynthesis/metabolism ; Cell Line, Tumor ; *Choline O-Acetyltransferase/metabolism ; Choline/metabolism ; Cell Membrane/metabolism ; Acetylcholinesterase/metabolism ; Butyrylcholinesterase/metabolism ; Signal Transduction ; },
abstract = {The cholinergic system is one of the most ancient and widespread signaling systems in the body, implicated in a range of pathological conditions-from neurodegenerative disorders to cancer. Given its broad relevance, there is growing interest in characterizing this system across diverse cellular models to enable drug screening, mechanistic studies, and exploration of new therapeutic avenues. In this study, we investigated four cancer cell lines: one of neuroblastoma origin previously used in cholinergic signaling studies (SH-SY5Y), one non-small cell lung adenocarcinoma line (A549), and two small cell lung carcinoma lines (H69 and H82). We assessed the expression and localization of key components of the cholinergic system, along with the cellular capacity for acetylcholine (ACh) synthesis and release. Whole-cell flow cytometry following membrane permeabilization revealed that all cell lines expressed the ACh-synthesizing enzyme choline acetyltransferase (ChAT). HPLC-MS analysis confirmed that ChAT was functionally active, as all cell lines synthesized and released ACh into the conditioned media, suggesting the presence of autocrine and/or paracrine ACh signaling circuits, consistent with previous reports. The cell lines also demonstrated choline uptake, indicative of functional choline and/or organic cation transporters. Additionally, all lines expressed the ACh-degrading enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), as well as the alfa seven (α7) nicotinic and M1 muscarinic ACh receptor subtypes. Notably, flow cytometry of intact SH-SY5Y cells revealed two novel findings: (1) ChAT was localized to the extracellular membrane, a feature not observed in the lung cancer cell lines, and (2) BChE, rather than AChE, was the predominant membrane-bound ACh-degrading enzyme. These results were corroborated by both whole-cell and surface-confocal microscopy. In conclusion, our findings suggest that a functional cholinergic phenotype is a shared feature of several carcinoma cell lines, potentially serving as a survival checkpoint that could be therapeutically explored. The discovery of extracellular membrane-bound ChAT uniquely in neuroblastoma SH-SY5Y cells points to a novel form of in situ ACh signaling that warrants further investigation.},
}

Humans
*Neuroblastoma/metabolism/pathology
*Acetylcholine/biosynthesis/metabolism
Cell Line, Tumor
*Choline O-Acetyltransferase/metabolism
Choline/metabolism
Cell Membrane/metabolism
Acetylcholinesterase/metabolism
Butyrylcholinesterase/metabolism
Signal Transduction

@article {pmid41226260,
year = {2025},
author = {Cutter, LR and Ren, AR and Banerjee, IA},
title = {Advances in Naturally and Synthetically Derived Bioactive Sesquiterpenes and Their Derivatives: Applications in Targeting Cancer and Neurodegenerative Diseases.},
journal = {Molecules (Basel, Switzerland)},
volume = {30},
number = {21},
pages = {},
pmid = {41226260},
issn = {1420-3049},
support = {N/A//Henry Luce Foundation/ ; N/A//Fordham University/ ; },
mesh = {Humans ; *Sesquiterpenes/chemistry/pharmacology/therapeutic use/chemical synthesis ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Neoplasms/drug therapy/metabolism ; Animals ; *Biological Products/chemistry/pharmacology/therapeutic use ; *Antineoplastic Agents/pharmacology/chemistry ; Antioxidants/chemistry/pharmacology ; },
abstract = {Sesquiterpenes are a diverse class of natural products that have garnered considerable interest for their potent bioactivity and structural variability. This review highlights advances in the derivatization of various sesquiterpene lactones, quinones, and alcohols, particularly in targeting cancer and neurodegenerative diseases. The structural modifications discussed include the incorporation of triazole, arylidene, or thiol moieties with eudesmane, guaiane, and germacranolide-type sesquiterpenes, among others. In addition, the conjugation with chemotherapeutics, as well as the development of nanoscale therapeutics, is also discussed. Such modifications have expanded the pharmacological potential, enabling improved specificity, cytotoxicity profiles, and sensitization toward tumor cells. Additionally, sesquiterpenes such as parthenolide (20), pterosinsade A (176), and cedrol (186) have demonstrated potential in mitigating neurodegeneration via anti-inflammatory and antioxidant signaling pathway-modulation mechanisms, with potential applications in Alzheimer's, Parkinson's, and ALS diseases. Mechanistic insights into redox signaling modulation, NF-κB inhibition, ROS regulation, and disruption of aggregation underscore their multifaceted modes of action. This review highlights the translational promise of sesquiterpene derivatives as dual-action agents for potential drug development in a plethora of diseases that are caused by inflammation and free-radical damage. It provides a framework for future rational design of multifunctional drug candidates and therapeutics.},
}

Humans
*Sesquiterpenes/chemistry/pharmacology/therapeutic use/chemical synthesis
*Neurodegenerative Diseases/drug therapy/metabolism
*Neoplasms/drug therapy/metabolism
Animals
*Biological Products/chemistry/pharmacology/therapeutic use
*Antineoplastic Agents/pharmacology/chemistry
Antioxidants/chemistry/pharmacology

@article {pmid41226231,
year = {2025},
author = {Ananda, SH and Kuragano, M and Tokuraku, K},
title = {Elucidation of the Neuroprotective Effects of Astaxanthin Against Amyloid β Toxicity in the SH-SY5Y Human Neuroblastoma Cell Line.},
journal = {Molecules (Basel, Switzerland)},
volume = {30},
number = {21},
pages = {},
pmid = {41226231},
issn = {1420-3049},
support = {SUNBOR GRANT//Suntory Foundation for Life Sciences/ ; JPMJPF2213//Japan Science and Technology Agency/ ; JP24K08627//JSPS KAKENHI/ ; },
mesh = {Humans ; Xanthophylls/pharmacology/chemistry ; *Amyloid beta-Peptides/metabolism/toxicity ; *Neuroprotective Agents/pharmacology ; Cell Line, Tumor ; *Neuroblastoma/metabolism/pathology/drug therapy ; Apoptosis/drug effects ; Cell Movement/drug effects ; Cell Survival/drug effects ; Alzheimer Disease/drug therapy/metabolism ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by memory loss and cognitive decline, primarily due to amyloid β (Aβ) aggregation in the brain. Astaxanthin (AxN), a xanthophyll carotenoid derived from Haematococcus pluvialis, possesses antioxidant and neuroprotective properties. This study investigated the neuroprotective effects of AxN against Aβ aggregation in human neuroblastoma SH-SY5Y cells. Initially, AxN inhibited Aβ aggregation in DMEM/F12 culture medium but not in PBS, suggesting a medium-dependent effect. Using quantum dot nanoprobes, Aβ aggregation was visualized in the presence of SH-SY5Y cells. AxN treatment (0.032-20 µM) significantly reduced Aβ aggregation and accumulation on SH-SY5Y cells. AxN also prevented Aβ-induced early apoptotic cell death but was less effective against late necrosis. Furthermore, a wound-healing assay showed that AxN restored the impaired cell motility caused by Aβ aggregation. Thioflavin T staining confirmed the reduction in Aβ fibril formation around the cells following AxN treatment. In conclusion, our study suggests that AxN prevents Aβ aggregation and accumulation on the cell surface, thereby restoring cell motility and preventing early apoptosis in neuronal cells.},
}

Humans
Xanthophylls/pharmacology/chemistry
*Amyloid beta-Peptides/metabolism/toxicity
*Neuroprotective Agents/pharmacology
Cell Line, Tumor
*Neuroblastoma/metabolism/pathology/drug therapy
Apoptosis/drug effects
Cell Movement/drug effects
Cell Survival/drug effects
Alzheimer Disease/drug therapy/metabolism

@article {pmid41226162,
year = {2025},
author = {Gambardella, MD and Wang, Y and Pang, J},
title = {The Selectivity of Butyrylcholinesterase Inhibitors Revisited.},
journal = {Molecules (Basel, Switzerland)},
volume = {30},
number = {21},
pages = {},
pmid = {41226162},
issn = {1420-3049},
mesh = {*Butyrylcholinesterase/metabolism/chemistry ; *Cholinesterase Inhibitors/chemistry/pharmacology/therapeutic use ; Humans ; *Alzheimer Disease/drug therapy/metabolism/enzymology ; Acetylcholinesterase/metabolism/chemistry ; Animals ; Amyloid beta-Peptides/metabolism ; },
abstract = {Acetylcholinesterase (AChE) inhibitors are the primary target for single-molecule anti-Alzheimer's disease (AD) therapeutics. Though AChE has historically been the focus of investigation for small-molecule inhibitors, interest in another cholinergic enzyme, butyrylcholinesterase (BChE), has grown in recent years. Attention stems from BChE's role in β-amyloid (Aβ) protein aggregation and an increase in BChE concentration during the late stages of AD, where a decrease in AChE concentration is also observed. Currently, five FDA-approved drugs are on the market for inhibiting AChE, though no BChE-selective drugs have been approved so far. In this review, we focus on newly identified BChE selective inhibitors and present the ideas behind these discoveries.},
}

*Butyrylcholinesterase/metabolism/chemistry
*Cholinesterase Inhibitors/chemistry/pharmacology/therapeutic use
Humans
*Alzheimer Disease/drug therapy/metabolism/enzymology
Acetylcholinesterase/metabolism/chemistry
Animals
Amyloid beta-Peptides/metabolism