@article {pmid40934999,
year = {2025},
author = {Eisa-Beygi, S and Arulsamy, K and Cui, K and Wu, H and Wang, B and Chen, K and Chen, H},
title = {The chemokine receptor CXCR4 and its ligand CXCL12 (SDF-1) localize to ependymal cilia in brain ventricles.},
journal = {Vascular pharmacology},
volume = {},
number = {},
pages = {107546},
doi = {10.1016/j.vph.2025.107546},
pmid = {40934999},
issn = {1879-3649},
}

@article {pmid40934766,
year = {2025},
author = {Xin, X and Zong, T and Hu, Z and Jin, L and Zhou, W and Sun, J and Li, G},
title = {Discovery of natural compounds and their derivatives against neuroinflammation: Pharmacological mechanisms and structure-activity relationship.},
journal = {Bioorganic chemistry},
volume = {165},
number = {},
pages = {108934},
doi = {10.1016/j.bioorg.2025.108934},
pmid = {40934766},
issn = {1090-2120},
abstract = {Neuroinflammation refers to the inflammatory response within the central nervous system mediated by immune and glial cells, constitutes a pivotal mechanism in the pathological progression of neurodegenerative diseases. Alzheimer's disease (AD) serves as a paradigmatic example of neuroinflammation role in driving cytokine-mediated neuronal damage and perpetuating of disease progression. AD, which is characterized by memory decline and progressive cognitive impairment as its core clinical manifestations, currently has no effective treatment. Recent advances have underscored natural products as promising candidates for the development of safer and more effective anti-AD agents, particularly through the targeting of neuroinflammatory pathways that have emerged as central pathological mechanisms in the progression of AD. This review aims to elucidate the pathogenesis of neuroinflammation in AD and provides a comprehensive overview of anti-AD drugs currently in clinical research as well as those already available on the market. Additionally, this paper highlights natural compounds and their derivatives discovered over the past decade that exhibit anti-AD neuroinflammatory properties, analyzing the structure-activity relationships of selected compounds and their permeability across the blood-brain barrier. The goal is to offer valuable insights and references for drug developers.},
}

@article {pmid40934542,
year = {2025},
author = {Liu, T and Zhang, W and Bao, W and Wang, X and Zhang, F and Guo, J and Li, M},
title = {Aβ impairs bone vascular homeostasis in APP/PS1 mice via disrupting the mitochondrial fission-efferocytosis axis in macrophages.},
journal = {International immunopharmacology},
volume = {165},
number = {},
pages = {115526},
doi = {10.1016/j.intimp.2025.115526},
pmid = {40934542},
issn = {1878-1705},
abstract = {Alzheimer's disease (AD) is associated with progressive bone loss, but the underlying mechanisms remain unclear. This study focused on how amyloid-β (Aβ) disrupted bone vascular homeostasis by impairing macrophage efferocytosis in APP/PS1 mice. We found that Aβ accumulation in bone tissue impaired MerTK-mediated macrophage efferocytosis and promoted excessive accumulation of apoptotic endothelial cells (ECs). Mechanistically, Aβ triggered excessive mitochondrial fission via GSK-3β-mediated DRP1 phosphorylation, resulting in elevated reactive oxygen species (ROS) and subsequent ADAM17 activation. ADAM17 cleaved MerTK, a critical efferocytosis receptor, impairing apoptotic cells (ACs) clearance. Pharmacological inhibition of GSK-3β (LiCl and TDZD-8) or mitochondrial fission (Mdivi-1) restored MerTK expression, improved efferocytosis, and reduced inflammatory cytokine release (such as TNF-α, IL-6), while enhancing vascular endothelial growth factors (VEGFs). In vivo, LiCl treatment ameliorated bone loss and vascular dysfunction in APP/PS1 mice. These findings revealed that Aβ disrupted the mitochondrial fission-efferocytosis axis in macrophages, contributing to AD-related bone pathology, and highlighted GSK-3β as a potential therapeutic target for preserving bone vascular homeostasis in AD.},
}

@article {pmid40934472,
year = {2025},
author = {Niyangoda, S and Kearney, J and Hettiarachchi, P and Theismann, J and Shigemoto, A and Hickey, EE and Burdette, SC and Johnson, MA},
title = {Quantitative Control of Zn[2+] Photorelease: A Step toward Decoding Mechanisms of Subsecond Metal Signaling in the Brain.},
journal = {Analytical chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.analchem.5c03208},
pmid = {40934472},
issn = {1520-6882},
abstract = {Free ionic zinc (Zn[2+]) exerts control over many aspects of neuronal function after its exocytotic release from vesicles by associating with conserved binding sites on regulatory proteins, including the dopamine transporter. While the use of photoreactive cages to investigate the influence of subsecond Zn[2+] transients on neurotransmitter release and uptake is useful, a quantitative understanding of Zn[2+]'s regulatory effects requires knowing how much Zn[2+] has been released. Here, we have addressed this issue by directly measuring 4-methoxy-3-nitrobenzaldehyde (3-NPA), a photoreaction byproduct from [Zn(DPAeCageOMe)][+], as a reporter to quantify Zn[2+] photorelease. We optimized a sawhorse waveform, which eliminated fouling and provided a linear oxidation current response as concentration was increased. We then demonstrated the utility of our method by measuring released zinc ions evoked by light exposure in whole brains harvested from adult zebrafish ex vivo. Our findings revealed that zinc, which was released at concentrations of about 1 to 4 μM in response to light application durations of 300 to 900 ms, significantly increased dopamine overflow and inhibited dopamine uptake. The profound effects of low concentrations of Zn[2+] on release and uptake raise the possibility that Zn[2+], which is released from terminals at concentrations of 10 to 20 μM, acts as a volume neuromodulator, with targets beyond respective postsynaptic terminals. Given that Zn[2+] dysregulation is a well-established phenomenon in Parkinson's and Alzheimer's diseases, application of our newly developed method may provide insight into these disorders.},
}

@article {pmid40934263,
year = {2025},
author = {Xu, K and Maydanchik, N and Kang, B and Chen, J and Chen, Q and Xu, G and Tasaki, S and Bennett, DA and Chen, LS},
title = {Integrative Mendelian randomization for detecting exposure-by-group interactions using group-specific and combined summary statistics.},
journal = {PLoS genetics},
volume = {21},
number = {9},
pages = {e1011819},
doi = {10.1371/journal.pgen.1011819},
pmid = {40934263},
issn = {1553-7404},
abstract = {Interactions between risk factors and covariate-defined groups are commonly observed in complex diseases. Existing methods for detecting interactions typically require individual-level data. The data availability and the measurements of risk exposures and covariates often limit the power and applicability in assessing interactions. To address these limitations, we propose int2MR, an integrative Mendelian randomization (MR) method that leverages GWAS summary statistics on exposure traits and group-separated and/or combined GWAS statistics on outcome traits. The int2MR can assess a broad range of risk exposure effects on diseases and traits, revealing interactions unattainable with incomplete or limited individual-level data. Simulation studies demonstrate that int2MR effectively controls type I error rates under various settings while achieving considerable power gains with the integration of additional group-combined GWAS data. We applied int2MR to two data analyses. First, we identified risk exposures with sex-interaction effects on ADHD, and our results suggested potentially elevated inflammation in males. Second, we detected age-group-specific risk factors for Alzheimer's disease pathologies in the oldest-old (age 95+); many of these factors were related to immune and inflammatory processes. Our findings suggest that reduced chronic inflammation may underlie the distinct pathological mechanisms observed in this age group. The int2MR is a robust and flexible tool for assessing group-specific or interaction effects, providing insights into disease mechanisms.},
}

@article {pmid40934150,
year = {2025},
author = {Zhou, Y and Su, T and Yuan, M and Li, WL and Zhou, Y and Kou, JX and Chang, JS and Liu, D and Chen, L and Zhan, K and Zhu, LQ},
title = {A new lens on Alzheimer's disease: Insights into the Edinger-Westphal nucleus and its circuits.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251372587},
doi = {10.1177/13872877251372587},
pmid = {40934150},
issn = {1875-8908},
abstract = {Alzheimer's disease (AD) is the primary cause of dementia, and as the population ages, the number of individuals affected by the disease continues to rise. However, effective treatments for AD are still lacking. In the initial stages of AD, many brain regions are susceptible to its characteristic pathological changes, such as the Edinger-Westphal nucleus (EW nucleus) located in the midbrain region, which functions primarily as the parasympathetic oculomotor nucleus regulating pupil constriction. In this review, we outline the characteristics of EW nucleus alterations in AD and their potential role in the disease's onset and progression from various perspectives, including molecular changes, pathological alterations, and synaptic circuits. We propose that cognitive functions governed by the EW nucleus and its associated circuits may undergo early changes in AD and could serve as potential targets for the early diagnosis and therapeutic development of AD.},
}

@article {pmid40934136,
year = {2025},
author = {Ji, Q and Lian, W and Liu, W and Tang, L and Hu, Z and Li, L and Wang, Y and Tao, E and Zhan, Y},
title = {Herpes Simplex Virus Infection and Risk of Alzheimer's Disease: A Systematic Review and Meta-Analysis.},
journal = {Neuroepidemiology},
volume = {},
number = {},
pages = {1-25},
doi = {10.1159/000548365},
pmid = {40934136},
issn = {1423-0208},
abstract = {INTRODUCTION: The relationship between Herpes Simplex Virus (HSV) infection and the risk of Alzheimer's Disease (AD) remains unclear.

METHODS: A systematic review and meta-analysis were conducted to investigate this potential association. Observational studies were sourced from PubMed, Embase, Web of Science, and the Cochrane Library up to July 31, 2024. The analysis utilized the generic inverse variance method with a random effects model. Effect sizes were calculated as odds ratios (OR) or hazard ratios (HR) with corresponding 95% confidence intervals (CI).

RESULTS: A total of 26 original studies, encompassing 1,213,193 participants, were included in the meta-analysis. The findings indicated a 32% higher likelihood of AD in individuals with HSV infection in case-control studies (OR = 1.32; 95% CI: 1.12, 1.55; I2 = 22.7%) and a 20% increased risk in cohort studies (HR = 1.20; 95% CI: 1.10, 1.31; I2 = 11.0%). Specifically, HSV-1 infection was associated with 46% higher odds of AD (OR = 1.46; 95% CI: 1.14, 1.86; I2 = 3.1%).

CONCLUSION: This meta-analysis demonstrates an association between HSV infection and increased risk of AD, particularly for HSV-1. Given the high global prevalence of HSV-1 and the heterogeneity of existing evidence, these findings should be regarded as hypothesis-generating, underscoring the need for rigorous, biomarker-informed studies to clarify causality and identify susceptible subgroups.},
}

@article {pmid40934101,
year = {2025},
author = {O'Caoimh, R},
title = {Navigating the landscape of cognitive screening in multicultural memory clinics.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251375431},
doi = {10.1177/13872877251375431},
pmid = {40934101},
issn = {1875-8908},
abstract = {As societies age and become more culturally diverse, memory clinics must adapt to serve individuals from varied educational, linguistic, and ethnic backgrounds. This has driven efforts to develop culturally appropriate and valid cognitive screening instruments (CSIs). Nielsen and colleagues compare the diagnostic accuracy of five brief CSIs in a multicultural memory clinic sample. While instruments were accurate, limitations in sample size and generalisability underscore persistent challenges studying diverse immigrant populations with cognitive impairment and highlight the importance of ongoing study. This editorial discusses the implications for clinical practice, potential bias, and need for truly cross-cultural assessment processes in memory clinics.},
}

@article {pmid40934100,
year = {2025},
author = {Finkel, D and Kårelind, F and Zarit, SH and Wijk, H and Bielsten, T and Johansson, L},
title = {Latent classes and progression of Mini-Mental State Examination scores in young-onset dementia: Data from the Swedish Dementia Register.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251376040},
doi = {10.1177/13872877251376040},
pmid = {40934100},
issn = {1875-8908},
abstract = {BackgroundStudies have shown significant heterogeneity in the longitudinal progression of dementias, including Alzheimer's disease. Growth mixture models have detected up to 4 classes that differ in both baseline Mini-Mental State Exam (MMSE) and rate of decline over time. Most analyses focus on adults over age 65 and investigate group differences in demographic and health variables.ObjectiveThe current analysis focused on adults with young onset dementia (YOD) and examined the role of demographic and support variables in differentiating latent classes of longitudinal progression of cognitive status.MethodsSample included 1025 adults (55% women) registered in the Swedish Dementia Register prior to age 65 with at least 3 registrations. Age at baseline was 38 to 64 (mean = 59.3, SD = 4.1); follow-up duration ranged from 1 to 12 years (mean = 4.6, SD = 2.0).ResultsGrowth mixture models identified 5 classes: high baseline MMSE and moderate decline over time (48.5%), intermediate baseline MMSE and moderate decline (34.5%), high baseline MMSE and steep decline (13.4%), low baseline and generally stable MMSE over time (2.6%), and high baseline with precipitous decline (1.0%). Latent classes differed in age at diagnosis, diagnostic categories, number of medications, and having home help services.ConclusionsResults highlight that YOD is just as heterogeneous as later onset dementia; therefore, it is vital that people with YOD get early diagnosis and a case manager to help identity and meet their individual needs.},
}

@article {pmid40934099,
year = {2025},
author = {Au-Yeung, WM and Usmani, M and Ramphul, R and Wu, CY and Dodge, H and Steele, J and Beattie, Z and Kaye, J},
title = {Estimating daily air quality exposure of the aging and dementia population.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251375966},
doi = {10.1177/13872877251375966},
pmid = {40934099},
issn = {1875-8908},
abstract = {BackgroundTo understand the effect of air quality on cognition, air quality measurements should reflect real-world exposure. Currently, air quality exposure is derived from outdoor air quality monitors despite older adults spending most of their time indoors.ObjectiveTo examine if there are discrepancies between indoor particulate matter 2.5 (PM2.5) at older adults' personal residences, PM2.5 levels measured with nearest outdoor public air monitors, and remotely accessed gridded ensemble air quality data.MethodsPM2.5 levels collected in older adults' residences, collected from the nearest outdoor public air quality monitors and ensemble data from Hazardous Air Quality Ensemble System (HAQES) were compared using Spearman correlation coefficients and Wilcoxon signed-rank tests. Daily PM2.5 profiles in these homes were also examined.ResultsAmbient air quality was assessed in 23 residences of older adults from October 2021 to August 2024. Indoor PM2.5 measurement was lower than outdoor public air monitors for all but 3 homes. Estimates of PM2.5 level from HAQES were also significantly higher than those indoors. High inter- and intra-home variability over time was observed. Spikes in daily indoor PM2.5 levels were common, and they could exceed the United States Environmental Protection Agency (US EPA)'s recommendation for 24 -hour average. Use of home appliances and indoor activities may contribute to changes in indoor PM2.5 level throughout the day.ConclusionsTo optimally estimate air quality exposure risk, monitoring both indoor and outdoor environments is likely needed.},
}

@article {pmid40934097,
year = {2025},
author = {Chatterjee, P and Ivanic, S and Southon, A and McCarthy, C and Patel, SK and Christensen, M and Darby, D and Bush, AI and Ayton, S and Werden, E and Brodtmann, A},
title = {Real world diagnostic performance of plasma p-tau217 for early-onset Alzheimer's disease in a cognitive disorders tertiary care setting.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251376694},
doi = {10.1177/13872877251376694},
pmid = {40934097},
issn = {1875-8908},
abstract = {BackgroundPlasma p-tau217 shows exceptional diagnostic performance for Alzheimer's disease (AD) in cohort studies. Recent real-world studies support its validity in more diverse populations.ObjectiveTest the performance of plasma p-tau217 in representative real-world early-onset cognitive disorders patients.Methods118 adult patients with cognitive complaints or potential neurodegenerative diseases (ND) from a single healthcare network in Melbourne, Australia, were categorized into three groups based on clinical diagnosis: non-ND (n = 52), early-onset AD (EOAD, n = 39), and non-AD ND (other-ND, n = 27). Plasma p-tau217 was measured using the Simoa[®] ALZpath p-Tau 217 Assay.ResultsPlasma p-tau217 was elevated in EOAD (mean ± SD: 1.13 ± 0.51) compared with non-ND (0.31 ± 0.27, p = 5.43e-23) and other-ND (0.23 ± 0.10, p = 9.65e-21). ROC analysis revealed excellent diagnostic performance, with AUCs of 0.944 [95% CI:0.893-0.996] for EOAD versus non-ND and 0.984 [0.962-1.000] for EOAD versus other-ND. Using a binary cut-off (p-tau217 > 0.42 pg/mL), 17% non-ND, 95% EOAD and 7% other-ND were A + . Using a two-tiered cut-off approach (0.40 pg/mL > p-tau217 > 0.63 pg/mL), 4% non-ND, 94% EOAD and 0% other-ND were A + . 10% of participants (n = 12) were within the intermediate range. Using the binary cut-off of p-tau217 > 0.64 pg/mL for T+, 100% EOAD and 0% other-ND A + participants, defined by the two-tiered cut-off approach, were T + . No associations of p-tau217 with age, sex, or ethnicity were found within ND groups. P-tau217 was elevated in individuals with severely impaired renal function.ConclusionsThe findings support the clinical utility of plasma p-tau217 in the real-world diagnostic evaluation of EOAD. However, careful interpretation of false positive results in patients with severe renal impairment is required.},
}

@article {pmid40934096,
year = {2025},
author = {Gu, H and Yu, K and Zhou, J and Chu, B and Zhang, W and Dong, J and He, J},
title = {Perturbations in lipid metabolism mediate the relationship between cholecystectomy and dementia: A mediation Mendelian randomization study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251376316},
doi = {10.1177/13872877251376316},
pmid = {40934096},
issn = {1875-8908},
abstract = {BackgroundThe relationship between surgical approaches and postoperative cognitive dysfunction remains controversial.ObjectiveTo investigate the causal effect of cholecystectomy on dementia and its subtypes, and the mediating role of circulating lipid metabolites.MethodsUsing large-scale genome-wide association studies (GWAS), the causal effect of genetically proxied cholecystectomy (18,319 cases and 444,614 controls) on dementia (20,667 cases and 428,053 controls), dementia due to Parkinson's disease (643 cases and 199, 772 controls), dementia in Alzheimer's disease (6741 cases and 428,053 controls), frontotemporal dementia (145 cases and 432,207 controls), vascular dementia (3116 cases and 433,066 controls), and dementia with Lewy bodies (2591 cases and 4027 controls) were explored by two-sample Mendelian randomization (TSMR). Mediating lipid metabolites were identified by TSMR. GWAS data used for analysis were obtained from the IEU Open GWAS Project and the FinnGen Consortium.ResultsCholecystectomy patients had an increased risk of dementia and dementia in Alzheimer's disease, with odds ratios (OR) of 2.33 (95% CI = 1.074-5.068, p = 0.032) and 3.43 (95% CI = 1.029-11.411, p = 0.045) respectively. Phospholipids in small high-density lipoprotein (HDL) partially mediated the causal effect between cholecystectomy and dementia, with a mediating effect of 9.06%.ConclusionsThis mediation MR study revealed a causal relationship between cholecystectomy and dementia, especially dementia in Alzheimer's disease, and revealed a partial mediating role of circulating phospholipids in small HDL. However, further studies are needed to verify whether phospholipids in small HDL can be a new biomarker for predicting, preventing or even treating dementia in cholecystectomy patients.},
}

@article {pmid40934094,
year = {2025},
author = {Duc Nguyen, H},
title = {Analysis of the Therapeutic Potential of Astragalin: Insights into Target Interactions and Mechanisms.},
journal = {Xenobiotica; the fate of foreign compounds in biological systems},
volume = {},
number = {},
pages = {1-25},
doi = {10.1080/00498254.2025.2559962},
pmid = {40934094},
issn = {1366-5928},
abstract = {Astragalin (AST), a flavonoid, shows promise for neurodegenerative diseases like Parkinson's disease (PD), cognitive impairment (CI), and depression. However, its efficacy in treating neurodegenerative diseases and the underlying molecular mechanisms remain unclear. This study aims to evaluate the metabolite profile, pharmacokinetics, toxicity, molecular targets, and potential biological activities of AST. Thirty-one AST metabolites formed through Phase II reactions (O-glucuronidation, O-sulfation, and methylation) were found. AST and its metabolites partially violate Lipinski's Rule of Five, including molecular weight and hydrogen bond donors, impacting drug-likeness. However, AST and its metabolites have favorable safety and potential anti-neurodegenerative and antidepressant effects. AST shows strong binding affinities with key neuroinflammatory targets, including IL1B, IL6, TNF, NOS2, PTGS2, SERT, caspase-3, caspase-8, and GABAa receptor, and network analysis highlights its association with neuroinflammatory pathways. Collectively, these findings support AST as a potential neurotherapeutic candidate and offer a basis for further in vitro and in vivo validation.},
}

@article {pmid40934091,
year = {2025},
author = {Hale, MR and Langhough, R and Basche, KE and Betthauser, TJ and Chin, NA and Christian, BT and Hermann, BP and Johnson, SC and Mueller, KD},
title = {Linking silent pause locations in speech to amyloid and tau deposition in cognitively unimpaired individuals.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251371720},
doi = {10.1177/13872877251371720},
pmid = {40934091},
issn = {1875-8908},
abstract = {BackgroundConnected speech and language (CSL) analysis can differentiate typically aging individuals from those with dementia by identifying subtle changes in language-dependent measures, such as lexical diversity and fluency. Prior studies have linked features like slower speech rates and increased silent pauses with Alzheimer's disease (AD) neuropathology, but the pause patterns in preclinical AD and their syntactic locations remain unclear.ObjectiveTo investigate silent pauses as a potential early detection tool for AD in cognitively unimpaired individuals and compare their sensitivity to traditional neuropsychological tests in distinguishing biomarker-positive and biomarker-negative groups.MethodsCognitively unimpaired participants from the Wisconsin Registry for Alzheimer's Prevention with amyloid (A) and tau (T) PET imaging were included. Twenty-six participants with A+/T+ profiles were matched 1:1 with A-/T- individuals using propensity score matching for age, sex, literacy, and race (n = 52). Participants were majority female (75.6%) and non-Hispanic white (91%) with a mean (sd) age of 67.5 (6.2). CSL samples were derived from the Cookie Theft picture description task closest to PET scans. Pauses were annotated using ELAN at utterance-initial, clause-initial, and within-clause locations, with further categorization of within-clause pauses by part of speech (nouns, verbs, adjectives/adverbs). Pause rates and durations were analyzed using Mann-Whitney U tests, with effect sizes measured by Cliff's delta (δ).ResultsA+/T+ individuals had longer adjective/adverb-initial pauses than A-/T- (p = 0.016; δ = 0.39), outperforming the preclinical Alzheimer's cognitive composite (p = 0.347, δ = 0.15).ConclusionsSilent pauses, especially adjective/adverb-initial, show promise as an early indicator of AD neuropathology. Replication in diverse cohorts with longitudinal analyses is warranted.},
}

@article {pmid40934078,
year = {2025},
author = {Palmer, JE and Puri, C and O'Rourke, RS and Son, SM and Sang, C and Huang, YA and Rubinsztein, DC},
title = {Coordination of autophagosome closure and release by the Alzheimer's disease-associated protein BIN1.},
journal = {Cell reports},
volume = {44},
number = {9},
pages = {116266},
doi = {10.1016/j.celrep.2025.116266},
pmid = {40934078},
issn = {2211-1247},
abstract = {Autophagosome closure by the endosomal sorting complex required for transport (ESCRT) complex is a prerequisite for their dynamin 2 (DNM2)-dependent release from the recycling endosome and subsequent lysosomal clearance. However, the mechanism that coordinates autophagosome closure and release is unknown. We identified that the Alzheimer's disease-associated protein bridging integrator 1 (BIN1) is a critical mediator of this coordination. Prior to autophagosome closure, BIN1 is held at autophagosomes by ESCRT-III and inhibits DNM2. Once the autophagosome has closed and ESCRT-III disassembles, BIN1 is released, removing the inhibition of DNM2. This mechanism provides insight into the functional consequences of increased BIN1 expression, as this occurs in microglia with Alzheimer's disease risk-associated polymorphisms. We find that the overexpression of BIN1 microglial isoforms inhibits DNM2-mediated autophagosome release and autophagic clearance. This provides a coherent explanation for the increased Alzheimer's disease risk associated with BIN1, as impaired microglial autophagy alters phagocytosis and is associated with microglial senescence and neuroinflammation.},
}

@article {pmid40934003,
year = {2025},
author = {Zheng, Y and Xu, L},
title = {Bidirectional crosstalk between microglia and serotonin signaling in neuroinflammation and CNS disorders.},
journal = {Frontiers in immunology},
volume = {16},
number = {},
pages = {1646740},
doi = {10.3389/fimmu.2025.1646740},
pmid = {40934003},
issn = {1664-3224},
abstract = {Neuroinflammatory processes are increasingly recognized as central to the pathophysiology of diverse central nervous system (CNS) disorders, including major depressive disorder (MDD), Alzheimer's disease (AD), and Parkinson's disease (PD). Microglia, the resident immune effector cells of the CNS, are key regulators of neuroimmune responses and engage in bidirectional communication with the serotonergic system. Activation of microglia toward a pro-inflammatory phenotype can disrupt serotonergic neurotransmission by altering the expression and function of the serotonin transporter (SERT) and modulating downstream 5-HT receptor signaling pathways. Conversely, serotonergic neurotransmission-mediated through receptor subtypes such as 5-HT1A, 5-HT2A/2B, and 5-HT7-can regulate microglial phenotypic polarization and cytokine production, thereby influencing the inflammatory milieu and CNS homeostasis. This review synthesizes current evidence on the dynamic interplay between microglial activation states and serotonergic signaling, emphasizing their mutual contributions to disease onset and progression. Furthermore, we examine the therapeutic potential of targeting this neuroimmune interface using pharmacological strategies, including selective serotonin reuptake inhibitors (SSRIs), anti-inflammatory agents, and receptor-specific ligands. Clarifying this bidirectional crosstalk may inform the development of innovative interventions for neuroinflammation-associated neuropsychiatric and neurodegenerative disorders.},
}

@article {pmid40933952,
year = {2025},
author = {Jomova, K and Alomar, SY and Valko, R and Nepovimova, E and Kuca, K and Valko, M},
title = {The role of redox-active iron, copper, manganese, and redox-inactive zinc in toxicity, oxidative stress, and human diseases.},
journal = {EXCLI journal},
volume = {24},
number = {},
pages = {880-954},
doi = {10.17179/excli2025-8449},
pmid = {40933952},
issn = {1611-2156},
abstract = {Given the key importance played by the redox-active metals iron (Fe), copper (Cu), and manganese (Mn) in vital cellular processes, such as DNA synthesis, oxidative phosphorylation, the detoxification of reactive oxygen species (ROS), and angiogenesis, it is not surprising that their dysregulation plays a causative role in many human diseases. The same applies to redox-inactive zinc (Zn), which is involved in numerous biological functions, and serves as a structural element, a catalyst, and a participant in both intracellular and intercellular signaling and in maintaining immune system function. An imbalance in redox active (Fe, Cu, Mn) or redox inactive (Zn) metal ions, whether in excess or deficiency, is harmful and may disrupt the structural, regulatory, and catalytic roles of various antioxidant enzymes (superoxide dismutases (SODs), catalase (CAT), glutathione peroxidases (GPxs)), proteins, receptors, transporters, alter sulfhydryl homeostasis, generate high levels of ROS (e.g., hydroxyl radicals by the Fenton reaction), initiate lipid peroxidation, cause DNA damage, and lead to cell death via mechanisms such as ferroptosis, cuproptosis, cellular senescence, or inflammation. Maintaining redox homeostasis is essential for regulating numerous cellular signaling pathways. Redox-sensitive signaling pathways, such as the nuclear factor kappa B (NF-κB), mitogen-activated protein kinase kinase (MAPK), and nuclear factor erythroid 2-related factor 2 (Nrf2) pathways, form an intricate network that governs cellular responses to redox metal-induced oxidative stress and inflammation. The Nrf2 pathway is primarily responsible for mediating antioxidant defenses, whereas the NF-κB and MAPK pathways play roles in proinflammatory and stress-related responses. Dysregulation of redox-active Fe, Cu, Mn, and redox-inactive Zn can alter epigenetic regulatory mechanisms such as DNA methylation, histone modification, and non-coding RNA expression. The dyshomeostasis of metal ions is closely related to the pathogenesis of lung, renal, and gastrointestinal diseases, neurodegenerative disorders (Alzheimer's disease, Parkinson's disease, and Huntington's disease), psychiatric conditions (schizophrenia), and various cancers. This review summarizes recent findings on the role of iron, copper, manganese, and zinc in maintaining physiological functions, redox homeostasis, and human diseases. See also the graphical abstract(Fig. 1).},
}

@article {pmid40933919,
year = {2025},
author = {Song, B and Yue, D and Yan, H and Feng, L and Li, M},
title = {Traditional Chinese Medicine Natural Products Targeting Shared Mechanisms of T2DM and AD: Potential Therapeutic Insights.},
journal = {Drug design, development and therapy},
volume = {19},
number = {},
pages = {7681-7705},
doi = {10.2147/DDDT.S531909},
pmid = {40933919},
issn = {1177-8881},
abstract = {As highly prevalent chronic diseases globally, AD (Alzheimer's disease) and T2DM (type 2 diabetes mellitus) not only severely affect the quality of life of patients but also impose a significant burden on their families. Numerous studies have gradually revealed that T2DM and AD are bidirectional risk factors, each capable of exacerbating the other. There is a notable correlation in their pathological mechanisms, primarily manifested in insulin resistance, OS (oxidative stress), and inflammatory responses. Currently, available drugs can only delay the progression of AD, such as Donepezil, Galantamine, and Carbamylcholine, making complete cures challenging to achieve. TCM (Traditional Chinese medicine) natural products exhibit characteristics such as multi-targeting, multi-pathway interactions, diverse biological activities, and relatively mild side effects, enabling synergistic intervention in both diseases. In recent years, TCM natural products have garnered increasing attention in research concentrated on the prevention and management of AD and T2DM. This article aims to comprehensively elucidate the collective pathogenic mechanism of AD and T2DM, and explore the progress of TCM natural products based on these mechanisms in the prevention and treatment of both diseases, thereby providing a theoretical foundation for the advancement of innovative treatment tactics.},
}

@article {pmid40933857,
year = {2025},
author = {Li, H and Zhu, J and Li, J and Wu, Y and Luo, C and Huang, Y and Wu, J and Liu, W and Wang, H and Mo, Z},
title = {Human brain organoids: an innovative model for neurological disorder research and therapy.},
journal = {Frontiers in cellular neuroscience},
volume = {19},
number = {},
pages = {1658074},
doi = {10.3389/fncel.2025.1658074},
pmid = {40933857},
issn = {1662-5102},
abstract = {The emergence of human brain organoids (hBOs) has transformed how we study brain development, disease mechanisms, and therapy discovery. These 3D in vitro neural models closely mimic the cellular diversity, spatial structure, and functional connectivity of the human brain, providing a groundbreaking platform that outperforms traditional 2D cultures and animal models in studying neurodevelopment and neurological disorders. To further explore the potential of hBOs technology, we review current literature focusing particularly on its applications for diagnosing and treating major neurological diseases such as Alzheimer's disease, Parkinson's disease, and other related neurological disorders. Using patient-derived induced pluripotent stem cells combined with cutting-edge gene-editing technologies, hBOs enable highly precise mechanistic studies and scalable drug screening. Moreover, we further discuss the advantages and current limitations of hBOs. Despite these challenges, hBOs remain a transformative platform for the development of targeted neurotherapeutics. Collectively, this review offers a solid foundation for advancing neuroscience research and fostering innovative treatment strategies for neurological disorders.},
}

@article {pmid40933828,
year = {2025},
author = {Agus, JK and Muñoz Herrera, OM and Rhodes, CH and Zheng, JJ and Zhu, C and Wong, M and Tang, X and Maezawa, I and Jin, LW and Lebrilla, CB and Harvey, DJ and Zivkovic, AM},
title = {HDL from 36-h fasted participants potently promotes efflux of cholesteryl ester from activated microglia.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1629496},
doi = {10.3389/fnagi.2025.1629496},
pmid = {40933828},
issn = {1663-4365},
abstract = {The potential impact of lifestyle changes such as prolonged fasting on brain health still remains unclear. Neurodegenerative diseases often exhibit two key hallmarks: accumulation of misfolded proteins such as amyloid beta oligomers (AβO) and intracellular cholesterol accumulation. In this study, we investigate how a 36-h fast affects the capacity of isolated high-density lipoproteins (HDLs) to modulate the effects of AβO and excess cholesterol in microglia. HDL from 36-h fasted individuals were significantly more effective in effluxing cholesteryl esters from treated microglia, showing a remarkable 10-fold improvement compared to HDL from the postprandial state. Furthermore, the ability of 36-h fasted HDL to mitigate the reduction of apolipoprotein E secretion in AβO- and cholesterol-loaded microglia surpassed that of postprandial HDL. In exploring differences among HDL parameters from postprandial, overnight fasted, and 36-h fasted individuals, we observed that plasma HDL-cholesterol and apolipoprotein A-I concentrations remained unchanged. However, nuclear magnetic resonance (NMR) analysis revealed reduced total HDL particle count, a decrease in the smallest HDL particles (HDL1, 7.4 nm diameter), and an increase in the largest HDL particles (HDL7, 12 nm) after the 36-h fast. Transmission electron microscopy (TEM) analysis further found an increase in even larger HDL particles (12-14 nm) in 36-h fasted individuals. Targeted mass spectrometry (MS)-based proteomics and glycoproteomics unveiled a reduction in HDL-associated apolipoprotein A-IV and disialylated apolipoprotein C-III content following the 36-h fast. These findings collectively suggest that prolonged fasting induces structural, compositional, and functional alterations in HDL particles, and influences their capacity to attenuate the effects of excess cholesterol and AβO in microglia.},
}

@article {pmid40933757,
year = {2025},
author = {Behrens, A and Anderberg, P and Berglund, JS and Cianchetta-Sivoriceruti, M and Dallora, AL},
title = {Blood biomarkers for Alzheimer's disease: Reliable change and impacts of renal and blood-brain barrier function.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {17},
number = {3},
pages = {e70181},
doi = {10.1002/dad2.70181},
pmid = {40933757},
issn = {2352-8729},
abstract = {INTRODUCTION: Blood-based biomarkers for Alzheimer's disease (AD) have the potential to improve diagnostic accessibility, but their clinical interpretation requires understanding of variability and biological influences.

METHODS: We repeatedly sampled blood from 57 adults referred for lumbar puncture as part of a cognitive evaluation at a memory clinic. We measured serum phosphorylated- tau-181 (s-p-tau181) and plasma amyloid beta (Aβ)42/40 ratio (p-Aβ42/Aβ40) and evaluated the impact of renal and blood-brain barrier (BBB) function.

RESULTS: Test-retest analysis revealed large variability of s-p-tau181 and small for p-Aβ42/Aβ40. Markers of renal function and BBB integrity significantly influenced s-p-tau181 levels, whereas p-Aβ42/Aβ40 was not affected.

DISCUSSION: This study emphasizes the need for caution when interpreting longitudinal changes in s-p-tau181. Inter-individual variability is to a large degree due to susceptibility to biological influences where a novel association with integrity of BBB function were identified. These results have implications for the clinical application of blood-based biomarkers in AD diagnostics and monitoring.

HIGHLIGHTS: Blood phosphorylated- tau-181 (p-tau181) shows high test-retest variability in memory clinic patients.Blood amyloid beta (Aβ)42/Aβ40 ratio is stable but has poor diagnostic accuracy.Renal function and blood-brain barrier (BBB) integrity affect blood p-tau181 levels.Caution is needed when interpreting longitudinal changes in blood p-tau181.Renal and BBB disorders should be considered when assessing blood p-tau181.},
}

@article {pmid40933754,
year = {2025},
author = {Baboni, F and Tembo, KM and Zhou, X and Li, Q and Dai, C and Zhao, Y and Batoko, S and Lan, P and Chen, Z},
title = {SETD7 Dual Role in Disease and Opportunities for Therapeutic Intervention: Current Perspectives.},
journal = {Journal of inflammation research},
volume = {18},
number = {},
pages = {12191-12225},
doi = {10.2147/JIR.S534623},
pmid = {40933754},
issn = {1178-7031},
abstract = {SET domain-containing lysine methyltransferase 7 (SETD7) is a critical enzyme that methylates lysine residues on both histone and non-histone proteins, thereby regulating gene expression and protein function. This methyltransferase plays a versatile and context-dependent role in a wide range of physiological processes, including cell differentiation, reactive oxygen species (ROS) signaling, oxidative stress regulation, and energy metabolism. SETD7's dual nature is highlighted by its paradoxical involvement in various diseases such as cancer, asthma, and Alzheimer's disease, where it can either promote or suppress pathological progression depending on the cellular environment and molecular context. The multifaceted functions of SETD7 underscore its importance in maintaining cellular homeostasis but also present significant challenges for therapeutic targeting. Although selective inhibitors like Cyproheptadine and (R)-PFI-2 have recently been identified, the development of highly specific and effective therapies remains complex due to SETD7's broad regulatory roles and the potential for unintended effects on normal physiological processes. These challenges necessitate nuanced therapeutic strategies, including the exploration of combination treatments and context-specific modulation to maximize efficacy while minimizing adverse outcomes. This review comprehensively explores SETD7's structure, subcellular localization, and diverse biological functions in both normal and disease states. By elucidating the dual and context-dependent nature of SETD7, it aims to provide a framework for future research focused on unraveling its molecular mechanisms and advancing targeted therapeutic approaches that leverage its unique regulatory capabilities.},
}

@article {pmid40933649,
year = {2025},
author = {Güth, MR and Reid, A and Zhang, Y and Huntgeburth, SC and Mill, RD and Dagher, A and Kerns, K and Holroyd, CB and Petrides, M and Cole, MW and Baker, TE},
title = {Right posterior theta reflects human parahippocampal phase resetting by salient cues during goal-directed navigation.},
journal = {Imaging neuroscience (Cambridge, Mass.)},
volume = {3},
number = {},
pages = {},
doi = {10.1162/IMAG.a.105},
pmid = {40933649},
issn = {2837-6056},
abstract = {Animal and computational work indicate that phase resetting of theta oscillations (4-12 Hz) in the parahippocampal gyrus (PHG) by salient events (e.g., reward, landmarks) facilitates the encoding of goal-oriented information during navigation. Although well studied in animals, this mechanism has not been empirically substantiated in humans. In the present article, we present data from two studies (Study 1: asynchronous electroencephalography (EEG)-magnetoencephalography (MEG) | Study 2: simultaneous EEG-fMRI) to investigate theta phase resetting and its relationship with PHG blood oxygenation level dependent (BOLD) activation in healthy adults (aged 18-34 years old) navigating a virtual T-maze to find rewards. In the first experiment, both EEG and MEG data revealed a burst of theta power over right-posterior scalp locations following feedback onset (termed right-posterior theta, RPT), and RPT power and measures of phase resetting were sensitive to the subject's spatial trajectory. In Experiment 2, we used probabilistic tractography data from the human connectome project to segment the anterior and posterior PHG based on differential connectivity profiles to other brain regions. This analysis resulted in a PHG subdivision consisting of four distinct anterior and two posterior PHG clusters. Next, a series of linear mixed effects models based on simultaneous EEG-fMRI data revealed that single-trial RPT peak power significantly predicted single-trial hemodynamic responses in two clusters within the posterior PHG and one in the anterior PHG. This coupling between RPT power and PHG BOLD was exclusive to trials performed during maze navigation, and not during a similar task devoid of the spatial context of the maze. These findings highlight a role of PHG theta phase resetting for the purpose of encoding salient information during goal-directed spatial navigation. Taken together, RPT during virtual navigation integrates experimental, computational, and theoretical research of PHG function in animals with human cognitive electrophysiology studies and clinical research on memory-related disorders such as Alzheimer's disease.},
}

@article {pmid40933625,
year = {2025},
author = {Hean, AC and Jones, J and Arena, M and Kavanagh, K},
title = {Memantine leading to physical aggression in the treatment of chronic catatonia secondary to schizophrenia: A case report.},
journal = {The mental health clinician},
volume = {15},
number = {4},
pages = {218-221},
doi = {10.9740/mhc.2025.08.218},
pmid = {40933625},
issn = {2168-9709},
abstract = {INTRODUCTION: Memantine is a noncompetitive N-methyl-D-aspartate receptor antagonist approved by the FDA for moderate to severe Alzheimer's dementia. Memantine is also recommended as an off-label treatment in current catatonia clinical guidelines when benzodiazepines alone are inadequate.

CASE: A 37-year-old male with a history of schizophrenia on psychiatric conservatorship, stimulant use disorder, and traumatic brain injury was stabilized on risperidone 4 mg twice daily, diphenhydramine 50 mg twice daily, divalproex delayed release 500 mg twice daily, and lorazepam 1 mg twice daily for catatonia. Lorazepam was titrated for unresolved chronic catatonic symptoms but was not tolerated beyond 5 mg total per day due to hemodynamic instability. Owing to barriers in initiating clozapine or electroconvulsive therapy, the patient was started on memantine to address residual catatonia symptoms. After the addition of memantine, the patient began to spontaneously speak in multiple languages and engage in discharge planning, but shortly after a dose increase to 15 mg daily also displayed increased aggressive behaviors. The aggression improved after decreasing the dose to 10 mg daily, and the patient was discharged.

CONCLUSIONS: This case adds to the body of evidence for memantine in catatonia with underlying schizophrenia and, to our knowledge, is the first described case of memantine uncovering aggression during catatonia treatment.},
}

@article {pmid40933596,
year = {2025},
author = {Wang, Y and Wang, G and Klinedinst, B and Willette, A and Wang, L},
title = {STATISTICAL INFERENCE FOR MEAN FUNCTIONS OF COMPLEX 3D OBJECTS.},
journal = {Statistica Sinica},
volume = {35},
number = {3},
pages = {1451-1477},
doi = {10.5705/ss.202023.0071},
pmid = {40933596},
issn = {1017-0405},
abstract = {The use of complex three-dimensional (3D) objects is growing in various applications as data collection techniques continue to evolve. Identifying and locating significant effects within these objects is essential for making informed decisions based on the data. This article presents an advanced nonparametric method for learning and inferring complex 3D objects, enabling accurate estimation of the underlying signals and efficient detection and localization of significant effects. The proposed method addresses the problem of analyzing irregular-shaped 3D objects by modeling them as functional data and utilizing trivariate spline smoothing based on triangulations to estimate the underlying signals. We develop a highly efficient procedure that accurately estimates the mean and covariance functions, as well as the eigenvalues and eigenfunctions. Furthermore, we rigorously establish the asymptotic properties of these estimators. Additionally, a novel approach for constructing simultaneous confidence corridors to quantify estimation uncertainty is presented, and the procedure is extended to accommodate comparisons between two independent samples. The finite-sample performance of the proposed methods is illustrated through numerical experiments and a real-data application using the Alzheimer's Disease Neuroimaging Initiative database.},
}

@article {pmid40933284,
year = {2025},
author = {Menardi, A and Saglam, C and La Rocca, B and Cecchin, D and Venneri, A and Cagnin, A and Vallesi, A},
title = {Cortical morphology changes in default mode network regions as predictors of cognitive decline in relation to amyloid and tau deposits.},
journal = {Brain communications},
volume = {7},
number = {5},
pages = {fcaf320},
doi = {10.1093/braincomms/fcaf320},
pmid = {40933284},
issn = {2632-1297},
abstract = {Alzheimer's disease can be classified based on amyloid, tau and neurodegeneration status. The Default Mode Network is notably vulnerable to these processes, making early structural alterations in this network of particular interest for identifying prodromal biomarkers. In this longitudinal cross-sectional study, we analysed data from 279 participants in the Alzheimer's Disease Neuroimaging Initiative (mean age = 73.7 ± 9 years, 53.2% males). Structural measures-sulcal depth, gyrification and cortical thickness-were extracted for all Default Mode Network regions. Their ability to predict memory performance (encoding, retrieval and recall) was tested at baseline and 2-year follow-up by means of multiple linear regression models, which were all corrected for the risk of multiple comparisons. Covariates included Mini Mental State Examination scores, amyloid status and regional tau burden, to examine interactions with structural changes. Our results showed distinct Default Mode Network alteration patterns based on tau burden and amyloid status, highlighting patterns of morphological features with different susceptibility to proteinopathy. In individuals with concordant (both positive or both negative) amyloid and tau status, preserved structural integrity and complexity were linked to better cognitive performance and appeared protective against decline. However, mainly negative associations were instead observed in individuals with discordant amyloid or tau status (i.e. positive for only either amyloid or tau accumulation). We discuss these findings as a possible reflection of a mismatch between abnormal protein accumulation and structural damage in these populations. The multimodal nature of this study helps clarifying the heterogeneous findings reported in existing literature regarding structural integrity and cognitive outcomes in Alzheimer's disease.},
}

@article {pmid40933257,
year = {2025},
author = {Titisari, N and Fauzi, A and Razak, ISA and Samsulrizal, N and Ahmad, H},
title = {Supplementation with fish oil reduces αβ 42 burden and shifts αβ precursor protein processing toward non-amyloidogenic pathways in a rat model of hyperglycaemic Alzheimer's disease.},
journal = {Journal of nutritional science},
volume = {14},
number = {},
pages = {e61},
doi = {10.1017/jns.2025.10036},
pmid = {40933257},
issn = {2048-6790},
abstract = {This study examines the influence of fish oil on brain amyloidogenesis in hyperglycaemic Alzheimer's disease animal models, emphasising the potential of omega-3 fatty acids in fish oil to prevent the development of Alzheimer's disease. Thirty males of Wistar rats were divided into five groups: 1) control rats (NS); 2) rats supplemented with 3 g/kg of fish oil (NS+FO3); 3) rats injected via intraperitoneal (i.p) with Streptozotocin-Lipopolysaccharide (STZ-LPS); 4) rats injected with STZ-LPS (i.p) and supplemented with 1 g/kg of fish oil (STZ-LPS+FO1), and 5) rats injected with STZ-LPS (i.p) and supplemented with 3 g/kg of fish oil (STZ-LPS+FO3). The cerebral brain was extracted for examination, and the αβ precursor protein (APP) level was measured using an immunoassay kit, while αβ 42 expression was evaluated using immunohistochemistry staining. Brain amyloidosis-related genes were quantified using real-time Polymerase Chain Reaction (PCR). The results revealed that fish oil supplementation significantly increased APP levels and reduced αβ 42 accumulations in STZ-LPS rats. Moreover, the Apolipoprotein E, ε4 isoform (ApoE-4) and Beta-site APP-cleaving enzyme 1 (Bace-1) genes were downregulated while the Low-density lipoprotein receptor-related protein 1 (Lrp-1) gene was upregulated in STZ-LPS rats treated with fish oil, thereby elucidating the impact of fish oil on diminishing αβ buildup in the brain. Therefore, this study contributes to a growing body of evidence supporting dietary interventions as adjunctive strategies for the prevention or delay of Alzheimer's disease progression in metabolic dysfunction.},
}

@article {pmid40933191,
year = {2025},
author = {Zhao, Y and Wang, X and Zhang, J and Zhao, Y and Li, Y and Shen, J and Yuan, Y and Li, J},
title = {Plasma FGF2 and YAP1 as novel biomarkers for MCI in the elderly: analysis via bioinformatics and clinical study.},
journal = {Frontiers in neuroscience},
volume = {19},
number = {},
pages = {1663276},
doi = {10.3389/fnins.2025.1663276},
pmid = {40933191},
issn = {1662-4548},
abstract = {The contemporary consensus firmly emphasizes the urgent need to reorient research efforts toward the early detection of preclinical Alzheimer's disease (AD) or mild cognitive impairment (MCI). However, there is still a notable absence of novel biomarkers that are both efficient, minimally invasive, and cost-effective in real-world clinical settings. To address this gap, datasets GSE29378 and GSE12685 were selected to screen differentially expressed genes (DEGs), and hub genes were identified by different algorithms. A total of 350 DEGs were identified in bioinformatics data mining. Functional enrichment analysis showed that fibroblast growth factor 2(FGF2) and yes-associated protein 1(YAP1) protein levels were highly expressed in AD samples, indicating their potential regulatory roles in AD. Between October and November 2024, a total of 146 elderly individuals diagnosed with MCI and 54 healthy elderly subjects were successfully recruited. Enzyme linked immunosorbent assay (ELISA) was used to detect plasma hub gene protein concentration. The results showed that the expression levels of plasma FGF2 and YAP1 proteins in the MCI group were significantly higher compared to the control group. Logistic regression analysis indicated that high plasma FGF2 and YAP1 expression levels were independently associated with MCI in the elderly. The Area under the curve (AUC) of FGF2 model and YAP1 model were 0.907 and 0.972, respectively. Therefore, the high expression of plasma FGF2 and YAP1 proteins may be independent predictive risk factors for MCI in the elderly. Our findings may provide targets for the development of early minimally invasive, efficient, and convenient screening tools, and even for the treatment of AD in the future.},
}

@article {pmid40933190,
year = {2025},
author = {Shen, X and Hu, X and Zhang, R and Fu, Y and Xu, J and Lyu, D and Xie, H and Shi, D and Shi, C and Li, L and Gao, Y},
title = {A lightweight triple-modal fusion network for progressive mild cognitive impairment prediction in Alzheimer's disease.},
journal = {Frontiers in neuroscience},
volume = {19},
number = {},
pages = {1637291},
doi = {10.3389/fnins.2025.1637291},
pmid = {40933190},
issn = {1662-4548},
abstract = {INTRODUCTION: As a progressive neurodegeneration, Alzheimer's disease (AD) represents the primary etiology of dementia among the elderly. Early identification of individuals with mild cognitive impairment (MCI) who are likely to convert to AD is essential for timely diagnosis and therapeutic intervention. Although multimodal neuroimaging and clinical data provide complementary information, existing fusion models often face challenges such as high computational complexity and limited interpretability.

METHODS: To address these limitations, we introduce TriLightNet, an innovative lightweight triple-modal fusion network designed to integrate structural MRI, functional PET, and clinical tabular data for predicting MCI-to-AD conversion. TriLightNet incorporates a hybrid backbone that combines Kolmogorov-Arnold Networks with PoolFormer for efficient feature extraction. Additionally, it introduces a Hybrid Block Attention Module to capture subtle interactions between image and clinical features and employs a MultiModal Cascaded Attention mechanism to enable progressive and efficient fusion across the modalities. These components work together to streamline multimodal data integration while preserving meaningful insights.

RESULTS: Extensive experiments conducted on the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset demonstrate the effectiveness of TriLightNet, showcasing superior performance compared to state-of-the-art methods. Specifically, the model achieves an accuracy of 81.25%, an AUROC of 0.8146, and an F1-score of 69.39%, all while maintaining reduced computational costs.

DISCUSSION: Furthermore, its interpretability was validated using the Integrated Gradients method, which revealed clinically relevant brain regions contributing to the predictions, enhancing its potential for meaningful clinical application. Our code is available at https://github.com/sunyzhi55/TriLightNet.},
}

@article {pmid40933160,
year = {2025},
author = {Qiao, WY and Guo, QM and Li, XH},
title = {Peripheral blood biomarkers and mild behavioral impairment in mild cognitive impairment: Clinical correlations and mechanistic insights.},
journal = {World journal of psychiatry},
volume = {15},
number = {9},
pages = {108910},
doi = {10.5498/wjp.v15.i9.108910},
pmid = {40933160},
issn = {2220-3206},
abstract = {In the context of global aging, mild behavioral impairment (MBI) is present in 48.9% of patients with mild cognitive impairment (MCI). MBI, a neurobehavioral syndrome in the elderly, is an independent risk factor for cognitive decline and is closely related to peripheral blood biomarkers associated with Alzheimer's disease, offering new diagnostic and interventional avenues for early MCI. To summarize evidence on peripheral blood biomarkers related to MBI and their underlying mechanisms involving neuroinflammation, tau pathology, and oxidative stress, a systematic review of studies published between 2015 and 2024 was conducted. MBI is closely associated with peripheral blood biomarker changes. Neuroinflammatory markers like glial fibrillary acidic protein and neurofilament light indicate astrocyte activation and neural circuit disruption, with glial fibrillary acidic protein levels correlating with impulse dyscontrol scores. Chitinase-3-like protein 1, a marker of blood-brain barrier integrity, exacerbates neuroinflammation and is linked to depressive symptoms and hippocampal atrophy. Elevated phosphorylated tau proteins in blood correlate with brain tau deposition, increasing the risk of MBI and impairing cognition. Oxidative stress markers damage neurons and disrupt neurotransmission, and concurrent alterations in malondialdehyde and superoxide dismutase levels significantly elevate the risk of MBI. The correlation between MBI and biomarkers offers new diagnostic and interventional directions for early MCI. Future research should standardize MBI assessment, conduct longitudinal studies, explore biomarker-MBI relationships, investigate psychosocial impacts, and develop advanced detection methods.},
}

@article {pmid40933087,
year = {2025},
author = {Ono, T and Terasaki, T and Domon, R and Miho, O and Yoshida, K and Takahashi, S and Dairaku, T and Kashiwagi, Y and Sato, K},
title = {Measurement of acetylcholinesterase activity by electrochemical analysis method utilizing organocatalytic reactions.},
journal = {RSC advances},
volume = {15},
number = {39},
pages = {32464-32469},
doi = {10.1039/d5ra04585a},
pmid = {40933087},
issn = {2046-2069},
abstract = {An electrochemical method for measuring acetylcholinesterase (AChE) activity was developed using nortropine-N-oxyl (NNO), an organocatalyst. The increase in catalytic current as NNO oxidizes choline allowed real-time monitoring of the AChE hydrolysis reaction. Compared to conventional H2O2-based sensors, this method eliminates one reaction step, enabling more direct and real-time monitoring of enzymatic activity. Amperometric measurements enable AChE activity determination over a range of 50-2000 U L[-1] and the limit of detection and limit of quantification in the low concentration range were calculated to be 14.1 U L[-1] and 46.9 U L[-1], respectively, with a correlation coefficient (R [2]) of 0.9989. These results demonstrate that serum cholinesterase measurement using this method can be utilized for various diagnoses, such as liver and heart diseases. Furthermore, given the relevance of AChE in neurotoxicity evaluation, diagnosis of neurological disorders such as Alzheimer's disease, and environmental toxicity monitoring, this method has diverse potential applications. Moreover, this approach can be extended to other enzymatic reactions, indicating its promise for various analytical and diagnostic applications.},
}

@article {pmid40933041,
year = {2025},
author = {He, C and Chen, B and Yan, C and Zhou, X},
title = {Stem cell and CRISPR/Cas9 gene editing technology in Alzheimer's disease therapy: from basic research to clinical innovation.},
journal = {Frontiers in genome editing},
volume = {7},
number = {},
pages = {1612868},
doi = {10.3389/fgeed.2025.1612868},
pmid = {40933041},
issn = {2673-3439},
abstract = {Alzheimer's disease (AD), a progressive neurodegenerative disorder characterized by Aβ plaques, tau protein neuronal fiber tangles, and neuroinflammation, poses a significant global health problem, and current therapies focus on the symptoms rather than the cause. This paper gives a new multidimensional therapeutic form to AD treatment by exploring the integrated application of stem cell therapy and CRISPR/Cas9 gene editing technology. The study comprehensively dissected the roles of neural stem cells (NSCs), induced pluripotent stem cells (iPSCs) and mesenchymal stem cells (MSCs) in neural replacement, neuroinflammation modulation and neuroplasticity enhancement, and also explored the application of CRISPR/Cas9 in modifying the pathogenic variants of AD-related genes (APP, PSEN1 and PSEN2). The key findings suggest that gene-edited iPSCs can reduce abnormal Aβ and tau protein accumulation in AD models, improve cognitive function, and provide a platform for disease modeling and drug screening. Stem cell transplantation promotes neurogenesis and synaptic plasticity by secreting neurotrophic factors to improve the brain microenvironment. Despite the challenges of off-target effects, immune rejection, and long-term safety, the synergistic application of these two technologies offers a breakthrough solution for AD treatment. This paper highlights the translational potential of combining stem cells with gene editing technology, which is expected to drive clinical applications in the next 5-10 years. The integration of these advanced technologies not only addresses the limitations of current AD treatments, but also paves the way for a personalized medical approach that is expected to revolutionize the AD treatment landscape and bring new hope to patients worldwide.},
}

@article {pmid40932994,
year = {2025},
author = {Katel, S and Cicalo, J and Vasciaveo, V and Vecchio, LM and Carrion, J and Mahadeo, L and Huerta, PT and Choksi, JD and Aubert, I and Marambaud, P and Giliberto, L and d'Abramo, C},
title = {AAV-mediated peripheral scFv's administration to reduce cerebral tau in adult P301S transgenic mice: Mono-vs. combination therapy.},
journal = {Molecular therapy. Methods & clinical development},
volume = {33},
number = {3},
pages = {101563},
doi = {10.1016/j.omtm.2025.101563},
pmid = {40932994},
issn = {2329-0501},
abstract = {Tau is a primary target for immunotherapy in Alzheimer's disease (AD). Recent studies have shown the potential of anti-tau fragment antibodies in lowering pathological tau levels in vitro and in vivo. Here, we compared the effects of single-chain variable fragments (scFvs) derived from the well-characterized monoclonal antibodies PHF1 and MC1. We used adeno-associated virus 1 (AAV1) to deliver scFvs to skeletal muscle cells in 8-week-old P301S tau transgenic mice. We evaluated motor and behavioral functions at 16 and 23 weeks of age and measured misfolded, soluble, oligomeric, and insoluble brain tau species. Monotherapy with scFv-MC1 improved motor and behavioral functions more effectively than scFv-PHF1 or combination therapy. Brain glucose metabolism also benefited from scFv-MC1 treatment. Surprisingly, combining scFvs targeting early (MC1) and late (PHF1) tau modifications did not produce additive or synergistic effects. These results confirm that intramuscular AAV1-mediated scFv-MC1 gene therapy holds promise as a potential treatment for AD. Our findings also suggest that combining scFvs targeting different tau epitopes may not necessarily enhance efficacy if administered together in a prevention paradigm. Further research is needed to explore whether other antibodies' combinations and/or administration schedules could improve the efficacy of scFv-MC1 alone.},
}

@article {pmid40932805,
year = {2025},
author = {Diaz, CS and Vu, DT and Bodelet, J and Can, DC and Blanc, G and Jiang, H and Yao, L and Pantaleo, G and Chen, OY},
title = {OPTIMUS[*]: Predicting Multivariate Outcomes in Alzheimer's Disease using Multi-modal Data amidst Missing Values.},
journal = {IEEE transactions on bio-medical engineering},
volume = {PP},
number = {},
pages = {},
doi = {10.1109/TBME.2025.3608207},
pmid = {40932805},
issn = {1558-2531},
abstract = {OBJECTIVE: Alzheimer's disease, a progressive neurodegenerative disorder, involves neural, genetic, and proteomic factors and impacts multiple cognitive and behavioral domains. Traditional AD prediction largely focuses on univariate disease outcomes, such as disease stages and severity. Multimodal data provide richer disease information than a single modality and may enhance prediction, but are often incomplete due to missing measurements. Recent machine learning approaches show promise in improving prediction accuracy, but their biological relevance remains insufficiently understood.

METHODS: Integrating missing data analysis, predictive modeling, multimodal data analysis, and explainable AI (XAI), we propose OPTIMUS, a predictive and explainable machine-learning framework, to unveil the many-to-many predictive pathways between multimodal input data and multivariate disease outcomes amidst missing values.

RESULTS: OPTIMUS first applies imputation to handle missing data within each modality type while optimizing overall prediction accuracy. It then maps multimodal biomarkers to multivariate outcomes using machine learning and extracts biomarkers that are respectively predictive of each outcome. Finally, OPTIMUS incorporates XAI to explain the identified multimodal biomarkers.

CONCLUSION: Using data from 348 cognitively normal subjects, 601 persons with mild cognitive impairment, and 256 AD patients, OPTIMUS identifies neural and transcriptomic signatures that jointly but differentially predict outcomes related to memory, executive function, visuospatial function, and language.

SIGNIFICANCE: Our work demonstrates the potential of building a predictive and biologically explainable machine-learning framework to uncover multimodal biomarkers that capture disease profiles across varying cognitive landscapes. The results improve our understanding of the complex many-to-many pathways in AD.},
}

@article {pmid40932786,
year = {2025},
author = {Akzam-Ouellette, MA and Rouleau, I and Monetta, L and Descoteaux, M and Joubert, S},
title = {Semantic processing in subjective cognitive decline: An eye-tracking study.},
journal = {Neuropsychology},
volume = {},
number = {},
pages = {},
doi = {10.1037/neu0001022},
pmid = {40932786},
issn = {1931-1559},
support = {//Research Centre of the Institut universitaire de gériatrie de Montréal/ ; //Fonds de recherche du Québec-Nature et technologies/ ; //J.A. DeSève Fondation/ ; //Cerebrum/ ; //Social Sciences and Humanities Research Council of Canada/ ; //Fonds de recherche du Québec - Santé/ ; },
abstract = {OBJECTIVES: Alzheimer's disease progresses through several stages, starting with a preclinical phase characterized by subjective cognitive decline (SCD), where individuals express concerns about their memory despite normal cognitive test results. Recent research has indicated subtle semantic difficulties in SCD, prompting the need for a deeper investigation into cognitive processing during this phase. This study aimed to investigate the cognitive processing of famous and unfamiliar faces in individuals with SCD compared to healthy controls, focusing on semantic memory deficits assessment.

METHOD: Twenty-seven participants with SCD and 26 control participants performed a judgment task involving famous and unfamiliar faces while their eye movements were recorded. Mean fixation times, number of revisitations, and number of fixations were analyzed between the two groups.

RESULTS: The SCD group exhibited no significant differences in mean fixation times and in the number of revisited regions between famous and unfamiliar faces, in contrast to the control group, which showed distinct patterns in processing these categories of stimuli.

CONCLUSION: These findings suggest that individuals with SCD process famous faces similarly to unfamiliar faces, indicating a potential weakening of semantic processing in SCD. This may have implications for early detection of cognitive decline in Alzheimer's disease. (PsycInfo Database Record (c) 2025 APA, all rights reserved).},
}

@article {pmid40932409,
year = {2025},
author = {Ngernnak, C and Wongsuwan, S and Ruchirawat, S and Thasana, N},
title = {Synthesis and Evaluation of Tacrinocerins, Tacrine Hybrids with α-Onocerin from Phlegmariurus nummulariifolius (Blume) Ching, as a Novel Class of Acetylcholinesterase Inhibitor.},
journal = {Chemistry, an Asian journal},
volume = {},
number = {},
pages = {e00705},
doi = {10.1002/asia.202500705},
pmid = {40932409},
issn = {1861-471X},
support = {FRB650039/0240//Thailand Science Research and Innovation/ ; 49895/4759814//Chulabhorn Royal Academy/ ; },
abstract = {This study reports the synthesis and biological evaluation of tacrinocerins, a series of hybrid compounds derived from tacrine (1) and the natural product α-onocerin (2), which was isolated from the Thai club moss Phlegmariurus nummulariifolius (Blume) Ching. The primary aim was to develop potent and safe therapeutics for Alzheimer's disease (AD). The compounds were assessed for their inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), as well as their cytotoxicity and potential for cancer chemoprevention. The results showed that compound 8b was the most potent AChE inhibitor but exhibited high cytotoxicity to neuronal and hepatic cells, making it a better candidate for anticancer applications. Additionally, tacrinocerin 4u, which exhibited moderate AChE inhibition, low toxicity, and anticancer potential, makes it an attractive candidate for the development of safer therapeutic agents. Meanwhile, tacrinocerin 4c emerged as the most promising candidate for AD therapy, combining potent AChE inhibition with a favorable safety profile. It showed moderate to low toxicity to neuronal and hepatic cells, while also demonstrating significant anticancer activity against MOLT-3 cells and excellent multitarget chemopreventive potential. This research successfully identified 4c as a leading dual-action agent, providing a strong foundation for designing next-generation tacrinocerins with optimized therapeutic indices.},
}

@article {pmid40932346,
year = {2025},
author = {Hu, S},
title = {Methodological gaps in cervical LVA for Alzheimer's disease: implications from regulatory intervention.},
journal = {International journal of surgery (London, England)},
volume = {},
number = {},
pages = {},
doi = {10.1097/JS9.0000000000003355},
pmid = {40932346},
issn = {1743-9159},
}

@article {pmid40931996,
year = {2025},
author = {Hüls, A and Tan, Y and Casey, E and Li, Z and Gearing, M and Levey, AI and Lah, JJ and Wingo, AP and Jones, DP and Walker, DI and Wingo, TS and Liang, D},
title = {Metabolic dysregulation in Alzheimer's disease: A brain metabolomics approach.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {9},
pages = {e70528},
doi = {10.1002/alz.70528},
pmid = {40931996},
issn = {1552-5279},
support = {//Rollins School of Public Health Dean's Pilot and Innovation/ ; R01AG087250/AG/NIA NIH HHS/United States ; P30AG055611/AG/NIA NIH HHS/United States ; R01AG079170/AG/NIA NIH HHS/United States ; U01AG088425/AG/NIA NIH HHS/United States ; R01ES035738/ES/NIEHS NIH HHS/United States ; P30ES019776/ES/NIEHS NIH HHS/United States ; R21ES032117/ES/NIEHS NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/metabolism/pathology/genetics ; *Metabolomics ; Female ; Male ; Aged ; *Brain/metabolism/pathology ; Aged, 80 and over ; Apolipoprotein E4/genetics ; },
abstract = {INTRODUCTION: This study aimed to identify specific biological pathways and molecules involved in Alzheimer's disease (AD) neuropathology.

METHODS: We conducted cutting-edge high-resolution metabolomics profiling of 162 human frontal cortex samples from the Emory Alzheimer's Disease Research Center (ADRC) brain bank with comprehensive neuropathological evaluations.

RESULTS: We identified 155 unique metabolic features and 36 pathways associated with three well-established AD neuropathology markers. Of these, 18 novel metabolites were confirmed with level 1 evidence, implicating their involvement in amino acid metabolism, lipid metabolism, carbohydrate metabolism, nucleotide metabolism, and metabolism of cofactors and vitamins in AD neuropathology. Genetic variability influenced these associations, with non-carriers of the apolipoprotein E (APOE) ε4 allele showing stronger perturbations in metabolites including glucose and adenosine 5'-diphosphoribose.

DISCUSSION: This study demonstrates the potential of high-resolution metabolomic profiling in brain tissues to elucidate molecular mechanisms underlying AD pathology. Our findings provide critical insights into metabolic dysregulation in AD and its interplay with genetic factors.

HIGHLIGHTS: This is one of the largest untargeted metabolomics studies of human brain tissue. 155 metabolic features, and 36 metabolic pathways were linked to Alzheimer's disease (AD) neuropathology. Of these, 18 unique metabolites were confirmed with level 1 evidence. Glucose and adenosine 5'-diphosphoribose identified as key metabolic alterations in AD.},
}

Humans
*Alzheimer Disease/metabolism/pathology/genetics
*Metabolomics
Female
Male
Aged
*Brain/metabolism/pathology
Aged, 80 and over
Apolipoprotein E4/genetics

@article {pmid40931963,
year = {2025},
author = {Nardi Cesarini, E and Falcicchio, G and Librizzi, L and Sciaccaluga, M and Assenza, G and Galimberti, CA and Giorgi, FS and DiFrancesco, JC and Costa, C and , },
title = {Etiological diagnosis of late-onset epilepsy: A key priority for Italian epileptologists - Insights from a LICE survey.},
journal = {Epilepsia open},
volume = {},
number = {},
pages = {},
doi = {10.1002/epi4.70131},
pmid = {40931963},
issn = {2470-9239},
abstract = {OBJECTIVE: The incidence of epilepsy rises markedly after age 50. While late-onset epilepsy (LOE) is often linked to structural brain abnormalities, non-structural factors, such as infections, autoimmune disorders, and neurodegenerative diseases, also contribute. Approximately 20% of LOE cases remain of unknown etiology (LOEU). This study evaluated the diagnostic and therapeutic strategies employed by Italian epileptologists in managing LOE and LOEU, with the ultimate goal of proposing a standardized diagnostic algorithm.

METHODS: Data were collected through a cross-sectional online survey administered to neurologists who are formal members of the Italian Chapter of the International League Against Epilepsy (LICE). Descriptive statistics were used to summarize responses, and inferential statistics were applied to derive meaningful conclusions.

RESULTS: Sixty-five epilepsy centers across 19 of the 20 Italian regions participated in the survey. EEG (100%; n = 65) and brain MRI (92.31%; n = 60) were routinely employed in the diagnostic evaluation of LOE. In over half of the centers (58.46%; n = 38), sleep-activated or sleep-influenced EEGs were also used. For LOEU cases, neuropsychological assessments were performed in 60% of centers. More than 30% of centers employed additional diagnostic tools, including lumbar puncture, FDG-PET, and serum antibody testing for neural autoantibodies. The most commonly prescribed anti-seizure medications (ASMs) for LOE were levetiracetam (86.15%; n = 56), lacosamide (81.54%; n = 53), and lamotrigine (61.54%; n = 40).

SIGNIFICANCE: These findings suggested that Italian epileptologists frequently evaluate patients with LOE during routine outpatient visits. LOEU is increasingly recognized as a distinct subtype of LOE that may warrant a targeted diagnostic approach due to the potential involvement of autoimmune and neurodegenerative mechanisms. There is a pressing need for focused cross-sectional or prospective multicenter studies to refine the diagnostic strategies for LOE, particularly for LOEU, and to enhance the characterization of its clinical and etiological features.

PLAIN LANGUAGE SUMMARY: After age 50, epilepsy rates rise, often linked to brain changes but sometimes with no clear cause (LOEU). We surveyed Italian epilepsy specialists and found that routine EEG and MRI are widely used, yet about 20% of cases require advanced tests to identify rare or autoimmune causes. Our findings will inform patient-focused diagnostic and treatment guidelines and underscore the need for standardized care pathways and further research in adult-onset epilepsy.},
}

@article {pmid40931834,
year = {2025},
author = {Liu, L and Zheng, Y and Luo, K and Ma, H and Jiang, W and Luo, R and Pan, C and He, T and Ren, H and Tse, G and Liu, T and Li, X},
title = {Estimated Glucose Disposal Rate and Risk of Stroke and Dementia in Nondiabetics: A UK Biobank Prospective Cohort Study.},
journal = {Arteriosclerosis, thrombosis, and vascular biology},
volume = {},
number = {},
pages = {},
doi = {10.1161/ATVBAHA.125.322702},
pmid = {40931834},
issn = {1524-4636},
abstract = {BACKGROUND: The estimated glucose disposal rate (eGDR) is a validated surrogate marker of insulin resistance. However, its association with stroke and dementia in nondiabetic populations remains insufficiently investigated.

METHODS: This prospective cohort study included nondiabetic participants from the UK Biobank. The outcomes in this study were stroke, ischemic stroke, hemorrhagic stroke, all-cause dementia, vascular dementia, and Alzheimer disease. Multivariable Cox regression and restricted cubic splines were used to examine the associations between eGDR and outcomes. Polygenic risk score analyses were applied to investigate interactions between eGDR and genetic risk.

RESULTS: Overall, 430 093 participants were included. During a follow-up of around 13.5 years, 10 307 stroke cases and 11 137 all-cause dementia cases were recorded. Restricted cubic splines analyses indicated nonlinear associations between eGDR and the risks of stroke and vascular dementia. Below specific thresholds (<7.64 for stroke, <7.60 for ischemic stroke, <7.75 for hemorrhagic stroke, and <8.31 for vascular dementia), eGDR levels were not significantly associated with these outcomes except a modest inverse association with overall stroke risk (hazard ratio [HR] 0.97 [95% CI, 0.95-0.99]; P=0.012). In contrast, above these thresholds, higher eGDR levels were associated with significantly reduced risks of stroke (HR, 0.80 [95% CI, 0.78-0.82]; P<0.001), ischemic stroke (HR, 0.80 [95% CI, 0.78-0.81]; P<0.001), hemorrhagic stroke (HR, 0.81 [95% CI, 0.78-0.84]; P<0.001), and vascular dementia (HR, 0.89 [95% CI, 0.84-0.94]; P<0.001). A linear inverse relationship was observed between eGDR and all-cause dementia and Alzheimer disease. The HR in the highest versus lowest quartile was 0.81 (95% CI, 0.75-0.88) for all-cause dementia and 0.73 (95% CI, 0.64-0.84) for Alzheimer disease. Stratified polygenic risk score analyses revealed a synergistic interaction between reduced eGDR and elevated genetic susceptibility.

CONCLUSIONS: eGDR exhibited nonlinear associations with stroke and vascular dementia risk and linear inverse associations with all-cause dementia and Alzheimer disease in nondiabetic populations.},
}

@article {pmid40931717,
year = {2025},
author = {Rogers, EA and Diorio, TC and Beauclair, T and Martinez, J and Mufti, SJ and Kim, D and Krishnan, N and Rayz, V and Shi, R},
title = {Concussive injuries induce neuronal stress-dependent tau mislocalization to dendritic spines with acrolein and functional network alteration in TBI-on-a-chip.},
journal = {Lab on a chip},
volume = {},
number = {},
pages = {},
pmid = {40931717},
issn = {1473-0189},
abstract = {Traumatic brain injuries (TBIs) are a risk factor for Alzheimer's disease (AD), and share several important pathological features including the development of neurofibrillary tangles (NFT) of tau protein. While this association is well established, the underlying pathogenesis is poorly defined and current treatment options remain limited, necessitating novel methods and approaches. In response we developed "TBI-on-a-chip", an in vitro trauma model utilizing murine cortical networks on microelectrode arrays (MEAs), capable of reproducing clinically relevant impact injuries while providing simultaneous morphological and electrophysiological readout. Here, we incorporate a digital twin of the TBI-on-a-chip model to resolve cell-scale mechanical deformation via shear stresses and demonstrate direct connections between impact forces with aberrations in tau and synaptic deficits, and correlate these changes with elevations of oxidative stress, a suspected key contributor to both trauma and neurodegeneration. This multi-disciplinary investigation combines computational modeling, electrophysiology, and imaging, to explore tau mislocalization and functional deficits as a function of force, in the context of a potential mechanism via acrolein. We hope that this novel, integrative approach will help improve our mechanistic understanding of trauma and neurodegeneration, solo and in concert, and ultimately assist in generating more effective treatment options.},
}

@article {pmid40931680,
year = {2025},
author = {Stone, WJ and Pair, FS and Ekkatine, R and Gannon, M and Scholz, K and Pattanayak, R and Syed, R and Yacoubian, TA},
title = {14-3-3 Proteins Negatively Regulate Microglial Activation via Inhibition of the NF-κB Pathway.},
journal = {Journal of neurochemistry},
volume = {169},
number = {9},
pages = {e70228},
doi = {10.1111/jnc.70228},
pmid = {40931680},
issn = {1471-4159},
support = {//Parkinson Association of Alabama/ ; F31ES034985/NH/NIH HHS/United States ; R01NS112203/NH/NIH HHS/United States ; },
mesh = {*Microglia/metabolism/drug effects ; *14-3-3 Proteins/metabolism/antagonists & inhibitors ; Animals ; Mice ; *NF-kappa B/metabolism/antagonists & inhibitors ; *Signal Transduction/physiology/drug effects ; Lipopolysaccharides/pharmacology ; Mice, Inbred C57BL ; Cells, Cultured ; },
abstract = {Microglia, the resident immune cells of the central nervous system (CNS), are involved in the pathogenesis of neurodegenerative diseases, such as Alzheimer's disease (AD), Dementia with Lewy Bodies (DLB), and Parkinson's disease (PD). 14-3-3 proteins act as molecular hubs to regulate protein-protein interactions, which are involved in numerous cellular functions, including cellular signaling, protein folding, and apoptosis. We previously revealed decreased 14-3-3 levels in the brains of human subjects with neurodegenerative diseases. In this study, we examined the role of 14-3-3 proteins in the microglial proinflammatory response to lipopolysaccharide (LPS). We found that LPS treatment induced 14-3-3 protein levels within 6 hours. With the use of BV02 and dimeric fourteen-three-three peptide inhibitor (difopein), a small molecule and peptide inhibitor of 14-3-3 protein-protein interactions, respectively, we found a dramatic increase in microglial activation markers in both immortalized BV-2 microglial cells and in primary mouse microglia. Both 14-3-3 inhibitors also increased LPS-induced microglial phagocytosis, lysosomal proteolysis, and cytokine release in primary microglia. In contrast, chemotaxis toward the cellular damage stimulus, adenosine triphosphate (ATP), was diminished with 14-3-3 inhibition. Inhibition of 14-3-3's hastened LPS-induced activation of the nuclear factor-kB (NF-κB) signaling pathway, as measured by its nuclear translocation. 14-3-3's reduced activation of the NF-κB pathway by binding and inhibiting the release of IκB kinase beta (IKKβ). Disruption of 14-3-3's binding to IKKβ with BV02 or difopein increased the downstream phosphorylation and degradation of the inhibitor of NF-κB alpha (IκBα). Collectively, our findings suggest 14-3-3 proteins play a critical role in the regulation of inflammatory responses in microglia and may serve as potential targets for immunotherapy of CNS diseases.},
}

*Microglia/metabolism/drug effects
*14-3-3 Proteins/metabolism/antagonists & inhibitors
Animals
Mice
*NF-kappa B/metabolism/antagonists & inhibitors
*Signal Transduction/physiology/drug effects
Lipopolysaccharides/pharmacology
Mice, Inbred C57BL
Cells, Cultured

@article {pmid40931640,
year = {2025},
author = {Castellana, M and Raynor, G and Schildkrout, B and McGinnis, SM and MacRae, C and Lukacs, M and Miller, MB and Feany, MB and Silbersweig, DA and Daffner, KR and Gale, SA},
title = {Case Study 10: A 51-Year-Old Man With Psychosis, Decline in Self-Care, and Cognitive Deterioration.},
journal = {The Journal of neuropsychiatry and clinical neurosciences},
volume = {},
number = {},
pages = {appineuropsych20250048},
doi = {10.1176/appi.neuropsych.20250048},
pmid = {40931640},
issn = {1545-7222},
}

@article {pmid40931498,
year = {2025},
author = {Alemán-Villa, KM and Armienta-Rojas, DA and Camberos-Barraza, J and Rábago-Monzón, ÁR and Camacho-Zamora, A and Osuna-Ramos, JF and Magaña-Gómez, JA and Guadrón-Llanos, AM and Calderón-Zamora, L and Norzagaray-Valenzuela, CD and Valdez-Flores, MA and Picos-Cárdenas, VJ and De la Herrán-Arita, AK},
title = {Neuroinflammation across the spectrum of neurodegenerative diseases: mechanisms and therapeutic frontiers.},
journal = {Neuroimmunomodulation},
volume = {},
number = {},
pages = {1-33},
doi = {10.1159/000548021},
pmid = {40931498},
issn = {1423-0216},
abstract = {Neuroinflammation has emerged as a central and dynamic component of the pathophysiology underlying a wide range of neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and multiple sclerosis. Far from being a secondary consequence of neuronal damage, inflammatory processes (mediated by microglia, astrocytes, peripheral immune cells, and associated molecular mediators) actively shape disease onset, progression, and symptomatology. This review synthesizes current knowledge on the cellular and molecular mechanisms that govern neuroinflammatory responses, emphasizing both shared and disease-specific pathways. We examine how innate and adaptive immune interactions contribute to neuronal vulnerability and neurodegenerative cascades, and explore the reciprocal communication between systemic and central immune compartments. Particular attention is given to emerging therapeutic strategies aimed at modulating neuroinflammation, including immunomodulatory drugs, glial-targeted interventions, and novel delivery platforms. By integrating findings across disciplines and disease models, we outline key translational challenges and propose future directions to harness neuroinflammation as a therapeutic target in the era of precision medicine. Ultimately, a deeper understanding of neuroimmune dynamics holds promise for redefining both the diagnosis and treatment of neurodegenerative disorders.},
}

@article {pmid40931359,
year = {2025},
author = {Ramonet, D and Daerr, A and Hallbeck, M},
title = {Stabilizing the retromer complex rescues synaptic dysfunction and endosomal trafficking deficits in an Alzheimer's disease mouse model.},
journal = {Acta neuropathologica communications},
volume = {13},
number = {1},
pages = {190},
pmid = {40931359},
issn = {2051-5960},
support = {2019-01016//Swedish Research Council/ ; },
mesh = {Animals ; *Alzheimer Disease/metabolism/pathology/genetics/drug therapy ; Mice ; *Endosomes/metabolism/drug effects/pathology ; Disease Models, Animal ; *Synapses/metabolism/drug effects/pathology ; Mice, Transgenic ; *Vesicular Transport Proteins/metabolism/genetics ; Protein Transport/drug effects/physiology ; Humans ; },
abstract = {Disruptions in synaptic transmission and plasticity are early hallmarks of Alzheimer's disease (AD). Endosomal trafficking, mediated by the retromer complex, is essential for intracellular protein sorting, including the regulation of amyloid precursor protein (APP) processing. The VPS35 subunit, a key cargo-recognition component of the retromer, has been implicated in neurodegenerative diseases, with mutations such as L625P linked to early-onset AD. Despite growing evidence for retromer dysfunction in AD, its role in synaptic pathology and neuroinflammation remains incompletely understood. Here, we investigate the acute molecular effects of retromer stabilization in the 5xFAD mouse model of AD using the pharmacological chaperones R55 and R33, previously identified to enhance VPS35 stability. Following intracranial stereotaxic injections, we performed transcriptomic profiling, quantitative histology, and immunohistochemistry to assess synaptic function, neuroinflammation, and endosomal trafficking. Our findings reveal that retromer stabilization reverses multiple AD-associated molecular changes. R55 treatment significantly reduced Aβ-related pathology, normalized synaptic gene expression, and restored long-term potentiation (LTP)-associated pathways, including Gria1 (AMPA receptors), Grip1, and semaphorin/plexin signaling. Additionally, retromer stabilization counteracted dysregulated calcium signaling by modulating Ryr2 and L-type calcium channel expression. Beyond synaptic effects, we observed broad transcriptional and structural changes in the endosomal system. Notably, R55 treatment decreased VPS13 family gene expression, implicated in membrane contact site regulation, while increasing RAB7 levels, suggesting enhanced late-endosomal recycling. VPS35-positive vesicles were redistributed away from the nucleus, indicating restored intracellular trafficking dynamics. In the neuroinflammatory domain, retromer stabilization modulated microglial activation, shifting towards a profile characterized by balanced pro-inflammatory (Il1, Nfkb2) and anti-inflammatory (Il4r, Il13ra1, Stat6) markers, consistent with disease-associated microglia (DAM) phenotypes. Together, these findings demonstrate that retromer dysfunction contributes to key AD pathologies, including synaptic dysfunction and neuroinflammation, and that pharmacological retromer stabilization can restore cellular homeostasis. Given that 5xFAD mice lack direct VPS35 mutations, our results suggest that retromer-targeting strategies may be applicable to both familial and sporadic AD, offering a promising therapeutic avenue for modifying disease progression.},
}

Animals
*Alzheimer Disease/metabolism/pathology/genetics/drug therapy
Mice
*Endosomes/metabolism/drug effects/pathology
Disease Models, Animal
*Synapses/metabolism/drug effects/pathology
Mice, Transgenic
*Vesicular Transport Proteins/metabolism/genetics
Protein Transport/drug effects/physiology
Humans

@article {pmid40931114,
year = {2025},
author = {Afshar, S and Dammer, EB and Bian, S and Bennett, DA and Mohs, R and Beauregard, D and Dwyer, J and Hales, CM and Goldstein, FC and Parker, MW and Trammell, AR and Watson, CM and Golde, TE and Seyfried, NT and Roberts, BR and Manzanares, CM and Lah, JJ and Levey, AI and Johnson, ECB},
title = {Plasma proteomic associations with Alzheimer's disease endophenotypes.},
journal = {Nature aging},
volume = {},
number = {},
pages = {},
pmid = {40931114},
issn = {2662-8465},
abstract = {Clinical Alzheimer's disease is currently characterized by cerebral β-amyloidosis associated with cognitive impairment. However, most cases of Alzheimer's disease are associated with multiple neuropathologies at autopsy. The peripheral protein changes associated with these disease endophenotypes are poorly understood. In this study, we analyzed the plasma proteomes of individuals from four cohorts (n = 2,139 participants) to identify proteins and pathways associated with cerebral β-amyloidosis and other neuropathologies, including tau, Lewy bodies, TDP43, cerebral amyloid angiopathy, atherosclerosis, arteriolosclerosis and infarcts as well as cognitive function. Analyses in a cohort with paired brain data showed that known neuropathologies could account for only half of proteins associated with cognitive function and that many plasma proteins associated with these neuropathologies are not strongly correlated to levels in brain, suggesting a potential contribution of peripheral factors to the development of Alzheimer's disease endophenotypes. Targeting pathways represented by these peripheral proteins may modify Alzheimer's disease risk or disease progression.},
}

@article {pmid40931113,
year = {2025},
author = {Hu, M and Kang, X and Liu, Z and Wang, S and Liu, S and Li, C and Lu, D and Qin, Q and Liu, Y and Yi, H and Yuan, L and Liu, Q and Lu, Z and Cai, W},
title = {Senescent-like border-associated macrophages regulate cognitive aging via migrasome-mediated induction of paracrine senescence in microglia.},
journal = {Nature aging},
volume = {},
number = {},
pages = {},
pmid = {40931113},
issn = {2662-8465},
support = {82271348//National Natural Science Foundation of China (National Science Foundation of China)/ ; },
abstract = {Aging is a major risk factor for various neurological disorders, including Alzheimer's disease, and is associated with the accumulation of senescent cells, which can themselves propagate the senescence process through paracrine signaling. Migrasomes are organelles that form during cellular migration, detach from parent cells and mediate intercellular communication. Here we demonstrate that border-associated macrophages (BAMs) acquire senescence-associated properties during early brain aging, possibly due to prolonged exposure to amyloid beta. Senescent-like BAMs show elevated production of migrasomes, which convey senescence-associated signals including the apoptosis inhibitor of macrophage to neighboring cells. We show that microglia are prominent recipients of senescent-like BAM-derived migrasomes, and that through activation of CD16 in recipient cells, the apoptosis inhibitor of macrophage inhibits apoptosis and promotes senescence induction. Blocking migrasome induction in senescent-like BAMs through treatment with Tspan4-targeting siRNA-encapsulated liposomes ameliorates cognitive deficits in aged mice. Our findings suggest that migrasomes are potent vehicles of senescence-regulatory signals and represent a promising target for senomorphic therapy.},
}

@article {pmid40931065,
year = {2025},
author = {von Maydell, D and Wright, SE and Pao, PC and Staab, C and King, O and Spitaleri, A and Bonner, JM and Liu, L and Yu, CJ and Chiu, CC and Leible, D and Ni Scannail, A and Li, M and Boix, CA and Mathys, H and Leclerc, G and Menchaca, GS and Welch, G and Graziosi, A and Leary, N and Samaan, G and Kellis, M and Tsai, LH},
title = {ABCA7 variants impact phosphatidylcholine and mitochondria in neurons.},
journal = {Nature},
volume = {},
number = {},
pages = {},
pmid = {40931065},
issn = {1476-4687},
abstract = {Loss-of-function variants in the lipid transporter ABCA7 substantially increase the risk of Alzheimer's disease[1,2], yet how they impact cellular states to drive disease remains unclear. Here, using single-nucleus RNA-sequencing analysis of human brain samples, we identified widespread gene expression changes across multiple neural cell types associated with rare ABCA7 loss-of-function variants. Excitatory neurons, which expressed the highest levels of ABCA7, showed disrupted lipid metabolism, mitochondrial function, DNA repair and synaptic signalling pathways. Similar transcriptional disruptions occurred in neurons carrying the common Alzheimer's-associated variant ABCA7 p.Ala1527Gly[3], predicted by molecular dynamics simulations to alter the ABCA7 structure. Induced pluripotent stem (iPS)-cell-derived neurons with ABCA7 loss-of-function variants recapitulated these transcriptional changes, displaying impaired mitochondrial function, increased oxidative stress and disrupted phosphatidylcholine metabolism. Supplementation with CDP-choline increased phosphatidylcholine synthesis, reversed these abnormalities and normalized amyloid-β secretion and neuronal hyperexcitability-key Alzheimer's features that are exacerbated by ABCA7 dysfunction. Our results implicate disrupted phosphatidylcholine metabolism in ABCA7-related Alzheimer's risk and highlight a possible therapeutic approach.},
}

@article {pmid40930705,
year = {2025},
author = {Morales-García, JA},
title = {Modeling neurodegeneration and neuroinflammation in Parkinson's Disease: Animal-based strategies.},
journal = {Methods in cell biology},
volume = {197},
number = {},
pages = {81-114},
doi = {10.1016/bs.mcb.2025.02.006},
pmid = {40930705},
issn = {0091-679X},
mesh = {Animals ; *Parkinson Disease/pathology ; *Disease Models, Animal ; Humans ; *Neuroinflammatory Diseases/pathology ; Mice ; Dopaminergic Neurons/pathology/metabolism ; Inflammation/pathology ; },
abstract = {Parkinson disease (PD) is the second most prevalent neurodegenerative disorder globally, trailing only Alzheimer´s disease. It currently affects nearly 3 % of individuals aged 65 and above. The disease is characterized by the progressive loss of dopaminergic neurons accompanied by a chronic neuroinflammatory process, which is responsible for both motor symptoms (tremor, rigidity, bradykinesia) and non-motor symptoms (depression, dysphagia, anxiety, constipation, and anosmia). To gain a deeper comprehension of the fundamental mechanisms underlying PD and to facilitate the development of efficacious therapeutic interventions, it is imperative to utilize animal models that accurately reflect the pathological characteristics observed in humans. This chapter provides a comprehensive overview of the methodologies employed in the generation of animal models of Parkinson's disease in laboratory settings. These models, which encompass a range of approaches, serve as invaluable tools for reproducing key aspects of neurodegeneration and neuroinflammation associated with PD. By establishing reliable animal models, we can investigate the cellular and molecular pathways driving disease progression, thereby gaining insights into potential therapeutic targets. Furthermore, the chapter discusses the limitations and advantages of different model systems, emphasizing their relevance in translational research aimed at finding effective treatments for PD patients.},
}

Animals
*Parkinson Disease/pathology
*Disease Models, Animal
Humans
*Neuroinflammatory Diseases/pathology
Mice
Dopaminergic Neurons/pathology/metabolism
Inflammation/pathology

@article {pmid40930702,
year = {2025},
author = {Tsakiri, E and Niforos-Garcia, G and Ackley, BD and Palikaras, K},
title = {Assessing mitochondrial number and morphology in a C. elegans model of human tauopathy.},
journal = {Methods in cell biology},
volume = {197},
number = {},
pages = {275-290},
doi = {10.1016/bs.mcb.2025.05.002},
pmid = {40930702},
issn = {0091-679X},
mesh = {Animals ; *Caenorhabditis elegans/metabolism/genetics ; *Mitochondria/pathology/metabolism ; *Tauopathies/pathology/metabolism/genetics ; Disease Models, Animal ; Humans ; tau Proteins/metabolism/genetics ; Neurons/metabolism/pathology ; Microscopy, Confocal/methods ; },
abstract = {Mitochondrial dysfunction is a shared hallmark of neurodegenerative disorders, including Alzheimer's disease (AD) and tauopathies among others. Pathological alterations of the microtubule-associated protein Tau can disrupt mitochondrial dynamics, transport, and function, ultimately leading to neuronal toxicity and synaptic deficits. Understanding these processes is crucial for developing therapeutic interventions. The nematode Caenorhabditis elegans serves as a powerful model to study mitochondrial morphology and Tau-induced neurotoxicity due to its well-characterized nervous system and genetic tractability. Here, we describe a robust methodology for assessing mitochondrial morphology, Tau aggregation, and neuronal integrity in a nematode model of tauopathy. By combining confocal laser scanning microscopy and motility assays, we provide a comprehensive framework for investigating mitochondrial deficits. This approach offers valuable insights into the interplay between Tau pathology and mitochondrial dysfunction, thereby advancing our understanding of neurodegenerative mechanisms and potential therapeutic targets.},
}

Animals
*Caenorhabditis elegans/metabolism/genetics
*Mitochondria/pathology/metabolism
*Tauopathies/pathology/metabolism/genetics
Disease Models, Animal
Humans
tau Proteins/metabolism/genetics
Neurons/metabolism/pathology
Microscopy, Confocal/methods

@article {pmid40930583,
year = {2025},
author = {Magill, N and Tank, R and Ferguson, D and Alston, D and O'Connor, A and Rice, H and Lu, K and Crutch, S and Fox, NC and Weston, PS},
title = {Accelerated long-term forgetting as a predictor of clinical onset in presymptomatic autosomal dominant Alzheimer's disease.},
journal = {Journal of neurology, neurosurgery, and psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1136/jnnp-2025-336750},
pmid = {40930583},
issn = {1468-330X},
abstract = {BACKGROUND: In Alzheimer's disease (AD), sensitive measures of cognitive decline prior to overt symptoms are urgently needed. Accelerated long-term forgetting (ALF), where new information is retained normally over conventional testing intervals but is then lost at an accelerated rate over the following days and weeks, has been identified cross-sectionally in presymptomatic autosomal dominant and sporadic AD cohorts. We aimed to assess whether ALF testing is predictive of proximity to future symptom onset.

METHODS: 20 asymptomatic autosomal dominant AD mutation carriers who performed normally on standard cognitive testing underwent ALF assessment with (1) a list, (2) a story and (3) a visual figure, with the testing of 30-min recall and 7-day recall. Participants were followed up annually for a median of 7 years and assessed each time with the Clinical Dementia Rating (CDR) scale.

RESULTS: 9/20 participants developed symptoms (CDR global>0) during follow-up. Those who became symptomatic had lower baseline ALF scores for both the list (progressors=30 (IQR, 30-36.4) and non-progressors=58.3 (IQR, 33-66.7), p=0.03) and story (progressors=58.8 (IQR, 44-66) and non-progressors=81.2 (IQR, 69.1-87.8), p<0.001). Story ALF (area under curve (AUC)=0.82) and list ALF (AUC=0.73) discriminated between those who did and did not develop symptoms.

CONCLUSIONS: Severity of ALF is not only associated with the presence of AD pathology but also predictive of clinical onset, identifying those at the highest risk of imminent decline. ALF testing offers promise in aiding presymptomatic trial recruitment, as a presymptomatic cognitive endpoint and potentially as a screening tool in the wider population.},
}

@article {pmid40930236,
year = {2025},
author = {Zhang, F and Ding, K and Zhang, LM and Liu, DY and Dong, X and Wang, MN and Zhou, FL and Sun, YW and Zhang, WK and Yan, Y and He, J and Xu, JK},
title = {The role of the gut microbiota in neuropsychiatric disorders and therapy.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {102894},
doi = {10.1016/j.arr.2025.102894},
pmid = {40930236},
issn = {1872-9649},
abstract = {The vast microbial community residing in the gut is known as the gut microbiota (GM). Alterations in the compositional equilibrium of the GM, a phenomenon termed GM dysbiosis, have been increasingly associated with the pathogenesis of various diseases, particularly neuropsychiatric disorders. The microbiota-gut-brain axis (MGBA) serves as a bidirectional communication system that connects the gut to the brain. Notably, several prevalent neuropsychiatric disorders, including depression, Alzheimer's disease (AD), and Parkinson's disease (PD), collectively affect over one billion individuals globally. Emerging scientific evidence has consistently demonstrated the presence of GM dysbiosis in various neuropsychiatric disorders, suggesting a potential etiological role of GM in these conditions through MGBA-mediated mechanisms. In this comprehensive review, we systematically discussed the GM and MGBA, and presented evidence from both animal and human studies that highlighted the significance of GM in the occurrence and development of neuropsychiatric disorders. Subsequently, we emphasized the potential impact of GM and its metabolites on neuropsychiatric disorders. Next, we summarized the drugs used to treat diseases by regulating the GM. Finally, we proposed strategies to ameliorate the malignant progression of neuropsychiatric disorders by manipulating the composition of the GM. These strategies encompass the application of probiotics, prebiotics and synbiotics, postbiotics, fecal microbiota transplantation (FMT), dietary interventions. Collectively, targeted GM therapy has the potential to be an effective treatment for neuropsychiatric disorders.},
}

@article {pmid40929913,
year = {2025},
author = {Fakhruddin, KS and Kamal, I and Maglaperidze, T and Marya, A and Samaranayake, L and Porntaveetus, T},
title = {Autism and the Oral Microbiome: A Systematic Review of Host-microbial Interactions and Diversity.},
journal = {International dental journal},
volume = {75},
number = {6},
pages = {100957},
doi = {10.1016/j.identj.2025.100957},
pmid = {40929913},
issn = {1875-595X},
abstract = {BACKGROUND: Emerging evidence suggests a link between the oral microbiome and autism spectrum disorder (ASD), a neurodevelopmental condition characterised by social and behavioural impairments. The vast microbial reservoirs in the gut complement those of the oral cavity, suggesting a potential oral-gut-brain axis that may influence ASD and perhaps other neurological diseases, such as Parkinson's syndrome and Alzheimer's disease. For the first time, this systematic review synthesises the current knowledge of oral microbiome composition, diversity, and functionality in ASD and its potential diagnostic and therapeutic implications.

METHODS: A comprehensive literature search was conducted using Medline (PubMed), Embase, Scopus, and Google Scholar for peer-reviewed case-control and cross-sectional studies published between January 2000 and January 2025. Study quality was assessed using the Newcastle-Ottawa scale.

RESULTS: Nine studies (n = 8533; 2536 ASD and 5937 controls) met the inclusion criteria. The overall findings on microbial diversity were inconsistent; some studies reported alterations in ASD, while others found no significant differences. Functional profiling revealed enrichment of pathways involved in dopamine and GABA degradation, as well as disruptions in lysine metabolism, suggesting possible links to neurotransmitter imbalances in ASD. Although external factors such as selective eating, oral hygiene, and cognitive function were proposed to influence microbial profiles, statistical evidence supporting these associations was lacking. Moreover, no consistent link was found between oral microbiota features and core ASD symptoms like repetitive behaviours or communication deficits.

CONCLUSION: This review highlights subtle yet potentially significant alterations in the oral microbiome of individuals with ASD, particularly in metabolic pathways that affect neurotransmitters. While direct associations with clinical symptoms remain unsubstantiated, the findings emphasise the importance of future multi-omics and longitudinal studies to clarify the oral microbiome's role in ASD pathophysiology and to explore its potential in personalised therapeutic strategies.},
}

@article {pmid40929907,
year = {2025},
author = {Ran, H and Zhang, X and Long, J and Wang, Z and Zhuang, S and Zhang, X and Jiang, Y and Zhang, J and Wang, G},
title = {Ultrasound-assisted extraction of naringin from Exocarpium Citri Grandis using a novel ternary natural deep eutectic solvent based on glycerol: Process optimization using ANN-GA, extraction mechanism and biological activity.},
journal = {Ultrasonics sonochemistry},
volume = {121},
number = {},
pages = {107551},
doi = {10.1016/j.ultsonch.2025.107551},
pmid = {40929907},
issn = {1873-2828},
abstract = {This study aimed to develop an efficient green ultrasound-assisted extraction (UAE) method for naringin (Nar) from Exocarpium Citri Grandis (ECG) using a glycerol-based ternary natural deep eutectic solvent (NADES) and explore its biofunctional relevance. After screening and single-factor optimization, the optimal NADES was identified as glycerol:malic acid:propanedioic acid (1:1:2 M ratio, 30 % water content). Extraction conditions (liquid-solid ratio, temperature, time) were optimized via response surface methodology (RSM) and an artificial neural network-genetic algorithm (ANN-GA), with ANN-GA demonstrating superior predictive capability. Optimal parameters (57 °C, 25.9 mL/g, 24.4 min) yielded a high Nar extraction yield of 175.30 ± 2.94 mg/g. Scanning electron microscopy (SEM) revealed structural changes in ECG, while extraction kinetics indicated an activation energy of 40.45 kJ/mol and molecular dynamics simulations elucidated improved solvation mechanisms. NADES was reusable for at least three cycles before efficiency decreased significantly at the fourth reuse. Furthermore, the extracted Nar showed significant inhibitory activity against key enzymes, with IC50 values of 19.6 μg/mL (α-glucosidase), 2.73 mg/mL (pancreatic lipase), and 1,086 μg/mL (acetylcholinesterase). These results indicate its potential for hypoglycemic, hypolipidemic, and anti-Alzheimer's therapeutic effects. This work establishes a sustainable strategy for efficient Nar extraction, integrating green solvent technology with bioactivity assessment to advance its therapeutic potential.},
}

@article {pmid40929704,
year = {2025},
author = {Liu, K},
title = {Circadian Rhythm Disruption and Sleep Disorders in Alzheimer's Disease: Mechanistic Insights and Therapeutic Potentials.},
journal = {Neuro endocrinology letters},
volume = {46},
number = {2},
pages = {59-69},
pmid = {40929704},
issn = {2354-4716},
abstract = {Alzheimer's Disease (AD) is the leading cause of dementia worldwide, with significant cognitive and behavioural impairments that devastate individuals and their families. Cohort-level findings, demonstrate the broader population-level implications of Sleep and Circadian Rhythm Disruption (SCRD) in AD and underscore the need for early interventions, emphasizing the importance of timely action. However, the mechanism remains unclear. SCRD impairs the glymphatic system, which is responsible for the clearance of neurotoxic proteins such as amyloid-β and tau during slow-wave sleep, accelerating neurodegeneration. Moreover, SCRD exacerbates neuroinflammation by disrupting the circadian regulation of immune responses, mainly through the dysregulation of microglial activity and pro-inflammatory cytokine release, which further promotes neuronal damage. This review summarizes the current understanding of SCRD in AD, outlining the mechanistic links, evidence from animal models, and emerging treatments targeting SCRD in AD, as well as promising new drug targets emerging from preclinical studies. Circadian modulation may represent a novel therapeutic avenue for AD.},
}

@article {pmid40929507,
year = {2025},
author = {Koh, Y and Tengesdal, IW and Jaiswal, S},
title = {Clonal Hematopoiesis in Nonmalignant Disease: Functional Consequences of Mutated Immune Cells by Clonal Hematopoiesis in the Diseased Tissue.},
journal = {Annual review of pathology},
volume = {},
number = {},
pages = {},
doi = {10.1146/annurev-pathmechdis-111523-023442},
pmid = {40929507},
issn = {1553-4014},
abstract = {Clonal hematopoiesis, originally identified as a precursor to hematologic malignancies, has emerged as a significant factor in various nonmalignant diseases. Recent research highlights how somatic mutations in hematopoietic stem cells lead to the expansion of circulating mutated immune cells that exert profound effects on organ function and disease progression. These mutated clones display altered inflammatory profiles and tissue-specific functional consequences, contributing to various diseases including atherosclerotic cardiovascular disease, osteoporosis, heart failure, and neurodegenerative conditions. Key mutations, particularly in genes regulating epigenetics (TET2, DNMT3A, ASXL1), splicing (SF3B1, U2AF1), and DNA damage repair (TP53, PPM1D), modify immune responses and promote chronic inflammation. Intriguingly, while clonal hematopoiesis exacerbates many inflammatory conditions, it has been linked to a protective effect in Alzheimer's disease, potentially due to enhanced microglial function. Understanding the mechanistic underpinnings of clonal hematopoiesis in nonmalignant disease may inform targeted therapeutic strategies, particularly those aimed at modulating inflammation. This review explores the gene- and organ-specific roles of clonal hematopoiesis, highlighting its implications for disease pathogenesis and potential interventions.},
}

@article {pmid40929163,
year = {2025},
author = {Schwertner, K and Basílio, J and Hoffmann-Sommergruber, K and Ellinger, I and Geiselhart, S},
title = {Global transcriptional analysis of human FHs 74 Int intestinal epithelial cells after exposure to advanced glycation end products.},
journal = {PloS one},
volume = {20},
number = {9},
pages = {e0331325},
doi = {10.1371/journal.pone.0331325},
pmid = {40929163},
issn = {1932-6203},
mesh = {Humans ; *Glycation End Products, Advanced/pharmacology ; *Intestinal Mucosa/metabolism/cytology/drug effects ; *Epithelial Cells/metabolism/drug effects ; S100A12 Protein/pharmacology ; *Transcriptome/drug effects ; Gene Expression Profiling ; Cell Line ; Gene Expression Regulation/drug effects ; Cell Proliferation/drug effects ; },
abstract = {Advanced glycation end products (AGEs) and reactive intermediates, such as methylglyoxal, are formed during thermal processing of foods and have been implicated in the pathogenesis of a series of chronic inflammatory diseases. AGEs are thought to directly interact with the intestinal epithelium upon ingestion of thermally processed foods, but their effects on intestinal epithelial cells are poorly understood. This study investigated transcriptomic changes in human intestinal epithelial FHs 74 Int cells after exposure to AGE-modified human serum proteins (AGE-HS), S100A12, a known RAGE ligand, and unmodified human serum proteins (HS). In contrast to previous studies employing cancer cell lines, RNA sequencing of FHs 74 Int cells treated with AGE-HS did not reveal transcriptional changes associated with increased proliferation, increased expression of tight junction proteins or proinflammatory responses. Surprisingly, neither AGE-HS nor S100A12 treatments resulted in significant differential gene expression at standard analysis thresholds, while unmodified HS induced minor transcriptional changes. Gene set enrichment analysis revealed that AGE-HS treatment induced downregulation of gene sets linked to MYC, interferon responses, and oxidative phosphorylation, as well as pathways related to neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's disease, paralleling some effects observed with S100A12. This is the first global transcriptomic analysis of FHs 74 Int cells and the first unbiased investigation of signaling pathway alterations in intestinal epithelial cells exposed to AGEs. In contrast to previous studies, this analysis did not reveal any significantly differentially expressed genes, thus challenging previous reports of robust AGE-induced inflammatory and proliferative effects and emphasizing the importance of an isolated experimental setting and rigorous endotoxin testing.},
}

Humans
*Glycation End Products, Advanced/pharmacology
*Intestinal Mucosa/metabolism/cytology/drug effects
*Epithelial Cells/metabolism/drug effects
S100A12 Protein/pharmacology
*Transcriptome/drug effects
Gene Expression Profiling
Cell Line
Gene Expression Regulation/drug effects
Cell Proliferation/drug effects

@article {pmid40929154,
year = {2025},
author = {Oliver, MD and Morrison, C and El-Hulu, S and Harvey, M and Lamar, M and Bennett, DA and Barnes, LL},
title = {The Relationship Between Blood Pressure and Cognitive Decline Differs by Race.},
journal = {The Gerontologist},
volume = {},
number = {},
pages = {},
doi = {10.1093/geront/gnaf189},
pmid = {40929154},
issn = {1758-5341},
abstract = {BACKGROUND AND OBJECTIVES: Cognition may be influenced by health-related factors such as blood pressure (BP). However, variations in BP may differentially affect cognition across race. This study investigates BP and cognitive decline in older Black and White adults.

RESEARCH DESIGN AND METHODS: 2,284 participants (1,139 Blacks, 1,145 Whites, M  Age=73.4) from 3 harmonized cohorts of older adults from the Rush Alzheimer's Disease Center, were divided into 3 groups (normal, high, variable) based on systolic BP mean and standard deviation. Cognitive scores were computed from 18 neuropsychological tests and averaged to summarize 5 domains (episodic memory, semantic memory, working memory, processing speed, visuospatial ability) and a measure of global cognition. Linear mixed-effects models examined racial differences between BP and cognition over an average of 6.7 years.

RESULTS: White adults with high BP declined faster in global cognition, perceptual speed, semantic memory, and working memory compared to Black adults with high BP, whereas White adults with variable BP had faster rates of decline in global cognition, all cognitive domains, compared to Black adults with variable BP. No differences in rate of cognitive decline were observed between Black and White older adults with normal BP.

DISCUSSION AND IMPLICATIONS: Variations in BP differentially relate to cognitive decline in Black and White older adults, highlighting the interplay between BP and cognitive health, and the importance of race in understanding this relationship.},
}

@article {pmid40929148,
year = {2025},
author = {Huo, M and Kim, K},
title = {Volunteering With Mild Cognitive Impairment: Implications for Subsequent Cognitive Changes.},
journal = {The Gerontologist},
volume = {},
number = {},
pages = {},
doi = {10.1093/geront/gnaf190},
pmid = {40929148},
issn = {1758-5341},
abstract = {BACKGROUND AND OBJECTIVES: Volunteering has cognitive benefits in later life and has been theorized to protect against Alzheimer's disease and related dementias (ADRD). A small but growing body of volunteer programs target people with mild cognitive impairment (MCI)-who are presumably at elevated risk for ADRD, but we know surprisingly little about who volunteers with MCI and how volunteering affects their subsequent cognitive changes. The current study sought to address these gaps.

RESEARCH DESIGN AND METHODS: We used longitudinal data from the Health and Retirement Study (2002-2018) and identified a pooled sample of 6,930 midlife and older adults (aged 50+) who met criteria for MCI based on their cognitive scores on the Telephone Interview for Cognitive Status (TICS). We tracked these participants' sociodemographic characteristics, volunteer activities, and cognitive scores in the subsequent 4 years.

RESULTS: A two-level logistic regression showed that among midlife and older adults with MCI, those who attained more years of education, had greater wealth, reported a history of volunteering, and had better self-rated health as well as fewer functional limitations were more likely to report volunteering in the presence of MCI. Volunteers with MCI-particularly those who continuously volunteered or initiated volunteering-exhibited more positive cognitive changes over time.

DISCUSSION AND IMPLICATIONS: This study highlights the importance of socioeconomic resources and health in predicting volunteering with MCI and reveals lasting cognitive benefits of volunteering as midlife and older adults adjust to their cognitive impairment. Findings call for more tailored volunteer opportunities for people with MCI.},
}

@article {pmid40929146,
year = {2025},
author = {He, C and Xu, Y and Zhou, Y and Fan, J and Cheng, C and Meng, R and Wu, L and Pan, R and Shah, RV and Gamazon, ER and Zhou, D},
title = {Integrating population-level and cell-based signatures for drug repositioning.},
journal = {Bioinformatics (Oxford, England)},
volume = {},
number = {},
pages = {},
doi = {10.1093/bioinformatics/btaf498},
pmid = {40929146},
issn = {1367-4811},
abstract = {MOTIVATION: Drug repositioning presents a streamlined and cost-efficient way to expand the range of therapeutic possibilities. Drugs with human genetic evidence are more likely to advance successfully through clinical trials towards FDA approval. Single gene-based drug repositioning methods have been implemented, but approaches leveraging a broad spectrum of molecular signatures remain underexplored.

RESULTS: We propose a framework called "TReD" (Transcriptome-informed Reversal Distance) that embeds the disease signatures and drug response profiles into a high-dimensional normed space to quantify the reversal potential of candidate drugs in a disease-related cell-based screening. We applied TReD to COVID-19, type 2 diabetes (T2D), and Alzheimer's disease (AD), identifying 36, 16, and 11 candidate drugs, respectively. Among these, literature supports 69% (25/36), 31% (5/16), and 64% (7/11) of the drugs, with clinical trials conducted for seven COVID-19 candidates and three AD candidates. In summary, we propose a comprehensive genetics-anchored framework integrating population-level signatures and cell-based screening that has the potential to accelerate the search for new therapeutic strategies.

AVAILABILITY: Source code and datasets considered in this study are available at Github (https://github.com/zdangm/TReD). An archived snapshot is deposited at Zenodo (https://doi.org/10.5281/zenodo.16791909).

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.},
}

@article {pmid40929145,
year = {2025},
author = {Quiñones-Cordero, MM and Norton, S and Rivas, C and Gallagher-Thompson, D and Silva, C},
title = {Exploring the Unmet Needs of Latino Dementia Caregivers: A Qualitative Study.},
journal = {The Gerontologist},
volume = {},
number = {},
pages = {},
doi = {10.1093/geront/gnaf191},
pmid = {40929145},
issn = {1758-5341},
abstract = {BACKGROUND AND OBJECTIVES: Over 12% of older Latinos in the United States have Alzheimer's disease and related dementias (ADRD), facing earlier onset of the disease and severe symptoms compared to non-Hispanic Whites. These disparities in ADRD among Latinos can lead to significant caregiver strain and burden in Latino ADRD caregivers. Notably, Latino ADRD caregivers have poor overall health outcomes and face systemic inequities including limited access to quality dementia care resources that impact their well-being significantly. This qualitative descriptive study aimed to investigate Latino caregivers' unmet needs and challenges in caring for someone with dementia.

RESEARCH DESIGN AND METHODS: Participants were twenty-three Latino ADRD caregivers, most of whom were caring for a parent with ADRD. Caregivers were recruited nationally through online research platforms or locally through community outreach and provider referrals. They completed in-depth semi-structured interviews in English or Spanish. Audio recordings were transcribed and analyzed in Atlas.ti 23 using a thematic content analysis approach.

RESULTS: Four themes were derived from the data analysis as key areas of caregiving needs for Latinos: need to connect socially with others; need for resources to provide care; need to understand dementia and navigating existing resources and future care planning; and need for empathic, culturally congruent healthcare.

DISCUSSION AND IMPLICATIONS: Results identify several areas of unmet needs among Latino ADRD caregivers, elucidating nuanced aspects about the challenging experiences of Latino caregivers. Findings highlight potential areas for future research to develop targeted and culturally attuned interventions to improve Latino ADRD caregiver well-being.},
}

@article {pmid40929122,
year = {2025},
author = {Moorthy, DK and Nagaraj, P},
title = {Attention Gated-VGG with deep learning-based features for Alzheimer's disease classification.},
journal = {Neurodegenerative disease management},
volume = {},
number = {},
pages = {1-12},
doi = {10.1080/17582024.2025.2554495},
pmid = {40929122},
issn = {1758-2032},
abstract = {BACKGROUND: Alzheimer's disease (AD) is considered to be one of the neurodegenerative diseases with possible cognitive deficits related to dementia in human subjects. High priority should be put on efforts aimed at early detection of AD.

RESEARCH DESIGN AND METHODS: Here, images undergo a pre-processing phase that integrates image resizing and the application of median filters. After that, processed images are subjected to data augmentation procedures. Feature extraction from WOA-based ResNet, together with extracted convolutional neural network (CNN) features from pre-processed images, is used to train proposed DL model to classify AD. The process is executed using the proposed Attention Gated-VGG model.

RESULTS: The proposed method outperformed normal methodologies when tested and achieved an accuracy of 96.7%, sensitivity of 97.8%, and specificity of 96.3%.

CONCLUSION: The results have proven that Attention Gated-VGG model is a very promising technique for classifying AD.},
}

@article {pmid40928913,
year = {2025},
author = {Huang, F and Chen, N and Qiu, A},
title = {3D-CNN Enhanced Multiscale Progressive Vision Transformer for AD Diagnosis.},
journal = {IEEE journal of biomedical and health informatics},
volume = {PP},
number = {},
pages = {},
doi = {10.1109/JBHI.2025.3607789},
pmid = {40928913},
issn = {2168-2208},
abstract = {Vision Transformer (ViT) applied to structural magnetic resonance images has demonstrated success in the diagnosis of Alzheimer's disease (AD) and mild cognitive impairment (MCI). However, three key challenges have yet to be well addressed: 1) ViT requires a large labeled dataset to mitigate overfitting while most of the current AD-related sMRI data fall short in the sample sizes. 2) ViT neglects the within-patch feature learning, e.g., local brain atrophy, which is crucial for AD diagnosis. 3) While ViT can enhance capturing local features by reducing the patch size and increasing the number of patches, the computational complexity of ViT quadratically increases with the number of patches with unbearable overhead. To this end, this paper proposes a 3D-convolutional neural network (CNN) Enhanced Multiscale Progressive ViT (3D-CNN-MPVT). First, a 3D-CNN is pre-trained on sMRI data to extract detailed local image features and alleviate overfitting. Second, an MPVT module is proposed with an inner CNN module to explicitly characterize the within-patch interactions that are conducive to AD diagnosis. Third, a stitch operation is proposed to merge cross-patch features and progressively reduce the number of patches. The inner CNN alongside the stitch operation in the MPTV module enhances local feature characterization while mitigating computational costs. Evaluations using the Alzheimer's Disease Neuroimaging Initiative dataset with 6610 scans and the Open Access Series of Imaging Studies-3 with 1866 scans demonstrated its superior performance. With minimal preprocessing, our approach achieved an impressive 90% accuracy and 80% in AD classification and MCI conversion prediction, surpassing recent baselines.},
}

@article {pmid40928843,
year = {2025},
author = {Chen, YC and Maupas, A and Nowick, K},
title = {Regulatory networks of KRAB zinc finger genes and transposable elements changed during human brain evolution and disease.},
journal = {eLife},
volume = {14},
number = {},
pages = {},
doi = {10.7554/eLife.103608},
pmid = {40928843},
issn = {2050-084X},
support = {NO 920/8-1//Deutsche Forschungsgemeinschaft/ ; NO 920/10-1//Deutsche Forschungsgemeinschaft/ ; },
mesh = {Humans ; *DNA Transposable Elements/genetics ; *Evolution, Molecular ; *Brain/metabolism ; Animals ; *Gene Regulatory Networks ; *Zinc Fingers/genetics ; Primates/genetics ; *Repressor Proteins/genetics/metabolism ; },
abstract = {Evidence indicates that transposable elements (TEs) can contribute to the evolution of new traits, with some TEs acting as deleterious elements while others are repurposed for beneficial roles in evolution. In mammals, some KRAB-ZNF proteins can serve as a key defense mechanism to repress TEs, offering genomic protection. Notably, the family of KRAB-ZNF genes evolves rapidly and exhibits diverse expression patterns in primate brains, where some TEs, including autonomous LINE-1 and non-autonomous Alu and SVA elements, remain mobile. This prompts questions about their interactions in primate brains and potential roles in human brain evolution and disease. For a systematic comparative analysis of TE interactions with other genes, we developed the tool TEKRABber and focused on strong and experimentally validated cases. Our bipartite network analysis revealed significantly more interactions between KRAB-ZNF genes and TEs in humans than in other primates, especially with recently evolved, i.e., Simiiformes-specific, TEs. Notably, ZNF528, under positive selection in humans, shows numerous human-specific TE interactions. Most negative interactions in our network, indicative of repression by KRAB-ZNF proteins, entail Alu TEs, while links to other TEs are generally positive. In Alzheimer's patients, a subnetwork involving 21 interactions with an Alu module appears diminished or lost. Our findings suggest that KRAB-ZNF and TE interactions vary across TE families, have increased throughout human evolution, and may influence susceptibility to Alzheimer's disease.},
}

Humans
*DNA Transposable Elements/genetics
*Evolution, Molecular
*Brain/metabolism
Animals
*Gene Regulatory Networks
*Zinc Fingers/genetics
Primates/genetics
*Repressor Proteins/genetics/metabolism

@article {pmid40928821,
year = {2025},
author = {Motolese, F and Norata, D and Iaccarino, G and Sapio, E and Lodico, S and Di Giesi, ML and Cruciani, A and Rossi, M and Pilato, F and Di Lazzaro, V and Capone, F},
title = {Predicting cognitive decline in Alzheimer's disease: A real-life proof-of-principle study on multimodal assessment.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251376676},
doi = {10.1177/13872877251376676},
pmid = {40928821},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is the most common neurodegenerative disorder. While AD diagnosis traditionally relies on clinical criteria, recent trends favor a precise biological definition. Existing biomarkers efficiently detect AD pathology but inadequately reflect the extent of cognitive impairment or disease heterogeneity. Alternative tools, such as neuroimaging and neurophysiological techniques, might better assess actual functional impairment.ObjectiveTo explore a multimodal approach-combining quantitative electroencephalography (EEG), cerebrospinal fluid (CSF), and cognitive assessment-to identify the most effective predictors of cognitive decline in AD patients.MethodsIn this observational study, 28 biologically confirmed AD patients underwent baseline evaluations including high-density EEG, CSF biomarker analysis, and cognitive assessment (Mini-Mental State Examination, MMSE). Cognitive assessment was repeated after one year. The rate of cognitive decline was calculated as monthly MMSE score change.ResultsMedian baseline age was 71.2 years. Median monthly MMSE decline was 0.25 points. Patients were classified into slow (≤0.25 MMSE/month) or fast (>0.25 MMSE/month) progressors. Fast progressors had significantly lower baseline individual alpha frequency (IAF) (6.8 Hz versus 9.1 Hz; p = 0.003), lower MMSE at one year (19 versus 24; p = 0.02), and more frequent diabetes and cardiovascular history. A multivariate regression analysis adjusted for age revealed that baseline IAF (p = 0.002), initial MMSE score (p = 0.028), and the p-tau/Aβ42 ratio (p < 0.01) significantly predicted monthly cognitive decline.ConclusionsCombining quantitative EEG-derived IAF, baseline cognitive status, and CSF biomarkers (p-tau/Aβ42 ratio) enhances prediction of AD progression. This integrated approach better captures disease heterogeneity, highlighting the need for multimodal strategies in the prognosis and management of AD.},
}

@article {pmid40928812,
year = {2025},
author = {Taragano, F and Seinhart, D and Epstein, P and Sylvestre, V and Barañano, C and Otero Castro, V and Sánchez, V and Kilstein, A and González, R and Franco-Trecu, V and Costa-Urrutia, P},
title = {A real-world study on the safety and efficacy of therapeutic plasma exchange in patients with Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251375430},
doi = {10.1177/13872877251375430},
pmid = {40928812},
issn = {1875-8908},
abstract = {BackgroundTherapeutic plasma exchange (TPE) with albumin replacement has emerged as a potential treatment for Alzheimer's disease (AD). The AMBAR trial showed that TPE could slow cognitive and functional decline, along with changes in core and inflammatory biomarkers in cerebrospinal fluid.ObjectiveTo evaluate the safety and effectiveness of TPE in a real-world setting in Argentina.MethodsFrom 2022 to 2024, 32 patients with mild-to-moderate AD received TPE and were compared to a historical control group (2008-2018, n = 194) matched for inclusion criteria and cognitive assessments. The protocol included six weekly intensive sessions followed by at least 10 monthly maintenance sessions. Outcomes were measured using the Mini-Mental State Examination (MMSE), and tests of memory, language, executive function, and attention. Linear models were used for analysis.ResultsPatients had a mean age of 72.1 years; 42.4% were female. Baseline MMSE scores ranged from 15 to 26. A total of 514 procedures were performed; 81.5% were uneventful. Mild-to-moderate adverse events occurred in 18.5% of sessions, mainly related to venipuncture; no severe events were reported. Mean plasma exchange volumes were 88.2% and 49.8% of estimated plasma volume during the intensive and maintenance phases, respectively. TPE significantly slowed MMSE decline (45% less than controls, p < 0.001) and reduced memory deterioration (88% less in immediate recall, p < 0.001; 74% in delayed recall, p = 0.04). Other domains were also better preserved.ConclusionsTPE appears to be a safe and effective intervention for slowing cognitive decline in AD, supporting the AMBAR findings.},
}

@article {pmid40928784,
year = {2025},
author = {Orom, H and Allard, NC},
title = {Information avoidance is associated with lower willingness to be screened for dementia.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251376720},
doi = {10.1177/13872877251376720},
pmid = {40928784},
issn = {1875-8908},
abstract = {BackgroundFear of developing Alzheimer's disease and other dementias could motivate defensive responses to dementia information, including public health messaging, and reduce willingness to undergo screening or diagnostic testing for the disease.ObjectiveWe sought to assess the pervasiveness of dementia information avoidance and test whether it is associated with lower willingness to be screened for dementia. We also tested whether lower generalized self-efficacy is associated with higher dementia information avoidance, as the former might be a point of intervention for decreasing defensive information avoidance.MethodsSurvey respondents (N = 285 recruited from Prolific; 34.7% ≥ 60 years old) answered questions about tendencies to avoid information about dementia, generalized self-efficacy, willingness to be screened for dementia, perceived risk for and worry about developing dementia, perceived preventability of dementia and dementia knowledge.ResultsNearly half of respondents believed they were somewhat (43.2%) or very (6.7%) likely to get dementia in their lifetimes. About a quarter were moderately (16.8%) or extremely (8.4%) worried about getting dementia. Although willingness to be screened was high (91.9%), there was a subgroup of respondents (9.5%) who tended to avoid dementia information and this was associated with being less likely to be willing to be screened for dementia (b = -0.40, 95% CI = -0.55, -0.25, p < 0.001). Having lower generalized self-efficacy was associated with greater dementia information avoidance (b = -0.31, 95% CI = -0.45, -0.17, p < 0.001).ConclusionsCommunication about dementia risk and prevention might include strategies for enhancing agency beliefs, such as self-efficacy, in order to reduce the potential for defensive avoidance.},
}

@article {pmid40928616,
year = {2025},
author = {Pandey, SN and Babu, MA and Goyal, K and Menon, SV and Ray, S and Kaur, M and Sharma, S and Rana, M and Rekha, A and Ali, H and Singh, SK and Gupta, G},
title = {Targeting NLRP3 inflammasome with curcumin: mechanisms and therapeutic promise in chronic inflammation.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {40928616},
issn = {1568-5608},
abstract = {The NOD‑like receptor family pyrin domain containing 3 (NLRP3) inflammasome is a key molecular complex that amplifies inflammatory cascades by maturing interleukin‑1 beta (IL-1β) and interleukin‑18 (IL-18) and inducing pyroptosis. It serves as a major driver and co-driver of numerous diseases associated with chronic inflammation. Dysregulated NLRP3 activation contributes to the progression of disorders such as rheumatoid arthritis, inflammatory bowel disease, neurodegenerative diseases and atherosclerosis. Curcumin, a natural polyphenol derived from Curcuma longa, offers a promising approach to inhibit NLRP3-induced inflammation owing to its multi-targeted actions and excellent safety profile. Preclinical models have demonstrated that curcumin inhibits nuclear factor kappa‑light‑chain‑enhancer of activated B cells (NF-κB) signaling, reduces mitochondrial reactive oxygen species (ROS) generation, and suppresses caspase-1 activation and apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) assembly, thereby inhibiting inflammasome activation. Curcumin has successfully prevented IL-1β-induced biological effects, tissue damage, and clinical manifestations in models of arthritis, colitis, and Alzheimer's disease (AD). In addition, advanced nanoformulations and structural analogs have enhanced their bioavailability and therapeutic reach. Here, we present a mechanistically focused, curcumin-oriented review synthesizing current knowledge on the NLRP3 inflammasome and its role in chronic inflammatory diseases. We also critically evaluated nanoformulations, curcumin analogs, and combination therapies and integrated evidence from rheumatologic, gastrointestinal, neurodegenerative, metabolic, and cardiovascular models. Furthermore, we explored the molecular mechanisms underlying the therapeutic effects of curcumin and highlighted the challenges of its clinical translation, offering insights for designing precision anti-inflammasome strategies to advance inflammation therapeutics.},
}

@article {pmid40928277,
year = {2025},
author = {Fu, JX and Wang, WP and Wang, YD and Wang, PC},
title = {Beams of Hope: Shedding New Light on Alzheimer's Treatment with Low-Dose Radiation Therapy.},
journal = {Biomedical and environmental sciences : BES},
volume = {38},
number = {8},
pages = {1001-1002},
doi = {10.3967/bes2025.100},
pmid = {40928277},
issn = {2214-0190},
}

@article {pmid40928238,
year = {2025},
author = {Wang, N and Cai, W and Pan, X and Wang, T and Gross, A and Jiang, C},
title = {Changes in Housework Frequency and Subsequent Cognitive Function and Rate of Decline Among Adults Aged ≥ 65 in the United States, 2008-2018.},
journal = {The Permanente journal},
volume = {},
number = {},
pages = {1-10},
doi = {10.7812/TPP/24.173},
pmid = {40928238},
issn = {1552-5775},
abstract = {INTRODUCTION: Physical activity level plays a role in modifying the likelihood of developing Alzheimer's disease and related dementias. However, little is known about how changes in housework affect cognitive function among US adults over the age of 65. This study investigates the correlation between changes in housework frequency and cognitive function over 10 years.

METHODS: Data from 8141 adults aged ≥ 65 years in the Health and Retirement Study were analyzed, with changes in housework frequency categorized as "consistently high," "low to high," "high to low," and "consistently low" from 2008 to 2010. Cognitive function was measured from 2010 to 2018 using a composite score (range = 0-35), and mixed-effects linear regression models were fitted.

RESULTS: Of 8141 participants (median age: 75 years [SD: 6.6] and 59.3% female), individuals who reported changes in housework frequency from high to low and consistently low were associated with an additional cognitive decline of 0.079 (95% CI, -0.117 to -0.042) and 0.090 (95% CI, -0.126 to -0.054), respectively, relative to those whose housework frequency remained consistently high. There was no statistically significant additional decline among adults reporting low to high frequency compared with those reporting consistently high housework frequency (β = -0.027; 95% CI, -0.074 to 0.019; P = .252). This association was similar among women and men (Pinteraction = .765) and was also similar among adults aged ≥ 80 years and those aged 65-79 years (Pinteraction = .069).

CONCLUSION: Transitioning from low to high or maintaining consistently high housework engagement in later life was associated with a delay in cognitive decline, regardless of gender and age.},
}

@article {pmid40928206,
year = {2025},
author = {Saeb, D and Lietzke, EE and Fuchs, DI and Aldrich, EC and Bruce, KD and Sprenger, KG},
title = {The flexible stalk domain of sTREM2 modulates its interactions with brain-based phospholipids.},
journal = {eLife},
volume = {13},
number = {},
pages = {},
doi = {10.7554/eLife.102269},
pmid = {40928206},
issn = {2050-084X},
support = {2024361899//National Science Foundation/ ; },
mesh = {*Membrane Glycoproteins/metabolism/chemistry/genetics ; *Receptors, Immunologic/metabolism/chemistry/genetics ; Humans ; *Phospholipids/metabolism ; Molecular Dynamics Simulation ; Protein Binding ; *Brain/metabolism ; Binding Sites ; Protein Domains ; },
abstract = {The microglial surface protein Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) plays a critical role in mediating brain homeostasis and inflammatory responses in Alzheimer's disease (AD). The soluble form of TREM2 (sTREM2) exhibits neuroprotective effects in AD, though the underlying mechanisms remain elusive. Moreover, differences in ligand binding between TREM2 and sTREM2, which have major implications for their roles in AD pathology, remain unexplained. To address these knowledge gaps, we conducted the most computationally intensive molecular dynamics simulations to date of human (s)TREM2, exploring their interactions with key damage- and lipoprotein-associated phospholipids and the impact of the AD-risk mutation R47H. Our results demonstrate that the flexible stalk domain of sTREM2 serves as the molecular basis for differential ligand binding between sTREM2 and TREM2, facilitated by its role in modulating the dynamics of the Ig-like domain and altering the accessibility of canonical ligand binding sites. We identified a novel ligand binding site on sTREM2, termed the 'Expanded Surface 2,' which emerges due to competitive binding of the stalk with the Ig-like domain. Additionally, we observed that the stalk domain itself functions as a site for ligand binding, with increased binding frequency in the presence of R47H. This suggests that sTREM2's neuroprotective role in AD may, at least in part, arise from the stalk domain's ability to rescue dysfunctional ligand binding caused by AD-risk mutations. Lastly, our findings indicate that R47H-induced dysfunction in TREM2 may result from both diminished ligand binding due to restricted complementarity-determining region 2 loop motions and an impaired ability to differentiate between ligands, proposing a novel mechanism for loss-of-function. In summary, these results provide valuable insights into the role of sTREM2 in AD pathology, laying the groundwork for the design of new therapeutic approaches targeting (s)TREM2 in AD.},
}

*Membrane Glycoproteins/metabolism/chemistry/genetics
*Receptors, Immunologic/metabolism/chemistry/genetics
Humans
*Phospholipids/metabolism
Molecular Dynamics Simulation
Protein Binding
*Brain/metabolism
Binding Sites
Protein Domains

@article {pmid40928125,
year = {2025},
author = {Giacomucci, G and Ingannato, A and Crucitti, C and Bagnoli, S and Marcantelli, E and Padiglioni, S and Moschini, V and Morinelli, C and Falsini, L and Sorbi, S and Berti, V and Nacmias, B and Bessi, V},
title = {Plasma p-tau181 as a Marker of Conversion to Alzheimer's Disease Dementia and Worsening in Cognitive Functions in Subjective Cognitive Decline and Mild Cognitive Impairment: A Longitudinal Study.},
journal = {Annals of clinical and translational neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/acn3.70190},
pmid = {40928125},
issn = {2328-9503},
support = {B83C22004800006//Ministero dell'Università e della Ricerca/ ; D19G22000640002//Regione Toscana/ ; },
abstract = {BACKGROUND: Plasma p-tau181 has proven to be a promising diagnostic and prognostic tool in the earliest phases of Alzheimer's disease (AD). We aimed to evaluate the prognostic role of p-tau181 in predicting conversion to AD dementia and worsening in cognition in mild cognitive impairment (MCI) and subjective cognitive decline (SCD).

METHODS: We consecutively enrolled 163 patients (50 SCD, 70 MCI, and 43 AD-demented (AD-d)), who underwent plasma p-tau181 analysis with the Simoa assay. Patients were classified according to the Revised Criteria of the Alzheimer's Association Workgroup as Core1+ or Core1- (based on amyloid-PET, CSF Aβ42/Aβ40, CSF p-tau181/Aβ42).

RESULTS: Plasma p-tau181 levels were significantly influenced by Core1 status (B = 1.41, p < 0.001) and clinical diagnosis (B = 0.63, p < 0.001). Plasma p-tau181 was highly accurate in discriminating between Core1+ and Core1- patients (AUC = 0.88 [95% CI 83.00-94.00]) with a cut-off value of 2.25 pg/mL presenting good accuracy (85.90%), specificity (74.58%), and excellent sensitivity (92.78%). Classifying patients according to p-tau181 cut-off, we found that p-tau181+ patients showed an increased risk of converting to AD dementia (HR = 11.65, p = 0.018). Moreover, SCD p-tau181+ worsened over time in tasks assessing long-term verbal (p = 0.012) and spatial memory (p = 0.009).

CONCLUSIONS: Plasma p-tau181 is not only a good diagnostic marker for AD pathology, but it also plays a role as a predictor of both conversion to AD dementia and of worsening of cognitive performance since the earliest phase of AD.},
}

@article {pmid40928027,
year = {2025},
author = {Juul-Madsen, K and Rudolph, IM and Gomes, JP and Meyer, K and Ovesen, PL and Gorniak-Walas, M and Kokoli, M and Telugu, NS and von Tangen Sivertsen, M and Febbraro, F and Sutherland, DS and Palmfeldt, J and Diecke, S and Andersen, OM and Selbach, M and Willnow, TE},
title = {Familial Alzheimer's disease mutation identifies novel role of SORLA in release of neurotrophic exosomes.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {9},
pages = {e70591},
doi = {10.1002/alz.70591},
pmid = {40928027},
issn = {1552-5279},
support = {#18003//Alzheimer Forschung Initiative/ ; NNF18OC0033928//Novo Nordisk Foundation/ ; R380-2021-1326//Lundbeck Foundation/ ; },
mesh = {Humans ; *Exosomes/metabolism ; *LDL-Receptor Related Proteins/genetics/metabolism ; *Alzheimer Disease/genetics/metabolism ; *Membrane Transport Proteins/genetics/metabolism ; *Mutation/genetics ; Neurons/metabolism ; Induced Pluripotent Stem Cells/metabolism ; Microglia/metabolism ; MicroRNAs/metabolism ; },
abstract = {INTRODUCTION: Mutations in SORL1, encoding the sorting receptor Sortilin-related receptor with A-type repeats (SORLA), are found in individuals with Alzheimer's disease (AD). We studied SORLA[N1358S], carrying a mutation in its ligand binding domain, to learn more about receptor functions relevant for human brain health.

METHODS: We investigated consequences of SORLA[N1358S] expression in induced pluripotent stem cell (iPSC)-derived human neurons and microglia, using unbiased proteome screens and functional cell assays.

RESULTS: We identified alterations in the SORLA[N1358S] interactome linked to biogenesis of exosomes. Consequently, the mutant receptor failed to promote release and neurotrophic qualities of exosomes, a defect attributed to altered exosomal content of microRNAs controlling neuronal maturation.

DISCUSSION: We identified a role for SORLA in controlling quantity and neurotrophic quality of exosomes secreted by cells, suggesting impaired cellular cross talk through exosomes as a pathological trait contributing to AD pathology in carriers of SORL1 variants.

HIGHLIGHTS: Familial Alzheimer's disease mutation in SORL1 changes interactome of mutant Sortilin-related receptor with A-type repeats (SORLA). Mutant SORLA impairs release of exosomes from neurons and microglia. Mutant exosomes lack neurotrophic qualities. Defect linked to alterations in microRNA content.},
}

Humans
*Exosomes/metabolism
*LDL-Receptor Related Proteins/genetics/metabolism
*Alzheimer Disease/genetics/metabolism
*Membrane Transport Proteins/genetics/metabolism
*Mutation/genetics
Neurons/metabolism
Induced Pluripotent Stem Cells/metabolism
Microglia/metabolism
MicroRNAs/metabolism

@article {pmid40928009,
year = {2025},
author = {Weden, MM and Frank, L and Dick, AW and Wang, Z and Peschin, S and Bovenkamp, DE and Rossi, SL and Sciullo, D and Hillerstrom, H and Fisher, RA},
title = {Investment in Alzheimer's disease research for the next generation of adults with Down syndrome will yield health benefits for future generations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {9},
pages = {e70348},
doi = {10.1002/alz.70348},
pmid = {40928009},
issn = {1552-5279},
support = {//LuMind IDSC Foundation/ ; //Alliance for Aging Research/ ; //BrightFocus® Foundation/ ; //National Down Syndrome Society/ ; },
mesh = {Humans ; *Down Syndrome/economics/complications/epidemiology/therapy ; *Alzheimer Disease/economics/therapy/epidemiology ; Life Expectancy ; Adult ; *Biomedical Research/economics ; Caregivers/economics ; },
abstract = {Recent innovations in Alzheimer's disease (AD) treatment highlight critical gaps in knowledge about how to support healthy aging of adults with Down syndrome (DS). RAND researchers updated demographic and epidemiological evidence about the DS population to assess the impact of increased investment in treatment innovations for DS-associated Alzheimer's disease (DS-AD). They estimated life expectancy at birth in 2020 to be 55 years, with ≈ 5 years of DS-AD. They found that the results of investment were dramatic. Between 2020 and 2070, adult years of life are expected to increase by 5 years without any increase in unhealthy years of life with DS-AD. Caregiving hours for individuals with DS-AD are expected to be reduced by 40%, which will generate large annual savings. The new evidence underscores the magnitude of the impact that investment in DS-AD treatments could have for individuals with DS, their families, and caregivers. HIGHLIGHTS: Evidence is sparse about treatment for Down syndrome (DS)-associated Alzheimer's disease (DS-AD) and healthy aging of DS adults. This population simulation model estimates DS-AD caregiving costs at ≈ $1 billion per year. DS-AD innovations could increase life expectancy by 5 years and reduce caregiving by 40% by 2070. This better forecasting can improve policy and service planning. DS-AD research investment could yield dramatic gains for individuals and families.},
}

Humans
*Down Syndrome/economics/complications/epidemiology/therapy
*Alzheimer Disease/economics/therapy/epidemiology
Life Expectancy
Adult
*Biomedical Research/economics
Caregivers/economics

@article {pmid40927880,
year = {2025},
author = {Wang, Z and Torres, K and Foster, H and Walker, G and Garza, MY and Palmer, A and LeRoy, EC and Facile, R and Kirwin, M and Zozus, MN},
title = {Measuring alignment between the ADRC UDS data elements, FDA, and EHR data standards.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {9},
pages = {e70628},
doi = {10.1002/alz.70628},
pmid = {40927880},
issn = {1552-5279},
mesh = {*Electronic Health Records/standards ; Humans ; United States ; *Alzheimer Disease ; *United States Food and Drug Administration/standards ; *Health Information Interoperability/standards ; *Common Data Elements ; },
abstract = {INTRODUCTION: We compared and measured alignment between the Health Level Seven (HL7) Fast Healthcare Interoperability Resources (FHIR) standard used by electronic health records (EHRs), the Clinical Data Interchange Standards Consortium (CDISC) standards used by industry, and the Uniform Data Set (UDS) used by the Alzheimer's Disease Research Centers (ADRCs).

METHODS: The ADRC UDS, consisting of 5959 data elements across eleven packets, was mapped to FHIR and CDISC standards by two independent mappers, with discrepancies adjudicated by experts.

RESULTS: Forty-five percent of the 5959 UDS data elements mapped to the FHIR standard, indicating possible electronic obtainment from EHRs. Ninety-four percent mapped to the CDISC standards, demonstrating high compatibility with industry standards.

DISCUSSION: The study highlights the feasibility of harmonizing ADRC data with industry and clinical standards. CDISC demonstrated superior alignment with ADRC UDS data, whereas FHIR showed potential for improvement through resource maturation and enhanced standardization.

HIGHLIGHTS: Forty-five percent of Alzheimer's Disease Research Center Uniform Data Set (ADRC UDS) data elements could be mapped to Fast Healthcare Interoperability Resources (FHIR), indicating potential electronic health records (EHRs) extraction. Ninety-four percent of ADRC UDS data elements could be mapped to Clinical Data Interchange Standards Consortium (CDISC) Study Data Tabulation Model (SDTM), showing high industry compatibility. Identified areas for improving data standards harmonization in Alzheimer's disease and related dementias (ADRD) research. Systematic mapping method aligns ADRC UDS with Health Level Seven (HL7) FHIR and CDISC SDTM standards. Results support feasibility of data sharing across ADRC research, EHRs, and industry.},
}

*Electronic Health Records/standards
Humans
United States
*Alzheimer Disease
*United States Food and Drug Administration/standards
*Health Information Interoperability/standards
*Common Data Elements

@article {pmid40927874,
year = {2025},
author = {Min, Y and Zhou, H and Li, Z and Wang, Y},
title = {Retinal biomarkers in cognitive impairment and dementia: Structural, functional, and molecular insights.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {9},
pages = {e70672},
doi = {10.1002/alz.70672},
pmid = {40927874},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/metabolism ; *Cognitive Dysfunction/diagnosis/pathology ; *Retina/pathology/metabolism/diagnostic imaging/physiopathology ; *Dementia/diagnosis/pathology ; },
abstract = {Cognitive impairment and dementia, including Alzheimer's disease (AD), pose a global health crisis, necessitating non-invasive biomarkers for early detection. This review highlights the retina, an accessible extension of the central nervous system (CNS), as a window to cerebral pathology through structural, functional, and molecular alterations. By synthesizing interdisciplinary evidence, we identify retinal biomarkers as promising tools for early diagnosis and risk stratification. Nevertheless, translating biomarkers into clinical practice faces significant translational hurdles, including methodological heterogeneity, confounding variables, lack of standardized protocols, and insufficient longitudinal validation in diverse populations. Overcoming these challenges through rigorous standardization and robust validation studies is essential to establish the clinical utility of retinal biomarkers. HIGHLIGHTS: Stage-specific diagnostic potential: Retinal biomarkers (e.g., OCT/OCTA changes, eye movements, molecular deposits) show alterations correlating with cognitive impairment stages (preclinical AD to dementia), assisting stage differentiation. Reflecting cerebral pathology: Multimodal retinal alterations (structural, functional, molecular) correlate with key brain pathologies (amyloid/tau burden, atrophy, small vessel disease), indicating shared pathways. Translation gaps and future: Clinical adoption faces barriers (method heterogeneity, confounders, limited validation). Future requires rigorous screening of candidate retinal biomarkers, extensive multicenter validation, and artificial intelligence (AI)-facilitated clinical translation.},
}

Humans
*Biomarkers/metabolism
*Cognitive Dysfunction/diagnosis/pathology
*Retina/pathology/metabolism/diagnostic imaging/physiopathology
*Dementia/diagnosis/pathology

@article {pmid40927871,
year = {2025},
author = {Lee, S and Chun, MY and Jang, H and Weiner, M and Schindler, SE and Shin, D and Kang, H and Yim, S and Lee, EH and Kim, K and Kim, HJ and Na, DL and Kim, JP and Seo, SW and , },
title = {Age-related amyloid beta dynamics modeled with the generalized additive model for location, scale, and shape (GAMLSS) across diverse populations: Cross-sectional trajectories and longitudinal validation.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {9},
pages = {e70675},
doi = {10.1002/alz.70675},
pmid = {40927871},
issn = {1552-5279},
support = {//Korea Dementia Research Center/ ; RS-2020-KH106434//Ministry of Health & Welfare and Ministry of Science and ICT, Republic of Korea/ ; //Korea Health Industry Development Institute/ ; RS-2025-02223212//Ministry of Health & Welfare, Republic of Korea/ ; #SMX1250081//Future Medicine 20*30 Project of the Samsung Medical Center/ ; 2024-ER1003-01//Korea National Institute of Health/ ; RS-2021-II212068//Institute of Information & communications Technology Planning & Evaluation/ ; NRF-2019R1A5A2027340//National Research Foundation of Korea/ ; },
mesh = {Humans ; *Amyloid beta-Peptides/metabolism ; Male ; Female ; Cross-Sectional Studies ; Positron-Emission Tomography ; Longitudinal Studies ; Aged ; Middle Aged ; Apolipoprotein E4/genetics ; *Aging/metabolism ; White People ; *Models, Statistical ; *Brain/diagnostic imaging/metabolism ; Reproducibility of Results ; Aged, 80 and over ; Alzheimer Disease ; },
abstract = {INTRODUCTION: We developed and validated age-related amyloid beta (Aβ) positron emission tomography (PET) trajectories using a statistical model in cognitively unimpaired (CU) individuals.

METHODS: We analyzed 849 CU Korean and 521 CU non-Hispanic White (NHW) participants after propensity score matching. Aβ PET trajectories were modeled using the generalized additive model for location, scale, and shape (GAMLSS) based on baseline data and validated with longitudinal data. Subgroup analyses examined apolipoprotein E (APOE) ε4 and sex effects.

RESULTS: Age-related centile curves of Aβ PET Centiloid values showed stable distributions in the lower percentiles, increasing with age in the upper percentiles. NHWs exhibited steeper Aβ accumulation trajectories, particularly among APOE ε4 carriers. Calibration with longitudinal data confirmed the reliability of this cross-sectional method.

DISCUSSION: We developed a statistical model of age-related Aβ PET trajectories using baseline data, validated with longitudinal data. NHWs exhibited steeper trajectories than Koreans, suggesting population-specific differences in Aβ accumulation.

HIGHLIGHTS: A generalized additive model for location, scale, and shape model was applied to examine age-related amyloid beta (Aβ) trajectories with baseline data. Trajectories were validated using longitudinal data, confirming model reliability. Non-Hispanic Whites exhibited steeper trajectories than Koreans, especially in apolipoprotein E ε4 carriers. Our approach enables scalable modeling of Aβ dynamics for Alzheimer's disease prevention strategies. Findings highlight the importance of multi-ethnic research in Aβ accumulation.},
}

Humans
*Amyloid beta-Peptides/metabolism
Male
Female
Cross-Sectional Studies
Positron-Emission Tomography
Longitudinal Studies
Aged
Middle Aged
Apolipoprotein E4/genetics
*Aging/metabolism
White People
*Models, Statistical
*Brain/diagnostic imaging/metabolism
Reproducibility of Results
Aged, 80 and over
Alzheimer Disease

@article {pmid40927759,
year = {2025},
author = {Aggarwal, A and Rajalekshmi, R and Aggarwal, A and Agrawal, DK},
title = {Plants, Pills, and the Brain: Exploring Phytochemicals and Neurological Medicines.},
journal = {International journal of plant, animal and environmental sciences},
volume = {15},
number = {3},
pages = {90-114},
pmid = {40927759},
issn = {2231-4490},
abstract = {Neurological disorders, such as Alzheimer's disease, Parkinson's disease, epilepsy, spinal cord injuries, and traumatic brain injuries, represent substantial global health challenges due to their chronic and often progressive nature. While allopathic medicine offers a range of pharmacological interventions aimed at managing symptoms and mitigating disease progression, it is accompanied by limitations, including adverse side effects, the development of drug resistance, and incomplete efficacy. In parallel, phytochemicals-bioactive compounds derived from plants-are receiving increased attention for their potential neuroprotective, antioxidant, and anti-inflammatory properties. This review will explore the therapeutic landscape of neurological diseases by providing a comprehensive overview of prevalent conditions and the current allopathic treatments available. Furthermore, this review will investigate specific phytochemicals, including flavonoids, alkaloids, and terpenoids, that exhibit promise in modulating various disease pathways. Emphasis will be placed on the interactions between plant-derived compounds and prescription medications, highlighting both potential synergistic effects and possible adverse interactions. A thorough understanding of these interactions is essential for the development of integrative treatment approaches that enhance therapeutic efficacy while minimizing harm. By bridging traditional herbal medicine with contemporary pharmacotherapy, this review aims to promote a more holistic perspective on the management of neurological diseases, while also encouraging further research into safe and effective combinatory therapies.},
}

@article {pmid40927740,
year = {2025},
author = {Huang, Q and Jonaitis, EM and Studer, RL and Wilson, R and Reyes, RER and Zetterberg, H and Du, L and Hermann, BP and Johnson, SC and Langhough, RE},
title = {Preclinical dementia rating scores are associated with plasma phosphorylated tau-217.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {17},
number = {3},
pages = {e70179},
pmid = {40927740},
issn = {2352-8729},
abstract = {INTRODUCTION: Simple screening tools are critical for assessing Alzheimer's disease (AD)-related pre-dementia changes. This study investigated longitudinal scores from the Quick Dementia Rating System (QDRS), a brief study partner-reported measure, in relation to baseline levels of the AD biomarker plasma pTau217 in individuals unimpaired at baseline.

METHODS: Data from the Wisconsin Registry for Alzheimer's Prevention (N = 639) were used to examine whether baseline plasma pTau217 (ALZpath assay on Quanterix platform) modified QDRS or Preclinical Alzheimer's Cognitive Composite (PACC3) trajectories (mixed-effects models; time = age). pTau217*age interaction effects (e.g., high vs low pTau217 simple age slopes) were compared across outcomes.

RESULTS: Higher baseline pTau217 levels were associated with faster functional (QDRS) and cognitive (PACC3) decline. Effect sizes were similar between PACC3 and QDRS. Exploratory analyses showed increased risk of transitioning to impaired QDRS classifications in those with high-baseline pTau217.

DISCUSSION: This study demonstrates the utility of QDRS for tracking pre-dementia AD-related decline.},
}

@article {pmid40927393,
year = {2025},
author = {Ning, G and Fan, X and Juan, D and Wenxue, Z and Sijia, W and Meinei, C and Xiaolong, D and Yiming, Q},
title = {The manipulator behind "Scissors": γ -secretase and its modulators in Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1637671},
pmid = {40927393},
issn = {1663-4365},
abstract = {The intramembrane aspartic protease, γ-secretase, is a heterotetrameric protein complex composed of four integral membrane proteins: presenilin (PSEN), nicastrin (NCT), Anterior pharynx defective-1 (APH-1), and presenilin enhancer 2 (PEN-2). These components are sequentially assembled into a functional complex. γ-secretase is ubiquitously expressed in all cells and tissues and exhibits enzymatic activity akin to "molecular scissors" by cleaving various type I transmembrane proteins. The primary substrates of this complex include amyloid precursor protein (APP) and Notch. The role of APP in the pathogenesis of Alzheimer's disease (AD) has been extensively investigated. Although γ-secretase inhibitors (GSIs) have been evaluated for their therapeutic potential in AD, their clinical application is limited due to significant toxic side effects. Recently, γ-secretase modulators (GSMs) have emerged as promising alternatives, offering new opportunities for the treatment of AD, especially the inherent γ-secretase modulatory proteins (GSMPs) within cells. Research on GSMPs has ushered in a new era for mitigating the side effects of AD drugs. In this review, we systematically summarize recent advancements in the study of γ-secretase in relation to AD and provide an overview of GSMs and GSMPs, thereby offering potential insights for the development of therapeutic strategies for AD.},
}

@article {pmid40927314,
year = {2025},
author = {Li, H and Fan, Y and Chen, C and Xu, Y and Wang, X and Liu, W},
title = {Identification of GABBR2 as a diagnostic marker and its association with Aβ in Alzheimer's disease.},
journal = {Biochemistry and biophysics reports},
volume = {42},
number = {},
pages = {102035},
pmid = {40927314},
issn = {2405-5808},
abstract = {BACKGROUND: Synaptic dysfunction and synapse loss occur in Alzheimer's disease (AD). The current study aimed to identify synaptic-related genes with diagnostic potential for AD.

METHODS: Differentially expressed genes (DEGs) were overlapped with phenotype-associated module selected through weighted gene co-expression network analysis (WGCNA), and synaptic-related genes. The overlapped hub genes were further processed using machine learning algorithms, intersected with module gene from protein-protein interaction (PPI) network constructed with DEGs, to yield co-hub genes. The diagnostic potentials of the co-hub genes were examined by receiver operating characteristic (ROC) analysis. Correlation between co-hub genes with clinical features and immune cell infiltration was analyzed. Finally, the expression of co-hub genes was analyzed in several datasets and validated in AD transgenic mice.

RESULTS: A total of three co-hub genes were identified, including MAP1B, L1CAM, and GABBR2. GABBR2 showed area under the curve (AUC) values of 0.98, 0.81, and 0.88 in the training and two external validation datasets. GABBR2 was negatively correlate with beta- and gamma-secretase activities, and infiltration of natural killer T cells and effector memory CD8 T cells. Finally, GABBR2 was validated to be downregulated in AD transgenic mice, aligning with bioinformatic findings. GABBR2 overexpression in N2a/APP cells increased ADAM10 while decreased of BACE1, leading to upregulation of sAPPα while downregulation of sAPPβ.

CONCLUSION: In conclusion, GABBR2 acts as a novel biomarker for the diagnosis of AD and negatively correlated with Aβ in AD.},
}

@article {pmid40927301,
year = {2025},
author = {Heller, LI and Lowe, AS and Del Rosario Hernández, T and Gore, SV and Chatterjee, M and Creton, R},
title = {Target the Heart: A New Axis of Alzheimer's Disease Prevention.},
journal = {Journal of dementia and alzheimer's disease},
volume = {2},
number = {2},
pages = {},
pmid = {40927301},
issn = {3042-4518},
abstract = {BACKGROUND/OBJECTIVE: Cyclosporine A and other calcineurin inhibitors have been identified as prospective treatments for preventing Alzheimer's disease. We previously found that calcineurin inhibitors elicit a unique behavioral profile in zebrafish larvae, characterized by increased activity, acoustic hyperexcitability, and reduced visually guided behaviors. Screening a large library of FDA-approved compounds using Z-LaP Tracker revealed that some heart medications produce a similar behavioral profile, suggesting these drugs may exert calcineurin-inhibitor-like effects relevant to prevent-ing or ameliorating Alzheimer's disease.

METHODS: Screening a large library of FDA-approved drugs using Z-LaP Tracker, a neural network model, revealed a cluster of 65 drugs demonstrating a cyclosporine A-like behavioral profile. Fourteen of these drugs were heart medications, including angiotensin receptor blockers, beta blockers, al-pha-adrenergic receptor antagonists, and a statin.

RESULTS: Dual administration of the heart medications with cyclosporine A in Z-LaP Tracker revealed synergistic effects: lower doses of each heart medication could be delivered in conjunction with a lower dose of cyclosporine A to evoke a similar or larger behavioral effect than higher doses of each drug independently. Other studies have shown that many of these heart medica-tions drugs directly or indirectly inhibit the calcineurin-NFAT pathway, like cyclo-sporine A, providing a potential mechanism.

CONCLUSIONS: Co-administering a low dose of cyclosporine A with select cardiac drugs could be a potentially effective treatment strategy for preventing Alzheimer's disease occurrence and simultaneously treating cardiovascular dysfunction, while mitigating the side effects associated with higher doses of cyclosporine A. Given that heart disease precedes Alzheimer's disease in many patients, physicians may be able to create a treatment regimen that addresses both con-ditions. Our results suggest that a calcineurin inhibitor combined with simvastatin, irbesartan, cilostazol, doxazosin, or nebivolol is the most promising candidate for future exploration.},
}

@article {pmid40927060,
year = {2025},
author = {Kim, J and Lee, J and Kim, Y and Woo, B and Ory, MG},
title = {The Longitudinal Risk of Alzheimer's Disease and Related Dementias Following Participation in Cognitively Stimulating Leisure Activities by Older Adults.},
journal = {Sage open aging},
volume = {11},
number = {},
pages = {30495334251374270},
pmid = {40927060},
issn = {3049-5334},
abstract = {OBJECTIVES: This study investigated the longitudinal relationship between participation in Cognitively Stimulating Leisure Activities (CSLAs) and the risk of Alzheimer's Disease and Related Dementias (ADRD) in two different groups of older adults with and without Mild Cognitive Impairment (MCI).

METHODS: We analyzed data from the Health and Retirement Study, a nationally representative survey of adults in the United States from 2012 to 2020 (MCI = 14,280; without MCI = 13,695) using a Generalized Estimated Equation. The Telephone Interview for Cognitive Status-27 was used to identify samples with MCI, with scores ranging from 7 to 11.

RESULTS: Study findings show that CSLA participation was associated with a reduced probability of reporting the presence of ADRD in both groups. Older adults both with and without MCI who frequently participated in CSLAs were less likely to develop ADRD over an 8 year timeframe.

CONCLUSIONS: Our study findings suggest that CSLAs can serve as an effective intervention to reduce the risk of developing ADRD. Importantly, our findings suggest that CSLAs have a higher probability of reducing the incidence of ADRD in older adults who are experiencing MCI than those who are not.},
}

@article {pmid40926975,
year = {2025},
author = {Eckhardt, JL and Isenberg, L and Aslanyan, V and Monreal, T and Stradford, J and Fenton, L and Contreras, JA and Mack, WJ and Pa, J},
title = {Circadian rhythms are associated with higher amyloid-β and tau and poorer cognition in older adults.},
journal = {Brain communications},
volume = {7},
number = {5},
pages = {fcaf322},
pmid = {40926975},
issn = {2632-1297},
abstract = {Several studies implicate circadian rhythm disturbances in Alzheimer's disease. However, very little is known about how circadian rhythms are associated with Alzheimer's pathological biomarkers in older adults at early stages of the disease, and how these relationships map onto cognition. This cross-sectional study used 24-h accelerometry data to investigate the relationships between circadian rhythms, amyloid-β (Aβ), tau, and cognition in 68 older adults with objective early cognitive impairment. Participants wore GENEActiv accelerometers for ∼1 month (mean = 31.8 days). Circadian rhythms measures were quantified from accelerometer data and included acrotime (average time of day of peak activity) and intradaily variability (IV) (average circadian rhythm fragmentation within a day). Aβ was measured as a composite, and tau (n = 67) was measured in Braak staging regions of interest I/II and III/IV using positron emission tomography. The cognitive domains used were verbal memory (California Verbal Learning Test short delay free recall) and attention/processing speed (Digit Symbol Substitution Test). Multivariable linear regression models were conducted to test for associations between circadian rhythms and the outcome variables of Aβ, tau, and cognition. The moderating effects of age, sex, and apolipoprotein E4 (APOE4) carrier status were assessed in these associations. To investigate mechanistic pathways through which circadian rhythms may impact cognition, exploratory mediation analyses were conducted post hoc. Models were adjusted for age, sex, APOE4 carrier status, and years of education. The study included 68 older adults (mean age = 66.8 years, age range = 55-80 years, 63.2% female, 26.5% APOE4 carriers). Earlier acrotime was associated with higher Aβ and tau, the former of which was stronger in APOE4 carriers relative to non-carriers. Higher IV was related to higher tau in Braak regions III/IV. Age and sex modified the association between IV and tau, in which the relationships strengthened with increasing age and disproportionately affected men. Earlier acrotime was associated with worse verbal memory, but later acrotime was associated with worse attention/processing speed. Tau in Braak regions I-IV mediated the relationship between acrotime and verbal memory. The insights from this study revealed that circadian rhythms were associated with Aβ, tau, and cognition in older adults with objective early cognitive impairment. We provide novel evidence for tau as a biological mediator in the relationship between circadian timing and cognition. This work identified circadian rhythms as a promising point of intervention to reduce Alzheimer's disease risk and potentially mitigate pathological progression and cognitive decline.},
}

@article {pmid40926822,
year = {2025},
author = {Guo, W and Dong, L and Lu, Q and Xie, M and Yang, Y and Zhang, Y and Lu, X and Yu, Q},
title = {Association Between Cannabis Use and Neuropsychiatric Disorders: A Two-sample Mendelian Randomization Study.},
journal = {Alpha psychiatry},
volume = {26},
number = {4},
pages = {46108},
pmid = {40926822},
issn = {2757-8038},
abstract = {BACKGROUND: The progressive legalization and widespread use of cannabis has led to its use as a treatment for certain neuropsychiatric disorders. Traditional epidemiological studies suggest that cannabis use has an effect on some neurocognitive aspects. However, it is unclear whether cannabis use is causally related to common neuropsychiatric disorders. The present study was conducted to illustrate the causal relationships of genetically predicted cannabis use with common neuropsychiatric disorders.

METHODS: We used a two-sample Mendelian randomization method using genome-wide association study (GWAS) summary statistics obtained from publicly available databases on lifetime cannabis use and 10 neuropsychiatric disorders, including multiple sclerosis (MS), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), autism spectrum disorder (ASD), epilepsy, generalized epilepsy, focal epilepsy, migraine, migraine with aura, migraine without aura, schizophrenia (SCZ), anorexia nervosa (AN), attention-deficit/hyperactivity disorder (ADHD), and Parkinson's disease (PD) were studied with a two-sample Mendelian randomization method for GWAS summary statistics. The inverse variance weighted (IVW) method was used as the main analysis model.

RESULTS: Our study suggests that lifetime cannabis use is associated with an increased risk of developing PD (odds ratio (OR) = 1.782; 95% CI 1.032-3.075; p = 0.038) and an increased risk of ADHD in female participants (OR = 1.650; 95% CI 1.051-2.590; p = 0.029).

CONCLUSIONS: Cannabis intake may cause adverse effects relating to certain neuropsychiatric disorders. Therefore, special attention should be paid to the side effects of addictive drugs during clinical treatment to avoid harmful effects on the brain and neurocognition.},
}

@article {pmid40926795,
year = {2025},
author = {Zhang, Y and Silang, Q and Wang, Y and Wang, N and Gesang, L and Tang, L and Liu, L},
title = {Integrated Gut Microbiota, Metabolomics, and Network Pharmacology to Investigate the Anti-Alzheimer's Mechanism of Tripterygium Glycoside.},
journal = {Neuropsychiatric disease and treatment},
volume = {21},
number = {},
pages = {1911-1933},
pmid = {40926795},
issn = {1176-6328},
abstract = {BACKGROUND: Tripterygium glycoside (TG) has been reported to have the effect of ameliorating Alzheimer's disease (AD)-like symptoms in mice model. However, the underlying mechanism is largely unknown. This study aimed to investigate the potential mechanism of TG against AD by integrating metabolomics, 16s rRNA sequencing, network pharmacology, molecular docking, and molecular dynamics simulation.

METHODS: Memory and cognitive functions were assessed in mice via the Morris water maze. The pathological changes were assessed using hematoxylin and Nissl's straining. Pathological changes in p-Tau and Aβ1-42 were assessed using immunohistochemistry, immunofluorescence, ELISA, and Western blotting. 16S rRNA sequencing and metabolomics were performed to analyze alterations in the structure of gut microbiota and hippocampus metabolites. Network pharmacology, molecular docking, and molecular dynamics simulation were performed to determine the putative molecular regulatory mechanism of TG in treating AD.

RESULTS: TG significantly could inhibit neuron loss, improved cognitive and memory functions, and significantly reduce the expression of p-Tau and Aβ1-42. In addition, 16s rRNA analysis revealed that TG could reverse AD-induced gut microbiota dysbiosis in AD model mice by reducing the abundance of Alistipes. Furthermore, metabolomic analysis revealed that TG may reverse AD-induced metabolic disorders by regulating glycerophospholipid metabolism. And spearman analysis revealed that glycerophospholipids metabolism might closely related to Alistipes. Moreover, network pharmacology, molecular docking, and molecular dynamics simulation analyses indicated that TG might regulate lipid metabolism-related pathways via SRC for the treatment of AD.

CONCLUSION: TG may serve as a potential therapeutic drug for preventing AD via the microbiota-gut-brain axis.},
}

@article {pmid40926761,
year = {2025},
author = {Hardiman, S and Cousins, R and Ryan, A and Kennedy, M and Hagan, L and Santos, FH},
title = {Proactive Cognitive Stimulation for Younger Adults With Down Syndrome. A Feasibility Randomised Control Trial.},
journal = {Journal of applied research in intellectual disabilities : JARID},
volume = {38},
number = {5},
pages = {e70120},
doi = {10.1111/jar.70120},
pmid = {40926761},
issn = {1468-3148},
support = {SF 09 2021//Saint John of God Research Foundation/ ; },
mesh = {Humans ; *Down Syndrome/rehabilitation ; Adult ; Female ; Male ; Feasibility Studies ; *Cognitive Behavioral Therapy/methods ; Young Adult ; *Psychotherapy, Group/methods ; *Outcome Assessment, Health Care ; *Memory, Episodic ; Follow-Up Studies ; },
abstract = {BACKGROUND: Most adults with Down syndrome develop Alzheimer's disease (AD) pathology in their 30s, yet research into cognitive health programmes for this group remains limited.

METHOD: A mixed-methods feasibility randomised control trial (RCT) evaluated an adapted, manualised group-based cognitive stimulation therapy (CST) programme for adults with Down syndrome (N = 12; Mage = 30) without dementia. Participants were randomly assigned to CST (n = 6) or control (services as usual; n = 6), with assessments at baseline, post-programme, and four-month follow-up by a blinded researcher.

RESULTS: The adapted CST was feasible, with high attendance, strong satisfaction, and good CST programme fidelity (all > 85%). CST participants showed significant gains in adaptive behaviour at post-programme, maintained at follow-up, and a trend towards improved episodic memory at post-programme.

CONCLUSION: Manualised group-based CST can be successfully adapted for younger adults with Down syndrome and shows promise in supporting cognitive health for this population.},
}

Humans
*Down Syndrome/rehabilitation
Adult
Female
Male
Feasibility Studies
*Cognitive Behavioral Therapy/methods
Young Adult
*Psychotherapy, Group/methods
*Outcome Assessment, Health Care
*Memory, Episodic
Follow-Up Studies

@article {pmid40926747,
year = {2025},
author = {Reddy, I and Dey, CS},
title = {Purinergic signaling by ATP induces exercise-like effects and ameliorates insulin resistance in HT22 mouse hippocampal cells.},
journal = {FEBS letters},
volume = {},
number = {},
pages = {},
doi = {10.1002/1873-3468.70158},
pmid = {40926747},
issn = {1873-3468},
support = {CRG/2020/001365//Science and Engineering Research Board/ ; DBT/2021-22/IIT-D/1520//Rajiv Gandhi Centre for Biotechnology, Department of Biotechnology, Ministry of Science and Technology, India/ ; },
abstract = {Neuronal insulin signaling is essential for regulating glucose metabolism and cognitive functions in the brain. Disruptions cause neuronal insulin resistance, potentially causing type 2 diabetes (T2D) and Alzheimer's disease (AD). Therefore, we investigated alternative pathways that maintain glucose homeostasis beyond traditional insulin signaling. Exercise positively impacts both body and brain well-being. However, brain exercise signaling remains unclear, and in vitro studies are limited. Here, we investigated the effects of extracellular ATP on HT22 mouse hippocampal neurons. ATP-mediated purinergic signaling elevated markers upregulated by exercise, increased glucose uptake, and activation of insulin signaling molecules. Under insulin resistance, ATP outperformed insulin, acting as an exercise-like bypass mechanism. This study provides new insights into purinergic receptors, ATP, and their potential to combat T2D and AD.},
}

@article {pmid40926627,
year = {2025},
author = {Powell, L and Silva, D and Kovacevich, A and Pillai, J and Lynn, A and Song, S and Appleby, BS},
title = {Understanding brain donation decisions: Predictors of indecision and change over time from the Cleveland Alzheimer's Disease Research Center.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {9},
pages = {e70698},
doi = {10.1002/alz.70698},
pmid = {40926627},
issn = {1552-5279},
support = {P30AG072959/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; Female ; Male ; Aged ; *Alzheimer Disease/psychology ; *Decision Making ; *Brain ; *Tissue Donors/psychology ; Middle Aged ; *Tissue and Organ Procurement ; Aged, 80 and over ; },
abstract = {INTRODUCTION: Little is known about factors influencing indecision or changes in brain donation program (BDP) enrollment status among Alzheimer's disease and related dementias research participants. This study examined demographic features associated with these decisions in participants from the Cleveland Alzheimer's Disease Research Center (CADRC).

METHODS: Demographics and BDP status were extracted from the CADRC database and analyzed based on initial and current BDP enrollment status.

RESULTS: At baseline, BDP enrollees were more likely to be older, cognitively impaired, White, partnered, have more years of education, and have a relative or partner serving as a study partner. Participants who changed BDP status over time were more often cognitively unimpaired and had more CADRC visits. Fewer years of education predicted changing from "undecided" to "yes." Enrollment rates varied significantly between study staff.

DISCUSSION: Several demographic features are associated with uncertainty or change in BDP enrollment. These factors should be further examined to optimize ADRC participants' experience.

HIGHLIGHTS: Twenty-one percent of participants changed their brain donation program (BDP) enrollment status during the study. BDP enrollment changers were more often cognitively normal and had more study visits. Fewer years of education predicted switching BDP status from undecided to yes. BDP enrollment and change rates varied between interactions with site staff members.},
}

Humans
Female
Male
Aged
*Alzheimer Disease/psychology
*Decision Making
*Brain
*Tissue Donors/psychology
Middle Aged
*Tissue and Organ Procurement
Aged, 80 and over

@article {pmid40926607,
year = {2025},
author = {Dutta, A and Phukan, BC and Roy, R and Bhattacharya, P and Kumar, D and Borah, A},
title = {Arsenic Exposure Induces Cognitive Impairment in Mice with Increased Acetylcholinesterase Activity and Inflammation in the Cortex and Hippocampus: Implications for Alzheimer's Disease.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050390649250904100840},
pmid = {40926607},
issn = {1875-5828},
abstract = {INTRODUCTION: Arsenic, a metalloid, is well associated as a risk factor for the development and progression of neurodegenerative diseases, including Alzheimer's Disease (AD), which is characterized by impairment in cognition. However, specific effects of arsenic on Acetylcholinesterase (AChE) activity and inflammatory markers in different brain regions, as well as its impact on behaviour, are not yet fully understood.

METHODS: Arsenic was administered (20 mg/kg by gavage for 4 weeks) to male and female mice, and its effects on behaviour were assessed by using the object recognition memory test and lightdark box test. AChE activity and neuronal Nitric Oxide (nNOS) were assessed by histoenzymology, and immunohistochemistry was employed for assessment of Glial Fibrillary Acidic Protein (GFAP).

RESULTS: Both the behavioural tests showed significant impairment of learning and memory functions and development of psychiatric abnormalities in arsenic-fed mice. The histoenzymology and immunohistochemistry analysis of the cortex and hippocampus region of these arsenic-fed mice revealed the increment of AChE activity and inflammatory markers, viz. GFAP and nNOS.

DISCUSSION: The observed increment in AChE activity in the cortex and hippocampus of arsenic-fed mice may contribute to the impairment of learning and memory functions, as well as to the development of psychiatric abnormalities. Furthermore, the enhancement of inflammatory processes in these brain regions may be either a consequence or a contributing factor to the elevated AChE activity, thus establishing a self-fuelling cycle of neuroinflammation and increased AChE activity.

CONCLUSION: Given the gender bias in neurodegenerative diseases, our findings indicate that arsenic exposure does not lead to significant differences in neuropathological and neurobehavioural outcomes between male and female mice. Moreover, current outcomes underscore the potential of arsenic to act as a neurotoxic agent in AD development.},
}

@article {pmid40926603,
year = {2025},
author = {Porwal, S and Malviya, R and Sridhar, SB and Wadhwa, T and Shareef, J and Meenakshi, DU},
title = {Trends and Advancements in Smart Electrospun Food Fibers for the Management of Neurological Disorders.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273375873250829060106},
pmid = {40926603},
issn = {1996-3181},
abstract = {Neurological disorders are complex conditions characterized by impairment of the nervous system, affecting motor, cognitive, and sensory functions. Current treatments meet substantial obstacles, primarily due to the difficulty of transporting drugs across the blood-brain barrier and ineffective therapy for nerve regeneration. Emerging technologies, such as electrospinning, offer innovative solutions to overcome these challenges. The study explores the potential of electrospun food fibers in managing and treating neurological disorders, concentrating on their role in drug delivery and nerve tissue regeneration. Electrospinning allows for the generation of nanofibers from diverse natural and synthetic polymers that imitate the extracellular matrix and stimulate brain healing. These fibers may be loaded with therapeutic drugs, permitting controlled, localized drug release while limiting systemic toxicity. For instance, electrospun fibers loaded with neuroprotective drugs, such as donepezil and levodopa, have exhibited better drug stability, enhanced bioavailability, and prolonged therapeutic efficacy in treating syndromes such as Alzheimer's and Parkinson's diseases. Furthermore, the biodegradable and biocompatible nature of food-based polymers like chitosan, cellulose, and zein makes them great candidates for medicinal applications, minimizing the risk of inflammation and unfavorable immunological reactions. In conclusion, electrospun food fibers show tremendous promise in resolving the issues of drug delivery and nerve regeneration in neurological illnesses. Their capacity to boost therapeutic results via targeted and regulated drug release makes them a possible alternative to established treatment procedures, bringing renewed hope to patients suffering from neurodegenerative disorders.},
}

@article {pmid40926398,
year = {2025},
author = {Nie, RZ and Zhang, QL and Tan, XR and Hu, SS and Zhou, XT and Jiang, WK and Guo, BW and Cao, X and Yuan, DH and Long, Y and Hong, H and Tang, SS},
title = {Cholinergic G protein-coupled bile acid receptor 1 (TGR5/GPBA) in the medial septal orchestrates adult hippocampal neurogenesis and cognition in Alzheimer's disease mice.},
journal = {British journal of pharmacology},
volume = {},
number = {},
pages = {},
doi = {10.1111/bph.70185},
pmid = {40926398},
issn = {1476-5381},
support = {82071202//National Natural Science Foundation of China/ ; 82173805//National Natural Science Foundation of China/ ; 82373860//National Natural Science Foundation of China/ ; 2024YFA1308200//National Key Research and Development Program of China/ ; },
abstract = {BACKGROUND AND PURPOSE: The pathological role of the bile acid receptor TGR5/GPBA in Alzheimer's disease (AD) is not fully understood. We investigated the pharmacological effects and mechanisms of TGR5 in AD model mice.

EXPERIMENTAL APPROACH: TGR5 expression was assessed in AD mice using immunofluorescence and immunoblotting. Bidirectional modulation of TGR5 expression was achieved via stereotaxic delivery of adeno-associated virus vectors, while localized pharmacological activation was conducted through intracerebral cannula implantation. Cognition was evaluated using the Morris water maze and novel object recognition test. Adult hippocampal neurogenesis was assessed via immunofluorescence. Neuronal activity was analysed using immunofluorescence, fibre photometry and chemogenetics-coupled fibre photometry. Acetylcholine dynamics were monitored using fibre photometry, both alone and in combination with chemogenetic manipulation.

KEY RESULTS: TGR5 expression was selectively decreased in the medial septal (MS) cholinergic neurons during middle-late AD stages. Bidirectional genetic regulation of TGR5 in MS cholinergic neurons significantly affected cognition and adult hippocampal neurogenesis in mice. Pharmacological activation of TGR5 in the MS not only increased cholinergic neuronal activity and acetylcholine release, but also enhanced DG glutamatergic neuronal activity, acetylcholine levels and neurogenesis in AD mice. TGR5 modulated cognition and neurogenesis via the MS[cholinergic(ChAT)]→ DG[glutamatergic(Glu)] circuit. Furthermore, α7 nAChRs in the DG were involved in TGR5-mediated improvements in cognition and neurogenesis.

CONCLUSION AND IMPLICATIONS: Our findings demonstrate that TGR5 in MS cholinergic neurons is critical during the middle-late stage of AD and provide valuable insights into the underlying neuronal circuit mechanisms. TGR5 (GPBA) represents a potential therapeutic target for AD treatment.},
}

@article {pmid40926280,
year = {2025},
author = {Hao, W and Luo, Q and Szabo, IM and Gasparoni, G and Tierling, S and Quan, W and Chang, HF and Wu, G and Schulze-Hentrich, J and Liu, Y},
title = {Intestinal epithelial Dicer1 regulates gut microbiome and Alzheimer's pathology in App-knock-in mice.},
journal = {Alzheimer's research & therapy},
volume = {17},
number = {1},
pages = {202},
pmid = {40926280},
issn = {1758-9193},
mesh = {Animals ; *Ribonuclease III/genetics/metabolism ; *Gastrointestinal Microbiome/physiology/genetics ; *Alzheimer Disease/pathology/metabolism/genetics ; Mice ; *DEAD-box RNA Helicases/genetics/metabolism ; *Intestinal Mucosa/metabolism ; Amyloid beta-Protein Precursor/genetics ; Brain/pathology/metabolism ; Mice, Transgenic ; Disease Models, Animal ; Male ; Gene Knock-In Techniques ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) patients and animal models exhibit an altered gut microbiome that is associated with pathological changes in the brain. Intestinal miRNA enters bacteria and regulates bacterial metabolism and proliferation. This study aimed to investigate whether the manipulation of miRNA could alter the gut microbiome and AD pathologies.

METHODS: The enzyme producing miRNA was deleted in App-knock-in mice by conditional knock-out of Dicer1 gene in intestinal epithelial cells. 16S rDNA sequencing/microbiome analysis was performed in both the gut and brain. Barrier integrity, inflammatory activation and T cell differentiation in the gut were analyzed by measuring transcripts of relevant marker genes. AD-associated pathologies in the brain, including amyloid pathology, neuroinflammation and synaptic impairment, were investigated by immunohistochemistry, ELISA, quantitative Western blot, mRNA-sequencing/transcriptomic analysis, real-time PCR and behavior tests. To investigate the mechanisms controlling Aβ level, β- and γ-secretase activities, protein levels of LRP1 and ABCB1 in isolated blood microvessels, CD68 immunofluorescence around Aβ deposits and transcription of neprilysin and IDE genes in the brain were analyzed.

RESULTS: Deletion of Dicer1 in intestinal epithelial cells of App-knock-in mice reduced the absolute number and altered the composition of bacteria in both the gut and brain, and inhibited inflammatory activation in the gut, but had no effect on the differentiation of CD4-positive T lymphocytes. It lowered Aβ load in the brain, possibly by inhibiting β-secretase activity, and increasing the expression of LRP1 and ABCB1 at the blood-brain barrier. Deletion of intestinal Dicer1 increased Il-10 transcription and decreased Ccl-2 transcription in the brain tissue. Transcriptomic analysis further showed that Dicer1 deletion reduced transcription of Ndufa2 and Ndufa5 genes. In behavior tests, deletion of intestinal Dicer1 induced anxiety symptoms without improving cognitive function in AD mice.

CONCLUSIONS: Deletion of Dicer1 in intestinal epithelial cells modulates the microbiome in both the gut and brain, and AD pathologies in the brain of App-knock-in mice. Future studies should focus on the identification of AD-specific miRNAs in the gut that can be therapeutically utilized to alter the gut microbiome and prevent AD progression.},
}

Animals
*Ribonuclease III/genetics/metabolism
*Gastrointestinal Microbiome/physiology/genetics
*Alzheimer Disease/pathology/metabolism/genetics
Mice
*DEAD-box RNA Helicases/genetics/metabolism
*Intestinal Mucosa/metabolism
Amyloid beta-Protein Precursor/genetics
Brain/pathology/metabolism
Mice, Transgenic
Disease Models, Animal
Male
Gene Knock-In Techniques

@article {pmid40926187,
year = {2025},
author = {Kavcic, V and Turaani, M and Pal, S and Reader, JM and Giordani, B},
title = {Cardiometabolic disorders and mild cognitive impairment in White and Black Americans.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {9},
pages = {e70642},
doi = {10.1002/alz.70642},
pmid = {40926187},
issn = {1552-5279},
support = {P30AG053760//National Institutes of Health/National Institute on Aging funding/ ; 1R01AG054484//National Institutes of Health/National Institute on Aging funding/ ; U24AG072122//National Institutes of Health/National Institute on Aging National Alzheimer's Disease Coordinating Center funding/ ; AG062429//National Institutes of Health/National Institute on Aging-funded ADRC P30s/ ; AG066468//National Institutes of Health/National Institute on Aging-funded ADRC P30s/ ; AG062421//National Institutes of Health/National Institute on Aging-funded ADRC P30s/ ; AG066509//National Institutes of Health/National Institute on Aging-funded ADRC P30s/ ; AG066514//National Institutes of Health/National Institute on Aging-funded ADRC P30s/ ; AG066530//National Institutes of Health/National Institute on Aging-funded ADRC P30s/ ; AG066507//National Institutes of Health/National Institute on Aging-funded ADRC P30s/ ; AG066444//National Institutes of Health/National Institute on Aging-funded ADRC P30s/ ; AG066518//National Institutes of Health/National Institute on Aging-funded ADRC P30s/ ; AG066512//National Institutes of Health/National Institute on Aging-funded ADRC P30s/ ; AG066462//National Institutes of Health/National Institute on Aging-funded ADRC P30s/ ; AG072979//National Institutes of Health/National Institute on Aging-funded ADRC P30s/ ; AG072972//National Institutes of Health/National Institute on Aging-funded ADRC P30s/ ; AG072976//National Institutes of Health/National Institute on Aging-funded ADRC P30s/ ; AG072975//National Institutes of Health/National Institute on Aging-funded ADRC P30s/ ; AG072978//National Institutes of Health/National Institute on Aging-funded ADRC P30s/ ; AG072977//National Institutes of Health/National Institute on Aging-funded ADRC P30s/ ; AG066519//National Institutes of Health/National Institute on Aging-funded ADRC P30s/ ; AG062677//National Institutes of Health/National Institute on Aging-funded ADRC P30s/ ; AG079280//National Institutes of Health/National Institute on Aging-funded ADRC P30s/ ; AG062422//National Institutes of Health/National Institute on Aging-funded ADRC P30s/ ; AG066511//National Institutes of Health/National Institute on Aging-funded ADRC P30s/ ; AG062715//National Institutes of Health/National Institute on Aging-funded ADRC P30s/ ; AG072973//National Institutes of Health/National Institute on Aging-funded ADRC P30s/ ; AG066506//National Institutes of Health/National Institute on Aging-funded ADRC P30s/ ; AG066508//National Institutes of Health/National Institute on Aging-funded ADRC P30s/ ; AG066515//National Institutes of Health/National Institute on Aging-funded ADRC P30s/ ; AG072947//National Institutes of Health/National Institute on Aging-funded ADRC P30s/ ; AG072931//National Institutes of Health/National Institute on Aging-funded ADRC P30s/ ; AG066546//National Institutes of Health/National Institute on Aging-funded ADRC P30s/ ; AG086401//National Institutes of Health/National Institute on Aging-funded ADRC P30s/ ; AG086404//National Institutes of Health/National Institute on Aging-funded ADRC P30s/ ; AG072958//National Institutes of Health/National Institute on Aging-funded ADRC P30s/ ; AG072959//National Institutes of Health/National Institute on Aging-funded ADRC P30s/ ; },
mesh = {Aged ; Aged, 80 and over ; Female ; Humans ; Male ; Middle Aged ; *Black or African American ; *Cardiovascular Diseases/epidemiology/ethnology ; *Cognitive Dysfunction/epidemiology/ethnology ; Cohort Studies ; *Diabetes Mellitus/epidemiology/ethnology ; Hypertension/epidemiology/ethnology ; United States/epidemiology ; *White ; },
abstract = {INTRODUCTION: Mild cognitive impairment (MCI) represents a transitional stage between normal aging and dementia. We investigate associations among cardiovascular and metabolic disorders (hypertension, diabetes mellitus, and hyperlipidemia) and diagnosis (normal; amnestic [aMCI]; and non-amnestic [naMCI]).

METHODS: Multinomial logistic regressions of participant data (N = 8737; age = 70.9 ± 7.5 years) from the National Alzheimer's Coordinating Center Uniform Dataset Version 3 protocol cohort were used.

RESULTS: Controlling for demographic/health variables, individuals with aMCI, though not naMCI, showed a higher likelihood of hypertension, diabetes, and hyperlipidemia compared to cognitively normal counterparts, though no differences between aMCI/naMCI. Black Americans, regardless of cognitive status, were more likely to fall into hypertension and diabetes groups compared to White Americans.

DISCUSSION: These findings underscore the critical role of diagnosis and race in MCI diagnosis and care, emphasizing the need for tailored interventions to address inequities and reduce the risk of progression to dementia.

HIGHLIGHTS: The study leverages a large, racially diverse cohort from the NACC database.  Black Americans with non-amnestic mild cognitive impairment(naMCI) show highest comorbidity burden. No significant differences in comorbidity burden between amnestic MCI (aMCI) and naMCI subtypes.  Education is protective, but less so for Black American individuals. Older age, male sex, body mass index (BMI), and low education associate with increased risk for comorbidities.},
}

Aged
Aged, 80 and over
Female
Humans
Male
Middle Aged
*Black or African American
*Cardiovascular Diseases/epidemiology/ethnology
*Cognitive Dysfunction/epidemiology/ethnology
Cohort Studies
*Diabetes Mellitus/epidemiology/ethnology
Hypertension/epidemiology/ethnology
United States/epidemiology
*White

@article {pmid40926078,
year = {2025},
author = {Devare, MN and Le, V and Chung, V and Vu, TJ and Kaeberlein, M},
title = {Fluphenazine, an antipsychotic compound, ameliorates Alzheimer's disease by clearing amyloid beta accumulation in C. elegans.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {40926078},
issn = {2509-2723},
abstract = {The aging population worldwide faces an increasing burden of age-related conditions, with Alzheimer's disease being a prominent neurodegenerative concern. Drug repurposing, the practice of identifying new therapeutic applications for existing drugs, offers a promising avenue for accelerated intervention. In this study, we utilized the yeast Saccharomyces cerevisiae to screen a library of 1760 FDA-approved compounds, both with and without rapamycin, to assess potential synergistic effects on yeast growth. We identified 87 compounds that showed synergistic effect with rapamycin and caused growth defects in yeast. Ten compounds from this list were further screened for their effects on paralysis in a Caenorhabditis elegans model of Alzheimer's disease. We found that three compounds synergistically delayed paralysis in combination with rapamycin, suggesting a potential functional redundancy or pathway convergence with mTOR signaling. Additionally, four other compounds delayed paralysis when tested at different concentrations. Moreover, we tested fluphenazine, an antipsychotic drug identified in our screen and found that it enhanced the overall health of treated worms. Western blot and X-34 staining confirmed that fluphenazine reduced amyloid-beta accumulation. Although these findings were obtained in yeast and C. elegans models, further validation in mammalian systems is required to confirm their translational relevance. Nevertheless, the results underscore the significant potential of repurposed drugs to accelerate the discovery of therapeutics for Alzheimer's disease.},
}

@article {pmid40925884,
year = {2025},
author = {Jang, YS and Kim, DH and Jeon, WK and Han, JS},
title = {Differences in Learning Strategy Selection and Object Location Memory Impairments in APP/PS1 Mice.},
journal = {Experimental neurobiology},
volume = {34},
number = {4},
pages = {156-167},
doi = {10.5607/en25013},
pmid = {40925884},
issn = {1226-2560},
abstract = {This study investigated the learning strategy preferences of 11-month-old APP/PS1 double transgenic (Tg) mice, a well-established murine model of Alzheimer's disease (AD). APP/PS1 Tg and non-Tg control mice were serially trained in visual and hidden platform tasks in the Morris water maze. APP/PS1 Tg mice performed poorly in visual platform training compared with non-Tg mice but performed as well as non-Tg mice in hidden platform training. Further analysis of their search paths for locating a hidden platform revealed that APP/PS1 Tg mice used more cued/response search patterns than place/spatial search patterns compared with non-Tg mice. Three months later, the object/location recognition memory of APP/PS1 Tg mice was assessed. Although their object recognition memory was intact, their object location memory was impaired. Neuropathological AD features of APP/PS1 transgenic mice were observed in the medial prefrontal cortex, retrosplenial cortex, and hippocampus, key brain regions involved in learning strategy shifts and spatial cognition. These results indicate that distinct search patterns and spatial memory deficits in APP/PS1 Tg mice are key features of AD animal models.},
}

@article {pmid40925761,
year = {2025},
author = {Eckenhoff, RG and Price, CC and Evered, LA and Scott, DA and Burhanullah, MH and Vasunilashorn, SM and Terrando, N and Schenning, KJ and Cunningham, EL and Eckenhoff, MF},
title = {Report of the 2024 Perioperative Cognition and Delirium Workshop.},
journal = {British journal of anaesthesia},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.bja.2025.07.082},
pmid = {40925761},
issn = {1471-6771},
}

@article {pmid40925676,
year = {2025},
author = {Du, X and Niu, L and Ragan, M and Fracz, Z and Wang, ZW},
title = {Presenilin loss impairs synaptic transmission and causes axonal degeneration through ryanodine receptor dysfunction, independent of γ-secretase activity.},
journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1523/JNEUROSCI.1052-25.2025},
pmid = {40925676},
issn = {1529-2401},
abstract = {Presenilin mutations are the most common cause of familial Alzheimer's disease (FAD), but the mechanisms by which they disrupt neuronal function remain unresolved, particularly in relation to γ-secretase activity. Using C. elegans, we show that the presenilin ortholog SEL-12 supports synaptic transmission and axonal integrity through a pathway involving the ryanodine receptor RYR-1. Loss-of-function mutations in either sel-12 or ryr-1 reduce neurotransmitter release and cause neuronal structural defects, with no additional impairment in double mutants, suggesting a shared pathway. Transgenic expression of a γ-secretase-inactive SEL-12 variant or human presenilin 1 restores normal synaptic transmission in sel-12 mutants. Notably, sel-12 loss does not alter ryr-1 transcript or protein levels. These findings define a novel γ-secretase-independent role for presenilin in maintaining neuronal function via ryanodine receptor signaling, providing new mechanistic insight into presenilin-linked neurodegeneration and pointing to potential therapeutic strategies for FAD.Significance Statement Mutations in presenilins are the major cause of familial Alzheimer's disease and are commonly associated with impaired synaptic transmission and neurodegeneration. However, the molecular mechanisms underlying these effects remain poorly understood. This study shows that loss of presenilin in C. elegans impairs neurotransmitter release and causes axonal degeneration through dysfunction of ryanodine receptors (RyRs), independent of presenilin's γ-secretase activity. Notably, RyR expression remains unchanged, suggesting that presenilins likely regulate RyR function. These findings uncover a γ-secretase-independent pathway linking presenilin dysfunction to synaptic and neuronal deficits. The findings of this study offer new insight into the pathogenesis of Alzheimer's disease.},
}

@article {pmid40925485,
year = {2025},
author = {Prokop-Millar, S and Di Passa, AM and Yaya, H and McIntyre-Wood, C and Farzan, F and Terpstra, A and Fein, A and Vandehei, E and MacKillop, E and MacKillop, J and Duarte, D},
title = {Predictive and mechanistic biomarkers of treatment response to Transcranial Magnetic Stimulation (TMS) in Psychiatric and Neurocognitive Disorders, identified via TMS-Electroencephalography (EEG) and Resting-State EEG: A systematic review.},
journal = {Journal of affective disorders},
volume = {},
number = {},
pages = {120194},
doi = {10.1016/j.jad.2025.120194},
pmid = {40925485},
issn = {1573-2517},
abstract = {Electroencephalography (EEG) is a comparatively inexpensive and non-invasive recording technique of neural activity, making it a valuable tool for biomarker discovery in transcranial magnetic stimulation (TMS). This systematic review aimed to examine mechanistic and predictive biomarkers, identified through TMS-EEG or resting-state EEG, of treatment response to TMS in psychiatric and neurocognitive disorders. Nineteen articles were obtained via Embase, APA PsycInfo, MEDLINE, and manual search; conditions included, unipolar depression (k = 13), Alzheimer's disease (k = 3), bipolar depression (k = 2), and schizophrenia (k = 2). Two mechanistic biomarkers were identified: one TMS-EEG marker, reductions in N100 post-dorsolateral prefrontal cortex (DLPFC) repetitive TMS or intermittent theta burst stimulation (iTBS) in unipolar depression (n = 120; k = 2), and one resting-state marker, reductions in theta connectivity post-DLPFC repetitive TMS in unipolar and bipolar depression (n = 89; k = 2). Whereas one predictive TMS-EEG biomarker was isolated: greater baseline N100 was predictive of unipolar depression improvement in DLPFC repetitive TMS and iTBS (n = 113; k = 2). Promising markers were briefly discussed for future research in Alzheimer's disease and schizophrenia. In conclusion, across the psychiatric and neurocognitive disorders considered in this study, TMS-EEG and resting-state mechanistic and predictive biomarkers of depression appear to hold the most promise. Further research is needed to validate the biomarkers identified in depression, to help guide treatment plans and advance precision medicine in psychiatry.},
}

@article {pmid40925435,
year = {2025},
author = {Liu, Y and Wang, Y and Liang, Y and Yang, S and Deng, Y and Zeng, S and Wang, Y and Shu, Z and Shuai, Y and Guo, H},
title = {Transcriptomics and metabolomics revealed the effects of Polygonatum Rhizoma polysaccharide on delaying C. elegans senescence and ameliorating Alzheimer's disease.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {147375},
doi = {10.1016/j.ijbiomac.2025.147375},
pmid = {40925435},
issn = {1879-0003},
abstract = {We explored the role of Polygonatum Rhizoma polysaccharide (PRP) in delaying aging and improving Alzheimer's disease (AD) and revealed its potential molecular mechanism. Through chemical characterizations to clarify the physicochemical properties of PRP, it was found that PRP mainly consists of mannose, glucose, galactose, and arabinose, with molecular weights ranging from 7.4 × 10[4] to 9.1 × 10[4] Da; using Caenorhabditis elegans (C. elegans) models, its anti-AD activity was verified by combining approaches using pharmacodynamics, molecular biology, metabolomics, and transcriptomics sequencing. The results of this study showed that PRP significantly extended the lifespan of C. elegans, reduced the accumulations of lipofuscin and increased the ability of C. elegans to resist oxidative stress, and reduced the aggregation of Aβ protein in the AD model C. elegans, and improved neuromuscular dysfunction. Transcriptomic analysis revealed that PRP modulated the expression of genes involved in key processes, including anti-stress and senescence (daf-12, skn-1, gst-4, ctl-1, sod-3, age-1, gcs-1), autophagy (unc-51, bec-1, lgg-1), and mitochondrial function (clk-1, mev-1, isp-1). Metabolomic analysis revealed that PRP improved metabolic disorders in C. elegans by regulating phenylalanine/purine metabolism pathway. These results indicated that PRP exerted its effects through multiple pathways to delay C. elegans aging and improve AD symptoms, providing a strong theoretical basis for the development of AD treatment drugs based on traditional Chinese medicine.},
}