@article {pmid41212655,
year = {2025},
author = {Cohen-Mansfield, J and Cohen, R},
title = {Evaluating the feasibility and perceived benefits of enhanced group activity kits for engaging persons living with dementia at home: A pilot study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251393479},
doi = {10.1177/13872877251393479},
pmid = {41212655},
issn = {1875-8908},
abstract = {BackgroundProviding meaningful activities to persons living with Alzheimer's disease or other dementias in home settings is challenging because it typically involves the expense of professionals instructing the caregivers. Enhanced group activity kits (EGAKs) have been shown to enhance the wellbeing of persons living with dementia (PLwD) in group settings.ObjectiveTo investigate the feasibility and potential benefits of EGAKs in one-on-one settings without the expense of visiting professionals.MethodsRecruitment started with 75 referrals, from nursing agencies, family caregivers' support groups, a health services organization for older persons and their families, and an occupational therapists WhatsApp group, resulting in 34 family caregivers from greater Tel Aviv and Jerusalem metropolitans, Israel, completing a baseline interview. From those who completed the baseline interview, 16 PLwD experienced EGAKs with facilitators (family members, formal caregivers, or friends). Facilitators completed EGAKs-related questionnaires and a post-EGAKs-use interview. This mixed methods study includes a quantitative analysis of the EGAKs' facilitators' perceptions of the extent of success and an inductive content analysis to identify EGAKs' benefits and potential outcomes.ResultsFor most PLwD, one-on-one EGAKs were perceived as successful, making PLwDs' and facilitators' shared time more interesting and enjoyable. Four EGAKs' use benefits emerged: Affecting mood, feelings, and emotions; Affecting cognition and behavior; Shifts in perceptions; and improving communication and relationship between the PLwD and facilitators.ConclusionsWhen used in a home setting, EGAKs are often feasible and are often perceived to increase PLwDs' engagement in activities and improve their wellbeing.},
}

@article {pmid41212653,
year = {2025},
author = {Vranceanu, AM and Szapary, CL and Cornelius, T and Monin, JK and Syme, M and Okereke, OI and Lyons, KS and Plys, E},
title = {Behavioral dyadic interventions in the context of Alzheimer's disease and related dementia: A call to action.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251392184},
doi = {10.1177/13872877251392184},
pmid = {41212653},
issn = {1875-8908},
abstract = {Alzheimer's disease and related dementias (ADRD) affect persons living with dementia (PLWD) and care partners, often disrupting emotional well-being and relationship dynamics. Despite growing evidence of dyadic interdependence in dementia care, most psychosocial interventions remain individually focused, missing an opportunity to improve relational and health outcomes. Dyadic dementia interventions (DDIs) aim to support both members of the dyad through shared communication, coping, and mutual support. The primary objective of this review is to introduce the guiding principles of the CONFIDE-ADRD Roybal Center at Massachusetts General Hospital, as these provide a useful roadmap for advancing scalable, theory driven, and person-centered DDIs. We explore the promise and challenges of DDIs, including inconsistent application of theory, measurement difficulties, and barriers to recruiting dyads from a broad range of populations with disparities. Drawing from chronic illness models and dementia-specific programs, we propose a roadmap for building scalable, theory-driven DDIs grounded in mechanistic science. We introduce CONFIDE-ADRD as a national initiative providing funding, training, and expert consultation to accelerate DDI development. The Center's 14 guiding principles support person-centered, context-sensitive intervention design that targets both individual and relational mechanisms of change. As dementia care becomes increasingly relational and dynamic, robust dyadic approaches are critical to reducing care burden, strengthening relationships, and improving outcomes for both PLWD and care partners. Readers are encouraged to engage with CONFIDE-ADRD's resources and contribute to the advancement of dyadic dementia care research.},
}

@article {pmid41212652,
year = {2025},
author = {DuBois, KN and Pal, S and Reader, JM and Jackman, B and Perkins, MD and Khobeir, N and Bakulski, KM and Heidebrink, J and Hampstead, BM and Morgan, DG and Kanaan, NM},
title = {Evaluation of a panel of plasma biomarkers for Alzheimer's disease in a diverse research cohort.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251393405},
doi = {10.1177/13872877251393405},
pmid = {41212652},
issn = {1875-8908},
abstract = {BackgroundPlasma biomarkers show significant promise for Alzheimer's disease (AD) diagnostics and risk prediction, however, much less is known about how these assays perform in a diverse research cohort of older adults.ObjectiveTo compare plasma biomarkers with clinical diagnoses and assess variability by demographic factors in a diverse research cohort.MethodsAmong 331 University of Michigan Memory and Aging Project (UM-MAP) participants, plasma biomarkers (pTau-217, pTau-181, GFAP, NfL, Aβ42, Aβ40, t-Tau) were measured. Demographic information (age, sex, education, race) was self-reported. Clinical consensus phenotypes (dementia of the Alzheimer Type (DAT), mild cognitive impairment (MCI), cognitively unimpaired (CU) were based on neuropsychological assessments. Logistic regression with machine learning for model variable selection was used to compare participants by clinical phenotypes.ResultsComparing CU and DAT participants, areas under the curve (AUCs) from receiver operator characteristic curves of single biomarker models ranged from 0.74-0.89. Optimal performance (AUC 99.7) was observed from stepwise regression with backward selection, which identified pTau-217, GFAP, sex, education, APOE ε4 allele, and race as model variables. When comparing MCI and DAT participants, only pTau-217 differed significantly (AUC 0.80). pTau-181 and pTau-217 levels were higher in white participants than Black/African American participants across all clinical phenotypes.ConclusionsPlasma biomarkers demonstrate promise for improving diagnostic accuracy in diverse research cohorts. Incorporating demographic variables facilitates enhanced interpretability of biomarker levels and the development of reference ranges.},
}

@article {pmid41212651,
year = {2025},
author = {Alphin, KH and Suerken, CK and Rudolph, MD and Gaussoin, S and Lockhart, SN and Craft, S and Brinkley, TE},
title = {Obesity, cardiometabolic health status, and brain health in community-dwelling older adults.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251393500},
doi = {10.1177/13872877251393500},
pmid = {41212651},
issn = {1875-8908},
abstract = {BackgroundThough mid-life obesity is a known risk factor for dementia, how obesity in late life impacts brain health is not well understood, especially in the presence of comorbid risk factors like hypertension (HTN) and impaired glucose tolerance (IGT).ObjectiveWe investigated associations between obesity, neuroimaging measures, and cognition in middle aged and older adults, specifically testing whether higher body mass index (BMI), waist circumference (WC), and waist-to-hip ratio are associated with brain health independent of HTN and IGT.MethodsA total of 599 participants with brain MRI, cognitive testing, and anthropometric measurements were examined. Chi square and one-way ANOVA tests were performed to compare participant characteristics across BMI categories. Linear regression models assessed relationships between anthropometric, neuroimaging, and cognitive outcomes with and without adjustment for relevant covariates. We also explored interactions between anthropometric measures and APOE ε4 status and cognitive status.ResultsHigher BMI was associated with higher cerebral blood flow (CBF) in both white matter (β = 0.2294 ± 0.0431, p < 0.001) and gray matter (β = 0.0872 ± 0.0405, p = 0.032), higher free water (β = 0.0906 ± 0.0425, p = 0.034), lower fractional anisotropy (β = -0.0891 ± 0.0433, p = 0.040), and better global cognition (β = 0.022 ± 0.007, p = 0.002) and cognitive composite scores (ps < 0.01), independent of IGT and HTN. Similar associations were observed for waist circumference. Evidence of effect modification by APOE ε4 carrier status and cognitive status were found for white matter CBF, white matter hyperintensities, fractional anisotropy, and cognition.ConclusionsObesity measures are positively associated with better brain structure, function, and cognition in aging adults, highlighting the importance of managing body weight in older age to maintain optimal brain health.},
}

@article {pmid41212649,
year = {2025},
author = {Rokach, MS and Gershfeld-Litvin, A},
title = {Against nature: The experiences of parents caring for an adult child with young-onset dementia.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251393589},
doi = {10.1177/13872877251393589},
pmid = {41212649},
issn = {1875-8908},
abstract = {BackgroundYoung-onset dementia (YOD), diagnosed before age 65, most often appears as Alzheimer's disease (AD) or frontotemporal dementia (FTD). Compared to late-onset dementia (LOD), YOD poses distinct caregiving, emotional, and social challenges. While research has expanded, it has largely centered on spouses and children, leaving the experiences of parents caring for an adult child with YOD underexplored and in need of greater scholarly attention.ObjectiveThis study aims to investigate the unique experiences of parents caring for an adult child diagnosed with YOD.MethodsQualitative semi-structured interviews were conducted with 12 Hebrew-speaking Jewish Israeli parents who provided informal care to an adult child diagnosed with YOD. The sample included cases of FTD and dementia with Lewy bodies (DLB). Participants were recruited through purposive sampling, and the data were analyzed using thematic analysis.ResultsThematic analysis revealed three themes. The first, "The Diagnosis," captured parents' descriptions of the long and complex diagnostic process, from initial recognition of symptoms to the formal diagnosis. The second, "Parent-Child Relationship," reflected experiences of loss and shifting dynamics within the relationship. The third, "Assimilation Into the Caregiver Role," highlighted significant changes in personal identity alongside emotional, and practical caregiving challenges.ConclusionsCaring for an adult child with YOD involves a profound sense of loss and presents substantial challenges to parental identity, particularly as parents themselves age. These findings highlight the critical need for tailored interventions, improved communication, and strengthened support within healthcare and mental health systems to effectively address the unique needs of parent caregivers.},
}

@article {pmid41212647,
year = {2025},
author = {Hamdi, A and Stathopoulou, P and Gharbi, A and Saadouli, I and Najjari, A and Kacem, I and Ouzari, HI and Bel Mokhtar, N and Tsiamis, G and Gouider, R and Klibi, N},
title = {Salivary microbiome dysbiosis in patients with Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251393229},
doi = {10.1177/13872877251393229},
pmid = {41212647},
issn = {1875-8908},
abstract = {BackgroundInvestigating human oral microbiota is now of great interest, being clinically significant for general and oral health. Many research studies have started to focus on the link between oral microbial dysbiosis and Alzheimer's disease. However, little is known about North African populations.ObjectiveWe aimed to distinguish the dissimilarity in the structure of microbial oral flora between the Alzheimer's disease patients and healthy controls in a Tunisian population.MethodsWe investigated the salivary microbiota using next-generation shotgun sequencing.ResultsThe overall structure of the oral microbial community of the Alzheimer's disease patient group was obviously different from the healthy control group. Significantly higher levels of Haemophilus (25.26%) were noticed in the AD group. However, Neisseria (10.17%) showed lower levels compared to the HC group. Considering the disease severity, Selenomonas and Aggregatibacter showed gradually higher levels as the disease progressed. Porphyromonas showed the highest levels in the mild stage of the disease, while Treponema, Selenomonas, and Peptostreptococcus were associated with severe stage. The presence of key taxa, Aggregatibacter and Selenomonas may constitute a dysbiosis signature in individuals with AD.ConclusionsThese findings may be of high relevance for orienting further studies on evaluating the physio-pathological process, confirming the implication of oral microbiota in AD and opening diagnostic and therapeutic avenues.},
}

@article {pmid41212646,
year = {2025},
author = {Song, W and Fang, M and Geng, Z and Pang, X and Yang, C and Chen, M and Song, B and Hu, C and Hu, Y and Hu, W and Zhou, S and Yan, Y and Wu, X and Wang, K},
title = {Mechanistic study of Alzheimer's disease with behavioral and psychological symptoms based on electroencephalography microstates.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251393715},
doi = {10.1177/13872877251393715},
pmid = {41212646},
issn = {1875-8908},
abstract = {BackgroundBehavioral and psychological symptoms of dementia (BPSD) are common in Alzheimer's disease (AD), yet their mechanisms remain unclear.ObjectiveWe aim to explore the possible neurophysiological mechanisms of BPSD using high temporal resolution electroencephalography (EEG) microstate technology, laying the foundation for clinical evaluation and subsequent treatment.MethodsWe enrolled 52 AD patients (25 with BPSD, 27 without) and 29 age- and gender-matched healthy controls (HC). All participants underwent various neuropsychological assessments and resting-state EEG recordings. Resting-state EEG data were analyzed employing microstate analysis techniques, with a focus on four key microstate parameters: duration, occurrence, coverage, and transition probability. Inter-group comparisons were performed using post-hoc tests, with statistical significance determined through False Discovery Rate (FDR) correction. Furthermore, the correlations between the indicators and neuropsychological assessment scores were analyzed.ResultsCompared to the HC and non-BPSD groups, the BPSD group showed an increase in the transition rate from microstate A to microstate C. Compared to the HC group, the BPSD group showed an extension in the duration of microstate A and a decrease in the frequency of microstate D. Compared to the HC group, the non-BPSD group showed prolonged durations (A, B, mean) and reduced occurrences (C, D, mean).The partial correlation analysis with years of education as a covariate showed that in the BPSD group, the duration of microstate A was correlated with the severity of the Neuropsychiatric Inventory (NPI) and the Hamilton Anxiety Scale (HAMA).ConclusionsAD with and without BPSD exhibits different altered brain dynamics.},
}

@article {pmid41212591,
year = {2025},
author = {Jo, T and Lee, EH and , },
title = {Uncertainty-aware genomic classification of Alzheimer's disease: a transformer-based ensemble approach with Monte Carlo dropout.},
journal = {Briefings in bioinformatics},
volume = {26},
number = {6},
pages = {},
doi = {10.1093/bib/bbaf587},
pmid = {41212591},
issn = {1477-4054},
support = {P30 AG072976, U19 AG024904, U01 AG068057, U19 AG074879, U01 AG072177, U24 AG074855/NH/NIH HHS/United States ; AARG 22-974053/ALZ/Alzheimer's Association/United States ; },
abstract = {Alzheimer's disease (AD) has complex genetic factors that make accurate prediction from genomic data challenging. Current methods lack confidence estimates for their predictions. Our objective is to develop and evaluate an uncertainty-aware deep learning framework for AD prediction that can identify which predictions are reliable. We developed Transformer-based, Uncertainty-aware, Ensemble Network (TrUE-Net), a deep learning framework that combines transformer and random forest models to predict AD from whole-genome sequencing data. The key innovation is using Monte Carlo Dropout to estimate prediction confidence, allowing the model to identify cases where it is uncertain. We analyzed 1050 individuals (607 AD, 443 controls) from Alzheimer's Disease Neuroimaging Initiative cohort. On 525 test samples, accuracy of TrUE-Net without uncertainty threshold was 65.1% with area under the receiver operating characteristic curve 0.664. Using uncertainty thresholds, the model classified 75.4% of samples (n = 396) as 'uncertain' and 24.6% (n = 129) as 'certain'. The uncertain group showed accuracy of 62.6% and F1 of 0.584, while the certain group showed accuracy of 72.9% and F1 of 0.821. Uncertainty quantification through Monte Carlo Dropout provides a framework for assessing prediction reliability in genomic AD classification, potentially allowing more informed interpretation of model outputs.},
}

@article {pmid41212562,
year = {2025},
author = {Boustani, MA and Ben Miled, Z and Owora, AH and Fowler, NR and Dexter, P and Puster, E and Grout, RW and Summanwar, D and Erazo, SF and Disla, S and Coppedge, K and Galvin, JE},
title = {Digital Detection of Dementia in Primary Care: A Randomized Clinical Trial.},
journal = {JAMA network open},
volume = {8},
number = {11},
pages = {e2542222},
doi = {10.1001/jamanetworkopen.2025.42222},
pmid = {41212562},
issn = {2574-3805},
abstract = {IMPORTANCE: Detection of Alzheimer disease and related dementias (ADRD) is a challenge in primary care settings. The Quick Dementia Rating System (QDRS) and the Passive Digital Marker (PDM) were developed as 2 scalable tools for early detection of ADRD. The QDRS is a patient-reported outcome measure, while the PDM is a machine learning algorithm that uses electronic health record (EHR) data. Both can be embedded in the EHR for ease of use.

OBJECTIVE: To evaluate the effect of the combined approach of QDRS plus PDM in improving the annual rate of new documented ADRD diagnoses in primary care practices.

This randomized clinical trial was performed between July 2, 2022, and July 1, 2024. Nine federally qualified primary health care clinics in Indianapolis, Indiana, were randomized to usual care (no routine screening for ADRD), PDM only, or QDRS plus PDM. Participants were treated as per the randomization arm. Participants included adults 65 years and older, without a diagnosis of mild cognitive impairment, dementia, or severe mental illness. Data analysis was based on intention to treat and was performed between November 1, 2024, and August 20, 2025.

INTERVENTION: Randomization of clinic to usual care, PDM only, or QDRS plus PDM.

MAIN OUTCOMES AND MEASURES: The primary outcome was 12-month cumulative incidence of ADRD diagnoses; the secondary outcome was any ADRD diagnostic workup, such as laboratory tests, neuropsychological testing, or brain imaging.

RESULTS: The study included 5325 patients (mean [SD] age, 71.1 [5.9] years), 3312 (62.2%) of whom were female. Compared with the usual care clinics (12-month incidence, 213 of 1724 [12.4%]), the odds of an incident ADRD diagnosis were higher in the clinics randomized to QDRS plus PDM (12-month incidence, 355 of 2301 [15.4%]; adjusted odds ratio [AOR], 1.31; 95% CI, 1.05-1.64) but not the clinics randomized to PDM only (12-month incidence, 134 of 1300 [10.3%]; AOR, 0.84; 95% CI, 0.63-1.11]). Compared with the usual care clinics (12-month incidence, 500 of 1724 [29.0%]), the odds of ADRD diagnostic assessments were higher in the QDRS plus PDM clinics (12-month incidence, 844 of 2301 [36.7%]; AOR, 1.41; 95% CI, 1.12-1.77) but not the PDM clinics (12-month incidence, 362 of 1300 [27.8%]; AOR, 0.94; 95% CI, 0.72-1.22).

CONCLUSIONS AND RELEVANCE: This randomized clinical trial found that the combined approach was effective at scale for the early detection of ADRD in primary care settings. This is an important feature in busy primary care settings that can benefit both the health care system and patients.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05231954.},
}

@article {pmid41212470,
year = {2025},
author = {Soni, U and Pujari, R},
title = {Therapeutic Potential of Phytocompounds Gentisic Acid and Alpha Resorcylic Acid against Alzheimer's Disease: A Network Pharmacology, In Silico, and In Vitro Approach.},
journal = {Cell biochemistry and biophysics},
volume = {},
number = {},
pages = {},
pmid = {41212470},
issn = {1559-0283},
}

@article {pmid41212436,
year = {2025},
author = {Vizuete, AFK and Moreira, AP and Zin, LEF and de Oliveira Marques, C and Pacheco, RF and Leal, MB and Menezes, L and Gonçalves, CA},
title = {Neuroprotective Roles of Metformin in a Streptozotocin-Induced Dementia Model in Rats.},
journal = {Neurotoxicity research},
volume = {43},
number = {6},
pages = {48},
pmid = {41212436},
issn = {1476-3524},
abstract = {Alzheimer's disease (AD) is the leading cause of dementia in humans, with high social and economic costs. AD is predominantly a sporadic disorder, and its risk increases with age and in individuals with type 2 diabetes mellitus (T2DM). Metformin is considered the first line drug for treatment of T2DM and has a plethora of effects in the peripheral and nervous system. However, the neuroprotective mechanism of action of this drug is still under debate. In order to assess the effects of metformin in dementia, we investigated the optimal time to start metformin treatment in animals that were submitted to intracerebroventricular (ICV) administration of streptozotocin (STZ) (3 mg/kg) to induce a sporadic AD-like rodent model of dementia. We used two protocols of metformin administration: early metformin (50 mg/Kg/daily) treatment (2 days after STZ model induction, lasting 28 days) and late metformin (50 mg/Kg/daily) treatment (20 weeks after STZ model induction, lasting 28 days). Both time points improved cognitive behavior in STZ rats, as evaluated by the novel object recognition and Morris's water maze tasks. Moreover, both treatments reduced neuroinflammatory parameters, such as TLR4, RAGE, TNF-α and NF-κB protein expression, induced in STZ animals. Metformin downregulated the methylglyoxal/RAGE/NOX‑2 signaling pathway by restoring glyoxalase 1 activity and GSH levels, which are impaired in the STZ-induced dementia model. Our data contribute to understanding the neuroprotective role of metformin, particularly in conditions involving insulin resistance, such as diabetic encephalopathy and AD.},
}

@article {pmid41212353,
year = {2025},
author = {Shademan, B and Yousefi, H and Sharafkhani, R and Nourazarian, A},
title = {LPS-Induced Neuroinflammation Disrupts Brain-Derived Neurotrophic Factor and Kinase Pathways in Alzheimer's Disease Cell Models.},
journal = {Cellular and molecular neurobiology},
volume = {45},
number = {1},
pages = {102},
pmid = {41212353},
issn = {1573-6830},
support = {(IR.KHOY.REC.1402.030//Khoy University of Medical Sciences/ ; },
abstract = {Alzheimer's disease (AD) leads to a progressive loss of cognitive abilities and memory. A critical factor now recognized as driving AD pathology is neuroinflammation-inflammation occurring in the nervous system, which contributes to neuronal harm and communication breakdowns. our research investigated the specific effects of neuroinflammation on neuronal signaling pathways. In this study, we primarily employed the SH-SY5Y neuroblastoma cell line as an in vitro neuronal model to investigate inflammatory responses relevant to AD etiology, alongside supplementary observations in primary neurons and 3D spheroids for comparative analysis. Our analysis focused on modifications of key molecules, including the neuroprotective protein Brain-Derived Neurotrophic Factor (BDNF), pro-inflammatory cytokines such as IL-6 and TNF-α, and crucial regulatory kinases. Our results demonstrated that LPS treatment dramatically lowered the vitality and decreased BDNF levels in the SH-SY5Y cells. Furthermore, we observed a considerable elevation in the pro-inflammatory cytokines IL-6 and TNF-α, coupled with elevated levels of COX-2 and iNOS. Gene expression data validated that LPS treatment altered the expression of essential signaling kinases (Protein Kinase A (PKA), Protein Kinase B (AKT), and Mitogen-Activated Protein Kinase (MAPK)). Our first comparative analysis revealed that 3D spheroid cultures may elicit more pronounced inflammatory responses than standard 2D cultures; nevertheless, our detailed investigation primarily focused on the SH-SY5Y model. This study revealed that LPS-induced neuroinflammation affects neuronal signaling in vitro, thereby revealing a relationship between inflammation and neuronal dysfunction in cellular models of neuroinflammation. These findings highlight pathways that may be relevant to AD pathophysiology; however, further in vivo studies are necessary to demonstrate their translational relevance to humans.},
}

@article {pmid41212342,
year = {2025},
author = {Zhong, R and Yang, H and Li, X and Wang, F and Zhai, L and Gao, J},
title = {Mitochondria-Mediated Mechanisms of Ferroptosis in Neurological Diseases.},
journal = {Neurochemical research},
volume = {50},
number = {6},
pages = {354},
pmid = {41212342},
issn = {1573-6903},
support = {202403070986//Health Science and Technology Project of Shandong Province/ ; RZ1900011598//post-doctoral foundation of Qingdao University/ ; },
abstract = {Ferroptosis, a regulated form of cell death driven by iron-dependent lipid peroxidation, is increasingly recognized as a critical contributor to the pathogenesis of various neurological disorders. Mitochondria, the powerhouses of cells, play dual roles as both initiators and mediators of ferroptosis by integrating lipid peroxidation cascades, oxidative stress responses, and iron homeostasis dysregulation. This review first comprehensively explores the multifaceted mechanisms by which mitochondria mediate ferroptosis in neurological diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Friedreich's ataxia (FRDA), amyotrophic lateral sclerosis (ALS), epilepsy, stroke, and brain injury, with a focus on mitochondrial lipid peroxidation and iron metabolism dysregulation. Building on these mechanistic insights, we further discuss emerging evidence suggesting that targeting mitochondrial pathways may represent a promising therapeutic strategy for mitigating ferroptosis-associated neuronal damage. By synthesizing these findings, our review establishes a conceptual foundation for developing innovative neuroprotective interventions through precise modulation of mitochondrial function within ferroptotic pathways.},
}

@article {pmid41212264,
year = {2025},
author = {Zhang, L and Ge, Y and Wu, J and Wang, M and Huang, N and Luo, Y},
title = {Research on the Application of Mesenchymal Stem Cells for Addressing Mitochondrial Damage in Neurodegenerative Diseases.},
journal = {Cellular and molecular neurobiology},
volume = {45},
number = {1},
pages = {101},
pmid = {41212264},
issn = {1573-6830},
support = {ZYK254//Graduate Research Fund of Zunyi Medical University/ ; 82160858//National Natural Science Foundation of China/ ; ZK (2024)-680//Science and Technology Department of Guizhou Province/ ; (2024) No. 6, HZ-2022-45//Zunyi Science and Technology Bureau/ ; R&D 2020-06//The First People's Hospital of Zunyi for Research and Experimental Development/ ; },
abstract = {Neurodegenerative diseases (NDs) such as Alzheimer's disease (AD) and Parkinson's disease (PD) pose serious threats to human health, and their pathogenesis is closely related to mitochondrial damage. Mitochondrial dysfunction includes abnormal energy metabolism, oxidative stress imbalance, disturbed calcium homeostasis and altered mitochondrial dynamics, which in turn trigger neuronal apoptosis and neuroinflammation. Mitochondrial dysfunction is a hallmark of many NDs. In addition to their multi-lineage differentiation potential, ability to promote neuronal repair, and capacity to modulate the neuroimmune microenvironment, Mesenchymal stem cells (MSCs) also hold potential for restoring mitochondrial dysfunction. MSCs have important therapeutic potential and mechanistic research value in the context of neurodegenerative disorders through the modulation of mitochondrial homeostasis and its transcellular transfer process. In this paper, we systematically summarize the mechanisms, technological advances, and translational challenges associated with mitochondrial damage in NDs and the role of MSCs in NDs through the modulation of mitochondrial damage and discuss their potential and limitations as a general therapeutic strategy.},
}

@article {pmid41211864,
year = {2025},
author = {Fallot, LB and Natarajan, C and Anderson, CA and Nagelli, EA and Burpo, FJ and Limbocker, R},
title = {From Pathology to Materials Science and Engineering: Harnessing the Amyloid State for Biotechnological Applications.},
journal = {ACS applied materials & interfaces},
volume = {},
number = {},
pages = {},
doi = {10.1021/acsami.5c11847},
pmid = {41211864},
issn = {1944-8252},
abstract = {The aberrant misfolding and aggregation process of specific peptides and proteins plays a seminal role in the onset and development of over 60 protein misfolding diseases, including Alzheimer's and Parkinson's diseases. These proteins can convert from the endogenous, monomeric, and often largely intrinsically disordered state to the pathological, highly ordered amyloid state, which results in the formation of long, thread-like fibrillar species with extensive β-sheet structure and hallmark tinctorial and biophysical properties. Beyond pathology, the amyloid state has been well-studied for its role in physiological processes in numerous organisms through functional amyloids. In this review, we consider principles governing amyloid formation, with a focus on leveraging the unique biophysical properties and templating abilities of amyloids to produce diverse amyloid-containing materials with wide-ranging biotechnological applications, including, but not limited to, aerogels and hydrogels of varied function, drug delivery, tissue engineering, antimicrobials, purification and detection, protein-based packaging and food science, chemical catalysis, and bioelectronics. We conclude with a brief discussion on the opportunities and challenges ahead for implementing amyloid-based biotechnologies in society.},
}

@article {pmid41211647,
year = {2025},
author = {Buhlin, K and Eriksdotter, M and Jansson, L and Pussinen, PJ and Schultzberg, M and Lira-Junior, R},
title = {The association of periodontal inflammation and inflammatory markers with cognitive dysfunction: A case-control study.},
journal = {Journal of periodontology},
volume = {},
number = {},
pages = {},
doi = {10.1002/jper.70020},
pmid = {41211647},
issn = {1943-3670},
abstract = {BACKGROUND: This study investigated the association of inflammatory markers in saliva, plasma, and cerebrospinal fluid (CSF) with cognitive decline and periodontitis.

METHODS: Patients with Alzheimer disease (AD, n = 52), mild cognitive impairment (MCI, n = 51), subjective cognitive decline (SCD, n = 51), and controls (n = 76) between 50 and 80 years were included. Participants underwent an oral examination, and blood and stimulated saliva were collected. In addition, CSF samples were collected from patients but not controls. Levels of interleukin (IL)-1β, IL-8, IL-10, IL-17A, and tumor necrosis factor-alpha (TNF-α) were analyzed by multiplex immunoassays.

RESULTS: Increased salivary levels of IL-1β, IL-10, and IL-17A were found in MCI compared to controls, while in plasma increased IL-8 levels were seen in all 3 patient groups compared to controls (p < 0.001). TNF-α plasma levels were higher in SCD and AD (p < 0.05). IL-17A levels in CSF were higher in participants with no/mild periodontitis compared to generalized periodontitis (p = 0.023). Participants with severe periodontitis showed higher levels of IL-8 both in saliva (p = 0.027) and plasma (p < 0.001), as well as higher TNF-α levels in plasma (p = 0.041).

CONCLUSIONS: Inflammation markers could indicate an increased risk for cognitive decline, especially in cases of more severe periodontitis.

PLAIN LANGUAGE SUMMARY: Evidence has indicated an association between periodontitis and cognitive impairment. Hence, this study investigated whether inflammatory markers in saliva, plasma, and cerebrospinal fluid are associated with cognitive decline. Cases with mild or more severe signs of cognitive impairment had more signs of periodontal disease. Levels of some, but not all, inflammation markers were elevated among patients compared to cognitively healthy controls. Oral inflammation could indicate an increased risk for cognitive decline, and chronic inflammation may act as a common pathway. Early periodontal intervention and maintaining oral health may contribute to cognitive well-being.},
}

@article {pmid41211332,
year = {2025},
author = {Guo, L and Gaunt, JR and Cheah, CCH and Chen, AI and Claudine, S and Dawe, GS and Goh, ELK and Kho, SH and Kumar, P and Lim, GGY and Lim, KL and Lim, YA and Saido, TC and Saito, T and Sasaguri, H and Sng, JCG and Yeap, YJ and Yip, AKK and Zainolabidin, N and Ch'ng, TH and Augustine, GJ},
title = {APOE4-APP interactions exert early influences on cerebrovascular structure and function: implications for Alzheimer's disease.},
journal = {Frontiers in neuroscience},
volume = {19},
number = {},
pages = {1629830},
pmid = {41211332},
issn = {1662-4548},
abstract = {BACKGROUND: APOE4 and APP are two of the main genetic risk factors for Alzheimer's disease (AD). Although there have been suggestions that these two factors interact, most of the in vivo evidence for such interactions comes from transgenic mouse models that suffer from complications associated with protein overexpression. Our goal was to examine the consequences of interactions between APOE4 and APP on brain function while avoiding the use of transgenic mice.

METHODS: We generated and characterized double-mutant knock-in mice incorporating familial APP mutations and humanized APOE4.

RESULTS: In the brains of 3-month-old double-mutant mice there were significant alterations in vascular remodeling genes, vascular structure and blood-brain barrier permeability. These changes were not observed in either APOE4 or APP single-mutant mice and, thus, were caused by interactions between the two genes. These interaction effects were transient, because they were absent in 8-month-old double-mutant mice.

CONCLUSION: These findings indicate that early vascular changes, driven by the interaction of APP and APOE4, may influence the progression of AD. Our work highlights the need to focus on the synergistic vascular actions of APOE4 and APP, particularly at younger ages.},
}

@article {pmid41211302,
year = {2025},
author = {Butterbrod, E and Rabin, L and Tommet, D and Jones, RN and Dubbelman, MA and Crane, PK and Jessen, F and van der Flier, WM and Gifford, KA and Sikkes, SAM and , },
title = {Perspectives on the measurement of self-perceived cognitive function in older adults.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {17},
number = {4},
pages = {e70158},
pmid = {41211302},
issn = {2352-8729},
abstract = {INTRODUCTION: This survey investigated perspectives of research and clinical professionals on optimal content and features of measurement of self-perceived cognitive functioning.

METHODS: Respondents were professionals working with older adults with self-reported cognitive concerns. The survey addressed views on harmonization and preferences for items, response formatting, practical features, and instrument validation. We evaluated item preferences in consideration of a previous statistical harmonization.

RESULTS: Ninety professionals from 20 different countries completed the survey. Most professionals (87%) indicated a need for a harmonized instrument. Respondents agreed that an instrument should measure current ability alongside change therein, focus on memory, and adopt Likert scale responses. Recommendations for assessment timeframe, practical features, and validation priorities varied. Respondents differentially endorsed items previously found to be statistically informative.

DISCUSSION: Respondents agreed on overarching measurement topics, with varying recommendations for specific content and features. Together with statistical information, these results provide a starting point for a harmonized instrument.

HIGHLIGHTS: Professionals see a need for a harmonized tool to measure cognitive concerns.Professionals have diverse preferences for measurement content and its validation.Item relevance as seen by professionals aligned considerably with statistical value.Integration of statistical information with expert and patient opinion is crucial.},
}

@article {pmid41211301,
year = {2025},
author = {McWilliam, OH and Bsoul, R and Lund, EL and Waldemar, G and Hasselbalch, SG and Simonsen, AH and Bruun, M and von Buchwald, C and Aanæs, K and Pedersen, CK and Andersen, ISB and Bech, M and Areškevičiūtė, A and Frederiksen, KS},
title = {α-Synuclein seed amplification assay in Lewy body dementia versus Alzheimer's disease.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {17},
number = {4},
pages = {e70203},
pmid = {41211301},
issn = {2352-8729},
abstract = {INTRODUCTION: Differentiating dementia with Lewy bodies (DLB) from Alzheimer's disease (AD) is challenging. Seed amplification assay (SAA) is sensitive for the detection of misfolded α-synuclein.

METHODS: Patients with DLB (N = 31) and AD (N = 25) were recruited and evaluated. Misfolded α-synuclein was assessed in cerebrospinal fluid (CSF), skin, urine, and olfactory mucosa using SAA.

RESULTS: The accuracy of α-synuclein-SAA for DLB was 87% (95% confidence interval [CI]: 77% to 98%) in CSF, 85% (95% CI: 75% to 98%) in skin, 58% (95% CI: 47% to 69%) in olfactory mucosa, and 59% (95% CI: 51% to 66%) in urine. The core symptoms - fluctuations, REM sleep behavior disorder, and parkinsonism - had accuracies for SAA positivity of ≥79%. Notably, 95% of SAA-positive patients also had hyposmia.

DISCUSSION: These findings support the use of CSF and skin α-synuclein-SAAs as diagnostic tools for DLB, with strong associations between SAA and clinical phenotype. In particular, intact olfactory function is associated with a lower risk of SAA positivity.

HIGHLIGHTS: CSF and skin biopsies show high diagnostic accuracy for α-synuclein, demonstrating good concordance.Strong correlations exist between core symptoms of DLB and pathological α-synuclein.A very high sensitivity of hyposmia for pathological α-synuclein is observed.A novel proof-of-concept is offered for the potential detection of pathological α-synuclein in urine, marking the first such comparative analysis between patients with DLB and AD.},
}

@article {pmid41211300,
year = {2025},
author = {Teipel, S and Lutz, M},
title = {Bayesian analyses for research on Alzheimer's disease and related disorders-updating one's knowledge.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {17},
number = {4},
pages = {e70109},
pmid = {41211300},
issn = {2352-8729},
}

@article {pmid41211299,
year = {2025},
author = {Marshall, GA and Ravona-Springer, R},
title = {Objective measures of instrumental activities of daily living and neuropsychiatric symptoms in aging and early-stage Alzheimer's disease.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {17},
number = {4},
pages = {e70097},
pmid = {41211299},
issn = {2352-8729},
}

@article {pmid41211293,
year = {2025},
author = {Nimworaphan, J and Markowitz, DM and Sergott, RC},
title = {Fluorescence lifetime imaging ophthalmoscopy adds the retina to cortical pathology for visual dysfunction in neurodegenerative diseases.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1659264},
pmid = {41211293},
issn = {1664-2295},
abstract = {Because neurodegenerative diseases such as Parkinson's and Alzheimer's Diseases [AD and PD] as well as the progressive forms of multiple sclerosis [MS] are invariably associated with clinically significant cortical symptoms such as language difficulties, motor skill deficits and cognitive impairments, especially memory, a tacit assumption evolved that visual disorders related to cortical dysfunction must localize only to the temporal, parietal and occipital lobes. Based upon our current understanding, retinal changes in MS are most likely secondary to optic neuropathy, whereas in AD and PD, they appear to represent primary retinal changes. The paradigm was reinforced by the lack of retinal findings using ophthalmoscopy. Spectral domain optical coherence tomography [OCT], optical coherence angiography [OCT-A], and fundus autofluorescence [FAF] have challenged this creed by uncovering structural changes within the retina over and above what can occur as a consequence of optic neuropathy in the case of MS. Still, definitive diagnostic and prognostic data have yet to emerge. Fluorescence lifetime imaging ophthalmoscopy [FLIO], a non-invasive, non-contact, painless imaging technology, measures nanosecond lifetimes of endogenous retinal fluorophores, some of which are linked to mitochondrial activity. Therefore, FLIO is a metabolic, not a structural imaging modality. Because mitochondrial dysfunction occurs in many neurodegenerative diseases, FLIO offers a unique strategy for investigating retinal metabolism in AD, PD, and MS. This article reviews the basic biomedical engineering of FLIO and reports preliminary data from these diseases, correlated with disease duration. These functional in vivo data are consistent with retinal metabolic changes in AD, PD, and progressive MS that were "hiding in plain sight" from structural examinations.},
}

@article {pmid41211282,
year = {2025},
author = {Olaolorun, F and Howes, MR and Elufioye, T and Odeku, OA and Olopade, J and Chazot, P},
title = {Iron chelation as a therapeutic target in vanadium neurotoxicity and Parkinson's disease: role of medicinal plants.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1667943},
pmid = {41211282},
issn = {1664-2295},
abstract = {Bioprospecting plant natural products has yielded significant success in the development of symptomatic treatment of neurodegenerative diseases, including the two most common, Alzheimer's and Parkinson's diseases (PD). Dysregulation of iron has been strongly implicated in the pathophysiology of these serious intractable diseases. A series of Nigerian endemic plants' methanolic extracts were explored using a Ferrozine binding iron chelation assay. This identified Spondias purpurea L. (SP) leaves as a potential therapeutic candidate and this was determined by evaluation of oxidative stress in 6-hydroxydopamine (6-OHDA)-exposed monoamine cell culture and Drosophila models of PD and vanadium neurotoxicity. SP treatment protected CAD cells against 6-OHDA toxicity and improved survival in PINK-1 mutant flies, though it had little effect on motor deficits. Furthermore, SP treatment reduced the vanadium-induced reactive oxygen species, and notably, staggered SP treatment significantly extended lifespan in vanadium-treated flies. Overall, Spondias purpurea L. leaf methanolic extract exhibited iron-chelating, antioxidant, neuroprotective, and life-extending properties, relevant to Parkinson's disease and vanadium-induced toxicity.},
}

@article {pmid41211099,
year = {2025},
author = {Viani, A and Custo, A and d'Angremont, E and Garibotto, V and Frisoni, GB and Gutman, BA and Lorenzi, M},
title = {Disease Progression Modeling and Stratification for detecting sub-trajectories in the natural history of pathologies: Application to Alzheimer's disease trajectory modeling.},
journal = {Imaging neuroscience (Cambridge, Mass.)},
volume = {3},
number = {},
pages = {},
pmid = {41211099},
issn = {2837-6056},
abstract = {Quantifying the progression of degenerative diseases remains crucial for early diagnosis, prevention, and treatment. However, accurately modeling disease biomarker evolution is hindered by substantial variability in disease trajectories among individuals, driven by demographic, genetic, and lifestyle factors. This variability gives rise to heterogeneous phenotypic manifestations, underscoring the need for stratification based on underlying disease subtypes. Recent advances have shown promise in unsupervised stratification of disease trajectories. Yet, current approaches face significant challenges related to robustness, biomarker specificity, interpretability, and temporal resolution of clustering results. To address these challenges, we introduce Disease Progression Modeling and Stratification (DPMoSt), a new probabilistic model designed to optimize clusters of continuous trajectories along a long-term disease time axis. This approach allows for the determination of subtype-specific biomarkers, improving the accuracy of patient stratification and generalization on external cohorts. We demonstrate DPMoSt on both synthetic and real-world data for the modeling of Alzheimer's disease (AD) evolution. In the synthetic experiments, DPMoSt shows high accuracy in reconstructing trajectory subtypes and identifying the biomarkers' specificity for the clustering problem. Our experiments in the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset demonstrate the ability of DPMoSt to identify AD subtypes associated with accelerated cognitive decline and higher prevalence of the APOE4 variants. This result was validated on the external memory clinic cohort of the Geneva University Hospitals, confirming the association between cognitive decline and APOE4 in the pathological subtype. These results highlight the robustness of DPMoSt as well as its potential for broader applicability, offering a powerful tool for studying disease progression and subtype differentiation across diverse populations.},
}

@article {pmid41211047,
year = {2025},
author = {Zhang, N and Hu, BW and Li, XM and Huang, H},
title = {Rethinking parvalbumin: From passive marker to active modulator of hippocampal circuits.},
journal = {IBRO neuroscience reports},
volume = {19},
number = {},
pages = {760-773},
pmid = {41211047},
issn = {2667-2421},
abstract = {Parvalbumin (PV)-expressing interneurons are critical regulators of neural circuit dynamics, and for decades, the PV protein has served as their definitive molecular marker. This review confronts a central, yet underappreciated, paradox: the incongruity of a kinetically slow Ca[2+] buffer (PV) being the defining feature of the brain's fastest-spiking neurons. We synthesize evidence from molecular biophysics, genetics, in vivo circuit analysis, and disease modeling to dissect the dual role of PV as both a cellular marker and an active functional regulator. We argue that PV's slow kinetics are not a coincidence but a crucial adaptation that shapes short-term synaptic plasticity, protects against metabolic stress during high-frequency firing, and allows the circuit to shift between states of plasticity and stability. This reframing resolves the paradox by demonstrating how a "slow" molecule is essential for "fast" neuronal function. Furthermore, we highlight that dysfunction of the PV system is a convergent hub of pathology in numerous neurological and psychiatric disorders, including schizophrenia, epilepsy, and Alzheimer's disease. By moving beyond its identity as a passive marker, we establish PV as an active modulator of neural computation and a potential therapeutic target for restoring network function in disease.},
}

@article {pmid41210976,
year = {2025},
author = {Thapa, R and Adhikari, N and Gautam, S and Sun, M and McOmie, S and Davydzenka, V and Smith, D and Syring, J and Kaligis, H and Kosmicki, JM and Chen, R and Li, Y},
title = {Single-nucleus RNA sequencing reveals GABAergic vulnerability and reactive gliosis driven by loss of TDP-43.},
journal = {iScience},
volume = {28},
number = {11},
pages = {113745},
pmid = {41210976},
issn = {2589-0042},
abstract = {TDP-43 is an RNA-binding protein important for RNA processing, whose loss of function is involved in multiple neurodegenerative disorders, including frontotemporal dementia, amyotrophic lateral sclerosis, and Alzheimer's disease (AD). We performed single-nucleus RNA-sequencing to study the convergent and divergent molecular signatures of short-term and long-term TDP-43 depletion in the medial prefrontal cortex (mPFC) using Tdp-43 [F/F] mice, compared with that of 5xFAD mice, a well-established AD mouse model with β-amyloid plaque pathology. Our results demonstrated a significant loss of GABAergic neurons in the mPFC after short-term TDP-43 depletion. This was accompanied by a remarkable reactive gliosis in the mPFC. Our results revealed a strong GABAergic and glial involvement during early stages of TDP-43 loss of function, suggesting that the GABAergic system is vulnerable to TDP-43 pathology and could be considered a potential target for developing therapeutic strategies and biomarkers for early detection in TDP-43 linked AD-related dementia.},
}

@article {pmid41210921,
year = {2025},
author = {Newlin, NR and Kim, ME and Kanakaraj, P and McMaster, E and Cho, C and Gao, C and Hohman, TJ and Beason-Held, L and Resnick, SM and O'Bryant, SE and Phillips, N and Barber, RC and Bennett, DA and Barnes, LL and Biber, S and Johnson, S and Archer, D and Li, Z and Zuo, L and Moyer, D and Landman, BA},
title = {Harmonizing 10,000 connectomes: site-invariant representation learning for multi-site analysis of network connectivity and cognitive impairment.},
journal = {Journal of medical imaging (Bellingham, Wash.)},
volume = {12},
number = {6},
pages = {064001},
pmid = {41210921},
issn = {2329-4302},
abstract = {PURPOSE: Data-driven harmonization can mitigate systematic confounding signals across imaging cohorts caused by variance in scanners and acquisition protocols. As diffusion magnetic resonance imaging data are often acquired with different hardware and software, harmonization is essential for integrating these scattered datasets into a cohesive analysis for improved statistical power. Large-scale, multi-site studies for Alzheimer's disease (AD), a neurodegenerative condition characterized by high data variability and complex pathology, pose the challenge of both site-based and biological variation.

APPROACH: We learn lower-dimensional representations of structural connectivity invariant to imaging cohort, geographical location, scanner, and acquisition factors. We design a conditional variational autoencoder that creates latent representations with minimal information about imaging factors and maximal information related to patient cognitive status. With this model, we consolidate 9 cohorts and 35 unique imaging acquisitions (for a total of 38 imaging "sites") into a cohesive dataset of 6956 persons (16.4% with mild cognitive impairment and 10.7% with AD) imaged for 1 to 16 sessions for a total of 11,927 diffusion-weighted imaging sessions.

RESULTS: These site-invariant representations successfully remove significant (p < 0.05) site effects in 12 network connectivity measures of interest and enhance the prediction of cognitive diagnosis (from 68% accuracy to 73% accuracy).

CONCLUSIONS: The proposed model yields reproducible precision across 15 data configurations. This approach demonstrates the effectiveness of representation learning in enhancing biological signals by mitigating acquisition-specific confounding factors in neuroimaging studies.},
}

@article {pmid41210797,
year = {2025},
author = {El-Sayed, AIM and Mokhtar, FA and Alfaifi, MY and Anazi, HK and Makhlof, MEM},
title = {Characterization and Phenolic Profiling of Anticandidal Polycladia myrica and Its Mediated Iron Nanoparticles with the Evaluation of Their Antioxidant, Anti-Alzheimer, Catalytic Degradation, and Anticancer Activity via the P53 Pathway.},
journal = {ACS omega},
volume = {10},
number = {43},
pages = {52032-52045},
pmid = {41210797},
issn = {2470-1343},
abstract = {As a potent reducing and capping agent, Polycladia myrica extract was used to create iron nanoparticles (FeNPs). UV-visible, Fourier transform infrared (FTIR), X-ray diffractive analysis (XRD), scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDX), zeta potential, hydrodynamic analysis with the determination of polydispersity index (PDI), and transmission electron microscopy (TEM) were used to characterize the produced iron nanoparticles. By examining the peak at 320 nm, UV-visible spectroscopy confirmed the production of PFeNPs. Additionally, various in vitro biological assays were conducted, demonstrating significant therapeutic potential. The cytotoxic assay was performed using lung carcinoma cells (A-549) and normal human lung fibroblast (MRC-5) cell lines, which demonstrated promising safe results with IC50 = 225.91 ± 8.93 μg/mL and CC50 = 488.80 ± 17.23 μg/mL, respectively, due to the forced apoptosis caused by the accumulation of both ROS and p53 levels inside cancer cells. PFeNPs demonstrated weak α-amylase inhibition with a percent of 33.96 ± 3.12 and potent acetylcholinesterase inhibition with a percent of 71.42 ± 3.64. The anticandidal activity of FeNPs biofabricated from P. myrica against C. albicans was estimated. The inhibition zone diameters of PFeNPs and Nystatin reference drug (mean ± SD) were about 18.82 ± 0.87 and 19.74 ± 0.98, respectively. MIC was determined to be about 500 and 312.5 μg/mL for both our algal FeNPs and the standard used drug, respectively. These results were confirmed by scanning electron microscopy, which revealed lysis and bursting of the exterior cell surface, along with deformation and death of Candida albicans cells in treated Candida isolate. These results strongly suggested the possibility of introducing PFeNPs as a cotherapy for Candida infections in diabetic cancer patients.},
}

@article {pmid41210610,
year = {2025},
author = {Thomas, ST and Palanikumar, L and Darby, DG and Brodtmann, AG},
title = {FDG-PET anterior cingulate cortex hypometabolism as a marker of cerebral small vessel disease in Alzheimer's and vascular cognitive impairment and dementia.},
journal = {Cerebral circulation - cognition and behavior},
volume = {9},
number = {},
pages = {100404},
pmid = {41210610},
issn = {2666-2450},
abstract = {BACKGROUND: The anterior cingulate cortex (ACC) is an important hub in the executive and salience networks. While fluorodeoxyglucose-positron emission tomography (FDG-PET) is valuable in dementia diagnosis, there is no FDG-PET imaging 'signature' in vascular cognitive impairment and dementia (VCID). We investigated whether ACC hypometabolism on FDG-PET brain imaging in people with VCID correlated with cerebral small vessel disease (CSVD), estimated via white matter hyperintensity (WMH) severity, and clinical features, comparing these results with an Alzheimer dementia (AD) cohort.

METHODS: We performed a retrospective clinical database review of patients seen at a specialist cognitive neurology service between 2009 and 2024 to identify patients with VCID and AD diagnoses. Demographic details, cognitive (Addenbrooke's Cognitive Examination-Revised, ACE-R) and behavioural (Cambridge Behavioural Inventory, CBI) screens were collated where available. Two clinicians independently performed unblinded, visual assessments of clinical FDG-PET maps, rating for the presence or absence of ACC hypometabolism. WMH severity was estimated via Fazekas scale on clinical MRI as a measure of CSVD.

RESULTS: 379 people were identified: 98 VCID (median (IQR) age: 71 (63-77)), and 281 CE (median (IQR) age 72 (66-79)). ACC hypometabolism was observed more frequently in people with VCID (74 %) than AD (34 %). ACC hypometabolism correlated with greater vascular risk factor burden and higher Fazekas scores.

CONCLUSION: ACC hypometabolism correlated with WMH severity but was not specific to VCID. ACC hypometabolism on FDG-PET may represent a functional marker of vascular damage to frontal-subcortical circuits.},
}

@article {pmid41210484,
year = {2025},
author = {Zhang, Q and Mao, JD and Chen, H and Wang, M and Wu, YM and Wang, C},
title = {Ferroptosis as a potential therapeutic target for post-traumatic stress disorder.},
journal = {Frontiers in molecular neuroscience},
volume = {18},
number = {},
pages = {1648047},
pmid = {41210484},
issn = {1662-5099},
abstract = {The underlying mechanisms of post-traumatic stress disorder (PTSD) are still not fully understood, creating significant obstacles for developing effective therapeutic strategies. Recently, ferroptosis, an iron-dependent form of regulated cell death, has been shown to play a role in several psychiatric disorders, such as major depressive disorder (MDD), stress-induced anxiety, Alzheimer's disease (AD), and Parkinson's disease (PD). While direct evidence for the role of ferroptosis in PTSD is still limited, an increasing number of studies suggest that the pathological features of PTSD may trigger the ferroptosis cascade. Additionally, the typical hallmarks of ferroptosis, such as iron dysregulation, lipid peroxidation, and failure of antioxidant defense systems, may intersect with the pathogenesis of PTSD. Importantly, some treatments for PTSD, such as antioxidants and free radical scavengers, have been proven to inhibit ferroptosis, which further supports the case for ferroptosis as a potential pathogenic mechanism in PTSD. To thoroughly investigate the mechanistic links between ferroptosis and PTSD, we analyze the relevant literature on ferroptosis and PTSD in this review. Our aim is to elucidate the potential relationships between ferroptosis and PTSD, thereby providing novel insights for future research directions. Furthermore, we call for more experimental and clinical studies to explore this relationship further, with the ultimate goal of developing more effective therapeutic strategies for PTSD.},
}

@article {pmid41210483,
year = {2025},
author = {Pereira Sena, P and Friedrich, L and Villarreal, A and Fath, F and Sopco, L and Hernández-Guillamon, M and Saraiva-Pereira, ML and Britton, G and Weber, JJ and Schmidt, T},
title = {Proteostasis disruption and lipid dyshomeostasis in neurodegeneration: exploring common druggable targets across sporadic and monogenic disorders.},
journal = {Frontiers in molecular neuroscience},
volume = {18},
number = {},
pages = {1681079},
pmid = {41210483},
issn = {1662-5099},
abstract = {Neurodegenerative disorders pose an increasing burden in the aging society. These conditions share several molecular pathomechanisms, some of which may offer opportunities for therapeutic intervention. In this review, we explore a representative selection of sporadic and hereditary neurodegenerative diseases-namely Alzheimer's disease, cerebral amyloid angiopathy, and the polyQ disorders spinocerebellar ataxia types 2 and 3, as well as Huntington's disease-which all feature the accumulation of intra- or extracellular protein deposits as a hallmark. We place particular emphasis on dysregulations in proteostasis-underlying the formation of these aggregates-and the less commonly addressed disturbances in lipid metabolism. By highlighting potential mechanistic links across different classes of neurodegenerative diseases, we aim to provide new insights that may guide the identification of shared druggable targets and the development of broad-spectrum therapeutic strategies.},
}

@article {pmid41209748,
year = {2025},
author = {Li, Y and Zhao, S and Chen, X and Wang, Z and Liang, X and Liu, Y and Dong, Y},
title = {Causal Association of Alzheimer's Disease with Low Back Pain: A Mendelian Randomization Study.},
journal = {Journal of pain research},
volume = {18},
number = {},
pages = {5857-5865},
pmid = {41209748},
issn = {1178-7090},
abstract = {PURPOSE: Previous observational studies have demonstrated that Low back pain (LBP) often coexists with Alzheimer's Disease (AD), however, the causal relationship remains unclear. The purpose of this study is to explore the causal relationship between AD and LBP through Mendelian randomized analysis.

METHODS: Instrumental variables (IVs) were derived from the genome-wide association study (GWAS) of AD. Information regarding Instrumental variables (IVs) in LBP was extracted from a GWAS database. MR-Egger, weighted median, inverse variance weighted (IVW)and Weighted mode were used to evaluate the causal effects. Cochran's Q test and MR-Egger intercept were applied to detect the heterogeneity and horizontal pleiotropy, respectively. Outliers were found and remove based on MR-PRESSO analysis to mitigate the effect of horizontal pleiotropy on the results. Deleting each genetic variant applying the leave-one-out analysis can help evaluate the robustness of results. Finally, MR-PRESSO Raw and Outlier-corrected were used to enhance the credibility of the results.

RESULTS: IVW assessment provided strong evidence that AD is positively associated with LBP (Odds Ratio (OR)= 1.046, 95% confidence interval(CI) = 1.023-1.070, P=5.8×10[-5]). There was no heterogeneity in our study (p > 0.05). The results of the pleiotropy test indicated that there was no pleiotropy in our IVW analysis (p > 0.05). MR-Egger, Weighted median, Weighted mode analysis results are consistent with our IVW analysis results. There is a genetic relationship between Alzheimer's disease and low back pain.

CONCLUSION: This study provides evidence for a causal relationship between AD and LBP. It emphasizes the necessity of improving pain management for patients with Alzheimer's disease in clinical practice. However, the data were derived from a European population, which may limit the generalizability of the results to other populations.},
}

@article {pmid41209583,
year = {2025},
author = {Bagheri, S and Saso, L},
title = {Biophysical insights into the molecular mechanisms of beta amyloid aggregation and its toxic effects in Alzheimer's disease.},
journal = {Frontiers in molecular biosciences},
volume = {12},
number = {},
pages = {1704653},
pmid = {41209583},
issn = {2296-889X},
abstract = {Alzheimer's disease is recognized as the most common neurodegenerative disorder, characterized by the presence of amyloid plaques, which have consistently garnered significant attention. Since the disease was first identified, extensive research has been devoted to investigating these plaques. As our understanding of the disease has progressed, the detrimental role of plaques has been questioned, leading to the hypothesis that amyloid oligomeric aggregates are the main culprits. Nevertheless, subsequent research indicated that the concentrations of amyloids employed in the experiments were considerably elevated compared to physiological conditions, and that at physiological concentrations, amyloids do not exhibit significant accumulation or toxicity. This article aims to offer a detailed biophysical perspective on the formation of amyloid aggregates under physiological conditions and their impact on membranes, providing valuable insights for researchers in this field.},
}

@article {pmid41209367,
year = {2025},
author = {Xie, Z and Hu, J and Stallings-Smith, S and Kulshreshtha, A and Hong, YR},
title = {Rural-urban differences in modifiable dementia risk factors among U.S. populations aged 45 years or older.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251395318},
pmid = {41209367},
issn = {2542-4823},
abstract = {BACKGROUND: Alzheimer's disease and related dementias (ADRD) have become a significant public health concern, and the burden is disproportionately concentrated in rural areas.

OBJECTIVE: To examine rural-urban differences in the prevalence of modifiable dementia risk factors and their treatment among U.S. adults aged 45 years and older, and to investigate how these disparities vary by age group and geographic region.

METHODS: This cross-sectional study analyzed nationally representative data from the 2023 National Health Interview Survey in 2025. Prevalence of 11 modifiable dementia risk factors (hypertension, high cholesterol, diabetes, obesity, hearing loss, visual impairment, traumatic brain injury, low education, depression, social isolation, smoking) and 7 corresponding treatments were assessed via self-report. Adjusted rate ratios (aRR) were estimated using robust Poisson regression models.

RESULTS: The study population consisted of 16,981 individuals (mean age: 62.4, 51.6% female, 68.7% non-Hispanic White, 15.5% in rural areas). Rural residents had significantly higher prevalence of hypertension (aRR, 1.11; 95% CI, 1.06-1.17), obesity (aRR, 1.22; 95% CI, 1.15-1.30), diabetes (aRR, 1.29; 95% CI, 1.15-1.45), and hearing loss (aRR, 1.22; 95% CI, 1.12-1.34) compared to urban residents. Disparities were most significant among adults aged 45-64 years and in South/Midwest regions. Treatment rates for cardiometabolic conditions were high (>85%) and similar across regions, but treatment for sensory/behavioral risk factors remained low.

CONCLUSIONS: Rural U.S. adults face higher burden of modifiable dementia risk factors, particularly cardiometabolic and sensory impairments. Targeted public health strategies are needed to address structural inequities and improve dementia prevention in rural communities.},
}

@article {pmid41209366,
year = {2025},
author = {Khan, H and Dayamba, L and Rafiq, A},
title = {Risk factors and gender disparity of cognitive impairment among cancer and neurological diseases regarding rural West Texas.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251395304},
pmid = {41209366},
issn = {2542-4823},
abstract = {BACKGROUND: The prevalence of Alzheimer's disease or dementia is rising among the elderly population in the United States and globally. Sociodemographic, cancer, and neurological disorders are associated with cognitive impairment of people living in rural communities.

OBJECTIVE: This study identified the association of cognitive impairment with cancer and neurological disorders of the elderly in Cochran and Parmer Counties of rural West Texas.

METHODS: Pearson's chi-squared, two-sample independent proportions, binary logistic regression, and multivariable logistic regression methods were utilized to analyze data.

RESULTS: Individuals aged 70 and above experiencing memory loss in Cochran and Parmer Counties had a statistically significant association with cognitive impairment (p < 0.001). In Parmer County, females diagnosed with breast cancer demonstrated a significant relationship with cognitive impairment (p < 0.05). Neurological factors, including muscle strength, cerebellar function, ability to rise from a chair, and Romberg test results, were significantly associated with an increased risk of cognitive impairments among females in both counties. After adjusting for covariates, males aged 60-69 in Parmer County, as well as memory loss among both genders, were significantly associated with cognitive impairment (p < 0.001). Additionally, females with cognitive impairment in Cochran County exhibited higher dependence on mental health services compared to males (p < 0.05).

CONCLUSIONS: Examining the association between cognitive impairment or Alzheimer's disease and cancer and neurological disorders is important for developing interventions aimed at reducing their prevalence in underserved rural West Texas Counties.},
}

@article {pmid41209083,
year = {2025},
author = {Wang 王子怡, Z and Li 李卉, H and Shi 史博文, B and Qin 秦琪凯, Q and Ye 叶琼, Q and Thompson, GJ},
title = {Female 3xTg-AD mice demonstrate hyperexcitability phenotype of Alzheimer's disease in structure-function and function-behavior relationships.},
journal = {Network neuroscience (Cambridge, Mass.)},
volume = {9},
number = {4},
pages = {1199-1220},
pmid = {41209083},
issn = {2472-1751},
abstract = {Alzheimer's disease (AD) causes cognitive decline with aging, hypothetically due to the accumulation of beta-amyloid (Aβ) plaques. The 3xTg-AD mouse model is increasingly used due to its initial absence of significant physical or behavioral impairments in youth and progressive Aβ plaque development with age. This mouse model thus provides an opportunity for comparison with human AD through two stages of study. Using wild-type (WT) and 3xTg-AD mice, aged 22 and 40 weeks (before and after the large increase in Aβ plaques), we measured functional connectivity (FC) and structural connectivity (SC) between brain regions. At 22 weeks, 3xTg-AD mice unexpectedly had higher SC and FC, and there was positive correlation between behavioral performance and FC density. By 40 weeks, SC and FC was lower in AD mice (similar to human AD patients), but the behavior-functional correlation was negative. Thus, our methods identified a shift in 3xTg-AD mice between two abnormal states relative to WT, moving from a hyperconnected to a hypoconnected state. Such a shift matches the hyperexcitability phenotype of AD observed in human patients, and thus suggests that 3xTg-AD mice can model the multistage etiology of AD of that phenotype.},
}

@article {pmid41208739,
year = {2025},
author = {Oomens, JE and Biber, SA and Albert, M and Alosco, ML and Arfanakis, K and Benzinger, TLS and Brewer, JB and Burns, JM and Chin, E and Chin, NA and Clark, LR and Cohen, AD and Dage, JL and Detre, JA and Dickerson, BC and DiFilippo, FP and Donohue, MC and van Dyck, CH and Fan, AP and Grabowski, TJ and Habes, M and Harrison, TM and Hedden, T and Hohman, TJ and Jagust, WJ and Jefferson, AL and Jicha, GA and Kecskemeti, SR and Kantarci, K and Keene, DC and Knoefel, JE and Kukull, WA and Lin, W and Lao, P and Lepping, RJ and Levendovszky, SR and Masurkar, AV and McConathy, JE and Rivera-Mindt, M and Morhardt, DJ and Noll, DC and Okonkwo, OC and Parrish, TB and Rabinovici, GD and Rahman-Filipiak, A and Reiman, EM and Risacher, SL and Rosen, H and Rudolph, MD and Schneider, LS and Silbert, LC and Song, AW and Stark, CEL and Swerdlow, RH and Thompson, PM and Vaillancourt, D and Villemagne, VL and Wolk, DA and Qiu, D and Foroud, TM and Johnson, SC and Mormino, EC},
title = {The Consortium for Clarity in ADRD Research Through Imaging (CLARiTI): Overview of consortium sites and anticipated enrollment.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70880},
doi = {10.1002/alz.70880},
pmid = {41208739},
issn = {1552-5279},
support = {U01-AG082350/NH/NIH HHS/United States ; },
abstract = {INTRODUCTION: The Consortium for Clarity in Alzheimer's disease related dementias (ADRD) Research Through Imaging (CLARiTI) is a study that aims to collect standardized imaging and plasma biomarkers on 2000 Clinical Core participants enrolled across all Alzheimer's Disease Research Centers (ADRC) sites. We sought to summarize the known heterogeneity across centers regarding scientific focus and initial enrollment plans for CLARiTI.

METHODS: We developed and distributed a survey capturing information on the 36 CLARiTI site's theme/expertise, recruitment plans, and the intersection of CLARiTI with other ADRC imaging efforts.

RESULTS: Anticipated CLARiTI enrollees spanned 11 different categories of suspected etiologies underlying impairment. A wide range of risk factors were endorsed across sites regarding the enrollment of unimpaired individuals. Variability also existed regarding site-level strategies in enrollment into CLARiTI versus other imaging efforts.

DISCUSSION: We anticipate that the 2000 individuals that will enroll into CLARiTI will reflect the clinical heterogeneity already in place across the ADRC network.

HIGHLIGHTS: The ADRC Consortium for Clarity in ADRD Research Through Imaging (CLARiTI) will leverage and contribute to the existing Alzheimer's Disease Research Centers (ADRC) program by supporting standardized imaging and plasma collection across all centers. We summarize the variation in scientific focus and enrollment plans across ADRC sites participating in CLARiTI. The anticipated CLARiTI cohort will reflect the clinical heterogeneity that already exists across the ADRC network. CLARiTI will contribute to scientific goals related to the detection of multi-etiological signatures relevant for Alzheimer's disease and related disorders (ADRDs).},
}

@article {pmid41208730,
year = {2025},
author = {Ke, J and Ding, J and Xu, Y and Yu, C and Hong, Y and Li, S and Meng, T and Ping, Y and Yuan, H and Hu, F},
title = {Engineering microglial exosome-mediated microRNA-124-3p delivery for Alzheimer's disease combinational therapy.},
journal = {Biomaterials science},
volume = {},
number = {},
pages = {},
doi = {10.1039/d5bm01080b},
pmid = {41208730},
issn = {2047-4849},
abstract = {Currently, single-target therapy and difficulty in brain drug delivery gravely impede the treatment of Alzheimer's disease (AD). The promising development of microRNA-124-3p (miR-124-3p) serves as a possibility for multiple therapeutic approaches for AD. However, the effective delivery of miR-124-3p to AD-affected brain regions remains a major challenge, primarily due to the blood-brain barrier (BBB) and the inherent instability of therapeutic miR-124-3p. Herein, we engineered miR-124-3p-enriched microglial exosomes (Exo-124-3p) as a biomimetic nanomedicine for the multifunctional treatment of AD. Exo-124-3p can traverse the BBB and facilitate activated-microglia targeting. Subsequently, the on-demand release of miR-124-3p from Exo-124-3p decreased the aggregation of β-amyloid (Aβ) plaques, attenuated the activation of microglia/astrocytes, and exhibited a valuable neuroprotective effect, thereby remolding the AD focal microenvironment. Notably, the in vivo results demonstrated that Exo-124-3p significantly improved the cognitive function in an AD mouse model. Mechanistically, it was elucidated that Exo-124-3p can bind to the 3'UTR region of MEKK3, ultimately inhibiting the MEKK3/NF-κB signaling pathway, thereby ameliorating AD neuroinflammation. Consequently, this study not only provides a promising therapeutic approach for AD combinational therapy, but also advances the development of miRNA delivery in other brain diseases.},
}

@article {pmid41208717,
year = {2025},
author = {Pavlik, VN and Weber, CJ and Masdeu, JC and Baker, LD and Yu, MM and York, M and Whitmer, RA and Landau, SM and Harrison, TM and Holland, TM and Lovato, L},
title = {Cognitive reserve predicts baseline tau burden in the U.S. POINTER trial imaging cohort.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70892},
doi = {10.1002/alz.70892},
pmid = {41208717},
issn = {1552-5279},
support = {/ALZ/Alzheimer's Association/United States ; R01AG062689 to SML/AG/NIA NIH HHS/United States ; K01AG078443 to TMH/AG/NIA NIH HHS/United States ; },
abstract = {INTRODUCTION: Higher cognitive reserve (CR) is associated with reduced dementia risk. We hypothesized that higher CR is associated with less baseline Alzheimer's disease (AD) pathology in the U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) cohort.

METHODS: A subsample of participants underwent amyloid beta and tau positron emission tomography imaging. Regression analysis was used to model the association between educational attainment (EA) as a CR proxy measure, amyloid positivity, and entorhinal cortex (ERC) and meta-temporal region of interest (meta-ROI) tau standardized uptake value ratio (SUVR).

RESULTS: In 911 participants with complete imaging data, higher CR was significantly associated with lower ERC tau SUVR. CR was not associated with amyloid status or meta-ROI tau.

DISCUSSION: In the U.S. POINTER cohort, higher EA predicted lower tau burden in the ERC. Meta-ROI tau levels may be too low in this cognitively unimpaired sample to reveal associations. CR may have a role in promoting biological resistance to AD pathology.

HIGHLIGHTS: Higher cognitive reserve is associated with a lower dementia risk and better cognitive performance after a diagnosis of Alzheimer's disease. The U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk trial imaging cohort was cognitively unimpaired at baseline and a subsample received amyloid and tau positron emission tomography scans. Higher educational attainment, a proxy measure of cognitive reserve, was significantly related to tau levels in the entorhinal cortex region of interest.},
}

@article {pmid41208712,
year = {2025},
author = {Godrich, D and Pasteris, J and Martin, ER and Kunkle, B and Naj, AC and Hamilton, K and Wang, H and Lee, WP and Dumitrescu, L and Hohman, TJ and Mayeux, R and Larson, EB and Crane, PK and Keene, CD and Latimer, C and Mukherjee, S and Kofler, J and Kamboh, MI and Bennett, DA and Molina-Porcel, L and Schellenberg, G and Pericak-Vance, MA and Cuccaro, M and Scott, WK and Rundek, T and Kukull, W and Montine, T and Beecham, GW and , },
title = {Genome-wide association studies of TDP-43 proteinopathy and hippocampal sclerosis reveal shared genetic associations with APOE and TMEM106B.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70760},
doi = {10.1002/alz.70760},
pmid = {41208712},
issn = {1552-5279},
support = {R01-AG062695//Primary Funding includes (additional funding in Acknowledgements)/ ; AG074855//Primary Funding includes (additional funding in Acknowledgements)/ ; U01-AG016976//National Alzheimer's Coordinating Center (NACC)/ ; U24-AG21886//National Cell Repository for Alzheimer's Disease (NCRAD)/ ; U24-AG041689//National Institute on Aging Alzheimer's Disease Data Storage Site (NIAGADS)/ ; U01-AG032984//Alzheimer's Disease Genetics Consortium (ADGC)/ ; RC2-AG036528//Alzheimer's Disease Genetics Consortium (ADGC)/ ; U24-AG074855//ADSP Phenotype Harmonization Consortium (ADSP-PHC)/ ; U01-AG068057//ADSP Phenotype Harmonization Consortium (ADSP-PHC)/ ; R01-AG059716//ADSP Phenotype Harmonization Consortium (ADSP-PHC)/ ; AG006781//Adult Changes in Thought (ACT)/ ; AG066567//Adult Changes in Thought (ACT)/ ; AG030653//University of Pittsburg/ ; AG041718//University of Pittsburg/ ; AG064877//University of Pittsburg/ ; P30-AG066468//University of Pittsburg/ ; P30-AG010161//Rush University (ROSMAP)/ ; R01-AG019085//Rush University (ROSMAP)/ ; R01-AG15819//Rush University (ROSMAP)/ ; R01-AG17917//Rush University (ROSMAP)/ ; R01-AG3014//Rush University (ROSMAP)/ ; },
abstract = {INTRODUCTION: Transactive response DNA binding protein 43 kDa (TDP-43) proteinopathy has been linked to cognitive decline and often co-occurs with hippocampal sclerosis (HS). To identify genetic markers of TDP-43 proteinopathy and HS, we performed genome-wide association studies (GWASs) of HS and TDP-43 inclusions.

METHODS: Genetic data were obtained through the Alzheimer Disease Genetics Consortium and collaborating sites (HS: N = 9509; TDP-43: N = 4669). Statistical analyses included association analysis with HS and TDP-43 inclusions and meta-analysis, a mediation analysis, and fine mapping of the transmembrane protein 106B (TMEM106B) region.

RESULTS: Two regions achieved genome-wide significance with TDP-43: apolipoprotein E (APOE) and TMEM106B. Three loci reached genome-wide significance with HS: APOE, TMEM106B, and granulin precursor (GRN). Fine mapping of TMEM106B identified 93 variants in the credible set. Mediation analyses showed that genetic effects on HS were partially mediated through TDP-43 proteinopathy.

DISCUSSION: We identified associations with TDP-43 inclusion and HS, showing shared genetic risk across frontotemporal lobar degeneration, amyotrophic lateral sclerosis, Alzheimer's disease, and limbic-predominant age-related TDP-43 encephalopathy.

HIGHLIGHTS: HS and TDP-43 contribute to dementia and often co-occur. The etiology and relationship of HS and TDP-43 remains unclear. HS and TDP-43 share genetic risk factors in the genes APOE and TMEM106B. Genes have direct effects on HS, with additional effects mediated through TDP-43.},
}

@article {pmid41208711,
year = {2025},
author = {Dong, X and Bai, M and Qian, J and Xiao, J and Zhang, S and Hou, X and Zhou, C},
title = {Harmful impact of blood lead on the prevalence of Alzheimer's disease among middle-aged and older adults and the modifying role of physical activity: Evidence from the National Health and Nutrition Examination Survey (NHANES) study.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70785},
doi = {10.1002/alz.70785},
pmid = {41208711},
issn = {1552-5279},
support = {ZR2024QG047//Natural Science Foundation of Shandong Province/ ; 2023M742059//China Postdoctoral Science Foundation/ ; SDCX-RS-202400011//Postdoctoral Innovation Project of Shandong Province/ ; 72274109//National Science Foundation of China/ ; 72574128//National Science Foundation of China/ ; },
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a major public health challenge. This study aims to explore the combined effects of blood lead levels (BLL) and physical activity (PA) on AD prevalence among middle-aged and older adults.

METHODS: A total of 13,426 middle-aged and older adults (57.8% over 60 years old; 49.7% males) were included. Firth's penalized logistic regression models were used for statistical analysis.

RESULTS: High blood lead level (High-BLL) was associated with an 86.7% increase in AD prevalence. For PA levels, engaging in sufficiently active PA was associated with a 72% reduction in AD prevalence. In addition, the combination of sufficiently active PA with high-BLL, moderate blood lead level (Moderate-BLL), or low blood lead level (Low-BLL) was associated with an 83.9%, 65.9%, or 76.5% reduction in AD prevalence, respectively.

DISCUSSION: Although higher BLL is associated with increased AD prevalence, engaging in PA can reduce the AD prevalence caused by BLL, with greater benefits observed from sufficiently active PA.

HIGHLIGHTS: Higher blood lead levels (BLL) are associated with an increased prevalence of Alzheimer's disease (AD), whereas engaging in physical activity (PA) is associated with a reduced prevalence. Furthermore, engaging in sufficient occupational PA and sufficient leisure-time PA are both associated with a lower prevalence of AD. Engaging in PA can reduce the AD prevalence caused by BLL, with greater benefits observed from engaging in sufficiently active PA. The combined effects of BLL and PA levels on AD prevalence may vary among populations with different gender, marital status, socioeconomic status, or smoking status.},
}

@article {pmid41208701,
year = {2025},
author = {Semenkova, A and Piguet, O and Johnen, A and Schroeter, ML and Godulla, J and Linnemann, C and Baumgartner, M and Otto, M and Felbecker, A and Wezel, S and Kressig, RW and Berres, M and Sollberger, M},
title = {Reference-Group Adjusted Behavioural Dysfunction Questionnaire Score Discriminates Highly Behavioural-Variant Frontotemporal Dementia From Major Depressive Disorder and Alzheimer's Disease Dementia.},
journal = {European journal of neurology},
volume = {32},
number = {11},
pages = {e70424},
doi = {10.1111/ene.70424},
pmid = {41208701},
issn = {1468-1331},
support = {//Alzheimer Schweiz/ ; //Stiftung EMPIRIS/ ; //Béatrice Ederer-Weber Stiftung/ ; //Freiwillige Akademische Gesellschaft/ ; GNT2008020//National Health and Medical Research Council/ ; 774/5-1//Deutsche Forschungsgemeinschaft/ ; 01GI1007A//German Federal Ministry of Education and Research/ ; //eHealthSax Initiative of the Sächsische Aufbaubank/ ; },
abstract = {BACKGROUND: Given the fact that behavioural variant frontotemporal dementia (bvFTD) is characterised by behavioural disorders, the assessment of these disorders is essential for early diagnosis of bvFTD. In this regard, the recently developed Behavioural Dysfunction Questionnaire (BDQ) that captures the bvFTD-specific behavioural disorders is promising in discriminating mild-stage bvFTD from other neurodegenerative and psychiatric disorders. In this study, we aimed to increase the discriminatory power of the BDQ by adaptation of its scoring depending on the reference group to bvFTD.

METHODS: In this combined prospective and retrospective cross-sectional study, data of 241 patients [i.e., 50 patients with mild-stage bvFTD, 71 patients with major depressive disorder (MDD) and 120 patients with mild-stage Alzheimer's disease dementia (ADD)] were analysed. We calculated the BDQ score in two ways: (1) as the average score of the domains' mean scores and (2) by adjusting the scoring depending on the reference group by using machine learning techniques, validated by fivefold cross-validation.

RESULTS: The adjusted BDQ score showed a higher (bvFTD vs. MDD) or similar (bvFTD vs. ADD) discriminatory power than the unadjusted BDQ score, with a considerably smaller difference between cut-offs with at least 90% sensitivity and at least 90% specificity.

CONCLUSIONS: We recommend using adjusted BDQ scores when MDD or ADD are the reference groups to bvFTD. Similar approaches should be taken for other reference groups to bvFTD to best reflect the thinking of clinicians who have specific reference groups in mind as differential diagnoses to bvFTD.},
}

@article {pmid41208653,
year = {2025},
author = {Kim, S and Shin, JJ and Kang, M and Yi, Y and Kim, E},
title = {Synaptic and Non-Synaptic Functions of PTPRD: A Receptor Tyrosine Phosphatase at the Crossroads of Neural Circuitry and Metabolism.},
journal = {Journal of neurochemistry},
volume = {169},
number = {11},
pages = {e70292},
doi = {10.1111/jnc.70292},
pmid = {41208653},
issn = {1471-4159},
support = {IBS-R002-D1//Institute for Basic Science/ ; },
abstract = {Protein-tyrosine phosphatase receptor-type D (PTPRD) is an adhesion-coupled phosphatase that translates extracellular binding codes into intracellular phosphotyrosine signaling from embryogenesis through adulthood. Alternative inclusion of the Ig-domain mini-exons meA and meB tailors the ectodomain surface, thereby dictating high-affinity engagement with IL1RAPL1, IL1RAP, Slitrks, LRFN4/5 (SALM3/5), neuroligin-3, and other postsynaptic partners. Intracellularly, the catalytically active D1 domain and scaffold-like D2 module, anchored to liprin-α, coordinate presynaptic vesicle release, postsynaptic receptor composition, and synaptic plasticity. Beyond synapses, PTPRD restrains embryonic neurogenesis, promotes STAT3-dependent gliogenesis, accelerates oligodendrocyte myelination, and guides Sema3a/Fyn-mediated axon and dendrite patterning. In the adult brain it serves as the high-affinity hypothalamic and cerebellar receptor for asprosin, thereby coupling systemic energy and hydration states to feeding and drinking behavior. Human genetic studies and mouse models link these molecular activities to a spectrum of conditions-including restless legs syndrome, addiction, Alzheimer's disease, ADHD, OCD, autism spectrum disorder, and metabolic syndrome. Because PTPRD functions are pathway-specific and shaped by mini-exon usage or redundancy with other family members (PTPRS/PTPRF), domain- or ligand-selective interventions represent plausible therapeutic strategies. Elucidating its full ligand repertoire, substrate landscape, and structural basis for allosteric regulation will be critical for converting this versatile receptor from a mechanistic curiosity into a tractable target for neurodevelopmental, neuropsychiatric, and metabolic disorders.},
}

@article {pmid41208522,
year = {2025},
author = {Wrigley, S and Huynh, ALH and Amadoru, S and Zeimer, H and Tan, I and Woodward, M and Braitberg, G and Yates, PA},
title = {Monoclonal Antibody Therapies in Alzheimer's Disease: A Guide for Emergency Physicians.},
journal = {Emergency medicine Australasia : EMA},
volume = {37},
number = {6},
pages = {e70167},
doi = {10.1111/1742-6723.70167},
pmid = {41208522},
issn = {1742-6723},
abstract = {Whilst the advent of novel disease-modifying medications for Alzheimer's disease represents potential benefit for patients and caregivers, they may be associated with adverse events that present important considerations for emergency and primary care. This article seeks to highlight some of the challenges Emergency Departments may encounter in relation to clinical presentations of people being treated with novel anti-amyloid monoclonal antibodies in the Australian context. Given the potential for harm if not recognised and managed appropriately, it is imperative that emergency clinicians are aware of possible treatment-related adverse events and have access to appropriate decision-making support and resources.},
}

@article {pmid41208407,
year = {2025},
author = {Ahn, SJ and Goya, B and Bertomo, C and Sciortino, R and Racchumi, G and Garcia Bonilla, L and Anrather, J and Iadecola, C and Faraco, G},
title = {Neutrophil stalling does not mediate the increase in tau phosphorylation and the cognitive impairment associated with high salt diet.},
journal = {Cardiovascular research},
volume = {},
number = {},
pages = {},
doi = {10.1093/cvr/cvaf217},
pmid = {41208407},
issn = {1755-3245},
abstract = {AIMS: High dietary salt intake has powerful effects on cerebral blood vessels and has emerged as a risk factor for stroke and cognitive impairment. In mice, high salt diet (HSD) leads to reduced cerebral blood flow (CBF), tau hyperphosphorylation and cognitive dysfunction. However, it is still unclear whether the reduced CBF is responsible for the effects of HSD on tau and cognition. Capillary stalling has been linked to cognitive impairment in models of Alzheimer's disease and diabetes. Therefore, we tested the hypothesis that capillary stalling also contributes to CBF reduction, tau accumulation, and cognitive impairment in HSD.

METHODS AND RESULTS: We used in vivo two-photon imaging to assess capillary stalling in C57BL6/J male mice fed a normal diet or HSD. We found that HSD increased stalling of neutrophils in brain capillaries and decreased CBF. Neutrophil depletion using anti-Ly6G antibodies reduced the number of stalled capillaries and restored CBF, measured by red blood cell speed. Despite the improved CBF, chronic neutrophil depletion did not rescue HSD-induced cognitive impairment, assessed by Barnes maze and nest building behavior. Furthermore, levels of phosphorylated tau in cortex and hippocampus remained elevated in HSD mice after neutrophil depletion.

CONCLUSIONS: These novel findings show that, capillary stalling contribute to CBF reduction in HSD, but not to tau phosphorylation and cognitive deficits. Therefore, the hypoperfusion caused by capillary stalling is not the main driver of the tau phosphorylation and cognitive impairment.},
}

@article {pmid41208143,
year = {2025},
author = {Zhang, ZY and Ding, T and Kong, J and Wang, QC and Zhang, XT and Shi, CM and Yang, JT and Liu, JF},
title = {Global Profiling of Lysine Ubiquitylation in the Human Hypothalamus.},
journal = {Proteomics. Clinical applications},
volume = {},
number = {},
pages = {e70029},
doi = {10.1002/prca.70029},
pmid = {41208143},
issn = {1862-8354},
support = {2023YFC2507102//National Key R&D Program of China/ ; CIFMS2022-I2M-1-011//Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, China/ ; CIFMS2022-I2M-2-001//Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, China/ ; CIFMS2021-I2M-1-057//Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, China/ ; CIFMS2021-I2M-1-049//Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, China/ ; CIFMS2021-I2M-1-044//Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, China/ ; CIFMS2021-I2M-1-016//Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, China/ ; CIFMS2021-I2M-1-001andCIFMS2022-I2M-1-020//Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, China/ ; 82341064//National Natural Science Foundation of China/ ; 82090010//National Natural Science Foundation of China/ ; 82090011//National Natural Science Foundation of China/ ; 22HHXBSS00008//Haihe Laboratory of Cell Ecosystem Innovation Fund/ ; 22HHKYZX0034//Haihe Laboratory of Cell Ecosystem Innovation Fund/ ; 2060204//State Key Laboratory Special Fund/ ; },
abstract = {PURPOSE: Ubiquitylation is a vital post-translational modification involved in various biological processes, yet its role in the human hypothalamus remains largely unexplored. This study aims to profile the ubiquitinome of the human hypothalamus, uncovering the ubiquitylation landscape and its potential implications in hypothalamic function.

EXPERIMENTAL DESIGN: We employed LC‒MS/MS to analyze hypothalamic tissues from six healthy elderly individuals, focusing on identifying and characterizing ubiquitinated sites and proteins. Motif analysis, functional enrichment, and protein-protein interaction (PPI) network were conducted to profile the landscape.

RESULTS: Our analysis identified 21,815 ubiquitinated sites across 5314 proteins and five types of modification motifs in the normal human hypothalamus. Ubiquitinated proteins were predominantly localized to the cell membrane. Functional enrichment related to neuronal and endocrine pathways, especially with MAPK signaling. PPI network analysis focused on five ubiquitinated proteins, including PRKACA, PRKACB, PRKCA, PRKCB, and PRKCG. Additionally, we analyzed their relationship with E3 ligases using UbiBrowser.

This study offers the first comprehensive analysis of the human hypothalamic ubiquitinome. Our work provides a reliable foundation for future research into the implications of ubiquitylation in neuroendocrine-related disorders.

SUMMARY: The human hypothalamus is crucial in regulating metabolism, stress response, and circadian rhythms. Dysfunctions in these processes are linked to various disorders, including Alzheimer's disease, obesity, and sleep disorders. Although ubiquitylation is a key protein modification that affects cellular function, its specific role within the hypothalamus remains poorly understood. This study provides the first detailed profile of lysine ubiquitylation in the human hypothalamus, identifying over 21,000 ubiquitinated sites on more than 5000 proteins. The findings provide valuable insights into the ubiquitylation landscape, highlighting key ubiquitinated proteins and pathways that may be involved in neuroendocrine diseases. This research provides a foundation for future research and highlights the potential of ubiquitylation as a therapeutic target for neurological and endocrine disorders.},
}

@article {pmid41208074,
year = {2025},
author = {Gupta, RA and Rajni, and Shah, K and Dewangan, HK},
title = {Review on Molecular Targeting, Pharmacological Action, and Advanced Biopharmaceutical Aspects for the Management of Alzheimer's Disease.},
journal = {Current pharmaceutical design},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113816128387875250805042824},
pmid = {41208074},
issn = {1873-4286},
abstract = {Alzheimer's disease (AD) is an ongoing progressive neurodegenerative disorder that predominantly affects elderly individuals. A systematic literature search was conducted using electronic databases such as PubMed, Scopus, Web of Science, and Google Scholar. Peer-reviewed articles, clinical trial reports, and experimental studies published in English within the last 15 years were considered. The keywords used for the search included "Alzheimer's disease," "amyloid-beta," "tau protein," "neuroinflammation," "immunotherapy," "drug repurposing," and "experimental treatment strategies." It is the most common form of dementia, ultimately leading to death in advanced stages. Recent advances in AD have featured the expected role of antiamyloid, anti-tau, and anti-inflammatory therapies. Nonetheless, these treatments are still in various stages of preclinical and clinical trials. Moreover, drug repurposing is another promising avenue to identify effective therapeutic alternatives for Alzheimer's disease. This review highlights the underlying pathophysiological mechanisms of AD along with the limits of existing treatments. It also includes two methodologies, specifically; active immunotherapy and passive immunotherapy. Active immunotherapy tactics include the administration of antigens to stimulate antibody production. Additionally, this study discusses several experimental drugs and novel pharmaceutical approaches for AD.},
}

@article {pmid41208050,
year = {2025},
author = {Mueller, KD and Soldan, A and Langhough, R and Bruno, D and Jauregi-Zinkunegi, A and Basche, K and Hale, MR and He, D and Moghekar, A and Hermann, B and Albert, M and Pettigrew, C},
title = {Proper Name Recall as an Early Indicator of Preclinical Alzheimer Disease Pathology.},
journal = {Alzheimer disease and associated disorders},
volume = {},
number = {},
pages = {},
doi = {10.1097/WAD.0000000000000695},
pmid = {41208050},
issn = {1546-4156},
abstract = {BACKGROUND: Early detection of Alzheimer disease (AD) is crucial; however, standard neuropsychological tests often lack sensitivity. Process scores, such as proper name (PN) recall from Logical Memory, may improve the detection of AD-related biomarker positivity. We examined whether baseline PN recall predicted future cerebrospinal fluid (CSF) amyloid (Aβ42/Aβ40) and tau (pTau181) status, and whether biomarker status predicted PN recall trajectories.

METHODS: We analyzed 271 cognitively unimpaired BIOCARD participants (mean age=57.3, 60.3% female, mean follow-up=15.5) using logistic regression and mixed-effects models to examine the associations between PN recall and CSF biomarkers.

RESULTS: Higher baseline PN recall predicted lower amyloid positivity [odds ratio (OR)=0.72, P=0.015]. Amyloid and tau positivity have been linked to a faster decline in PN. Biomarker-positive participants in the biomarker-negative group lacked practice effects.

CONCLUSIONS: PN recall predicts future AD biomarker positivity and may enhance early detection of AD-related cognitive decline.},
}

@article {pmid41207874,
year = {2025},
author = {Luna-Viramontes, NI and Morlett-Paredes, A and Ordoñez-Lozano, I and de la Cruz-López, F and Gonzalez-Chavez, VE and Vargas-Hernández, G and Pérez-Pérez, EG and Méndez-Llaca, RE and Villanueva-Fierro, I and Ortiz-Butron, R and Hernandes-Alejandro, M and Garcés-Ramírez, L and Luna-Muñoz, J},
title = {Brain banks in Latin America: Infrastructure for diagnosis, research, and scientific equity in Mexico and the Caribbean.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70819},
doi = {10.1002/alz.70819},
pmid = {41207874},
issn = {1552-5279},
abstract = {The establishment of brain banks is a strategic initiative to advance research on neurodegenerative diseases in Latin America. This article highlights the development, operations, and multidisciplinary framework of the National Dementia BioBank in Mexico and the National Brain Bank in the Dominican Republic. Both centers focus on the molecular characterization of pathological proteins central to Alzheimer's disease, such as tau and amyloid beta. Standardized protocols have been implemented for tissue donation, preservation, and post mortem analysis. Beyond supporting diagnostics and research, these centers promote scientific literacy and public engagement through traveling exhibitions and outreach initiatives. Together, these brain banking efforts enhance regional scientific capacity, strengthen international collaboration, and advance the representation of historically underserved populations. Their work contributes to a more equitable and globally relevant neuroscience landscape, positioning Latin America as a growing contributor to translational research in aging and dementia. HIGHLIGHTS: Creation of two national brain banks in Mexico (National Dementia BioBank) and the Dominican Republic (National Brain Bank-UNPHU) with standardized protocols for donation, preservation, and post mortem analysis of tau and amyloid beta under international parameters. Integration of advanced histopathological and molecular diagnostic platforms combining classical stains (H&E, Bielschowsky) with immunoperoxidase, multiplex immunofluorescence staining, confocal microscopy, and AI-powered automated analysis for quantification and recognition of topographic patterns. Design of an inclusive tissue collection model that prioritizes the genomic and sociocultural representation of mestizo, Afro-Caribbean, and Indigenous populations, reducing Eurocentric bias and enhancing the global validity of studies on Alzheimer's and other dementias. Development of a culturally sensitive, ethical, and neuroethical framework, with an informed consent process accessible in multiple languages and literacy levels, and safeguarding confidentiality through rigorous data coding. Implementation of innovative outreach strategies (traveling exhibitions, augmented/virtual reality, public lectures) to promote a culture of brain donation and democratize knowledge about neurodegeneration in diverse communities.},
}

@article {pmid41207870,
year = {2025},
author = {Magana-Ramirez, CM and Gillen, DL and Hom, CL and Jaimes, L and Chilukuri, SS and McMahon, N and Lin, C and Kuhlman, R and Hu, T and Head, E and Lott, IT and Sultzer, DL},
title = {Neuropsychiatric symptoms and emerging dementia in people with Down syndrome and older adults.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70871},
doi = {10.1002/alz.70871},
pmid = {41207870},
issn = {1552-5279},
support = {P30AG066519//NIH/NIA/ ; R25AI170491//NIH/NIAID/ ; DGE-1839285//NSF/ ; UO1 AG051406//NIA/NICHD/ ; UO1 AG051412//NIA/NICHD/ ; U24 AG072122/AG/NIA NIH HHS/United States ; P30AG062429//NIA/NIH/ ; P30AG066468//NIA/NIH/ ; P30AG062421//NIA/NIH/ ; P30AG066509//NIA/NIH/ ; P30AG066514//NIA/NIH/ ; P30AG066530//NIA/NIH/ ; P30AG066507//NIA/NIH/ ; P30AG066444//NIA/NIH/ ; P30AG066518//NIA/NIH/ ; P30AG066512//NIA/NIH/ ; P30AG066462//NIA/NIH/ ; P30AG072979//NIA/NIH/ ; P30AG072972//NIA/NIH/ ; P30AG072976//NIA/NIH/ ; P30AG072975//NIA/NIH/ ; P30AG072978//NIA/NIH/ ; P30AG072977//NIA/NIH/ ; P30AG066519//NIA/NIH/ ; P30AG062677//NIA/NIH/ ; P30AG079280//NIA/NIH/ ; P30AG062422//NIA/NIH/ ; P30AG066511//NIA/NIH/ ; P30AG072946//NIA/NIH/ ; P30AG062715//NIA/NIH/ ; P30AG072973//NIA/NIH/ ; P30AG066506//NIA/NIH/ ; P30AG066508//NIA/NIH/ ; P30AG066515//NIA/NIH/ ; P30AG072947//NIA/NIH/ ; P30AG072931//NIA/NIH/ ; P30AG066546//NIA/NIH/ ; P30AG086401//NIA/NIH/ ; P30AG086404//NIA/NIH/ ; P20AG068082//NIA/NIH/ ; P30AG072958//NIA/NIH/ ; P30AG072959//NIA/NIH/ ; },
abstract = {INTRODUCTION: Neuropsychiatric symptoms (NPS) are common as Alzheimer's disease (AD) dementia emerges, both in older adults (OA) and in individuals with Down syndrome (DS).

METHODS: We compared neuropsychiatric inventory (NPI) scores and NPI score trajectories in large cohorts of individuals with DS and OA. Participants were stratified as cognitively normal/stable, mild cognitive impairment, or dementia.

RESULTS: The pattern of NPI domain scores in cohorts with DS (n = 396) or OA (n = 35,217) were qualitatively similar across the cognitive groups. The relationships between cognitive group and both the NPI total score and the rate of NPI score change over time were similar in the two cohorts (multivariate Wald test, p = 0.28 and p = 0.52, respectively).

DISCUSSION: These findings support a conjecture that the shared pathophysiology among individuals with DS and OA may be reflected in the similar clinical profiles and clinical trajectories. NPS are important considerations in the early diagnosis and clinical management.

HIGHLIGHTS: Neuropsychiatric symptoms (NPS) often precede cognitive decline in late-onset AD. People with Down syndrome (DS) are a vulnerable population for AD. Psychiatric symptoms in people with DS and emergent dementia are poorly understood. Symptoms in people with DS and older adults (OA) were similar across cognitive groups. Similar symptoms in the two groups may reflect shared amyloid or related pathology.},
}

@article {pmid41207832,
year = {2025},
author = {Wang, J and Fan, DY and Huang, S and Liu, C and Zhao, PW and Wu, N and Gao, XL and Wang, QZ and Li, Y and Liu, B and Ma, YY and Zhao, RC and Zhu, YP and Li, QY and Liu, XY and Chen, X and Lai, YJ and Zeng, F and Liu, YH and Bu, XL and Guo, T and Tang, Y and Yu, JT and Masters, CL and Guo, J and Mao, Q and Yang, J and Wang, YJ and , },
title = {Performance of blood biomarkers in internal jugular vein for Alzheimer's disease pathologies: the Delta Method study.},
journal = {Science bulletin},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.scib.2025.10.044},
pmid = {41207832},
issn = {2095-9281},
abstract = {Systemic factors confound blood tests for the diagnosis of Alzheimer's disease (AD). The Delta Method study explored whether blood biomarkers from the vein proximal to the brain perform better in detecting cerebral Alzheimer's pathologies using PET or cerebrospinal fluid (CSF) biomarkers as reference standards in two independent cohorts (n = 463). Blood was collected from the internal jugular vein (IJV) and median cubital vein (MCV), and AD biomarkers were measured with Lumipulse G and Simoa methods. The results showed that the levels of Aβ42, Aβ40, p-tau217, p-tau181, GFAP, and NfL were higher in the IJV than in MCV and were highly correlated between the two sites. IJV-Aβ42/40 had stronger correlations with Aβ PET Centiloids and tau PET meta-temporal SUVR than MCV-Aβ42/40. In detecting cerebral Aβ positivity, IJV-Aβ42/40 demonstrated a significantly higher accuracy (79.9%-92.9% vs. 72.4%-88.8%) and a lower percentage of uncertain individuals (17.8%-54.5% vs. 31.3%-70.1%) than MCV-Aβ42/40. Moreover, the diagnostic accuracy of Lumipulse G IJV-Aβ42/40 (88.2%-92.9%) was statistically equivalent to that of MCV-p-tau217 (90.2%-94.3%), although the intermediate percentage of IJV-Aβ42/40 was higher (17.8%-34.0% vs. 0.7%-17.5%). These findings were verified in the validation cohort. This study demonstrated the superior performance of IJV-Aβ42/40 to MCV-Aβ42/40 in detecting cerebral Alzheimer's pathologies, offering a novel perspective to reduce the impacts of systemic factors and comorbidities on blood tests.},
}

@article {pmid41207713,
year = {2025},
author = {Liu, Y and Song, YE and Lynn, A and Wang, W and Miskimen, K and Fuzzell, SL and Hochstetler, SD and Laux, RA and Caywood, LJ and Clouse, JE and Herington, SD and Wang, P and Gulyayev, AV and Dorfsman, DA and Moore, NC and Main, LR and Prough, MB and Zaman, AF and Adams, LD and Whitehead, P and Ogrocki, P and Lerner, AJ and Vance, J and Cuccaro, ML and Scott, WK and Pericak-Vance, MA and Haines, JL},
title = {No association of Alzheimer disease with the joint effect of HFE and TF in the mid-western Amish.},
journal = {Journal of medical genetics},
volume = {},
number = {},
pages = {},
doi = {10.1136/jmg-2025-111085},
pmid = {41207713},
issn = {1468-6244},
}

@article {pmid41207394,
year = {2025},
author = {Yang, S and Xie, B and Liao, D and Sun, Y and Wang, Z and Zhang, H and Yang, Y and Guo, C},
title = {Trajectory of olfactory cortex degeneration from normal cognition to Alzheimer's disease: Insights from multimodal neuroimaging.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107181},
doi = {10.1016/j.nbd.2025.107181},
pmid = {41207394},
issn = {1095-953X},
abstract = {OBJECTIVE: The olfactory cortex is among the earliest brain regions affected by Alzheimer's disease (AD), with olfactory deficits frequently preceding cognitive decline. This study aimed to characterize the functional and structural degeneration trajectory of the olfactory cortex from normal cognition (NC) to mild cognitive impairment (MCI) and eventually to AD using multimodal neuroimaging techniques.

MATERIALS AND METHODS: A total of 105 participants (28 with NC, 35 with MCI, and 42 with AD) were subjected to olfactory [University of Pennsylvania Smell Identification Test (UPSIT)] and cognitive [e.g., Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA)] assessments. This was followed by olfactory task-based functional magnetic resonance imaging (fMRI; olfactory activation), resting-state fMRI [amplitude of low-frequency fluctuations (ALFF) and regional homogeneity (ReHo)], and structural MRI [gray matter volume (GMV) and white matter volume (WMV)] in 12 olfactory-related regions of interest. Group comparisons using one-way analysis of variance/Kruskal-Wallis and multivariate logistic regression analyses were performed to identify stage-specific imaging biomarkers and evaluate diagnostic performance.

RESULTS: From the NC to MCI and then to AD groups, a consistent pattern of declining olfactory activation values, GMV, and WMV, coupled with increased ALFF and ReHo in olfactory subregions, was observed. Moreover, corresponding decreases in olfactory and cognitive scores were noted. Our multivariate logistic regression models yielded the following classification performance: NC versus MCI [right primary olfactory cortex (POC) olfactory activation, right insula olfactory activation, left POC GMV, left insula ReHo, right amygdala ALFF, and MMSE scores] achieved 90.5 % accuracy; MCI versus AD (left hippocampal GMV, left insula ReHo, and MMSE scores) reached 94.8 % accuracy; and NC versus AD (left hippocampal GMV and UPSIT scores) achieved 92.9 % accuracy.

CONCLUSIONS: Our findings delineate a spatiotemporal progression of olfactory cortex degeneration, with early POC alterations in MCI evolving into widespread atrophy and functional dysregulation in AD. Multimodal MRI metrics and logistic modeling yield highly accurate stage classification, underscoring their potential as sensitive biomarkers for early AD detection and monitoring.},
}

@article {pmid41207328,
year = {2025},
author = {Usmani, SA and Ishaq, S and Majeed, A and Zaman, Q and Aziz, A and Afzal, S and Tahir, R and Ahmad, A and Ullah, A},
title = {Network Pharmacology and Molecular Simulations Reveal Multi-Target Neuroprotective Potential of Rhamnolipid and Surfactin against Alzheimer's disease.},
journal = {Brain research bulletin},
volume = {},
number = {},
pages = {111613},
doi = {10.1016/j.brainresbull.2025.111613},
pmid = {41207328},
issn = {1873-2747},
abstract = {BACKGROUND: Alzheimer's disease (AD), the primary cause of dementia and lacks potent therapeutic interventions. Natural biosurfactants containing Surfactin and Rhamnolipids, with neuroprotective capability and anti-inflammatory, extend favorable multi-target approaches.

OBJECTIVES: This study examined the therapeutic potential of Surfactin and Rhamnolipids against Alzheimer's disease operating network pharmacology and molecular docking to manifest their multi-target pathways.

METHODS: Network pharmacology was devoted to investigate Alzheimer's comparable targets of Rhamnolipids and Surfactin, observed by enrichment and network assay. Molecular docking and molecular dynamics simulations were then conducted to measure drug-target interactions and stability.

RESULTS: Network pharmacology recognized 87 overlapping targets of Rhamnolipids and Surfactin with Alzheimer's disease, with hub genes involving CASP3, SRC, CTNNB1, HSP90AA1 and STAT3. GO and KEGG assessment identified enhancement in pathways related to synaptic signaling, immune regulation, kinase activity, and neuroinflammation. Docking explorations illustrated Rhamnolipids exhibited strong binding affinities, distinctly with 1BYQ (-11.1kcal/mol), 7SEO (-9.1kcal/mol), and 2SRC (-9.0kcal/mol) while Surfactin confirmed weaker interactions. Molecular dynamics simulations (MD) affirmed stable complexes, with the Rhamnolipids CASP3 complex revealing the highest conformational stability.

CONCLUSION: These findings indicate that biosurfactants, especially Rhamnolipids, exert neuroprotective effects against Alzheimer's disease through multi-target and multi-pathway functions. Their strong binding to crucial Alzheimer disease related proteins and stable interactions in dynamic simulations highlight their potential therapeutic agents, validating promote experimental validation.},
}

@article {pmid41207217,
year = {2025},
author = {Wu, Y and Huang, S and Sha, Q and Yu, J},
title = {Emerging and Re-emerging viruses as triggers of human endogenous retrovirus activation: Implications for aging and age-related pathologies.},
journal = {Molecular aspects of medicine},
volume = {106},
number = {},
pages = {101422},
doi = {10.1016/j.mam.2025.101422},
pmid = {41207217},
issn = {1872-9452},
abstract = {The human genome contains a substantial legacy of ancient retroviral infections known as Human Endogenous Retroviruses (HERVs), composing 8 % of our DNA. In healthy young individuals, these elements are kept dormant by robust epigenetic mechanisms, primarily DNA methylation and repressive H3K9me3 histone marks. However, this epigenetic silencing deteriorates with age, leading to the reactivation of HERVs, particularly the youngest HERV-K subfamily. This report posits that this HERV awakening is not a passive byproduct of aging but an active, transmissible driver of pathology. The reactivation of HERVs leads to the production of retrovirus-like particles (RVLPs) that can induce senescence in healthy neighboring cells, propagating a contagious aging phenomenon. Furthermore, the accumulation of HERV-derived dsRNA and reverse-transcribed DNA triggers chronic innate immune responses through pathways including cGAS-STING and IFIH1-MAVS, fueling the systemic, low-grade inflammation characteristic of inflammaging, catalytically accelerated by exogenous viral infections. Pathogens such as SARS-CoV-2, Epstein-Barr Virus (EBV), and Herpes Simplex Virus (HSV-1) can directly transactivate HERVs via their own viral proteins, overwhelming the already compromised epigenetic controls in an aging host. This mechanistic link between viral triggers and endogenous retroviral activity is strongly implicated in a range of age-related diseases, including neurodegenerative disorders such as Alzheimer's disease and Amyotrophic Lateral Sclerosis (ALS), where the HERV-K envelope protein is directly neurotoxic. It is also linked to autoimmune diseases like Multiple Sclerosis and various cancers. This report synthesizes these findings and identifies a novel mechanistic link between viral activity, chronic inflammation, and the onset of age-related diseases.},
}

@article {pmid41207195,
year = {2025},
author = {Zhu, C and Fu, J},
title = {Letter to the editor: The role of blood-based biomarkers in Parkinsonian disorders, Alzheimer's disease and frontotemporal dementia.},
journal = {Journal of the neurological sciences},
volume = {479},
number = {},
pages = {123749},
doi = {10.1016/j.jns.2025.123749},
pmid = {41207195},
issn = {1878-5883},
}

@article {pmid41207102,
year = {2025},
author = {Chen, X and Huang, L and Liu, R and Nan, D and Li, Y and Chen, W and Shi, L and Wang, Y and Liang, X and Tang, J and Zhang, H and Lu, Y},
title = {Cuproptosis as a regulator in human diseases: From basic mechanisms to clinical relevance.},
journal = {International immunopharmacology},
volume = {168},
number = {Pt 1},
pages = {115788},
doi = {10.1016/j.intimp.2025.115788},
pmid = {41207102},
issn = {1878-1705},
abstract = {Cuproptosis is a novel, copper-dependent regulated cell death (RCD) pathway identified in 2022. It is distinct from other forms of cell death, such as ferroptosis, due to its unique mechanism involving mitochondrial copper overload, aggregation of lipoylated TCA-cycle proteins, and subsequent proteotoxic stress. Although secondary reactive oxygen species (ROS) production may occur, cuproptosis is not driven by lipid peroxidation, highlighting its specificity. The significance of cuproptosis extends beyond cancer, notably to neurodegenerative disorders such as Alzheimer's disease (AD), where copper dyshomeostasis exacerbates pathology. In oncology, cuproptosis induction has emerged as a promising therapeutic strategy, with agents including copper ionophores, nanomaterials, and repurposed drugs showing efficacy. This review highlights the molecular uniqueness of cuproptosis, its clinical relevance, and translational challenges in therapeutic applications.},
}

@article {pmid41206947,
year = {2025},
author = {Gupta, NK and Yadav, N and Tiwari, V},
title = {Brain aging and cognitive decline accelerate beyond a threshold of periventricular white matter hyperintensity.},
journal = {Cerebral cortex (New York, N.Y. : 1991)},
volume = {35},
number = {11},
pages = {},
doi = {10.1093/cercor/bhaf302},
pmid = {41206947},
issn = {1460-2199},
support = {//IISER Berhampur Seed Fund/ ; 5/13/2022/NCD/III//Indian Council of Medical Research/ ; },
abstract = {A substantial subset of cognitively normal (CN) older adults accumulates high burdens of Periventricular (PVWMH) and Deep White Matter Hyperintensities (DWMH), surrogate neuroimaging-markers of cerebral small-vessel disease, while others have minimal or no white matter hyperintensity (WMH). Using multi-modal Magnetic Resonance Imaging (MRI) from National Alzheimer's Coordinating Centre (NACC) (n = 986) and Alzheimer's Disease Neuroimaging Initiative (ADNI) (n = 382) cohorts spanning CN, cognitively impaired (CI), and CI with Alzheimer's etiology (CI-AD) aged 50-94 years, we investigated whether total WMH burden or specifically PVWMH and DWMH, surpassing a threshold disrupts neuroanatomy and cognition. PVWMH and DWMH volume increased exponentially with age, but PVWMH rose twice as fast, with inflection at 61 years. PVWMH > 2.3 mL, independent of age, was associated with structural atrophy (rostralmiddlefrontal, pre/postcentral gyri, lingual-gyrus, nucleus-accumbens), global fiber disintegration, and impairments in executive, attentional, semantic domains. DWMH effects were negligible. Longitudinal mixed-models in NACC and ADNI confirmed that PVWMH progression, not DWMH, predicted accelerated atrophy. PVWMH-related neuroanatomic loss mediates cognitive decline. The 2.3 mL threshold was validated in ADNI3. While both are visible on routine MRI, only PVWMH demonstrated threshold-dependent effects. Progression to ≥2.3 mL marks a threshold, demanding clinical surveillance, vascular-risk management, and recognition of accelerated brain-aging. Neuroimaging-based quantification of PVWMH, combined with domain-specific cognitive testing provides robust measures of clinical surveillance, definitive of brain health.},
}

@article {pmid41206819,
year = {2025},
author = {Buonocore, J and Fratto, E and Arcuri, F and Vescio, B and Calomino, C and Talarico, M and Cristiani, CM and Quattrone, A and Quattrone, A},
title = {Plasma NfL and GFAP in the preclinical stages of neurodegenerative diseases: insights from the UK Biobank.},
journal = {Journal of neurology},
volume = {272},
number = {12},
pages = {755},
pmid = {41206819},
issn = {1432-1459},
abstract = {BACKGROUND: Plasma neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) are promising blood-based biomarkers of neuroaxonal injury and astrocytic activation, relevant in neurodegeneration. We investigated their pre-diagnostic profiles across common neurodegenerative diseases, including Parkinson's disease (PD), atypical parkinsonian disorders (APD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS).

METHODS: Forty-eight thousand five hundred and twenty-four UK Biobank participants with baseline plasma proteomic data for NfL and GFAP were included. Incident diagnoses of PD, APD, AD, and ALS were identified through ICD-10-coded health records, after careful inclusion/exclusion procedures. Baseline plasma NfL and GFAP concentrations were standardized as z-scores adjusted for relevant covariates. The hazard ratio (HR) for incident neurodegenerative diseases was estimated using Cox regression models adjusted for demographic, clinical, socioeconomic and genetic factors.

RESULTS: The final sample included 1196 cases (505 PD, 26 APD, 476 AD, 189 ALS) and 44,107 control subjects. In Cox regression models, NfL was associated with higher risk of incident ALS (HR 1.69; 95% CI, 1.58-1.80, p < 0.001), APD (HR 1.51; 95% CI, 1.22-1.87, p < 0.001), AD (HR 1.31; 95% CI, 1.22-1.41, p < 0.001), and PD (HR 1.14; 95% CI, 1.05-1.23, p < 0.001). GFAP was independently associated with incident AD only (HR 1.72; 95% CI, 1.63-1.82, p < 0.001).

CONCLUSION: Plasma NfL and GFAP showed distinct pre-diagnostic profiles. NfL was associated with incident diagnosis of several neurodegenerative diseases, while GFAP was specific to AD, reinforcing its role in dementia. These results may help optimize the identification of target populations at risk of neurodegenerative diseases for future neuroprotective treatments.},
}

@article {pmid41206815,
year = {2025},
author = {Tian, S and Liu, Y and Hu, H and Li, S},
title = {Tau Liquid-Liquid Phase Separation in Alzheimer's Disease: Mechanisms, Pathogenesis, and Therapeutic Implications.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {18},
pmid = {41206815},
issn = {1559-1182},
support = {U24A20806//National Natural Science Foundation of China/ ; 82404605//National Natural Science Foundation of China/ ; U23A20510//National Natural Science Foundation of China/ ; BX20220048//National Postdoctoral Program For Innovative Talents/ ; 2022MD723713//China Postdoctoral Science Foundation/ ; },
abstract = {Tau protein undergoes liquid-liquid phase separation (LLPS), forming dynamic condensates that act as intermediates in the transition to neurofibrillary tangles in Alzheimer's disease (AD). This review highlights tau's dynamic and reversible LLPS behavior, an underexplored aspect of tau's role, particularly as an early pathogenic driver in AD. We summarize the molecular mechanisms and regulatory factors governing tau LLPS, with a focus on its physiological functions in microtubule stability, synaptic activity, and cellular stress responses. Additionally, we discuss how metal ions, RNA, and neurodegenerative cofactors influence tau's phase behavior in a cell-type-specific manner. Emerging strategies targeting tau LLPS-such as nanobodies, AAV-based delivery, engineered degradation platforms, and CRISPR tools-show promise for early, reversible intervention. We also explore the potential of LLPS-informed biomarkers for diagnosing and monitoring disease progression. Overall, LLPS provides a dynamic, targetable framework linking early AD pathogenesis with therapeutic innovation, opening opportunities for earlier intervention and more effective treatment strategies.},
}

@article {pmid41206776,
year = {2025},
author = {Mulet I Piera, X and Del Campo-Montoya, R and Cuadrado-Tejedor, M and Garcia-Osta, A and Garbayo, E and Blanco-Prieto, MJ},
title = {Intranasal delivery of lipid-based nanoparticles for the treatment of neurodegenerative diseases: advances, challenges and future perspectives.},
journal = {Expert opinion on drug delivery},
volume = {},
number = {},
pages = {},
doi = {10.1080/17425247.2025.2587903},
pmid = {41206776},
issn = {1744-7593},
abstract = {INTRODUCTION: Neurodegenerative diseases such as Parkinson's or Alzheimer's disease urgently require new therapeutic approaches. Despite significant efforts, no disease-modifying therapies targeting specific molecular pathways have demonstrated consistent clinical efficacy. This challenge has shifted attention toward drug delivery strategies that improve bioavailability, targeting, and patient accessibility. Intranasal delivery has emerged as a promising, noninvasive approach that bypasses the blood-brain barrier, and improves patient compliance. Lipid-based systems, especially following the success of COVID-19 vaccines, have gained attention as versatile platforms for delivering RNAs and other therapeutic molecules. Their ability to encapsulate diverse payloads and tunable composition makes them ideal candidates for targeting neurodegenerative disorders via the intranasal route.

AREAS COVERED: This review discusses recent advances in intranasal delivery for the treatment of neurodegenerative disorders, with emphasis on lipid-based nanoparticle formulations. It addresses formulation challenges such as stability, targeting efficiency, and compatibility with nasal physiology, and outlines key design parameters affecting brain delivery. Future directions are explored to advance formulation development and clinical translation.

EXPERT OPINION: Intranasal lipid-based drug delivery represents a promising strategy to bypass the blood-brain barrier in neurogenerative disorder treatment. Although regulatory gaps and the absence of long-term safety evaluation, intranasal administration offers clear advantages for CNS targeting underscoring strong potential for future clinical translation.},
}

@article {pmid41206462,
year = {2025},
author = {Chan, KCG and Dodge, HH and Sano, M and Au, R and Craft, S and Levey, AI and Weintraub, S and Kukull, WA and Saykin, AJ and Barnes, LL},
title = {Comparable performance of the NACC Uniform Data Set version 3 neuropsychological test battery in assessing longitudinal cognitive change for African American and White participants.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70889},
pmid = {41206462},
issn = {1552-5279},
support = {U24AG072122/AG/NIA NIH HHS/United States ; P30AG066518/AG/NIA NIH HHS/United States ; P30AG062421/AG/NIA NIH HHS/United States ; P30AG066514/AG/NIA NIH HHS/United States ; P30AG072978/AG/NIA NIH HHS/United States ; P30AG072947/AG/NIA NIH HHS/United States ; P30AG066511/AG/NIA NIH HHS/United States ; P30AG072977/AG/NIA NIH HHS/United States ; P30AG072976/AG/NIA NIH HHS/United States ; P30AG072975/AG/NIA NIH HHS/United States ; },
abstract = {INTRODUCTION: Alzheimer's Disease Research Centers have used the Uniform Data Set Version 3 (UDS3) neuropsychological battery since 2015, but whether it exhibits differential sensitivity to change across race is unknown. We examined whether the UDS3 cognitive battery was comparably sensitive to longitudinal change between African American and White participants.

METHODS: Data were obtained from the National Alzheimer's Coordinating Center (NACC). Linear mixed-effects models examined racial differences in baseline and longitudinal change in standardized test scores, controlling for age, sex, education, recruitment source, health factors, family history of dementia, and diagnostic groups defined by baseline and longitudinal changes in Clinical Dementia Rating (CDR) scores.

RESULTS: Compared to White participants, African American participants had significantly lower baseline Z-scores on all tests (difference: -0.097 to -0.592). Nevertheless, differences in longitudinal decline were non-significant (annualized difference: -0.018 to 0.031).

DISCUSSION: Despite baseline score differences, longitudinal change relative to clinical ratings appears comparable across racial groups.

HIGHLIGHTS: Version 3 of the NACC Uniform Data Set neuropsychological battery (UDS3) has been implemented since 2015 and administered to over 14,000 participants. We observed small differences in longitudinal decline across all test scores when comparing White and African American participants. The findings support the continued use of the UDS3 battery in ADRCs and its potential applicability in other studies of cognitive aging and decline.},
}

@article {pmid41206345,
year = {2025},
author = {Ren, X and Zhang, G and Zhou, B and Gu, W and Zhu, Q and Liu, X},
title = {Cerebrovascular mechanisms between type 2 diabetes and Alzheimer's disease: Insights from ultrasound localization microscopy.},
journal = {Medical physics},
volume = {52},
number = {11},
pages = {e70131},
doi = {10.1002/mp.70131},
pmid = {41206345},
issn = {2473-4209},
support = {12274092//National Natural Science Foundation of China/ ; 2023YFC2410903//National Key Research and Development Program of China/ ; 24490710400//International Science and Technology Cooperation Program of Shanghai/ ; FudanX24AI016//AI for Science Foundation of Fudan University/ ; },
abstract = {BACKGROUND: Type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) are two major global health challenges, both associated with increased incidence and mortality. Although their pathologies differ, mounting evidence points to a shared vascular dysfunction that may drive the onset and progression of both conditions. Ultrasound localization microscopy (ULM) offers a promising approach for high-resolution imaging and quantification of cerebral microvasculature.

PURPOSE: To investigate changes in cerebral micro-vessels induced by T2DM, AD, and their coexistence, aiming to uncover the underlying interactions between the two diseases.

METHODS: Twenty-four Sprague Dawley (SD) rats were randomly assigned into four groups: (1) normal, (2) DM combined with AD, (3) DM, and (4) AD. Cerebral vascular density in the caudate putamen (CPu), thalamus (TH), and hippocampus (HIP) was quantified using ULM. Statistical analysis was conducted using one-way ANOVA followed by Tukey's honestly significant difference (HSD) post-hoc test, after confirming normality and homogeneity of variance (Shapiro-Wilk and Levene's tests). A p-value < 0.05 was considered statistically significant. To validate the model and examine the relationship between T2DM and AD, pathological staining was performed to assess cellular and neuronal changes, as well as Aβ deposition.

RESULTS: Both single diseases and their combination led to a reduction in cerebral vascular density across all three brain regions. The blood glucose-vessel density distributions in the DM and DM&AD groups showed substantial overlap, indicating similar patterns of cerebrovascular changes. In the CPu region, vascular density in diabetic rats decreased by 34.13% compared to controls (p = 0.003), while in the HIP of the DM&AD group, vascular density was reduced by 29.98% (p = 0.002).

CONCLUSION: T2DM triggers an increased risk of AD. ULM provides the possibility to be used as an emerging technological tool to detect early cerebral microangiopathy.},
}

@article {pmid41206330,
year = {2025},
author = {Attali, RS and Farfara, D and Cooper, I and Levin, A and Ben-Romano, T and Trudler, D and Vientrov, M and Shaltiel-Karyo, R and Shalev, DE and Segev-Amzaleg, N and Gazit, E and Segal, D and Frenkel, D},
title = {Corrigendum to "Naphthoquinone-tyrptophan reduces neurotoxic Aβ*56 levels and improves cognition in Alzheimer's disease animal model" Neurobiol Dis. 46(3) (2012):663-72.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107170},
doi = {10.1016/j.nbd.2025.107170},
pmid = {41206330},
issn = {1095-953X},
}

@article {pmid41206326,
year = {2025},
author = {Weissberger, GH and Yassine, HN and Axelrod, J and Fenton, L and Noriega-Makarskyy, DT and Molinare, C and Williams, JT and Oyen, E and Kim, P and Lai, MHC and Han, SD},
title = {Cognitive functioning predicts vulnerability to financial exploitation in APOE e4 carriers.},
journal = {International psychogeriatrics},
volume = {},
number = {},
pages = {100162},
doi = {10.1016/j.inpsyc.2025.100162},
pmid = {41206326},
issn = {1741-203X},
abstract = {An emerging body of work suggests that financial exploitation vulnerability (FEV) may be an early marker of Alzheimer's disease (AD). We examined how APOE e4 genotype and cognition at baseline interact to predict subsequent FEV one year later. Participants were 95 older adults without dementia aged 50 or older (M age = 69.09, SD = 7.51; 72.63 % female; 72.63 % White non-Hispanic). Participants completed two annual assessments that included comprehensive neuropsychological testing and a measure of FEV. Saliva samples for APOE genotyping were collected. Linear regression models regressed Year 2 FEV on APOE, global cognition, and their interaction. Age, sex, education, and Year 1 FEV scores were covaried. Models were re-run considering cognitive domains separately (memory, language, and attention/working memory and executive functioning). Main effects of APOE and cognition were not found. However, cognition and APOE status interacted to predict Year 2 FEV. Specifically, worse cognitive functioning predicted higher FEV only for e4 carriers. Cognitive domain analyses revealed more nuanced relationships. Findings suggest that cognition is a relevant risk factor of FEV for e4 carriers, and support the emerging idea that FEV may be an early marker of AD-related neuropathological changes.},
}

@article {pmid41206011,
year = {2025},
author = {Ravichandran, KA and Brosseron, F and McManus, RM and Ising, C and Görgen, S and Schmidt, S and Santarelli, F and Lee, SY and Jung, H and Chung, WS and Kim, CH and Laza, AR and de Almodóvar, CR and Ramirez, A and Latz, E and Heneka, MT},
title = {Enhancing Tyro3 signalling ameliorates IL-1β production through STAT1 in Alzheimer's disease models.},
journal = {Journal of leukocyte biology},
volume = {},
number = {},
pages = {},
doi = {10.1093/jleuko/qiaf157},
pmid = {41206011},
issn = {1938-3673},
abstract = {Neuroinflammation plays a vital role in determining the trajectory of Alzheimer's disease (AD) progression. In AD brain, microglial exposure to pathological amyloid β (Aβ42) and tau peptide aggregates results in an NLRP3 inflammasome-activated pro-inflammatory response that ranges from mild to severe. Recently we have shown that dementia subjects with higher levels of soluble TAM receptors Tyro3 and AXL in the cerebrospinal fluid (CSF) indicated cognitive protection. The molecular mechanism for this protective effect of TAM receptors is unknown. Here, we identified a beneficial role of TAM receptors using Tyro3-overexpressing (Tyro3OE) and Axl-overexpressing (AxlOE) THP-1 cells. In the Tyro3OE cells, the levels of the pro-inflammatory cytokine IL-1β were markedly decreased in the AD microenvironment (tau + Aβ42) and the classical NLRP3 inflammasome model (LPS + Nigericin) in comparison to the control cells. This was mediated by increased STAT1 phosphorylation and reduced IL-1β transcription enhancer C-EBP- β in Tyro3OE cells. The use of the JAK1/2 inhibitor Ruxolitinib reduced the phosphorylation of STAT1, leading to a partial restoration of IL-1β in the Tyro3OE cells. Lastly, we found a significantly reduced IL-1β in the brains of AD mice that has activated TAM signalling through Gas6-α-Aβ lentiviral injection. In summary, TAM receptor Tyro3 overexpression decreased AD-associated IL-1β release from macrophages thereby uncovering a potential beneficial role for TAM receptors during neuroinflammation in AD.},
}

@article {pmid41205924,
year = {2025},
author = {Shapley, SM and Shantaraman, A and Gadhavi, J and Kearney, MA and Dammer, EB and Duong, DM and Bowen, CA and Watson, CM and Bagchi, P and Guo, Q and Rangaraju, S and Seyfried, NT},
title = {Proximity labeling of the Tau repeat domain enriches RNA-binding proteins that are altered in Alzheimer's disease and related tauopathies.},
journal = {Molecular & cellular proteomics : MCP},
volume = {},
number = {},
pages = {101458},
doi = {10.1016/j.mcpro.2025.101458},
pmid = {41205924},
issn = {1535-9484},
abstract = {In Alzheimer's disease (AD) and other tauopathies, tau dissociates from microtubules and forms toxic aggregates that contribute to neurodegeneration. Although some of the pathological interactions of tau have been identified from postmortem brain tissue, these studies are limited by their inability to capture transient interactions. To investigate the interactome of aggregate-prone fragments of tau, we applied an in vitro proximity labeling technique using split TurboID biotin ligase (sTurbo) fused with the tau microtubule repeat domain (TauRD), a core region implicated in tau aggregation. We characterized this sTurbo TauRD tagging interactors with the requirement for both ligase fragment co-expression for robust enzyme activity and nuclear and cytoplasmic localization of the recombinant proteins. Following enrichment of biotinylated proteins and mass spectrometry, we identified over 700 TauRD interactors. Gene ontology analysis of enriched TauRD interactors highlighted processes often dysregulated in tauopathies, including spliceosome complexes, RNA-binding proteins (RBPs), and nuclear speckles. The disease relevance of these interactors was supported by integrating recombinant TauRD interactome data with human AD tau interactome datasets and protein co-expression networks from individuals with AD and related tauopathies. This revealed an overlap with the TauRD interactome and several modules enriched with RBPs and increased in AD and progressive supranuclear palsy. These findings emphasize the importance of nuclear pathways in tau pathology, such as mRNA surveillance and RNA splicing, establishing the sTurbo TauRD system as a valuable tool for exploring the tau interactome.},
}

@article {pmid41205906,
year = {2025},
author = {Ma, J and Liu, Y and Lu, D and Sun, Q},
title = {The association of the Wnt/β-catenin signaling pathway with Alzheimer's disease.},
journal = {Neuropharmacology},
volume = {},
number = {},
pages = {110754},
doi = {10.1016/j.neuropharm.2025.110754},
pmid = {41205906},
issn = {1873-7064},
abstract = {With the global rise in population aging, the incidence of Alzheimer's disease (AD) continues to increase, posing a substantial burden on individuals, families, and healthcare systems. However, at present, the drugs approved by FDA for treating AD can only relieve symptoms, but cannot cure or reverse the disease. Therefore, it is urgent to study the signal pathways related to AD and the drugs to improve the pathological changes of AD.The Wnt/β-catenin signaling pathway, known for its functional diversity, evolutionary conservation, and relevance to multiple diseases, holds a pivotal role in both basic research and therapeutic development. This pathway is essential for regulating critical biological processes, including embryonic development, tissue homeostasis, cell proliferation, differentiation, and apoptosis.In AD , downregulation of the Wnt/β-catenin signaling pathway has been implicated in key pathological features, such as tau hyperphosphorylation, amyloid-β (Aβ) accumulation, neuronal degeneration, synaptic loss, cognitive impairment, oxidative stress, mitochondrial dysfunction, blood-brain barrier disruption, and neuroinflammation. This review comprehensively discusses the deregulation of the Wnt/β-catenin pathway in AD and how it contributes to disease progression. Furthermore, we highlighted emerging pharmacological activators of this pathway exhibiting potential as therapeutic agents for AD.},
}

@article {pmid41205899,
year = {2025},
author = {Ali, S and Kosar, S and Sina, RM and Sima, A and Mohammad, A and Mohammad, S and Zahra, Z and Vida, HH and Fatemeh, K and Zohreh, Z and Fatemeh, SE and Farhang, G and Mahan, S and Mahsa, M and , and , },
title = {Serum bile acids and brain hypometabolism in patients across Alzheimer's disease continuum: An [[18]F]FDG-PET study.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2025.11.001},
pmid = {41205899},
issn = {1873-7544},
abstract = {The present study compares the predictive performance of serum bile acids with that of traditional Cerebrospinal Fluid (CSF) biomarkers for brain hypometabolism in the Alzheimer's disease (AD) continuum using [[18]F]-Fluorodeoxyglucose Positron Emission Tomography ([[18]F]-FDG-PET). Data were extracted from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Conventional CSF biomarker data, serum bile acid measurements, and [[18]F]-FDG-PET data were used. We studied 556 participants, including 185 cognitively normal (CN) individuals, 289 patients with mild cognitive impairment (MCI), and 82 patients with AD. Glucose Standardized Uptake Value Ratios (SUVRs) were significantly lower in the CN group compared to the MCI and AD groups. Serum levels of lithocholic acid and Glycolithocholic acid were significantly elevated in AD compared to MCI and CN participants. Overall, CSF biomarkers had lower predictive power compared to brain hypometabolism in distinguishing AD from other groups. Stronger correlations with brain glucose hypometabolism were observed for conventional CSF biomarkers compared to bile acids in MCI and AD patients. Regression analyses indicated that while certain bile acids predicted brain hypometabolism in CN subjects better than conventional biomarkers, their predictive performance underperformed CSF biomarkers in MCI and AD. Overall, FDG-PET remains more effective than traditional CSF biomarkers for staging the AD continuum. While bile acids show potential, their ability to predict brain glucose metabolism in the AD spectrum has not yet surpassed that of established CSF biomarkers.},
}

@article {pmid41205896,
year = {2025},
author = {Easton, A and Parui, A},
title = {Driving forward a new perspective on everyday memory in the real world.},
journal = {Neuroscience},
volume = {590},
number = {},
pages = {93-94},
doi = {10.1016/j.neuroscience.2025.10.058},
pmid = {41205896},
issn = {1873-7544},
}

@article {pmid41205777,
year = {2025},
author = {Boreland, AJ and Abbo, Y and Li, X and Stillitano, AC and Zhang, S and Duan, J and Pang, ZP and Hart, RP},
title = {Ethanol induces neuroimmune dysregulation and soluble TREM2 generation in a human iPSC neuron, astrocyte, microglia triculture model.},
journal = {Alcohol (Fayetteville, N.Y.)},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.alcohol.2025.10.006},
pmid = {41205777},
issn = {1873-6823},
abstract = {Alcohol use disorders (AUDs) affect substantial populations worldwide and increase the risk of developing cognitive impairments and alcohol-associated dementia. While chronic inflammatory signaling likely plays an important role in alcohol-associated neurological sequalae, the precise mechanisms underlying alcohol-associated neuropathology remain enigmatic. We hypothesize that alcohol leads to neuroimmune dysregulation among neurons, astrocytes, and microglia; and is perpetuated by innate immune signaling pathways involving cell-cell signaling. To investigate how alcohol dysregulates neuroimmune interactions in a human context, we constructed a triculture model comprising neurons, astrocytes, and microglia derived from human induced pluripotent stem cells. After exposure to ethanol, we observed significant differential gene expression relating to innate immune pathways, inflammation, and microglial activation. Microglial activation was confirmed with morphological analysis and expression of CD68, a lysosomal-associated membrane protein and marker for phagocytic microglial activation. A striking finding in our study was the elevation of TREM2 expression and, specifically, TREM2 alternatively spliced isoforms that are predicted to give rise to soluble TREM2. TREM2 loss-of-function variants have been reported to be a risk factor for Alzheimer's disease. These results suggest that ethanol exposure in the brain may lead to increased microglial activation and production of soluble isoform named TREM2[219] through alternate splicing. Deciphering the molecular and cellular mechanisms underpinning ethanol-related neuroimmune dysregulation within a human context promises to shed light on the etiology of AUD-related disorders, potentially contributing to the development of effective therapeutic strategies.},
}

@article {pmid41205745,
year = {2025},
author = {Maramai, S and Taddei, M and Castagnetti, A and Viciani, E and Koufi, FD and Neri, I and Boschetti, E and Evangelisti, C and Ratti, S and Baldelli, L and Calandra-Buonaura, G and Cani, I and Cortelli, P and Sambati, L and Scorziello, A and Taglialatela, M and Pardini, M and Corsaro, A and Florio, T and Giannini, G},
title = {Drug enteric metabolism in gut microbiota-brain crosstalk.},
journal = {Life sciences},
volume = {},
number = {},
pages = {124075},
doi = {10.1016/j.lfs.2025.124075},
pmid = {41205745},
issn = {1879-0631},
abstract = {Neurodegenerative diseases (NDs), such as Alzheimer's (AD) and Parkinson's disease (PD) represent the leading cause of illness and disability worldwide. In the effort to unveiling the etiopathogenesis of these neurological diseases, increasing attention has recently been paid to the emerging role of the gut microbiota (GMB) in the so-called gut-brain axis, and to the correlation of neurodegenerative processes with intestinal dysbiosis, either of genetic bases or induced by drugs and their metabolites. Over time, there has been a notable surge in the quantity of scientific publications pertaining to the gut-brain axis and GMB metabolism, reaching top levels in 2023-2024. As a result, the body of research on the effects of the gut-brain axis on AD and PD has begun to increase. Nonetheless, the identification of gut-derived metabolites and their effects on the central nervous system (CNS) is frequently missing or only partially reported. It is therefore necessary to raise awareness on the importance of enteric metabolism and its assessment while designing new drugs and investigating their pharmacokinetic properties, since both healthy and dysbiotic gut can hamper or modify drugs activity and efficacy. This review aims at providing a critical overview of gut-derived metabolism of different drugs, focusing on their effects on the GMB and gut-brain axis. The discussion focused on common therapeutic agents against AD and PD, as well as non-prescription drugs and food supplements with known beneficial effects on the CNS, reviewing relevant literature of the last decade.},
}

@article {pmid41205698,
year = {2025},
author = {Dunk, MM and Delac, L and Rapp, SR and Driscoll, I and Latorre-Leal, M and Farland, LV and Haring, B and Harris, HR and Jung, SY and Manson, JE and Ochs-Balcom, HM and Shadyab, AH and Weitlauf, JC and Xu, H and Maioli, S},
title = {Exploring biomarkers of neurodegenerative risk: Associations of oxysterols, sex hormones, and reproductive characteristics in older women.},
journal = {Journal of lipid research},
volume = {},
number = {},
pages = {100938},
doi = {10.1016/j.jlr.2025.100938},
pmid = {41205698},
issn = {1539-7262},
abstract = {Women face a higher lifetime risk of developing neurodegenerative diseases such as Alzheimer's disease (AD) and related dementia (ADRD). The menopausal transition, characterized by a decline in estrogen levels, may affect cholesterol metabolism and neurodegenerative processes. Oxysterols, oxidized cholesterol derivatives, play a role in these pathways, with 24(S)-hydroxycholesterol (24HC) reflecting brain cholesterol turnover and 27-hydroxycholesterol (27HC) linked to systemic cholesterol metabolism. We investigated associations of plasma oxysterols with circulating sex hormones and characteristics of reproductive history in 1,974 postmenopausal women with no history of dementia from the Women's Health Initiative, taking into account APOE4 status and cholesterol-lowering medication. We found that higher levels of bioavailable estradiol were associated with higher 24HC and 27HC levels, and higher estrone was associated with higher 24HC (all p-values < 0.05). Associations of estradiol with 24HC and 27HC were stronger among those not using cholesterol medication and APOE4 carriers, with a significant interaction between 27HC and APOE4 in relation to 27HC (p for interaction = 0.04). Having an older age at menopause was associated with lower 24HC among those taking cholesterol medication (p for interaction = 0.03). Our findings suggest that 24HC and 27HC may be proxy biomarkers of neuronal health and estrogen status in postmenopausal women. The stronger associations between estradiol and oxysterols among APOE4 carriers and those not using cholesterol-lowering medication suggest the need to account for hormonal, genetic, and pharmacological factors when evaluating neurodegenerative risk. Longitudinal studies are warranted to further investigate oxysterols as potential early biomarkers of ADRD risk.},
}

@article {pmid41205642,
year = {2025},
author = {Kishi, T and Matsunaga, S and Saito, Y and Iwata, N},
title = {Lithium for Alzheimer's Disease: Insights from a Meta-analysis.},
journal = {Neuroscience and biobehavioral reviews},
volume = {},
number = {},
pages = {106458},
doi = {10.1016/j.neubiorev.2025.106458},
pmid = {41205642},
issn = {1873-7528},
}

@article {pmid41205639,
year = {2025},
author = {Bhosale, S and Chakor, R and Lohidasan, S and Sivakkumar, S and Arulmozhi, S},
title = {Neuroprotective and Nootropic Effects of a Standardised Siddha Polyherbal Formulation, Bhiramiyadhi Bhavanai Choornam, Against β-Amyloid-Induced Neurodegeneration.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {120850},
doi = {10.1016/j.jep.2025.120850},
pmid = {41205639},
issn = {1872-7573},
abstract = {Bhiramiyadhi bhavanai choornam (BBC) is a traditional Siddha polyherbal formulation composed of 15 medicinal plants. The classical text claims that regular intake of BBC strengthens cognitive function, improves memory, boosts morale, enhances longevity, and promotes overall physical vitality Aim of the study: The present investigation focused on standardising Bhiramiyadhi bhavanai choornam and assessing its neuroprotective effect against β-amyloid-induced neurodegeneration in Wistar rats.

MATERIALS AND METHODS: Standardisation of BBC was carried out following AYUSH guidelines. A validated HPTLC method was developed for the marker compounds ascorbic acid, gallic acid, quercetin, piperine, and asiaticoside. Experimental neurodegeneration was induced by intracerebroventricular administration of Aβ1-42 in male Wistar rats. The effects of BBC were evaluated using behavioural paradigms, such as the Morris water maze, locomotor activity, social recognition, and novel object recognition tests. Biochemical assessments included acetylcholinesterase activity, brain-derived neurotrophic factor (BDNF), oxidative stress and antioxidant indices, and inflammatory cytokines. Brain histopathology was performed to assess neuronal architecture and the deposition of amyloid plaques.

RESULTS: and discussion: The HPTLC method developed provided accurate and reliable chemical profiling of BBC. Treatment with BBC significantly improved cognitive and memory performance in Aβ1-42-treated rats. It enhanced brain BDNF levels, improved antioxidant defence mechanism, reduced acetylcholinesterase activity, and suppressed oxidative stress and inflammatory cytokines. Histological studies further confirmed its protective effect by attenuating neuronal damage and plaque formation.

CONCLUSION: A validated HPTLC method was developed for the standardisation of BBC. Pharmacological findings indicate its strong neuroprotective and nootropic activities, highlighting its potential for Alzheimer's disease and related neuro disorders.},
}

@article {pmid41205623,
year = {2025},
author = {Wisch, JK and Jiao, Z and Kennedy, JT and Cohen, AD and Schlachetzki, Z and Petersen, M and Handen, BL and Christian, BT and Mapstone, M and Rosas, HD and Lai, F and Lee, JH and Krinsky-McHale, SJ and Schmitt, FA and Harp, JP and Hom, C and Lott, IT and Hartley, S and Zaman, S and Ptomey, L and Burns, JM and Tudorascu, D and Ibanez, L and Rafii, MS and Head, E and Ances, BM},
title = {Imaging and plasma biomarkers for pathological accumulation in Down syndrome.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awaf418},
pmid = {41205623},
issn = {1460-2156},
abstract = {Down syndrome is characterized by triplication of chromosome 21, leading to early-onset Alzheimer disease pathology, with nearly all individuals with Down syndrome developing amyloid and tau pathology. In the new era of amyloid modifying therapies, it is vital to identify early biomarkers for Alzheimer disease (AD) pathology in Down syndrome. Striatal amyloid may begin to accumulate sooner than cortical amyloid in Down syndrome. Tau phosphorylation at specific sites, including 217, can be quantified in plasma and may represent an important mechanistic step in the development of tau pathology. This study had two aims: 1. To compare the relative age at increase of multiple biomarkers (cortical amyloid, striatal amyloid, plasma pTau217 and summary tau pathology) 2. To test whether plasma pTau217 can identify both the current presence and likely future accumulation of amyloid and tau pathology. To identify optimal biomarkers for early intervention, we examined longitudinal cortical and striatal amyloid PET, plasma pTau217, and tau PET in 328 individuals with Down syndrome enrolled in the Alzheimer Biomarker Consortium - Down Syndrome study. To compare the timing of biomarker changes, we modeled longitudinal biomarkers using generalized additive mixed models relative to age. We used receiver operating characteristic curve analysis to identify thresholds for both current and likely future accumulation of amyloid and tau pathology. For all comparisons, we used age as the null model, performing Delong tests to evaluate the performance of age relative to biomarker-based prediction. Imaging biomarkers increased around 40 years old, with plasma pTau217 increasing somewhat later than the three PET biomarkers. Striatal amyloid increased before cortical amyloid in some participants; however, this was not uniform across individuals. If an individual was classified as a reliable accumulator with one biomarker, he or she was likely to be a reliable accumulator in other biomarkers. Age was as sensitive as plasma pTau217 in its ability to both detect preclinical Alzheimer disease pathology and predict near future accumulation of both amyloid and tau. These results suggest that all adults with Down syndrome should be screened for Alzheimer disease pathology starting shortly before age 40 and considered for clinical trials. Age alone was as effective at detecting both current pathology and likely future accumulation as plasma pTau217. Because this disease is so closely concurrent with age in individuals with Down Syndrome, plasma pTau217 may not provide more diagnostic benefits than age.},
}

@article {pmid41205374,
year = {2025},
author = {Venkatraman, S and P R, JD and Kavitha, MS},
title = {Hierarchical graph-guided contextual representation learning for Neurodegenerative pattern recognition in MRI.},
journal = {Computers in biology and medicine},
volume = {199},
number = {},
pages = {111276},
doi = {10.1016/j.compbiomed.2025.111276},
pmid = {41205374},
issn = {1879-0534},
abstract = {Neurodegenerative (ND) diseases are autoimmune diseases that affect the central nervous system, including the brain and spinal cord. In recent years, deep learning has demonstrated its potential in medical imaging for diagnostic purposes. However, for these techniques to be fully accepted in clinical settings, they must achieve high performance and gain the confidence of medical professionals regarding their interpretability. Therefore, an interpretable model should make decisions based on clinically relevant information like a domain expert. To achieve this, we present an interpretable classifier dedicated to the most common autoimmune ND diseases. The lesions associated with ND diseases exhibit irregular distributions and spatial dependencies in different regions of the brain, challenging traditional models to effectively capture both local and global relationships. To address this issue, we present a Residual Graph Neural Network enhanced Vision Transformer (RG-ViT) that represents MRI data as a graph of interconnected patches. By integrating residual connections into the GNN framework, we preserve critical features while promoting effective message passing. This approach overcomes the problem of spatial disconnection prevalent in standard patch-based methods and provides a cohesive and context-aware analysis of MRI data. Experimental results in detecting multiple sclerosis (MS), Parkinson's (PD), and Alzheimer's disease (AD) demonstrated our approach's consistent accuracy scores of 98.7%, 99.6%, and 99.1%, respectively. On the combined dataset for the global classification of ND diseases, it achieved an F1 score of 99.2%, justifying its generalizability.},
}

@article {pmid41205203,
year = {2025},
author = {Channalli, SR and Pattanashetti, L and Patil, SB and Yaraguppi, DA and Prasanth, DSNBK and Halkavatagi, SG and Naik, R},
title = {Deciphering the Multitarget Neuroprotective Potential of Ficus microcarpa L. f. Leaf Extract: Insights From Phytochemical, Computational, and Experimental Approaches.},
journal = {Chemistry & biodiversity},
volume = {},
number = {},
pages = {e02568},
doi = {10.1002/cbdv.202502568},
pmid = {41205203},
issn = {1612-1880},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by memory loss, cognitive decline, and cholinergic dysfunction. This study evaluated the neuroprotective potential of Ficus microcarpa leaf extract via a multidisciplinary approach that integrates phytochemical profiling, in silico analysis, and in vivo validation. LC‒MS analysis revealed key bioactive compounds, including fortunellin, thalsimine, and vocalristine, which are flavonoids, alkaloids, and terpenoids, that are known for their neuroprotective effects. Drug-likeness and toxicity evaluations via SwissADME and ProTox-II revealed favorable pharmacokinetic properties. Network pharmacology and KEGG enrichment analyses identified AChE, APP, and GSK3β as central AD-related targets. Molecular docking (AutoDock 4.2) revealed strong binding affinities of fortunellin (-9.2 kcal/mol) and donepezil (-9.0 kcal/mol) with AChE, which was supported by active site interactions. Molecular dynamics (200 ns, GROMACS) confirmed the complex stability via RMSD, RMSF, SASA, and hydrogen bond analyses. The MM-PBSA calculations further validated the binding stability. In vivo studies revealed that F. microcarpa (100 and 200 mg/kg, po) and donepezil (3 mg/kg, po) administered for 21 days significantly reversed scopolamine-induced (2 mg/kg, ip) memory deficits in Wistar rats, as assessed by the Morris water maze, elevated plus maze, and novel object recognition tests. Biochemical analysis revealed reduced oxidative stress, increased antioxidant enzyme levels, and the restoration of cholinergic function. Histopathological studies revealed that the integrity of the hippocampus was preserved. Overall, these findings support F. microcarpa, particularly fortunellin, as a promising multitarget candidate for AD therapy, meriting further pharmacological investigation.},
}

@article {pmid41205178,
year = {2025},
author = {Royo Marco, A and Bruch, KR and Cowan, MN and Dill, JG and Moore, KA and Bolte, AC and Lukens, JR},
title = {Therapeutic VEGFC treatment provides protection against traumatic-brain-injury-driven tauopathy pathogenesis.},
journal = {Cell reports},
volume = {44},
number = {11},
pages = {116521},
doi = {10.1016/j.celrep.2025.116521},
pmid = {41205178},
issn = {2211-1247},
abstract = {Traumatic brain injury (TBI) increases one's risk of developing Alzheimer's disease and tauopathy. Yet, the mechanisms linking TBI to neurodegenerative disease remain poorly defined. Mounting recent evidence indicates that defects in brain lymphatic drainage contribute to multiple neurodegenerative diseases. Here, we investigated whether promoting brain lymphatic drainage recuperation following TBI via treatment with the lymphangiogenic factor vessel endothelial growth factor C (VEGFC) mitigates the ability of TBI to exacerbate tauopathy. In this study, we show that a single mild TBI leads to worsened neuropathology, brain macrophage activation, and neurodegeneration in the PS19 mouse model of tauopathy. Moreover, we find that viral-vector-based delivery of VEGFC into the meningeal compartment 24 h post-TBI ameliorates tau-mediated neurodegenerative disease pathogenesis. Findings from these studies offer new insights into how TBI leads to the development of tauopathy later in life and suggest that VEGFC-based treatments might offer a therapeutic strategy to limit tauopathy after sustaining a head injury.},
}

@article {pmid41205094,
year = {2025},
author = {Manzano, S and Maurino, J and Balasa, M and Piñol-Ripoll, G and Boada, M and Landete, L and Abellán, I and Berbel, Á and Espejo, B and Almagro, M and Rodrigo, J and Sánchez-Juan, P and García-Arcelay, E and Ballesteros, J},
title = {Psychometric Properties of the 7-Item Sense of Competence Questionnaire: Assessing Informal Caregivers' Self-Perceived Competence in Mild Cognitive Impairment.},
journal = {Neurology and therapy},
volume = {},
number = {},
pages = {},
pmid = {41205094},
issn = {2193-8253},
support = {ML44177//Roche/ ; },
abstract = {INTRODUCTION: Caregivers provide essential support to patients with mild cognitive impairment (MCI). However, limited research has been conducted to validate instruments that assess their self-perceived competence in caregiving. This study aimed to assess the psychometric properties of the 7-item Sense of Competence Questionnaire (S-SCQ) in informal caregivers of patients with MCI.

METHODS: A non-interventional, cross-sectional study was conducted in collaboration with the Spanish Confederation of Alzheimer's Disease, enrolling informal caregivers of patients with MCI. A non-parametric item response theory procedure (Mokken analysis) was performed to evaluate the S-SCQ's dimensional structure using scalability coefficients. Internal reliability was assessed using Cronbach's α. Concurrent validity was examined through Spearman's correlations between S-SCQ scores and measures of caregiver burden, psychological distress, resilience, and the caregiver-patient relationship.

RESULTS: A total of 196 caregivers were studied. Caregivers had a mean age of 63.5 (SD 13.1) years, and most (63%) were female. The care recipients had a mean age of 72.9 (7.0) years, with a mean disease duration of 2.9 (2.2) years. The mean S-SCQ score was 26.1 (6.1). The S-SCQ demonstrated strong unidimensionality (H = 0.52) and good internal reliability (Cronbach's α = 0.86). Higher S-SCQ scores (greater sense of competence) correlated with lower caregiver burden (ρ = - 0.63, p < 0.001), reduced anxiety and depressive symptoms (ρ = - 0.32, p < 0.001), stronger caregiver-patient relationship (ρ = 0.72, p < 0.001), and greater resilience (ρ = 0.34, p < 0.001).

CONCLUSIONS: The S-SCQ is a reliable tool for assessing self-perceived competence in informal caregivers of patients with MCI. Its integration into clinical and research settings may offer an opportunity to enhance the early detection of caregiver burden and facilitate timely, targeted interventions.},
}

@article {pmid41205072,
year = {2025},
author = {Sun, Y and Meng, D and Yu, H and Yin, G and Zhang, X and Yu, W and Liu, H and Jiang, W and Zhang, F},
title = {Genetic evidence for a causal relationship between 179 lipid species and cognitive function and alzheimer's disease: a bidirectional Mendelian randomization study.},
journal = {European archives of psychiatry and clinical neuroscience},
volume = {},
number = {},
pages = {},
pmid = {41205072},
issn = {1433-8491},
support = {No.81573945//National Natural Science Foundation of China/ ; No.ZR2021MH054//Natural Science Foundation of Shandong Province/ ; },
abstract = {The public health burden of cognitive decline escalates with population aging. While lipid species alterations are associated with cognitive function and Alzheimer's disease (AD), causal evidence remains limited. We applied two-sample Mendelian randomization (TSMR) and Bayesian-weighted MR (BWMR) to investigate the causal effects of lipid species on cognitive function and to assess the bidirectional causal relationships between lipid species and AD. We analyzed genome-wide association study (GWAS) data from large-scale cohorts: AD (East African Development Bank [EADB], N = 487,511); cognitive function (UK Biobank, N = 20,346); and lipid species (THL Biobank, N = 7,174). Analyses were conducted using multiple MR methods, including inverse variance weighting (IVW), BWMR, MR-Egger regression, and false discovery rate (FDR) correction. Sensitivity analyses-MR-Egger intercept test, MR-Pleiotropy Residual Sum and Outlier (MR-PRESSO), Cochran's Q test, and leave-one-out analysis-were conducted to evaluate horizontal pleiotropy and heterogeneity. TSMR results identified 51 lipid species with causal associations for cognitive function and AD, among which 27 showed protective effects. Conversely, AD was found to influence 17 lipid species, with 14 exhibiting negative effects. These genetically supported findings highlight potential lipid-related targets for preventive and therapeutic interventions aimed at combating cognitive decline.},
}

@article {pmid41205008,
year = {2025},
author = {Jana, K and Ghosh, S and Parua, P and Debnath, B and Halder, J and Sahoo, RK and Rai, VK and Pradhan, D and Dash, P and Das, C and Kar, B and Ghosh, G and Rath, G},
title = {Insights into the Versatile Role of Extracellular Vesicles in the Treatment of CNS Disorders.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {14},
pmid = {41205008},
issn = {1559-1182},
mesh = {Humans ; *Extracellular Vesicles/metabolism ; Animals ; *Central Nervous System Diseases/therapy/metabolism ; Drug Delivery Systems/methods ; Blood-Brain Barrier/metabolism ; },
abstract = {E xtracellular vesicles (EVs) are lipid bilayer-enclosed nanocarriers composed primarily of phospholipids and membrane proteins. They are released by cells into the surrounding extracellular environment and vary in size, composition, and biogenesis pathways. Beyond their natural role in intercellular communication, mediating the transfer of proteins, lipids, and nucleic acids (like mRNA and miRNA) between cells, EVs have emerged as a highly versatile and promising therapeutic platform for a range of challenging disorders, particularly those affecting the central nervous system (CNS) and various cancers. The CNS presents unique therapeutic challenges, notably the formidable blood-brain barrier (BBB), which restricts the entry of most conventional drugs. EVs, however, possess an inherent capacity to traverse this barrier, either naturally or through engineered modifications. This characteristic positions them as ideal nanocarriers for delivering therapeutic payloads such as neurotrophic factors, gene therapy constructs, or anti-inflammatory agents directly to target neural cells for conditions like Alzheimer's disease, Parkinson's disease, stroke recovery, multiple sclerosis, and even glioblastoma. Their biocompatibility and low immunogenicity further reduce systemic side effects, making them a safer alternative to synthetic delivery systems. This review outlines recent progress in extraction techniques using EVs for treating neurological disorders. It covers clinical applications in neurodegenerative, infectious diseases, inflammatory, genetic, and oncological diseases and highlights current limitations and considerations for advancing future research in this evolving field.},
}

Humans
*Extracellular Vesicles/metabolism
Animals
*Central Nervous System Diseases/therapy/metabolism
Drug Delivery Systems/methods
Blood-Brain Barrier/metabolism

@article {pmid41204969,
year = {2025},
author = {Phuong, HT and Tomas, RF and Akmese, C and Mijares, A and Gerstin, IM and Guo, S and Bell, LR and Ellwood, R and Yegorova, S and Ng, SK and Massey, G and Phillips, J and Melloni, A and Pletnikova, O and Lou, X and Clark, HB and Troncoso, JC and Hyman, BT and Prokop, S and Ranum, LPW and Nguyen, L},
title = {PolyGR-containing aggregates link with pathology and clinical features of Alzheimer's disease.},
journal = {Acta neuropathologica},
volume = {150},
number = {1},
pages = {49},
pmid = {41204969},
issn = {1432-0533},
mesh = {Humans ; *Alzheimer Disease/pathology/metabolism ; Male ; Female ; Aged ; Aged, 80 and over ; *Brain/pathology/metabolism ; tau Proteins/metabolism ; Plaque, Amyloid/pathology/metabolism ; Middle Aged ; Amyloid beta-Peptides/metabolism ; Protein Aggregates ; *Protein Aggregation, Pathological/pathology/metabolism ; Neurofibrillary Tangles/pathology/metabolism ; },
abstract = {Alzheimer's disease is the most common form of dementia; however, its molecular mechanisms are not fully understood. We recently identified polymeric glycine-arginine-containing (polyGR+) aggregates as a novel type of proteinopathy in AD autopsy brains. Here, we performed a comprehensive analysis to study if polyGR+ aggregates are associated with AD neuropathological changes (ADNC) and clinical features of AD cases. We show polyGR+ aggregates are detected in ~ 60% of AD postmortem brains from three AD cohorts but not age-similar controls or disease controls with primary age-related tauopathy (PART). A subtype of polyGR+ aggregates with a clustered-punctate morphology that is positive for the markers of dystrophic neurites is associated with earlier onset and shortened survival in AD cases. Increased levels of Aβ plaques and phosphorylated tau (pTau) tangles are detected in the hippocampus of AD autopsy brains with high levels of polyGR+ aggregates compared to AD autopsy brains with minimal polyGR+ staining. In addition to ADNC, a subset of polyGR+ aggregates coexists with limbic-predominant age-related TDP-43 encephalopathy neuropathological changes (LATE-NC) or Lewy body pathology (LBP). Hippocampal polyGR+ aggregate levels are ~ 3.8- and ~ 3.71-fold higher in late-onset AD cases who experienced stroke or high blood pressure, respectively. In SH-SY5Y cells, hydrogen peroxide treatment which mimics oxidative stress leads to increased levels of polyGR+ proteins produced by the CASP8 GGGAGA repeat expansion, which was recently shown to associate with increased AD risk. In addition, we show the accumulation of pTau induced by CASP8 polyGR+ protein aggregates is elevated upon hydrogen peroxide treatment. In summary, our results demonstrate polyGR+ aggregates are a frequent and understudied type of proteinopathy in AD autopsy brains and that polyGR proteinopathy is associated with ADNC.},
}

Humans
*Alzheimer Disease/pathology/metabolism
Male
Female
Aged
Aged, 80 and over
*Brain/pathology/metabolism
tau Proteins/metabolism
Plaque, Amyloid/pathology/metabolism
Middle Aged
Amyloid beta-Peptides/metabolism
Protein Aggregates
*Protein Aggregation, Pathological/pathology/metabolism
Neurofibrillary Tangles/pathology/metabolism

@article {pmid41204877,
year = {2025},
author = {Pini, L and Tuzzato, C and Griffa, A and Brusini, L and Cruciani, F and Allali, G and Corbetta, M and Menegaz, G and Boscolo Galazzo, I and , },
title = {Brain Connectivity Gradients Alterations in Discordant Cerebrospinal Fluid Profile for Alzheimer's Disease Biomarkers.},
journal = {Human brain mapping},
volume = {46},
number = {16},
pages = {e70406},
doi = {10.1002/hbm.70406},
pmid = {41204877},
issn = {1097-0193},
support = {IZSEZ0_229208//Swiss National Science Foundation (SNSF)/ ; 68076//Fondazione Cariparo/ ; //The Ministero della Salute Italiano/ ; RF-2018-1236689//NEUROCONN/ ; 101071900//HORIZON-ERC-SyG/ ; 101147319//HORIZON-INFRA-2022/ ; //MIUR D.M. 737/2021/ ; 202292PHR2//MUR PRIN 2022/ ; //Alzheimer's Disease Neuroimaging Initiative/ ; U01 AG024904/NH/NIH HHS/United States ; W81XWH-12-2-0012//DOD ADNI/ ; /AG/NIA NIH HHS/United States ; /EB/NIBIB NIH HHS/United States ; //AbbVie/ ; /ALZ/Alzheimer's Association/United States ; //Alzheimer's Drug Discovery Foundation/ ; //Araclon Biotech/ ; //BioClinica Inc./ ; //Biogen/ ; //Bristol-Myers Squibb Company/ ; //CereSpir Inc./ ; //Cogstate/ ; //Eisai Inc./ ; //Elan Pharmaceuticals Inc./ ; //Eli Lilly and Company/ ; //EuroImmun/ ; //F. Hoffmann-La Roche Ltd./ ; //Genentech Inc./ ; //Fujirebio/ ; //GE Healthcare/ ; //IXICO Ltd./ ; //Janssen Alzheimer Immunotherapy Research & Development LLC./ ; //Johnson & Johnson Pharmaceutical Research & Development LLC./ ; //Lumosity/ ; //Lundbeck/ ; //Merck & Co. Inc./ ; //Meso Scale Diagnostics LLC./ ; //NeuroRx Research/ ; //Neurotrack Technologies/ ; //Novartis Pharmaceuticals Corporation/ ; //Pfizer Inc./ ; //Piramal Imaging/ ; //Servier/ ; //Takeda Pharmaceutical Company/ ; //Transition Therapeutics/ ; /CAPMC/CIHR/Canada ; //Foundation for the National Institutes of Health/ ; //Northern California Institute for Research and Education/ ; },
mesh = {Humans ; *Alzheimer Disease/cerebrospinal fluid/diagnostic imaging/physiopathology/pathology ; Male ; Female ; *tau Proteins/cerebrospinal fluid ; *Amyloid beta-Peptides/cerebrospinal fluid ; Aged ; Biomarkers/cerebrospinal fluid ; Magnetic Resonance Imaging ; *Peptide Fragments/cerebrospinal fluid ; *Brain/diagnostic imaging/physiopathology ; *Connectome ; Aged, 80 and over ; Middle Aged ; *Nerve Net/diagnostic imaging/physiopathology ; *Cognitive Dysfunction/cerebrospinal fluid/physiopathology/diagnostic imaging ; Diffusion Magnetic Resonance Imaging ; },
abstract = {Alzheimer's disease (AD) is a heterogeneous disorder characterized by brain accumulation of amyloid-beta (Aß, simplified as A for the AD biological model) and tau (T) proteins, with Aß emerging first. However, a significant proportion of individuals exhibit discordant biomarkers' profiles, such as elevated phosphorylated tau181 (p-tau181) with normal Aß42 from cerebrospinal fluid (CSF), posing diagnostic and mechanistic challenges. This study investigated whether functional and structural brain connectivity can distinguish individuals with discordant CSF profiles (A-T+) from those with concordant patterns (A+T+), hypothesizing that distinct connectivity patterns may reflect early divergent pathophysiological processes. Data from cognitively unimpaired or mildly impaired individuals in the ADNI3 repository were analyzed, selecting those with resting-state functional MRI (rsfMRI) and/or diffusion MRI (dMRI) within 18 months of CSF testing for Aß and p-tau181. Participants were grouped into A-T+ or A+T+ groups. Structural and functional connectivity gradients were generated for each participant and summarized using a Euclidean distance measure from reference gradient templates derived from cognitively unimpaired individuals without pathology (A-T-). We applied linear mixed models and analysis of variance to assess connectivity-based gradient differences between A-T+ and A+T+ groups, adjusting for relevant variables. Classification analyzes using logistic regression and support vector machine, along with feature importance via the Boruta algorithm, evaluated the discriminative power of gradient connectivity profiles. Multimodal integration was performed using partial least square canonical analysis (PLSC), and relationships between gradients and cognition were assessed via UMAP-based dimensionality reduction and bootstrapped linear regressions. Results were compared with a classical network analysis examining within- and between-network connectivity differences. Among 424 participants, n = 67 were classified as A-T+, n = 106 as A+T+, and n = 56 as cognitively healthy A-T-. The remaining 195 participants (n = 86 A+T+ and n = 109 cognitively impaired A-T-) were not included. A-T+ individuals (age = 75 ± 8.2) exhibited less cognitive impairment but greater functional connectivity gradients' distance to the reference templates (false discovery rate-corrected p < 0.05) in the temporo-occipital axis compared to A+T+ (age = 76.1 ± 7.7). Structural connectivity differences were not significant. FC-based models classified A-T+ and A+T+ with good accuracy (AUC = 0.77), loading on the same temporo-occipital regions, unlike SC (AUC = 0.52). The posterior brain involvement in A-T+ was confirmed by PLSC analyzes. A+T+ individuals showed a significant relation between cognitive scores and functional connectivity, primarily mapping the default mode network (DMN). A shift was observed in relation to executive functions and functional connectivity in A-T+. Discordant CSF profiles (A-T+) exhibit distinct functional connectivity patterns, particularly in posterior brain regions, compared to concordant CSF patterns (A+T+), which are characterized by a significant cognitive-DMN connectivity association. These results suggest that CSF p-tau181 accumulation in the absence of Aß42 may be associated with specific functional trajectories, suggesting specific pathophysiological patterns.},
}

Humans
*Alzheimer Disease/cerebrospinal fluid/diagnostic imaging/physiopathology/pathology
Male
Female
*tau Proteins/cerebrospinal fluid
*Amyloid beta-Peptides/cerebrospinal fluid
Aged
Biomarkers/cerebrospinal fluid
Magnetic Resonance Imaging
*Peptide Fragments/cerebrospinal fluid
*Brain/diagnostic imaging/physiopathology
*Connectome
Aged, 80 and over
Middle Aged
*Nerve Net/diagnostic imaging/physiopathology
*Cognitive Dysfunction/cerebrospinal fluid/physiopathology/diagnostic imaging
Diffusion Magnetic Resonance Imaging

@article {pmid41204697,
year = {2025},
author = {Fu, J and Huang, T and Li, G and Zhang, X and Tan, L and Zhu, C and Zhang, W and Zhang, W},
title = {Toxicological Perspectives on RNA m1A Methylation: Biological Processes and Pathological Consequences.},
journal = {Journal of applied toxicology : JAT},
volume = {},
number = {},
pages = {},
doi = {10.1002/jat.4981},
pmid = {41204697},
issn = {1099-1263},
support = {2023A1515010353//Natural Science Foundation of Guangdong Province of China/ ; 2025A1515012372//Natural Science Foundation of Guangdong Province of China/ ; （R2022PY-QY004）//Special Fund for Scientific Innovation Strategy-Construction of High-level Academy of Agriculture Science/ ; 2023B1212060038//Science and Technology Plan Project of Guangdong Province/ ; },
abstract = {RNA N1-methyladenosine (m1A) methylation is dynamically regulated by methyltransferases (TRMT6/61/61B/10C), demethylases (ALKBH1/3), and binding proteins (YTHDF1/2/3), which collectively fine-tune gene expression through site-specific modifications. Exogenous environmental factors such as persistent organic pollutants, heavy metals, and radiation can trigger cellular oxidative stress and stimulate the secretion of reactive oxygen species and senescence-associated secretory phenotypes. The concurrent accumulation of these damaging agents, along with dysregulation of intracellular conditions including temperature, pH, and divalent metal ion concentrations under pathological states, disrupts m1A methylation and alters the expression of associated genes, ultimately leading to adverse cellular outcomes. In addition, we searched a large number of literature and found that m1A methylation exhibits elevated levels in neurodegeneration, ischemia-reperfusion injury, and hepatocellular and bladder cancer, whereas decreased levels are observed in Alzheimer's disease and myocardial infarction. Correspondingly, methyltransferases and binding proteins involved in m1A modification are generally upregulated across multiple disease contexts. We propose that m1A methylation serves as a molecular sensor for environmental-cell interactions, dynamically regulating gene expression through regulators and exerting bidirectional control in disease processes. Given its regulatory versatility, m1A modification holds promise for applications in toxicological risk assessment, precision medicine, and the development of targeted therapies against exogenous factor-induced pathologies.},
}

@article {pmid41204665,
year = {2025},
author = {Pallbo, J and Linse, S and Olsson, U},
title = {Does amyloid fibril nucleation occur at surfaces only?.},
journal = {Biophysical journal},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.bpj.2025.11.002},
pmid = {41204665},
issn = {1542-0086},
abstract = {The Aβ42 peptide (APP(672-713)), associated with Alzheimer's disease, is highly prone to form amyloid fibrils and has been extensively studied through in vitro experiments. Such experiments represent a basis for understanding the biophysical chemistry of amyloid-related diseases. In this communication we show that homogeneous primary nucleation in vitro of Aβ42 fibrils is a very rare event, implying that primary nucleation occurs almost exclusively at interfaces, by heterogeneous nucleation. Recognizing that the protein molecules in amyloid fibrils possess a two-dimensional fold, we discuss the nucleation in relation to protein folding and Levinthal's paradox. In the much more rapid heterogeneous nucleation, we suggest that one catalyzing effect is the significant reduction of the effective conformational space when a monomer polypeptide chain (strongly) adsorbs to a surface, facilitating its search for the target fold.},
}

@article {pmid41204331,
year = {2025},
author = {Choe, K and Ahmad, R and Kang, MH and Lee, HJ and Ahmad, S and Park, TJ and Kim, MO},
title = {The novel sphingolipids cP1P and P1P attenuate neuroinflammation and enhance S1PR1/Akt/mTOR signaling to mitigate cognitive decline in an Alzheimer's disease mouse model.},
journal = {Cell communication and signaling : CCS},
volume = {23},
number = {1},
pages = {482},
pmid = {41204331},
issn = {1478-811X},
support = {RS-2024-00441331//National Research Foundation of Korea/ ; },
mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism/pathology/complications ; Male ; *Sphingosine-1-Phosphate Receptors/metabolism ; Mice ; Disease Models, Animal ; *Cognitive Dysfunction/drug therapy/metabolism/pathology ; *Proto-Oncogene Proteins c-akt/metabolism ; *Signal Transduction/drug effects ; *TOR Serine-Threonine Kinases/metabolism ; *Sphingolipids/pharmacology/therapeutic use ; Mice, Inbred C57BL ; Amyloid beta-Peptides ; *Neuroinflammatory Diseases/drug therapy/pathology/metabolism ; Sphingosine/analogs & derivatives/pharmacology ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is the leading cause of dementia, characterized by the accumulation of amyloid-βeta (Aβ) peptides and hyperphosphorylated tau protein. Altered sphingosine 1-phosphate (S1P) metabolism is associated with abnormal Aβ peptide accumulation in the brain. S1P receptors are increasingly being targeted for modulating the neuroinflammatory process in AD.

METHODS: Wild-type male C57BL/6J mice were administered Aβ to induce the pathological state. The study included four experimental groups: (1) Control group (saline-treated), (2) Aβ group (Aβ + saline-treated), (3) Aβ + cP1P group (Aβ + cP1P at doses of 0.1 mg/kg and 1 mg/kg), and (4) Aβ+ P1P group (Aβ + P1P at doses of 0.1 mg/kg and 1 mg/kg). Behavioral experiments were conducted to assess cognitive and memory functions. Additionally, western blotting and confocal microscopy were performed to investigate molecular and cellular changes.

RESULTS: The findings demonstrate that administration of S1P analogs cP1P and P1P at 0.1 mg/kg and 1 mg/kg significantly reduced Aβ burden by inhibiting the amyloidogenic pathway and decreasing hyperphosphorylated tau protein levels in the mouse brain. Additionally, cP1P and P1P inhibited glial cell activation, as indicated by reduced GFAP and Iba-1 expression, and modulated neuroinflammatory markers, including p-NF-κB, TNF-α, and IL-1β. Furthermore, they regulated S1PR1-mediated Akt/mTOR signaling while preserving mitochondrial function by decreasing the expression levels of p-JNK, Caspase-3, and PARP-1. Moreover, the cP1P and P1P effectively restored synaptic markers such as PSD-95, SNAP-25, and Syntaxin, and significantly improved behavioral outcomes in the Aβ-treated mice. In vitro, results also demonstrated that the novel cP1P and P1P enhanced cell viability against Aβ toxicity.},
}

Animals
*Alzheimer Disease/drug therapy/metabolism/pathology/complications
Male
*Sphingosine-1-Phosphate Receptors/metabolism
Mice
Disease Models, Animal
*Cognitive Dysfunction/drug therapy/metabolism/pathology
*Proto-Oncogene Proteins c-akt/metabolism
*Signal Transduction/drug effects
*TOR Serine-Threonine Kinases/metabolism
*Sphingolipids/pharmacology/therapeutic use
Mice, Inbred C57BL
Amyloid beta-Peptides
*Neuroinflammatory Diseases/drug therapy/pathology/metabolism
Sphingosine/analogs & derivatives/pharmacology

@article {pmid41204243,
year = {2025},
author = {Schechter, M and Fishkin, A and Mosenzon, O and Sehtman-Shachar, DR and Cukierman-Yaffe, T and Leibowitz, G and Aharon-Hananel, G},
title = {Neurodegeneration onset with glucagon-like peptide-1 receptor agonists in people with type 2 diabetes: a real-world multinational cohort study.},
journal = {Cardiovascular diabetology},
volume = {24},
number = {1},
pages = {426},
pmid = {41204243},
issn = {1475-2840},
mesh = {Humans ; Female ; Male ; *Diabetes Mellitus, Type 2/drug therapy/diagnosis/epidemiology/blood ; *Glucagon-Like Peptide-1 Receptor Agonists ; Retrospective Studies ; Middle Aged ; Aged ; *Neurodegenerative Diseases/epidemiology/diagnosis/prevention & control ; Risk Factors ; *Dipeptidyl-Peptidase IV Inhibitors/therapeutic use/adverse effects ; *Incretins/therapeutic use/adverse effects ; Time Factors ; Treatment Outcome ; Risk Assessment ; Biomarkers/blood ; *Blood Glucose/drug effects/metabolism ; *Hypoglycemic Agents/therapeutic use/adverse effects ; Electronic Health Records ; Glucagon-Like Peptide-1 Receptor ; },
abstract = {BACKGROUND: Type 2 diabetes (T2D), affecting approximately 12% of the global population and over 30% of older adults, is among the most prevalent and fast-growing risk factors for neurodegenerative disorders. Evidence is lacking on whether specific glucose-lowering agents may reduce the risk of neurodegeneration onset in people living with T2D.

METHODS: In this retrospective cohort study, we utilized the TriNetX platform, which contains electronic health records of over 170 million people worldwide. We propensity-score matched (1:1) people with T2D lacking evidence of neurodegeneration who initiated glucagon-like peptide-1 receptor agonists (GLP-1 RAs) or dipeptidyl peptidase-4 inhibitors (DPP4i) (2010-2021). In a separate analytical cohort, we compared individuals initiating GLP-1 RA with those initiating basal insulin. Follow-up continued for ≤ 5 years. We used Cox proportional-hazard regression models to assess the risk of the composite outcome of developing new neurodegenerative conditions, including Alzheimer's disease, Parkinson's disease, dementia subtypes, and other synucleinopathies. We also assessed each component individually. Analyses were repeated among subgroups defined by sex, age, and the specific GLP-1 RA initiated.

RESULTS: Overall, 214,442 matched individuals initiated GLP-1 RAs or DPP4i (109,731 women, mean age 58.6 years [SD 12], and mean HbA1c 7.7% [1.4]). During a 4.0-year mean follow-up, neurodegenerative disorder onset occurred in 2,393 (2.2%) and 3,062 (2.9%) people initiating GLP-1 RAs and DPP4i, respectively (hazard ratio of 0.81 [95% CI 0.77 to 0.86]; absolute risk difference - 0.6% [- 0.8 to - 0.5]). The associations were separately observed among women (0.78 [0.72 to 0.84]) and men (0.90 [0.83 to 0.98]), individuals aged ≥ 65 years old (0.82 [0.78 to 0.87]) or < 65 years old (0.84 [0.70 to 1.00]), and in those initiating semaglutide (0.75 [0.67 to 0.84]), liraglutide (0.77 [0.70 to 0.84]), or dulaglutide (0.82 [0.77 to 0.88]). The hazard ratios for dementia, Alzheimer's disease, vascular dementia, and Parkinson's disease onset were 0.76 [0.72 to 0.81], 0.77 [0.68 to 0.87], 0.75 [0.67 to 0.85], and 1.04 [0.93 to 1.17] with GLP-1 RAs versus DPP4i, respectively. The results were in the same direction when comparing individuals initiating GLP-1 RAs with those initiating basal insulin.

CONCLUSIONS: In a real-world cohort of people living with T2D with a multinational representation, the initiation of GLP-1 RAs, compared to DPP4i or basal insulin, was associated with a lower risk of new-onset neurodegeneration. These data support the rationale for dedicated clinical trials to assess the potential neuroprotective properties of GLP-1 RAs in this population.},
}

Humans
Female
Male
*Diabetes Mellitus, Type 2/drug therapy/diagnosis/epidemiology/blood
*Glucagon-Like Peptide-1 Receptor Agonists
Retrospective Studies
Middle Aged
Aged
*Neurodegenerative Diseases/epidemiology/diagnosis/prevention & control
Risk Factors
*Dipeptidyl-Peptidase IV Inhibitors/therapeutic use/adverse effects
*Incretins/therapeutic use/adverse effects
Time Factors
Treatment Outcome
Risk Assessment
Biomarkers/blood
*Blood Glucose/drug effects/metabolism
*Hypoglycemic Agents/therapeutic use/adverse effects
Electronic Health Records
Glucagon-Like Peptide-1 Receptor

@article {pmid41204236,
year = {2025},
author = {Li, L and Yang, H and Yu, L and Zhou, Y and Xiao, S and Bian, G and Zhu, F},
title = {The independent association of social isolation and loneliness with cognitive frailty in Chinese older adults: a cross-sectional study.},
journal = {BMC public health},
volume = {25},
number = {1},
pages = {3860},
pmid = {41204236},
issn = {1471-2458},
support = {2024J367//General Program of Ningbo Municipal Natural Science Foundation/ ; PPXK2024-07//Ningbo Medical and Health Brand Discipline/ ; 2022-F28//Ningbo Medical & Health Leading Academic Discipline Project/ ; 2022030410//Ningbo Top Medical and Health Research Program/ ; 2022030410//Ningbo Top Medical and Health Research Program/ ; },
mesh = {Humans ; *Loneliness/psychology ; *Social Isolation/psychology ; Aged ; Female ; Male ; Cross-Sectional Studies ; China/epidemiology ; *Frail Elderly/statistics & numerical data/psychology ; Aged, 80 and over ; *Frailty/epidemiology ; *Cognitive Dysfunction/epidemiology ; Surveys and Questionnaires ; Risk Factors ; East Asian People ; },
abstract = {BACKGROUND: Cognitive frailty (CF) is a distinct clinical phenotype characterized by the co-occurrence of physical frailty and cognitive impairment (excluding Alzheimer's disease and other forms of dementia). Both of social isolation and loneliness are risk factors for cognitive frailty in older adults. However, limited research has explored their independent and combined associations with CF.

METHODS: A multi-stage cluster sampling approach was employed to recruit adults aged ≥ 65 years from communities in Ningbo. Basic demographic and health-related information was collected through face-to-face interviews using self-reported questionnaires. CF was defined as the co-occurrence of physical frailty, assessed using the FRAIL scale, and cognitive impairment, evaluated with the Brief Screening Scale for Dementia. Social isolation and loneliness were assessed using standardized questions. Logistic regression was employed to examine their associations with CF, and multiplicative and additive interactions were analyzed to assess potential interaction effects.

RESULTS: Overall, 10,151 older adults with a mean age of 72.83 years were included in our study. The prevalence of social isolation, loneliness and CF were 32.3%, 11.8% and 7.22%. After adjusting for covariates, social isolation (odds ratio [OR] = 1.325, 95% confidence interval [CI]: 1.106-1.586) and loneliness (OR = 1.492, 95% CI: 1.196-1.862) were independently associated with CF. However, social isolation and loneliness showed no multiplicative or additive interaction effects on CF (Both P > 0.05).

CONCLUSION: Social isolation and loneliness are independently associated with CF in Chinese older adults, highlighting the necessity of implementing effective and feasible interventions to concurrently address both factors in the prevention of CF among the elderly population.},
}

Humans
*Loneliness/psychology
*Social Isolation/psychology
Aged
Female
Male
Cross-Sectional Studies
China/epidemiology
*Frail Elderly/statistics & numerical data/psychology
Aged, 80 and over
*Frailty/epidemiology
*Cognitive Dysfunction/epidemiology
Surveys and Questionnaires
Risk Factors
East Asian People

@article {pmid41204210,
year = {2025},
author = {Afxenti, S and Zachariou, M and Athieniti, E and Lambrianides, A and Pantzaris, M and Spyrou, GM},
title = {Integrating imaging and omics for enhanced subtyping of mild cognitive impairment associated with Alzheimer's disease.},
journal = {Journal of translational medicine},
volume = {23},
number = {1},
pages = {1240},
pmid = {41204210},
issn = {1479-5876},
support = {This research was supported by the Muscular Dystrophy Association Cyprus/Telethon Cyprus.//This research was supported by the Muscular Dystrophy Association Cyprus/Telethon Cyprus./ ; },
mesh = {Humans ; *Cognitive Dysfunction/diagnostic imaging/complications/classification ; *Alzheimer Disease/diagnostic imaging/complications/cerebrospinal fluid ; Male ; *Neuroimaging ; Female ; Aged ; Magnetic Resonance Imaging ; *Proteomics ; Biomarkers/metabolism ; Cluster Analysis ; },
abstract = {BACKGROUND: Mild Cognitive Impairment (MCI), considered the prodromal stage of Alzheimer's disease (AD), is a heterogeneous condition characterised by mild but measurable cognitive decline. However, not all individuals with MCI follow the same trajectory-some remain stable, while others progress rapidly to AD. Understanding variation in clinical, molecular, and imaging features is crucial for reducing disease heterogeneity, improving prognosis, and developing targeted interventions. This study aims to increase MCI subtyping resolution by generating enriched individual-level profiles through the integration of imaging and omics data, facilitating precision medicine approaches for AD prevention and treatment.

METHODS: We used data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), including structural MRI, CSF peptidomics/proteomics, and clinical indices. Using a multi-modal integration and clustering framework, we identified distinct MCI subgroups, characterised by clinical and neuropsychological scores, AD biomarkers, biological pathway enrichments, and imaging patterns. We further employed supervised multi-modal integration and correlation analyses to explore the links between imaging, peptidomic/proteomic and clinical features within each subgroup. Additionally, we labelled individuals by future conversion to AD and analysed longitudinal cognitive function (CDRSB and MMSE scores). Finally, we performed in silico drug repurposing to identify candidate drugs targeting each subgroup's molecular profile.

RESULTS: (1) Multi-modal integration revealed two distinct MCI subgroups. (2) The Resilient Neuronal Hyperplasticity subgroup was characterised by elevated markers of neuronal plasticity, minimal brain atrophy and cortical thinning, better clinical scores, and upregulated peptide/protein markers associated with less severe structural changes. In contrast, the Vulnerable Neurodegenerative subgroup exhibited AD-like disturbances, pronounced atrophy and cortical thinning, primarily affecting executive functions, and downregulation of peptide/protein markers linked to significant structural changes. (3) Future conversion analysis revealed the second subgroup predominantly comprised fast converters, while the first predominantly consisted of stable individuals. (4) Longitudinal cognitive analysis showed a more pronounced decline in the second subgroup compared to the first. (5) Drug repurposing identified both shared and subgroup-specific candidate compounds aligned with the underlying pathologies.

CONCLUSIONS: This study delineates two MCI subgroups, using multi-modal integration, offering insights into disease heterogeneity and laying the foundation for precision medicine and AI-driven strategies in MCI and AD research and clinical care.},
}

Humans
*Cognitive Dysfunction/diagnostic imaging/complications/classification
*Alzheimer Disease/diagnostic imaging/complications/cerebrospinal fluid
Male
*Neuroimaging
Female
Aged
Magnetic Resonance Imaging
*Proteomics
Biomarkers/metabolism
Cluster Analysis

@article {pmid41203949,
year = {2025},
author = {Feng, X and Zhao, X and Zhang, L},
title = {Innovative D-peptide strategy for targeting tau fibrils in Alzheimer's disease.},
journal = {Science China. Life sciences},
volume = {},
number = {},
pages = {},
pmid = {41203949},
issn = {1869-1889},
}

@article {pmid41203876,
year = {2025},
author = {Chirmade, S and Wang, Z and Mastromatteo, S and Sanders, E and Thiruvahindrapuram, B and Nalpathamkalam, T and Pellecchia, G and Lin, F and Keenan, K and Patel, RV and Sung, WW and Roshandel, D and Whitney, J and Allana, S and Avolio, J and Eckford, PD and Ratjen, F and Strug, LJ},
title = {GWAS SVatalog: a visualization tool to aid fine-mapping of GWAS loci with structural variations.},
journal = {Heredity},
volume = {},
number = {},
pages = {},
pmid = {41203876},
issn = {1365-2540},
abstract = {Genome-wide association studies (GWAS) have been successful in identifying single nucleotide polymorphisms (SNPs) associated with phenotypic traits. However, SNPs form an incomplete set of variation across the genome and since a large percentage of GWAS-significant SNPs lie in non-coding regions, their impact on a given trait is difficult to decipher. Recognizing whether these SNPs are tagging other polymorphisms, like structural variations (SV), is an important step towards understanding the putative causal variation at GWAS loci. Here, we develop GWAS SVatalog (https://svatalog.research.sickkids.ca/), a novel open-source web tool that computes and visualizes linkage disequilibrium (LD) between SVs and GWAS-associated SNPs throughout the human genome. The tool combines GWAS Catalog's SNP-trait association data across 14,479 phenotypes with LD statistics calculated between 35,732 SVs and 116,870 SNPs identified in 101 whole-genome long-read sequences. We show that different SV types are more likely to overlap regulatory features, and that SVs less directly tagged by GWAS-associated SNPs more frequently overlap CpG islands and promoters. We use GWAS SVatalog to identify SVs that may explain GWAS loci for iron levels, refractive error, and Alzheimer's disease, where previously SNPs were unable to provide a causal explanation. GWAS SVatalog advances the fine-mapping of GWAS loci with structural variations, enabling researchers to associate 35,732 common SVs with 14,479 phenotypes, accelerating the understanding of disease etiology.},
}

@article {pmid41203507,
year = {2025},
author = {Zhang, YP and Kedia, S and Klenerman, D},
title = {Rethinking neurodegeneration through a co-proteinopathy lens.},
journal = {Trends in neurosciences},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.tins.2025.10.006},
pmid = {41203507},
issn = {1878-108X},
abstract = {Neurodegenerative diseases have long been considered distinct proteinopathies: amyloid-β and tau in Alzheimer's disease, α-synuclein in Parkinson's disease, and TDP-43 in amyotrophic lateral sclerosis. This single-protein paradigm has guided therapeutic development for decades; yet clinical outcomes remain modest. Mounting evidence, however, reveals that protein aggregates rarely occur in isolation; instead, they coexist, colocalise, and modulate each other's pathogenicity. Here, we propose a co-proteinopathy framework that views neurodegeneration as an interactive network of misfolded proteins rather than as isolated disorders. Adopting this framework demands multiplexed quantification of protein aggregates and disease models that better reflect the biological complexity of human neurodegeneration. The co-proteinopathy perspective offers a more realistic foundation for next-generation approaches to neurodegeneration research and treatment.},
}

@article {pmid41202963,
year = {2025},
author = {Padhy, DS and Dhanve, P and Chaturvedi, K and Banerjee, S},
title = {Ambroxol rescues cognitive impairment by ameliorating oxidative stress and autophagic dysfunction in the streptozotocin-induced Alzheimer's disease model.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {178334},
doi = {10.1016/j.ejphar.2025.178334},
pmid = {41202963},
issn = {1879-0712},
abstract = {Alzheimer's disease (AD) is the most prevalent neurodegenerative disease, contributing to the majority of dementia cases worldwide. Due to its multifaceted and complex pathogenesis, drugs that completely halt the disease progression are still elusive. Several reports suggest that repurposing a clinically approved drug could be an excellent strategy to tackle this devastating disease. Ambroxol, a US-FDA and EMA-approved generic mucolytic drug, possess ameliorative action on various neurological ailments. However, its role as a disease-modifying drug targeting AD is yet to be studied. In this study, we elucidate the therapeutic potential of ambroxol in the streptozotocin (STZ)-induced AD model by assessing the behavioural, biochemical, and histological parameters. Intracerebroventricular (ICV) administration of STZ (3 mg/kg) was performed to mimic the AD pathology in rats. Ambroxol was administered (p.o.) at doses of 500 and 1000 mg/kg for three weeks. On day 21, behavioural tests, including the Y-maze test, novel object recognition test, and passive avoidance test, were performed to assess memory function. Subsequently, the animals were euthanised and the hippocampus was collected for biochemical, molecular and histological analysis. Three weeks of ambroxol treatment improved the cognitive performance in ICV-STZ-treated rats. Ambroxol treatment reduces oxidative stress by upregulating heme oxygenase-1 (HO-1) and lowering inducible nitric oxide synthase (iNOS) levels in the hippocampus of diseased rats. It also attenuates inflammatory and autophagic dysfunction, facilitating the clearance of amyloid beta (Aβ) aggregates in the hippocampus of ICV-STZ rats. The findings of this study suggest that ambroxol could be a viable repurposed drug candidate for AD treatment.},
}

@article {pmid41202949,
year = {2025},
author = {Prešern, U and Goličnik, M and Bavec, A},
title = {Genetic and functional dynamics of Butyrylcholinesterase in Alzheimer's disease: From mechanisms to clinical relevance.},
journal = {Chemico-biological interactions},
volume = {423},
number = {},
pages = {111809},
doi = {10.1016/j.cbi.2025.111809},
pmid = {41202949},
issn = {1872-7786},
abstract = {Butyrylcholinesterase (BChE), once regarded as a redundant cholinesterase, has emerged as an important modulator of Alzheimer's disease (AD). Unlike acetylcholinesterase (AChE), which declines during disease progression, BChE activity is preserved or elevated in the AD brain and becomes the predominant cholinesterase in advanced stages. Beyond its enzymatic role in acetylcholine hydrolysis, BChE is directly associated with amyloid plaques and tau pathology and has been implicated in neuroinflammatory processes. Genetic variants of the BCHE gene, most notably the K-variant, further contribute to inter-individual differences in AD susceptibility, disease onset, and therapeutic response, particularly in the context of APOE4. Evidence from biochemical, histological, and clinical studies indicates that BChE influences both the pathophysiology of AD and the effectiveness of cholinesterase inhibitor therapy, with rivastigmine providing unique benefits through dual AChE and BChE inhibition. Recent efforts to develop selective or multitarget BChE inhibitors underscore the enzyme's potential as a therapeutic target, while BChE-specific positron emission tomography tracers highlight its diagnostic promise by distinguishing AD-related amyloid plaques from those of normal aging. Despite these advances, uncertainties remain regarding the precise dynamics of BChE activity across disease stages, its contribution to plaque maturation and inflammation, and its influence on responses to novel anti-amyloid antibody therapies. Overall, BChE represents a multifaceted factor in AD pathogenesis, therapy, and biomarker development, warranting further genotype-stratified and mechanistic investigations to clarify its clinical utility.},
}

@article {pmid41202930,
year = {2025},
author = {Dong, W and Bai, J and Wu, B and Zhou, K and Jiang, H},
title = {Incidence and synergistic Association of Type 2 diabetes and apolipoprotein E epsilon 4 with dementia risk in the Kunshan aging research with E-health cohort study.},
journal = {Preventive medicine},
volume = {},
number = {},
pages = {108439},
doi = {10.1016/j.ypmed.2025.108439},
pmid = {41202930},
issn = {1096-0260},
abstract = {OBJECTIVE: To investigate the independent and combined associations of type 2 diabetes (T2D) and APOE genotype on dementia risk.

METHODS: We analyzed 104,911 participants aged ≥50 years from the Kunshan Aging Research with E-Health cohort (2018-2024). Incident dementia was identified using electronic medical records. Cox proportional hazards models and additive interaction analyses assessed associations and interactions.

RESULTS: Over a median follow-up of 6.19 years, 8115 participants developed dementia. T2D was associated with higher risks of all-cause dementia (HR:2.06), Alzheimer's disease (HR:2.16), and vascular dementia (HR:1.62). APOE ε4 carriers had higher Alzheimer's risk (HR:1.35), while ε2 carriers had lower risk (HR:0.87). The combination of T2D and ε4 was associated with the highest Alzheimer's risk (HR:2.87) with a significant positive additive interaction. In men, T2D interacted with ε2 on a multiplicative scale, whereas in women, a positive additive interaction was observed between T2D and ε2 for Alzheimer's disease.

CONCLUSIONS: T2D was associated with higher dementia risk. APOE ε4 was associated with higher and ε2 with lower Alzheimer's risk. A positive additive T2D-ε4 interaction and sex-specific ε2 associations underscore integrating diabetes management with genetic profiling to optimize dementia risk reduction strategies.},
}

@article {pmid41202895,
year = {2025},
author = {Gupta, G and Ali, H and Singh, SK and Dua, K and Jha, SK},
title = {Exploring the Causal Relationship between Telomere Regulation, Aging and Neurological Disorders.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {102930},
doi = {10.1016/j.arr.2025.102930},
pmid = {41202895},
issn = {1872-9649},
abstract = {Telomere biology is important for aging and is the cause of the pathogenesis of many neurological disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), stroke, and brain tumors. Telomere shortening is considered to play a role in neurodegeneration, immune senescence, and cerebrovascular dysfunction. Shorter leukocyte telomere length (LTL) is associated with increased risk and severity of stroke, poorer cognitive outcomes in AD, and increased neuroinflammation in MS, highlighting a possible biomarker for disease progression. Glioblastoma and medulloblastoma are characterized as adult and childhoodd neoplasms,respectively; however they aree similarinn terms of telomere regulatio,nwhicht allows malignant growth. However, disease pathophysiology has been associated with telomere dynamics, oxidative stress, and neuroinflammation, but the causal association between telomere attrition and neurological disorders is still unclear. In studies of Mendelian randomization, neurodegenerative diseases have been associated with telomere length regulation in addition to telomere attrition. Approaches to target telomeres include telomerase activators for neuroprotection, telomerase inhibitors, and ALT-directed therapies for brain tumors. These telomere-derived biomarkers should be further refined, and their mechanistic links to the acceleration of neurodegeneration should be determined. Telomere-modifying therapies should be balanced to optimize benefits with minimal oncogenic risks. This review explores the causal relationship between telomere biology, aging, and neurological disorders, indicating novel therapeutic strategies and future directions in telomere research.},
}

@article {pmid41202775,
year = {2025},
author = {Long, X and Zhang, Z and Wen, S and Mo, L and Lin, J and Xu, M and , },
title = {Longitudinal trajectories of neuropsychological functions of MCI subtypes in population-based cohort of older adults.},
journal = {Asian journal of psychiatry},
volume = {114},
number = {},
pages = {104757},
doi = {10.1016/j.ajp.2025.104757},
pmid = {41202775},
issn = {1876-2026},
abstract = {OBJECTIVES: To identify different mild cognitive impairment (MCI) subtypes depending on overall cognitive function and daily function, and then describe the complex changes of neuropsychological functions in MCI subtypes over time.

METHODS: 815 MCI participants were recruited from the Alzheimer's Disease Neuroimaging Initiative (ADNI) at baseline. Data-driven MCI subtypes were obtained on the basis of group-based multi-trajectory modeling (GBMTM) to analyze longitudinal trajectory changes in overall cognitive function and daily function. Neuropsychological functions were characterized in terms of longitudinal trajectory changes by linear mixed models.

RESULTS: This study included MCI subjects with an average age of 73.71 ± 6.85 years (range: 60-91 years), of whom 77.7 % were married. Three data-driven subtypes of MCI were obtained through the GBMTM modeling, defined as the "Rapid cognitive decline group" (RCD, 15.5 %), the "Slow cognitive decline group" (SCD, 34.4 %), and the "No cognitive decline group" (NCD, 50.1 %). The RCD individuals had the greatest mean age (75.22 years) at baseline, the most APOE ε4 carriage (66.4 %), the highest dementia conversion rates (89.6 %) and the shortest time to dementia progression (10.41 months). Importantly, the fastest changes in neuropsychological function trajectories were observed in the RCD subtype during the first 36 months, with attention declining the fastest, followed by visuospatial function, whereas the slowest changes were detected in the NCD subtype.

CONCLUSION: MCI subjects may produce finer-grained cognitive subtypes with unique longitudinal neuropsychological function declines. Identifying the above may improve prediction of clinical course, which has important implications for providing more accurate risk assessment for MCI individuals.},
}

@article {pmid41202483,
year = {2025},
author = {Yuan, C and Li, L and Lin, HY and Aubry, AV and Parise, LF and Morel, C and Chen, F and Wong, J and Russo, SJ and Wang, J},
title = {Targeting neuronal activity and neuroinflammation for the treatment of Alzheimer's disease in a mouse model.},
journal = {Neurobiology of aging},
volume = {157},
number = {},
pages = {111-118},
doi = {10.1016/j.neurobiolaging.2025.10.006},
pmid = {41202483},
issn = {1558-1497},
abstract = {Alzheimer's disease (AD) is characterized by progressive cognitive decline driven by complex pathological processes, including tau hyperphosphorylation (p-Tau), amyloid-beta (Aβ) accumulation, and neuroinflammation. In this study, we investigated the effects of two bioactive compounds, dihydrocaffeic acid (DHCA) and malvidin-glucoside (Mal-gluc), targeting inflammation and neuronal activity, respectively, on cognitive function and AD pathology in a mouse model of AD. Our results demonstrate that chronic DHCA/Mal-gluc treatment significantly improves recognition memory in 3xTg-AD mice without reducing p-Tau or Aβ burden. Employing a newly developed whole-brain cFOS and IBA-1 mapping technique, we found that this combination treatment enhances neuronal activity and promotes microglial homeostasis across multiple brain regions in 3xTg-AD mice. These findings underscore the potential of restoring neuronal function and immune homeostasis as a therapeutic approach for AD. Future study will explore the underlying mechanisms and evaluate whether DHCA/Mal-gluc, combined with currently approved Aβ monoclonal therapy, can synergistically prevent or delay AD onset and progression.},
}

@article {pmid41202479,
year = {2025},
author = {Samsami, S and Parvar, MD and Mehralitabar, H and Dehghanbanadaki, N and Naderi-Manesh, H},
title = {In silico investigation of CNS-11 as a potential inhibitor of Aβ42 aggregation and its protofibril disassembly.},
journal = {Biochemical and biophysical research communications},
volume = {790},
number = {},
pages = {152899},
doi = {10.1016/j.bbrc.2025.152899},
pmid = {41202479},
issn = {1090-2104},
abstract = {Amyloidogenic peptide aggregation and fibril formation are key components in neurodegenerative diseases such as Alzheimer's disease (AD). One effective strategy for treating these conditions involves preventing amyloid peptide aggregation by using interfering agents, such as small molecules, at the onset of amyloid peptide assembly. Another approach could involve destabilizing the formed fibrils using small molecules as well. In this study, we utilized both all-atom and coarse-grained molecular dynamics (MD) simulation methods to investigate the aggregation mechanistic details of amyloid-β42 (Aβ42) peptides, the impact of CNS-11 (a small molecule inhibitor with proven Tau fibrils decomposing agent) on this Aβ42 aggregation, and the destabilization effect of CNS-11 on an Aβ42 fiber section, alongside the Aβ42 fiber section itself. Our results demonstrated that Aβ42 monomers in the free state strongly tend to dimerize and form beta-sheets by integrating the hydrophobic sections of the Aβ42 peptides. Still, as CNS-11 was added to the system, the ligand formed a hydrophobic core composed of CNS-11 and Aβ42 peptides surrounding this core, resulting in an amorphous and significantly disordered structure. Additionally, CNS-11 could interact with the Aβ42 pre-formed fiber section, partially destabilizing it through interactions with the buried hydrophobic core. Moreover, simulating the Aβ42 fiber section revealed that the N-terminal region of these peptide aggregates is naturally flexible and capable of becoming disorganized even without the addition of external disrupting agents. This study provides comprehensive insights into the molecular-level mechanisms underlying the dual effects of CNS-11 on amyloid beta aggregation and fibril degradation. This study can provide a computational framework with the potential to be applied to various small molecules, exploring their potential in the prevention and treatment of Alzheimer's disease.},
}