@article {pmid41263427,
year = {2025},
author = {Wang, Y and Wang, Y and Zhang, W and Xu, Y and Narayan, NS and Cheng, H and Yang, H and Huang, Y and Zhang, C and Wang, C},
title = {Development of a Novel PET Radioligand Targeting PKM2 for Brain Imaging and Alzheimer's Disease Characterization.},
journal = {Journal of medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jmedchem.5c02549},
pmid = {41263427},
issn = {1520-4804},
abstract = {Targeting pyruvate kinase M2 (PKM2) offers a route to probe neuroinflammatory metabolism in Alzheimer's disease (AD). We report the radiosynthesis and preclinical evaluation of a PKM2-targeted PET radioligand, [[11]C]7d. [[11]C]7d was produced in 21.6-29.4% decay-corrected yield from trapped [[11]C]CH3I with >95% radiochemical purity. Whole-body PET (0-60 min) indicated predominantly hepatobiliary clearance with modest renal excretion. In wild-type mice, [[11]C]7d showed rapid brain entry followed by washout consistent with reversible kinetics. Pharmacological pretreatment with 7d reduced whole-brain AUC, indicating displaceable binding. Ex vivo autoradiography showed a 62.8% signal reduction with 7d and ∼20.1% higher binding in 5xFAD versus NonTg sections. In vivo, 5xFAD mice displayed higher uptake; cerebellum normalized SUVR(20-60 min) increased across multiple regions. PKM2 immunohistochemistry supported regional target engagement. These data support [[11]C]7d as a tool for noninvasive visualization of PKM2-linked glycolytic alterations in the living brain and motivate further quantitative and translational studies.},
}

@article {pmid41263380,
year = {2025},
author = {Haciosmanoglu Aldogan, E and Elibol, B and Korkmaz, ND and Karakayali, ZC and Yildiz, GB},
title = {Plasma Levels of Chitinase 3-Like 1 Protein Increase in Patients With Neurodegenerative Diseases: A Small Cohort Study.},
journal = {Geriatrics & gerontology international},
volume = {},
number = {},
pages = {},
doi = {10.1111/ggi.70253},
pmid = {41263380},
issn = {1447-0594},
abstract = {INTRODUCTION: Neuroinflammation, widely regarded as a chronic inflammatory response of the central nervous system, is thought to be a key player in the initiation of neurodegeneration. While there is a great effort in finding useful biomarkers for early detection of neurodegenerative diseases such as Alzheimer's disease (AD) or Parkinson's disease (PD), a precise biomarker capable of elucidating the disease progression and effectiveness of therapeutic interventions is needed.

METHODS: The plasma NLRP3, ASC, IL-1β, IL-6, IL-10, and CHI3L1 levels were measured in control subjects and patients with AD and PD by ELISA to evaluate whether these molecules can be biomarkers with a high diagnostic power.

RESULTS: While there is no significant difference in the levels of NLRP3, ASC, IL-1β, and IL-10, CHI3L1 was significantly elevated in the AD and PD patients compared to the healthy controls. In addition, in AD patients, IL-6 levels significantly increased and there was a positive correlation between IL-6 and CHI3L1 levels. In the PD patients, there was a negative correlation between IL-6 and CHI3L1. According to the ROC curves, the levels of CHI3L1 had better sensitivity and specificity than other parameters to distinguish AD and PD.

CONCLUSION: In summary, our results indicated that plasma CHI3L1 level can be useful as one of the biomarkers in AD and PD patients.},
}

@article {pmid41263026,
year = {2025},
author = {},
title = {Correction to "TNEA Regulates Hippocampal Oscillation by Improving Inhibitory Synaptic Plasticity to Ameliorates Cognitive Impairment in Alzheimer's disease".},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e21837},
doi = {10.1002/advs.202521837},
pmid = {41263026},
issn = {2198-3844},
}

@article {pmid41262942,
year = {2025},
author = {Pfutzenreuter, KC and Losada-Baltar, A and Márquez-González, M and Falcão, DVDS},
title = {Psychometric properties of the Brazilian version of the "Caregiver Guilt Questionnaire" (CGQ-BR).},
journal = {Dementia & neuropsychologia},
volume = {19},
number = {},
pages = {e20250325},
pmid = {41262942},
issn = {1980-5764},
abstract = {UNLABELLED: The "Caregiver Guilt Questionnaire" CGQ was originally developed in Spain and contains 22 self-report items covering the following factors: guilt about doing wrong by the care recipient, guilt about failing to meet the challenges of caregiving, guilt about self-care, guilt over feeling negative emotions while caregiving, and guilt about neglecting other relatives.

OBJECTIVE: To analyze the psychometric properties of the Brazilian version of the CGQ.

METHODS: The sample was established for convenience, consisting of 153 family caregivers of people with Alzheimer's disease. The following measures were applied: a sociodemographic questionnaire, the CGQ, the Depression, Anxiety and Stress Scale (DASS-21), and the Life Satisfaction Scale. An exploratory factor analysis was performed for analyzing construct validity to obtain evidence of validity with internal structure and external correlation measures.

RESULTS: The exploratory factor analysis identified five factors with 22 items, which explained 71% of the total variance. Criterion validity was supported by positive associations between CGQ-BR scores and levels of depression, anxiety, and stress, and a negative association with life satisfaction. Good to excellent reliability indexes were found for the total score and subscales.

CONCLUSION: The psychometric properties of the CGQ-BR, when applied to a sample of family caregivers of people with Alzheimer's disease in the Brazilian population, proved to be a valid tool for measuring feelings of guilt. The findings suggest that this tool can be used in clinical and research settings with caregivers.},
}

@article {pmid41262771,
year = {2025},
author = {Fonseca, LM and Queiroz, UT and Queiroz, MT and Forlenza, OV},
title = {Inclusive research with individuals with Down syndrome at risk for dementia.},
journal = {Dementia & neuropsychologia},
volume = {19},
number = {Suppl 1},
pages = {e20240280},
pmid = {41262771},
issn = {1980-5764},
abstract = {Inclusive research is a relatively new concept that has received attention in recent years as a scientific priority to respond to health disparities and maximize the practical implications of research. This approach involves a partnership between academics and the individuals who are experiencing the problem to be investigated. Despite the high incidence of dementia and asymptomatic Alzheimer's disease in aging individuals with Down syndrome, inclusive research with this population or those with intellectual disability (ID) at risk of dementia is an area that is little approached and not well documented. Here, we describe the evolution of inclusive research on ID and dementia, some of the challenges and benefits of its implementation, and key aspects to consider when planning such studies. There is an urgent need for national and international guidelines to support inclusive research involving this population. Such frameworks should ensure accessibility, ethical rigor, the meaningful participation of co-researchers, ultimately advancing equity and scientific quality in this underrepresented field.},
}

@article {pmid41262682,
year = {2025},
author = {Romano, RR and Roby, D and Wilhoite, S and Velez, M and Jefferson, AL and Bolton, CJ},
title = {Developing educational materials to aid in Alzheimer's blood biomarker disclosure.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {11},
number = {4},
pages = {e70182},
pmid = {41262682},
issn = {2352-8737},
abstract = {INTRODUCTION: A crucial step before clinical use of Alzheimer's disease (AD) blood biomarkers is the development of effective methods for disclosing results. This mixed-method study developed educational materials to disclose the dementia risk based on plasma phosphorylated tau (p-tau) results.

METHODS: Participants diagnosed with mild cognitive impairment (MCI; n = 8) and their care partners (n = 7) participated in focus groups discussing the utility of an educational tool and communication preferences. Focus groups were recorded, transcribed, and analyzed using NVivo, with two independent coders conducting thematic analysis.

RESULTS: Participants rated the materials highly regarding value and comprehension. Thematic analysis revealed confusion about dementia progression and terminology. Participants preferred varied communication modes. Participants found utility in these materials but sought additional information on risk reduction.

DISCUSSION: These findings highlight the utility of educational materials to aid in the disclosure of AD dementia risk based on plasma p-tau to individuals with MCI and their loved ones.

HIGHLIGHTS: Individuals with mild cognitive impairment (MCI) find value in receiving blood biomarker results.Additional risk reduction information is helpful when communicating dementia risk.Individuals prefer medical information communicated visually.},
}

@article {pmid41262573,
year = {2025},
author = {Demsey, LL and Burch, D and Lin, E and Quach, D and Podvin, S and Boyarko, B and Levey, AI and Weinshenker, D and Edland, S and Galasko, D and Jacobs, H and Bang, A and Neil, A and Silverman, J and Feldman, HH and Hook, V},
title = {Atomoxetine Drug Properties for Repurposing as a Candidate Alzheimer's Disease Therapeutic Agent.},
journal = {ACS pharmacology & translational science},
volume = {8},
number = {11},
pages = {3757-3772},
pmid = {41262573},
issn = {2575-9108},
abstract = {Ongoing Alzheimer's disease (AD) drug development research addresses the need for therapeutic agents that can ameliorate cognitive symptoms and attenuate the course of AD synaptic deficits and neurodegeneration. There is growing interest in evaluating FDA-approved drugs for repurposing as candidate AD therapeutics. Such drugs have the advantage that data are available about their pharmaceutical properties, including doses, pharmacokinetics, pharmacodynamics, biomarkers, metabolism, and safety, to inform the design of clinical drug trials. Importantly, the suitability of such drugs with properties needed for AD requires evaluation. In the early stage of AD, degeneration of the locus coeruleus (LC) brain region results in the reduction of noradrenergic neurons and the loss of the neurotransmitter norepinephrine (NE) that regulates cognition and degeneration. Elevation of extracellular NE through inhibition of the NE transporter (NET) is hypothesized to ameliorate AD deficits. Notably, the NET reuptake inhibitor atomoxetine, an FDA-approved drug for the treatment of attention deficit hyperactivity disorder (ADHD), provides an attractive candidate as an AD therapeutic agent because it may attenuate cognitive decline in AD patients, positively impact AD biomarkers, and reduce neuropathology. The goal of this review is to assess atomoxetine for repurposing in AD based on its ability to improve cognition, regulate NE, impact AD biomarkers, and preserve LC neuronal function, with suitable pharmacokinetics, drug metabolism, and safety based on analysis of clinical and preclinical studies. Evidence for neuroprotective effects of atomoxetine in the early stage of AD at clinically safe doses with suitable pharmaceutical properties supports its candidacy as a repurposed drug for AD therapeutics.},
}

@article {pmid41262391,
year = {2025},
author = {Latella, D and Calderone, A and Casella, C and De Luca, R and Gangemi, A and Impellizzeri, F and Caliri, S and Quartarone, A and Calabrò, RS},
title = {Cognitive behavioral therapy for insomnia in neurodegenerative disorders-targeting sleep disturbances in Alzheimer's and Parkinson's disease: a scoping review.},
journal = {Frontiers in psychology},
volume = {16},
number = {},
pages = {1700496},
pmid = {41262391},
issn = {1664-1078},
abstract = {INTRODUCTION: Insomnia is highly prevalent in neurodegenerative disorders, yet pharmacological options carry safety and tolerability concerns. This scoping review mapped contemporary evidence for cognitive behavioral therapy for insomnia (CBT-I) across Alzheimer's disease (AD), mild cognitive impairment (MCI), and Parkinson's disease (PD).

METHODS: Following a preregistered protocol (OSF DOI: 10.17605/OSF.IO/8VP3F), we searched PubMed, Cochrane Library, Web of Science, and Scopus for studies published 2015-2025. We screened English-language studies in adults and applied dual independent review with consensus resolution. Of 105 records, 70 were screened after de-duplication, and 8 met eligibility criteria.

RESULTS: Across randomized trials, pilot and feasibility studies, and single-case experimental designs, CBT-I-delivered in person or via telehealth-consistently reduced insomnia severity and improved sleep quality, with frequent ancillary gains in mood, anxiety, and daytime functioning. Remote and digitally augmented delivery appeared feasible and acceptable for cognitively vulnerable adults and caregivers. Early signals suggested potential cognitive benefits in prodromal populations (AD/MCI), and exploratory observations linked improved sleep with plausible neurobiological mechanisms such as amyloid-beta dynamics. In PD, findings aligned with a mechanistic pathway in which presleep cognitive arousal, safety behaviors, and dysfunctional sleep beliefs are modifiable targets. Non-pharmacological comparators (e.g., mindfulness, therapeutic exercise, neuromodulation) also showed benefits, helping contextualize where CBT-I may offer disorder-relevant leverage on insomnia outcomes.

DISCUSSION: The overall strength of evidence is tempered by small samples, heterogeneity in comparators and dosing, short follow-up, and inconsistent reporting of clinically meaningful change. Priorities include multicenter randomized trials with standardized sleep and cognitive endpoints, longer observation, head-to-head comparative effectiveness with economic evaluation, adaptive protocols tailored to PD-specific disruptors, and mechanistic studies integrating digital phenotyping and biomarkers to test durability and downstream clinical impact.},
}

@article {pmid41262332,
year = {2025},
author = {Rahm, KK and Kinghorn, BS and Moody, MJ and Stone, BC and Strong, KC and Kim, BS and Chang, YJ and Sleight, SN and Nitz, AA and Hansen, DV and Bailey, MH},
title = {Cellf-deception: human microglia clone 3 (HMC3) cells exhibit more astrocyte-like than microglia-like gene expression.},
journal = {Frontiers in bioinformatics},
volume = {5},
number = {},
pages = {1681811},
pmid = {41262332},
issn = {2673-7647},
abstract = {INTRODUCTION: Recent advances in Alzheimer's research suggest that the brain's immune system plays a critical role in the development and progression of this devastating disease. Microglial cells are vital as immune cells in the brain's defense system. Human Microglia Clone 3 (HMC3) is a cell line developed as a promising experimental model to understand the role of microglial cells in human diseases including Alzheimer's and other neurodegenerative diseases. The frequency of HMC3 cell usage has increased in recent years, with the idea that this cell line could serve as a convenient model for human microglial cell functions.

METHODS: We utilized gene-pair ratios from bulk and single-cell RNA sequencing (scRNA-seq) expression data to create predictive models of cell-type origins.

RESULTS: Our model reveals that the HMC3 cell line represents various cell types, with the highest cell similarity score relating to astrocytes, not microglia.

DISCUSSION: These findings suggest that the HMC3 cell line is not a reliable human microglia model and that extreme caution should be taken when interpreting the results of studies using the HMC3 cell line.},
}

@article {pmid41262225,
year = {2025},
author = {Bayram, E},
title = {Sex and gender differences in Lewy body dementia: a narrative review.},
journal = {Equity neuroscience},
volume = {1},
number = {2},
pages = {},
pmid = {41262225},
issn = {3050-8401},
abstract = {Lewy body dementia (LBD), including Parkinson's disease dementia and dementia with Lewy bodies, is one of the most prevalent and burdensome type of dementias. Clinical diagnostic accuracy during life remains limited and there are currently only symptomatic therapy options without disease modification. However, recent advances in biomarkers and clinical trials are promising. Literature so far showed sex and gender differences in older adults without cognitive changes, people with all-cause dementia, Alzheimer's disease, and Parkinson's disease. While the number of studies in LBD are lower, understanding sex and gender differences and the underlying reasons can improve both diagnosis and treatment for LBD. Accordingly, the aim of this narrative review is to provide a summary of the literature for sex and gender differences in LBD. Majority of the studies for LBD investigating sex/gender differences so far focused on sex, with sex and gender terms being misused at times. Experiences of people in non-binary categories for sex or gender have yet to be investigated. While more research is needed, findings so far outline sex differences in prevalence, risk factors, biomarkers, symptoms, progression, treatment, daily life, and pathology for LBD. Sex-specific risk factors have also been reported, emphasizing the value of sex-stratified analyses and investigating female/male-specific factors such as sex hormones, menopause, and sex chromosomes. Lack of adequate research representation for females and women, as well as people from non-binary categories, is an important limitation that should be addressed to obtain more applicable findings in LBD.},
}

@article {pmid41262081,
year = {2025},
author = {Jamalinia, M and Zare, F and Lonardo, A},
title = {Liver Fibrosis and Risk of Incident Dementia in the General Population: Systematic Review With Meta-Analysis.},
journal = {Health science reports},
volume = {8},
number = {11},
pages = {e71530},
pmid = {41262081},
issn = {2398-8835},
abstract = {BACKGROUND AND AIMS: The relationship between liver fibrosis and the risk of developing dementia remains unclear, with studies yielding inconsistent results. This systematic review and meta-analysis seek to synthesize the available evidence.

METHODS: We systematically searched PubMed, Scopus, Embase, and Web of Science from their respective inception through October 2024 to identify observational studies diagnosing liver fibrosis non-invasively or via histology. The primary outcome was new-onset dementia. Risk of bias was evaluated using the Newcastle-Ottawa Scale (NOS), and pooled estimates of hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using a random-effects model.

RESULTS: Eight longitudinal cohorts, including 1,115,759 middle-aged individuals (31,129 with liver fibrosis at baseline), identified 29,923 new dementia cases over a mean follow-up of 14 years. Liver fibrosis exhibited a 32% increased risk of developing all-cause dementia (pooled HR: 1.32, 95% CI: 1.08-1.61; I² = 76.06%). Dementia risk increased with fibrosis severity: HR 1.06 (95% CI: 0.67-1.68) in ≥F2, HR 1.32 (95% CI: 1.06-1.64) in ≥F3, and HR 1.69 (95% CI: 1.01-2.83) in F4. Geographically, the risk appeared higher in Western than Eastern countries. Women had a greater risk, and vascular dementia was more strongly associated with fibrosis than Alzheimer's disease. Sensitivity analyses confirmed the robustness of the findings, and no publication bias was observed.

CONCLUSION: Liver fibrosis is linked to a 32% increased long-term dementia risk, independent of common demographic, social, anthropometric, and cardiometabolic factors. Fibrosis severity further increases this risk. Based on our findings, healthcare professionals should recognize the moderately increased risk of developing dementia in individuals with liver fibrosis and perform close surveillance of these patients to enable early detection and timely intervention.},
}

@article {pmid41261930,
year = {2025},
author = {Sutnikiene, V and Pakulaite-Kazliene, G and Audronyte, E and Kuzmickaite, J and Kaubrys, G},
title = {Time/Movement Estimation and Mental Rotation Tasks as Early Cognitive Markers in Alzheimer's Disease.},
journal = {Brain and behavior},
volume = {15},
number = {11},
pages = {e71077},
doi = {10.1002/brb3.71077},
pmid = {41261930},
issn = {2162-3279},
mesh = {Humans ; *Alzheimer Disease/diagnosis/physiopathology/psychology ; Male ; Female ; Aged ; Cross-Sectional Studies ; *Cognitive Dysfunction/diagnosis/physiopathology ; Neuropsychological Tests ; *Time Perception/physiology ; Aged, 80 and over ; Middle Aged ; Rotation ; Cognition/physiology ; },
abstract = {INTRODUCTION: Cognitive impairments, including memory decline and executive dysfunction, are well-documented in Alzheimer's disease (AD); however, distortions in temporal judgment, motion perception and mental rotation in the early stages remain underexplored. Existing research has predominantly relied on verbal time-estimation tasks, with a limited investigation into alternative paradigms, such as time reproduction or bisection tasks. This study investigated the diagnostic utility of time-movement estimation and mental rotation tasks from the psychology experiment building language (PEBL) test battery for identifying early cognitive impairment. Moreover, it assessed correlations among task performance, cognitive test scores, and demographic variables.

METHODS: This cross-sectional study included 28 patients with mild dementia (MD), 27 with amnestic mild cognitive impairment (MCI), and 26 with normal cognitive function as the control cohort (CC). Participants completed the mini-mental state examination, clinical dementia rating assessments, Alzheimer's disease assessment scale-cognitive subscale 13 (ADAS-Cog 13), and PEBL-based Time-Wall and mental rotation tasks.

RESULTS: Time-Wall task inaccuracy scores exhibited strong diagnostic accuracy in distinguishing between the CC and early AD (MCI and MD), with an AUC of 0.9, and effectively differentiated CC from MCI, with an AUC of 0.86. Conversely, the mental rotation task exhibited weaker diagnostic properties, with AUC values of 0.75 for distinguishing CC from early AD and 0.71 for distinguishing CC from MCI. The multinomial logistic regression model accurately categorized 75.3% of participants (CC = 92.3%, MCI = 59.3%, and MD = 75%), utilizing demographic data and ADAS-Cog 13 and Time-Wall inaccuracy scores as predictors. Both ADAS-Cog 13 and Time-Wall task inaccuracy scores were statistically significant predictors (X[2] = 49.41, p < 0.001; X[2] = 9.24, p = 0.01, respectively). Time-Wall task inaccuracy scores did not notably correlate with age.

CONCLUSIONS: The Time-Wall task showed strong diagnostic utility in identifying early AD, independent of age. The mental rotation task exhibited low sensitivity and requires further investigation regarding its potential to reflect compensatory brain network functions.},
}

Humans
*Alzheimer Disease/diagnosis/physiopathology/psychology
Male
Female
Aged
Cross-Sectional Studies
*Cognitive Dysfunction/diagnosis/physiopathology
Neuropsychological Tests
*Time Perception/physiology
Aged, 80 and over
Middle Aged
Rotation
Cognition/physiology

@article {pmid41261682,
year = {2025},
author = {Huang, X and Wang, X and Yang, Y and Chen, H},
title = {Assessing the potential causal influence of myasthenia gravis on neurodegenerative diseases via multivariable Mendelian randomization.},
journal = {Medicine},
volume = {104},
number = {44},
pages = {e45340},
pmid = {41261682},
issn = {1536-5964},
mesh = {Humans ; Mendelian Randomization Analysis ; *Myasthenia Gravis/genetics/complications/epidemiology ; Genome-Wide Association Study ; *Neurodegenerative Diseases/genetics/etiology/epidemiology ; Amyotrophic Lateral Sclerosis/genetics ; Alzheimer Disease/genetics/epidemiology/etiology ; Parkinson Disease/genetics ; Genetic Predisposition to Disease ; Risk Factors ; },
abstract = {Myasthenia gravis (MG), an autoimmune condition known for impairing neuromuscular signaling, has increasingly been implicated in broader neurological dysfunctions. Recent studies point toward a possible connection between autoimmune and neurodegenerative processes. However, whether MG contributes causally to the onset of major neurodegenerative disorders such as Alzheimer disease (AD), Parkinson disease (PD), and amyotrophic lateral sclerosis (ALS) remains unclear. This study utilizes Mendelian randomization (MR) to explore the potential causal influence of MG on these disorders from a genetic standpoint. A univariable Mendelian randomization (UVMR) framework was employed using summary-level data from genome-wide association studies (GWAS) to evaluate the effect of MG on the risk of AD, PD, and ALS. To confirm the robustness of the association between MG and AD, 2 independent AD GWAS datasets were incorporated for external replication, followed by a meta-analysis to combine the evidence. Additionally, multivariable Mendelian randomization (MVMR) was conducted to adjust for smoking behavior as a potential confounding factor. The UVMR analysis revealed a statistically significant causal relationship between MG and increased susceptibility to AD (odds ratio (OR): 1.037; 95% confidence interval (CI): 1.007-1.068; P = .016). No significant causal effects were observed for PD (OR: 1.019; 95% CI: 0.964-1.077; P = .509) or ALS (OR: 1.055; 95% CI: 0.977-1.140; P = .171). The association between MG and AD was consistently validated in 2 independent datasets (ieu-a-297: OR = 1.084; 95% CI: 1.017-1.156; P = .013; ieu-b-2: OR = 1.054; 95% CI: 1.006-1.104; P = .027). Meta-analysis reinforced the evidence supporting MG as a risk factor for AD (OR: 1.047; 95% CI: 1.023-1.072; P < .001). Furthermore, MVMR adjusting for smoking confirmed that MG independently contributes to AD risk (OR: 1.037; 95% CI: 1.006-1.069; P = .020). This study provides robust genetic evidence suggesting that MG is a causal and independent risk factor for AD. These findings highlight a novel link between autoimmunity and neurodegeneration, offering new directions for mechanistic and therapeutic research.},
}

Humans
Mendelian Randomization Analysis
*Myasthenia Gravis/genetics/complications/epidemiology
Genome-Wide Association Study
*Neurodegenerative Diseases/genetics/etiology/epidemiology
Amyotrophic Lateral Sclerosis/genetics
Alzheimer Disease/genetics/epidemiology/etiology
Parkinson Disease/genetics
Genetic Predisposition to Disease
Risk Factors

@article {pmid41261525,
year = {2025},
author = {Wu, S and Chen, L and He, Y and Liu, J and Deng, Z and Chen, Y and Sheng, Z and Xia, B and Tan, Y and Pan, S and Lu, N and Yu, W and Lü, Y},
title = {MIND diet adherence and cognitive function in Alzheimer's disease: Mediating roles of neural oscillatory markers from resting-state EEG.},
journal = {Psychiatry and clinical neurosciences},
volume = {},
number = {},
pages = {},
doi = {10.1111/pcn.13923},
pmid = {41261525},
issn = {1440-1819},
support = {CYB240194//Chongqing Municipal Education Commission/ ; KJZD-K202200405//Chongqing Municipal Education Commission/ ; cstc2022ycjh-bgzxm0184//Chongqing Municipal Education Commission/ ; 2021ZD0201802//National Natural Science Foundation of China/ ; CYYY-BSYJSKYCXXM202439//Chongqing Medical University/ ; W0166//Chongqing Medical University/ ; },
abstract = {AIM: Adherence to the Mediterranean-dietary approaches to stop hypertension (DASH) intervention for neurodegenerative delay (MIND) diet has been associated with a reduced risk of dementia, yet clinical and mechanistic evidence is limited. This study aims to explore the relationship between MIND diet adherence and cognitive function in Alzheimer's disease (AD), with a specific focus on resting-state EEG to investigate the underlying mechanisms.

METHODS: We evaluated 841 memory clinic participants: 119 cognitively normal, 255 with mild cognitive impairment, and 467 with AD. Cognitive, dietary, neuropsychiatric, and functional data were collected. EEG from 204 participants was analyzed for spectral and connectivity features.

RESULTS: MIND scores were significantly lower in the AD group (P < 0.001). Higher MIND adherence was linked to better global cognition, lower dementia severity, fewer mood symptoms, and greater daily functioning (P < 0.05). Individuals in the lowest adherence tertile had 6.78 times higher odds of cognitive impairment compared to those in the highest tertile (OR = 6.78, 95% CI: 4.54-10.13, P < 0.001). EEG analyses revealed that greater MIND adherence was associated with increased alpha power, reduced occipital theta/beta and delta/alpha ratios, and stronger frontoparietal connectivity. Mediation analysis indicated that frontal and global alpha power partially mediated the associations between MIND diet adherence and dementia severity, mood symptoms, and functional status.

CONCLUSIONS: High MIND adherence is associated with improved cognitive and functional outcomes in AD. EEG signatures may partially mediate these effects, highlighting the clinical potential of the MIND diet for early intervention and neurophysiological monitoring.},
}

@article {pmid41261494,
year = {2025},
author = {Yang, HJ and Song, JM and Park, JH},
title = {Independent Role of White Matter Hyperintensity Volume and Location in Alzheimer's Disease Risk Beyond Hippocampal Atrophy.},
journal = {Psychiatry investigation},
volume = {},
number = {},
pages = {},
doi = {10.30773/pi.2025.0127},
pmid = {41261494},
issn = {1738-3684},
abstract = {OBJECTIVE: Increases in white matter hyperintensities (WMH) observed on brain MRI are associated with the onset of Alzheimer's disease (AD) and cognitive decline. Recent hypotheses suggest that the impact of WMH on cognition may differ by their distance from the ventricular surface. This study aimed to investigate the effects of WMH volume and location, classified by distance from the ventricular surface, on cognitive function in individuals with AD.

METHODS: A total of 112 normal cognition (NC) individuals and 171 patients with AD underwent clinical evaluation, volumetric MRI, and neuropsychological testing using the Korean version of the Consortium to Establish a Registry for Alzheimer's Disease. WMH volume was categorized as juxtaventricular (JVWMH, <3 mm from ventricle), periventricular (PVWMH, 3-13 mm), and deep (DWMH, >13 mm).

RESULTS: The mean WMH volume was significantly higher in AD group (20.7±18.2 mL) than in the NC group (6.8±8.1 mL, p<0.001). A tenfold increase in WMH volume led to a 5.967-fold increased risk of AD (95% confidence interval [CI]=1.550-22.986). A similar risk association was observed for PVWMH (OR=4.021, 95% CI=1.592-10.156), and DWMH showed a significant risk association (OR= 2.873, 95% CI=1.227-6.731). Total WMH, JVWMH, and PVWMH were associated with poorer performance in verbal fluency and memory tasks, while DWMH showed no significant cognitive association.

CONCLUSION: WMH volume and location independently contribute to AD risk and cognitive decline, with PVWMH and JVWMH particularly affecting executive and memory functions, regardless of hippocampal atrophy.},
}

@article {pmid41261421,
year = {2025},
author = {Etani, H and Takatori, S and Wang, W and Omi, J and Amiya, Y and Akahori, A and Watanabe, H and Sonn, I and Okano, H and Hara, N and Hasegawa, M and Miyashita, A and Kikuchi, M and Ikeuchi, T and Morishima, M and Saito, Y and Murayama, S and Saito, T and Saido, TC and Takai, T and Ohwada, T and Aoki, J and Tomita, T},
title = {Selective agonism of GPR34 stimulates microglial uptake and clearance of amyloid β fibrils.},
journal = {Alzheimer's research & therapy},
volume = {17},
number = {1},
pages = {248},
pmid = {41261421},
issn = {1758-9193},
mesh = {*Microglia/metabolism/drug effects ; Animals ; *Amyloid beta-Peptides/metabolism ; Humans ; Mice ; *Receptors, G-Protein-Coupled/agonists/metabolism ; Alzheimer Disease/metabolism/pathology ; Phagocytosis/drug effects ; Mice, Transgenic ; Male ; Mice, Inbred C57BL ; Cells, Cultured ; },
abstract = {BACKGROUND: Microglia play a crucial role in brain homeostasis through phagocytosis of amyloid-β (Aβ) fibrils, a hallmark of Alzheimer disease (AD) pathology. The balance between Aβ production and clearance is critical for AD pathogenesis, with impaired clearance mechanisms potentially contributing to disease progression. G-protein coupled receptor 34 (GPR34), a microglia-enriched Gi/o-coupled receptor, is highly expressed in homeostatic microglia and may regulate phagocytic functions, yet its role in Aβ clearance remains poorly understood.

METHODS: Using flow cytometry-based assays, we investigated the effect of a selective GPR34 agonist (M1) on Aβ uptake in mouse primary microglia and human induced pluripotent stem cell-derived microglia. We evaluated uptake specificity across different Aβ species and phagocytic substrates, and measured intracellular cyclic adenosine monophosphate (cAMP) levels to determine the signaling mechanism. We performed in vivo studies using human amyloid precursor protein knock-in mice with intrahippocampal M1 injections. Additionally, we analyzed GPR34 expression in Japanese AD patient brain samples using single-nucleus RNA sequencing and examined age-dependent expression changes across multiple datasets.

RESULTS: M1 specifically enhanced uptake of Aβ fibrils through reduction of intracellular cAMP levels, without affecting monomeric or oligomeric Aβ internalization. Gpr34 knockdown experiments confirmed GPR34 as the molecular target of M1. An intrahippocampal injection of M1 significantly increased microglial Aβ uptake in vivo, an effect that required functional TREM2 signaling. GPR34 expression was significantly reduced in microglia from AD patients and showed age-dependent decline in both humans and mice.

CONCLUSIONS: Our findings identify GPR34 as a promising therapeutic target for enhancing microglial Aβ clearance and highlight the potential of GPR34 agonists for AD treatment. The age-dependent decline in GPR34 expression may contribute to reduced Aβ clearance efficiency in aging brains, exacerbating amyloid accumulation. Pharmacological activation of GPR34 represents a novel strategy to counteract impaired Aβ clearance in both aging and AD brains, potentially modifying disease progression through enhancement of microglial phagocytic function.},
}

*Microglia/metabolism/drug effects
Animals
*Amyloid beta-Peptides/metabolism
Humans
Mice
*Receptors, G-Protein-Coupled/agonists/metabolism
Alzheimer Disease/metabolism/pathology
Phagocytosis/drug effects
Mice, Transgenic
Male
Mice, Inbred C57BL
Cells, Cultured

@article {pmid41261328,
year = {2025},
author = {İlhan, N and Şahin, E and Ildız, S and Samancı, B and Sordu, P and Alaylıoğlu, M and Bilgiç, B and Hanağası, HA and Gürvit, İH and Dursun, E and Gezen-Ak, D},
title = {The CSF Levels of Mitochondrial Phosphoenolpyruvate Carboxykinase 2 as a Novel Biomarker in Alzheimer's Disease.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {98},
pmid = {41261328},
issn = {1559-1182},
support = {22AG017 - APYOK2//Türkiye Bilimsel ve Teknolojik Araştırma Kurumu/ ; TYL-2023-37292//Istanbul Üniversitesi-Cerrahpasa/ ; },
mesh = {Humans ; *Alzheimer Disease/cerebrospinal fluid/enzymology ; Biomarkers/cerebrospinal fluid ; Male ; Female ; Aged ; *Mitochondria/enzymology ; Amyloid beta-Peptides/cerebrospinal fluid ; Middle Aged ; Cognitive Dysfunction/cerebrospinal fluid ; ROC Curve ; },
abstract = {Studies have shown that the expression patterns of neurons and glia can be altered by the Aβ fragments. We hypothesized that genes regulated by Aβ-affected transcription factors (TFs) are most impacted by amyloid pathology, leading to significant expression changes. To test this, we focused on three key TFs namely, Jun, Fos, and RELA, and identified 13 common genes they regulate. Given AD-related neurodegeneration disrupts essential cellular processes like mitochondrial function and glucose metabolism, we selected PCK2 as a biomarker candidate from these 13 common genes. The present study included core CSF biomarker validated 154 AD, 41 non-AD MCI patients, and 16 individuals with subjective cognitive impairment. We measured the PCK2 levels in CSF of the cases and controls with ELISA. The PCK2 levels were significantly lower in the CSF of AD cases compared to SCI or non-AD MCI cases. The PCK2 levels of A - individuals were significantly lower than that of A + individuals. Similarly, T - or (N) - individuals exhibit significantly lower levels of CSF PCK2 compared to their + counterparts. Each area under the curve for the ROC analysis of CSF pTau(181)/CSF PCK2 ratio in SCI vs. AD, non-AD MCI vs. AD, A - vs. A + , T - vs. T + and (N) - vs. (N) + were higher than 84%. The sensitivity and specificity of each analysis were at least 76% and 83%; respectively. A positive correlation was determined between CSF PCK2 and Aβ1-42 in AD. PCK2, along with other mitochondrial proteins, could be utilized as a mitochondrial biomarker for neurodegeneration, and PCK2 levels should be investigated in large cohorts for verification.},
}

Humans
*Alzheimer Disease/cerebrospinal fluid/enzymology
Biomarkers/cerebrospinal fluid
Male
Female
Aged
*Mitochondria/enzymology
Amyloid beta-Peptides/cerebrospinal fluid
Middle Aged
Cognitive Dysfunction/cerebrospinal fluid
ROC Curve

@article {pmid41261326,
year = {2025},
author = {Li, S and Wang, D and Li, A and Wang, T and Chen, X and Li, H and Wang, T and Xie, Y and Liang, J and Cai, X},
title = {ZuoGui Pill Ameliorates Alzheimer's Disease-Like Pathology in 3xTg-AD Mice by Targeting Aβ Production, Tau Phosphorylation, Synaptic Loss, and Neuroinflammation.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {96},
pmid = {41261326},
issn = {1559-1182},
support = {No. LH2022H059//Heilongjiang University of Chinese Medicine/ ; No. 2021GZ57//Public Welfare Application Research Project of the Huzhou Municipal Science and Technology Bureau/ ; },
mesh = {Animals ; *Alzheimer Disease/drug therapy/pathology/metabolism ; *tau Proteins/metabolism ; *Amyloid beta-Peptides/metabolism/biosynthesis ; *Drugs, Chinese Herbal/pharmacology/therapeutic use ; Mice, Transgenic ; Phosphorylation/drug effects ; *Synapses/drug effects/pathology/metabolism ; *Neuroinflammatory Diseases/drug therapy/pathology/metabolism ; Mice ; Hippocampus/drug effects/pathology/metabolism ; Disease Models, Animal ; Male ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) accumulation, tau hyperphosphorylation, synaptic dysfunction, and chronic neuroinflammation. Current single-target interventions fail to halt disease progression, highlighting the need for multi-target strategies. This study investigates the therapeutic potential and mechanisms of ZuoGui Pill (ZGP), a traditional Chinese medicine formula, in a transgenic AD mouse model. 3xTg-AD mice were treated with ZGP for 60 days. Behavioral performance was assessed using the Morris water maze, novel object recognition, and open field test. Aβ deposition, tau phosphorylation, and synaptic integrity were evaluated via immunohistochemistry, Western blotting, RT-qPCR, and Golgi staining. Neuroinflammation and RAGE/NF-κB signaling were analyzed by ELISA and protein expression profiling. Statistical analyses included ANOVA with post hoc Tukey or Bonferroni tests following Shapiro-Wilk and Bartlett's validation. ZGP significantly improved cognitive performance, reduced hippocampal Aβ deposition and BACE1 expression, and suppressed tau phosphorylation at multiple pathological sites (T205, S396, S404). Synaptic markers (Syn, PSD95) were restored, accompanied by increased dendritic spine density. ZGP also reduced hippocampal IL-1β, IL-6, and TNF-α levels and inhibited the RAGE/p-NF-κB pathway. ZGP exerts multi-target neuroprotective effects in 3xTg-AD mice by modulating Aβ and tau pathologies, preserving synaptic structure, and attenuating RAGE-mediated neuroinflammation. These findings support ZGP as a promising integrative therapeutic strategy for AD.},
}

Animals
*Alzheimer Disease/drug therapy/pathology/metabolism
*tau Proteins/metabolism
*Amyloid beta-Peptides/metabolism/biosynthesis
*Drugs, Chinese Herbal/pharmacology/therapeutic use
Mice, Transgenic
Phosphorylation/drug effects
*Synapses/drug effects/pathology/metabolism
*Neuroinflammatory Diseases/drug therapy/pathology/metabolism
Mice
Hippocampus/drug effects/pathology/metabolism
Disease Models, Animal
Male

@article {pmid41261317,
year = {2025},
author = {Zhou, R and Tian, G and Yu, J and Wang, R and Peng, N and Guo, X and Li, R},
title = {Echinacoside Improves Memory Function and Bone Mineral Density in the Aged SAMP8 Mouse Model.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {102},
pmid = {41261317},
issn = {1559-1182},
mesh = {Animals ; Male ; Mice ; *Bone Density/drug effects ; *Aging/drug effects/pathology ; Disease Models, Animal ; *Memory/drug effects ; *Glycosides/pharmacology/therapeutic use ; Osteoporosis/drug therapy ; },
abstract = {Alzheimer's disease (AD) and osteoporosis (OP) are prevalent age-related degenerative diseases that often coexist. Echinacoside (ECH) has been extensively studied for its potential to mitigate AD and bone mineral density (BMD) loss. This study aimed to evaluate the simultaneous therapeutic effects of ECH on AD-OP comorbidity using the senescence-accelerated mouse-prone 8 (SAMP8) model, which exhibits both age-related memory deficits and bone metabolism abnormalities. Six-month-old male SAMP8 mice (n = 8-9) were used as the model group, while age-matched senescence-accelerated mouse resistant 1 (SAMR1) mice served as normal controls. SAMP8 mice were administered ECH intragastrically (100 mg/kg/day) for 10 weeks, while control groups received saline. Behavioral tests, including the open field test (OFT), novel object recognition test (NORT), and Morris Water Maze (MWM), assessed locomotor ability, emotionality, and cognitive functions. Bone microstructure was evaluated using micro-computed tomography (micro-CT), and pathological changes in the brain were analyzed via Western blotting and immunofluorescence. As compared to SAMR1 mice, SAMP8 mice exhibited significant locomotor activity issues, impaired memory (P < 0.05), glial activation (P < 0.01), reduced trabecular bone number (P = 0.007), and altered trabecular separation (P = 0.040). ECH treatment improved memory function and inhibited glial activation (P < 0.05). Bone-related parameters showed that ECH intervention had a trend of improvement in bone health, but this did not reach statistical significance. The SAMP8 model exhibits key features of both AD and OP, making it a valuable tool for investigating their comorbidity and underlying mechanisms. ECH improves cognitive functions and alleviates bone loss, indicating its potential as a therapeutic candidate for AD-OP comorbidity.},
}

Animals
Male
Mice
*Bone Density/drug effects
*Aging/drug effects/pathology
Disease Models, Animal
*Memory/drug effects
*Glycosides/pharmacology/therapeutic use
Osteoporosis/drug therapy

@article {pmid41261299,
year = {2025},
author = {Zhang, R and Wu, K and Yang, Q and Kong, M and Guo, L and You, Q},
title = {Hyperprolactinemia and Brain Health: Exploring the Gut-Brain Axis and Therapeutic Strategies.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {101},
pmid = {41261299},
issn = {1559-1182},
mesh = {Humans ; *Hyperprolactinemia/therapy/metabolism ; *Brain/pathology/metabolism ; Animals ; *Gastrointestinal Tract ; Gastrointestinal Microbiome/physiology ; Prolactin/metabolism ; *Brain-Gut Axis/physiology ; },
abstract = {Prolactin is a pituitary anterior lobe hormone that plays a crucial role in milk secretion from the mammary glands. Hyperprolactinemia is a common endocrine disorder characterized by abnormally elevated levels of prolactin in the serum. Recent research findings indicate that prolactin also exerts important physiological effects beyond lactation, including effects on brain health and the central nervous system. The gut-brain axis has become an important area of neuroscience research, providing insights into the complex interactions between the gastrointestinal system and the central nervous system. Future research may involve developing new probiotic therapies or optimizing the gut microbiota through dietary and lifestyle interventions. In addition, understanding the mechanisms by which hyperprolactinemia contributes to various neurological disorders and targeting prolactin for treatment are crucial areas of research. Therefore, this study aimed to investigate the correlation between hyperprolactinemia and brain health from the perspective of the gut-brain axis, with the goal of discovering new approaches for preventing and treating neurodegenerative and mental health conditions. This synthesis highlights potential strategies for future therapeutic interventions.},
}

Humans
*Hyperprolactinemia/therapy/metabolism
*Brain/pathology/metabolism
Animals
*Gastrointestinal Tract
Gastrointestinal Microbiome/physiology
Prolactin/metabolism
*Brain-Gut Axis/physiology

@article {pmid41261295,
year = {2025},
author = {Kritika, and Sood, R and Sanjay, and Lee, HJ},
title = {Nobiletin Reduces LPS-Induced Neuroinflammation through TLR4/MyD88/NF-κB and Oxidative Stress via Nrf2/HO-1 Signaling in Human Microglial HMC3 Cells.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {103},
pmid = {41261295},
issn = {1559-1182},
support = {GCU-202401020001//Gachon University research fund of 2023 (GCU-202401020001)/ ; (project No. RS-2022-RD010230)//Cooperative Research Program for Agriculture Science and Technology Development (project No. RS-2022-RD010230), Rural Development Administration, Republic of Korea./ ; },
mesh = {Humans ; *Oxidative Stress/drug effects ; *Myeloid Differentiation Factor 88/metabolism ; *NF-E2-Related Factor 2/metabolism ; *Toll-Like Receptor 4/metabolism ; *Signal Transduction/drug effects ; Lipopolysaccharides ; *NF-kappa B/metabolism ; *Microglia/drug effects/metabolism/pathology ; *Heme Oxygenase-1/metabolism ; *Flavonols/pharmacology ; *Neuroinflammatory Diseases/metabolism/drug therapy/chemically induced/pathology ; *Flavones/pharmacology ; Cell Line ; Inflammation/metabolism/drug therapy ; Reactive Oxygen Species/metabolism ; },
abstract = {Neuroinflammation and oxidative stress (OS) are the major contributors to the onset and progression of neurodegenerative diseases (NDs), where microglial activation and dysregulated inflammatory signaling exacerbate neuronal injury. Nobiletin (NOB), a polymethoxylated flavonoid abundant in citrus fruits, has been reported to possess excellent bioactivities; however, its effects in combating inflammation and OS in human microglial cells (HMC3) have not been comprehensively examined. In this study, we investigated the effects of NOB on lipopolysaccharide (LPS)-induced inflammatory and oxidative responses in HMC3 cells. The HMC3 cells exposed to LPS (1 µg/mL) in the presence/absence of NOB (5, 10, 20, and 40 µM) for 24 h showed that NOB could attenuate LPS-induced cytotoxicity. NOB treatment attenuated LPS-induced upregulation of pro-inflammatory cytokines including interleukin (IL)-1β, and IL-6, and suppressed activation of the toll-like receptor 4/myeloid differentiation primary response 88/nuclear factor kappa-light-chain-enhancer of activated B (TLR4/MyD88/NF-κB) pathway. NOB enhanced the protein expression levels of TLR10, a negative regulator of TLR4-mediated inflammatory signaling. In addition, NOB increased the nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) expression, along with other antioxidants including catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD), leading to reduced intracellular reactive oxygen species (ROS). These findings suggest that NOB has promising anti-inflammatory and antioxidant effects in an in vitro model of LPS-induced neuroinflammation, potentially through modulation of TLR4/MyD88/NF-κB and Nrf2/HO-1 signaling pathways. However, further in vivo studies are needed to validate these effects and explore NOB's potential as a candidate for therapeutic development in NDs.},
}

Humans
*Oxidative Stress/drug effects
*Myeloid Differentiation Factor 88/metabolism
*NF-E2-Related Factor 2/metabolism
*Toll-Like Receptor 4/metabolism
*Signal Transduction/drug effects
Lipopolysaccharides
*NF-kappa B/metabolism
*Microglia/drug effects/metabolism/pathology
*Heme Oxygenase-1/metabolism
*Flavonols/pharmacology
*Neuroinflammatory Diseases/metabolism/drug therapy/chemically induced/pathology
*Flavones/pharmacology
Cell Line
Inflammation/metabolism/drug therapy
Reactive Oxygen Species/metabolism

@article {pmid41261291,
year = {2025},
author = {Singh, L},
title = {Paeonol Mitigates Neurodegeneration: Molecular Insights into Its Anti-inflammatory, Antioxidant, and Synaptoprotective Mechanisms.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {94},
pmid = {41261291},
issn = {1559-1182},
mesh = {Humans ; Animals ; *Anti-Inflammatory Agents/pharmacology/therapeutic use ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Acetophenones/pharmacology/therapeutic use ; *Antioxidants/pharmacology/therapeutic use ; *Neurodegenerative Diseases/drug therapy/metabolism/pathology ; *Synapses/drug effects/metabolism/pathology ; Signal Transduction/drug effects ; },
abstract = {Neurodegeneration is the gradual atrophy of the structure and functionality of the neurons, which culminates in the death of the neurons. This pathological process is central to numerous neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. The global prevalence of neurodegenerative diseases is increasing rapidly, posing a significant public health burden. The various interconnected molecular pathways are disrupted in the pathogenesis of neurodegenerative diseases. Among them, TLR/MyD88/NF-κB and MAPK/NF-κB signaling cascades are critical ones that activate neuroinflammation. Whereas, NLRP3 inflammasome-mediated pyroptosis contributes to inflammatory cell death. Moreover, the BDNF/Trk-B-mediated PI3K/Akt/mTOR pathway controls the synaptic plasticity that is necessary in the learning and memory processes. In addition, caspase and AIF-mediated apoptotic signaling pathways are disrupted in neurodegenerative diseases. Till now, various natural phenolic compounds have shown high potential in combating different neurodegenerative diseases. Paeonol is a 2'-hydroxy-4'-methoxyacetophenone, commonly found in the root bark of Paeonia suffruticosa and other Paeonia species. It possesses diverse pharmacological actions, including neuroprotection, anti-inflammatory, antioxidant and cardioprotective. Various cell lines and preclinical reports have documented that paeonol confers neuroprotection through modulation of various mediators, including TLR4, MAPK, PI3K, mTOR, BDNF, NF-κB, ROS, AMPK, NLRP3, apoptotic proteins and inflammatory mediators, among others. Given that paeonol can modulate these mediators, the current study was designed to investigate the mechanistic interactions that underlie its neuroprotective effects. Examining these interrelated pathways will give future researchers the fundamental knowledge to fill the existing gaps and better understand the potential of paeonol in neurodegenerative diseases.},
}

Humans
Animals
*Anti-Inflammatory Agents/pharmacology/therapeutic use
*Neuroprotective Agents/pharmacology/therapeutic use
*Acetophenones/pharmacology/therapeutic use
*Antioxidants/pharmacology/therapeutic use
*Neurodegenerative Diseases/drug therapy/metabolism/pathology
*Synapses/drug effects/metabolism/pathology
Signal Transduction/drug effects

@article {pmid41261263,
year = {2025},
author = {Peng, XQ and Yang, ZK and Guo, HS and Wu, XY and Ruganzu, JB and Liu, ZZ and Wu, SD and Yang, WN},
title = {TREM2 Alleviates Neuroinflammation and Improves Neurogenesis in ApoE[-/-] Mice by Regulating M1/M2 Microglial Polarization.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {105},
pmid = {41261263},
issn = {1559-1182},
support = {2024003//Open Project Program of Xi'an Key Laboratory for Innovation and Translation of Neuroimmunological Diseases/ ; 2023-JC-YB-735; 2024JC-YBMS-615//Natural Science Basic Research Plan in Shaanxi Province of China/ ; },
mesh = {Animals ; *Microglia/metabolism/pathology ; *Neurogenesis/physiology ; *Receptors, Immunologic/metabolism ; Doublecortin Protein ; *Neuroinflammatory Diseases/pathology/metabolism ; *Membrane Glycoproteins/metabolism ; Mice ; *Apolipoproteins E/deficiency ; *Cell Polarity ; Mice, Inbred C57BL ; Hippocampus/pathology/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Mice, Knockout ; Male ; Signal Transduction ; },
abstract = {Triggering receptor expressed on myeloid cells 2 (TREM2) is an innate immune receptor abundantly expressed in microglia in the brain. Our previous study indicated that TREM2 promoted microglia polarization to the M2 phenotype in APP/PS1 transgenic mice and BV2 cells. It is reported that M2 microglia release brain-derived neurotrophic factor (BDNF) to enhance adult neurogenesis in the hippocampus. However, the role of TREM2 in hippocampal neurogenesis and the underlying mechanism are still less known. Apolipoprotein E knockout (ApoE[-/-]) mice exhibit cholinergic dysfunction, tau hyperphosphorylation, synaptic loss and dysfunction that may affect brain function and simulate Alzheimer's disease (AD). In this study, overexpression of TREM2 significantly increased the number of minichromosome maintenance 2 (MCM2) and doublecortin (DCX) cells in the subgranular zone (SGZ) of ApoE[-/-] mice. Additionally, the protein levels of MCM2 and DCX showed a similar trend. Furthermore, we found that overexpression of TREM2 promoted a phenotypical switch from M1 to M2 in microglia, as the levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and CD86 were decreased, whereas the levels of IL-4, Arginase-1(Arg-1), BDNF, and CD206 were increased. Importantly, overexpression of TREM2 activated the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) and extracellular signal-regulated protein kinase 1 and 2 (ERK1/2) signaling pathways. In vitro, overexpression of TREM2 in primary microglia increased the production of anti-inflammatory factors (IL-4, Arg-1) and BDNF, while decreasing the production of pro-inflammatory factors (TNF-α, IL-1β). Furthermore, conditioned medium (CM) from TREM2 overexpressing primary microglia facilitated neural stem cells (NSCs) proliferation and differentiation into neurons. Moreover, the mechanistic study indicated that overexpression of TREM2 modulated microglial M2 polarization and promoted the proliferation and differentiation of NSCs partly via the PI3K/Akt and ERK1/2 signaling pathways. Collectively, these findings revealed that TREM2 may modulate microglial M2 polarization to inhibit neuroinflammation and increase the M2 microglia-derived BDNF to rescue hippocampal neurogenesis in ApoE[-/-] mice, and TREM2 can be considered a promising therapeutic factor to promote neurogenesis in AD and other brain diseases.},
}

Animals
*Microglia/metabolism/pathology
*Neurogenesis/physiology
*Receptors, Immunologic/metabolism
Doublecortin Protein
*Neuroinflammatory Diseases/pathology/metabolism
*Membrane Glycoproteins/metabolism
Mice
*Apolipoproteins E/deficiency
*Cell Polarity
Mice, Inbred C57BL
Hippocampus/pathology/metabolism
Phosphatidylinositol 3-Kinases/metabolism
Mice, Knockout
Male
Signal Transduction

@article {pmid41261258,
year = {2025},
author = {Rahmani, D and Chodari, L and Kakallahpour, M and Niknam, Z},
title = {Therapeutic Potential of Sodium Butyrate in Neurological and Psychiatric Disorders.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {90},
pmid = {41261258},
issn = {1559-1182},
mesh = {Humans ; *Mental Disorders/drug therapy ; Animals ; *Butyric Acid/therapeutic use/pharmacology ; *Nervous System Diseases/drug therapy ; Histone Deacetylase Inhibitors/therapeutic use/pharmacology ; },
abstract = {Neurodegenerative diseases (NDDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD), are characterized by progressive neuronal loss associated with neuroinflammation, oxidative stress, and epigenetic dysregulation. Emerging evidence suggests that histone deacetylases (HDACs) are overexpressed in these conditions, making HDAC inhibitors (HDACIs) like sodium butyrate (NaB) promising candidates for therapeutic intervention. In addition, NaB has shown beneficial effects in various psychiatric disorders, including depression, anxiety, and schizophrenia, suggesting a broader neurotherapeutic potential. This review synthesizes findings from various in vitro and in vivo studies investigating the mechanisms and therapeutic applications of NaB, in both neurological and psychiatric disorders. We focus on its role as an HDACI, its impact on histone acetylation and gene expression, its ability to modulate gut microbiota, and its capacity to cross the blood-brain barrier (BBB) to exert neuroprotective effects. NaB demonstrates anti-inflammatory, antioxidant, anti-apoptotic, and neurotrophic properties, contributing to improved cognitive, motor, and behavioral outcomes in multiple models of central nervous system (CNS) dysfunction. Accumulating evidence supports its efficacy not only in NDDs but also in mental health disorders, highlighting its potential as a complementary treatment alongside conventional therapies. Given its multifaceted mechanisms and favorable safety profile, NaB holds promise as a novel therapeutic agent across a spectrum of neurological and psychiatric conditions. Further clinical investigation is warranted to fully establish its translational value.},
}

Humans
*Mental Disorders/drug therapy
Animals
*Butyric Acid/therapeutic use/pharmacology
*Nervous System Diseases/drug therapy
Histone Deacetylase Inhibitors/therapeutic use/pharmacology

@article {pmid41261002,
year = {2025},
author = {Canney, M and Bouchoux, G and Carpentier, A and De Rossi, P},
title = {Repeated blood-brain barrier opening using low-intensity pulsed ultrasound mitigates amyloid pathology.},
journal = {Ultrasound in medicine & biology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.ultrasmedbio.2025.10.008},
pmid = {41261002},
issn = {1879-291X},
abstract = {OBJECTIVE: The delivery of large molecules to the pathological brain is one of the main obstacles in the development of disease-modifying drugs. This is partly due to the presence of the blood-brain barrier (BBB), which blocks the free passage of lipophobic molecules and those larger than 400 Da. One strategy to bypass this natural barrier is to use low-intensity pulsed ultrasound to oscillate circulating micro-sized microbubbles, which then exert mechanical stress on the vessel walls. This procedure allows for temporary disruption of the BBB and enhanced local delivery of therapeutics from the blood to the brain parenchyma. In this study, the effect of repeated BBB opening on neuroinflammation in a healthy mouse model was first explored, followed by the effect of repeated opening on amyloid-beta (Aβ) pathology in an Alzheimer's disease model.

METHODS: A cohort of wild-type mice was used to determine the effect of a single BBB opening session mediated by ultrasound/microbubbles (US/MBs) on the inflammatory profile via real-time quantitative polymerase chain reaction on brain extracts at 2, 4, 8 and 15 d post-opening. A second cohort of ARTE10 mice, a mouse model for Aβ pathology, was treated with a different sequence of repeated US/MB-mediated BBB opening to explore the effect on Aβ pathology. Tissues were also analyzed for immune cell infiltration, microglia and astrocyte activation, as well as inflammatory response.

RESULTS: Our results demonstrate that opening the BBB leads to a mild inflammatory response in wild-type animals. However, repeated opening of the BBB in the ARTE10 model resulted in a mild decrease in Aβ pathology, along with a mild increase in growth factor.

CONCLUSION: Altogether, this study suggests that sonication is not only a safe method to deliver therapeutics to the brain but could also have synergistic effects in the treatment of neurodegenerative disease.},
}

@article {pmid41260778,
year = {2025},
author = {Yue, C and Chen, B and Chen, L and Xiong, L and Gong, C and Wang, Z and Liu, G and Li, W and Wang, R and Tang, Y},
title = {KG-CNNDTI: a knowledge graph-enhanced prediction model for drug-target interactions and application in virtual screening of natural products against Alzheimer's disease.},
journal = {Chinese journal of natural medicines},
volume = {23},
number = {11},
pages = {1283-1292},
doi = {10.1016/S1875-5364(25)60980-0},
pmid = {41260778},
issn = {1875-5364},
mesh = {*Alzheimer Disease/drug therapy ; *Biological Products/chemistry/pharmacology/therapeutic use ; Humans ; Neural Networks, Computer ; Machine Learning ; Drug Discovery/methods ; Algorithms ; Drug Evaluation, Preclinical/methods ; },
abstract = {Accurate prediction of drug-target interactions (DTIs) plays a pivotal role in drug discovery, facilitating optimization of lead compounds, drug repurposing and elucidation of drug side effects. However, traditional DTI prediction methods are often limited by incomplete biological data and insufficient representation of protein features. In this study, we proposed KG-CNNDTI, a novel knowledge graph-enhanced framework for DTI prediction, which integrates heterogeneous biological information to improve model generalizability and predictive performance. The proposed model utilized protein embeddings derived from a biomedical knowledge graph via the Node2Vec algorithm, which were further enriched with contextualized sequence representations obtained from ProteinBERT. For compound representation, multiple molecular fingerprint schemes alongside the Uni-Mol pre-trained model were evaluated. The fused representations served as inputs to both classical machine learning models and a convolutional neural network-based predictor. Experimental evaluations across benchmark datasets demonstrated that KG-CNNDTI achieved superior performance compared to state-of-the-art methods, particularly in terms of Precision, Recall, F1-Score and area under the precision-recall curve (AUPR). Ablation analysis highlighted the substantial contribution of knowledge graph-derived features. Moreover, KG-CNNDTI was employed for virtual screening of natural products against Alzheimer's disease, resulting in 40 candidate compounds. 5 were supported by literature evidence, among which 3 were further validated in vitro assays.},
}

*Alzheimer Disease/drug therapy
*Biological Products/chemistry/pharmacology/therapeutic use
Humans
Neural Networks, Computer
Machine Learning
Drug Discovery/methods
Algorithms
Drug Evaluation, Preclinical/methods

@article {pmid41260674,
year = {2025},
author = {Finn, Q and Pascual, B and Schultz, PE and Masdeu, JC},
title = {β-amyloid PET signal reduction in prior ARIA-E regions after anti-amyloid therapy for Alzheimer's disease.},
journal = {AJNR. American journal of neuroradiology},
volume = {},
number = {},
pages = {},
doi = {10.3174/ajnr.A9111},
pmid = {41260674},
issn = {1936-959X},
abstract = {BACKGROUND AND PURPOSE: The relationship between regional brain edema caused by anti-amyloid monoclonal antibodies (ARIA-E) and the degree of regional β-amyloid (Aβ) positron emission tomography (PET) signal reduction is unknown.

MATERIALS AND METHODS: In patients with moderate or severe ARIA-E, we quantified changes in Aβ PET signal before and after ARIA-E resolution, comparing regions affected by ARIA-E with unaffected regions.

RESULTS: In four of five patients treated with lecanemab or donanemab and who had moderate or severe ARIA-E, Aβ PET signal decreased significantly more in regions that had been involved with ARIA-E.

CONCLUSIONS: Greater regional Aβ PET signal reduction in areas affected by ARIA-E may reflect enhanced local Aβ clearance, reduced tracer binding site availability, impaired glymphatic flow from immune complex deposition, or other mechanisms. The finding of greater regional Aβ PET signal reduction in ARIA-E regions refines the characterization of ARIA-E and raises the possibility that its occurrence may have beneficial as well as adverse implications.

ABBREVIATIONS: ARIA＝ amyloid related imaging abnormalities; Aβ＝ β-amyloid; SUVR = standard uptake value ratio.},
}

@article {pmid41260654,
year = {2025},
author = {Horiuchi, K and Ishikawa, K and Nunomura, S},
title = {Cognitive Impairment and Central Sleep Apnea Secondary to Tortuous Vertebral Artery Compression of the Medulla, Mimicking Alzheimer's Disease: A Case Report.},
journal = {Internal medicine (Tokyo, Japan)},
volume = {},
number = {},
pages = {},
doi = {10.2169/internalmedicine.6282-25},
pmid = {41260654},
issn = {1349-7235},
abstract = {We report the case of a man in his 60s, who was previously diagnosed with Alzheimer's disease and presented with acute respiratory failure. Investigations revealed severe hypercapnia and central sleep apnea. Imaging revealed a tortuous right vertebral artery compressing the ventral medulla. Cerebrospinal fluid analysis showed a normal amyloid-β 1-42/1-40 ratio, and he exhibited pyramidal and autonomic signs of brainstem involvement. Despite microvascular decompression, the patient remained ventilator dependent. This case illustrates that medullary compression can cause central hypoventilation that mimics a neurodegenerative disorder, with cognitive decline driven by chronic hypoxia rather than by Alzheimer's pathology.},
}

@article {pmid41260559,
year = {2025},
author = {Peng, D and Wu, L and Zhang, L and Chen, H and Hu, B and Zhang, Q and Huang, Y},
title = {haFGF14-154 attenuates Aβ1-42-induced neurotoxicity by facilitating BDNF maturation in a neuron-astrocyte co-culture system.},
journal = {Molecular and cellular neurosciences},
volume = {},
number = {},
pages = {104056},
doi = {10.1016/j.mcn.2025.104056},
pmid = {41260559},
issn = {1095-9327},
abstract = {haFGF14-154 improves cognitive impairment in animal models of Alzheimer's disease (AD), but the effects and mechanisms of astrocytes on the neuroprotection mediated by haFGF14-154 remain unclear. Here, a neuron-astrocyte co-culture system was established to investigate the functions of astrocytes. The results showed that astrocytes strengthened the protective effect of haFGF14-154 on Aβ1-42-treated neurons. This enhanced protective function of haFGF14-154 correlates with phenotypic transition in astrocytes, as demonstrated by the suppression of Aβ1-42-induced A1-like genes and the elevation of A2-like markers in vitro. These observations are consistent with the reduction of GFAP and C3 levels in the hippocampus and prefrontal cortex of APP/PS1 mice treated with haFGF14-154. haFGF14-154 modified the function of astrocytes by activating the AKT/CREB/BDNF pathway, thereby promoting neurite growth. Moreover, haFGF14-154 up-regulated the expression of Furin and MMP9 in astrocytes, leading to the processing of pro-BDNF. This effect was replicated in APP/PS1 mice administered with haFGF14-154. Compared to the Aβ group, the BDNF level in the co-culture system supernatant was increased, while the IL-1β level was decreased following haFGF14-154 treatment. Additionally, haFGF14-154 inhibited neuronal apoptosis in the co-culture system, as evidenced by a decrease in pro-BDNF/P75[NTR], an increase in Bcl-2, and a reduction of Bad and Cleaved-caspase-3. In conclusion, current results demonstrate that astrocytes are crucial for mediating the protective effect of haFGF14-154 against neuronal damage, and underline the importance of the AKT/CREB/BDNF pathway in promoting neurite growth and attenuating neuronal apoptosis.},
}

@article {pmid41260522,
year = {2025},
author = {Park, JK and Kim, HG and Lee, JS and Joo, JH and Yoo, HR},
title = {Traditional Herbal Medicine Ga-Mi Gongjindan Improves Muscarinic Cholinergic Dysfunction through Regulation of BDNF/CREB Signaling Pathway Using a Scopolamine-Induced Cognitive Impairment of Mouse Model.},
journal = {Brain research bulletin},
volume = {},
number = {},
pages = {111644},
doi = {10.1016/j.brainresbull.2025.111644},
pmid = {41260522},
issn = {1873-2747},
abstract = {BACKGROUND: Neurodegenerative diseases, such as Alzheimer's disease (AD), are characterized by progressive memory loss and cognitive dysfunction, often linked to cholinergic system deterioration and hippocampal oxidative stress. Current pharmacological treatments offer only modest symptomatic relief and are often accompanied by adverse effects. In traditional Korean medicine, Ga-Mi Gongjindan (GJD), a modified formulation of Gongjindan, has long been used for enhancing cognitive function, but its neuropharmacological basis remains largely unexplored.

OBJECTIVE: This study aimed to investigate the neuroprotective potential and underlying mechanisms of GJD in a murine model of scopolamine-induced cognitive impairment, which mimics aspects of muscarinic cholinergic dysfunction observed in Alzheimer's disease (AD).

METHODS: C57BL/6J mice were administered GJD or tacrine (positive control) for 14 days. Cognitive impairment was induced by a single intraperitoneal injection of scopolamine (2mg/kg), and behavioral analysis was assessed using the Morris Water Maze. Hippocampal tissues were analyzed for markers of oxidative stress, inflammation, cholinergic function, and neurotrophic signaling by focusing on the BDNF/CREB signaling pathway.

RESULTS: GJD treatment significantly improved spatial learning and memory performance. It restored cholinergic function by reducing acetylcholinesterase (AChE) activity and increasing choline acetyltransferase (ChAT) levels. GJD also suppressed oxidative stress and neuroinflammation and markedly enhanced hippocampal expression of brain-derived neurotrophic factor (BDNF), cAMP response element-binding protein (CREB), and their receptors (TrkA, TrkB, and M1 mAChR).

CONCLUSION: GJD exerted significant neuroprotective effects in a scopolamine-induced model of cognitive dysfunction, potentially via modulation of cholinergic and BDNF/CREB signaling pathways. These findings provide a scientific rationale for the traditional use of GJD in cognitive disorders and support its further development as a candidate for treating neurodegenerative diseases such as AD.},
}

@article {pmid41260441,
year = {2025},
author = {Hu, K and Mecca, T and Sabatino, G and Satriano, C and Brambilla, L and Dattilo, S and Giglio, V and Di Natale, G and Castiglioni, C and Cunsolo, F and Pappalardo, G},
title = {Functionalizing cryogels with the GPGKLVFF peptide for amyloid-β binding: A comparative study of two synthetic pathways.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {149079},
doi = {10.1016/j.ijbiomac.2025.149079},
pmid = {41260441},
issn = {1879-0003},
abstract = {Macroporous cryogels (Cry) represent a versatile class of scaffolds with broad applicability in biomedical fields, including biomolecular immobilization, diagnostic sensing, and tissue engineering. More recently, their application in neuroscience has gained increasing interest as a viable alternative to conventional systems for drug delivery and neural tissue regeneration. A novel aspect of this work is the design and synthesis of cryogels functionalized with a peptide sequence capable of selectively binding β-amyloid (Aβ) peptides, key biomarkers of Alzheimer's Disease (AD). The peptide GPGKLVFF (KL), was covalently linked into the cryogel matrix using two distinct chemical protocols. The first, a one-step procedure, involves the simultaneous polymerization of a 2-hydroxyethyl methacrylate (HEMA)-N,N'-methylenebisacrylamide (MBAA) and different amounts of a methacrylate-conjugate peptide (maa-KL), enabling precise control over the degree of functionalization. The second, a two-step procedure, involves peptide grafting onto a preformed poly-methacrylic acid (pMAA) cryogel, resulting in significantly higher functionalization yields, albeit with less homogeneity in the material. Successful peptide incorporation was confirmed by infrared (IR) and Raman spectroscopy. A straightforward quantification protocol based on comparing the intensities of selected Raman marker bands was developed, allowing detection of grafted peptides even at low concentrations. The morphology of the cryogels was characterized by scanning electron microscopy (SEM) and atomic force microscopy (AFM). The ability of the functionalized cryogels to reversibly bind and release Aβ40 was assessed by electrospray-ionization mass spectrometry (ESI-MS). This study represents a crucial first step toward developing a diagnostic platform for the early detection of β-amyloid proteins in AD.},
}

@article {pmid41260424,
year = {2025},
author = {Yi, L and Tian, Q and Xu, B and Pang, Y and Dong, Z},
title = {Targeting the PS1-ELK1 protein-protein interaction with a peptide-based inhibitor reduces Aβ production and alleviates memory decline in Alzheimer's disease.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {149074},
doi = {10.1016/j.ijbiomac.2025.149074},
pmid = {41260424},
issn = {1879-0003},
abstract = {Alzheimer's disease (AD) is a common neurodegenerative disorder among the elderly. Our recent research revealed that increased ELK1 (E-twenty-six (ETS)-like protein 1) in AD competitively binds to the C-terminal fragment of presenilin-1 (PS1-CTF), thereby inhibiting E3 ubiquitin ligase synoviolin (SYVN1)-mediated ubiquitination and degradation of PS1, ultimately aggravating pathological progression. However, the precise molecular interface of this interaction and the therapeutic potential of its targeted disruption remain unknown. In the present study, we identified the critical ELK1-binding epitope within PS1 (amino acids 408-429) and, based on this discovery, developed Tat-PS1408-429, a cell-penetrating peptide containing this sequence that specifically disrupts pathological PS1-ELK1 interaction. Tat-PS1408-429 competitively bound to ELK1, attenuating its interaction with PS1 and promoting SYVN1-mediated PS1 degradation. Importantly, disruption of the PS1-ELK1 interaction with Tat-PS1408-429 substantially diminished amyloidogenic processing of amyloid-β (Aβ) precursor protein (APP), leading to reduced Aβ accumulation and improved cognitive and synaptic function in APP23/PS45 double transgenic AD model mice. Collectively, these findings demonstrate that ELK1 interacts with the PS1408-429 domain and disruption of this interaction by Tat-PS1408-429 can alleviate AD-related neuropathology and memory deficits, highlighting its potential as a promising therapeutic peptide for AD.},
}

@article {pmid41260404,
year = {2025},
author = {Lan, S and Gao, F and Ji, R and Wang, Z and Zang, Z and Wei, Y and Kuang, H and Wang, Z},
title = {Bushen Yinao pill improves cognitive function in Alzheimer's disease rats by regulating PI3K/Akt pathway and intestinal microbiota.},
journal = {Fitoterapia},
volume = {},
number = {},
pages = {106999},
doi = {10.1016/j.fitote.2025.106999},
pmid = {41260404},
issn = {1873-6971},
abstract = {Bushen Yinao Pill (BSYN), a traditional Chinese medicine (TCM), is commonly employed to treat forgetfulness and kidney deficiency. The objective of this research was to explore the curative effect of BSYN in Alzheimer's disease (AD) rats and to delve into its underlying mechanism of action. The chemical composition of BSYN was examined by means of UPLC-Q-TOF-MS/MS. The rat model of AD was established using Aβ1-42, alumina, and D-galactose. Through the Morris Water Maze test (MWM), cognitive function was evaluated. To observe the pathological changes in the hippocampus, Hematoxylin and eosin (HE) staining was applied. The oxidative stress level and cholinergic nerve factors were measured using the enzyme-linked immunosorbent assay (ELISA). Moreover, Western blot was utilized for detecting proteins related to the PI3K/Akt pathway. Gut microbiota composition was analyzed using 16S rDNA sequencing. In total, 203 compounds of BSYN were identified. BSYN significantly improved cognitive performance, reduced hippocampal histopathological damage, and restored markers of oxidative stress. Additionally, BSYN modulated the PI3K/Akt pathway by enhancing p-PI3K and p-Akt expression and downregulating GSK-3β. Gut microbiota analysis revealed that BSYN restored microbial diversity and composition, increasing beneficial bacteria such as Lactobacillus while reducing pro-inflammatory genera like Lachnospiraceae NK4A136. In conclusion, the study revealed that BSYN can improve AD-like pathology in rats by modulating several aspects. These findings provide a mechanistic basis for BSYN's therapeutic potential in AD and support its further development as a novel intervention for neurodegenerative diseases.},
}

@article {pmid41260370,
year = {2025},
author = {Xiao, K and Sayed, H and Xing, J and Zhang, XY and Ai, J and Kirichek, E and Le, GH and Wong, S and Valentino, K and Teopiz, KM and Vinberg, M and Rosenblat, JD and Lo, HKY and Zhang, MC and McIntyre, RS},
title = {The effects of Lithium on Beta-amyloid deposition and tau phosphorylation: A systematic review.},
journal = {Journal of affective disorders},
volume = {},
number = {},
pages = {120721},
doi = {10.1016/j.jad.2025.120721},
pmid = {41260370},
issn = {1573-2517},
abstract = {BACKGROUND: Current anti-amyloid treatments often cause amyloid-related imaging abnormalities in the treatment of Alzheimer's disease (AD). Lithium demonstrates neuroprotective and neurotrophic effects, and preclinical studies indicate it reduces intracerebral amyloid deposition and tau phosphorylation. This systematic review evaluates lithium's effects on beta-amyloid, tau, and cognitive deficits in major neurocognitive disorders.

METHODS: A systematic review of primary research was conducted using Embase, PsycInfo, MEDLINE, and PubMed databases from inception to September 2024, following PRISMA criteria. Animal and adult human studies evaluating lithium monotherapy's effects on AD were included.

RESULTS: Long-term low-dose lithium treatment demonstrates inconsistent efficacy in lowering intracerebral amyloid deposition and reversing AD-related cognitive deficits in preclinical and clinical trials. Lithium potentially slows amyloid plaque formation in pre-plaque stages through increasing heat shock proteins and suppressing protein synthesis in preclinical trials. Intracerebral lithium concentrations above 1 mM reduced phosphorylated tau through promoting tau ubiquitination and inhibiting CDK5 signalling in preclinical trials.

LIMITATIONS: AD currently needs a comprehensive animal model accurately representing human AD symptoms and progression, and more clinical trials are needed. Several included studies utilize peripheral lithium administration, which complicates assessment of effective intracerebral concentrations.

CONCLUSIONS: Lithium potentially reduces intracerebral amyloid deposition and tau phosphorylation in AD animal models and may reverse associated cognitive deficits. Further research should seek to replicate similar findings in larger samples and explore lithium's optimal dosage range in promoting intracerebral amyloid clearance.},
}

@article {pmid41260337,
year = {2025},
author = {Katsinelos, T and Lövestam, S and Qi, C and Ryskeldi-Falcon, B and Macdonald, JA and Stephenson, G and Ghetti, B and McKee, A and Scheres, SHW and Goedert, M},
title = {Seeding biosensor cell line that reproduces the Alzheimer tau fold.},
journal = {The Journal of biological chemistry},
volume = {},
number = {},
pages = {110952},
doi = {10.1016/j.jbc.2025.110952},
pmid = {41260337},
issn = {1083-351X},
abstract = {The assembly of tau protein into amyloid filaments through templated seeding is believed to underlie the propagation of pathology in neurodegenerative diseases, such as Alzheimer's disease (AD) and other tauopathies. A commonly used model system for studying this process is through the induction of tau filament formation in cultured cells following the addition of tau seeds isolated from the human brain. However, little is known about the structures of seeded filaments; some biosensor cell lines are unable to reproduce the tau filament structures from AD, because they overexpress tau fragments that do not cover the whole of the ordered filament core. Here, we describe a novel tau seeding biosensor model in HEK293T cells that overexpress residues K297-E391 of human 4R human tau. The construct contains an N-terminal HA-tag, which allows the specific detection of the amplified template. The biosensor cells detected filaments seeded by material from sporadic 3R + 4R tauopathies, with little activity by seeds from 3R-only or 4R-only tauopathies. The sensitivity of seed detection from 3R + 4R tauopathies in our system was similar or higher than for previously reported biosensors. We also structurally characterised the AD-seeded tau filaments by electron cryo-microscopy (cryo-EM). Most of the cell-derived filaments consisted of two protofilaments with the Alzheimer fold, but with a 'head-to-head' inter-protofilament packing. Our results establish a sensitive biosensor cell line with specificity towards seeds from 3R + 4R tauopathies.},
}

@article {pmid41260286,
year = {2025},
author = {Altındağ, F and Bayır, MH and Alhalboosi, JKI and Yıldızhan, K},
title = {Syringic acid mitigates scopolamine-induced cognitive impairment by regulating PSD-95 and GSK-3β and by preventing neurodegeneration in an Alzheimer-like rat model.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115556},
doi = {10.1016/j.expneurol.2025.115556},
pmid = {41260286},
issn = {1090-2430},
abstract = {Alzheimer's disease (AD) is a disorder characterized by progressive cognitive impairment. Syringic acid (SA) is a phenolic compound with many beneficial effects, such as antioxidant, anti-inflammatory, anti-diabetic, anti-carcinogenic, and neuroprotective. Our study aimed to investigate the effects of SA (50 mg/kg/day) on scopolamine (SCO)-induced AD-like condition in rats. Immunohistochemical evaluation was performed using antibodies to postsynaptic density protein 95 (PSD-95), Glycogen synthase kinase-3β (GSK-3β), TNF-α, and caspase-3. The hippocampus was stained with Hematoxylin-Eosin, and the total number of hippocampal neurons and hippocampal volume were calculated using the stereological method. The Y-maze task behavioral test was performed. SCO decreased PSD-95 expression while increasing GSK-3β, TNF-α, and caspase-3 expression. SA treatment increased PSD-95 expression while decreasing GSK-3β, TNF-α, and caspase-3 expression. Compared to the control group, the number of hippocampal neurons was significantly decreased in the Alzheimer's group, but the number of neurons in the SA group was significantly higher than in the Alzheimer's group. Hippocampal volume was lower in the Alzheimer's group, although there was no statistical difference between the groups. SA also improved SCO-induced cognitive impairment. Our study findings suggest that SA may mitigate SCO-induced cognitive impairment in the AD rat model, modulating PSD-95 and GSK-3β and decreasing neuroinflammation and apoptosis.},
}

@article {pmid41260167,
year = {2025},
author = {Wang, X and Li, W and Liu, X and Liang, J and Wang, L and Liu, G and Liu, Y and Song, M and Li, Z and Guo, Y and Li, S and Fu, N and Zhang, B},
title = {Celastrol as a neuroprotective drug: current status and challenges.},
journal = {International immunopharmacology},
volume = {168},
number = {Pt 2},
pages = {115846},
doi = {10.1016/j.intimp.2025.115846},
pmid = {41260167},
issn = {1878-1705},
abstract = {Neurological disorders are increasing worldwide, imposing a major social and economic burden. Therefore, there is an urgent need to explore effective treatment methods to alleviate neurological disorders. Celastrol, derived from the traditional Chinese medicine Tripterygium wilfordii Hook. f., has been shown in multiple studies to exhibit promising neuroprotective effects in neurodegenerative, including Parkinson's disease, Alzheimer's disease, and spinal cord injury. The targets or pathways through which celastrol exerts its neuroprotective effects are diverse. This paper primarily focuses on in vivo animal models (such as Parkinson's disease mouse models, Alzheimer's disease mouse models) and in vitro cell models (such as neuronal cell lines, primary cultured neurons) experiments to comprehensively summarize the molecular mechanisms underlying celastrol's neuroprotective effects. Celastrol exerts its neuroprotective effects through pathways such as reducing inflammation, activating the autophagy-lysosome pathway, and inhibiting ferroptosis. Additionally, we discuss the current challenges faced by celastrol and potential strategies to address them. Collectively, these findings highlight celastrol as a promising therapeutic candidate, although further pharmacokinetic optimization and clinical validation are essential.},
}

@article {pmid41260107,
year = {2025},
author = {Wang, Y and Li, Y and Zhang, C and Li, M and Zheng, Q},
title = {MRomicsNet: A morphomics-radiomics-driven adaptive topological model for AD diagnosis on clinically routine T1-weighted images.},
journal = {Computer methods and programs in biomedicine},
volume = {274},
number = {},
pages = {109160},
doi = {10.1016/j.cmpb.2025.109160},
pmid = {41260107},
issn = {1872-7565},
abstract = {BACKGROUND AND OBJECTIVE: Both morphomics and radiomics are typical features when constructing brain networks on the clinically routine T1-weighted images (T1WI) in Alzheimer's disease (AD) diagnosis but the integration was rarely reported. The study was to devise a morphomics-radiomics-driven adaptive topological model (MRomicsNet) by leveraging the strengths of morphomics and radiomics in AD representation.

METHODS: An experimental validation between morphomics and radiomics was conducted to clarify the individual strengths in capturing brain topology and brain region features. The MRomicsNet was then conducted by integrating the individual strengths via a deep learning framework. Specifically, the MRomicsNet consisted of a morphomics-based graph convolution channel (morphGCN channel) and a morphomics-radiomics-based graph convolution channel (mrGCN channel). The morphGCN channel was fed with morphomics-based brain network to establish a sparse brain topology by strengthening important inter-regional connections while suppressing irrelevant ones. Given the generated sparse topology and the brain region features by radiomics, the new graph was then established and fed into the mrGCN channel for AD diagnosis.

RESULTS: The MRomicsNet was validated on the ADNI and EDSD datasets with a 10-fold cross-validation strategy. The experimental results demonstrated that the MRomicsNet achieved a relatively large improvement of 5.27% to 13.79% on the ADNI dataset and 3.70% to 10.22% on the EDSD dataset in diagnostic accuracy when compared to the existing methods. The complementary mechanism of the morphomics- vs radiomics-based brain network in AD representation was also validated by a visualization result.

CONCLUSIONS: The MRomicsNet highlighted the potential value of the morphomics and radiomics integration in facilitating T1WI-based structural brain network establishment and its associated AD diagnosis.},
}

@article {pmid41260033,
year = {2025},
author = {Zhang, Q and Zhang, S and Cao, X and Zhi, Y and Guo, Y},
title = {The gut microbiota in post-stroke depression: A systematic review of microbial mechanisms and therapeutic targeting of neuroinflammation.},
journal = {Microbiological research},
volume = {303},
number = {},
pages = {128391},
doi = {10.1016/j.micres.2025.128391},
pmid = {41260033},
issn = {1618-0623},
abstract = {Post-stroke depression (PSD), a frequent and debilitating complication after stroke, severely hinders rehabilitation. Emerging evidence underscores the role of neuroinflammation and the gut microbiota in PSD pathogenesis. This review systematically elaborates the mechanisms by which gut dysbiosis contributes to PSD-related neuroinflammation via immune cell regulation (e.g., Treg/Th17 balance), microbial metabolites (e.g., SCFAs, tryptophan derivatives), and neural pathways (vagus nerve, HPA axis). A key focus is the comparative analysis of the gut microbiota in PSD against major depressive disorder (MDD) and Alzheimer's disease (AD), revealing a unique, stroke-induced microbial signature characterized by a loss of protective symbionts and a bloom of pro-inflammatory taxa. We further discuss the translational potential of microbiota-targeted interventions (e.g., probiotics, prebiotics) for PSD. By integrating clinical microbial ecology with mechanistic insights, this review synthesizes evidence suggesting that the gut microbiome may represent a promising diagnostic and therapeutic target for PSD, offering a distinct perspective from previous literature.},
}

@article {pmid41260015,
year = {2025},
author = {Zhao, S and Dong, Y and Jiang, B and Bai, Y and Wei, W and Wu, Y and Li, C and Chen, J and Wang, M},
title = {Cerebral phosphorus metabolite as imaging biomarkers in Alzheimer's disease: a [31]P magnetic resonance spectroscopy study.},
journal = {NeuroImage. Clinical},
volume = {48},
number = {},
pages = {103904},
doi = {10.1016/j.nicl.2025.103904},
pmid = {41260015},
issn = {2213-1582},
abstract = {This study employed phosphorus-31 magnetic resonance spectroscopic imaging (31P-MRSI) to characterize hippocampal and frontal metabolic alterations in Alzheimer's disease (AD) and to evaluate their associations with cognitive decline. We enrolled 30 patients with AD, 26 with amnestic mild cognitive impairment (aMCI), and 25 healthy controls (HC), all of whom underwent [31]P-MRSI using a 3.0 T MRI scanner with a dual-tuned [1]H/[31]P head coil. Spectroscopic data were acquired from the hippocampus, prefrontal gray matter, and prefrontal white matter regions for subsequent analysis.The results of this study indicate that compared to the HC groups, patients with AD showed a significantly reduced phosphocreatine to inorganic phosphate ratio in the hippocampal region (p = 0.018). Meanwhile, the phosphomonoesters to phosphodiesters (PME/PDE) ratio in both the hippocampus and prefrontal gray matter exhibited a progressive increase along the HC-aMCI-AD disease continuum(all p < 0.001), although the difference between the aMCI and HC groups did not reach statistical significance in the frontal gray matter. Further analysis revealed a association between the elevated PME/PDE ratios in these brain regions and the decline in cognitive function. These findings support the potential of [31]P-MRSI as a noninvasive imaging tool for detecting metabolic alterations associated with Alzheimer's disease, providing important insights for future clinical research and early diagnosis.},
}

@article {pmid41259985,
year = {2025},
author = {Lin, C and Li, Q and Liu, G and Xi, Z and Yan, X and Li, S and He, L and Bai, P},
title = {Fe3O4@MoS2@Au-Ag microsphere-based ultrasensitive immunobiosensor for the early diagnosis of Alzheimer's disease.},
journal = {Talanta},
volume = {299},
number = {},
pages = {129127},
doi = {10.1016/j.talanta.2025.129127},
pmid = {41259985},
issn = {1873-3573},
abstract = {Alzheimer's Disease (AD), a most common neurodegenerative disease, has aroused people's great attention. Amyloid-β 1-42 (Aβ42) from serum/plasma has been listed as Core 1 biomarker in diagnostic guide and explore an ultrasensitive detection method of Aβ42 is of great significance for early AD diagnosis and treatment. Herein, an ultrasensitive fluorescent biosensor for Aβ42 detection is designed, which is composed of Fe3O4@MoS2 microsphere and Au-Ag alloy. Compared with typical single gold nanoparticles in traditional fluorescent biosensor, alloy nanoparticles can generate a stronger electromagnetic field to enhance the fluorescence of quantum dots via surface plasmon resonance, achieve the effect of signal amplification. Importantly, our design significantly improved the limit of detection to 11 ag/mL, with a linear response ranging from 0.1 to 10[4] fg/mL. Moreover, by replacing the detection antibody in the biosensor, it can also be applied to other common AD biomarkers, such as Aβ40 (linear range: 0.1 to 10[5] fg/mL, LOD: 61 ag/mL) and total Tau protein (linear range: 0.1 to 10[5] fg/mL, LOD: 40 ag/mL). The biosensor exhibited excellent performance in both spiked and real serum samples. This fluorescent biosensor based on Au-Ag alloy strategy with ultra-sensitivity and good selectivity, provides a reliable solution for AD's early diagnosis.},
}

@article {pmid41259881,
year = {2025},
author = {Zuliani, G and Gianfredi, V and Veronese, N and Volpe, M and Maggi, S and Onder, G and Silano, M and Nucci, D and Zanetti, M and Benussi, A and Burgio, MI and Fadda, M and Guindani, P and Sollai, S and Cereda, E and Caffarra, P},
title = {Efficacy of Mediterranean diet for the prevention of neurological diseases: A systematic review and meta-analysis featured in the Italian National Guidelines "La Dieta Mediterranea".},
journal = {Nutrition (Burbank, Los Angeles County, Calif.)},
volume = {142},
number = {},
pages = {112990},
doi = {10.1016/j.nut.2025.112990},
pmid = {41259881},
issn = {1873-1244},
abstract = {BACKGROUND: Neurological diseases, including Alzheimer's disease, depression, and Parkinson's disease, pose a growing public health challenge. Dietary patterns, particularly the Mediterranean diet (MD), have been proposed as modifiable factors for prevention. The aim of this systematic review and meta-analysis was to evaluate the association between adherence to the MD and the risk or progression of neurological conditions.

METHODS: This review was conducted in accordance with PRISMA 2020 and MOOSE guidelines. A comprehensive search of PubMed/MEDLINE, Scopus, Embase, and Cochrane Library was performed up to February 28, 2024. Study quality was assessed using the Newcastle-Ottawa Scale, and the certainty of evidence was evaluated with the NUTRIGRADE approach. Pooled effect sizes were computed using a random-effects model and expressed as risk ratios (RR), hazard ratios, or odds ratios, as appropriate.

RESULTS: Forty-five studies involving over 730 000 participants were included. Higher MD adherence was associated with reduced risk or prevalence of Alzheimer's disease (odds ratios = 0.92), mild cognitive impairment (RR = 0.93), depression (RR = 0.96), and Parkinson's disease (RR = 0.90), with moderate certainty of evidence. Limited evidence suggested reduced anxiety and lower mortality among patients with Alzheimer's disease. No significant associations were observed for dementia prevalence or progression from mild cognitive impairment to dementia.

CONCLUSIONS: Greater adherence to the MD is consistently associated with a lower risk of several neurological and mental health conditions. These findings support the promotion of MD-based dietary patterns in clinical and public health strategies to prevent cognitive decline and enhance healthy aging.},
}

@article {pmid41260074,
year = {2025},
author = {Alzarea, SI and Alsaidan, OA and Qasim, S and Alhassan, HH and Alzarea, AI and Alsahli, TG and Alharbi, M and Almutairi, M},
title = {A network pharmacology and in silico approach to target NEU1-mediated microglial activation in neuroinflammation: Validation in an LPS-induced mouse model.},
journal = {Computers in biology and medicine},
volume = {199},
number = {},
pages = {111318},
doi = {10.1016/j.compbiomed.2025.111318},
pmid = {41260074},
issn = {1879-0534},
abstract = {BACKGROUND: Neuroinflammation is a critical driver of neurodegenerative diseases such as Alzheimer's and Parkinson's. Activation of microglia through Toll-like receptor 4 (TLR4) signaling contributes to neuronal dysfunction. Neuraminidase 1 (NEU1) enhances TLR4 activation via desialylation, amplifying inflammatory cascades. This study investigates the therapeutic potential of NEU1 inhibition using Osthole (OST), identified through integrated network pharmacology and in silico modeling, with subsequent in vivo validation.

METHODS: NEU1 inhibitors were predicted using network pharmacology, followed by analysis of NEU1-related neuroinflammatory pathways via protein-protein interaction (PPI) networks, Gene Ontology (GO), and KEGG enrichment. OST, the top-ranked candidate, was evaluated in an LPS-induced neuroinflammation mouse model through behavioral assessments (Locomotor Activity, Y-Maze, Morris Water Maze). qPCR was used to quantify NEU1, CD11b, and cytokines (TNF-α, IL-1β, IL-6) in the hippocampus and prefrontal cortex. Molecular docking and molecular dynamics (MD) simulations were performed to assess OST-NEU1 binding and interaction stability.

RESULTS: OST significantly improved spatial memory in LPS-treated mice, reduced escape latency, and enhanced Y-maze performance. It downregulated NEU1 and CD11b expression, attenuating microglial activation, and suppressed pro-inflammatory cytokine expression. Docking showed a strong binding affinity of OST to NEU1 (-17 kcal/mol), with stable interactions confirmed by MD simulations (low RMSD and residue fluctuations).

CONCLUSION: NEU1 inhibition via OST reduces neuroinflammation and cognitive deficits in vivo. Computational modeling supports OST's stable and specific binding to NEU1, highlighting its potential as a lead compound against neuroinflammation in neurodegenerative disorders.},
}

@article {pmid41259504,
year = {2025},
author = {Sun, Y and Liu, S and Chen, L and Zhou, Z and Yin, X and Shi, Y and Li, H and Li, J and Lu, Y and Jiang, W and Zhao, Y and Dai, T and Yao, T and Li, A and Bi, X and Zhang, B and Shen, X and Zhu, Z and Wang, G and Li, X},
title = {AI-driven discovery of dual antiaging and anti-AD therapeutics via PROTAC target deconvolution of a super-enhancer-regulated axis.},
journal = {Science advances},
volume = {11},
number = {47},
pages = {eadz9283},
doi = {10.1126/sciadv.adz9283},
pmid = {41259504},
issn = {2375-2548},
mesh = {Humans ; *Melatonin/pharmacology/blood/therapeutic use ; *Alzheimer Disease/drug therapy/metabolism/genetics ; *Aging/drug effects ; *Artificial Intelligence ; Animals ; Proteolysis ; Mice ; *Drug Discovery/methods ; Male ; },
abstract = {The lack of safe, durable therapeutics that act against both biological aging and Alzheimer's disease is an unmet clinical need. To bridge this gap, we devised an artificial intelligence (AI)-enabled approach that pairs rapid compound triage with mechanistic target deconvolution. Our AI-driven screening highlighted melatonin (MLT) as a promising candidate. Serum profiling of 161 human individuals confirmed an age-related fall in circulating MLT level, while subsequent in vivo and in vitro experiments showed that MLT rescues cognition, suppresses neuroinflammation, and alleviates senescence phenotypes. Proteolysis targeting chimera (PROTAC)-guided chemoproteomic deconvolution next pinpointed the histone acetyltransferase p300 as MLT's target. Integrated Cleavage Under Targets and Tagmentation, single-cell RNA sequencing, and spatial transcriptomics revealed that MLT-bound p300 cooperates with specificity protein 1 (SP1) at a brain and muscle ARNT-like protein 1 super-enhancer, elevating histone H3 lysine-27 acetylation and reengaging a circadian-epigenetic program that links redox resilience to neuroprotection. By combining AI-driven discovery with PROTAC-based target mapping and super-enhancer-centric mechanistic resolution, our study identifies MLT as a dual-action candidate and sets out a reproducible "AI-to-clinic" paradigm for multitarget drug innovation in aging-related neurodegeneration.},
}

Humans
*Melatonin/pharmacology/blood/therapeutic use
*Alzheimer Disease/drug therapy/metabolism/genetics
*Aging/drug effects
*Artificial Intelligence
Animals
Proteolysis
Mice
*Drug Discovery/methods
Male

@article {pmid41259272,
year = {2025},
author = {von Salzen, D and Senn, K and Cho, HK and Cahill, CM and Rogers, JT and Cho, HD},
title = {PROTEIMERs as catalytic inhibitors of APP mRNA translation: Toward a new therapeutic for Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251393907},
doi = {10.1177/13872877251393907},
pmid = {41259272},
issn = {1875-8908},
abstract = {BackgroundThe rising prevalence of Alzheimer's disease (AD) highlights the urgent need for novel therapeutic approaches capable of suppressing further neurodegeneration. Aberrant aggregation of the amyloid-β peptide fragment of the amyloid-β protein precursor (APP) has long been considered to be a central feature of AD pathology. However, directly targeting the amyloid-β peptide is complicated by its conformational flexibility. Instead, reducing APP expression at the translational level represents a promising alternative. The highly structured 5' untranslated region (UTR) of APP mRNA provides a targetable element for selective inhibition using RNA-binding therapeutics.ObjectiveTo develop and evaluate engineered protein-based RNA binders (PROTEIMERs) that selectively target the APP 5'-UTR to inhibit translation.MethodsWe applied high-throughput phage display screening techniques to identify two PROTEIMERs with high affinity for the APP 5'-UTR, confirmed via surface plasmon resonance. Domain engineering enabled the fusion of these binders to an RNase domain to facilitate catalytic degradation of APP mRNA.ResultsPROTEIMERs bound the APP 5'-UTR with nanomolar affinity. Structural modeling of the PROTEIMER-RNA complexes revealed that the engineered mutations within the binding pocket predominantly interact with the 5'-AGA-3' cleft of the APP mRNA. RNase-fused PROTEIMERs mediated sequence-specific APP mRNA cleavage in vitro, demonstrating robust target engagement and degradation. The PROTEIMER ProAPPS3-11 effectively inhibited APP translation in SH-SY5Y cells, reducing protein levels by up to 60% in a dose-dependent manner.ConclusionsThese findings establish the feasibility of PROTEIMERs as novel RNA-targeting biologics with therapeutic potential to reduce APP mRNA and protein levels, mitigating downstream AD-related neurodegeneration.},
}

@article {pmid41259271,
year = {2025},
author = {So, I and Bouzigues, A and Russell, LL and Foster, PH and Ferry-Bolder, E and van Swieten, JC and Jiskoot, LC and Seelaar, H and Sanchez-Valle, R and Laforce, R and Graff, C and Galimberti, D and Vandenberghe, R and de Mendonça, A and Tiraboschi, P and Santana, I and Gerhard, A and Levin, J and Sorbi, S and Otto, M and Pasquier, F and Ducharme, S and Butler, CR and Le Ber, I and Tartaglia, MC and Masellis, M and Rowe, JB and Synofzik, M and Moreno, F and Borroni, B and Kolander, T and Mester, C and Brushaber, D and Kantarci, K and Heuer, HW and Forsberg, LK and Rohrer, JD and Boeve, BF and Boxer, AL and Rosen, HJ and Finger, EC and , },
title = {Neurodevelopmental effects of genetic frontotemporal dementia mutations revealed by total intracranial volume differences.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251393414},
doi = {10.1177/13872877251393414},
pmid = {41259271},
issn = {1875-8908},
abstract = {BackgroundConverging evidence hints at neurodevelopmental effects in people at risk of genetic frontotemporal dementia (FTD).ObjectiveWe investigated total intracranial volume (TIV), a neuroimaging marker of neurodevelopment, and years of education differences between adult mutation carriers and familial non-mutation carriers, as measures of the structural and functional neurodevelopmental effects of FTD-causing genetic mutations.MethodsThis cross-sectional cohort study, facilitated through the FTD Prevention Initiative (FPI), included 902 adult pathogenic mutation carriers of GRN, MAPT, or C9orf72, and 532 familial non-carriers. ANCOVAs were computed to compare TIV and education between groups per gene. Pearson's correlations were used to examine associations between TIV and education.ResultsMutation carriers (mean ± SD age = 50.0 ± 13.2 years, sex = 55% female, n(GRN) = 298, n(MAPT) = 187, n(C9orf72) = 417) were compared to familial non-carriers (age = 48.0 ± 12.9 years, sex = 58% female, n(GRN) = 201, n(MAPT) = 114), n(C9orf72) = 217). Consistent with prior findings in young adults, GRN carriers showed larger TIV, on average by 20531 mm[3], compared to familial non-carriers (95% CI [85.4, 40977], p = 0.049, η[2]p = 0.008). Larger TIV correlated with higher years of education in GRN carriers (95% CI [0.01, 0.24], r(295) = 0.12, p = 0.03) and GRN non-carriers (95% CI [0.08, 0.34], r(198) = 0.21, p = 0.002). MAPT carriers demonstrated smaller TIV than non-carriers, on average by 29896 mm[3] (95% CI [-58248, -1545], p = 0.039, η[2]p = 0.02). Models with C9orf72 and education as outcome variables did not reveal significant differences.ConclusionsIn support of the neurodevelopmental hypothesis of FTD, GRN and MAPT mutations are linked to structural neurodevelopmental changes in TIV. Further research is needed to identify mechanisms underlying neurodevelopmental influences of FTD mutations and ascertain their suitability as intervention targets.},
}

@article {pmid41259269,
year = {2025},
author = {Wang, K and Zhu, Y and Albert, M and Miller, M and Davatzikos, C and Moghekar, A and Soldan, A and Wang, MC and , },
title = {Modeling the age-specific incidence of mild cognitive impairment incorporating the time-varying relationship of Alzheimer's disease biomarkers over 28 years.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251393729},
doi = {10.1177/13872877251393729},
pmid = {41259269},
issn = {1875-8908},
abstract = {BackgroundAs life expectancy increases, the prevalence of mild cognitive impairment (MCI) due to Alzheimer's disease is expected to rise. Biomarkers from cerebrospinal fluid (CSF) and magnetic resonance imaging (MRI), combined with age-specific modeling, may enhance understanding of the timing and risk factors of MCI onset.ObjectiveTo estimate age-specific incidence rates of MCI onset and examine the impact of biomarkers and demographic factors on risk.MethodsWe analyzed data from 307 cognitively unimpaired BIOCARD participants with one or more CSF and MRI measurements. To account for competing risk of death, we applied age-specific cumulative incidence functions and cause-specific Cox proportional hazard models. Time-varying biomarker values were incorporated to assess their influence on MCI risk.ResultsThe cumulative incidence rate of MCI onset estimated in age brackets from 50 to 80 was 2.33% at age 55, 5.03% at age 60, 12.38% at age 65, 17.91% at age 70, 28.84% at age 75, and 46.91% at age 80. APOE4 carriers had a significantly increased risk before age 70 (HR = 9.55, p = 0.005). Female APOE4 carriers showed a non-significant trend toward reduced risk compared to males (HR = 0.35, p = 0.127). Faster decline in entorhinal cortex volume (HR = 1.24, p = 0.028) and elevated p-tau181 levels (HR = 1.51, p = 0.012) were both associated with increased MCI risk.ConclusionsThis study presents age-specific incidence rates of MCI and highlights the age-dependent influence of genetic and biomarker risk factors. Incorporating time-varying biomarkers provides valuable insights into dynamic risk prediction for MCI onset.},
}

@article {pmid41259262,
year = {2025},
author = {Potts, Y and Daykin, H and Bossche, MVD and McDougall, SJ and Jacobson, LH},
title = {Characterization of locus coeruleus neuronal properties with aging in two mouse models of tauopathy.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251393515},
doi = {10.1177/13872877251393515},
pmid = {41259262},
issn = {1875-8908},
abstract = {BackgroundThe locus coeruleus (LC) is involved in the modulation of sleep and wakefulness. In humans, tau pathology develops in the LC decades before Alzheimer's disease (AD) cognitive symptoms manifest. Widespread LC degeneration is observed with disease progression; however, there is a paucity of research exploring the effect of tau pathology on the functional properties of LC neurons prior to cell death.ObjectiveTo investigate the intrinsic electrical properties of LC neurons in aged PS19 and rTg4510 tau transgenic murine models.MethodsWhole cell recordings of LC neurons were performed in two murine models of tauopathy, the PS19 and rTg4510 strains, versus respective age-matched wildtype (WT) littermate controls.ResultsBasic LC neuronal properties were not significantly different from WT in either PS19 or rTg4510 mice at 9 months of age, which represents a stage where AD-like symptoms are evident, and tau pathology is present in the LC. However, the resting membrane potential of LC neurons was significantly depolarized in 9-month-old PS19 transgenic mice, compared to 5-month-old PS19 transgenic mice.ConclusionsTau pathology may act to accelerate aging, contributing to hyperactivity of the LC and consequent sleep disruption in patients with tauopathy.},
}

@article {pmid41259166,
year = {2025},
author = {Deng, Z and Wang, S and Aviles-Rivero, AI and Kourtzi, Z and Schonlieb, CB},
title = {HIBMatch: Hypergraph Information Bottleneck for Semi-Supervised Alzheimer's Progression.},
journal = {IEEE journal of biomedical and health informatics},
volume = {PP},
number = {},
pages = {},
doi = {10.1109/JBHI.2025.3634534},
pmid = {41259166},
issn = {2168-2208},
abstract = {Alzheimer's disease progression prediction is critical for patients with early Mild Cognitive Impairment (MCI) to enable timely intervention and improve their quality of life. While existing progression prediction techniques demonstrate potential with multimodal data, they are highly limited by their reliance on labelled data and fail to account for a key element of future progression prediction: not all features extracted at the current moment may be relevant for predicting progression several years later. To address these limitations in the literature, we design a novel semi-supervised multimodal learning hypergraph architecture, termed HIBMatch, by harnessing hypergraph knowledge based on information bottleneck and consistency regularisation strategies. Firstly, our framework utilises hypergraphs to represent multimodal data, encompassing both imaging and non-imaging modalities. Secondly, to harmonise relevant information from the currently captured data for future MCI conversion prediction, we propose a Hypergraph Information Bottleneck (HIB) that discriminates against irrelevant information, thereby focusing exclusively on harmonising relevant information for future MCI conversion prediction. Thirdly, our method enforces consistency regularisation between the HIB and a discriminative classifier to enhance the robustness and generalisation capabilities of HIBMatch under both topological and feature perturbations. Finally, to fully exploit the unlabeled data, HIBMatch incorporates a cross-modal contrastive loss for data efficiency. Extensive experiments on the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset demonstrate that our proposed HIBMatch framework surpasses existing state-of-the-art methods in Alzheimer's disease prognosis.},
}

@article {pmid41259024,
year = {2025},
author = {Marino, FR and Lyu, C and Li, Y and Liu, T and Au, R and Hwang, PH},
title = {Physical Activity Over the Adult Life Course and Risk of Dementia in the Framingham Heart Study.},
journal = {JAMA network open},
volume = {8},
number = {11},
pages = {e2544439},
doi = {10.1001/jamanetworkopen.2025.44439},
pmid = {41259024},
issn = {2574-3805},
mesh = {Humans ; Female ; Male ; *Exercise/physiology ; Middle Aged ; *Dementia/epidemiology/prevention & control ; Aged ; Prospective Studies ; Risk Factors ; Adult ; Alzheimer Disease/epidemiology ; },
abstract = {IMPORTANCE: Being physically active is protective against dementia. Yet, it is unknown when during the adult life course physical activity is most associated with dementia risk.

OBJECTIVE: To determine whether higher physical activity levels in early adult life, midlife, or late life are associated with lower risk of all-cause or Alzheimer disease (AD) dementia.

This prospective cohort study used data from the Framingham Heart Study Offspring cohort. The offspring of participants in the original Framingham Heart Study cohort who were dementia free and had physical activity measured at baseline (early adult life [1979-1983], midlife [1987-1991], or late life [1998-2001]) were followed up for a mean (SD) of 37.2 (7.1), 25.9 (8.5), or 14.5 (6.6) years for the development of incident all-cause or AD dementia until December 31, 2023.

EXPOSURE: Physical activity was self-reported using the physical activity index, a composite score weighted by hours spent sleeping and in sedentary, slight, moderate, or heavy activities. Physical activity was divided into quintiles (Q).

MAIN OUTCOME AND MEASURE: All-cause and AD dementia were classified by expert consensus based on established diagnostic criteria.

RESULTS: This study included 1526 early adult-life (mean [SD] age, 36.7 [4.7] years; 821 [53.8%] female), 1943 midlife (mean [SD] age, 54.0 [5.8] years; 1010 [52.0%] female), and 885 late-life (mean [SD] age, 71.0 [4.5] years; 473 [53.4%] female) participants. There were 567 cases of incident all-cause dementia during follow-up. Higher levels of midlife and late-life physical activity were associated with lower risk of all-cause dementia. Midlife and late-life physical activity levels in Q4 or Q5 were associated with lower risk of all-cause dementia compared with Q1 (midlife Q4: HR, 0.60; 95% CI, 0.41-0.89; midlife Q5: HR, 0.59; 95% CI, 0.40-0.88; late-life Q4: HR, 0.64; 95% CI, 0.42-1.00; late-life Q5: HR, 0.55; 95% CI, 0.35-0.87). There were no associations between early adult-life physical activity and dementia risk. Findings were similar for incident AD (369 cases).

CONCLUSIONS AND RELEVANCE: In this cohort study of adults in the Framingham Heart Study Offspring cohort, higher levels of midlife and late-life physical activity were associated with similar reductions in risk of all-cause and AD dementia. These findings may inform future efforts to delay or prevent dementia through timing interventions during the most relevant stages of the adult life course.},
}

Humans
Female
Male
*Exercise/physiology
Middle Aged
*Dementia/epidemiology/prevention & control
Aged
Prospective Studies
Risk Factors
Adult
Alzheimer Disease/epidemiology

@article {pmid41258757,
year = {2025},
author = {Saini, TC and Randhawa, S and Bathla, M and Nisha, A and Teji, N and Acharya, A},
title = {Nanoengineered Polyphenol-Quantum Dot Conjugates Inhibit Biofilm Protein-Aβ42 Heterotypic Fibrillogenesis, Restore Synaptic Transmission, and Suppress Apoptosis in Alzheimer's Disease.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00467},
pmid = {41258757},
issn = {1948-7193},
abstract = {The gut microbiota influences neurodegenerative disease progression, including Alzheimer's disease (AD), through microbial metabolites like amyloids in bacterial biofilms, such as the curli protein in Eshcherichia coli biofilm. In this context, the study focuses on two key aspects, namely, (i) how cross-kingdom bacterial biofilm proteins accelerate Aβ42 aggregation and induce neurotoxicity and (ii) whether a nanochaperone with hydrophobic sheets and hydrophilic polyphenolic moieties could inhibit cross-seeded aggregation. Considering this, we chemically synthesized and further characterized gallic acid-conjugated molybdenum disulfide quantum dots (GA@MoS2 QDs, ∼9.6 ± 4.2 nm) using spectroscopy and microscopy techniques, which showed ∼1.84-fold reduction in E. coli biofilm thickness, indicating interaction with biofilm components. The presence of the curli protein in E. coli was confirmed by dot blot and MALDI-TOF studies. Subsequent biophysical studies showed that isolated E. coli biofilm protein accelerated Aβ42 aggregation (heterotypic) by ∼6.76-fold, while GA@MoS2 QDs reduced this heterotypic aggregation by ∼9.49-fold reduction in Aβ42+ECBFP fluorescence relative to Aβ42 aggregates. In vitro studies with SH-SY5Y cells showed that heterotypic protein aggregation led to increased ROS production, intracellular calcium influx, and apoptosis induction, which were mitigated by GA@MoS2 QDs. The neuroprotective effect of GA@MoS2 QDs was also studied on Caenorhabditis elegans. Overall, the present studies suggested that the bacterial amyloid proteins may play a crucial role in Aβ42 aggregation, suggesting that targeting coaggregation could provide a novel therapeutic approach for the treatment of early onset AD.},
}

@article {pmid41258645,
year = {2025},
author = {Katsuse, K and Kakinuma, K and Niimi, Y and Iseki, C and Kawakami, N and Ota, S and Kawamura, A and Ogawa, N and Yano, S and Kakumoto, T and Takao, H and Hamada, M and Kanno, S and Toda, T and Suzuki, K},
title = {Lecanemab for posterior cortical atrophy: Two contrasting cases.},
journal = {The Clinical neuropsychologist},
volume = {},
number = {},
pages = {1-23},
doi = {10.1080/13854046.2025.2590527},
pmid = {41258645},
issn = {1744-4144},
abstract = {OBJECTIVE: This study aimed to evaluate the clinical implications, limitations, and potential risks of lecanemab treatment for posterior cortical atrophy (PCA) by conducting a comparative analysis of two cases.

METHOD: We retrospectively analyzed two patients with biomarker-confirmed PCA-pure who met the eligibility criteria for lecanemab. Clinical history, neuropsychological profiles, imaging findings, and treatment outcomes for more than 1 year were comprehensively reviewed.

RESULTS: At treatment initiation, Patients 1 and 2 were one year post-onset and five years post-onset, respectively, with comparable baseline Mini-Mental State Examination (25-26) and Clinical Dementia Rating (0.5) scores. Patient 1, who exhibited prominent agraphia with left-dominant parieto-occipital atrophy, began lecanemab early and maintained stable daily functioning despite a gradual decline in reading, figure copying, and visual cancelation tasks. Patient 2, with right-dominant posterior atrophy and more severe visuospatial deficits, including simultanagnosia and prosopagnosia, developed parkinsonism and hallucinations after treatment initiation, followed by rapid functional decline, possibly due to mixed pathology, ultimately leading to treatment discontinuation. Patient 1 reported high treatment satisfaction, whereas Patient 2 expressed regret.

CONCLUSION: These cases raise concerns regarding the direct application of treatment eligibility criteria developed for typical Alzheimer's disease to PCA. Clinical decision-making in PCA requires visual cognition-specific assessments that are less vulnerable to floor effects and tailored to phenotypic heterogeneity and hemispheric lateralization. Coexisting pathologies may influence the treatment response and complicate the interpretation of outcomes. A tailored, multimodal approach that integrates longitudinal neuropsychological assessments with advanced imaging is essential to ensure appropriate use of disease-modifying therapies for PCA.},
}

@article {pmid41258314,
year = {2025},
author = {Zhang, C and Tu, X and Cui, Z and Gu, X and Li, K and Lu, Y},
title = {A general lightweight image super-resolution with sharpening enhancement and double attention network.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {40848},
pmid = {41258314},
issn = {2045-2322},
support = {252102210147, 252102210083//Henan Province Science and Technology Research Project/ ; 2025TJJBKY008//Fundamental Research Funds for the Central Universities/ ; 23A520042//Key Research Projects of Higher Education Institutions in Henan Province/ ; },
abstract = {In recent years, single image super-resolution (SISR) based on deep learning has achieved excellent results. However, the consequent elevated computational and storage expenses limit its practicability in real life. Researchers seek a lightweight SISR network that minimizes computational load while maintaining high performance. To address this challenge, we introduce a general lightweight image super-resolution with sharpening enhancement and double attention network (ESDAN) to optimize the trade-off between model complexity and performance. The network achieves a balance between model complexity and performance through the Sharpening Enhancement Module (SEM) and the Dual Attention Upsampling module (DAU). Specifically, SEM effectively integrates the Attention-Driven Feature Sharpening module (ADFS) to enhance feature contrast and the Multi-Way Feature Enhancement module (MWFE) to reinforce key information, optimizing both the representation ability of composite features and the nonlinear mapping ability of the model. Moreover, DAU dynamically fuses shallow and deep features to enhance the model's reconstruction capability. Extensive experimental results demonstrate that the proposed network surpasses contemporary state-of-the-art lightweight SISR methods. Additionally, we explore the potential of ESDAN in other SISR-related tasks, such as super-resolution of Alzheimer's disease brain MRI, stereo endoscopic images, and surveillance images. The experimental results demonstrate the high versatility of the proposed network. The source code is available at https://github.com/Czs138/ESDAN .},
}

@article {pmid41258170,
year = {2025},
author = {Dong, W and Tian, Z and Bai, J and Wu, B and Zhao, M and Zhang, Y and Shao, J and Xie, T and Li, Q and Wu, P and Xue, J and Chen, Y and Zhou, X and Du, Y and Gao, S and Pan, H and Peng, A and Pan, Y and Zhou, K and Jiang, H},
title = {Polygenic risk score and cluster-based analysis suggests links between type 2 diabetes and vascular dementia in the KARE study.},
journal = {Nature communications},
volume = {16},
number = {1},
pages = {10135},
pmid = {41258170},
issn = {2041-1723},
mesh = {Humans ; *Diabetes Mellitus, Type 2/genetics/complications/epidemiology ; *Dementia, Vascular/genetics/epidemiology ; Male ; Female ; Aged ; Risk Factors ; *Multifactorial Inheritance/genetics ; Genetic Predisposition to Disease ; Cluster Analysis ; Middle Aged ; China/epidemiology ; Alzheimer Disease/genetics/epidemiology ; Aged, 80 and over ; Cohort Studies ; Hyperinsulinism/genetics ; Asian People/genetics ; Genome-Wide Association Study ; Incidence ; Genetic Risk Score ; },
abstract = {Type 2 diabetes is an established risk factor for dementia. However, how its genetic heterogeneity affects different dementia subtypes remains unclear. In this study, we investigate the associations between genetic risk of type 2 diabetes and dementia subtypes among 33,136 older Chinese adults from the KARE cohort. We find that a higher overall polygenic risk score for type 2 diabetes is significantly associated with an increased risk of vascular dementia, but not Alzheimer's disease. Further analyses using cluster-specific partitioned polygenic score show that elevated genetic risk specific to the hyperinsulinemia pathway is strongly associated with increased incidence of vascular dementia. These findings highlight the potential role of insulin-related metabolic abnormalities in the pathogenesis of vascular dementia and provide genetic evidence to support the use of the hyperinsulinaemia pathway as a clinically relevant marker for early risk stratification and precision prevention strategies.},
}

Humans
*Diabetes Mellitus, Type 2/genetics/complications/epidemiology
*Dementia, Vascular/genetics/epidemiology
Male
Female
Aged
Risk Factors
*Multifactorial Inheritance/genetics
Genetic Predisposition to Disease
Cluster Analysis
Middle Aged
China/epidemiology
Alzheimer Disease/genetics/epidemiology
Aged, 80 and over
Cohort Studies
Hyperinsulinism/genetics
Asian People/genetics
Genome-Wide Association Study
Incidence
Genetic Risk Score

@article {pmid41258123,
year = {2025},
author = {Shamsi, A and Zain, NNM and Dinislam, K and Alzahrani, AA and Khan, MS and Shahwan, M},
title = {Exploring the binding of cinchonine with human transferrin: combined experimental and computational approaches.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {40660},
pmid = {41258123},
issn = {2045-2322},
mesh = {Humans ; *Transferrin/metabolism/chemistry ; Molecular Docking Simulation ; Protein Binding ; Binding Sites ; Molecular Dynamics Simulation ; Ligands ; },
abstract = {Neurodegenerative diseases (NDs), like Alzheimer's disease (AD), present immense global health challenges, marked by progressive and irreversible neuronal loss. While many studies have reported the neuroprotective potential of various phytochemicals, the neurotherapeutic relevance of alkaloids, like cinchonine remains largely unexplored. This study for the first time investigates cinchonine, a natural Cinchona alkaloid with reported antioxidant, anti-inflammatory, and amyloid-inhibitory properties, for its interaction with human transferrin (hTf), a glycoprotein central to iron homeostasis and neuroprotection employing a combination of computational and experimental approaches. UV-Vis spectroscopy revealed significant changes in hTf's absorbance upon cinchonine binding, confirming stable protein-ligand complex formation, with a binding constant (K) of 0.7 × 10[5] M[- 1]. Fluorescence binding assay further validated the formation of a stable protein-ligand complex. Cinchonine binds with hTf with a binding constant (K) of 0.4 × 10[6] M[- 1], signifying the strength of interaction. Molecular docking pinpointed cinchonine's specific binding site on hTf with a binding affinity of - 6.9 kcal/mol and its interactions with critical residues like Thr392. These findings were reinforced by molecular dynamics (MD) simulations and MM-PBSA, which showcased the stability and conformational integrity of the hTf-cinchonine complex over time. Additionally, hydrogen bonding and free energy analyses provided deeper insights into the molecular basis of the protein-ligand complex. All the findings imply the formation of a stable hTf-cinchonine complex. This study underscores cinchonine's potential as a therapeutic lead, generating hypotheses for future experimental validation of its efficacy in preventing or mitigating NDs.},
}

Humans
*Transferrin/metabolism/chemistry
Molecular Docking Simulation
Protein Binding
Binding Sites
Molecular Dynamics Simulation
Ligands

@article {pmid41258051,
year = {2025},
author = {Shu, J and Zheng, R and Chirinos, J and Copana, C and Li, B and Fan, Z and Yang, X and Yang, Y and Wang, X and Li, Y and Xi, B and Li, T and Zhu, H and Zhao, B},
title = {Inferring multi-organ genetic connections using imaging and clinical data through Mendelian randomization.},
journal = {Nature biomedical engineering},
volume = {},
number = {},
pages = {},
pmid = {41258051},
issn = {2157-846X},
abstract = {Understanding the complex relationships among major clinical outcomes and the interplay among multiple organs remains a considerable challenge. By using imaging phenotypes, we can characterize the functional and structural architecture of major human organs. Mendelian randomization (MR) provides a valuable framework for uncovering robust relationships between phenotypes by leveraging genetic variants as instrumental variables. Here we conduct a systematic multi-organ MR analysis involving 402 imaging traits and 372 clinical outcomes. Our analysis reveals 184 MR associations for 58 diseases and 56 imaging traits across various organs, tissues and systems, including the brain, heart, liver, kidney, lung, pancreas, spleen, adipose tissue and skeletal system. We identify intra-organ MR connections, such as the putative bidirectional genetic links between Alzheimer's disease and brain function, and interorgan associations, such as heart diseases and brain health. Metabolic disorders, such as diabetes, show genetically rooted putative MR effects across multiple organs. These findings shed light on the genetic links spanning multiple organs, providing targets for future mechanistic follow-up for clinical disease research.},
}

@article {pmid41258002,
year = {2025},
author = {Yang, C and Wang, P and Zhu, Z and Wu, H and Su, Q and Zhu, S and Shao, Y and Lin, H and Biswal, BB},
title = {Individualized functional connectome biomarkers predict clinical symptoms after rTMS treatment in Alzheimer's disease.},
journal = {Translational psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41398-025-03726-4},
pmid = {41258002},
issn = {2158-3188},
abstract = {Pharmacological treatments for Alzheimer's disease (AD) often show limited effectiveness, prompting growing interest in non-drug approaches such as repetitive transcranial magnetic stimulation (rTMS). However, the effects of rTMS can vary widely between individuals with AD, highlighting the need to better understand brain characteristics that may influence treatment response. In this study, we applied a personalized method to divide each participant's brain cortex into functionally meaningful regions based on their brain activity patterns, rather than relying on a standard brain template. Using this individualized brain mapping approach, we examined how rTMS changes functional connectivity (FC) across the brain. We further used support vector regression to estimate whether these individualized FC patterns could predict the severity of clinical symptoms. The results showed that rTMS significantly increased whole-brain individualized FC strength during resting state, with the most prominent effects observed in the default mode and visual networks (Cohen's d > 0.27, corrected p < 0.05). Importantly, the personalized FC features served as predictive biomarkers, demonstrating greater accuracy in forecasting clinical outcomes compared to the conventional group-based approach. These findings suggest that individualized brain connectivity holds significant potential for guiding personalized therapeutic strategies and improving treatment efficacy in AD.},
}

@article {pmid41257901,
year = {2025},
author = {Pezhouh, MK and Chen, G and Meints, J and Hemmy, LS and SantaCruz, KS and Lee, MK},
title = {Tau pathology in the brainstem monoaminergic neurons reflect resilience to Alzheimer's disease pathology in the Nun study cases.},
journal = {Acta neuropathologica communications},
volume = {13},
number = {1},
pages = {239},
pmid = {41257901},
issn = {2051-5960},
support = {AG029401/NH/NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/pathology/metabolism ; *tau Proteins/metabolism ; Female ; Male ; *Brain Stem/pathology/metabolism ; Aged ; *Neurons/pathology/metabolism ; Aged, 80 and over ; Locus Coeruleus/pathology/metabolism ; Middle Aged ; *Biogenic Monoamines/metabolism ; },
abstract = {The presence of amyloid and tau pathologies is the pathological hallmark of Alzheimer's disease (AD). However, the presence of non-demented individuals with sufficient AD pathology indicates that AD-linked pathology does not always lead to dementia. The current view is that a non-demented (ND) individual with sufficient AD pathology represents an individual resilient to AD pathology. To gain insight about resilience to AD pathology, we examined the neuropathology in the brainstem monoaminergic (MAergic) neurons in the Nun Study participants with equally high Braak AD stage (V-VI) with dementia and without clinical dementia. Because MAergic pathology is thought to occur in response to cortical AD pathology, any differences in MAergic pathology between the AD and ND groups with similarly advanced AD pathology could reflect the resilience of MAergic neurons to cortical AD pathology. Examination of Locus Coeruleus (LC) and/or Raphe for the presence of tau pathology showed that, despite the similar forebrain pathology, relative levels of perikaryal and neuritic tau pathology were significantly lower in ND than in AD subjects. The ND subjects exhibit greater pathology than control subjects without AD pathology, indicating that cortical AD pathology does impact subcortical neurons in both AD and ND cases. Significantly, the extent of neurodegenerative pathology in LC and Raphe neurons correlated with cognitive performance in AD cases, while no such correlation was seen in ND cases. Our results show that while cortical AD pathology is associated with increased MAergic neuropathology, quantitative differences in the extent of MAergic pathology in the brainstem may reflect underlying resistance to AD pathology.},
}

Humans
*Alzheimer Disease/pathology/metabolism
*tau Proteins/metabolism
Female
Male
*Brain Stem/pathology/metabolism
Aged
*Neurons/pathology/metabolism
Aged, 80 and over
Locus Coeruleus/pathology/metabolism
Middle Aged
*Biogenic Monoamines/metabolism

@article {pmid41257741,
year = {2025},
author = {Kovbasyuk, Z and Tefera, E and Li, C and Baete, SH and Steriade, C},
title = {Imaging brain inflammation and blood brain barrier permeability in neurological and psychiatric diseases: a review.},
journal = {Journal of neuroinflammation},
volume = {22},
number = {1},
pages = {275},
pmid = {41257741},
issn = {1742-2094},
support = {R01NS126156/NS/NINDS NIH HHS/United States ; },
mesh = {Humans ; *Blood-Brain Barrier/diagnostic imaging/metabolism ; *Mental Disorders/diagnostic imaging/metabolism ; Animals ; *Neuroinflammatory Diseases/diagnostic imaging/metabolism ; Positron-Emission Tomography/methods ; *Neuroimaging/methods ; Magnetic Resonance Imaging/methods ; *Encephalitis/diagnostic imaging/metabolism ; *Nervous System Diseases/diagnostic imaging ; },
abstract = {Neuroinflammation involving glial cell activation and BBB dysfunction has increasingly been recognized as a key feature of neuropsychiatric disorders. In vivo imaging methods, particularly translocator protein positron emission tomography (TSPO-PET) and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), have advanced our understanding of glial activation and BBB permeability in conditions such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, Huntington's disease, schizophrenia, and depression. We present key findings from the clinical application of these imaging modalities and highlight critical methodological challenges-including variability in study protocols, tracer selection, input function derivation, and parameter estimation-that currently limit cross-study comparability and clinical translation. TSPO-PET and DCE-MRI provide valuable clinical insights on the inflammatory mechanisms contributing to CNS disease at various disease stages. Future methodological standardization, co-localization studies, and longitudinal multi-modal applications will be crucial for using these tools as markers of disease in the context of immune interventions in at-risk populations.},
}

Humans
*Blood-Brain Barrier/diagnostic imaging/metabolism
*Mental Disorders/diagnostic imaging/metabolism
Animals
*Neuroinflammatory Diseases/diagnostic imaging/metabolism
Positron-Emission Tomography/methods
*Neuroimaging/methods
Magnetic Resonance Imaging/methods
*Encephalitis/diagnostic imaging/metabolism
*Nervous System Diseases/diagnostic imaging

@article {pmid41257439,
year = {2025},
author = {Vázquez-Oliver, A and Pérez-García, S and Romero-Pérez, R and Pizarro, N and Galarraga-Shinin, D and Molina-Porcel, L and de la Torre, R and Maldonado, R and Ozaita, A},
title = {Targeting dysregulated CB1 receptors in a Down syndrome mouse model improves neurological outcomes.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70874},
doi = {10.1002/alz.70874},
pmid = {41257439},
issn = {1552-5279},
support = {RTI2018-099282-B-I00//Ministerio de Ciencia, Innovación y Universidades/ ; PID2021-123482OB-I00-/MICIN/AEI/10.13039/501100011033/FEDER//Ministerio de Ciencia, Innovación y Universidades/ ; PID2020- 120029GB-I00/MICIN/AEI/10.13039/501100011033//Ministerio de Ciencia, Innovación y Universidades/ ; 1896_GRT-2019B//Fondation Jérôme Lejeune/ ; #2416_GRT-2024B//Fondation Jérôme Lejeune/ ; CA2018010//Bright Focus foundation/ ; RD16/0017/0020//Ministerio de Sanidad, Servicios Sociales e Igualdad/ ; 2017SGR-669//Departament de Recerca i Universitats, Generalitat de Catalunya/ ; 2017SGR-138//Departament d'Economia i Coneixement, Generalitat de Catalunya/ ; //Institució Catalana de Recerca i Estudis Avançats, ICREA-Acadèmia 2021/ ; },
mesh = {Animals ; *Down Syndrome/metabolism/drug therapy ; *Receptor, Cannabinoid, CB1/metabolism/antagonists & inhibitors ; Mice ; Disease Models, Animal ; *Hippocampus/metabolism/drug effects ; *Rimonabant/pharmacology ; Humans ; Male ; Female ; Alzheimer Disease/metabolism ; *Cannabinoid Receptor Antagonists/pharmacology ; Mice, Transgenic ; Middle Aged ; },
abstract = {INTRODUCTION: Down syndrome (DS) is the most common genetic cause of intellectual disability, affecting cognitive function and increasing the risk of early-onset Alzheimer's disease (AD). The endocannabinoid system may serve as a therapeutic target for cognitive deficits by inhibiting cannabinoid type-1 receptor (CB1R) function.

METHODS: CB1R expression was analyzed in the hippocampi of aged DS-associated AD (DSAD) individuals and middle-aged Ts65Dn mice. Long-term oral treatment with the CB1R antagonist rimonabant was used to assess its effects on memory and neuroinflammation in the Ts65Dn mouse model of DS.

RESULTS: CB1R expression was significantly increased in both aged DSAD subjects (specifically in the dentate gyrus and CA2 posterior hippocampal subregions) and Ts65Dn mice. Long-term rimonabant treatment improved memory performance, normalized microglial morphology, and reduced plasma inflammatory markers in trisomic mice without preventing neuron decline.

DISCUSSION: These findings suggest that sustained CB1R inhibition may enhance cognitive function by modulating neuroinflammation, highlighting its therapeutic potential for cognitive impairments in DS.

HIGHLIGHTS: Cannabinoid type-1 receptor (CB1R) expression is increased in the posterior hippocampus of aged Down syndrome (DS) subjects and Ts65Dn mice. Long-term rimonabant treatment enhances memory in middle-aged Ts65Dn mice. CB1R inhibition shifts neuroinflammatory features in Ts65Dn mice. CB1R inhibition does not halt noradrenergic/cholinergic neurodegeneration in Ts65Dn. CB1R inhibition presents potential for memory improvement in DS-related deficits.},
}

Animals
*Down Syndrome/metabolism/drug therapy
*Receptor, Cannabinoid, CB1/metabolism/antagonists & inhibitors
Mice
Disease Models, Animal
*Hippocampus/metabolism/drug effects
*Rimonabant/pharmacology
Humans
Male
Female
Alzheimer Disease/metabolism
*Cannabinoid Receptor Antagonists/pharmacology
Mice, Transgenic
Middle Aged

@article {pmid41257351,
year = {2025},
author = {Zeiss, CJ and Duque, A and Huttner, A},
title = {Neuropathology and Biomarker Correlates of Late Onset Alzheimer's Disease in Aged Old World Monkeys.},
journal = {Toxicologic pathology},
volume = {},
number = {},
pages = {1926233251388069},
doi = {10.1177/01926233251388069},
pmid = {41257351},
issn = {1533-1601},
abstract = {Non-invasive predictive biomarkers for preclinical Alzheimer's disease (AD) may inform future dementia risk and support early intervention for AD. In this review, we describe clinical, biomarker and neuropathologic characteristics in spontaneously aged Old World monkeys (OWMs) in the context of preclinical AD. Reliable age-related amyloid-β (Aβ) plaque deposition occurs in OWMs. Plaque composition is complex, signifying significant disruption of synaptic connectivity. Pretangle pTau pathology in brainstem nuclei and limbic system prevails, consistent with Braak Stage 1b in macaques. Soluble pTau distribution approximates Braak Stage III-IV stage in perfused frozen macaque tissue, and colocalizes with Aβ and acetylcholinesterase labeling in AD-vulnerable circuits. Tau and Aβ pathology in OWMs is accompanied by fluid biomarker changes consistent with Core 1 AD diagnosis in humans but cannot be visualized using amyloid or tau tracers. Despite age-related cognitive decline, aging OWMs do not experience significant hippocampal atrophy or neuropathologic co-morbidities. Minimal expression of senescence markers implicates differences in rates of biological brain aging between OWMs and humans. OWMs support mechanistic studies and biomarker discovery in the areas of Aβ plaque and pTau evolution and resolution following anti-amyloid or Tau-directed therapeutics, as well as effects of senotherapeutics, lifestyle intervention or co-morbidities on biological brain aging.},
}

@article {pmid41257331,
year = {2025},
author = {Marien, J and Prévost, C and Sacquin-Mora, S},
title = {Across (Conformational) Space and (Relaxation) Time: Using Coarse-Grain Simulations to Probe the Intra- and Interdomain Dynamics of the Tau Protein.},
journal = {The journal of physical chemistry. B},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jpcb.5c06282},
pmid = {41257331},
issn = {1520-5207},
abstract = {The biological importance of intrinsically disordered proteins (IDPs) has been established for over two decades, yet these systems remain difficult to characterize, as they are better described by conformational ensembles instead of a single reference structure for their folded counterparts. Tau is a prominent member of the IDP family, which sees its cellular function regulated by multiple phosphorylation sites and whose hyperphosphorylation is involved in neurodegenerative diseases such as Alzheimer's. We used coarse-grain MD simulations with the CALVADOS model to investigate the conformational landscape of tau without and with phosphorylations. Characterizing the local compactness of IDPs allows us to highlight how disorder comes in various flavors, as we can define different domains along the tau sequence. We define the IDP's Statistical Tertiary Organization (STO) as the average spatial arrangements of domains, which constitute an extension of the tertiary structure of folded proteins. We also use IDP-specific metrics to characterize the local curvature and flexibility of tau. Comparing the local flexibilities with T2 relaxation times from NMR experiments, we show how this metric is related to the protein dynamics. A curvature and flexibility pattern in the repeat domains can also be connected to tau binding properties, without having to explicitly model the protein's interaction partner. Finally, we rediscuss the original paperclip model that describes the spatial organization of tau and how phosphorylations impact it. The resulting changes in the protein intradomain and interdomain interaction pattern allow us to propose experimental setups to test our hypothesis.},
}

@article {pmid41257254,
year = {2024},
author = {da Costa, PJ and Perret, A and Buée, L and Hamdane, M and Martin, F},
title = {FTLD-MAPT mutations and short 5'UTR Tau mRNAs increase Tau translation.},
journal = {NAR molecular medicine},
volume = {1},
number = {4},
pages = {ugae023},
pmid = {41257254},
issn = {2976-856X},
abstract = {Tau protein plays a central role in Alzheimer's disease (AD) and other tauopathies. Tau proteins aggregate in degenerating neurons and their expression level is critical for disease development and progression. In addition, the generation of truncated Tau species is involved in the pathological process. In the human brain, several N-terminally truncated Tau species (including Met11- and Met127-Tau) have been detected. However, both the mechanisms of their synthesis and their relevance for the diseases remain largely unclear. Several Tau messenger RNA (mRNA) isoforms with distinct 5' untranslated regions (5'UTRs) were found in brains with tauopathies. In addition, single substitutions in the N-terminal coding sequence of Tau, namely R5H, R5L and R5C, have been associated with AD, progressive supranuclear palsy and Parkinson's disease, respectively. Here, we investigated how the 5' end of Tau mRNAs and the N-terminal mutations affect Tau protein synthesis. We show that both the length of the 5'UTR of Tau mRNAs and the N-terminal coding sequence largely modulate the expression level of Tau. Truncated Tau protein species are generated by an alternative translation initiation event. Thereafter, we show that the disease-associated mutations at codon #5 also increase the expression, mostly due to secondary structure modifications of the corresponding mRNAs.},
}

@article {pmid41257084,
year = {2025},
author = {Elshahary, A and Safwan, H and Abdelwaly, A and Arafa, RK and Helal, MA},
title = {Discovery of indole- and quinolone-based inhibitors of the mTOR/Akt/Pi3K pathway for the potential treatment of autism and certain types of cancer.},
journal = {RSC medicinal chemistry},
volume = {},
number = {},
pages = {},
pmid = {41257084},
issn = {2632-8682},
abstract = {Mammalian target of rapamycin (mTOR) is a serine/threonine kinase that belongs to the PI3K-related protein kinase family. It is an integral part of two functionally distinct protein complexes: mTOR complex 1 and mTOR complex 2. Its signaling pathway is linked to cell survival, growth, proliferation, and motility. Deregulation of the mTOR pathway has been reported in many types of cancer. Hence, mTOR is an attractive target for the treatment of certain cancers such as renal cell carcinoma and pancreatic tumors. In addition, hyperactivity in mTOR-mediated signaling is associated with the pathogenesis of autism spectrum disorder (ASD) and Alzheimer's disease. Recently, mTOR inhibitors have been considered as emerging pharmacotherapy for these disorders. In this research, we have used molecular modeling techniques to design three series of compounds, indoles, β-carbolines, and 4-aminoquinolines, targeting the ATP site of the mTOR kinase. Based on insights from molecular docking, we developed twenty eight derivatives of these scaffolds to explore the SAR and optimize their affinities. The prepared compounds were evaluated for their inhibitory activity against mTOR as well as other closely related kinases such as PI3K and AKt. To our delight, twenty compounds have shown sub-micromolar activities towards the mTOR kinase. Compounds HA-2l and HA-2c showed a superior IC50 of 66 and 75 nM, respectively, for mTOR, while being selective against AKt and Pi3K. Upon optimization, these selective inhibitors could be useful for the management of ASD due to their relatively higher safety and, hence, suitability for long-term use. On the other hand, derivatives HA-1e, HA-2g, and HA-3d exhibited high affinities for the three enzymes, suggesting their potential utility as anticancer agents. Also, the cytotoxicity of the most active compounds was assessed using different cell-lines. Compounds HA-2g, HA-2l, and HA-3d showed sub-micromolar inhibition, in the range of 0.610-0.780 μM, against the tested cancer cell lines MDA-MB231 and HCT-116. The discovery of a clinically useful mTOR inhibitor would represent a new hope for patients of two important non-communicable diseases, cancer and ASD.},
}

@article {pmid41257022,
year = {2025},
author = {Abdel-Magid, AF},
title = {Inhibitors of Stearoyl-Coenzyme A Desaturase 1 and 5 May Provide a Novel Therapeutic Strategy for the Treatment of Neurological Disorders and Brain Cancer.},
journal = {ACS medicinal chemistry letters},
volume = {16},
number = {11},
pages = {2191-2193},
pmid = {41257022},
issn = {1948-5875},
abstract = {The invention in this patent application relates to heterocyclic compounds represented herein generally by formula 1. These compounds are inhibitors of stearoyl-coenzyme A desaturases (SCD1 and/or SCD5) and may provide a useful treatment for neurological disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD) as well as primary brain cancer such as glioblastoma (GBM).},
}

@article {pmid41257016,
year = {2025},
author = {Song, Z and Liang, SH},
title = {Novel 2H‑Pyrazolo[3,4‑d]thiazole Compounds Targeting NLRP3 for the Treatment of Neurodegenerative Diseases.},
journal = {ACS medicinal chemistry letters},
volume = {16},
number = {11},
pages = {2200-2201},
pmid = {41257016},
issn = {1948-5875},
abstract = {The invention discloses novel NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inhibitors featuring a 2H-pyrazolo-[3,4-d]-thiazole scaffold. These NLRP3 inhibitors exhibit significant potential as therapeutic candidates for neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease.},
}

@article {pmid41256995,
year = {2025},
author = {Sabnis, RW},
title = {Novel Compounds as TREM2 Agonists for Treating Alzheimer's Disease.},
journal = {ACS medicinal chemistry letters},
volume = {16},
number = {11},
pages = {2183-2184},
pmid = {41256995},
issn = {1948-5875},
abstract = {Provided herein are novel compounds as TREM2 agonists, pharmaceutical compositions, use of such compounds in treating Alzheimer's disease, and processes for preparing such compounds.},
}

@article {pmid41256885,
year = {2025},
author = {Cottrell, S and Yoon, S and Wei, X and Dickson, A and Wei, GW},
title = {Computational Drug Repurposing for Alzheimer's Disease via Sheaf Theoretic Population-Scale Analysis of snRNA-seq Data.},
journal = {ArXiv},
volume = {},
number = {},
pages = {},
pmid = {41256885},
issn = {2331-8422},
abstract = {Single-cell and single-nucleus RNA sequencing (scRNA-seq /snRNA-seq) are widely used to reveal heterogeneity in cells, showing a growing potential for precision and personalized medicine. Nonetheless, sustainable drug discovery must be based on a population-level understanding of molecular mechanisms, which calls for the population-scale analysis of scRNA-seq/snRNA-seq data. This work introduces a sequential target-drug selection model for drug repurposing against Alzheimer's Disease (AD) targets inferred from population-level snRNA-seq studies of AD progression in microglia cells as well as different cell types taken from an AD affected brain vascular tissue atlas, involving hundreds of thousands of nuclei from multi-patient and multi-regional studies. We utilize Persistent Sheaf Laplacians (PSL) to facilitate a Protein-Protein Interaction (PPI) analysis of AD targets inferred from differential gene expression (DEG), and then use machine learning models to predict repurpose-able DrugBank compounds for molecular targeting. We screen the efficacy of different DrugBank small compounds and further examine their central nervous system (CNS)-relevant ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity), resulting in a list of lead candidates for AD treatment. The list of significant genes establishes a target domain for effective machine learning based AD drug repurposing analysis of DrugBank small compounds to treat AD related molecular targets.},
}

@article {pmid41256774,
year = {2025},
author = {Yu, J and Bao, X and Shan, C and Yu, Z and Yu, Y and Wang, H and Zhang, Y},
title = {Traditional Chinese medicine's holistic approach: regulating microglia-driven neuroinflammation for the resolution of Alzheimer's disease.},
journal = {Frontiers in cellular neuroscience},
volume = {19},
number = {},
pages = {1691253},
pmid = {41256774},
issn = {1662-5102},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by cognitive dysfunction, motor abnormalities, and memory disorders, with a persistently high and rising incidence. The pathological features of AD include the extracellular deposition of the amyloid beta peptide (Aβ), the accumulation of neurofibrillary tangles (NFTs), and neuroinflammation. Microglia (MG), the main immune cells in the central nervous system (CNS), can transform into different phenotypes. An imbalance in their phenotypic transformation may induce neuroinflammation and lead to neurological diseases, playing a central role in the onset and progression of AD.

PURPOSE: This article aims to briefly review the key role of microglia-mediated neuroinflammation in the pathogenesis of AD and to summarize and analyze the strategies of traditional Chinese medicine (TCM) for targeting microglia in AD treatment.

METHODS: Literature review and analysis were conducted to summarize the role of microglia-mediated neuroinflammation in AD pathogenesis and to collate TCM therapeutic strategies aimed at modulating microglia.

RESULTS AND CONCLUSION: Microglia-mediated neuroinflammation plays a central role in the pathological progression of AD. TCM demonstrates potential in intervening in AD neuroinflammation by regulating the microglial phenotype and function. These related therapeutic strategies warrant further summary and analysis.},
}

@article {pmid41256727,
year = {2025},
author = {Espinosa-Garcia, C and Srivastava, U and Kumar, P and Kour, D and Malepati, S and Tobin, BR and Xiao, H and Sunna, S and Bowen, CA and Cheng, L and Bagchi, P and Duong, DM and Whitworth, TJ and Xinran, L and Seyfried, NT and Wood, LB and Faundez, V and Rangaraju, S},
title = {Neuroinflammatory Stress Preferentially Impacts Synaptic MAPK Signaling and Mitochondria in Excitatory Neurons.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.10.03.680087},
pmid = {41256727},
issn = {2692-8205},
abstract = {BACKGROUND: Understanding synapse-specific effects of neuroinflammation can provide mechanistic and therapeutically relevant insights across the spectrum of neurological diseases.

METHODS: We applied neuron-specific proteomic biotinylation in vivo , differential centrifugation of brain for crude synaptosome enrichment (P2 fraction) and mass spectrometry (MS) analysis of biotinylated proteins to derive native-state proteomes of Camk2a-positive neurons and their corresponding P2 synaptic compartments. Next, in an in vivo model of systemic lipopolysaccharide (LPS) dosing, we examined the effects of neuroinflammation on whole neuron and synaptic compartments using a combination of MS, network analysis, confirmatory biochemical and ultrastructural assays and integrative approaches across our mouse-derived and existing human datasets.

RESULTS: Ultrastructural and biochemical analyses of P2 fractions verified enrichment in synaptic elements, including synaptic vesicles and mitochondria. MS of biotinylated proteins from Camk2a-specific bulk brain homogenates (whole neuron) and P2 fractions (synaptosome) showed enrichment of >1000 proteins, consistent with neuron-specific biotinylation, also confirmed by immunofluorescence microscopy. Camk2a-specific synaptic proteome revealed molecular signatures related to mitochondrial function, synaptic transmission, protein translation. LPS-treated mice displayed body weight loss and neuroinflammation, characterized by glial activation, increased pro-inflammatory cytokine levels and upregulated expression of Alzheimer's disease (AD)-related microglial genes. LPS-induced neuroinflammation exerted distinct effects on the synaptic proteome, including increased mitochondrial and reduced cytoskeletal-synaptic proteins, while suppressed synaptic MAPK signaling. Importantly, these changes were not observed at the whole neuron level, indicating unique vulnerability of the synapse to neuroinflammation. In line with synapse proteomic and signaling changes, LPS altered the ultrastructure of asymmetric synapses, suggesting dysregulation of excitatory neurotransmission. Co-expression network analysis of Camk2a neuronal proteins further resolved mitochondria- and synapse-specific protein modules, some of which were neuroinflammation-dependent. Neuroinflammation increased levels of a mitochondria-enriched module, and decreased levels of a pre-synaptic vesicle module, without impacting a post-synaptic membrane module. LPS-dependent mitochondrial and LPS-independent post-synaptic modules in mouse neurons mapped to post-mortem human AD brain proteomic modules which were decreased in cases with AD dementia and positively correlated to cognitive function, including pro-resilience markers for AD.

CONCLUSION: Our findings using native-state proteomics of Camk2a neurons combined with synaptosome enrichment identify proteome-level mechanisms of early synaptic vulnerability to neuroinflammation relevant to AD.},
}

@article {pmid41256716,
year = {2025},
author = {Palmer, JA and Billinger, SA},
title = {APOE4 carriers resistant to cognitive decline show unique relationships between cerebrovascular response to exercise and dual-task cognitive-balance performance.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
pmid = {41256716},
issn = {2692-8205},
abstract = {BACKGROUND: Emerging research indicates cognitive dual-tasking is an early marker for cognitive impairment, with particular implications for Apolipoprotein E4 (APOE4) carriers who are at higher genetic risk for Alzheimer's disease. While APOE4 carriers typically show accelerated cognitive decline and impaired cerebrovascular function with aging, exceptions to this norm exist and may provide insights into resilience mechanisms. The relationship between cerebrovascular response and cognitive-motor dual-task performance in cognitively-normal APOE4 carriers who maintain preserved function remains unclear.

METHODS: Thirty cognitively-normal older adults (76±4 years, 8 APOE4 carriers, 22 noncarriers) completed clinical balance and cognitive testing under single-task and dual-task conditions. Balance performance was assessed as distance traversed during challenging beam walking. Cognitive performance was assessed as response time during an auditory Stroop test. Transcranial Doppler ultrasound measured cerebrovascular response to moderate-intensity aerobic exercise. We tested group differences in cognitive-balance dual task performance and relationships between cerebrovascular response and dual-task interference (DTI) in balance and cognitive domains, and effects of APOE4 genotype on these relationships.

RESULTS: No differences in cerebrovascular response or dual-task performance were observed between APOE4 carriers and noncarriers. However, APOE4 carriers displayed unique cerebrovascular-behavioral relationships. In APOE4 carriers, higher cerebrovascular response to exercise was associated with less balance DTI (r=0.839, p=0.009) and less cognitive DTI (r=0.832, p=0.020), while no relationships were observed in noncarriers (p>0.187).

CONCLUSIONS: Cognitively-normal APOE4 carriers with preserved cognitive-balance dual-task function represent exceptions that may model aging resilience mechanisms. The unique cerebrovascular-behavioral relationships suggest that maintaining cerebrovascular function provides preliminary support for neuromotor and neurocognitive resilience to dual-task challenges in genetically vulnerable populations.},
}

@article {pmid41256711,
year = {2025},
author = {Villalón-Reina, JE and Zhu, AH and Benavidez, S and Moreau, CA and Feng, Y and Chattopadhyay, T and Nabulsi, L and Kushan, L and John, JP and Joshi, H and Thomopoulos, SI and Lawrence, KE and Nir, TM and Jahanshad, N and Bearden, CE and Kia, SM and Marquand, AF and Thompson, PM and , },
title = {Lifespan Normative Modeling of Brain Microstructure.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2024.12.15.628527},
pmid = {41256711},
issn = {2692-8205},
abstract = {Normative models of brain metrics based on large populations could be extremely valuable for detecting brain abnormalities in patients with a variety of disorders, including degenerative, psychiatric and neurodevelopmental conditions, but no such models exist for the brain's white matter (WM) microstructure. Here we present the first large-scale normative model of brain WM microstructure - based on 19 international diffusion MRI datasets covering almost the entire lifespan (totaling N=54,583 individuals; age: 4-91 years). We extracted regional diffusion tensor imaging (DTI) metrics using a standardized analysis and quality control protocol and used hierarchical Bayesian regression (HBR) to model the statistical distribution of derived WM metrics as a function of age and sex. We extracted the average lifespan trajectories and corresponding centile curves for each WM region. We illustrate the utility of the method by applying it to detect and visualize profiles of WM microstructural deviations in a variety of contexts: in mild cognitive impairment, Alzheimer's disease, and 22q11.2 deletion syndrome - a neurogenetic condition that markedly increases risk for schizophrenia. The resulting large-scale model provides a common reference to identify disease effects on the brain's microstructure in individuals or groups, and to compare disorders, and discover factors affecting WM abnormalities. The derived normative models are a new resource publicly available to the community, adaptable and extendable to future datasets as the available data expands.},
}

@article {pmid41256702,
year = {2025},
author = {Jonson, C and Makarious, MB and Koretsky, MJ and Vitale, D and Rabkina, L and Lago, AL and Eslami-Amirabadi, M and Ramos, EM and Narayan, P and Yokoyama, JS and Singleton, AB and Blauwendraat, C and Cookson, MR and Nalls, MA and Leonard, HL},
title = {Random forest model improves annotation and discovery of variants of uncertain significance in Alzheimer's and other neurological disorders.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.10.02.680068},
pmid = {41256702},
issn = {2692-8205},
abstract = {Variants of uncertain significance (VUS) are a bottleneck for genetic discovery and complicate clinical decision-making in Alzheimer's disease and related neurological disorders (ADRD). We developed MoVUS: Model for Variants of Unknown Significance, a random-forest approach that integrates functional predictors to classify missense VUS. MoVUS leverages a balanced random forest model trained on dbNSFP v5.1a with high-confidence ClinVar and HGMD labels, using harmonized functional prediction rankscores. MoVUS produced confident, explainable calls, with ∼98% accuracy (AUC ∼0.998), prioritizing potentially pathogenic candidates and down-ranked likely benign variants on independent validation sets of ClinVar-only and HGMD-only variants. In our discovery analyses on ADRD-implicated variants in dbNSFP and from independent collaborator cohorts, we achieved high-confidence classifications on a majority of the unknown variants (average of 55% of discovery variants). We also had access to medical records and family trees for some variants, further validating our findings. Across held-out and external datasets, MoVUS reports high accuracy alongside confidence scores and helps prioritize actionable candidates, and reduces bias by considering multiple scores for each variant. To facilitate use, we developed a web app for users to browse across 100+ ADRD genes. MoVUS provides transparent, reproducible triage for research follow-up by pairing consensus predictors with SHAP-based visualizations and explanations.},
}

@article {pmid41256678,
year = {2025},
author = {Duncan, MJ and Hawkins, MR and Bytyqi, L and Whitlock, HR and Shepard, S and Cox, MF and Drinkard, EG and Macheda, T and Roberts, KN and Kohler, K and Schmidt, MC and Johnson, CE and Sunderam, S and O'Hara, BF and Murphy, MP and Bachstetter, AD},
title = {Dim light at night impacts circadian rhythms and Alzheimer's disease-like neuroinflammation and neuropathology in humanized APP SAA knock-in mice.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.10.02.680043},
pmid = {41256678},
issn = {2692-8205},
abstract = {UNLABELLED: Artificial light at night (light pollution) is widespread but understudied in the context of Alzheimer's disease (AD). Sleep and circadian disruption have been linked to amyloid-β (Aβ) accumulation and neuroinflammation, but whether dim light at night (dLAN) modifies these processes remains unclear. We tested whether chronic dLAN exposure (8 lux during the dark phase, 8 weeks) alters circadian rhythms, amyloid pathology, and neuroinflammation in 12-13 month-old humanized APP knock-in (KI) mice. hAPP [SAA] KI mice, which develop plaques, were compared with hAPP [WT] KI controls carrying only a humanized APP sequence. dLAN reduced circadian rhythm amplitude and stability while increasing fragmentation in both genotypes within two weeks. In hAPP [SAA] KI mice, dLAN modestly increased hippocampal plaque burden and soluble neocortical Aβ. Astrocyte reactivity was elevated by genotype but not altered by nighttime light exposure. In contrast, microglial markers (CD45, MHCII) were increased with dLAN with CD45+ area elevated in hippocampus, and MHCII+ cell counts greater in the cortex and hippocampus of hAPP [SAA] KI mice. There were also distinct spatial responses between the microglia markers suggesting that dLAN primes microglia toward an antigen-presenting phenotype (MHCII) in the presence of Aβ. Yet, the microglia/macrophage priming was not associated with amplified cytokine or chemokine levels at the 8-week dLAN exposure timepoint in the brain. These findings add to growing evidence that nighttime light exposure can disrupt circadian and immune regulation, and suggest that environmental light pollution should be further explored as a modifiable factor contributing to Alzheimer's disease progression.

STATEMENT OF SIGNIFICANCE: Light at night is a common feature of modern life, yet its influence on Alzheimer's disease remains poorly understood. We show that dim light at night disrupts circadian rhythms, modestly increases amyloid pathology, and shifts microglia toward an antigen-presenting state in an amyloid-prone model. These findings identify light at night as a modifiable factor that may worsen risk or progression of neurodegenerative disease. A critical gap is whether circadian and immune changes resolve after darkness at night is restored. If they persist, early exposure could leave lasting imprints on brain aging. Addressing this question is essential for guiding strategies to mitigate the impact of light pollution.},
}

@article {pmid41256650,
year = {2025},
author = {Bimali, B and Khasayeva, N and Ballem, AR and Nagaboina, G and Chen, J and Fedorov, A and Lah, JJ and Levey, A and Calhoun, VD and Iraji, A},
title = {Multimodal Fusion Analysis of [18F]Florbetapir PET and Multiscale Functional Network Connectivity in Alzheimer's Disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.09.26.678805},
pmid = {41256650},
issn = {2692-8205},
abstract = {Accumulation of amyloid-beta plaques and disruption of intrinsic brain networks are two important characteristics of Alzheimer's disease (AD), yet the relationship between amyloid accumulation and network dysfunction remains unclear. In this study, we integrated [18F]Florbetapir PET and resting-state fMRI (rsfMRI) derived Functional Network Connectivity (FNC) from 552 temporally matched longitudinal PET-rsfMRI sessions across 395 participants spanning Cognitively Normal (CN), Mild Cognitive Impairment (MCI), and AD stages. With a model order of 11, joint Independent Component Analysis (jICA) was applied to the fused PET-FNC data, identifying 11 stable components, of which 9 PET-derived components corresponded to previously characterized brain regions or networks. The multimodal analysis revealed disease progression markers, including (1) a pattern of reduced subject loadings across clinical stages (CN > MCI > AD) in white matter and cerebellar regions, reflecting structural degeneration; (2) increased amyloid accumulation in affected individuals in grey matter regions, particularly in frontal, sensorimotor, extended hippocampal, and default mode network (DMN) regions, accompanied by functional connectivity alterations that reflected both compensatory and disruptive network dynamics. We identified PET-derived components that captured distinct stages of disease progression, with the DMN component emerging as a late-stage biomarker and a white matter component showing early-stage changes with limited progression thereafter. Additionally, several components showed significant variation in loadings between APOE ε 4 carriers and non-carriers, linking the multimodal signatures to a well-established genetic risk factor for AD.},
}

@article {pmid41256631,
year = {2025},
author = {Zhu, X and Haure-Mirande, JV and Bicak, M and Dong, P and Kruglikov, I and Al-Subaie, A and Fossati, V and Noggle, S and Gandy, S and Ehrlich, ME},
title = {miR155 triplicated in Down syndrome regulates hippocampal GABAergic neurogenesis in Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.09.28.679053},
pmid = {41256631},
issn = {2692-8205},
abstract = {MicroRNA dysregulation is implicated in neurodegenerative disorders, including Alzheimer's disease (AD). The role of neuronal microRNA155 (miR155), elevated in both AD and Down syndrome (DS), remains unknown. We found that MIR155HG (miR155 host gene) colocalizes with APP (amyloid-beta precursor protein) in a neuron-specific, topologically-associated domain (TAD) within a regulatory network, in the obligate portion of chromosome 21 triplicated in DS which causes AD neuropathology and in most cases, dementia. We investigated miR155 role during neuron development and then validated these findings in an amyloidopathy model. In human induced pluripotent stem cell (hiPSC)-derived neural stem cells (NSCs), cortical neurons and cortical organoids, MIR155 deletion enhanced NSC proliferation, ventral patterning and GABAergic interneuron generation. However, MIR155 overexpression inhibited NSC marker expression and GABAergic interneuron generation. MIR155 upregulates its mRNA targets, NR2F1 / 2 , key modulators of hippocampal GABAergic interneuron development. In an amyloidopathy mouse model, miR155 deletion induced the expansion of hippocampal NSCs and increased hippocampal GABAergic interneurons. These findings reveal previously unrecognized miR155 roles in NSC dynamics and GABAergic interneuron development which directionally diverge from extensively studied microglial miR155 in their beneficial vs negative impact on AD mouse models, suggesting that approaching miR155 therapeutically may require balancing the effects in neurons and microglia.},
}

@article {pmid41256600,
year = {2025},
author = {Wang, T and Chen, Y and Tian, J and Emam, K and Guo, L and Ma, T and Du, H},
title = {Association of cytochrome c oxidase dysfunction with amyloidosis in Alzheimer's disease and patient-derived cerebral organoids.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.10.01.679889},
pmid = {41256600},
issn = {2692-8205},
abstract = {Patients with Alzheimer's disease (AD) demonstrate brain mitochondrial dysfunction and energy deficiency that are closely associated with cognitive impairment. Cytochrome c oxidase (CCO), also known as mitochondrial complex IV, is the terminal enzyme in mitochondrial electron transport chain (ETC). Consistent with the pivotal role of CCO in mitochondrial bioenergetics and high demand for energy to sustain neuronal function, CCO dysfunction has been linked to neurological disorders including AD. However, it remains unclear whether mitochondrial CCO dysfunction represents an adaptive response to AD-associated toxic molecules versus a bona fide pathology to promote AD development. In this study, by meta-analysis of publicly available proteomics analysis of post-mortem frontal lobe tissues from four large cohorts of patients with AD we identified loss of key CCO subunits including mitochondrial DNA (mtDNA)-encoded COX1 and COX3 as well as nuclear DNA (nDNA)-encoded COX5A, COX6B1, COX7C, COX8A, and NDUFA4 in patients with AD. Further biochemical analysis using post-mortem frontal lobe tissues showed lowered CCO activity of neuronal mitochondria from patients with AD, suggesting CCO vulnerability and its potential association with amyloidosis in AD. Lastly, in addition to the inverse relationship between neuronal CCO activity and brain amyloidosis in the tested AD cohort, pharmacological inhibition of CCO promoted amyloid production and elevated beta-secretase 1 (BACE1) activity in cerebral organoids derived from human induced pluripotent stem cells (hiPSCs) from one nonAD and one AD subject. The simplest interpretation of the results is that CCO dysfunction in the frontal lobe is a phenotypic mitochondrial change accompanying AD, which may contribute to the development of brain amyloidosis.},
}

@article {pmid41256571,
year = {2025},
author = {Wang, W and Berube, P and Yang, B and Castanon, R and Bartlett, A and Komandur, K and Nery, JR and Barragan, C and Kenworthy, M and Valadon, C and Altshul, J and Petrella, A and Chan, D and Chen, C and Acerbo, AS and Luo, J and Jain, M and Soma, E and Chen, H and Liem, M and Marrin, M and O'Connor, C and Zemke, N and Oakley, D and Ren, B and Hyman, BT and Ecker, JR},
title = {Brain Region-Specific Epigenomic Reorganization and Altered Cell States in Alzheimer's Disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.09.29.678849},
pmid = {41256571},
issn = {2692-8205},
abstract = {Alzheimer's disease (AD) is the most common neurodegenerative disorder, yet the molecular mechanisms underlying its region- and cell-type-specific pathogenesis remain poorly defined. Here, we generated a large-scale, single-cell multi-omic atlas-integrating DNA methylation and 3D genome architecture-from postmortem brain tissue of matched AD patients and cognitively normal controls. Samples were collected from three brain regions with distinct vulnerability to AD pathology: the temporal cortex (TC), primary visual cortex (VC), and prefrontal cortex (PFC). Our dataset comprises over 230,000 individual cells, spanning major neuronal and glial populations, and provides a high-resolution view of multi-layer epigenomic regulation. We identified widespread AD-associated DNA methylation changes and marked reorganization of 3D genome structure, including alterations in A/B compartments, topologically associating domains (TADs), and chromatin loops. These changes are strongly region-specific: TC displays pronounced hypermethylation, transcriptional downregulation, and elevated boundary density, whereas VC shows opposing trends and PFC an intermediate profile. We further uncovered previously unrecognized AD-associated glial and neuronal states defined by coordinated epigenomic dysregulation and recurrent genomic deletions, particularly near telomeric regions. This region-resolved, single-cell multi-omic atlas reveals divergent epigenomic trajectories across brain regions and cell types in AD, offering new mechanistic insights and a framework for targeted therapeutic strategies.},
}

@article {pmid41256544,
year = {2025},
author = {Ma, IW and Cheng, GW and Yeung, SH and Yeung, MH and Kofler, J and Herrup, K and Tse, KH},
title = {Nuclear BIN1 isoforms regulate c-Myc-mediated cell cycle control in oligodendrocytes.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.09.30.676706},
pmid = {41256544},
issn = {2692-8205},
abstract = {Bridging integrator 1 (BIN1) is a nucleocytoplasmic protein that inhibits c-Myc and acts as a tumour suppressor. BIN1 is ubiquitously expressed, but it is most abundant in skeletal myocytes and brain oligodendrocytes (OLs). BIN1 expression in the OL lineage is of particular interest, as the loss of myelin integrity is highly correlated with the progress of sporadic AD. More importantly, GWAS studies have identified rare BIN1 variants as the second strongest risk factor for sporadic Alzheimer's disease (AD), after the ε4 variant of APOE gene. Despite these inherent interests, the control of the nucleocytoplasmic localisation as well as the modulation of the alternative splicing of the 20 exons of BIN1 are poorly understood in OLs. We report here the characterisation of BIN1 isoforms in OLs from two independent cohorts of postmortem AD brains using immunoblotting and immunohistochemistry and extend the findings to experimental APP/PS1 mice and primary murine OL cultures. Neuronal isoforms of BIN1 (BIN1:H, 95kDa) were significantly reduced (P < 0.0001), and the white matter/OL-specific isoforms (BIN1:L, 70kDa) were increased (P = 0.0349) in both AD cases and APP/PS1 mice. Importantly, the OL-specific BIN1 isoforms, identified by three different antibodies, were found in the nucleus of OL in human and mouse. Nuclear BIN1 was expressed by both the OL progenitor cells (OPCs) and mature OLs in vitro. Silencing Bin1 in OPCs led to a transcriptomic shift with a perturbed p53 pathway and cell cycle regulation, consistent with reduced Bin1-mediated c-Myc inhibition. The putative interacting sites between OL-specific BIN1:L and c-Myc were also identified by in silico analysis. The present findings suggest that nuclear BIN1 acts as a regulator of OL cell cycle control and support the hypothesis that BIN1 dysregulation in OL may contribute mechanistically to myelin pathology observed in sporadic AD.},
}

@article {pmid41256509,
year = {2025},
author = {Behjat, HH and Vogel, JW and Strandberg, O and Spotorno, N and Rittmo, J and Stampacchia, S and Collij, LE and Pichet Binette, A and Xiao, Y and Chaggar, P and van Westen, D and Stomrud, E and Palmqvist, S and Mattsson-Carlgren, N and Van De Ville, D and Smith, R and Hansson, O and Ossenkoppele, R},
title = {Patient-specific functional brain architecture explains cortical patterns of tau PET in Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.10.02.679969},
pmid = {41256509},
issn = {2692-8205},
abstract = {The spatial distribution of tau pathology, the core driver of neurodegeneration in Alzheimer's disease (AD), varies markedly across individuals. While tau is thought to spread along brain networks, the role of inter-individual variability in shaping these patterns remains underexplored. Using resting-state fMRI and tau- PET from 805 participants across the AD continuum, we studied whether subject-specific functional connectivity (FC) profiles enhance the characterization of tau deposition patterns. A hybrid approach integrating individual and group- average FC outperformed both alone, particularly in symptomatic individuals and at finer spatial resolutions, the latter underscoring a critical but often overlooked role of spatial scale. Individualized FC also better captured individual tau topographies than canonical tau-PET maps derived from cohort-level data. These effects were specific to tau, and not seen for β-amyloid, and their predictive power increased with spatial granularity. Furthermore, baseline FC also predicted future tau accumulation at the individual level, supporting its prognostic value. Together, these findings provide strong evidence that individual functional brain architecture shapes tau propagation in humans, supporting the network spread hypothesis by showing that variability in connectivity translates into heterogeneity in tau distribution. This work advances biological understanding of tau propagation in AD, highlighting functional connectivity as a mechanistic substrate that supports prognostic assessment of tau trajectories.},
}

@article {pmid41256466,
year = {2025},
author = {Waldron, FM and Spence, H and Taso, OS and Read, FL and Sinha, IR and Irwin, KE and Wong, PC and Ling, JP and Gregory, JM},
title = {Brain Iron as a Surrogate Biomarker of Pathological TDP-43 Identifies Brain Region-Specific Signatures in Ageing, Alzheimer's Disease and Amyotrophic Lateral Sclerosis.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.10.02.680028},
pmid = {41256466},
issn = {2692-8205},
abstract = {BACKGROUND: TDP-43 pathology is a defining feature of several neurodegenerative diseases, but its prevalence and regional distribution in ageing and disease are not well characterised. We investigated the burden of brain TDP-43 pathology across ageing, Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS), and examined ferritin as a region-specific correlate of TDP-43 pathology.

METHODS: Pathological TDP-43 was detected using an HDGFL2 cryptic exon in situ hybridisation probe and a TDP-43 RNA aptamer, providing greater sensitivity and specificity than antibody-based approaches. Amygdala, hippocampus, and frontal cortex tissue was analysed from non-neurological controls (ages 40-80), AD cases, and ALS cases. Ferritin (as a proxy for iron accumulation) was quantified in parallel to assess its association with TDP-43 pathology.

FINDINGS: TDP-43 pathology was detectable from the fourth decade of life, with a 4.5-fold increase in hippocampal involvement after age 60 years. In AD, pathology was present in 90% of cases and distinguished from ageing by selective amygdala involvement. In ALS, TDP-43 pathology was nearly ubiquitous across all regions studied. Regional ferritin strongly predicted TDP-43 burden: amygdala ferritin explained 87% of TDP-43 variance in ALS and 66% in AD, while hippocampal ferritin differentiated AD from controls. Across AD, ferritin explained between 43-81% of regional TDP-43 variance.

INTERPRETATION: TDP-43 brain pathology emerges in midlife with increased involvement after age 60 years, exhibits disease-specific regional signatures in AD and ALS, and is closely linked to ferritin accumulation. As TDP-43 confers a worse prognosis in AD, the capacity of ferritin, detectable with iron-sensitive MRI, to serve as a proxy for regional TDP-43 burden highlights its promise as a biomarker for disease stratification and prognosis.

SHORT ABSTRACT: Here we show that pathological TDP-43 emerges during normal ageing from the fourth decade of life, with a 4.5-fold increase in hippocampal involvement after 60 years. In Alzheimer's disease (AD), TDP-43 pathology was present in 90% of cases and distinguished from ageing by disproportionate amygdala involvement, while in amyotrophic lateral sclerosis (ALS) it was nearly ubiquitous across hippocampus, amygdala, and frontal cortex. Using sensitive detection tools, we demonstrate that region-specific ferritin strongly predicts TDP-43 burden: amygdala ferritin explained 87% of variance in ALS and 66% in AD, while hippocampal ferritin differentiated AD from controls. Across AD, ferritin levels in all three regions explained 43-81% of TDP-43 variance. As TDP-43 pathology confers a worse prognosis in AD, the ability of ferritin, quantifiable with iron-sensitive MRI, to serve as a proxy for regional TDP-43 burden highlights its potential as a biomarker for disease stratification and prognostic assessment.

HIGHLIGHTS: TDP-43 brain pathology occurs in normal ageing from early in the fourth decade, characterised by a 4.5-fold increase in hippocampus pathology from the sixth decade.TDP-43 brain pathology is detectable in 90% of AD cases, with a disease-signature of increased amygdala pathology relative to age-matched controls.In ALS, TDP-43 is nearly ubiquitous in amygdala, hippocampus and frontal cortex.Hippocampus high brain ferritin distinguishes AD from and age-matched controlsBrain ferritin is a brain region-specific marker of TDP-43 pathology in ageing and disease, with amygdala ferritin explaining 87% of the variance in amygdala TDP-43 pathology in ALS, and 66% of amygdala TDP-43 pathology in ADIn AD, ferritin levels for all three brain regions explain between 43-81% of variance in their TDP-43 pathology levels.},
}

@article {pmid41256457,
year = {2025},
author = {Moallem, EZ and Vekaria, HJ and Macheda, T and Hawkins, MR and Roberts, KN and Patel, SP and Sullivan, PG and Bachstetter, AD},
title = {Traumatic brain injury exacerbates mitochondrial dysfunction in APP/PS1 knock-in mice through time-dependent pathways.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.10.01.679790},
pmid = {41256457},
issn = {2692-8205},
abstract = {UNLABELLED: Cerebral hypometabolism occurs in both traumatic brain injury (TBI) and Alzheimer's disease (AD), but whether these conditions act through distinct or overlapping mechanisms is unclear. TBI disrupts cerebral metabolism via blood-brain barrier damage, altered glucose transporter expression, calcium buffering abnormalities, and oxidative damage to metabolic enzymes. AD-related hypometabolism is linked to amyloid-β (Aβ) effects on mitochondria, including impaired respiration, oxidative stress, and altered mitophagy, fusion, and fission. We tested whether TBI-induced mitochondrial dysfunction exacerbates Aβ-mediated impairment using a closed-head injury (CHI) model in APP/PS1 knock-in (KI) mice. Injuries were delivered at 4-5 months of age, before plaque formation and mitochondrial deficits in KI mice. Bioenergetics were measured at 1, 4, and 8 months post-injury in hippocampus and cortex using Seahorse assays on isolated mitochondria. At 1 month, genotype-by-injury interactions revealed greater dysfunction in KI mice than either condition alone, with males more vulnerable than females. At 4-8 months, amyloid-mediated effects predominated, while TBI-specific changes were no longer apparent, suggesting recovery or convergence onto shared mechanisms. These results indicate that TBI can temporarily worsen mitochondrial dysfunction in the context of early amyloidosis, with sex influencing vulnerability. Findings provide insight into the temporal relationship between TBI and amyloid-induced mitochondrial deficits and support the importance of sex as a biological variable in neurodegenerative disease progression.

HIGHLIGHTS: TBI and APP/PS1 genotype interact to worsen early mitochondrial dysfunction.Hippocampus exhibits greater susceptibility to combined TBI and amyloid pathology.Sex-specific effects and temporal patterns underscore TBI's role in AD risk.Male mice show heightened vulnerability to TBI-induced mitochondrial dysfunction.},
}

@article {pmid41256428,
year = {2025},
author = {Baddam, NG and Pijani, BA and Bozdag, S},
title = {A Systematic Fairness Evaluation of Racial Bias in Alzheimer's Disease Diagnosis Using Machine Learning Models.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.09.30.678854},
pmid = {41256428},
issn = {2692-8205},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a major global health concern, expected to affect 12.7 million Americans by 2050. Machine learning (ML) algorithms have been developed for AD diagnosis and progression prediction, but the lack of racial diversity in clinical datasets raises concerns about their generalizability across demographic groups, particularly underrepresented populations. Studies show ML algorithms can inherit biases from data, leading to biased AD predictions.

METHODS: This study investigates the fairness of ML models in AD diagnosis. We hypothesize that models trained on a single racial group perform well within that group but poorly in others. We employ feature selection and model training techniques to improve fairness.

RESULTS: Our findings support our hypothesis that ML models trained on one group underperform on others. We also demonstrated that applying fairness techniques to ML models reduces their bias.

DISCUSSION: This study highlights the need for racial diversity in datasets and fair models for AD prediction.},
}

@article {pmid41256419,
year = {2025},
author = {Ding, S and Choi, SH and Kim, YS and Nazarenkov, N and Miller, YI},
title = {Progressive Loss of Astrocytic AIBP Expression during Alzheimer's Disease Pathology.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.10.03.680289},
pmid = {41256419},
issn = {2692-8205},
abstract = {Astrocytes and microglia play crucial roles in mediating neuroinflammation during Alzheimer's disease (AD) progression. ApoA-I binding protein (APOA1BP, also known as AIBP/NAXE) attenuates neuroinflammation by blocking amyloid β-induced TLR4 inflammaraft formation and oxidative stress. Apoa1bp knockout in APP/PS1 mice exacerbates microgliosis, increases amyloid plaque burden, neuronal cell loss, and reduces survival at 6 months. Although APOA1BP mRNA is ubiquitously expressed in humans, its cell-type-specific distribution in the brain remains unclear. To examine AIBP protein expression in the human brain, we performed immunohistochemistry on hippocampal sections from postmortem brain specimens from subjects aged 75-96 of both sexes. Using GFAP and IBA1 to label astrocytes and microglia, respectively, we found that AIBP protein was highly expressed in astrocytes, but not in microglia. Stratification of subjects by Braak stage (I-II, III-IV, V-VI) revealed a progressive decline in astrocytic AIBP expression with advancing AD pathology. Meta-analysis of RNA-seq profiling indicated enriched Apoa1bp expression in adult mouse astrocytes. Systemic Apoa1bp knockout in the APP/PS1 mouse exacerbated astrogliosis. These findings demonstrate that AIBP is predominantly expressed in astrocytes and its expression declines with AD progression, suggesting a potential role for AIBP in astrocyte-mediated neuroprotection and AD pathogenesis.},
}

@article {pmid41256374,
year = {2025},
author = {Ives, AN and Fulcher, JM and Bautista, AR and Kitata, RB and Williams, SM and Bennett, DA and De Jager, PL and Petyuk, VA},
title = {Single-cell nanodroplet processing proteomics pipeline for analysis of human-derived microglia.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.10.02.680067},
pmid = {41256374},
issn = {2692-8205},
abstract = {UNLABELLED: Single-cell omics tools provide unique insights into heterogeneous cell populations and their responses to stimuli. For example, single-cell RNA sequencing has identified several transcriptionally distinct populations of microglia, which are resident immune cells of the central nervous system (CNS) that are responsive to CNS injury, infection, and neurodegeneration. To date, single cell studies of microglia have focused on RNA-sequencing or cytometry by time of flight (CyTOF) which provide indirect readouts of protein abundance or quantification of a limited number of targets. Herein, we present a workflow based on FACS-assisted isolation, cryopreservation and nanodroplet-based processing for single-cell mass spectrometry proteomics analysis of the postmortem human brain cortex-derived microglia. From a single microglial cell, 1039 proteins could be identified on average. As a proof-of-principle we applied single-cell proteomics for exploring the heterogeneity of brain microglia at the cellular level. This pilot proteomics data partially recapitulates the prior microglia subtypes. Specifically, we determined mitochondrial proteins, in particular members of NADH dehydrogenase (Complex I), cytochrome b-c1 (Complex III), cytochrome c oxidase (Complex IV), F1-ATPase (Complex V), and Na+/K+-ATPase complex drive variation across microglia. This pipeline offers the potential for identifying functionally and analytically relevant protein targets for microglia in Alzheimer's disease and other neurological disorders.

SIGNIFICANCE OF STUDY: Microglia are a key brain cell type that may contribute to pathogenesis in neurodegenerative disease. Transcriptomic profiling of microglia from the central nervous system of humans and animal models has identified several subtypes of microglia, and complementary proteomic profiling of microglia is likely to provide functionally and therapeutically relevant targets, however single-proteomics studies of human-derived microglia are lacking. This work describes a label-free, single-cell proteomics approach for microglia isolated by fluorescence-activated cell sorting from a human donor that yields comparable numbers of identifications in comparison to prior single-cell RNA sequencing studies of microglia. This approach holds promise for enabling large-scale proteomics-based subtyping of microglia and studying their roles in neurodegenerative diseases.},
}

@article {pmid41256289,
year = {2025},
author = {Ramesh, M and Govindaraju, T},
title = {MiR-7a-Klf4 axis as a regulator and therapeutic target of neuroinflammation and ferroptosis in Alzheimer's disease.},
journal = {NAR molecular medicine},
volume = {2},
number = {3},
pages = {ugaf022},
pmid = {41256289},
issn = {2976-856X},
abstract = {Neuroinflammation and ferroptosis significantly contribute to neuronal death in Alzheimer's disease (AD) and other neurodegenerative disorders. MicroRNAs (miRNAs) are crucial regulators of these pathological processes. We employed transcriptomic analysis in an APP/PSEN1 Tg AD mouse model to identify dysregulated miRNAs and construct a miRNA-mRNA pathway network. We discovered increased miR-7a expression in the AD brain, targeting Krüppel-like factor 4 (Klf4), a transcriptional factor implicated in amyloid-β (Aβ) oligomer-induced neuroinflammation and RSL3-induced neuronal ferroptosis. Elevated Klf4 levels in AD mice brains suggest its involvement in AD pathology. The miR-7a mediated silencing of Klf4 alleviates neuroinflammation by modulating NF-κB, iNOS, and NLRP3 pathways, and inhibition of ferroptosis by targeting labile iron levels, GPX4, Nrf2 pathway, and mitochondrial damage. These findings highlight the neuroprotective role of miR-7a and its potential as RNA therapeutic. Pharmacological targeting of the miR-7a-Klf4 axis with blood-brain barrier (BBB)-permeable compound effectively mitigates neuroinflammation and ferroptosis, suggesting the miR-7a-Klf4 axis as a novel therapeutic target for AD.},
}

@article {pmid41256288,
year = {2025},
author = {LeBlanc, KR and Eck, RJ and Saxton, AD and McMillan, PJ and Wheeler, JM and Liachko, NF and Keene, CD and Latimer, CS and Kow, RL and Kraemer, BC},
title = {Tri-snRNP activity modulates tauopathy phenotypes.},
journal = {NAR molecular medicine},
volume = {2},
number = {3},
pages = {ugaf032},
pmid = {41256288},
issn = {2976-856X},
abstract = {Alzheimer's disease (AD) and other tauopathies are neurodegenerative disorders with devastating consequences for cognition and memory. Pathogenic accumulation of tau can be modeled in Caenorhabditis elegans, which recapitulate human neurodegeneration including aging-dependent accumulation of phosphorylated tau, tau aggregation, neuronal dysfunction, and neuron degeneration. Using forward genetic screens to identify genes modulating tau pathology, we identified a single point mutation in dib-1 that ameliorates tau-driven behavioral defects, prevents neurodegeneration, and decreases tau protein levels. The dib-1 gene encodes a small, highly conserved protein, known as TXNL4A in humans, and participates in mRNA splicing via the U4/U6.U5 tri-snRNP. Notably, heterozygous loss of prp-8, a neighboring protein within the tri-snRNP, also prevents tau-driven neurodegeneration. RNA sequencing of dib-1 mutants demonstrates widespread intron retention consistent with disruption of tri-snRNP functions. Disruption of nonsense-mediated decay further rescues tau-driven phenotypes only in the presence of the dib-1 mutation. TXNL4A levels are decreased in AD in human frontal cortex, demonstrating the translational relevance of dib-1. Taken together, these findings suggest pathological tau impacts splicing function, and spliceosomal activity modulation can ameliorate tauopathy.},
}

@article {pmid41256161,
year = {2025},
author = {Peters, M and Steinbart, D and Hammers, A and Heckemann, RA and , },
title = {Segmentation-Guided Development of Visual Classification Criteria for Alzheimer's Disease.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.09.29.25336750},
pmid = {41256161},
abstract = {Alzheimer's disease (AD) causes progressive structural brain changes that precede clinical symptoms by years. Detecting these changes using structural MRI remains challenging, especially in early stages and when relying on visual interpretation alone. Automated semantic segmentation methods offer anatomical precision and objective measurements, but their outputs are rarely used to support human visual assessment. In this study, we explored whether such segmentation outputs can be used to guide a non-expert investigator in developing and applying interpretable diagnostic criteria. We used images from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and implemented a structured, segmentation-informed workflow in which a novice with no prior training in radiology or neuroanatomy developed classification rules based on visual appearance and volumetric readouts through three guided pilot phases. In a fourth phase, the investigator applied these criteria to an independent subset of ADNI images while blinded to the respective ADNI participants' diagnostic labels. Using an anatomical segmentation model (MAPER) with training data from a pre-release version of the Hammers Adult Brain Atlas Database (120 brain regions), the investigator focused on the piriform cortex (PC). The choice of PC was context-driven, reflecting an ongoing quantitative study of PC volume. A binary classification (AD-like versus CN-like) rule based on PC volume (< or > 430 mm [3]), supported by assessments of PC shape and global atrophy, yielded an accuracy of 0.71 across 200 cases spanning four diagnostic groups. Accuracy increased to 0.77 when the analysis was restricted to CN and AD cases (with intermediate pathology (MCI) excluded). These results show that segmentation-guided visual workflows can enable non-experts to apply anatomically grounded classification criteria with moderate accuracy. Our framework can be expanded to other regions and promises to be useful for generating interpretable models, for supporting explainable AI, and for accelerating the acquisition of diagnostic skills.},
}

@article {pmid41256155,
year = {2025},
author = {Su, CW and Chen, K and Wu, T and Reiman, EM and Wang, Q and , },
title = {TAS2R38-Linked MGAM Expression in Alzheimer's Disease: A Novel Target for Precision Drug Repurposing.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.09.09.25334938},
pmid = {41256155},
abstract = {OBJECTIVE: TAS2R38 is a taste receptor implicated in innate immunity. Identifying its genetic connection with Alzheimer's disease (AD) could aid in developing new drugs or repurposing existing ones for treatment.

METHODS: We examined the relationship between TAS2R38 taster variants and AD risk using linear mixed-effects models, utilizing data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) (n = 2,342). We investigated molecular mechanisms of the association by identifying expression quantitative trait loci (eQTLs) using RNA-seq data from postmortem tissues from the Religious Orders Study/Memory and Aging Project (ROSMAP) (n = 947). We evaluated whether FDA-approved drugs targeting the identified gene could reduce dementia risk using 1:1 propensity score-matched groups in the National Alzheimer's Coordinating Center (NACC) study, comparing cognitive performance between drug-taking and non-taking patients with linear mixed-effects models (n = 76).

RESULTS: TAS2R38 supertasters were linked to reduced AD risk with advancing age in various AD biomarkers (P < 0.001). eQTL analysis connected the nontaster allele to increased expression of the gene MGAM in AD-affected brain regions (P < 0.001). Elevated MGAM expression was also associated with more severe Tau burdens (P < 0.05). A significant group difference was observed in clinical dementia rating (CDR) progression (P < 0.001) in various domains for individuals taking MGAM-inhibiting diabetes drugs (Acarbose and Miglitol) compared to the non-taking group.

INTERPRETATION: The genetic association between TAS2R38 and AD biomarkers implicates MGAM as a novel drug target with existing FDA-approved inhibitors. This supports the potential of TAS2R38 haplotypes in guiding precision drug repurposing strategies for AD, warranting clinical trials.},
}

@article {pmid41256153,
year = {2025},
author = {Balogun, WG and Zeng, X and Triana-Baltzer, G and Saeed, A and Aigbogun, HE and Gogola, A and Lopresti, BJ and Villemagne, VL and Ganguli, M and Kolb, H and Snitz, BE and Lopez, OL and Cohen, AD and Reis, SE and Karikari, TK},
title = {Cross-cohort validation and cutpoint estimation of the Janssen plasma p-tau217+ assay in predominantly cognitively normal community cohorts.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.10.02.25331921},
pmid = {41256153},
abstract = {INTRODUCTION: Cross-cohort validation studies for plasma p-tau217 are limited. We evaluated the Janssen plasma p-tau217+ assay and proposed a cutpoint value in three independent community-based cohorts.

METHODS: We included n=441 participants (age=70.3±7.3), with Aβ-PET, tau-PET, clinical and cognitive information.

RESULTS: The cohorts had low pre-test probability (%Aβ positivity=14.9-24.7) and were predominantly cognitively normal (>73%). Plasma p-tau217+ had high accuracy for abnormal Aβ PET (AUCs=81-86%), good correlation with Aβ-PET burden (0.336-0.397) that was highest in the cohort with the most Aβ-PET-positive participants, and the biomarker concentrations were highest in the joint Aβ-PET and tau-PET positive group. NPV was high across cohorts (≤93%) but PPV was consistently poor (<57%). Sensitivity and specificity averaged 75% and 84% respectively. A combined cohort cutpoint of 0.05pg/ml gave AUC=84.5%, NPV=94%, PPV=50%, sensitivity=75%, and specificity=84%.

DISCUSSION: Plasma p-tau217+ can rule out Aβ pathophysiology due to Alzheimer's disease at the population level. Cohort-level %Aβ-PET positivity influences accuracies.},
}

@article {pmid41256147,
year = {2025},
author = {Tavakoli, M and Dadgostar, M and Green, JR and Salat, DH and Arnold, SE and Connaghan, KP and Richburg, B and Barnett, N and Tkeshelashvili, M and Eshghi, M},
title = {Speech Acoustic Markers Detect APOE-ε4 Carrier Status in Cognitively Healthy Individuals.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.10.03.25337276},
pmid = {41256147},
abstract = {BACKGROUND: APOE-ε4, the strongest genetic risk factor for Alzheimer's disease (AD), is linked to early motor vulnerability, including subtle speech control changes. Because speech integrates fine neuromotor processes, acoustic analysis could offer a sensitive, noninvasive marker of preclinical effects.

OBJECTIVES: To determine if speech acoustics distinguish cognitively healthy APOE-ε4 carriers from non-carriers, and to assess which speech tasks provide optimal classification performance.

DESIGN: A cross-sectional observational study employing supervised machine learning to analyze acoustic features extracted from multiple speech tasks. Genetic algorithms (GAs) were used for feature selection, and model performance was compared across task contexts.

SETTING: All assessments and recordings were conducted in a sound-attenuated laboratory at MGH Institute of Health Professions.

PARTICIPANTS: Forty-four cognitively healthy adults (19 APOE-ε4 carriers, 25 non-carriers), aged 57-79 with no history of neurological and psychiatric conditions.

MEASUREMENTS: Digitized speech was analyzed for 88 eGeMAPS acoustic features. Random Forest classifiers were trained to distinguish genotypes; model optimization employed GAs and stratified cross-validation. Performance was evaluated using F1 scores and subgroup analyses for sex effects.

RESULTS: Random Forest classification of spontaneous speech achieved F1 scores above 0.90 for distinguishing APOE-ε4 carrier status, outperforming performance on structured tasks. GA-based feature selection consistently improved classification. Accuracy was highest among female participants. The combined speech dataset confirmed the robustness and generalizability of results.

CONCLUSIONS: Automated analysis of speech acoustics especially from spontaneous speech, detects APOE-ε4 carrier status in asymptomatic adults, supporting speech as a scalable digital biomarker for early Alzheimer's risk.},
}

@article {pmid41256144,
year = {2025},
author = {Yakoub, Y and Qiu, T and Peyrot, C and Salvadó, G and Villeneuve, S and Binette, AP and , },
title = {Trajectories of plasma biomarkers, amyloid-beta burden and cognitive decline in Alzheimer's disease: A Longitudinal ADNI Study.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.09.30.25337003},
pmid = {41256144},
abstract = {As novel amyloid-β targeted therapies emerge, plasma biomarkers have promising potential to serve as screening tools and as surrogate measures for treatment outcomes. Understanding longitudinal trajectories of these biomarkers and how their changes relate to changes in AD pathology and cognition is needed to help track treatment response and guide patient care. We analyzed data from 394 individuals in the ADNI-FNIH dataset who had plasma biomarkers available across 14 assays, Aβ-PET scans and cognitive assessments over a 10-year period. Plasma p-tau217, regardless of the assay used, had the greatest rate of change over time. This increase was related to concurrent increase in Aβ-PET burden only in individuals with low levels of Aβ. The rate of p-tau217 change, rather than its baseline level, was the strongest predictor of future Aβ-PET positivity. On the other hand, in individuals with elevated levels of Aβ, higher rate of change in p-tau217 was associated with faster cognitive decline. These findings highlight a "dual" role of plasma p-tau217 rate of change, being either predictive of accumulating Aβ pathology at early stages and of cognitive decline at later stages of the AD continuum.},
}

@article {pmid41256143,
year = {2025},
author = {Mohamed Ismail, N and Miller, M and Crossland, H and Sharif, JA and Chapple, JP and Wahlestedt, C and Shkura, K and Volmar, CH and Slabaugh, G and Timmons, JA},
title = {A new ANMerge-based blood transcriptomic resource to support Alzheimer's disease research.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.10.02.25337067},
pmid = {41256143},
abstract = {INTRODUCTION: Alzheimer's disease (AD) has greater prevalence in women and lacks effective treatments. Integrating multimodal data using machine learning (ML) may help improve diagnostics and prognostics.

METHODS: We produced a large and updatable blood transcriptomic dataset (n=1021, with n=317 replicates). Technical robustness was assessed using sampling-at-random, batch adjustment and classification metrics. Transcriptomic and MRI features were concatenated to develop models for AD classification.

RESULTS: Reprofiling of blood transcriptomics resolved previous technical artefacts (sampling-at-random AUC; Legacy=0.732 vs. New=0.567). AD-associated molecular pathways were influenced by cell counts and sex, including unchanged mitochondrial DNA-encoded RNA and altered B-cell receptor biology. Several genes linked to AD-associated neuroinflammatory pathways, including BLNK , TREM2 , and MS4A1 , showed significant enrichment. Concatenation of transcriptomics and MRI models modestly improved classification performance (AUC; MRI=0.922 vs. transcriptomics-MRI=0.930).

DISCUSSION: We provide a new large-scale and technically robust blood AD transcriptomic dataset, highlighting details of molecular sexual dimorphism in AD and potential literature false positives, while providing a novel resource for future multimodal ML and genomic studies.},
}

@article {pmid41256138,
year = {2025},
author = {Garcia Condado, J and Verdugo Recuero, I and Tellaetxe Elorriaga, I and Birkhenbil, C and Carrigan, M and Diez, I and Buckley, RF and Erramuzpe, A and Cortes, JM and , },
title = {Aging as an active player in Alzheimer's Disease Classification: Insights from feature selection in BrainAge Models.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.04.16.25325953},
pmid = {41256138},
abstract = {BACKGROUND: BrainAge models estimate the biological age of the brain using neuroimaging or clinical features, making them promising tools for studying neurodegenerative diseases like Alzheimer's disease. However, the reliance of BrainAge models on neuroimaging features such as grey matter volume and hippocampal atrophy, can introduce biases linked to individuals' ages as these features are influenced both by normal aging and Alzheimer's disease progression. The potential presence of such age-biases raises a critical question: can BrainAge models trained to estimate biological brain aging make meaningful contributions to Alzheimer's diagnosis, or does any introduced age-bias conflate aging effects with disease pathology? Understanding how deliberate feature selection impacts this confounding effect is essential for developing reliable age-related biomarkers.

METHODOLOGY: We ranked neuroimaging and neuropsychological features based on their mutual information with age and their discriminative power across four clinical groups: cognitively normal, Mild Cognitive Impairment, Alzheimer's Disease, stable Mild Cognitive Impairment and progressive Mild Cognitive Impairment. Iteratively, we trained BrainAge models using different subsets of these features, some optimized for predicting aging and others for discrimination of clinical Alzheimer's disease stages. We assess the error in BrainAge delta, the difference between predicted biological age and chronological age, and evaluate its classification performance across clinical groups. Finally, we compare using deltas for classification with a logistic regression model directly trained on the neuroimaging features used in the BrainAge models.

RESULTS: Neuroimaging features are more strongly correlated with aging, while neuropsychological features exhibit greater discriminative power for Alzheimer's disease classification. BrainAge models optimized for age prediction yield deltas that are suboptimal when used for classifying Alzheimeŕs disease, whereas models trained to generate deltas optimized to be used for classifying Alzheimer's disease have reduced age prediction accuracy. This trade-off suggests that BrainAge models may not optimally separate aging-related changes from disease-specific alterations. BrainAge models have varying classification accuracy as compared to direct utilization of features in logistic regression. However, BrainAge provides a continuous measure, offering a single output that can be used across clinical stages, in contrast to classification approaches that require explicit labels for each disease stage.

CONCLUSION: Aging significantly affects BrainAge-based classification of Alzheimer's disease. Feature selection plays a critical role in mitigating this effect, as the outputs of models trained to predict age, the deltas, may fail in Alzheimeŕs disease classification. These findings underscore the need for task-specific feature selection and model design to ensure that BrainAge models are appropriately applied in neurodegenerative disease research.},
}

@article {pmid41256136,
year = {2025},
author = {Tang, AS and Zeng, BZD and Rankin, KP and Miller, B and Gorno-Tempini, ML and Seeley, WW and Rosen, HJ and Rabinovici, GD and Oskotsky, TT and Sirota, M and Pinheiro-Chagas, P},
title = {Characterizing Dementia Phenotypes from Unstructured EHR Notes with Generative AI and Interpretable Machine Learning.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.10.01.25336815},
pmid = {41256136},
abstract = {Dementia encompasses diverse clinical syndromes where diseases of the brain can manifest as impaired cognitive abilities, such as in Alzheimer's disease (AD) and behavioral-variant frontotemporal dementia (bvFTD). The diversity of symptom presentations often results in challenges in diagnosis. Crucial clinical information remains in unstructured narrative notes within electronic health records (EHRs). We leverage large language models (LLMs) for symptom phenotyping from notes in UCSF Information Commons, focusing on patients with expert dementia syndrome diagnosed from a multidisciplinary team of specialists from the UCSF Memory and Aging Center. We developed a pipeline to extract findings in a validated structured output, clustered into symptom groups, and then classified patients into syndromes with traditional machine learning paradigms. From over 9,000 cross-referenced patients and over 350,000 specialty-related notes, matched cohorts of bvFTD (122 patients) and AD (170) syndromes were identified. From notes, 12,637 distinct symptom phrases were extracted, with clustering analysis revealing 51 symptom groups. A logistic regression model separated AD and bvFTD with an AUC of 0.83. Disinhibition and obsessive-compulsive behaviors favored bvFTD, while anxiety and visuospatial abnormalities favored AD. This novel approach, combining LLM-based structured information extraction with traditional interpretable prediction paradigms, demonstrates a promising approach for enhanced symptom characterization in dementia. Our findings suggest potential future applications in improving diagnostic accuracy, developing prediction models, and optimizing treatment strategies in dementia care.},
}

@article {pmid41256130,
year = {2025},
author = {Zhao, F and Puerta, R and Wang, Y and Beckett, E and Garcia Gonzalez, P and Valero, S and Orellana, A and Sanz, P and Kautz, TF and Cavazos, JE and Fernandez, MV and Cano, A and Seshadri, S and Boada, M and Garbarino, VR and Ruiz, A},
title = {Lactoferrin levels in cerebrospinal fluid exhibits isoform-specific associations with Alzheimer's disease.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.09.24.25336349},
pmid = {41256130},
abstract = {BACKGROUND: Pathological changes in Alzheimer's disease (AD) begin years before the onset of clinical symptoms. Developing cost-effective and minimally invasive biomarkers for preclinical diagnosis remains a critical goal in the field. Lactoferrin, an iron-binding glycoprotein, has emerged as a promising candidate due to its multifunctional roles reported in previous studies. However, whether lactoferrin levels in biofluids are associated with established AD biomarkers, and whether it can serve as a reliable diagnostic indicator, remains controversial.

METHODS: We analyzed SOMAscan proteomic data from 1,367 paired plasma and cerebrospinal fluid (CSF) samples from the ACE Alzheimer's Center Barcelona cohort to evaluate lactoferrin levels. Associations between two lactoferrin-targeting SOMAmers and classical AD biomarkers, including total tau (t-tau), phosphorylated tau (p-tau181), and amyloid-beta 42 (Aβ42), were assessed. The age, sex, proteomic principal components were considered as covariates for sensitive analysis. The prognostic value of lactoferrin in predicting dementia progression was further evaluated using survival analysis.

FINDINGS: Among the two lactoferrin-targeting SOMAmers, Seq.2780.35 (LTF2) showed a weak and exclusive association with CSF Aβ42 and syndromic status, whereas Seq.14755.4 (LTF1) was weakly associated with CSF p-tau and t-tau AD biomarker levels displayed expression-dependent stratification consistent with a ventricular- volume-related dilution effect rather than disease. Furthermore, lactoferrin levels were not significantly associated with the progression from mild cognitive impairment (MCI) to dementia.

INTERPRETATION: Isoform-specific lactoferrin expression changes in cerebrospinal fluid (CSF), but not plasma, appears to have biological relevance and diagnostic biomarker potential for AD.},
}

@article {pmid41256116,
year = {2025},
author = {Cody, KA and Sokołowski, A and Johns, E and Guerra, LM and Winer, JR and Young, CB and Younes, K and Dumitrescu, L and Archer, DB and Durant, A and Sathe, A and Koran, MEI and Mez, J and Saykin, AJ and Toga, A and Cuccaro, M and Tosun, D and Insel, PS and Johnson, SC and Harrison, TM and Hohman, TJ and Mormino, EC and , },
title = {Characterizing amyloid and tau PET-based stages across the clinical continuum.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.09.26.25336751},
pmid = {41256116},
abstract = {Staging the severity of Alzheimer's disease pathology using biomarkers is central to early detection and therapeutic trial design. In this cross-sectional study, we standardized amyloid and tau PET data across multiple cohorts to characterize the frequency of amyloid and tau PET-based stages across the clinical continuum. We examined amyloid and tau severity in 10,396 participants (mean [SD] age, 71.9 [7.1] years) with amyloid PET imaging and a subset (n = 3,295) with tau PET imaging. Clinical stage was defined using cohort-specific criteria and categorized as cognitively unimpaired (n = 7,764), mild cognitive impairment (n = 1,480), or dementia (n = 1,152). Amyloid positivity was defined as ≥25 centiloids and amyloid severity was staged using centiloids bins (e.g., <10, 10-24, 25-49, 50-74, 75-99, ≥100). Tau PET severity was staged using a hierarchical Braak staging schema (e.g., T-, T12+, T34+, T56+), and combined with amyloid status to operationalize PET-based Alzheimer's disease biological stages (e.g., Stage A: A+T-; Stage B: A+T12+; Stage C: A+T34+; Stage D: A+T56+). The cumulative probabilities of PET-based stages were estimated using ordinal logistic regression models. In cognitively unimpaired individuals, the frequency of amyloid levels ≥10 centiloids increased with age. Similarly, amyloid levels ≥25 centiloids increased with age in mild cognitive impairment. Overall, elevated amyloid (≥25 CL) was more likely with increasing age among non-demented individuals. By contrast, this age association was attenuated in dementia where severe amyloid burden (e.g., ≥100 CL) was most common. In the tau PET subsample (n = 3,295), there was a three-way interaction between amyloid, age, and clinical impairment on likelihood of tau severity. Both higher amyloid and greater clinical impairment were associated with increased tau severity; however, the strength and direction of these associations varied with age. At lower amyloid levels, the odds of tau severity increased with older age among cognitively unimpaired and mild cognitive impairment. Conversely, at higher amyloid levels, the odds of higher tau severity (e.g., T56+) decreased with older age in mild cognitive impairment and dementia. A similar age-related pattern was observed in the frequency of biological stages (n = 1,154), where Stage D (e.g., A+T56+) was most frequent in younger individuals with dementia. These findings underscore the dual importance of amyloid and tau PET severity as biomarkers for staging and characterizing Alzheimer's disease progression. They also demonstrate the feasibility of applying PET-based staging frameworks for the diagnosis of Alzheimer's disease across multiple tracers and cohorts.},
}

@article {pmid41256114,
year = {2025},
author = {Mehta, RI and Wang, T and Lewis, A and Walker, CE and Gebczak, C and Barnes, LL and Bennett, DA and Mehta, RI},
title = {Arachnoid Granulation Morphologies Associate with β-Amyloid and Tau Pathology in Older Adults.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.09.30.25336940},
pmid = {41256114},
abstract = {INTRODUCTION: Arachnoid granulations (AG) enlarge with age, yet limited studies evaluate AG in neurodegeneration. Here, we investigate associations of AG morphology with Alzheimer's disease (AD) pathology.

METHODS: Macroscopic AG properties were systematically evaluated along dorsal postmortem brain specimens from older adults (n=882). Regression models were used to analyze their associations with AD neuropathologic indices, controlling for demographic factors.

RESULTS: Participants died at mean age of 90.62 (SD=6.98) years. β-amyloid (Odds ratio/OR, 0.79 [95% CI, 0.66-0.95]) and neurofibrillary tangles (OR, 0.84 [95% CI, 0.71-0.98]) inversely associated with global AG count. Similarly, β-amyloid (OR, 0.78 [95% CI, 0.65-0.92]) and B (Braak) score (OR, 0.80 [95% CI, 0.66-0.96]) inversely associated with global AG patch count.

DISCUSSION: β-amyloid and tau pathology are associated with AG morphologies. Future studies should explore the mechanisms underlying these associations across disease stage and demographic factors.},
}

@article {pmid41256014,
year = {2025},
author = {Frazier, M and Kaur, T and Stauff, J and Winton, WP and Henderson, BD and Dumond, AS and Shao, X and Raffel, DM and Frey, KA and Kilbourn, MR and Brooks, AF and Scott, PJH},
title = {IND-Enabling Preclinical Studies of [[11]C]COU, a Trapped Metabolite PET Radiotracer for Monoamine Oxidase-B.},
journal = {Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents},
volume = {},
number = {},
pages = {},
pmid = {41256014},
issn = {1054-2523},
abstract = {[[11]C]COU is a trapped metabolite radiotracer for in vivo analysis of Monoamine Oxidase B activity using positron emission tomography (PET) imaging. [[11]C]COU has the potential to quantify astrocytosis in the early stages of Alzheimer's disease, providing an earlier marker of disease than currently available for staging disease progression. Prior preclinical studies have demonstrated the efficacy of this radiotracer in preclinical imaging studies, warranting the translation for clinical evaluation. In this paper, we describe results of the requisite preclinical studies required to obtain approval for translation of [[11]C]COU into first-in-human studies. Development and validation of a production method that conforms to the quality requirements described in the US Pharmacopeia was accomplished, along with preclinical rodent studies to determine human radiation dose estimates and a single acute dose pharmacology and toxicology study to establish that an injected mass dose 100-fold higher than the proposed PET imaging dose was below the no-observed-adverse-effect level (NOAEL). The production method was validated in triplicate, yielding [[11]C]COU in sufficient radiochemical yield (9.3±0.008%), radiochemical purity (99.2±0.002%) and molar activity (165±65 TBq/mmol) for routine clinical use, and providing a product that was sterile and met (or exceeded) all quality control requirements for human use. Dosimetric analysis determined that the effective human dose of [[11]C]COU is 0.005mSv/MBq, also acceptable for clinical use. Lastly, no observable adverse effects were noted at 86 μg/kg in rodent toxicology studies (100x the proposed human dose). From these results we received approval to advance [[11]C]COU into clinical studies.},
}

@article {pmid41256012,
year = {2025},
author = {Suresh, V and Nahar, T and Sharma, A and Panchawagh, S and Mohammed, O and Muneer, MA and Mishra, D and Verma, A and Sanker, V and Mishra, A and Malhotra, HS and Garg, RK},
title = {A lightweight machine learning tool for Alzheimer's disease prediction.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {17},
number = {4},
pages = {e70187},
pmid = {41256012},
issn = {2352-8729},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegenerative disorder that needs better predictive tools. Using the National Alzheimer's Coordinating Center Uniform Data Set, this study developed machine learning (ML) models and a practical clinical tool for AD prediction.

METHODS: Data from 52,537 individuals (22,371 with AD) and more than 200 variables were processed with MissForest imputation and genetic algorithm-based selection. Multiple ML models were trained, and interpretability was performed using SHAP and permutation importance. A LightGBM model was refined through iterative backward feature elimination (IBFE) followed by manual refinement.

RESULTS: LightGBM performed best (receiver operating characteristic-area under the curve [ROC-AUC] 0.91, accuracy 82.0%). Key predictors included arthritis, age, body mass index, and heart rate. A 19-feature model retained accuracy (81.2%) and ROC-AUC (0.90).

DISCUSSION: This lightweight tool predicts AD using mostly routine variables. Limitations include its cross-sectional nature, and would need external validation. An interactive web app and GitHub resource are available.

HIGHLIGHTS: Developed a lightweight ML based tool using 19 routinely available features.The lightweight model achieved an ROC-AUC of 0.90 for Alzheimer's disease prediction on NACC multicenter data.Genetic algorithm, IBFE, and manual refinement enabled optimal feature selection.Tool hosted on an open-access platform for clinical and research use.SHAP analysis provided model interpretability and feature-level insights.},
}