@article {pmid40640892,
year = {2025},
author = {Noh, MY and Kwon, HS and Kwon, MS and Nahm, M and Jin, HK and Bae, JS and Kim, SH},
title = {Biomarkers and therapeutic strategies targeting microglia in neurodegenerative diseases: current status and future directions.},
journal = {Molecular neurodegeneration},
volume = {20},
number = {1},
pages = {82},
pmid = {40640892},
issn = {1750-1326},
support = {RS-2024-00348451//Korea Dementia Research Center/ ; },
abstract = {Recent advances in our understanding of non-cell-autonomous mechanisms in neurodegenerative diseases (NDDs) have highlighted microglial dysfunction as a core driver of disease progression. Conditions such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and frontotemporal dementia (FTD) share features of impaired microglial phagocytosis, chronic neuroinflammation, and metabolic dysregulation. These insights have prompted new therapeutic strategies targeting microglial function and emphasized the need for reliable biomarkers to monitor disease progression and treatment response. Well-established therapeutic targets, such as triggering receptor expressed on myeloid cells 2 (TREM2), progranulin (PGRN), and sortilin (SORT1), along with emerging candidates including LILRB4, P2Y6R, TAM receptors, and neuroinflammation-related markers, are discussed alongside novel blood, cerebrospinal fluid (CSF), and imaging biomarkers. Despite notable progress, many of these biomarkers remain restricted to preclinical studies and face translational challenges due to species-specific differences, lack of standardization, and clinical heterogeneity. Emerging technologies-including single-cell omics, spatial transcriptomics, and artificial intelligence (AI)-driven integration of multimodal data-offer new opportunities to align biomarker profiles with evolving disease states and improve patient stratification. Building on the model of companion diagnostics (CDx) in oncology, integrating multimodal biomarker strategies holds promise for guiding personalized interventions, improving clinical outcomes, and deepening our mechanistic understanding of microglial contributions across the neurodegenerative spectrum.},
}

@article {pmid40640729,
year = {2025},
author = {Ghaderi, S and Mohammadi, S and Fatehi, F and Sisakhti, M and Batouli, SAH and , },
title = {Validation of dementia-free status in the iranian brain imaging database using ADNI data: a transition point from middle age to older adulthood.},
journal = {BMC neurology},
volume = {25},
number = {1},
pages = {286},
pmid = {40640729},
issn = {1471-2377},
abstract = {OBJECTIVE: To validate the Iranian Brain Imaging Database (IBID) for dementia-free status in middle-aged to older adults (over 55 years old) by comparing dementia probability metrics with Alzheimer's disease (AD) patients from the Alzheimer's Disease Neuroimaging Initiative (ADNI).

METHODS: This cross-sectional study included 41 cognitively normal participants from IBID (age > 55 years; median (IQR) = 64 (62, 68) years; females = 51.2%) and 41 age/sex-matched AD patients from ADNI (age > 55 years; median (IQR) = 69 (62, 71) years; females = 53.7%). High-resolution 3D T1-weighted MPRAGE MRI data were harmonized across Siemens 3.0 Tesla scanners, preprocessed via the AssemblyNet-AD pipeline (volBrain), and analyzed for grading scores and hippocampal-amygdalo-ventricular atrophy scores (HAVAs), along with hippocampus, amygdala, and inferior lateral ventricle atrophy scores. Non-parametric Mann-Whitney U tests were used to compare group differences, and quantile regression (25th, 50th, and 75th quantiles) model atrophy severity-dependent associations.

RESULTS: IBID participants exhibited minimal dementia probability (median grading score = 0.20% vs. ADNI = 99.93%; U = 84.0, p < 0.0001) and markedly lower atrophy across all regions (HAVAs: 14.76 vs. 86.41; U = 75.0, p < 0.0001), with non-overlapping interquartile ranges. Quantile regression revealed stable hippocampal contributions (q₀.₅ coefficient = 0.311, p < 0.001) and increasing group disparities at higher atrophy severities (q₀.₇₅: IBID vs. ADNI coefficient = - 11.82, p < 0.001).

CONCLUSION: We provided validated dementia-free IBID neuroimaging data to distinguish normal aging from dementia-AD status.},
}

@article {pmid40640460,
year = {2025},
author = {Heimler, SR and Amick, KA and Bergstrom, J and Moliné, M and Mahapatra, G and Craft, S and Molina, AJA},
title = {Nervonic acid and 15-epi-PGA1 mediate systemic mitochondrial dysfunction in AD dementia.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {40640460},
issn = {2509-2723},
support = {R01 AG054523/GF/NIH HHS/United States ; R01 AG061805/GF/NIH HHS/United States ; P30 AG068635/GF/NIH HHS/United States ; P30 AG 072947/GF/NIH HHS/United States ; },
abstract = {Systemic mitochondrial dysfunction is apparent in the pathophysiology of Alzheimer's disease (AD). However, the factors driving bioenergetic decline remain unclear. This study utilized serum samples from older adults with normal cognition, mild cognitive impairment, and dementia to identify circulating molecules that can drive mitochondrial dysfunction in the context of AD. We used mass spectrometry to measure the abundance of lipid metabolites and applied tiered selection criteria to identify candidate "mito-inhibitory" molecules. These criteria were based on correlations with (1) in vitro bioenergetic effects of whole serum samples on naïve cells, (2) the bioenergetic capacity of blood cells from the serum donor, and (3) cognition, as measured by the modified mini-mental state exam. Mito-inhibitory lipid candidates were validated by examining their bioenergetic effects on neurons, myoblasts, and fibroblasts in vitro. Our results indicate that nervonic acid and 15-epi Prostaglandin A1 (15-epi-PGA1) are elevated in participants with dementia compared to those with normal cognition. Importantly, both metabolites inhibited mitochondrial function across multiple cell types in vitro. High resolution respirometric analyses reveal that inhibitory effects from lipid treatment occur via broad inhibition of the electron transfer system (ETS) with no change in overall mitochondrial content. This study provides insights into the mechanisms underlying systemic bioenergetic decline associated with AD dementia. The identification of circulating factors that drive mitochondrial bioenergetic decline may inform the development of mitochondrial therapeutics for AD.},
}

@article {pmid40640358,
year = {2025},
author = {Zhu, L and Zhou, T and Wu, L and Zhu, X and Chen, L and Zhang, M and Zhou, J and Wang, F},
title = {Microglial exosome TREM2 ameliorates ferroptosis and neuroinflammation in alzheimer's disease by activating the Wnt/β-catenin signaling.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {24968},
pmid = {40640358},
issn = {2045-2322},
support = {2024YFZD063, 2018YFZD025, and 2023YFZD006//Key Science and Technology Plan Project of Jingmen/ ; 2024AFB1021//Hubei Provincial Natural Science Foundation General Project/ ; WJ2023M171//Health Commission of Hubei Province/ ; B2023223 and D20234302//Hubei Provincial Department of Education research project/ ; },
mesh = {Animals ; *Alzheimer Disease/metabolism/pathology ; *Ferroptosis ; Mice ; *Wnt Signaling Pathway ; *Exosomes/metabolism ; *Microglia/metabolism ; *Membrane Glycoproteins/metabolism/genetics ; *Receptors, Immunologic/metabolism/genetics ; Disease Models, Animal ; Oxidative Stress ; Amyloid beta-Peptides/metabolism ; *Neuroinflammatory Diseases/metabolism/pathology ; Mitochondria/metabolism ; Neurons/metabolism ; Male ; beta Catenin/metabolism ; Cell Line ; Humans ; Inflammation/metabolism ; },
abstract = {Microglia and exosomes are intimately connected with the pathogenesis of Alzheimer's disease (AD). We aim to investigate the role and potential mechanisms of M2-like (anti-inflammatory) microglia-derived exosomes (M2-Exos) in AD. We utilized an Aβ1-42-induced AD model in HT-22 neurons and mouse. The effects of M2-Exo on mitochondrial damage, ferroptosis, oxidative stress, and inflammation levels in the AD cell/animal models were evaluated using transmission electron microscopy, immunoblotting, and biochemical assay kits. Cognitive function in mouse was assessed through behavioral tests. In the AD cell/animal models, the effects of M2-Exo on the Wnt/β-catenin pathway were investigated through immunofluorescence and immunoblotting. AD cells were treated with HLY78 (Wnt/β-catenin pathway activator) to explore the modulation of the pathway. After knocking down TREM2 in M2-Exo, mitochondrial damage, ferroptosis, oxidative stress, and inflammation markers were reevaluated in AD cell and animal models. Aβ1-42 induced mitochondrial shrinkage and deformation in neurons, upregulated ACSL4, PTGS2, Fe2+/Fe, lipid peroxide (LPO), ROS, MDA, IL-6, IL-1β, and TNF-α, while it downregulated GPX4, FTH1, and GSH-PX. M2-Exo reversed the effects induced by Aβ1-42 both in vitro and in vivo, and M2-Exo improved cognitive function in AD mouse. HLY78 also reversed the effects induced by Aβ1-42. M2-Exo increased the levels of β-catenin. BV2 cells converting to M2-like type increased TREM2 levels. Knocking down TREM2 in M2-Exos resulted in decreased neuronal β-catenin levels, reversing the beneficial effects of M2-Exo on AD cell and mouse models. M2-Exo TREM2 alleviates neuronal ferroptosis, inflammation, and oxidative stress in AD by activating the Wnt/β-catenin signaling pathway.},
}

Animals
*Alzheimer Disease/metabolism/pathology
*Ferroptosis
Mice
*Wnt Signaling Pathway
*Exosomes/metabolism
*Microglia/metabolism
*Membrane Glycoproteins/metabolism/genetics
*Receptors, Immunologic/metabolism/genetics
Disease Models, Animal
Oxidative Stress
Amyloid beta-Peptides/metabolism
*Neuroinflammatory Diseases/metabolism/pathology
Mitochondria/metabolism
Neurons/metabolism
Male
beta Catenin/metabolism
Cell Line
Humans
Inflammation/metabolism

@article {pmid40640319,
year = {2025},
author = {Chen, S and Ye, X and Wang, Q},
title = {Association of CSF neurogenin-1 levels with cognitive decline and structural MRI features in older adults.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {24944},
pmid = {40640319},
issn = {2045-2322},
mesh = {Humans ; Male ; Aged ; *Cognitive Dysfunction/cerebrospinal fluid/diagnostic imaging/pathology ; Female ; Magnetic Resonance Imaging ; *Nerve Tissue Proteins/cerebrospinal fluid ; *Basic Helix-Loop-Helix Transcription Factors/cerebrospinal fluid ; Aged, 80 and over ; Hippocampus/pathology/diagnostic imaging ; Alzheimer Disease/cerebrospinal fluid ; Biomarkers/cerebrospinal fluid ; Middle Aged ; },
abstract = {Neurogenesis has been implicated in the pathogenesis of Alzheimer's disease (AD). However, the relationship between CSF neurogenin-1 levels and cognitive decline, as well as neurodegeneration in older adults, both with and without cognitive impairment, remains unclear. The current study included 666 individuals, comprising 161 cognitively unimpaired (CU) older adults and 505 cognitively impaired (CI) older adults. To examine the association of CSF neurogenin-1 levels with changes in cognitive performance and neurodegeneration over time, we performed a series of linear mixed-effects models. In these models, baseline CSF neurogenin-1 levels served as the predictor of interest, while cognitive measures, such as Mini-Mental State Examination (MMSE) scores, and hippocampal and ventricular volumes, served as the dependent variables. Higher CSF neurogenin-1 levels were associated with a slower rate of cognitive decline over time in the CI individuals but not in the CU individuals. Regarding structural MRI features, we found that higher baseline CSF neurogenin-1 levels were associated with a slower rate of ventricular enlargement in the CI individuals but not in the CU individuals. No association was observed between CSF neurogenin-1 levels and hippocampal atrophy in either group. Our findings suggest that neurogenin-1 may play a neuroprotective role in CI individuals, potentially slowing cognitive decline and structural brain changes associated with the disease.},
}

Humans
Male
Aged
*Cognitive Dysfunction/cerebrospinal fluid/diagnostic imaging/pathology
Female
Magnetic Resonance Imaging
*Nerve Tissue Proteins/cerebrospinal fluid
*Basic Helix-Loop-Helix Transcription Factors/cerebrospinal fluid
Aged, 80 and over
Hippocampus/pathology/diagnostic imaging
Alzheimer Disease/cerebrospinal fluid
Biomarkers/cerebrospinal fluid
Middle Aged

@article {pmid40640137,
year = {2025},
author = {Luan, Y and Wang, W and Huang, Q and Wang, Y and Nussbaumer, J and Wang, J and Steward, A and Roemer-Cassiano, SN and Guan, Y and Ewers, M and Schöll, M and Ni, R and Li, B and Franzmeier, N and Xie, F},
title = {Synaptic loss pattern is constrained by brain connectome and modulated by phosphorylated tau in Alzheimer's disease.},
journal = {Nature communications},
volume = {16},
number = {1},
pages = {6356},
pmid = {40640137},
issn = {2041-1723},
support = {81801752,82171473, 82201583, 82071962//National Natural Science Foundation of China (National Science Foundation of China)/ ; },
mesh = {Humans ; *Alzheimer Disease/metabolism/pathology/diagnostic imaging ; *tau Proteins/metabolism/blood ; *Connectome ; Phosphorylation ; Female ; Male ; *Brain/metabolism/pathology/diagnostic imaging ; *Synapses/pathology/metabolism ; Aged ; Aged, 80 and over ; Positron-Emission Tomography ; Nerve Tissue Proteins/metabolism ; Middle Aged ; Membrane Glycoproteins/metabolism ; Case-Control Studies ; },
abstract = {Synaptic loss strongly correlates with cognitive impairment in Alzheimer's disease (AD), yet the mechanism linking its origin and pattern remain unclear. Given that connected brain regions share molecular and synaptic features, and pathological tau, a key driver of synaptic degeneration, propagates through brain networks, we hypothesize that network architecture may influence synaptic loss in AD. By combining synaptic vesicle glycoprotein 2 A (SV2A) PET in 91 AD patients and 54 controls with normative connectome data, we show strongly connected regions exhibit similar levels of synaptic loss, and synaptic loss in one region is associated with connectivity-weighted synaptic loss in connected regions. Regions strongly connected to the epicenter show greater and faster synaptic loss. Plasma p-tau181 levels correlate with network-constrained synaptic loss, and post-mortem data confirm reduced SV2A expression in tau-rich areas. These findings support that synaptic vulnerability in AD is partially constrained by network topology and is modulated by phosphorylated tau.},
}

Humans
*Alzheimer Disease/metabolism/pathology/diagnostic imaging
*tau Proteins/metabolism/blood
*Connectome
Phosphorylation
Female
Male
*Brain/metabolism/pathology/diagnostic imaging
*Synapses/pathology/metabolism
Aged
Aged, 80 and over
Positron-Emission Tomography
Nerve Tissue Proteins/metabolism
Middle Aged
Membrane Glycoproteins/metabolism
Case-Control Studies

@article {pmid40640062,
year = {2025},
author = {Jessen, F and Arbizu, J and Boada, M and Balasa, M and Bennys, K and Boban, M and Bürger, K and Chincarini, A and Cagnin, A and De Deyn, PP and Düzel, E and Engelborghs, S and Ewers, M and Exalto, LG and van der Flier, WM and Fortea, J and Frederiksen, KS and Frisoni, GB and Frölich, L and Garza-Martinez, AJ and Grimmer, T and Hanseeuw, B and Hort, J and Ivanoiu, A and Kehoe, PG and Kennelly, SP and Kern, S and Klöppel, S and Krajčovičová, L and Kramberger, MG and McGuinness, B and Mecocci, P and Oberstein, TJ and Ousset, PJ and Paquet, C and Perneczky, R and Piazza, F and Plantone, D and Rainero, I and Sacco, G and Salmon, E and Santana, I and Scarmeas, N and Schneider, A and Schott, JM and Solje, E and Stefanova, E and Stögmann, E and Strauss, M and Sutovsky, S and Waldemar, G and Winblad, B},
title = {Comment by European Alzheimer's Disease Consortium (EADC) investigators on the negative recommendation of the CHMP on the marketing authorization of donanemab for early Alzheimer' s disease.},
journal = {The journal of prevention of Alzheimer's disease..},
volume = {},
number = {},
pages = {100259},
doi = {10.1016/j.tjpad.2025.100259},
pmid = {40640062},
issn = {2426-0266},
}

@article {pmid40639970,
year = {2025},
author = {Franceschi, AM and Keir, G and Benzinger, TLS and Cogswell, PM and Ali, FZ and Petrella, JR and Prescott, JW and Whitlow, CT and Zaharchuk, G and Allen, JW and , },
title = {Clinical Role of Brain PET in Alzheimer Disease in the Era of Disease-Modifying Therapies.},
journal = {AJNR. American journal of neuroradiology},
volume = {},
number = {},
pages = {},
doi = {10.3174/ajnr.A8738},
pmid = {40639970},
issn = {1936-959X},
abstract = {Alzheimer disease (AD) is the leading cause of dementia, with an estimated 6.9 million Americans aged 65 and older living with Alzheimer dementia today, with this number projected to grow to 13.8 million by 2060. Amyloid and τ accumulation underpin our understanding of the pathophysiology of AD, with the abnormal accumulation of these proteins leading to neurodegeneration. With the recent approval of antiamyloid monoclonal antibody therapies for patients with early-stage Alzheimer disease by the Food and Drug Administration, there is renewed energy and focus on brain imaging for diagnosis, triage, and monitoring of patients with neurodegenerative disease. Furthermore, PET imaging of amyloid and τ has revolutionized our understanding of dementia progression and staging, and influences patient management in the clinical setting. We aim to update radiologists on the evolving role of amyloid and τ PET in clinical practice, emphasizing the need for standardized workflows and the integration of molecular imaging data with other disease biomarkers. We also discuss the clinical implications of amyloid and τ PET, including their impact on diagnosis and treatment decisions, as well as the challenges of reimbursement and workforce capacity. With recent shifts in the AD management landscape, it is crucial for radiologists to keep abreast of recent advances in clinical practice, thereby ensuring effective patient care.},
}

@article {pmid40639927,
year = {2025},
author = {Das, S},
title = {Alzheimer's disease basics: we all should know.},
journal = {Neurological research},
volume = {},
number = {},
pages = {1-30},
doi = {10.1080/01616412.2025.2529560},
pmid = {40639927},
issn = {1743-1328},
abstract = {BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia worldwide, affecting over 55 million individuals and projected to rise drastically in the coming decades. Characterized by progressive cognitive decline and memory impairment, AD involves complex pathological mechanisms including amyloid-beta (Aβ) plaque accumulation, neurofibrillary tangles (NFTs) of hyperphosphorylated tau, and chronic neuroinflammation.

OBJECTIVE: This comprehensive review aims to provide a foundational understanding of the molecular, genetic, and immunological underpinnings of AD, with a focus on pathogenic proteins, glial cell responses, and current monoclonal antibody (mAb)-based therapeutic strategies.

METHODS: Literature on key pathological players such as Aβ, tau, microglia, and astrocytes was mentioned to explain their roles in neurodegeneration. The impact of key genetic mutations (APP, PSEN1, PSEN2, APOE, BACE1, MAPT) was outlined. Additionally, recent clinical trial data of anti-Aβ monoclonal antibodies (aducanumab, lecanemab, donanemab) were reviewed, with comparative analysis of efficacy, safety, and trial outcomes.

RESULTS: Neuroinflammation, mediated by activated microglia and astrocytes, exacerbates Aβ and tau pathology, contributing to synaptic loss and neuronal death. Genetic mutations alter APP processing and promote plaque formation. Monoclonal antibodies show promise in reducing Aβ burden and slowing cognitive decline: donanemab achieved 60% slower decline in mild cognitive impairment, while lecanemab showed 27% cognitive benefit in early AD. Aducanumab, despite initial promise, was discontinued in 2024 due to limited efficacy and safety concerns. Adverse events like amyloid-related imaging abnormalities (ARIA), particularly in APOE-4 carriers, remain significant.

CONCLUSION: AD pathology is multifactorial, involving an interplay between protein aggregation, immune dysregulation, and genetic risk. While mAb therapies mark progress in disease modification, their success depends on patient stratification, early intervention, and safety profiling. Future directions must emphasize combinatorial and personalized approaches incorporating early biomarkers, neuroimaging, and emerging technologies to effectively combat the rising global burden of AD.},
}

@article {pmid40639914,
year = {2025},
author = {Peña-Bautista, C and Álvarez-Sánchez, L and Balaguer, Á and Ferré-González, L and Peretó, M and Baquero, M and Cháfer-Pericás, C},
title = {Plasma Proteomic Analysis for Alzheimer's Disease Biomarkers, Pathways, and Subgroup Identification.},
journal = {Journal of proteome research},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jproteome.5c00513},
pmid = {40639914},
issn = {1535-3907},
abstract = {The proteomic profile in plasma samples from patients with complex diseases such as Alzheimer's disease (AD) is a useful tool for identifying potential biomarkers in minimally invasive samples and describing impaired pathways and early disease subgroups. Untargeted proteomics by mass spectrometry was performed on plasma samples from patients of a cognitive disorders unit (data available in BioStudies (S-BSST1631)). Participants were classified as mild cognitive impairment due to AD (MCI-AD, n = 30) or subjective cognitive impairment (SCI, n = 30) based on cerebrospinal fluid (CSF) biomarkers, neuropsychological assessment, and neuroimaging. Discriminant analysis, using partial least-squares (PLS) regression and volcano plot, was performed using the STRING database, and cluster analysis identified AD subtypes. From 1094 detected proteins, 71 differed significantly between groups. PLS and volcano plot analyses identified 45 and 22 variables, respectively (e.g., CRIP1, CRTAC1, LTBP2, MMP14, PLIN3, REG3A, SHH). Most of them were elevated in MCI-AD and correlated to CSF biomarkers and cognition. Altered pathways included the immune system, cell adhesion, and proteolysis, and two MCI-AD subgroups were found based on protein profiles. This study identified 10 proteins as potential plasma biomarkers for early AD detection and highlighted the affected biological pathways, contributing to the understanding of AD physiopathology.},
}

@article {pmid40639583,
year = {2025},
author = {Fatima, E and Fatima, A},
title = {Intranasal Administration of Stem Cell Therapy: A Promising Approach For Early Alzheimer's Disease Intervention.},
journal = {The American journal of the medical sciences},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.amjms.2025.07.002},
pmid = {40639583},
issn = {1538-2990},
}

@article {pmid40639550,
year = {2025},
author = {Mondal, M and Chouksey, A and Gurjar, V and Tiwari, R and Srivasatava, RK and Mishra, PK},
title = {Micro(nano)plastics in the brain: Epigenetic perturbations in progression to neurodegenerative diseases.},
journal = {Neurotoxicology and teratology},
volume = {},
number = {},
pages = {107521},
doi = {10.1016/j.ntt.2025.107521},
pmid = {40639550},
issn = {1872-9738},
abstract = {As global plastic production escalates, micro(nano)plastics (MNPs) have become pressing ecological and biomedical concerns. These pollutants are increasingly implicated in the pathogenesis of neurodegenerative diseases. Due to their nanoscale size and surface reactivity, MNPs can cross the blood-brain barrier, accumulating in neural tissues. Once internalized, they disrupt neuronal homeostasis by inducing oxidative stress, mitochondrial dysfunction, and chronic neuroinflammation, key processes in neurodegenerative progression. Mitochondria, central to neuronal energy and redox regulation, are particularly vulnerable, leading to impaired ATP production, elevated ROS, and pro-apoptotic signaling. Recent studies reveal that MNPs also induce epigenetic changes, including aberrant DNA methylation, histone modifications, and dysregulation of non-coding RNAs. These alterations can result in synaptic instability, persistent transcriptional reprogramming, and heightened susceptibility to diseases like Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis. The mitochondrial epigenome is a vital target of MNP-induced disruption, offering potential biomarkers like methylated mtDNA and microRNAs for early diagnosis and prognosis. Understanding the molecular mechanisms behind these epigenetic alterations is essential for developing practical diagnostic tools and therapies. This review provides a comprehensive overview of MNP-induced neurodegeneration, focusing on mitochondrial and epigenetic disruptions. Moreover, it explores emerging biosensing technologies for detecting MNP-induced epigenetic alterations, highlighting the urgent need for further investigation to fully understand the neurotoxic potential of MNPs and develop preventive and therapeutic strategies for mitigating their effects on brain health.},
}

@article {pmid40639477,
year = {2025},
author = {Ghasemi, A and Saadinezhad, A and Halalkhor, S and Sadeghi, F and Hosseini, SM and Karami, M and Hosseinzadeh, S},
title = {Piperine improves learning deficit through modulation of Wnt/β-catenin signaling pathway: Involvement of the dorsal hippocampus serotonin-1A receptors.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {177922},
doi = {10.1016/j.ejphar.2025.177922},
pmid = {40639477},
issn = {1879-0712},
abstract = {BACKGROUND: In the hippocampal region, piperine raised serotonin levels. Nevertheless, little is currently understood about how piperine acts through the Wnt/β-catenin pathway and regulates neurogenesis.

METHODS: Electroencephalogram electrodes were implanted in the frontoparietal and hippocampal regions of a streptozotocin (STZ)-induced rat model of Alzheimer's disease (AD). The involvement of serotonin-1A receptors in hippocampus was evaluated by microinjection of one microliter of [8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT)/ N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexane-carboxamide (WAY 100635), in the mediation of the behavioral effects of piperine at 1, 10, and 50 μg/ml, 30 minutes before the probe trial and before recording. The left hemisphere was placed in 10% formalin to make a tissue incision. To identify potential genes regulated by the Wnt/β-catenin pathway, the right hippocampal tissue was dissected on a cold phosphate-buffered saline plate and stored in the freezer.

RESULTS: Memory-enhancing effect of piperine at 50 μg/ml, was efficiently prevented by the 8OH-DPAT. Moreover, the animals in the Saline/8OH, AD/Pip50, and AD/WAY/Pip50 groups demonstrated notably higher mean absolute power in theta, beta, and gamma frequencies than the AD/Tween, AD/8OH, and AD/8OH/Pip50. Neuroprotection was induced morphologically in the dentate gyrus following co-administration of WAY-100635 and 50 μg/ml of piperine. The expression of serum- and glucocorticoid-inducible kinase 1 was significantly higher in the AD/Tween and AD/8OH groups than the Saline/8OH groups. The administration of WAY-100635 and piperine 50, markedly increased the expression of the c-myc gene.

CONCLUSIONS: Understanding more about the signal transduction pathways associated with piperine may develop a strategy for treating symptoms and pathological conditions related to AD.},
}

@article {pmid40639429,
year = {2025},
author = {Burgdorf, JG and Wolff, JL and Barrón, Y and Amjad, H},
title = {Family Caregiver Availability and Capacity Associated With Home Health Service Types for Patients With Dementia.},
journal = {Journal of the American Medical Directors Association},
volume = {},
number = {},
pages = {105744},
doi = {10.1016/j.jamda.2025.105744},
pmid = {40639429},
issn = {1538-9375},
abstract = {OBJECTIVES: To investigate the relationship between unmet needs for family caregiver support, defined as lack of caregiver availability or capacity, and home health care (HH) service types delivered to patients with dementia.

DESIGN: Cross-sectional study of national claims and assessment data.

SETTING AND PARTICIPANTS: 325,148 older adults (aged ≥65 years) with diagnosed dementia receiving Medicare-funded HH in 2018.

METHODS: Service types were measured from Medicare claims and refers to patient receipt of each of 6 service types covered during HH: nursing, physical therapy, occupational therapy, speech therapy, social work, and personal care aide. We fit multivariable logistic regression models estimating the odds of receiving each service type as a function of unmet caregiving needs and patient and HH agency characteristics, while clustering at the HH agency level.

RESULTS: In adjusted models, lack of caregiver availability to help with medical, functional, or instrumental tasks was associated with higher odds of receiving skilled nursing [adjusted odds ratio (aOR) 1.63, 95% CI 1.47-1.81], aide (aOR 1.61, 95% CI 1.54-1.68), and social work (aOR 2.71, 95% CI 2.56-2.86), respectively. Lack of caregiver capacity to help with medical, functional, or instrumental tasks was associated with higher odds of receiving skilled nursing (aOR 1.29, 95% CI1.20-1.39), physical therapy (aOR 1.74, 95% CI1.68-1.81), and social work (aOR 1.24, 95% CI 1.17-1.28), respectively.

CONCLUSIONS AND IMPLICATIONS: We observed significant associations between unmet needs for caregiving support and HH service delivery for patients with dementia. Expanding HH quality measurement and risk adjustment data elements to include measures of caregiver availability and capacity are necessary steps toward supporting HH providers' efforts to meet patients' needs regardless of their caregiving context.},
}

@article {pmid40639349,
year = {2025},
author = {Yang, QQ and Chen, T and Chen, LL and Jiang, W and Ding, XB and Yang, XX},
title = {Public knowledge of Alzheimer's disease and attitudes toward Alzheimer's disease in Chongqing, China: a cross-sectional analysis.},
journal = {Neuroepidemiology},
volume = {},
number = {},
pages = {1-19},
doi = {10.1159/000547358},
pmid = {40639349},
issn = {1423-0208},
abstract = {INTRODUCTION: Dementia, particularly Alzheimer's disease (AD), represents a significant public health challenge in China, with Chongqing experiencing rapid population aging and a rising prevalence of dementia. Early prevention and public education are critical to mitigating dementia risk; however, public awareness of AD remains low, with significant knowledge gaps and misconceptions. This study aimed to assess the knowledge and attitudes toward AD among the general public in Chongqing to inform effective public health strategies.

METHODS: A multistage stratified random sampling approach was employed to recruit 5,994 permanent residents aged 18 years and above from 17 districts in Chongqing between November and December 2024. Face-to-face interviews were conducted via the Chinese versions of the Alzheimer's Disease Knowledge Scale (ADKS) and the Dementia Attitudes Scale (DAS). Descriptive statistics and multivariable linear regression models were used to analyze the data and identify factors influencing AD knowledge and attitudes.

RESULTS: The mean ADKS score was 16.81 (55.78% accuracy), indicating low AD knowledge among participants. Knowledge was highest regarding the life impact but lowest concerning caregiving, symptoms, and risk factors. The mean DAS score was 78.61 (SD=10.709), reflecting generally positive attitudes toward dementia patients. Multivariable analysis revealed that ethnic minority status (OR=0.718, 95% CI: 0.561-0.918), junior high school education (OR=1.261, 95% CI: 1.055-1.507), high school/vocational education (OR=1.703, 95% CI: 1.277-2.271), associate or bachelor's degrees or higher (OR=2.624, 95% CI: 1.805-3.815), institution/enterprise-related personnel (OR=1.461, 95% CI: 1.003-2.127), and other workers (OR=1.241, 95% CI: 1.024-1.502) were associated with AD knowledge. High school/vocational education (OR=3.484, 95% CI: 1.115-10.884), associate or bachelor's degrees (OR=4.558, 95% CI: 1.035-20.075), CNY 1000-2999 (OR=3.731, 95% CI: 1.905-7.309), CNY 3000-5999 (OR=14.973, 95% CI: 6.091-36.811), above CNY 6000 (OR=10.761, 95% CI: 2.361-49.038) and prior dementia-related training (OR=5.573, 95% CI: 2.185-14.210) were associated with more positive attitudes toward dementia patients. However, production/transport personnel (OR=0.157, 95% CI: 0.054-0.453) and other workers (OR=0.182, 95% CI: 0.085-0.387) presented lower DAS scores.

CONCLUSION: This study highlights significant gaps in AD knowledge and attitudes among the Chongqing public, emphasizing the need for targeted interventions to improve awareness and reduce stigma, particularly among underserved populations.},
}

@article {pmid40639271,
year = {2025},
author = {Mao, Y and Zhang, L and Zhang, C and Qin, L and Liao, X and Zhao, L},
title = {The close relationship between trace elements (Cu, Fe, Zn, Se, Rb, Si, Cr, and V) and Alzheimer's disease: Research progress and insights.},
journal = {Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS)},
volume = {90},
number = {},
pages = {127692},
doi = {10.1016/j.jtemb.2025.127692},
pmid = {40639271},
issn = {1878-3252},
abstract = {Alzheimer's disease (AD) is a typical neurodegenerative disorder primarily characterized by the deposition of β-amyloid (Aβ) plaques and the hyperphosphorylation of tau protein, leading to the formation of neurofibrillary tangles (NFTs). These pathological changes are closely associated with the imbalance of trace element homeostasis. Trace elements are extensively involved in fundamental physiological processes, including DNA synthesis, protein synthesis, energy metabolism, and enzymatic reactions, all of which are essential for cognitive function and brain development. This review summarizes the alterations in homeostasis and the biological roles of trace elements such as copper, iron, zinc, selenium, rubidium, silicon, chromium, and vanadium, as well as their relationship with the onset and progression of AD. Additionally, we discuss recent advancements in therapeutic strategies targeting the balance of trace element ions, including metal chelators, supplements, nanomedicines, and small-molecule drugs, to provide new perspectives for AD research and treatment.},
}

@article {pmid40639266,
year = {2025},
author = {Kim, T and Zhang, K and Zhu, T and Song, IU and Na, S and Hippe, DS and Canton, G and Hatsukami, T and Yuan, C and Mossa-Basha, M and Balu, N},
title = {Quantitative analysis of cerebral vasculature and its clinical effect on cognitive change in Alzheimer's dementia and mild cognitive impairment.},
journal = {Journal of the neurological sciences},
volume = {476},
number = {},
pages = {123598},
doi = {10.1016/j.jns.2025.123598},
pmid = {40639266},
issn = {1878-5883},
abstract = {BACKGROUND: Cerebrovascular disease (CVD) and Alzheimer's disease (AD) share common risk factors and often coexist. This study investigates the relationship between cerebral arterial features and cognitive decline in patients with clinical AD dementia and amnestic mild cognitive impairment (MCI) using quantitative analysis of Time-Of-Flight (TOF) magnetic resonance angiography (MRA).

METHODS: 131 patients (101 AD dementia, 30 amnestic MCI) underwent baseline TOF-MRA and cognitive assessments and 24-month follow-up cognitive tests. Total distal arterial length was measured using a custom-designed semi-automatic intracranial vascular map construction software. Associations between total distal arterial length and cognitive changes were analyzed using multiple linear regression and repeated measures analysis of covariance.

RESULTS: Shorter total distal arterial length was significantly associated with greater 2-year decline in Montreal Cognitive Assessment (MoCA) scores over 2 years (r = 0.199, p = 0.020). This association remained significant after adjusting for various confounding factors, including age, sex, education, brain parenchymal fraction, white matter hyperintensities, ApoE4 status, and vascular risk factors. Similar trends were observed for Mini-Mental State Examination (MMSE) scores, although not reaching statistical significance.

CONCLUSIONS: Quantitative measurements of cerebral vasculature on TOF-MRA are independently associated with cognitive decline in patients with clinical AD dementia and amnestic MCI. This suggests that reduced cerebral blood flow may contribute to cognitive decline in these patients, highlighting the potential role of vascular factors in AD progression. These findings support the use of quantitative cerebral arterial measurements as a potential imaging biomarker for cognitive decline in AD.},
}

@article {pmid40638744,
year = {2025},
author = {Keil, SA and Jansson, D and Braun, M and Iliff, JJ},
title = {Glymphatic dysfunction in Alzheimer's disease: A critical appraisal.},
journal = {Science (New York, N.Y.)},
volume = {389},
number = {6756},
pages = {eadv8269},
doi = {10.1126/science.adv8269},
pmid = {40638744},
issn = {1095-9203},
mesh = {*Alzheimer Disease/physiopathology ; Humans ; *Glymphatic System/physiopathology ; Animals ; *Brain/physiopathology ; },
abstract = {Thirteen years after the initial publication defining the glymphatic system, we critically reappraise the role of its dysfunction in Alzheimer's disease (AD). Our understanding of glymphatic function and its involvement in the pathogenesis of AD derives primarily from correlative clinical data and rodent studies. A causal role for glymphatic dysfunction in AD has not yet been established in humans. We review current approaches to assess glymphatic function clinically, which capture different features of perivascular fluid dynamics or their results. The absence of clinically suitable imaging approaches to measuring glymphatic exchange in the human brain is an obstacle to evaluating whether glymphatic function is impaired in AD populations and to developing and evaluating therapeutics to modulate glymphatic function in the treatment and prevention of AD.},
}

*Alzheimer Disease/physiopathology
Humans
*Glymphatic System/physiopathology
Animals
*Brain/physiopathology

@article {pmid40638114,
year = {2025},
author = {de Leeuw, DM and Trieu, C and Vromen, EM and Blujdea, ER and Verberk, IMW and Duits, FH and Teunissen, CE and Pijnenburg, YAL and van der Flier, WM and van Harten, AC and Visser, PJ and Tijms, BM},
title = {Cerebrospinal Fluid Amyloid and Tau Biomarker Changes Across the Alzheimer Disease Clinical Spectrum.},
journal = {JAMA network open},
volume = {8},
number = {7},
pages = {e2519919},
doi = {10.1001/jamanetworkopen.2025.19919},
pmid = {40638114},
issn = {2574-3805},
mesh = {Humans ; *Alzheimer Disease/cerebrospinal fluid/diagnosis ; *tau Proteins/cerebrospinal fluid ; Male ; Female ; Biomarkers/cerebrospinal fluid ; *Amyloid beta-Peptides/cerebrospinal fluid ; Aged ; Longitudinal Studies ; *Peptide Fragments/cerebrospinal fluid ; Middle Aged ; Aged, 80 and over ; Cognitive Dysfunction/cerebrospinal fluid ; Disease Progression ; },
abstract = {IMPORTANCE: The trajectories of core Alzheimer disease (AD) cerebrospinal fluid (CSF) biomarkers and the concurrent cognitive changes across the clinical spectrum remain unclear yet are important for clinical trial design.

OBJECTIVE: To map longitudinal CSF amyloid, tau, and cognitive trajectories along the clinical spectrum of AD and amyloid-negative controls.

This longitudinal cohort study included participants with a minimum of 2 CSF samples from Alzheimer Centrum Amsterdam cohorts across the AD clinical spectrum (ie, abnormal amyloid levels at first visit, in different clinical stages) and cognitively normal controls with initially normal CSF markers from November 2003 to July 2019. The maximum follow-up period was 19.5 years (median [IQR], 2 [0-3] years). Data were analyzed from March 2024 to May 2025.

EXPOSURES: AD biomarkers (ß-amyloid [Aß]1-42 to Aß1-40 ratio, total tau [t-tau], and phosphorylated tau [p-tau]) detected in serially collected CSF.

MAIN OUTCOMES AND MEASURES: CSF AD biomarkers were measured with Lumipulse G600II. Cognition was measured using the Mini-Mental State Examination (MMSE) and delayed memory recall component of the of the Rey Auditory Verbal Learning Test. Analysis was conducted using linear mixed models, including random intercepts and slopes, adjusting for age, education level, and sex. Each model included an interaction term of time and clinical stage to study stage-specific slopes. Biomarker conversion rates per clinical stage were studied by comparing biomarker status between visits.

RESULTS: The sample included 197 individuals (103 male [52.3%]), including 83 controls (mean [SD] age, 63 [8] years), 31 individuals with amyloid positivity who were cognitively unimpaired (mean [SD] age, 67 [9] years), 30 individuals with amyloid-positive mild cognitive impairment (MCI; mean [SD] age, 67 [7] years), and 53 individuals with amyloid-positive dementia (mean [SD] age, 65 [8] years). Aβ1-42/1-40 ratios decreased in controls (β [SE] = -8.55 × 10-4 [1.87 × 10-4]; P < .001) and the amyloid-positive cognitively unimpaired group (β [SE] = -1.05 × 10-3 [3.14 × 10-4]; P < .001), and remained low in amyloid-positive MCI and dementia groups. There were 10 controls (12.0%) who reached abnormal amyloid over a mean (SD) of 4.8 (3.4) years. In controls, CSF t-tau (β [SE] = 8.49 [2.55] pg/mL per year; P = .002) and p-tau (β [SE] = 1.36 [0.41] pg/mL per year; P = .001) levels increased over time, and levels also increased for those in the amyloid-positive cognitively unimpaired (t-tau: β [SE] = 17.24 [4.58] pg/mL per year; P < .001; p-tau: β [SE] = 3.10 [0.72] pg/mL per year; P < .001) and amyloid-positive MCI (t-tau: β [SE] = 30.80 [5.99] pg/mL per year; P < .001; p-tau: β [SE] = 4.40 [0.93] pg/mL per year; P < .001) groups, with t-tau increasing further in the dementia group (β [SE] = 24.97 [7.80] pg/mL per year; P = .002). Longitudinal increases in p-tau and t-tau were steeper in the amyloid-positive cognitively unimpaired and MCI groups than in controls, with 10 controls (12.0%) reaching abnormal p-tau and 12 controls (14.5%) reaching abnormal t-tau levels. Delayed recall declined most in the amyloid-positive cognitively unimpaired group (β [SE] = -0.31 [0.07]; P < .001) and was associated with CSF amyloid levels (β [SE] = 102.29 [47.30]; P = .03). MMSE scores declined most in individuals with amyloid-positive MCI (β [SE] = -1.25 [0.12]; P < .001) and dementia (β [SE] = -1.89 [0.13]; P < .001).

CONCLUSIONS AND RELEVANCE: In this cohort study, CSF amyloid decreased toward abnormal levels in controls, declined further in the amyloid-positive cognitively unimpaired group , and was concurrent with decline of delayed recall; CSF amyloid stabilized in those with amyloid-positive MCI and dementia, while tau markers became increased (ie, more abnormal) in the amyloid-positive cognitively unimpaired and amyloid-positive MCI groups, suggesting that increase in CSF tau requires abnormal amyloid.},
}

Humans
*Alzheimer Disease/cerebrospinal fluid/diagnosis
*tau Proteins/cerebrospinal fluid
Male
Female
Biomarkers/cerebrospinal fluid
*Amyloid beta-Peptides/cerebrospinal fluid
Aged
Longitudinal Studies
*Peptide Fragments/cerebrospinal fluid
Middle Aged
Aged, 80 and over
Cognitive Dysfunction/cerebrospinal fluid
Disease Progression

@article {pmid40637922,
year = {2025},
author = {Vataja, E and Ratti, G and Safa, A and Pagano, M and Ferrante, L and Meri, S and Haapasalo, K},
title = {Exploring the intersection of atherosclerosis and Alzheimer's disease: the role of inflammation and complement activation.},
journal = {Inflammation research : official journal of the European Histamine Research Society ... [et al.]},
volume = {74},
number = {1},
pages = {102},
pmid = {40637922},
issn = {1420-908X},
mesh = {*Alzheimer Disease/immunology ; Humans ; *Atherosclerosis/immunology ; *Inflammation/immunology ; *Complement Activation ; Animals ; },
abstract = {BACKGROUND: Atherosclerosis (AS) and Alzheimer's disease (AD) are both multifactorial in nature and share many risk factors. Vascular dementia and AD may occur together, and a substantial proportion of AD cases also have signs of cardiovascular disease, a relationship well-established by cohort studies. The risk factors could contribute to persistent smoldering inflammation, including activation of complement at sites of endothelial injury and/or by accumulation of molecular aggregates.

METHODS: To examine the possible bridging points between AD and AS, we constructed a comprehensive narrative review.

RESULTS: A connecting point between AD and AS is inflammation. Contrary to prior assumptions, a significant linkage exists between systemic inflammation and neuroinflammation. Activities of complement, a key effector of innate immunity, are of special interest in the pathogenesis of both diseases.

CONCLUSION: AS and AD share a partially overlapping array of pathophysiological mechanisms.},
}

*Alzheimer Disease/immunology
Humans
*Atherosclerosis/immunology
*Inflammation/immunology
*Complement Activation
Animals

@article {pmid40637746,
year = {2025},
author = {Xu, D and Wu, J and Zhao, X and Shen, J and Lu, Z and Yang, Z},
title = {A bibliometric analysis of the current research status and hotspots regarding Aducanumab treatment for Alzheimer's disease.},
journal = {Naunyn-Schmiedeberg's archives of pharmacology},
volume = {},
number = {},
pages = {},
pmid = {40637746},
issn = {1432-1912},
abstract = {BACKGROUND: The prevalence of Alzheimer's disease is steadily increasing, and Aducanumab has garnered significant attention as a treatment since 2021. There is a growing body of research on Aducanumab and its relationship with Alzheimer's disease; however, there is currently a lack of bibliometric analysis regarding the use of Aducanumab in the treatment of Alzheimer's disease.

OBJECTIVE: This study employs bibliometric methods to analyze the current research landscape and hotspots surrounding Alzheimer's disease and Aducanumab, providing a reference for subsequent investigations in this field and the promotion of Aducanumab as a treatment for Alzheimer's disease.

METHODS: This study retrieved articles related to Alzheimer's disease and Aducanumab from the WOS core database, covering the period from the establishment of the database until Dec 31, 2024. After a rigorous selection process, analyses were conducted using GraphPad Prism 10, VOSviewer, and CiteSpace to obtain insights into publication and citation metrics, collaboration networks among countries, institutions, and authors, as well as clustering analysis of reference papers and keywords.

RESULTS: The number of articles regarding Aducanumab treatment for Alzheimer's disease has been increasing annually, with a notable surge occurring after 2021. The three countries with the highest publication output are the United States, the United Kingdom, and China. The leading institutions in terms of publication volume are Biogen, Harvard Medical School, and the University of California, San Francisco. The top three authors contributing to this body of work are Poul F. Høilund-Carlsen, Abass Alavi, and Mona-Elisabeth Revheim. The journals with the highest publication rates include Alzheimer's & Dementia, the International Journal of Molecular Sciences, and the Journal of Alzheimer's Disease. The most cited article is "Lecanemab in Early Alzheimer's Disease," authored by van Dyck CH et al., published in 2023 in the New England Journal of Medicine. The ten most frequently occurring keywords are Alzheimer's disease, Aducanumab, dementia, amyloid-beta, immunotherapy, tau, a-beta, mouse model, amyloid, and mild cognitive impairment. The keyword and cluster "pharmacokinetics" currently represent a research hotspot in this field.

CONCLUSION: This study employs bibliometric methods to reveal the publication trends related to Aducanumab in the context of Alzheimer's disease, examining collaborations among countries, regions, and authors, as well as recent research hotspots. It provides objective data that serves as a reference for scientific research and clinical practice concerning Aducanumab treatment for Alzheimer's disease.},
}

@article {pmid40637617,
year = {2025},
author = {Pini, L and Pigato, P and Menegaz, G and Boscolo Galazzo, I},
title = {Neural networks and econometric models: Advancing brain connectivity for Alzheimer's drug development.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00317},
pmid = {40637617},
issn = {1673-5374},
}

@article {pmid40637583,
year = {2025},
author = {Bonomi, CG and Motta, C and Di Donna, MG and Poli, M and Koch, G and Martorana, A},
title = {Rethinking dementia in the oldest old: Lessons to learn for the diagnosis and treatment of Alzheimer's disease.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00312},
pmid = {40637583},
issn = {1673-5374},
}

@article {pmid40637574,
year = {2025},
author = {Fantini, J and Yahi, N},
title = {Targeting gangliosides to treat Alzheimer's and Parkinson's diseases: A disruptive approach with the first-in-class peptide AmyP53.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00076},
pmid = {40637574},
issn = {1673-5374},
}

@article {pmid40637569,
year = {2025},
author = {Barichello, T and Dal-Pizzol, F},
title = {NLRP3 inflammasome: A link between systemic infection and Alzheimer's disease.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00073},
pmid = {40637569},
issn = {1673-5374},
}

@article {pmid40637566,
year = {2025},
author = {Yuan, Q and Omoluabi, T and Hannam, BF},
title = {Shifting focus to preclinical stages: Locus coeruleus tau pathology as a driver and therapeutic target in Alzheimer's disease.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00140},
pmid = {40637566},
issn = {1673-5374},
}

@article {pmid40637522,
year = {2025},
author = {Nonino, F and Colosimo, C and Massacesi, L},
title = {[Lecanemab and Alzheimer-Perusini's disease: between therapeutic hopes and regulatory challenges.].},
journal = {Recenti progressi in medicina},
volume = {116},
number = {7-8},
pages = {407-410},
doi = {10.1701/4530.45309},
pmid = {40637522},
issn = {2038-1840},
mesh = {Humans ; *Alzheimer Disease/drug therapy/physiopathology ; *Amyloid beta-Peptides/metabolism/immunology ; *Antibodies, Monoclonal, Humanized/adverse effects/therapeutic use/administration & dosage ; Aged ; *Antibodies, Monoclonal/therapeutic use/adverse effects ; },
abstract = {Alzheimer-Perusini's disease (AD) represents a growing health crisis. The lack of effective disease-modifying treatments and its increasing prevalence in the elderly population contribute to a major burden for patients and their caregivers, challenging health systems globally. The accumulation of beta-amyloid protein (Aβ) within the brain tissue plays an important pathogenic role in the inflammatory and degenerative mechanisms leading to cognitive and functional impairment. In recent years monoclonal antibodies targeting (Aβ) have been developed and one of them (lecanemab) recently received marketing authorization by the European Medicines Agency (Ema). Although they represent an important innovation in the treatment of AD, their clinical net benefit is uncertain, due to modest efficacy and the threat of potentially severe side effects. Cost, mode od delivery and complexity of programs aimed at minimizing risks for people with AD may limit access to these therapies and pose equity issues within health systems.},
}

Humans
*Alzheimer Disease/drug therapy/physiopathology
*Amyloid beta-Peptides/metabolism/immunology
*Antibodies, Monoclonal, Humanized/adverse effects/therapeutic use/administration & dosage
Aged
*Antibodies, Monoclonal/therapeutic use/adverse effects

@article {pmid40637232,
year = {2025},
author = {Hsieh, YH and Tai, CH and Yeh, MT and Chen, YC and Yang, PC and Yen, CP and Shen, HJ and Yeh, CH and Kuo, HC and Han, DS and Chu, HC},
title = {Telomeric repeat-containing RNA increases in aged human cells.},
journal = {Nucleic acids research},
volume = {53},
number = {13},
pages = {},
doi = {10.1093/nar/gkaf597},
pmid = {40637232},
issn = {1362-4962},
support = {NSTC 112-2628-B-002-008//National Science and Technology Council/ ; NSTC 112-2320-B-002-058//National Science and Technology Council/ ; NSTC 113-2320-B-002-009//National Science and Technology Council/ ; NSTC 113-2628-B-002-010-MY3//National Science and Technology Council/ ; NTU-111L7880//National Taiwan University/ ; NTU-AS-112L104312//National Taiwan University/ ; NTU-CDP-112L7721//National Taiwan University/ ; NTU-CDP-113L7705//National Taiwan University/ ; H-P.C.C.//National Taiwan University/ ; NHRI-EX111-11107SI//National Health Research Institutes/ ; NHRI-EX112-11107SI//National Health Research Institutes/ ; NHRI-EX113-11107SI//National Health Research Institutes/ ; NHRI-EX114-11411SI//National Health Research Institutes/ ; },
mesh = {Humans ; *Telomere/genetics ; *Aging/genetics ; *RNA/genetics ; Alzheimer Disease/genetics/pathology/metabolism ; Promoter Regions, Genetic ; *Repetitive Sequences, Nucleic Acid ; Single-Cell Analysis ; Cell Differentiation/genetics ; Brain/metabolism ; Aged ; CCCTC-Binding Factor/genetics ; Histones/metabolism ; Fibroblasts/metabolism ; *Cellular Senescence/genetics ; Transcription, Genetic ; RNA-Seq ; },
abstract = {Telomeric repeat-containing RNA (TERRA), transcribed from subtelomeric regions toward telomeric ends, poses challenges in deciphering its complete sequences. Utilizing TERRA-capture RNA-seq and Oxford Nanopore direct RNA sequencing to acquire full-length TERRA, we annotate TERRA transcription regions in the human T2T-CHM13 reference genome. TERRA transcripts encompass hundreds to over a thousand nucleotides of telomeric repeats, predominantly originating from 61-29-37 bp repeat promoters enriched with H3K4me3, RNA Pol II, CTCF, and R-loops. We develop a bioinformatics tool, TERRA-QUANT, for quantifying TERRA using RNA-seq datasets and find that TERRA increases with age in blood, brain, and fibroblasts. TERRA upregulation in aged leukocytes is confirmed by reverse transcription quantitative polymerase chain reaction. Single-cell RNA-seq analysis demonstrates TERRA expression across various cell types, with upregulation observed in neurons during human embryonic stem cell differentiation. Additionally, TERRA levels are elevated in brain cells in the early stage of Alzheimer's disease. Our study provides evidence linking TERRA to human aging and diseases.},
}

Humans
*Telomere/genetics
*Aging/genetics
*RNA/genetics
Alzheimer Disease/genetics/pathology/metabolism
Promoter Regions, Genetic
*Repetitive Sequences, Nucleic Acid
Single-Cell Analysis
Cell Differentiation/genetics
Brain/metabolism
Aged
CCCTC-Binding Factor/genetics
Histones/metabolism
Fibroblasts/metabolism
*Cellular Senescence/genetics
Transcription, Genetic
RNA-Seq

@article {pmid40637155,
year = {2025},
author = {Coşkun, E and İnel Manav, A},
title = {Evaluation of the effects of cognitive stimulation therapy on cognitive status and apathy in older adults with mild cognitive impairment: A randomized controlled trial.},
journal = {Applied neuropsychology. Adult},
volume = {},
number = {},
pages = {1-12},
doi = {10.1080/23279095.2025.2527732},
pmid = {40637155},
issn = {2327-9109},
abstract = {This study was conducted to evaluate the effects of cognitive stimulation therapy on cognitive status and apathy in older adults with mild cognitive impairment. It is a randomized controlled experimental study. The research was conducted in a care center located in a province in Turkey between October 30, 2023, and December 25, 2023. A total of 62 individuals, including 31 in the intervention group and 31 in the control group, were included in the study, forming the research sample. The data for the study were collected using the "Personal Information Form," the "Standardized Mini-Mental Test (SMMSE)," and the " Apathy Rating Scale (ARS)." Cognitive Stimulation Therapy was administered twice a week for a total of 14 sessions in the form of group therapy. Following the implementation of Cognitive Stimulation Therapy, a comparison between the intervention and control groups revealed significant differences in post-test outcomes. The Standardized Mini-Mental State Examination (SMMSE) post-test scores averaged 24.3 ± 1.3 in the intervention group, whereas the control group recorded a lower mean score of 19.6 ± 1.5. Similarly, in the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ARS), the intervention group achieved a mean score of 47.5 ± 3.5, compared to 36.2 ± 3.0 in the control group. It was determined that the mean scores of individuals in the intervention group increased significantly (p < 0.001). Cognitive Stimulation Therapy has been found to be effective in improving cognitive functions and reducing apathy levels in older adults with mild cognitive impairment. Therefore, it is recommended that psychiatric nurses providing care for geriatric individuals implement Cognitive Stimulation Therapy.},
}

@article {pmid40637134,
year = {2025},
author = {Sajjadi, SA and Khan, Z and El-Khoury, A and Bubbico, G and Akhlaghipour, G and Corrada, MM and Kawas, CH and Paganini-Hill, A},
title = {Association of language markers with future cognitive impairment and presence of limbic predominant age related TDP-43 encephalopathy.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {7},
pages = {e70450},
doi = {10.1002/alz.70450},
pmid = {40637134},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; *TDP-43 Proteinopathies/pathology ; *Cognitive Dysfunction/pathology/diagnosis ; Aged, 80 and over ; Biomarkers ; Cohort Studies ; *Language ; Neuropsychological Tests ; Aged ; Longitudinal Studies ; },
abstract = {INTRODUCTION: Accessible biomarkers for prediction of cognitive impairment and diagnosis of limbic predominant age related TDP-43 encephalopathy neuropathologic change (LATE-NC) are needed.

METHODS: Written descriptions of the cookie-theft picture were produced by 134 participants of the Leisure World Cohort Study who subsequently joined the 90+ Study and underwent regular assessments and autopsy. We examined the relationships between linguistic markers and future cognitive impairment and the presence of neuropathologic changes.

RESULTS: Mean age at writing was 85 and there was an average interval of 8 years to the development of cognitive impairment. Future cognitive impairment was associated with less grammatical units, fewer clauses, and fewer pictorial themes. LATE-NC was the only neuropathologic change associated with language markers, including higher proportions of content words, less complete units, and more closed class word errors.

DISCUSSION: Our results suggest that linguistic markers obtained long before the development of cognitive impairment might serve as biomarkers for future cognitive impairment and LATE-NC.

HIGHLIGHTS: We analyzed the writing samples of 134 participants in the Leisure World Cohort Study who later joined the 90+ Study and had longitudinal assessments and came to autopsy. We found that features extracted from these writing samples differed between participants who died with cognitive impairment and those who died with normal cognition. Of note, participants who developed cognitive impairment were all cognitively normal at the time of writing of the samples and developed cognitive impairment on average 8 years later. We found a different set of features were related to the presence of limbic predominant age related TDP-43 encephalopathy (LATE) at post mortem. No features were related to either Alzheimer's disease neuropathology or Lewy body (LB) pathology.},
}

Humans
Male
Female
*TDP-43 Proteinopathies/pathology
*Cognitive Dysfunction/pathology/diagnosis
Aged, 80 and over
Biomarkers
Cohort Studies
*Language
Neuropsychological Tests
Aged
Longitudinal Studies

@article {pmid40637125,
year = {2025},
author = {Tsai, WF and Yu, RL and Chuang, WL and Huang, JF and Dai, CY and Huang, YA and Tan, CH},
title = {Association of CD33 genetic variants with neurocognitive profiles in chronic viral hepatitis.},
journal = {BJPsych open},
volume = {11},
number = {4},
pages = {e147},
doi = {10.1192/bjo.2025.10048},
pmid = {40637125},
issn = {2056-4724},
abstract = {BACKGROUND: CD33 has been implicated in the pathogenesis of Alzheimer's disease primarily through its role in inhibiting the clearance of beta-amyloid (Aβ). However, genetic studies yield mixed results and it is unclear whether the impact of CD33 is specific to Alzheimer's disease or related to broader neurodegenerative processes. Interestingly, CD33 has also been shown to interact with the hepatitis B (HBV) and C viruses (HCV).

AIMS: This study aims to investigate the effects of CD33 single-nucleotide polymorphisms (SNPs) on cognitive functions across diverse populations, including healthy controls, individuals with chronic HBV or HCV and those diagnosed with Parkinson's disease.

METHOD: We genotyped CD33 SNPs in 563 participants using the Affymetrix platform. Participants' cognitive functions were cross-sectionally assessed using a neuropsychological test battery spanning six domains.

RESULTS: Our analysis revealed that CD33 SNP variations had no significant cognitive impact on healthy individuals or Parkinson's disease patients. However, chronic HBV and HCV patients exhibited significant cognitive differences, particularly in memory, related to CD33 SNP genotypes. Moderation analysis indicated a heightened influence of CD33 SNPs on cognitive functions in chronic HBV and HCV individuals. Our data also suggest that inflammation severity may modulate the cognitive effects in hepatitis patients with specific CD33 SNPs.

CONCLUSIONS: This study highlights the importance of CD33 SNPs in cognitive outcomes, emphasising their role in the context of chronic viral hepatitis. It contributes to understanding the cognitive profiles influenced by CD33 SNPs and posits CD33's potential contribution to neurodegenerative disease progression, potentially intensified by HBV/HCV-induced inflammation.},
}

@article {pmid40637118,
year = {2025},
author = {Perez-Corredor, P and Arevalo-Alquichire, S and Mazzarino, RC and O'Hare, M and Muriel-Torres, AF and Vacano, GN and Vanderleest, TE and Miller, WP and Pineda-Lopez, L and Patel, S and Obar, RA and Polat, N and Kim, LA and Arboleda-Velasquez, JF and Marino, C},
title = {ApoE3 Christchurch and tau interaction as a protective mechanism against Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {7},
pages = {e70396},
doi = {10.1002/alz.70396},
pmid = {40637118},
issn = {1552-5279},
support = {//Remondi Family Foundation/ ; //Edward N. & Della L. Thome Memorial Foundation/ ; //Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation/ ; //Good Ventures Foundation/ ; },
mesh = {*tau Proteins/metabolism/genetics ; *Alzheimer Disease/genetics/metabolism ; Animals ; Mice ; Humans ; *Apolipoprotein E3/genetics/metabolism ; Brain/metabolism/pathology ; Protein Binding ; Intercellular Signaling Peptides and Proteins/metabolism ; },
abstract = {INTRODUCTION: We described a protected case with familial Alzheimer's disease, homozygous for apolipoprotein E3 (APOE3) Christchurch variant (ApoE3Ch), exhibiting low tau protein levels despite genetic predisposition to the disease due to presenilin (PSEN)1-E280A. We reported the loss of interaction between ApoE3Ch and heparan sulfate proteoglycans (HSPGs) as a critical protective pathway. Here, we characterized differential interacting partners for both wild-type and Christchurch variants to identify additional protective mechanisms of ApoE3Ch.

METHODS: We performed pull-down of mouse brain lysates using His-tag-ApoE3 recombinant proteins and determined interacting partners of ApoE3 via mass-spectrometry. We then performed in vitro and in vivo assays to validate the top interactors.

RESULTS: We found enhanced binding of ApoE3Ch to tau and Dickkopf-1 (Dkk1, a WNT/β-catenin antagonist) that resulted in reduced tau aggregation in vitro. We demonstrated that ApoE3Ch interacts directly with Dkk1 and tau, reducing tau pathology. These findings supported the hypothesis of novel protective effects of direct ApoE3Ch interactions.

HIGHLIGHTS: ⁠Apolipoprotein E3 (ApoE3) Christchurch variant (ApoE3Ch) exhibits different protein interaction profiles compared to wild-type ApoE3, as revealed by proteomic analyses and pull-down experiments. The ApoE3Ch variant alters the protein's interaction with tau, thus affecting its aggregation in a tau biosensor cell assay and the retina of microtubule-associated protein tau (MAPT*P301S) transgenic mice. ⁠Gene ontology and pathway analyses indicate that ApoE3Ch interactors are associated with brain-related disorders and specific upstream regulators, including MAPT, a gene encoding for tau. ⁠Protein-protein interaction studies showed increased binding of ApoE3Ch to Dickkopf1 (Dkk1), a Wnt/β-catenin pathway antagonist, as compared to ApoE3WT, thus indicating that multiple protective mechanisms are regulated by the ApoE3Ch variant Our study uncovers a novel protective effect of the ApoE3Ch variant against tau pathology, thus proposing new insights into Alzheimer's disease mechanisms and potential therapeutic targets.},
}

*tau Proteins/metabolism/genetics
*Alzheimer Disease/genetics/metabolism
Animals
Mice
Humans
*Apolipoprotein E3/genetics/metabolism
Brain/metabolism/pathology
Protein Binding
Intercellular Signaling Peptides and Proteins/metabolism

@article {pmid40636899,
year = {2025},
author = {Li, K and Xie, D and Zhang, Z and Fu, C and Li, C},
title = {Voxel- and surface-based morphometry in the cortical thickness and cortical and subcortical gray matter volume in patients with mild-to-moderate Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1546977},
pmid = {40636899},
issn = {1663-4365},
abstract = {AIM: This study aimed to investigate alterations in whole-brain cortical thickness (CT) and cortical and subcortical gray matter volume (GMV) in patients with Alzheimer's disease (AD) compared with healthy controls (HC) using voxel-based morphometry (VBM) and surface-based morphometry (SBM). Furthermore, we sought to develop a combined predictive model based on these neuroimaging markers and assess their potential clinical utility for the early detection and diagnosis of AD.

METHODS: A total of 42 patients diagnosed with mild-to-moderate AD and 49 demographically matched HC were recruited for this study. VBM and SBM analyses were performed on three-dimensional T1-weighted magnetization-prepared rapid gradient echo (3D T1-MPRAGE) imaging sequences to identify brain regions that exhibited statistically significant differences between the AD and HC groups. Brain regions showing significant group differences were selected as the regions of interest (ROIs). Pearson's correlation analysis was used to assess the relationship between extracted neuroimaging metrics (CT, cortical GMV, and subcortical GMV) and cognitive performance. Predictive models were constructed using CT (from SBM), cortical GMV, and subcortical GMV (from VBM) metrics derived from ROIs, both individually and in combination. Model performance in discriminating between patients with AD and HCs was evaluated using a receiver operating characteristic (ROC) curve analysis.

RESULTS: Compared to HCs, patients with AD exhibited significant CT reductions primarily in the transverse temporal gyrus, superior temporal gyrus, supramarginal gyrus, insula, temporal pole, entorhinal cortex, and fusiform gyrus. Significant GMV reductions in patients with AD were observed predominantly in the hippocampus, parahippocampal gyrus, posterior temporal lobe, inferior temporal gyrus, middle temporal gyrus, limbic lobe structures, fusiform gyrus, amygdala, and thalamus, as detected by VBM analysis. Extracted CT, cortical GMV, and subcortical GMV measurements from the ROIs demonstrated significant positive correlations with both MMSE and MoCA scores.

CONCLUSION: In patients with AD, VBM and SBM showed overlapping cortical GMV and CT reductions. Volume/thickness reduction was correlated with lower MMSE/MoCA scores, confirming functional relevance. ROC analysis revealed that combining CT and GMV improved cognitive impairment prediction compared to single measures. This integrated approach may enhance clinical diagnosis and early risk identification of AD.},
}

@article {pmid40636898,
year = {2025},
author = {Lu, Y and Cui, L and Huang, L and Xie, F and Guo, QH},
title = {Predicting amyloid status in mild cognitive impairment: the role of semantic intrusions combined with plasma biomarkers.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1624513},
pmid = {40636898},
issn = {1663-4365},
abstract = {BACKGROUND: The efficacy of traditional semantic intrusion measurements in identifying amyloid deposition in mild cognitive impairment (MCI) patients remains suboptimal. It is anticipated that integrating innovative cognitive assessments with blood biomarker analyses will enhance the effectiveness of screening for Alzheimer's disease (AD).

METHODS: The research included 204 participants from the Chinese Preclinical Alzheimer's Disease Study cohort, assessed between March 2019 and February 2023. The Bi-list Verbal Learning Test (BVLT) was utilized to measure semantic intrusions, while amyloid burden was quantified using neuroimaging with 18F-florbetapir PET/CT scans. Additionally, the study analyzed Apolipoprotein E loci and plasma biomarkers, including Aβ42, Aβ40, Tau, p-tau181, p-tau217, Nfl, and GFAP.

RESULTS: The study revealed that semantic intrusion errors on the BVLT are highly predictive of amyloid deposition in MCI participants. Binary logistic regression analysis confirmed that semantic intrusion errors on the Bi-list Verbal Learning Test, along with p-tau217 levels and GFAP levels, can effectively predict amyloid positive MCI. Correlation analysis further established a positive association between p-tau217, GFAP, and semantic intrusion errors among patients with A+ MCI. The combined predictors (p-tau217, GFAP, semantic intrusion errors) demonstrated outstanding performance in ROC analysis, achieving an AUC of 0.964, with a sensitivity of 92.7% and a specificity of 85.7%.

CONCLUSION: The study suggests that semantic intrusion errors from the BVLT, along with plasma biomarkers p-tau217 and GFAP, may serve as sensitive indicators for AD-related MCI. Combining these biomarkers with semantic intrusion errors offers a strong predictive model for assessing amyloid status in MCI patients.},
}

@article {pmid40636801,
year = {2025},
author = {Sato, K and Shioda, K and Suda, S},
title = {Accuracy of Death Certificates in Attributing Mortality to Alzheimer's Disease and Other Dementias in Japanese Psychiatric Hospitals.},
journal = {Neuropsychiatric disease and treatment},
volume = {21},
number = {},
pages = {1325-1337},
pmid = {40636801},
issn = {1176-6328},
abstract = {AIM: Dementia, including Alzheimer's disease (AD), is a leading cause of mortality in Europe and the United States. Interestingly, while Japan is recognized for its high life expectancy, dementia-related diseases account for a comparatively lower proportion of recorded deaths. This study aimed to investigate the actual mortality attributed to clinically diagnosed AD in Japan, particularly in psychiatric hospital settings.

METHODS: Total 653 cases Death certificates and medical records from psychiatric hospitals in Japan were analyzed to investigate the actual death rate associated with dementia diseases.

RESULTS: In total, 134 of the 653 cases (20.5%) were determined to have AD as the direct cause of death, a significant increase from the 34 cases initially identified from death certificates alone (P<0.01). And more, after reviewing the death certificates and medical records of 653 patients, 203 (134 with AD and 69 with other dementias) were identified as having dementia as the direct cause of death, representing 31.1% of all deaths. This rate was significantly higher than the rate identified before the medical record review (P<0.01). Dementia diagnoses were frequently omitted from death certificates, with complications often recorded as the primary cause of death. This suggests that the true incidence of dementia-related mortality in Japan may be approximately four times higher than reported.

CONCLUSION: We found that the true incidence of dementia-related mortality in Japan may be higher than reported. These findings underscore the critical need to increase awareness about dementia as a cause of death and to educate the public and healthcare professionals on accurately documenting it on death certificates.},
}

@article {pmid40636703,
year = {2025},
author = {Patricio-Martínez, A and Patricio, F and Macuil-Chapuli, E and Martínez-Juárez, EÁ and Flores-Díaz, S and Cedillo-Ramírez, ML and Limón, ID},
title = {The role of probiotics, prebiotics, and postbiotics: cellular and molecular pathways activated on glial cells in Alzheimer's disease.},
journal = {Frontiers in neuroscience},
volume = {19},
number = {},
pages = {1598011},
pmid = {40636703},
issn = {1662-4548},
abstract = {Supplementation with prebiotics and probiotics can modulate the intestinal microbiota, returning it to a more physiological state; therefore, they can be considered as a possible treatment in many prevalent conditions, including neurodegenerative diseases. Alzheimer's disease (AD) is the most common form of dementia, accounting for 60 to 70% of cases. The neuropathological features of AD include neuritic plaques (extracellular deposits of the beta-amyloid protein, Aβ), neurofibrillary tangles (resulting from hyperphosphorylation of the tau protein), a predominantly cholinergic synaptic decrease, and the presence of inflammatory markers, all these characteristics together trigger the neurodegenerative process and cognitive deterioration. The etiology of AD is multifactorial, however, in recent years evidence has been shown on the significant association between dysbiosis, neuroinflammation, and neurodegeneration. In the present review, we will discuss the role of gut microbiota in the pathogenesis of AD, as well as the underlying mechanisms that trigger the use of probiotics, prebiotics, and postbiotics in neuroinflammation. Our attention will focus on the cellular and molecular mechanisms triggered by astrocytes and microglia, cells involved in mediating neuroinflammation and neurodegeneration in AD.},
}

@article {pmid40636676,
year = {2025},
author = {De Puit, JK and Challinor, KL},
title = {Critical Review of Neurobiological Evidence for Relationships Between Social Isolation, Loneliness and the Risk of Developing of Alzheimer's Disease: A New Model.},
journal = {Journal of aging research},
volume = {2025},
number = {},
pages = {9924448},
pmid = {40636676},
issn = {2090-2204},
abstract = {Background: It is known that people who are socially isolated and lonely are more likely to develop Alzheimer's disease (AD) than people who are neither socially isolated nor lonely. This work addresses the direct impact of socially isolation and loneliness on the brain. Aim: To review the neurobiological evidence on the relationships between social isolation, loneliness and AD pathogenesis. Method: Neurobiological literature in relation to social isolation, loneliness and how these factors impact risk of AD was reviewed. A new model providing a framework to describe the links between these pieces of evidence was created. Results: Social isolation contributes to AD pathogenesis via neuroinflammation and stress pathways. Loneliness is linked to AD risk mainly through its strong association with depression. Conclusion: Although social isolation and loneliness are typically linked together, they should be considered separately in the context of AD because, neurobiologically, social isolation is more closely linked to AD than loneliness is linked to AD. Implications: Clinicians should be cognisant that socially isolated people who are not lonely may be at higher risk for AD than people experiencing loneliness who are not socially isolated. Measures of depression are likely more appropriate for appraising AD risk than measures of loneliness.},
}

@article {pmid40636588,
year = {2025},
author = {Roy, D and Sarkar, S and Biswas, SC},
title = {N-acetyl L-cysteine and Growth Factors Impede Endoplasmic Reticulum Stress and Inflammatory Responses in Astrocytes to Amyloid-β in Serum-free Culture.},
journal = {Annals of neurosciences},
volume = {},
number = {},
pages = {09727531251340150},
pmid = {40636588},
issn = {0972-7531},
abstract = {BACKGROUND: Astrocytes play an integral role in Alzheimer's disease (AD) pathology, where they may act as a double-edged sword. The existing serum-supplemented in vitro astrocyte culture models are not suitable to study certain stress response mechanisms that occur in AD.

PURPOSE: Here, we tried to develop a serum-free murine primary cortical astrocyte culture model to study endoplasmic reticulum (ER) stress and inflammation to investigate the effect of amyloid-beta (Aβ1-42).

METHODS: Astrocytes were cultured in a controlled serum-free environment to minimise interference from serum components. Serum-free astrocytes were exposed to oligomeric Aβ and subjected to imaging, immunocytochemistry, real-time PCR and western blot analysis.

RESULTS: Using an established protocol, no significant activation of eIF2α, a key marker of ER stress, was observed under serum-free conditions, but with the removal of N-acetyl cysteine (NAC), ER stress response was enhanced after 24 hours of Aβ exposure. Subsequently, the Aβ-induced inflammatory response, assessed through TNF-α expression, which was minimal in the presence of growth factors, became pronounced when these factors were withdrawn. Concomitantly, a significant increase in astrocytes reactivity, assessed by GFAP expression upon 24 hours of Aβ exposure, was observed. Transcript analysis revealed a time-dependent shift in the expression of inflammatory molecules, with early time points showing an increase in anti-inflammatory markers, while late exposure promoting pro-inflammatory responses.

CONCLUSION: This study identifies that NAC and growth factors impede ER stress and inflammatory responses in astrocytes upon Aβ exposure in serum-free culture. These findings also highlight the potential of a serum-free culture system for studying ER stress and inflammation in astrocytes to understand the complex role of these cells in AD pathophysiology.},
}

@article {pmid40636532,
year = {2025},
author = {Ghosson, A and Soufan, F and Kaddoura, H and Fares, E and Uwishema, O},
title = {Understanding the Intersection Between Hormonal Dynamics and Brain Plasticity in Alzheimer's Disease: A Narrative Review for Implementing New Therapeutic Strategies.},
journal = {Health science reports},
volume = {8},
number = {7},
pages = {e70975},
pmid = {40636532},
issn = {2398-8835},
abstract = {BACKGROUND AND AIMS: Alzheimer's disease (AD), a chronic neurodegenerative disorder, is portrayed by neurocognitive decline in the structure and function of the human brain. Various factors are implicated in the pathogenesis to neuroplasticity alteration in the brain of an individual afflicted with AD. The subset of these elements known as "hormonal dynamics" is paramount in the pathophysiology of AD. This review dives into the complex relationship between hormonal dynamics and brain neuroplasticity with special handling of AD considering the impediments and opportunities for the implementation of therapeutic strategies.

METHODS: A comprehensive review was conducted using online search databases PubMed/Medline and ScienceDirect, identifying-with a thematic approach-articles handling the interaction between the hormonal fluctuation and neuroplasticity in AD with special consideration sought from the emerging therapeutic strategies.

RESULTS: This review reveals the influence of various hormonal fluctuations, including estrogens and androgens, on neuroplasticity alteration in the structure and function of the brain in AD. Furthermore, the forms of neuroplasticity and synaptic plasticity processes are significantly altered with underlying neuronal loss and cognitive impairment in AD. Therefore, pharmacological and nonpharmacological therapy approaches as virtual reality and repetitive transcranial magnetic stimulation (rTMS), that promote synaptic plasticity advancements, play a key role in decreasing the rate of deterioration and progression in AD.

CONCLUSION: Apprehending the intricate interactions between hormonal dynamics and neuroplasticity of the brain is necessary for advancing targeted therapeutics for AD. Upcoming studies should be directed toward the pathophysiological mechanism of hormonal neuroprotection and regeneration with the long-term effects of hormonal replacement therapies, advocating personalized management plans. It should also work on identifying specific imaging and biological markers for the monitoring of HRT. Furthermore, other influences such as environmental, epigenetic, physical, and psychological illness should be tackled.},
}

@article {pmid40636522,
year = {2025},
author = {Wang, J and Chen, Y and Chen, S and Mu, Z and Chen, J},
title = {How endothelial cell metabolism shapes blood-brain barrier integrity in neurodegeneration.},
journal = {Frontiers in molecular neuroscience},
volume = {18},
number = {},
pages = {1623321},
pmid = {40636522},
issn = {1662-5099},
abstract = {BACKGROUND/OBJECTIVE: Endothelial cells, a monolayer of cells adjacent to blood vessels, play a critical role in maintaining vascular function through metabolic pathways such as glycolysis, fatty acid, and amino acid metabolism. Recent studies have revealed their significant involvement in neurodegenerative diseases, although the underlying mechanisms remain unclear.

METHODS: By reviewing literature from the past decade, we summarized the metabolic alterations and functional changes of endothelial cells in neurological disorders.

RESULTS: In neurodegenerative diseases such as stroke, Alzheimer's disease, multiple sclerosis, and aging, metabolic dysregulation in cerebral vascular endothelial cells disrupts their normal function and is closely associated with blood-brain barrier impairment.

CONCLUSION: Aberrant endothelial cell metabolism compromises the integrity of the blood-brain barrier and exacerbates the pathological progression of neurodegenerative diseases. Our review further explores the therapeutic potential of targeting endothelial cell metabolism in various pathological contexts, aiming to provide novel insights for the prevention and treatment of related disorders.},
}

@article {pmid40636521,
year = {2025},
author = {Sharma, E and Mehta, D and Jadhav, N and Gujrati, G and Dhananya, S and Moorthy, M and Ramaswamy, G and Zhou, Y and Nair, S},
title = {Whole-genome sequencing shows modulation of neurodegenerative genes by Withania somnifera in human SK-N-SH cells.},
journal = {Frontiers in molecular neuroscience},
volume = {18},
number = {},
pages = {1512727},
pmid = {40636521},
issn = {1662-5099},
abstract = {BACKGROUND: Aging is driven by several primary and secondary hallmarks that manifest with age, of which neurodegenerative diseases are important manifestations. The ability to decelerate or reverse aging, and promote healthy aging, has garnered great interest in recent times. In traditional medicine, Withania somnifera (WS) or Ashwagandha has been recognized for its adaptogenic and rejuvenative effects.

METHODS: To investigate WS-modulated global gene expression profiles, we performed whole-genome sequencing of WS-treated human neuroblastoma SK-N-SH cells at different doses (50 and 100 μg/mL) and time points (3 h and 9 h) and validation by quantitative real-time PCR (qRT-PCR) and immunoblotting. Disease enrichment analysis for brain-related disorders was performed by DisGeNET.

RESULTS: Using differential gene expression analyses, we identified 19,945 WS-modulated genes. Of these, 2,403 and 177 genes were significantly (p ≤ 0.05) upregulated and downregulated, respectively, by WS treatment. Interestingly, different patterns of gene expression were exhibited in dose-dependent (9 upregulated, 1 downregulated, 100 μg/mL 3 h vs. 50 μg/mL 3 h; 21 upregulated, 86 downregulated, 100 μg/mL 9 h vs. 50 μg/mL 9 h) and temporal kinetics (210 upregulated, 6 downregulated, 50 μg/mL 9 h vs. 50 μg/mL 3 h; 8 upregulated, 49 downregulated, 100 μg/mL 9 h vs. 100 μg/mL 3 h). Furthermore, qRT-PCR experiments validated the RNA-seq results. WS-modulated genes were implicated in Alzheimer's disease, migraine, Parkinson's disease, bipolar disorder, cognition, stress, anxiety, forgetfulness, sleep disorders, and substance abuse among others.

CONCLUSION: Taken together, our transcriptomic profiling study revealed for the first time that WS may modulate key genes in neurodegenerative disorders with potential beneficial implications for brain-related disorders and healthy aging.},
}

@article {pmid40636428,
year = {2025},
author = {Imamura, T and Koga, H and Miyazato, A and Xu, Z and Shigehisa, R and Ohki, S and Mori, M},
title = {Identification of CqCYP76AD5v1, a gene involved in betaxanthin biosynthesis in Chenopodium quinoa, and its product, betaxanthin, which inhibits amyloid-β aggregation.},
journal = {Plant biotechnology (Tokyo, Japan)},
volume = {42},
number = {2},
pages = {111-119},
pmid = {40636428},
issn = {1342-4580},
abstract = {Betalain pigments, primarily produced by the order Caryophyllales, are categorized into betacyanins (red/purple) and betaxanthins (yellow/orange). While the biosynthetic pathways of these pigments are well-studied, the genes responsible for betaxanthin biosynthesis in quinoa were previously unknown. This study identified three candidate genes, CqCYP76AD5v1, CqCYP76AD5v2, and CqCYP76AD130, as quinoa orthologs of beet CYP76AD5 and CYP76AD6. Agroinfiltration experiments in Nicotiana benthamiana revealed that CqCYP76AD5v1 exhibited L-DOPA synthesis activity, whereas CqCYP76AD130 did not. To enable large-scale production of betaxanthins, we developed a tobacco BY-2 cell line expressing CqCYP76AD5v1 and CqDODA1-1, with vulgaxanthin I identified as the predominant product. Furthermore, the betaxanthin mixture extracted from this line inhibited amyloid-β (Aβ) aggregation, a key factor associated with Alzheimer's disease. These findings demonstrate the potential of betaxanthins derived from quinoa betaxanthin-biosynthesis genes for applications in health supplements and pharmaceuticals.},
}

@article {pmid40636064,
year = {2025},
author = {O'Brien, JT},
title = {Commentary on "It is time to share Alzheimer biomarker results in dementia with Lewy bodies".},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {17},
number = {3},
pages = {e70145},
pmid = {40636064},
issn = {2352-8729},
abstract = {Many people with dementia with Lewy bodies (DLB) have evidence of Alzheimer's disease (AD) co-pathology, which can be assessed in vivo using biomarkers. In this issue, Armstrong and colleagues argue that it is now timely to disclose such AD biomarker results to people with DLB. They provide logical and powerful arguments, including the right for people to know and the value of this information in informing outcome and management. However, there are also important caveats to consider and a careful balance needs to be maintained between, on the one hand, the right to know and convey clinically useful information and, on the other, acknowledging the real uncertainty that exists regarding the true diagnostic and management implications of AD biomarkers in an individual with a DLB rather than an AD clinico-pathological syndrome.},
}

@article {pmid40636063,
year = {2025},
author = {Armstrong, MJ and Grill, JD and Tropea, TF},
title = {It is time to share Alzheimer biomarker results in dementia with Lewy bodies.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {17},
number = {3},
pages = {e70144},
pmid = {40636063},
issn = {2352-8729},
abstract = {UNLABELLED: There are increasing calls for sharing individual biomarker results with participants in dementia research. No studies investigate returning Alzheimer's disease (AD) biomarker results to individuals with syndromic dementia with Lewy bodies (DLB) even though most of these individuals have both pathologies. This perspective argues that AD biomarkers are valid, interpretable, and actionable, particularly relating to expected prognosis and treatment effects, in people with DLB. Thus, there is an ethical imperative to study AD biomarker result sharing in these patients. This will require revising current disclosure practices. Areas of need include unique pre- and post-test education and careful assessment of the readiness to receive results and post-result responses in people with DLB given the frequency of neuropsychiatric symptoms in this group. Studying responses to sharing AD biomarkers in people with DLB will also inform other dementia settings (e.g., returning synuclein results to individuals with syndromic AD) and neurodegenerative diseases more broadly.

HIGHLIGHTS: There are increasing calls for biomarker result sharing in dementia research.No processes exist to guide result sharing in dementia with Lewy bodies (DLB).Alzheimer biomarker results in DLB are valid, interpretable, and actionable.Research is needed on the methods and effects of sharing with people with DLB.Research is needed for sharing evidence of co-pathology across neurodegenerations.},
}

@article {pmid40635873,
year = {2025},
author = {Yao, M and Sun, N and Linville, R and Wei, Z and Kakazu, A and Ouyang, Y and Li, R and Du, L and Wang, H and Zhou, Y and Jiang, Y and Zhang, Z and Li, A and Lu, H and Xu, J and Kellis, M and Heiman, M and Duan, W},
title = {Cell type-specific contributions to impaired blood-brain barrier and cerebral metabolism in presymptomatic 5XFAD mice.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.04.23.650260},
pmid = {40635873},
issn = {2692-8205},
abstract = {Altered cerebral metabolism and blood-brain barrier (BBB) dysfunction are emerging as critical contributors to the preclinical phase of Alzheimer's disease (AD), underscoring their role in early pathogenesis. To identify sensitive biomarkers before irreversible neuronal loss and cognitive decline, we examined 5XFAD mice at 3 months of age by applying multiple advanced MRI techniques. Arterial spin tagging based MRI revealed increased BBB permeability and water extraction fraction, indicating compromised BBB integrity at the early stage of pathogenesis in 5×FAD mice. Despite preserved cerebral blood flow, a decreased unit mass cerebral metabolic rate of oxygen (CMRO2) was evident in the same cohorts of 5XFAD mice. Interestingly, a region-specific decrease of tissue pH values was detected in the hippocampus of these 5XFAD mice by creatine chemical exchange saturation transfer MRI. Elevated neuronal H4K12 lactylation in the hippocampus supports the reduced pH values. To further dissect the cellular and molecular mechanisms underlying these MRI-detectable changes in 5XFAD mice, we conducted single-nucleus RNA sequencing (snRNA-Seq) with optimized blood vessel enrichment protocols. Our results revealed cell type-specific transcriptomic changes in the hippocampus of 3-month-old 5XFAD mice, including downregulation of synaptogenesis and synaptic transmission genes in the CA1 and dentate gyrus excitatory neurons, impaired endothelial gene expression linked to brain barrier function and angiogenesis, altered innate immune response genes in astrocytes, as well as upregulation of cholesterol biosynthesis and metabolism genes in the CA1 excitatory neurons. These findings underlie the intricate interplay between BBB disruption and metabolic dysregulation before the onset of cognitive decline in AD. Our study demonstrates that BBB dysfunction and cerebral metabolic alterations preceded brain hypoperfusion and cognitive decline, emphasizing potential molecular pathways for early intervention. These findings, once validated in human studies, could significantly enhance early diagnosis and inform novel therapeutic strategies targeting early AD pathogenesis.},
}

@article {pmid40635765,
year = {2025},
author = {Yan, X and Shi, L and Zhu, X and Zhao, Y and Luo, J and Li, Q and Xu, Z and Zhao, J},
title = {From Microbial Homeostasis to Systemic Pathogenesis: A Narrative Review on Gut Flora's Role in Neuropsychiatric, Metabolic, and Cancer Disorders.},
journal = {Journal of inflammation research},
volume = {18},
number = {},
pages = {8851-8873},
pmid = {40635765},
issn = {1178-7031},
abstract = {As a pivotal ecological regulator in humans, the gut microbiota profoundly participates in the pathological processes of neurodegenerative diseases, psychiatric disorders, metabolic syndromes, and cancers through metabolite exchange, epigenetic regulation, and gut-brain axis signaling. This review focuses on analyzing relationships between gut microbial communities and four major disease spectra: neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, Huntington's disease)-revealing microbiota-derived lipopolysaccharide activation of microglia and gut-brain transmission pathways of α-synuclein; mental health disorders (depression, schizophrenia, bipolar disorder)-elucidating dysregulated tryptophan metabolism and gut-derived neurotransmitter imbalances; metabolic diseases (obesity, diabetes, gout)-analyzing molecular mechanisms by which short-chain fatty acids regulate insulin sensitivity and uric acid metabolism; malignant tumors (lung cancer, breast cancer, prostate cancer)-exploring microbial remodeling of immune checkpoint inhibitor responses and regulatory effects on estrogen metabolism. We integrate existing evidence to systematically expound the roles of gut microbiota alterations in the pathogenesis of neurodegenerative diseases, psychiatric disorders, metabolic dysregulation, and malignant tumors, with in-depth analysis of mechanisms through which dysbiosis promotes disease progression, aiming to provide a theoretical foundation and scientific recommendations for developing microbiota-targeted precision intervention strategies (including, but not limited to synthetic microbial community transplantation and metabolite-directed regulation).},
}

@article {pmid40635745,
year = {2025},
author = {Siafaka, PI and Okur, ME and Üstündağ Okur, N},
title = {Editorial: Innovative therapies against neurodegenerative disorders: from new active molecules to novel drug delivery systems.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1640758},
pmid = {40635745},
issn = {1663-9812},
}

@article {pmid40635663,
year = {2025},
author = {Edmunds, KJ and Nelson, AR and Brach, TL and Glittenberg, M and Christian, BT and Betthauser, TJ and Johnson, SC and Asthana, S and Okonkwo, OC},
title = {Depression modifies age-associated [[11]C]PiB-PET amyloid burden in a cohort enriched with risk for Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251353098},
doi = {10.1177/13872877251353098},
pmid = {40635663},
issn = {1875-8908},
abstract = {BackgroundDepression-especially late-life onset-is associated with age-related cognitive decline and may be a key risk factor for amyloid-β (Aβ) deposition in preclinical Alzheimer's disease (AD).ObjectiveThis study assesses whether depressive symptoms modify the relationship between age and Aβ burden in a cohort at-risk for AD.MethodsN = 238 cognitively unimpaired participants from the Wisconsin Alzheimer's Disease Research Center participated in Pittsburgh Compound-B positron emission tomography ([11]C-PiB-PET), where distribution volume ratio scores were used to quantify Aβ burden in nine regions of interest (ROIs) susceptible to early Aβ burden. Depressive symptoms were assessed using the Geriatric Depression Scale (GDS). Cross-sectional linear regression models examined interactions between age and GDS scores, adjusting for sex, apolipoprotein ε4 (APOE ε4) carriage, and age difference between PET imaging and GDS assessment. GDS-stratified analyses were performed to test within-group associations between age and [11]C-PiB-PET Aβ aggregation in each ROI, and item-level analyses identified specific depressive symptoms that modified these relationships.ResultsParticipants had a mean age of 68.0 years (SD ± 8.4), 39.7% were APOE ε4 carriers, 64% were female, and 85.3% were White. GDS scores were largely normal (M = 1.29, SD = 1.61). Age × GDS interactions were significant across all ROIs, and stratified models revealed progressively stronger associations as GDS scores increased. Finally, item-level analyses identified the second and tenth GDS items as significant modifiers across six ROIs and the global composite.ConclusionsIn a cohort enriched with risk for AD, emerging depressive symptoms amplified the association between age and Aβ burden.},
}

@article {pmid40635533,
year = {2025},
author = {Tae, WS and Ham, BJ and Pyun, SB and Kim, BJ},
title = {Current Clinical Applications of Structural MRI in Neurological Disorders.},
journal = {Journal of clinical neurology (Seoul, Korea)},
volume = {21},
number = {4},
pages = {277-293},
doi = {10.3988/jcn.2025.0185},
pmid = {40635533},
issn = {1738-6586},
support = {2022R1F1A1074517/NRF/National Research Foundation of Korea/Korea ; RS-2023-00241730/NRF/National Research Foundation of Korea/Korea ; RS-2025-00515464/NRF/National Research Foundation of Korea/Korea ; },
abstract = {Structural magnetic resonance imaging (sMRI) plays a pivotal role in the evaluation of neurological disorders by providing high-resolution anatomical information. Recent advances in quantitative postprocessing techniques have expanded the utility of sMRI beyond visual assessments by enabling the detection of subtle morphological changes associated with various neurological and psychiatric conditions. This review summarizes current clinical applications of sMRI-based analysis, including brain volumetry, shape analysis, voxel-based morphometry (VBM), surface-based morphometry, source-based morphometry, and voxel-based lesion-symptom mapping (VLSM). Volumetric and shape-based analyses allow for assessments of region-specific atrophy and subregional morphological alterations, while VBM and surface-based morphometry provide complementary insights into tissue volumes and the architecture of the cortical surface. Source-based morphometry reveals network-level patterns of structural covariance, and VLSM directly correlates lesion locations with functional outcomes, particularly in stroke. It has been demonstrated that these methodologies are clinically relevant in conditions such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, epilepsy, and major depressive disorder. By quantifying structural brain alterations that are not readily detectable using conventional imaging methods, these tools improve diagnostic accuracy, support prognostication, and facilitate monitoring of treatment effects. This review highlights the growing integration of sMRI postprocessing techniques into clinical neurology.},
}

@article {pmid40635532,
year = {2025},
author = {Al-Rubaie, A},
title = {Traumatic Brain Injury and Dementia: Mechanisms, Risk Stratification, and Clinical Management.},
journal = {Journal of clinical neurology (Seoul, Korea)},
volume = {21},
number = {4},
pages = {265-276},
doi = {10.3988/jcn.2025.0079},
pmid = {40635532},
issn = {1738-6586},
abstract = {Traumatic brain injury (TBI) is one of the main mechanisms underlying health issues associated with functional and structural brain changes. While direct effects such as cognitive and physical impairments are well documented, recent research has linked TBI to neurodegenerative changes similar to dementia. TBI-related neurodegeneration includes progressive brain-tissue degeneration that leads to behavioral changes, cognitive decline, and dementia-like symptoms. The exact underlying mechanisms are complex, and include neuroinflammation, oxidative stress, excitotoxicity, and disruption to protein homeostasis. Neuroinflammation is controlled by the activation of astrocytes and microglia and causes neuronal damage and the prolonged release of proinflammatory cytokines. Oxidative stress damages cell and impairs mitochondrial function, while the accumulation of misfolded proteins such as tau and β-amyloid mimics the pathology of Alzheimer's disease. Excitotoxicity involves excessive neurotransmitter release that may lead to further injuries. Epidemiological studies show that the risk of dementia is increased after moderate-to-severe TBI and influenced by age and genetic factors. Current management strategies focus on symptom relief, and there is ongoing research aimed at improving the understanding of the underlying mechanisms and the development of effective treatments.},
}

@article {pmid40635531,
year = {2025},
author = {Park, KH and Choi, SH and Shim, Y and Youn, YC and Yang, DW and Kim, S},
title = {Use of Amyloid Positron-Emission Tomography to Diagnose Alzheimer's Disease in Clinical Practice in South Korea: Expert Recommendations.},
journal = {Journal of clinical neurology (Seoul, Korea)},
volume = {21},
number = {4},
pages = {251-264},
doi = {10.3988/jcn.2025.0037},
pmid = {40635531},
issn = {1738-6586},
abstract = {Amyloid positron-emission tomography (PET) is the optimal method for detecting amyloid plaque deposition in patients experiencing cognitive decline, which is essential for diagnosing Alzheimer's disease. However, its clinical application globally has been restricted by the high cost, short radiotracer half-life, and significant accessibility challenges. In particular, the lack of treatment options following diagnosis has been considered the largest obstacle to using amyloid PET as a diagnostic tool. Consequently, the current appropriate-use recommendations for amyloid PET tend to support restricting its use. However, the relatively low cost and superior accessibility of amyloid PET in South Korea have resulted in it being used much more frequently in clinical settings than in other countries. The recent introduction of disease-modifying drugs has increased the importance and frequency of amyloid PET usage. Considering these circumstances, this article presents expert opinions on the appropriate use of amyloid PET in South Korea based on existing recommendations and survey results from dementia experts in South Korea.},
}

@article {pmid40635465,
year = {2025},
author = {Liu, XC and Zhou, J and Cheng, GR and Yang, ML and Hu, FF and Liu, D and Xie, XY and Ji, Y and Lv, Y and Niu, JP and Cai, P and Gang, BZ and You, Y and Meng, XL and Wu, ZX and Li, XY and Tan, W and Zeng, Y},
title = {Association between insomnia and its symptoms and cognitive impairment in community-dwelling older adults in China: A multicenter study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251353119},
doi = {10.1177/13872877251353119},
pmid = {40635465},
issn = {1875-8908},
abstract = {BackgroundLimited evidence exists on insomnia symptoms' association with mild cognitive impairment (MCI) and dementia in older Chinese adults across rural and urban areas.ObjectiveTo examine associations between insomnia symptoms, sleep duration, and cognitive impairment.MethodsThis cross-sectional study utilized data from China's Multicenter Dementia Survey (2019-2020), examining the association between insomnia symptoms, sleep duration, and cognitive impairment, using logistic and linear regression models. The cognitive score was obtained using the Mini-Mental State Examination (MMSE).ResultsWe included 10,725 participants (5964 females) aged between 65 and 100 years. Insomnia was significantly associated with an increased risk of MCI (odd ratio [OR], 1.16; 95% confidence interval [CI], 1.05 to 1.29) and lower MMSE scores (β, -0.13; 95% CI, -0.15 to -0.10). Difficulties initiating sleep (DIS; OR, 1.16; 95% CI, 1.03 to 1.31) and sleepiness during the day (SDD; OR, 1.32; 95% CI, 1.02 to 1.70) increased MCI risk, and the latter (OR, 1.79; 95% CI, 1.26 to 2.56) also increased risk of dementia. Insomnia's negative association with MMSE scores was stronger in rural (β, -0.17; 95% CI, -0.20 to -0.14) than urban residents (β, -0.05; 95% CI, -0.08 to -0.02). Sleep duration and MMSE scores showed an inverted U-shaped relationship (peak at 7-8 h/night).ConclusionsInsomnia symptoms, particularly DIS and SDD, are associated with higher MCI risk and poorer cognition in older adults, with amplified effects in rural China.},
}

@article {pmid40635450,
year = {2025},
author = {Li, J and Li, Y and Wang, Z and Yao, Y and Yao, D and Chen, K and Xia, Y},
title = {Oxytocin Intervention Mitigates Pathological and Behavioral Impairments in APP/PS1 Mice Subjected to Early Social Isolation.},
journal = {CNS neuroscience & therapeutics},
volume = {31},
number = {7},
pages = {e70511},
doi = {10.1111/cns.70511},
pmid = {40635450},
issn = {1755-5949},
support = {2022ZD0208500//STI 2030-Major Project/ ; 2024YFHZ0359//Sichuan Province Science and Technology Support Program/ ; },
mesh = {Animals ; *Oxytocin/pharmacology/therapeutic use ; *Social Isolation/psychology ; Mice ; *Alzheimer Disease/pathology/psychology/drug therapy/genetics/metabolism ; Mice, Transgenic ; Male ; Presenilin-1/genetics ; Gastrointestinal Microbiome/drug effects ; Amyloid beta-Protein Precursor/genetics ; Mice, Inbred C57BL ; Anxiety/drug therapy ; Depression/drug therapy ; Receptors, Oxytocin/metabolism ; Disease Models, Animal ; },
abstract = {BACKGROUND: Neuropsychiatric symptoms, such as anxiety and depression, are prevalent during the prodromal phase of Alzheimer's disease (AD). Social isolation (SI) has been implicated as a potential exacerbating factor for emotional disturbances in AD pathogenesis. Despite the well-established role of oxytocin (OXT) in regulating social behavior and mental health, its function and mechanisms in alleviating AD-related psychiatric symptoms remain poorly understood.

MATERIALS AND METHODS: We utilized a 12-week SI model to assess its effects on anxiety, depression-like behaviors, and social cognition in early-stage AD mice. Through immunofluorescence, enzyme-linked immunosorbent assay, and 16S rDNA sequencing, we examined the changes in AD pathology and gut microbiota composition induced by SI, as well as the effects of OXT intervention.

RESULTS: Our findings revealed that SI markedly intensified anxiety-like behaviors, depression-like phenotypes, and social cognitive impairments in AD mice. Mechanistically, SI resulted in decreased OXT levels and upregulated OXT receptor expression while also exacerbating AD-related pathological features, including increased Aβ plaque deposition, aberrant microglial proliferation, and reduced PSD-95 expression in the prefrontal cortex. Furthermore, SI induced significant changes in gut microbiota composition. OXT intervention demonstrated therapeutic efficacy by mitigating behavioral deficits, alleviating AD-related pathological damage, and restoring gut microbiota homeostasis in SI AD mice.

CONCLUSION: These results underscore OXT as a promising therapeutic avenue for AD, offering novel insights into treatment strategies and identifying potential therapeutic targets through the restoration of gut homeostasis and mitigation of pathological processes.},
}

Animals
*Oxytocin/pharmacology/therapeutic use
*Social Isolation/psychology
Mice
*Alzheimer Disease/pathology/psychology/drug therapy/genetics/metabolism
Mice, Transgenic
Male
Presenilin-1/genetics
Gastrointestinal Microbiome/drug effects
Amyloid beta-Protein Precursor/genetics
Mice, Inbred C57BL
Anxiety/drug therapy
Depression/drug therapy
Receptors, Oxytocin/metabolism
Disease Models, Animal

@article {pmid40635393,
year = {2025},
author = {Kopecky, L and Sands, CJ and Gómez-Romero, M and Misra, S and Want, EJ and Ebbels, TMD},
title = {MAMSI: Integration of Multiassay Liquid Chromatography-Mass Spectrometry Metabolomics Data Using Multiview Machine Learning.},
journal = {Analytical chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.analchem.5c01327},
pmid = {40635393},
issn = {1520-6882},
abstract = {Liquid chromatography-mass spectrometry (LC-MS) is a commonly used analytical technique in untargeted metabolomics. However, the diverse chemical and physical properties of metabolites often require the use of several different analytical assays for broad metabolome coverage. Conventionally, each assay is analyzed separately, but this fails to capture interassay relationships, making multiassay biomarker discovery and data interpretation difficult. Here we propose a workflow to integrate multiassay metabolomics data, designed to enable biomarker discovery and elucidation of unknown metabolites. We employ a multiblock-partial least-squares model (MB-PLS) coupled with multiblock variable importance in projection to estimate the importance of predictors to the outcome variable. Then we cluster the selected predictors and compare them to groups defined by their structural properties based on retention time and mass-to-charge ratio. To demonstrate and evaluate the approach, we used three multiassay data sets predicting biological sex, Alzheimer's disease status, and blood bilirubin levels as the outcomes of interest. The MB-PLS models outperformed single-assay models in both classification and regression tasks, indicating that modeling interblock relationships enabled an improved estimate of phenotypic outcome. Additionally, the MB-PLS models shed valuable insight into each data block's contribution to the predicted outcome. Our workflow enabled us to determine a set of potential cross-assay biomarkers. Following putative annotation, the majority of these and their signs of association agreed with results previously reported in the literature. Our workflow has the potential to benefit the metabolomics community and beyond as it offers interpretable integrative analysis of multiassay LC-MS data and facilitates discovery of potential biomarkers.},
}

@article {pmid40635220,
year = {2025},
author = {Abubakar, M and Giri, A and Goel, F and Khan, M and Gupta, J and Kumar, D and Kaushik, M and Rai, SN and Kumar, N},
title = {Diabetes, Alzheimer's Disease Risk Factors, and the Cafeteria Diet: A Comprehensive Review.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X384737250626094315},
pmid = {40635220},
issn = {1875-6190},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder with multifaceted risk factors, including diet and metabolic dysfunction. The rising prevalence of AD and diabetes has drawn attention to their shared pathophysiological mechanisms. The "cafeteria diet," characterized by high-fat, high-sugar, and energy-dense foods, has emerged as a significant contributor to metabolic dysfunctions, including obesity and insulin resistance, which are risk factors for both diabetes and neurodegenerative diseases. This study explores the effects of the cafeteria diet on cognitive impairment, AD pathology, and its potential role in exacerbating diabetes-related neurological complications. Animal models were subjected to cafeteria diets, mimicking human dietary patterns, to investigate changes in brain structure, amyloid-beta accumulation, tau hyperphosphorylation, and cognitive function. Additionally, metabolic profiling demonstrated the development of insulin resistance and other hallmarks of diabetes, which were closely correlated with the severity of cognitive deficits. Neuropathological analyses revealed exacerbated amyloid-beta accumulation and increased neuroinflammation, linking dietary-induced diabetes to AD pathophysiology. These findings underscore the critical role of dietary habits in modulating the risk and progression of AD, highlighting the importance of interventions targeting metabolic health to mitigate cognitive decline. This study emphasizes the need for further research to unravel the molecular mechanisms underlying the diet-diabetes- AD axis and develop targeted therapeutic strategies.},
}

@article {pmid40635217,
year = {2025},
author = {Guo, L and Lin, Y and Sun, B},
title = {Highly Efficient and Eco-friendly Synthesis and Bio-activities of 1,3-benzazoles as Cu (II) Chelators in Alzheimer's Disease Therapy.},
journal = {Current medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0109298673371011250612094752},
pmid = {40635217},
issn = {1875-533X},
abstract = {INTRODUCTION: Dyshomeostasis of Cu2+ and abnormal interactions between Cu2+ and β Amyloid peptide (Aβ) can promote Aβ aggregation and oxidative stress, which are considered to trigger Alzheimer's Disease (AD). Metal chelating therapy is a promising approach for the treatment of AD.

METHOD: In this study, 2-(2-hydroxyphenyl)benzazoles were synthesized via microwave irradiation promotion. Chelators inhibiting Cu2+-induced Aβ aggregation were determined through turbidity assay and BCA protein assay, while anti-oxidants were detected via HRP/Amplex red assay and fluorescent probe of DCFH-DA. Cell viability was measured by MTT assay.

RESULTS: The bio-activity for inhibiting Cu2+ induced-Aβ aggregation of chelators S-1, S-3, S-4, S-5, S-7, S-10, N-5, N-9, N-10 O-2, O-4, X-N-2 was better than that of CQ. The ability of the chelators (S-1, S-10, O-2, O-5, N-9, and X-N-2) to decrease the level of ROS in Aβ+Cu2+ treated SH-SY5Y cells was better than that of CQ. The ability to attenuate Aβ-mediated cytotoxicity in SH-SY5Y cells of S-10 (O-2, O-5, and N-9) was better than that of CQ.

CONCLUSION: After the evolution of the bio-activities for the treatment of AD in vitro, it was found that 4 chelators (S-10, O-2, O-5, and N-9) exhibited better bio-activities than CQ in all aspects.},
}

@article {pmid40635213,
year = {2025},
author = {A Shaldam, M and Carradori, S and Melfi, F and Guglielmi, P and Diomede, F and Piattelli, M and O Tawfik, H},
title = {Potential of MAO-B Inhibitors with Multi-Target Inhibition and Antioxidant Properties for the Treatment of Neurodegenerative Disorders.},
journal = {Mini reviews in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113895575392491250630195630},
pmid = {40635213},
issn = {1875-5607},
abstract = {Millions of people worldwide are affected by neurodegenerative disorders (NDs), which include a broad range of clinical ailments that affect the brain or peripheral nervous system, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease, etc. Neuronal cell death in NDs is often linked to oxidative stress; thus, antioxidant treatment can combat oxidative cell damage, and this strategy has been studied in neurodegenerative processes. Over the past 10 years, we have witnessed intense research activity on the biological potential of human monoamine oxidase (hMAO) inhibitors that have been associated with the prevention of oxidative stress and inflammation. These inhibitors have emerged as promising therapeutic agents, especially in the treatment of neurodegenerative diseases (NDs), where their core activity may help mitigate disease progression. An overview of the current state of numerous scaffolds, such as chromones, coumarins, chalcones, propargylamines, benzothiazoles, aminoisoquinolines, and the natural compounds, including ferulic acid, resveratrol, and chrysin, which combine antioxidant capability and hMAO inhibition is given in this review, with particular attention given to each scaffold's mechanism of action and structure-activity relationships (SARs), which are thoroughly discussed. Focusing on the dual mechanism of action, combining inhibition and antioxidant properties, as a potential therapy for neurodegenerative diseases, we have reviewed the different chemical classes of multi-targetdirected ligand (MTDL) inhibitors developed within this framework. Other central nervous system (CNS)-related enzymes, such as cholinesterases, carbonic anhydrases, and BACE-1, have also been explored as targets in the MTDL strategy. By understanding their biological activity, medicinal chemists can better comprehend biological activity and recommend more effective and specific ND treatments.},
}

@article {pmid40635209,
year = {2025},
author = {Kakkar, A and Singh, H and Anand, A and Chopra, H and Mishra, AK},
title = {Neuroprotective Effects of Eugenol in Alzheimer's Disease: Mitigating Oxidative Stress, Inflammation and Amyloid Plaques.},
journal = {Current pharmaceutical design},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113816128373290250620054118},
pmid = {40635209},
issn = {1873-4286},
abstract = {Eugenol, a phenolic phytochemical found in many medicinal plants, exhibits various pharmacological properties, including analgesic, antipyretic, antioxidant, anti-inflammatory, antimicrobial, anticancer, neuroprotective, and anaesthetic effects. It has shown potential in addressing neurodegenerative diseases like Alzheimer's disease (AD), Parkinson's disease, and motor neuron disease, which are primarily caused by mechanisms such as apoptosis, protein accumulation, aging, and oxidative stress within the central nervous system (CNS). This review explores the mechanisms through which eugenol may influence AD. Eugenol appears to counter oxidative stress, reduce inflammation, and prevent amyloid beta (Aβ) plaque accumulation, suggesting it could delay the onset or progression of AD. However, more research is required to establish its safety and effectiveness in treating or preventing this disease.},
}

@article {pmid40635200,
year = {2025},
author = {Oh, YR and Shin, MK},
title = {Decoding tau acetylation in Alzheimer's disease and tauopathies: from site-specific mechanisms to therapeutic horizons.},
journal = {BMB reports},
volume = {},
number = {},
pages = {},
pmid = {40635200},
issn = {1976-670X},
abstract = {Tau acetylation has been recognized as a pivotal post-translational modification associated with the pathogenesis of Alzheimer's disease (AD) and other tauopathies. This review offers a detailed synthesis of the current understanding of site-specific tau acetylation, its regulatory enzymes, and its profound impacts on tau biology. Acetylation influences tau degradation, aggregation, propagation, and microtubule-binding properties in a residue-specific manner, often in conjunction with other modifications such as phosphorylation and ubiquitination. Furthermore, this review emphasizes emerging therapeutic strategies targeting tau acetylation, including small-molecule inhibitors of p300/CBP and monoclonal antibodies against acetylated tau epitopes. While several of these approaches are currently undergoing clinical trials, many acetylation sites are still inadequately characterized, emphasizing the need for additional mechanistic studies. An enhanced understanding of tau acetylation will be vital for devising targeted therapies to halt or reverse the progression of tau-mediated neurodegeneration.},
}

@article {pmid40635163,
year = {2025},
author = {Sordo, L and Du, A and Sandadi, V and Dustagheer, FB and Pascual, J and Ngo, P and Hom, CL and Doran, E and Head, E},
title = {Leptin levels are associated with body mass index and Alzheimer's disease in Down syndrome.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {7},
pages = {e70448},
doi = {10.1002/alz.70448},
pmid = {40635163},
issn = {1552-5279},
support = {P30AG066519/AG/NIA NIH HHS/United States ; A2022021F//BrightFocus Foundation/ ; },
mesh = {Humans ; *Leptin/blood/metabolism ; *Down Syndrome/blood/complications/pathology ; *Alzheimer Disease/blood/pathology/complications ; Female ; Male ; *Body Mass Index ; Middle Aged ; Receptors, Leptin/metabolism ; Aged ; Biomarkers/blood ; },
abstract = {INTRODUCTION: Higher body mass index (BMI) is linked to greater risk of Alzheimer's disease (AD) and elevated plasma leptin levels correlate with cognitive decline and AD. Since obesity is a frequent feature in individuals with Down syndrome (DS), we investigated the association between obesity, the leptin pathway, and AD neuropathology in people with DS.

METHODS: Plasma concentrations of leptin and AD biomarkers were measured in 40 individuals (aged controls, Down syndrome and Alzheimer's disease [DSAD], and AD participants). Frontal cortex leptin, leptin receptors (LepRs), and leptin-associated proteins were measured in 73 individuals with DS, DSAD, and AD, and compared to age-matched controls using immunohistochemistry.

RESULTS: Individuals with DSAD had the highest plasma leptin levels, as well as the highest leptin resistance index and brain leptin deficiency. Plasma leptin levels were significantly associated with staging of AD neuropathology.

DISCUSSION: Leptin has the potential to be an early indicator and therapeutic target for AD in people with and without DS.

HIGHLIGHTS: Plasma leptin levels are increased in Down syndrome and Alzheimer's disease (DSAD). Leptin resistance and brain leptin deficiency are present in Down syndrome (DS) and DSAD. Plasma leptin levels are positively associated with staging of Alzheimer's disease (AD) neuropathology.},
}

Humans
*Leptin/blood/metabolism
*Down Syndrome/blood/complications/pathology
*Alzheimer Disease/blood/pathology/complications
Female
Male
*Body Mass Index
Middle Aged
Receptors, Leptin/metabolism
Aged
Biomarkers/blood

@article {pmid40635030,
year = {2025},
author = {Nedelkov, D and Tsokolas, ZE and Rodrigues, MS and Sible, I and Han, SD and Kerman, BE and Renteln, M and Mack, WJ and Pascoal, TA and Yassine, HN and , },
title = {Increased cerebrospinal fluid and plasma apoE glycosylation is associated with reduced levels of Alzheimer's disease biomarkers.},
journal = {Alzheimer's research & therapy},
volume = {17},
number = {1},
pages = {151},
pmid = {40635030},
issn = {1758-9193},
support = {RF1AG076124, R01AG055770, R01AG067063, R01AG054434, R21AG056518, and P30AG066530/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/cerebrospinal fluid/blood/genetics ; Glycosylation ; Male ; Female ; Aged ; Biomarkers/cerebrospinal fluid/blood ; *Apolipoproteins E/blood/cerebrospinal fluid ; Cognitive Dysfunction/cerebrospinal fluid/blood ; tau Proteins/cerebrospinal fluid/blood ; Aged, 80 and over ; Amyloid beta-Peptides/cerebrospinal fluid ; Cohort Studies ; Middle Aged ; },
abstract = {The apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late-onset Alzheimer's disease (AD). ApoE is glycosylated with an O-linked Core-1 sialylated glycan at several sites; however, the impact and function of this glycosylation on AD biomarkers remain unclear. We examined apoE glycosylation (total and secondary) in a cohort of cerebrospinal fluid (CSF, n = 181) and plasma (n = 178) samples from the Alzheimer's Disease Neuroimaging Initiative (ADNI) stratified into 4 groups: cognitively normal (CN), Mild Cognitive Impairment (MCI), progressors, and non-progressors based on delayed word recall performance over 4 years. We observed decreasing glycosylation (reduced % of apoE being glycosylated) from apoE2 > apoE3 > apoE4 in the CSF and in plasma (apoE3 > apoE4), with stronger effect sizes for secondary glycosylation in CSF (total glycosylation in CSF: E2 > E3 (4.6%), E3 > E4 (5.1%), E2 > E4 (9.4%); secondary glycosylation in CSF: E2 > E4 (33.1%), E3 > E4 (25.4%); total glycosylation in plasma: E3 > E4 (24.2%). Secondary ApoE glycosylation was reduced (8%, p = 0.009) in the MCI group compared with the CN group and in the progressor group compared with the non-progressor group (7%, p = 0.01). In CSF, higher apoE glycosylation was cross-sectionally associated with lower total tau (t-tau) and p-tau181. In CSF, greater apoE4 glycosylation was associated with lower t-tau and p-tau181 levels. These results indicate strong associations between apoE glycosylation and biomarkers of AD pathology independent of apoE genotype, warranting a deeper understanding of the functional role of apoE glycosylation in AD tau pathology.},
}

Humans
*Alzheimer Disease/cerebrospinal fluid/blood/genetics
Glycosylation
Male
Female
Aged
Biomarkers/cerebrospinal fluid/blood
*Apolipoproteins E/blood/cerebrospinal fluid
Cognitive Dysfunction/cerebrospinal fluid/blood
tau Proteins/cerebrospinal fluid/blood
Aged, 80 and over
Amyloid beta-Peptides/cerebrospinal fluid
Cohort Studies
Middle Aged

@article {pmid40634935,
year = {2025},
author = {Wei, J and Hu, L and Xu, S and Yang, F and Liao, F and Tang, Y and Shen, X and Zhang, X and Fang, X and Li, Y and Ding, L and Chen, Z and Su, S and Cheng, J and Huang, Y and Chen, Q and Ma, D and Zhang, Q and Guo, X},
title = {Liver-specific expression of ANGPTL8 promotes Alzheimer's disease progression through activating microglial pyroptosis.},
journal = {Journal of neuroinflammation},
volume = {22},
number = {1},
pages = {177},
pmid = {40634935},
issn = {1742-2094},
support = {82471628//National Natural Science Foundation of China/ ; 82371596//National Natural Science Foundation of China/ ; },
abstract = {INTRODUCTION: Liver dysfunction contributes to Alzheimer's disease (AD) pathogenesis, and evidence suggests that the liver is involved in amyloid β (Aβ) clearance, and regulates Aβ deposition in the brain. However, the specific regulatory mechanism remains elusive.

OBJECTIVES: Angiopoietin-like protein 8 (ANGPTL8), a high expression of liver-specific secreted proinflammatory factor, crosses the blood‒brain barrier from the bloodstream to abnormally activate microglia and promote AD progression.

METHODS: The ANGPTL8[-/-] mice and 5 × FAD mice were crossed mutated and subjected to the Morris water maze test and novel object recognition test to assess cognitive ability in different cohorts. Thioflavin-S, NeuN, and Nissl staining were used to assess Aβ deposition and neuron loss. The number of phagocytic microglia was evaluated with Fitc latex beads. Adeno-associated virus 8 (AAV8) hydrodynamically injected restored the liver ANGPTL8 levels of ANGPTL8[-/-] 5 × FAD mice for further experiments. Single-cell RNA sequencing, bulk RNA sequencing and transmission electron microscopy were used to explore the role of ANGPTL8 in regulating AD progression, and drug screening was carried out to identify an effective inhibitor of ANGPTL8.

RESULTS: ANGPTL8 knockout improved cognitive function and reduced Aβ deposition by reducing microgliosis and microglial activation in 5xFAD mice. Mechanistically, ANGPTL8 crossed the blood‒brain barrier and interacted with the microglial membrane receptor PirB/LILRB2. This interaction subsequently activated the downstream NLRP3 inflammasome, leading to microglial pyroptosis and exacerbating the Aβ-induced release of inflammatory factors, thereby accelerating AD progression. Furthermore, the administration of metformin, an ANGPTL8 inhibitor, improved learning and memory deficits in 5 × FAD mice by negating microglial pyroptosis and neuroinflammation.

CONCLUSIONS: ANGPTL8 aggravates microglial pyroptosis via the PirB/NLRP3 pathway to accelerate the pathogenesis of AD. Targeting high expression of ANGPTL8 in the liver may hold potential for developing therapies for AD.},
}

@article {pmid40634792,
year = {2025},
author = {Brandt, M and Oliveira, F and Belfort, T and Nogueira, M and Baptista, MA and Lacerda, I and de Lucena, AT and Rangel, R and Dourado, MCN},
title = {The Relationship Between Facial Emotion Recognition and Executive Function Varies Depending on the Level of Cognitive Impairment.},
journal = {International journal of geriatric psychiatry},
volume = {40},
number = {7},
pages = {e70127},
doi = {10.1002/gps.70127},
pmid = {40634792},
issn = {1099-1166},
support = {//Carlos Chagas Filho Foundation/ ; //The National Council for Scientific and Technological Development/ ; },
abstract = {BACKGROUND: Cognitive domains related to attention and executive functions (a set of cognitive processes that regulate, control, and manage other cognitive abilities) seem to influence the recognition of facial expressions in people with Alzheimer's disease (AD).

PURPOSE: We examined the relationship between facial expression recognition, global cognition and executive function in people with AD according to their cognitive level.

RESEARCH DESIGN: In a cross-sectional design, we included 130 participants with AD divided into three groups based on their Mini-Mental State Examination (MMSE) scores: MMSE 1 (scores 23-28), MMSE 2 (scores 17-22), and MMSE 3 (scores 11-16). Facial expression recognition ability was analyzed using the Faces Test. Executive function was analyzed using the Trail Making Test (TMT), the Verbal Fluency Test (VFT), the Semantic Fluency Test (SFT), the Digit Span Forward (DSF) and Backward (DSB) tests, and the Clock Drawing Test (CDT).

RESULTS: In MMSE 1 group difficulties in divided attention and cognitive flexibility impacted the accuracy of facial expression recognition. In the MMSE 2 group, facial expression recognition was related to impairment in working memory. In the MMSE 3 group, the impact on facial expression recognition was directly related to visuoconstructive abilities.

CONCLUSIONS: We observed that the executive resources involved in each evaluated group differed in terms of facial recognition task performance efficacy. Interventions at stimulating executive and visuoconstructive abilities in people with AD may contribute to better preservation of facial expression recognition.},
}

@article {pmid40634788,
year = {2025},
author = {Wang, Z and Zhang, Z and Shi, J and Zhao, R},
title = {The Crosstalk Between Sepsis-Associated Encephalopathy and Alzheimer's Disease: Identifying Potential Biomarkers and Therapeutic Targets for Cognition.},
journal = {Molecular neurobiology},
volume = {},
number = {},
pages = {},
pmid = {40634788},
issn = {1559-1182},
abstract = {Patients with sepsis are at a heightened risk of long-term cognitive impairment, including neurodegenerative diseases; however, the underlying pathophysiological mechanisms remain incompletely understood. This study examines key genes associated with sepsis and Alzheimer's disease (AD), as well as their potential molecular mechanisms. We downloaded the GSE135838 dataset from the Gene Expression Omnibus (GEO) database and performed comparative analysis of differentially expressed genes (DEGs) using the AlzData database to identify co-expressed DEGs. Functional and protein-protein interaction (PPI) network analyses were used to identify hub genes and their associated molecular mechanisms. Animal experiments were conducted to validate the role of the central gene C5aR1 in the pathological processes of sepsis-related cognitive impairment, blood-brain barrier (BBB) disruption, and microglial activation. Co-culture experiments were performed to assess the protective effect of C5aR1 against inflammation-induced neuronal damage. In GSE135838, 25 DEGs exhibited consistent expression changes in the brain tissue of AD patients. Notably, LYZ, C5AR1, ZFP36, MPZL2, APOL4, CD163, SERPINA3, and CCL2 showed significant differential expression in the cortex and hippocampus of AD patients. KEGG pathway enrichment analysis revealed that among the 14 pathways meeting the criteria, the TNF signaling pathway demonstrated the highest significance. Key intersections of multiple GO enrichment terms included IL-6, ICAM1, CLEC4E, and PCK1. The top ten hub genes identified from the PPI network analysis included IL6, CCL2, ICAM1, CXCL1, CD163, C5AR1, SOCS3, CLEC4E, HSPB1, and HSPA1A. Pharmacological inhibition of the hub gene product C5aR1 using PMX205 improved cognitive and emotional dysfunction in CLP-induced septic mice and reduced BBB damage and microglial activation. Inhibition of C5aR1 also alleviated microglia-induced neuronal injury. In summary, the neuroimmune dysregulation caused by sepsis is correlated with potential pathological mechanisms in AD. This study provides additional molecular evidence for potential biomarkers and therapeutic targets for drug intervention in the risk of AD among sepsis survivors.},
}

@article {pmid40634782,
year = {2025},
author = {Oh, HS and Le Guen, Y and Rappoport, N and Urey, DY and Farinas, A and Rutledge, J and Channappa, D and Wagner, AD and Mormino, E and Brunet, A and Greicius, MD and Wyss-Coray, T},
title = {Plasma proteomics links brain and immune system aging with healthspan and longevity.},
journal = {Nature medicine},
volume = {},
number = {},
pages = {},
pmid = {40634782},
issn = {1546-170X},
support = {P50AG047366//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; P30AG066515//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; AG072255//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG048076//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R21AG058859//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; },
abstract = {Plasma proteins derived from specific organs can estimate organ age and mortality, but their sensitivity to environmental factors and their robustness in forecasting onset of organ diseases and mortality remain unclear. To address this gap, we estimate the biological age of 11 organs using plasma proteomics data (2,916 proteins) from 44,498 individuals in the UK Biobank. Organ age estimates were sensitive to lifestyle factors and medications and were associated with future onset (within 17 years' follow-up) of a range of diseases, including heart failure, chronic obstructive pulmonary disease, type 2 diabetes and Alzheimer's disease. Notably, having an especially aged brain posed a risk of Alzheimer's disease (hazard ratio (HR) = 3.1) that was similar to carrying one copy of APOE4, the strongest genetic risk factor for sporadic Alzheimer's disease, whereas a youthful brain (HR = 0.26) provided protection that was similar to carrying two copies of APOE2, independent of APOE genotype. Accrual of aged organs progressively increased mortality risk (2-4 aged organs, HR = 2.3; 5-7 aged organs, HR = 4.5; 8+ aged organs, HR = 8.3), whereas youthful brains and immune systems were uniquely associated with longevity (youthful brain, HR = 0.60 for mortality risk; youthful immune system, HR = 0.58; youthful both, HR = 0.44). Altogether, these findings support the use of plasma proteins for monitoring of organ health and point to the brain and immune systems as key targets for longevity interventions.},
}

@article {pmid40634770,
year = {2025},
author = {Wen, Z and Ghafouri, A and Biros, G and , },
title = {A single-snapshot inverse solver for two-species graph model of tau pathology spreading in human Alzheimer's disease.},
journal = {Brain informatics},
volume = {12},
number = {1},
pages = {18},
doi = {10.1186/s40708-025-00264-z},
pmid = {40634770},
issn = {2198-4018},
support = {OAC 22042261//NSF/ ; DE-SC0023171//U.S. Department of Energy, Office of Science, Office of Advanced Scientific Computing Research, Applied Mathematics program, Mathematical Multifaceted Integrated Capability Centers (MMICCS) program/ ; R21AG074276-01//U.S. National Institute on Aging/ ; },
abstract = {We propose a method that uses a two-species ordinary differential equation (ODE) model for subject-specific misfolded tau protein spreading in Alzheimer's disease (AD) and calibrates it from magnetic resonance imaging (MRI) and positron emission tomography (PET) scans. The ODE model is a variant of the heterodimer Fisher-Kolmogorov (HFK) model. The unknown model parameters are the initial condition (IC) for tau and three scalar parameters representing the migration, proliferation, and clearance of tau proteins. Driven by imaging data, these parameters are estimated by formulating a constrained optimization problem with a sparsity regularization for the IC. This optimization problem is solved with a projection-based quasi-Newton algorithm. We evaluate the performance of our method on both synthetic and clinical data. Subjects are from the AD Neuroimaging Initiative (ADNI) datasets: 455 cognitively normal (CN), 212 mild cognitive impairment (MCI), and 45 AD subjects. We compare the performance of our approach to the commonly used Fisher-Kolmogorov (FK) model with a fixed IC at the entorhinal cortex (EC). Our method demonstrates an average improvement of 19.6% relative error compared to the FK model on the AD dataset. HFK also achieves an R-squared score of 0.591 for fitting AD data compared with 0.256 from FK model results with IC fixing at EC. The inverted IC from our scheme indicates that the EC is the most likely initial seeding region if subcortical regions are excluded from the analysis. However, other regions also have probability to be the IC seeding regions. Furthermore, for cases that have longitudinal data, we estimate a subject-specific AD onset time.},
}

@article {pmid40634647,
year = {2025},
author = {Hammers, DB and Schulman, D and Fowler, NR and Musema, J and Brosch, JR and Summanwar, D and Swartzell, K and Higgins, C and Banks, R and Selzler, KJ and MacLeod, T and Tobyne, S and Willis, DR},
title = {Performance of Older Adults on the Digital Clock and Recall Test Compared to the Montreal Cognitive Assessment in Primary Care Settings.},
journal = {Journal of general internal medicine},
volume = {},
number = {},
pages = {},
pmid = {40634647},
issn = {1525-1497},
abstract = {BACKGROUND: Digital cognitive assessment solutions can overcome some barriers to cognitive screening in primary care by providing rapidly obtained objective insights without requiring specialty trained examiners. Real-world comparison of digital assessments to standard screenings in primary care is limited.

OBJECTIVE: Our objective was to compare performance on the Linus Health Digital Clock and Recall (DCR™) to the Montreal Cognitive Assessment (MOCA), which is a traditional "gold standard" cognitive screening test in primary care.

PARTICIPANTS: A total of 114 primary care patients ≥ 65 years old completed a DCR as part of routine primary care and scored in the "Borderline" or "Impaired" ranges, and subsequently completed a MOCA at a follow-up primary care visit.

DESIGN: Criterion and convergent validity analyses were conducted using Mann-Whitney U tests, concordance (agreement) rates, polychoric or polyserial correlations, and exploratory factor analysis.

MAIN MEASURES: DCR and MOCA Total Scores and subcomponent scores.

KEY RESULTS: DCR Total Score and select process scores successfully discriminated impairment on the MOCA using traditional cutoffs, and both agreement rates and correlations were strong between DCR and MOCA components-especially Total Scores comparisons. Exploratory factor analysis revealed a five-factor model whereby one factor was comprised of memory subtests from both the DCR and MOCA, and another was comprised of non-memory MOCA subtests and Information Processing/Spatial Reasoning subcomponents of the DCR.

CONCLUSIONS: Screening in primary care using the DCR is feasible, and shows criterion and convergent validity with a "gold standard" screening tool for detecting cognitive impairment-the MOCA. When paired with parallel advancements in detection of plasma-based biomarkers and recent FDA approvals for disease-modifying treatments for Alzheimer's disease, the DCR and similar digital cognitive assessment tools have the potential to triage patients for both Alzheimer's disease diagnostic workups and subsequent treatments beyond specialty care.},
}

@article {pmid40634605,
year = {2025},
author = {Hou, K and Ge, P and Sawaya, MR and Lutter, L and Dolinsky, JL and Yang, Y and Jiang, YX and Boyer, DR and Cheng, X and Pi, J and Zhang, J and Lu, J and Abskharon, R and Yang, S and Yu, Z and Feigon, J and Eisenberg, DS},
title = {How short peptides disassemble tau fibrils in Alzheimer's disease.},
journal = {Nature},
volume = {},
number = {},
pages = {},
pmid = {40634605},
issn = {1476-4687},
abstract = {Reducing fibrous aggregates of the protein tau is a possible strategy for halting the progression of Alzheimer's disease (AD)[1]. Previously, we found that in vitro, the D-enantiomeric peptide (D-peptide) D-TLKIVWC disassembles ultra-stable tau fibrils extracted from the autopsied brains of individuals with AD (hereafter, these tau fibrils are referred to as AD-tau) into benign segments, with no energy source other than ambient thermal agitation[2]. To consider D-peptide-mediated disassembly as a potential route to therapeutics for AD, it is essential to understand the mechanism and energy source of the disassembly action. Here, we show that the assembly of D-peptides into amyloid-like ('mock-amyloid') fibrils is essential for AD-tau disassembly. These mock-amyloid fibrils have a right-handed twist but are constrained to adopt a left-handed twist when templated in complex with AD-tau. The release of strain that accompanies the conversion of left-twisted to right-twisted, relaxed mock-amyloid produces a torque that is sufficient to break the local hydrogen bonding between tau molecules, and leads to the fragmentation of AD-tau. This strain-relief mechanism seems to operate in other examples of amyloid fibril disassembly, and could inform the development of first-in-class therapeutics for amyloid diseases.},
}

@article {pmid40634379,
year = {2025},
author = {Latif, S and Islam, NU and Uddin, Z and Cheema, KM and Ahmed, SS and Khan, MF},
title = {Deep ensemble learning with transformer models for enhanced Alzheimer's disease detection.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {24720},
pmid = {40634379},
issn = {2045-2322},
support = {QA-APC-2025//Qassim University/ ; },
mesh = {*Alzheimer Disease/diagnosis ; Humans ; *Deep Learning ; Neural Networks, Computer ; Biomarkers ; Ensemble Learning ; },
abstract = {The progression of Alzheimer's disease is relentless, leading to a worsening of mental faculties over time. Currently, there is no remedy for this illness. Accurate detection and prompt intervention are pivotal in mitigating the progression of the disease. Recently, researchers have been developing new methods for detecting Alzheimer's at earlier stages, including genetic testing, blood tests for biomarkers, and cognitive assessments. Cognitive assessments involve a series of tests to measure memory, language, attention, and other brain functions. For disease detection, optimal performance necessitates enhanced accuracy and efficient computational capabilities. Our proposition involves the data augmentation of textual data; after this, we deploy our proposed BERT-based deep learning model to make use of its advanced capabilities for improved feature extraction and text comprehension. Our proposed model is a two-branch network. The first branch is based on the BERT encoder, which is used to encode the text data into a fixed-length vector; the BERT output is fed into the convolution layer, followed by the LSTM layer, and finally, the fully connected layer to predict whether a patient has AD or not. The second branch is based on the recurrent convolutional neural network. The recurrent convolutional neural network also takes text data as input and generates the final classification output. Finally, these branches are fused using the ensemble learning approach to give a more robust and accurate output. The proposed model is trained on a corpus of clinical notes from patients with AD and healthy control subjects. Evaluated on the Cookie Theft subset of the DementiaBank Pitt Corpus, our ensemble achieves 94.98% accuracy, 0.9523 F1-score, and 0.93 AUC. The results show that the proposed model outperforms state-of-the-art models for the early diagnosis of AD from text.},
}

*Alzheimer Disease/diagnosis
Humans
*Deep Learning
Neural Networks, Computer
Biomarkers
Ensemble Learning

@article {pmid40634156,
year = {2025},
author = {Jakabek, D and Isaacs, AM and De Strooper, B and Tuszynski, M and Lane, R and Uspenskaya, O and McDade, E and Rafii, MS and Mummery, CJ},
title = {CTAD taskforce: genetic therapies in Alzheimer's disease.},
journal = {The journal of prevention of Alzheimer's disease..},
volume = {},
number = {},
pages = {100269},
doi = {10.1016/j.tjpad.2025.100269},
pmid = {40634156},
issn = {2426-0266},
abstract = {There are an increasing number of genetic approaches to treating Alzheimer's disease and other dementias, with some promising results from early-phase trials. This prompted the convention of the first EU-US CTAD Task Force on genetic therapies in Alzheimer's disease in October 2024. Preclinical studies and clinical trials of genetic therapies in Alzheimer's disease and other dementias are presented here with key lessons for the field. Importantly, there are several challenges and opportunities unique to neurogenetic therapies which were reviewed and discussed, including means of genetic manipulation, adverse events, monitoring, timing of therapy, and the importance of patient involvement in trial design. Continued collaboration across disciplines will accelerate development of neurogenetic therapeutics.},
}

@article {pmid40634123,
year = {2025},
author = {Daudelin, D and Sama-Borbon, D and Zhang, N and Sockanathan, S},
title = {Novel roles for the GPI-anchor cleaving enzyme, GDE2, in hippocampal synaptic morphology and function.},
journal = {eNeuro},
volume = {},
number = {},
pages = {},
doi = {10.1523/ENEURO.0102-25.2025},
pmid = {40634123},
issn = {2373-2822},
abstract = {Hippocampal synaptic activity is tightly regulated to ensure appropriate synaptic function and plasticity, which are important for critical cognitive processes such as learning and memory. Altered hippocampal synaptic function can lead to cognitive and behavioral deficits observed in neurodegenerative diseases such as Alzheimer's Disease (AD), necessitating a deeper fundamental understanding of hippocampal synaptic control mechanisms. Glycerophosphodiester phosphodiesterase 2 (GDE2 or GDPD5) is a surface transmembrane enzyme that cleaves the glycosylphosphatidylinositol (GPI) anchor that tethers some proteins to the membrane. Mice lacking GDE2 (Gde2KO) display behavioral deficits in learning and memory that are hippocampal-dependent. However, roles for GDE2 in mouse hippocampal function are not known. Here, we show that GDE2 is expressed in pre- and post-synaptic compartments along apical dendrites in hippocampal CA1 cells. Gde2KO CA1 cells showed increased dendritic length and complexity and increased numbers of mushroom spines localized to the stratum radiatum Further, adult Gde2KOs displayed an increased frequency of miniature excitatory post-synaptic currents (mEPSCs), impaired paired-pulse facilitation (PPF), and disrupted N-methyl-D-aspartate (NMDAR)-mediated long-term depression (LTD). The phosphatidylinositol 3-Kinase-AKT-glycogen synthase kinase 3 (PI3K-AKT-GSK3) signaling pathway, implicated in the inhibition of NMDAR-mediated LTD, was abnormally activated in Gde2KO hippocampus, and inhibition of PI3K restored Gde2KO NMDAR-mediated LTD to WT levels. These observations identify GDE2 as an essential physiological regulator of CA1 synaptic morphology and hippocampal pre- and post-synaptic function, including the modulation of NMDAR-mediated LTD via the PI3K-AKT-GSK3 signaling axis.Significance statement Hippocampal synaptic function is critical for important cognitive functions such as learning and memory. Understanding how hippocampal synaptic activity is regulated could help clarify the basis of diseases such as Alzheimer's Disease, where these cognitive functions are impaired. This study identifies a new player that is important for regulating hippocampal synaptic morphology and function. GDE2 is essential for maintaining normal dendritic structure and synaptic activity in hippocampal CA1 cells. Loss of GDE2 leads to altered synaptic plasticity, including disrupted NMDAR-mediated long-term depression (LTD), which is due to aberrant activation of the PI3K-AKT-GSK3 signaling pathway. These results provide new insight into the molecular mechanisms underlying hippocampal synaptic regulation.},
}

@article {pmid40634107,
year = {2025},
author = {Badesso, S and Perez-Gonzalez, M and Exposito, S and Espelosin, M and Cambria, C and D'Andrea, L and Imperato, G and Moeini, P and Vales, A and Gonzalez-Aseguinolaza, G and Mitro, N and Antonucci, F and Martín, ED and Marcello, E and Cuadrado-Tejedor, M and Garcia-Osta, A},
title = {Loss of PLA2G4E compromises synaptic structure and cognitive outcomes in mice.},
journal = {Life science alliance},
volume = {8},
number = {9},
pages = {},
doi = {10.26508/lsa.202503323},
pmid = {40634107},
issn = {2575-1077},
mesh = {Animals ; Mice ; *Synapses/metabolism ; Mice, Knockout ; *Cognition/physiology ; Neuronal Plasticity/genetics/physiology ; *Group IV Phospholipases A2/genetics/metabolism ; Neurons/metabolism ; Brain/metabolism ; Alzheimer Disease/metabolism/genetics ; Dendrites/metabolism ; Male ; Mice, Inbred C57BL ; Memory Disorders/genetics ; },
abstract = {Given its potential role in supporting cognitive resilience, PLA2G4E has emerged as a compelling therapeutic target in the context of Alzheimer's disease (AD). However, its physiological functions in the central nervous system remain largely unexplored. In this study, we demonstrate that Pla2g4e expression peaks during early postnatal brain development, coinciding with the rapid formation of synapses. Loss-of-function experiments in primary neuronal cultures revealed that Pla2g4e expression is essential for proper dendritic development and neuronal maturation. In constitutive Pla2g4e knockout mice, we observed significant disruptions in the developmental profiles of cortical synaptic plasticity markers, accompanied by impairments in memory-related behaviors. Notably, the adeno-associated virus-mediated overexpression of PLA2G4E rescued memory deficits, highlighting its functional relevance in cognitive processes. Furthermore, selective deletion of Pla2g4e in excitatory neurons of the adult brain resulted in moderate memory impairments in aged animals, suggesting an ongoing role in synaptic maintenance. Together, these findings establish PLA2G4E as a key regulator of dendritic architecture, synaptic function, and cognitive performance, and highlight its potential as a gene therapy target for neurodegenerative diseases characterized by synaptic dysfunction.},
}

Animals
Mice
*Synapses/metabolism
Mice, Knockout
*Cognition/physiology
Neuronal Plasticity/genetics/physiology
*Group IV Phospholipases A2/genetics/metabolism
Neurons/metabolism
Brain/metabolism
Alzheimer Disease/metabolism/genetics
Dendrites/metabolism
Male
Mice, Inbred C57BL
Memory Disorders/genetics

@article {pmid40633621,
year = {2025},
author = {Limone, A and Di Napoli, C and De Rosa, G and Bagnoli, S and Izzo, A and Procaccini, C and Matarese, G and Nacmias, B and Lavecchia, A and Sarnataro, D},
title = {Modulation of mitochondrial quality control through autophagic pathway in familial Alzheimer's disease.},
journal = {Biochimica et biophysica acta. Molecular cell research},
volume = {},
number = {},
pages = {120019},
doi = {10.1016/j.bbamcr.2025.120019},
pmid = {40633621},
issn = {1879-2596},
abstract = {Autophagy is a highly conserved cellular catabolic process recognized as an essential pathway for the maintenance of cellular homeostasis. Growing evidence implicates autophagic dysfunction in the pathogenesis of several neurodegenerative disorders, including Alzheimer's disease (AD), thus its modulation might represent an interesting therapeutic tool. Searching for a compound that stimulates autophagic pathway, led us to identify the inhibitor of RPSA receptor, NSC47924. In this study, we show that, NSC47924 down-modulated Akt-mTOR-axis pathway, the master regulator of autophagy, which was abnormally hyperactivated in fibroblasts from genetic AD-affected patients. Consistently, by monitoring the conversion of LC3, we found that inhibition of RPSA enhanced and restored the compromised autophagic flux. Moreover, by qRT-PCR analysis we found that inhibitor treatment upregulated the expression of autophagy-linked genes. Importantly, AD-affected fibroblasts exhibited massive mitochondrial network fragmentation and mitophagy defects, which were restored through the stimulation of autophagy induced by RPSA inhibition. Consistent with an efficient elimination of dysfunctional mitochondria, we found that the turnover of both the mitophagy regulators PINK1 and Parkin and the autophagic receptors p62, NDP52, OPTN, was modulated, thus restoring a highly interconnected organelle's network. In addition, the improvement of mitochondrial morphology correlated with a functional recovery, as assessed by Seahorse analysis and mitochondrial ROS production evaluation. Collectively, our findings suggest that RPSA inhibition stimulates an autophagic pathway promoting the efficient removal of damaged mitochondria, favouring the recovery of cellular homeostasis, and counteracting crucial AD pathogenic mechanisms.},
}

@article {pmid40633584,
year = {2025},
author = {Bagheri, N and Marvelani, G and Chiang, TW and Nelson, PT and Chuang, TJ and Stamm, S},
title = {Circular RNAs from the MAPT and TARDP genes: Novel players in neurodegeneration?.},
journal = {Neurochemistry international},
volume = {},
number = {},
pages = {106019},
doi = {10.1016/j.neuint.2025.106019},
pmid = {40633584},
issn = {1872-9754},
abstract = {The microtubule associated protein tau (MAPT) and TAR DNA binding protein (TARDBP) genes play crucial roles in neurodegeneration. The tau protein encoded by MAPT is the main component of tau tangles, a pathologic hallmark of "tauopathies" such as Alzheimer's disease (AD). Cytosolic accumulations of TDP-43, encoded by TARDBP are characteristic for LATE (Limbic-predominant age-related TDP-43 encephalopathy) and other TDPopathies. In addition to the well-characterized mRNA splicing isoforms, both genes generate a multitude of circular RNAs (circRNAs). Both MAPT and TARDBP express circular RNA-specific exons characterized by suboptimal splice sites and lengths and are frequently derived from Alu-elements. Most circTau and likely all circTARDBP RNAs expressed in brain are human-specific, suggesting a possible unique contribution to human brain disease. TARDBP and MAPT circRNAs harbor open reading frames and circTau RNAs were shown to be translated into polypeptides in cells. Thus, circRNAs from the MAPT and TARDBP genes should be considered in molecular analysis of AD, LATE and other neurological diseases.},
}

@article {pmid40633469,
year = {2025},
author = {Al Shamsi, HSS and Gardener, SL and Sohrabi, HR and Taddei, K and Masters, CL and Rainey-Smith, SR and Martins, RN and Fernando, WMADB},
title = {The moderating effect of dietary patterns on the association of depression and anxiety with cognitive function.},
journal = {Clinical nutrition (Edinburgh, Scotland)},
volume = {51},
number = {},
pages = {278-286},
doi = {10.1016/j.clnu.2025.06.013},
pmid = {40633469},
issn = {1532-1983},
abstract = {BACKGROUND AND AIMS: Investigating modifiable risk factors, such as diet, is crucial in understanding their effects on the relationship between Alzheimer's disease (AD)-related cognitive decline and related conditions. This study assesses whether dietary patterns moderate the relationship between symptoms of depression, anxiety, and cognitive function in older adults. Given that biological and psychosocial differences between sexes may influence dietary behaviours, mental health symptoms, and cognitive outcomes, conducting sex-stratified analyses will allow for identification of differential associations.

METHOD: Cross-sectional data from cognitively unimpaired older adults (n = 1174, age ≥60 years) from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study were included. Participants completed the Cancer Council of Victoria food frequency questionnaire, provided depression and anxiety symptom data, and underwent neuropsychological testing. Composite scores for six cognitive domains were generated from individual test scores (episodic recall, recognition, executive function, language, attention processing, and the AIBL Preclinical Alzheimer Cognitive Composite (PACC)). Dietary pattern scores were calculated for the Mediterranean diet (MeDi), Dietary Approaches to Stop Hypertension (DASH), and Western diet. Moderation analysis explored interactions between dietary patterns, depression, anxiety, and cognitive performance.

RESULTS: The MeDi was found to moderate the relationship between depressive symptoms and attention processing in males, where low to moderate MeDi adherence was linked to poorer attention with higher depressive symptoms. The Western diet moderated the relationship between anxiety and the AIBL PACC score in males, with high adherence to the Western diet associated with worse PACC performance in those with greater anxiety. No significant moderating effects were observed in females for the MeDi and Western diet, or in either sex for the DASH diet on the association of depression and anxiety with cognitive function.

CONCLUSION: These findings also emphasise the importance of sex-specific approaches in research on symptoms of depression and anxiety, cognitive health, and diet. Our results highlight the need for further investigation into sex-specific pathways using longitudinal study designs and randomised controlled trials to establish causal relationships.},
}

@article {pmid40633409,
year = {2025},
author = {Khaliq, A and Ahmad, F and Rehman, HU and Alanazi, SA and Haleem, H and Junaid, K and Andrikopoulou, E},
title = {Revolutionizing medical imaging: A cutting-edge AI framework with vision transformers and perceiver IO for multi-disease diagnosis.},
journal = {Computational biology and chemistry},
volume = {119},
number = {},
pages = {108586},
doi = {10.1016/j.compbiolchem.2025.108586},
pmid = {40633409},
issn = {1476-928X},
abstract = {The integration of artificial intelligence in medical image classification has significantly advanced disease detection. However, traditional deep learning models face persistent challenges, including poor generalizability, high false-positive rates, and difficulties in distinguishing overlapping anatomical features, limiting their clinical utility. To address these limitations, this study proposes a hybrid framework combining Vision Transformers (ViT) and Perceiver IO, designed to enhance multi-disease classification accuracy. Vision Transformers leverage self-attention mechanisms to capture global dependencies in medical images, while Perceiver IO optimizes feature extraction for computational efficiency and precision. The framework is evaluated across three critical clinical domains: neurological disorders, including Stroke (tested on the Brain Stroke Prediction CT Scan Image Dataset) and Alzheimer's (analyzed via the Best Alzheimer MRI Dataset); skin diseases, covering Tinea (trained on the Skin Diseases Dataset) and Melanoma (augmented with dermoscopic images from the HAM10000/HAM10k dataset); and lung diseases, focusing on Lung Cancer (using the Lung Cancer Image Dataset) and Pneumonia (evaluated with the Pneumonia Dataset containing bacterial, viral, and normal X-ray cases). For neurological disorders, the model achieved 0.99 accuracy, 0.99 precision, 1.00 recall, 0.99 F1-score, demonstrating robust detection of structural brain abnormalities. In skin disease classification, it attained 0.95 accuracy, 0.93 precision, 0.97 recall, 0.95 F1-score, highlighting its ability to differentiate fine-grained textural patterns in lesions. For lung diseases, the framework achieved 0.98 accuracy, 0.97 precision, 1.00 recall, 0.98 F1-score, confirming its efficacy in identifying respiratory conditions. To bridge research and clinical practice, an AI-powered chatbot was developed for real-time analysis, enabling users to upload MRI, X-ray, or skin images for automated diagnosis with confidence scores and interpretable insights. This work represents the first application of ViT and Perceiver IO for these disease categories, outperforming conventional architectures in accuracy, computational efficiency, and clinical interpretability. The framework holds significant potential for early disease detection in healthcare settings, reducing diagnostic errors, and improving treatment outcomes for clinicians, radiologists, and patients. By addressing critical limitations of traditional models, such as overlapping feature confusion and false positives, this research advances the deployment of reliable AI tools in neurology, dermatology, and pulmonology.},
}

@article {pmid40633205,
year = {2025},
author = {Metzendorf, NG and Godec, A and Petrovic, A and Chourlia, A and Napoleone, A and Syvänen, S and Rofo, F and Hultqvist, G},
title = {Somatostatin therapy, neprilysin activation, and amyloid beta reduction: A novel approach for Alzheimer's treatment.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {189},
number = {},
pages = {118325},
doi = {10.1016/j.biopha.2025.118325},
pmid = {40633205},
issn = {1950-6007},
abstract = {INTRODUCTION: Neprilysin is the primary enzyme responsible for the degradation of amyloid beta (Aβ), with its levels regulated by the hormone somatostatin (SST).

METHODS: We have developed a novel treatment mechanism for Alzheimer's disease (AD) by combining SST with a blood-brain barrier (BBB) transporter and a Fc fragment to extend its half-life. This treatment was tested in a murine AD model overexpressing amyloid precursor protein (APP) with the Arctic mutation in Aβ (APPArcSwe).

RESULTS: Our findings demonstrate a significant increase in neprilysin levels, which correlates with a reduction in various forms of Aβ, including membrane-bound and intracellular Aβ aggregates, as well as Aβ42 in insoluble aggregates.

DISCUSSION: These results suggest that neprilysin can effectively degrade Aβ with the Arctic mutation. Additionally, this treatment strategy successfully reduces both oligomeric and larger Aβ, aggregates, a challenge for other therapeutic approaches. This novel strategy holds promise as a potential therapeutic approach for AD.},
}

@article {pmid40632863,
year = {2025},
author = {Shao, L and Zhang, Y and Yang, Z and Shi, C and Yue, X and Li, C and Liu, Y and Fu, Z and Tang, C and Zhao, X and Han, M and Zhang, J and Sun, W and Yao, Z and Xi, K and Fang, Z and Wang, Z and Feng, F and Ma, C and Zhao, K and Zhang, Y and Ni, S and Jiang, X and Chen, C},
title = {Synthetic efferocytic receptor microglia enhances anti-inflammatory clearance of amyloid-β for AD treatment in mice.},
journal = {Science advances},
volume = {11},
number = {28},
pages = {eads6613},
doi = {10.1126/sciadv.ads6613},
pmid = {40632863},
issn = {2375-2548},
mesh = {Animals ; *Amyloid beta-Peptides/metabolism ; *Microglia/metabolism ; *Alzheimer Disease/metabolism/therapy/pathology ; Mice ; Disease Models, Animal ; Phagocytosis ; Humans ; Inflammation ; Nanoparticles/chemistry ; Anti-Inflammatory Agents ; Mice, Transgenic ; },
abstract = {Monoclonal antibody immunotherapy targeting the clearance of amyloid-β (Aβ) has shown promise in Alzheimer's disease (AD). However, current antibody treatments trigger Fc receptors and induce proinflammatory responses, in turn exacerbating neuronal damage. Here, we report a synthetic efferocytic receptor (SER) integrating Aβ-targeting scFv, efferocytosis receptor backbone based on TIM4 and downstream signal for microglia (MG) reprogramming, which enabled selective elimination of Aβ without inducing an inflammatory response. Specifically, our in-house-customized MG-editing mRNA lipid nanoparticles (MERLINs) efficiently introduced SER mRNA into MG to generate Aβ-specific SER-MG in situ. SER-MG exhibited robust Aβ-specific phagocytosis and stimulated anti-inflammatory efferocytosis typical signaling in vitro. In a mouse model of AD, SER expression in the MG markedly increased the clearance of Aβ and dampened inflammation, resulting in improved behavioral outcomes along with substantially reduced synapse elimination. Our findings establish that AD-associated aberrant MG can be in situ reprogrammed with SER for Aβ clearance in an anti-inflammatory manner, with broad application in other inflammation-related diseases.},
}

Animals
*Amyloid beta-Peptides/metabolism
*Microglia/metabolism
*Alzheimer Disease/metabolism/therapy/pathology
Mice
Disease Models, Animal
Phagocytosis
Humans
Inflammation
Nanoparticles/chemistry
Anti-Inflammatory Agents
Mice, Transgenic

@article {pmid40632500,
year = {2025},
author = {Prasad, H and Rao, R},
title = {Linking Endo-lysosomal pH, Sterol and Trafficking to Neurodegenerative Disease.},
journal = {FEMS yeast research},
volume = {},
number = {},
pages = {},
doi = {10.1093/femsyr/foaf034},
pmid = {40632500},
issn = {1567-1364},
abstract = {Although endo-lysosomal abnormalities have been recognized as a pathognomonic feature of Alzheimer's disease, the lack of druggable targets has hampered the translation from bench to bedside. This article provides an overview of the insights gained from yeast research with a focus on understudied luminal acidification mechanisms and their major impact on disease progression. The yeast-to-human discovery and validation strategy identified a "druggable" triad featuring luminal pH, sterol content, and trafficking that (dys)regulate reciprocally. Endosomal Na+/H+ exchangers (eNHE), discovered in yeast and later described in mammals, provide independent support for this pathogenic model. The brain is often the most severely affected organ in patients with eNHE mutations, and a subset is causally linked to progressive and severe neurodegeneration, demonstrating that neurons heavily rely on fine-tuning of endosomal pH. We present recent advances on the role of eNHE in ageing related neurodegenerative diseases, which has implications for pathogenesis and therapy. Future studies should unravel the broader landscape of endo-lysosomal pH in neurodegenerative diseases. Given that pharmacologic correction of luminal hyper-acidification defect completely ameliorates endo-lysosomal deficits in eNHE deletion yeast, there is compelling reason to believe that efforts to target endo-lysosomal acid-base homeostasis will eventually lead to novel therapeutic approaches for neurodegenerative diseases.},
}

@article {pmid40632335,
year = {2025},
author = {Banu, Z and Das, NR},
title = {In Vitro Assessment of Cholinesterase Inhibition and Neuroprotective Effects of Elaeocarpus angustifolius Blume Against Amyloid-Beta Peptide-Induced Toxicity in SH-SY5Y and BV-2 Cells.},
journal = {Neurochemical research},
volume = {50},
number = {4},
pages = {226},
pmid = {40632335},
issn = {1573-6903},
mesh = {*Amyloid beta-Peptides/toxicity ; Humans ; *Neuroprotective Agents/pharmacology/isolation & purification ; *Cholinesterase Inhibitors/pharmacology/isolation & purification ; Animals ; *Plant Extracts/pharmacology ; Mice ; Butyrylcholinesterase/metabolism ; Cell Survival/drug effects/physiology ; *Peptide Fragments/toxicity ; Acetylcholinesterase/metabolism ; Cell Line, Tumor ; Cell Line ; Dose-Response Relationship, Drug ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder primarily characterized by memory impairment and cognitive decline. Pathophysiological mechanisms contributing to AD include oxidative stress, increased acetylcholinesterase activity, neuroinflammation, and the accumulation of hyperphosphorylated tau proteins and amyloid-β (Aβ) plaques in the brain. The shortcomings of existing therapeutic approaches have necessitated the exploration of alternative treatment strategies. Elaeocarpus angustifolius Blume, traditionally used for neurological disorders, has been investigated for its neuroprotective potential through its alkaloid-rich fraction. This study evaluated the acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory activities of E. angustifolius alkaloid-rich fraction (EAF) and its protective effects against Aβ1-42-induced cytotoxicity in human neuron-like SH-SY5Y cells and murine microglial BV-2 cells using the MTT assay. The results demonstrated that for AChE and BuChE, EAF showed significant inhibition with IC50 of 145.1 ± 4.782 µg/mL and 165.8 ± 1.10 µg/mL, respectively. In the MTT assay, EAF effectively mitigated Aβ1-42-induced cytotoxicity in a dose-dependent manner, with the highest dose (100 µg/mL) restoring viability from 67.91 to 75.31% in SH-SY5Y cells and from 60.29 to 76.01% in BV-2 cells. From these results, it is apparent that EAF has anticholinesterase and neuroprotective properties. However, further research on this may help decipher underlying mechanisms before establishing EAF as an effective alternative in treating AD.},
}

*Amyloid beta-Peptides/toxicity
Humans
*Neuroprotective Agents/pharmacology/isolation & purification
*Cholinesterase Inhibitors/pharmacology/isolation & purification
Animals
*Plant Extracts/pharmacology
Mice
Butyrylcholinesterase/metabolism
Cell Survival/drug effects/physiology
*Peptide Fragments/toxicity
Acetylcholinesterase/metabolism
Cell Line, Tumor
Cell Line
Dose-Response Relationship, Drug

@article {pmid40632121,
year = {2025},
author = {Daly, T},
title = {Review of Doctored: Fraud, Arrogance and Tragedy in the Quest to Cure Alzheimer's by Charles Piller.},
journal = {AJOB neuroscience},
volume = {16},
number = {3},
pages = {W1-W2},
doi = {10.1080/21507740.2025.2519434},
pmid = {40632121},
issn = {2150-7759},
}

@article {pmid40632028,
year = {2025},
author = {Fang, S and Guan, L and Jian, H and Dai, X and Gong, L},
title = {Body weight and BMI variability linked to dementia risk: A meta-analysis.},
journal = {Biomolecules & biomedicine},
volume = {},
number = {},
pages = {},
doi = {10.17305/bb.2025.12626},
pmid = {40632028},
issn = {2831-090X},
abstract = {Emerging evidence suggests that fluctuations in body weight (BW) or body mass index (BMI), independent of average levels, may influence dementia risk. However, the association between intra-individual variability in BW or BMI and incident dementia remains unclear. This meta-analysis aimed to clarify this relationship. A systematic search of PubMed, Embase, and Web of Science was conducted through March 25, 2025, to identify longitudinal observational studies reporting dementia outcomes in relation to BW or BMI variability. Relative risks (RRs) comparing the highest versus lowest variability categories were pooled using a random-effects model. Subgroup and sensitivity analyses were performed to explore heterogeneity and assess the robustness of the results. Nine cohort studies (10 datasets; 4,232,666 participants) were included. Overall, high BW or BMI variability was associated with a significantly increased risk of dementia (RR = 1.36, 95% CI: 1.27-1.46; p < 0.001; I[2] = 84%). The association was consistent for both BW (RR = 1.45) and BMI (RR = 1.34) variability. Subgroup analyses showed stronger associations in prospective studies than in retrospective ones, and in studies that did not adjust for baseline BW/BMI compared to those that did (p for subgroup difference < 0.05). Associations remained robust in sensitivity analyses and across dementia subtypes, including Alzheimer's disease and vascular dementia. No significant publication bias was detected (Egger's test, p = 0.22). In conclusion, greater intra-individual variability in BW or BMI may be independently associated with increased dementia risk. These findings underscore the importance of maintaining weight stability in mid-to-late life as a potential preventive strategy for dementia.},
}

@article {pmid40631882,
year = {2025},
author = {Anand, C and Abdelnour, F and Sipes, B and Ma, D and Maia, PD and Torok, J and Raj, A},
title = {Selective vulnerability and resilience to Alzheimer's disease tauopathy as a function of genes and the connectome.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awaf179},
pmid = {40631882},
issn = {1460-2156},
support = {R01NS092802/GF/NIH HHS/United States ; RF1AG062196/GF/NIH HHS/United States ; R01AG072753/GF/NIH HHS/United States ; },
abstract = {Brain regions in Alzheimer's disease exhibit distinct vulnerability to its hallmark pathology with the entorhinal cortex and hippocampus succumbing early to tau tangles while others like the primary sensory cortices remain resilient. The quest to understand how local/regional genetic factors, pathogenesis and network-mediated pathology spread, together govern this selective vulnerability (SV) or resilience (SR) is ongoing. Although many Alzheimer's risk genes are known from gene association and transgenic studies, it is still unclear whether and how their baseline expression confers SV/SR to pathology. Prior analyses have yielded conflicting results, pointing to a disconnect between the location of genetic risk factors and downstream tau pathology. The spatial distribution of vulnerability doesn't always align with genetic factors, suggesting a role for non-cell-autonomous mechanisms like transneuronal tau transmission. We hypothesize that a full accounting of the role of genes in mediating SV/SR would require modelling of network-based vulnerability, whereby tau misfolds, aggregates and propagates along fibre projections. We employed an extended network diffusion model (eNDM) and fitted it on tau PET data from 196 patients from the Alzheimer's Disease Neuroimaging Initiative. The fitted eNDM then becomes a reference from which to assess the role of innate genetic factors. Using the residual (observed - model-predicted) tau as a novel target outcome, we obtained its association with 100 Alzheimer's risk genes, whose baseline spatial transcriptional profiles were obtained from the Allen Human Brain Atlas. Our eNDM was successful in capturing tau pathology distribution in patients. After regressing out the model, we found that while many risk genes have spatial expression patterns that correlate with regional tau, many others showed a stronger association with residual tau. This suggests that direct vulnerability aligned with the network, as well as network-independent vulnerability, are conferred by risk genes. We report four classes of risk genes: network-aligned SV (SV-NA), network-independent SV (SV-NI), network-aligned SR (SR-NA) and network-independent SR (SR-NI), each with a distinct spatial signature and associated vulnerability to tau. Remarkably, using gene ontology analysis, we found that the identified gene classes have distinct and sometimes surprising functional enrichment patterns. Network-aligned genes broadly participate in cell death, stress response and metabolic processing; network-independent genes in amyloid-β processing and immune response. These previously unreported segregated roles point to multiple distinct pathways by which risk genes confer vulnerability or resilience in Alzheimer's disease. Our findings offer new insights into vulnerability signatures in Alzheimer's disease and may prove helpful in identifying potential intervention targets.},
}

@article {pmid40631789,
year = {2025},
author = {Zhao, F and Yang, H and Liu, H and Yu, H and Zhao, Y},
title = {FGF21 restores metabolic function in Alzheimer's disease via activation of PI3K/Akt signaling.},
journal = {Neurological research},
volume = {},
number = {},
pages = {1-16},
doi = {10.1080/01616412.2025.2521721},
pmid = {40631789},
issn = {1743-1328},
abstract = {BACKGROUND AND OBJECTIVE: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline, oxidative stress, and mitochondrial dysfunction. Fibroblast growth factor 21 (FGF21) has demonstrated neuroprotective effects, though its role in AD pathogenesis remains unclear. The present study aims to discover neuroprotective effects of FGF21 in AD by examining its influence on energy metabolism and neuronal survival through the PI3K/Akt signaling pathways.

METHODS: In vivo experiments were performed using 5×FAD transgenic mice, while in vitro assays utilized amyloid beta 1-42 (Aβ1-42)-treated SH-SY5Y cells and a co-culture system of primary rat astrocytes with SH-SY5Y cells. To evaluate the effects of FGF21 modulation, we performed both gain- and loss-of-function experiments and assessed outcomes using behavioral testing, histopathological and ultrastructural analyses, oxidative stress and mitochondrial function assays, and Western blotting. The involvement of the PI3K/Akt/mTOR pathway was explored using the PI3K inhibitor LY294002.

RESULTS: Both in vivo and in vitro AD models exhibited reduced FGF21 expression. FGF21 downregulation impaired PI3K/Akt signaling, induced neuronal apoptosis, and disrupted metabolic homeostasis. Loss of FGF21 resulted in cognitive and metabolic dysfunction in AD mice. Conversely, FGF21 overexpression activated PI3K/Akt signaling, suppressed neuronal apoptosis, and restored metabolic functions in AD models.

CONCLUSION: FGF21 alleviates AD-related cognitive impairment and restores metabolic function by activating the PI3K/Akt pathway.},
}

@article {pmid40631777,
year = {2025},
author = {LaBarge, B and Lorenz, FJ and Gniady, JP},
title = {Association of Laryngeal Dystonia With Common Neurologic Disorders.},
journal = {The Laryngoscope},
volume = {},
number = {},
pages = {},
doi = {10.1002/lary.32407},
pmid = {40631777},
issn = {1531-4995},
support = {UL1 TR002014/TR/NCATS NIH HHS/United States ; },
abstract = {OBJECTIVE: Laryngeal dystonia is a heterogenous disorder consisting of involuntary spasms of laryngeal muscles. There are multiple forms including adductor, abductor, and mixed phenotypes. The disorder is thought to be multifactorial, with various reported associations with family history of dystonia or movement disorders. The relationship between laryngeal dystonia and various neurologic disorders is not well defined in the literature.

METHODS: We utilized the TriNetX de-identified electronic medical record database system spanning 2010-2023 to assess the prevalence of laryngeal dystonia with common neurologic disorders, compared to an age-sex matched control population. We included patients with the laryngeal spasm J38.5 ICD-10 code and 64617 CPT code, in order to categorize laryngeal dystonia patients undergoing chemodenervation.

RESULTS: The patient cohort consisted of approximately 4000 patients. 75% were female, 71% were white, and the mean age was 61 years. The laryngeal dystonia population had an elevated relative risk of Parkinson's disease (RR = 2.7, 1.8-3.9, 95% CI). In contrast, the relative risk of Alzheimer's disease was decreased in the laryngeal dystonia population (RR = 0.28, 0.16-0.48, 95% CI). There were no differences between the laryngeal dystonia and control populations for multiple sclerosis, amyotrophic lateral sclerosis, epilepsy, migraine, muscular dystrophy, or cerebral palsy.

CONCLUSION: Laryngeal dystonia patients have a significantly greater association with Parkinson's disease and less association with Alzheimer's disease compared to the control population. There were no meaningful associations with the remainder of the neurologic conditions included in the study.},
}

@article {pmid40631607,
year = {2025},
author = {Gavriel, Y and Voinsky, I and Klin, H and Squassina, A and Gurwitz, D},
title = {Reduced Taurine Transporter Expression in Lymphoblastoid Cell Lines From Alzheimer's Disease Patients Compared With Age-Matched Controls: Therapeutic Implications?.},
journal = {Drug development research},
volume = {86},
number = {5},
pages = {e70124},
doi = {10.1002/ddr.70124},
pmid = {40631607},
issn = {1098-2299},
support = {//The authors received no specific funding for this work./ ; },
mesh = {Humans ; *Alzheimer Disease/metabolism/genetics ; *Membrane Transport Proteins/genetics/metabolism ; Aged ; *Taurine/metabolism ; Male ; Female ; Cell Line ; RNA, Messenger/metabolism ; *Membrane Glycoproteins/genetics/metabolism ; Aged, 80 and over ; Glutathione Peroxidase/genetics/metabolism ; *Lymphocytes/metabolism ; Case-Control Studies ; },
abstract = {Taurine is an atypical amino acid that cannot form peptide bonds and thus does not take place in building proteins. Yet, taurine takes part in regulating many cell functions, including cell osmolarity and volume, mitochondrial function, membrane ion channels and neuronal activity, and cell survival. Taurine is synthesized by the liver, and available from consumption of meat and fish, but not plants. It has millimolar concentrations in the brain, skeletal muscle, blood, heart, retina, and other tissues. Taurine is transported from the liver (following synthesis) or the intestine (following consumption) to blood by the taurine transporter, encoded in humans by SLC6A6. A recent study reported that blood taurine declines dramatically in aged individuals. Several studies indicated that dietary taurine slows cognitive decline in Alzheimer's disease (AD) model mice. We therefore measured SLC6A6 mRNA expression in human lymphoblastoid cell lines (LCLs) from AD patients and age-matched controls and observed 2.8-fold lower expression in AD LCLs (p = 0.0005). Additionally, glutathione peroxidase 1 (GPX1), a key free-radical scavenging selenoenzyme, had reduced mRNA expression in LCLs from AD patients compared with controls. Our observations suggest that reduced taurine transporter expression may contribute to AD pathogenesis and that dietary taurine might be beneficial for slowing disease progression in early-stage AD. Clinical trials with dietary taurine supplementation of individuals with mild cognitive impairment (MCI) or early-stage AD are required to assess its tentative therapeutic potential.},
}

Humans
*Alzheimer Disease/metabolism/genetics
*Membrane Transport Proteins/genetics/metabolism
Aged
*Taurine/metabolism
Male
Female
Cell Line
RNA, Messenger/metabolism
*Membrane Glycoproteins/genetics/metabolism
Aged, 80 and over
Glutathione Peroxidase/genetics/metabolism
*Lymphocytes/metabolism
Case-Control Studies

@article {pmid40631452,
year = {2025},
author = {Gupta, AK and Martin, W and Pieper, AA and Wang, Y and Saykin, AJ and Cheng, F},
title = {Comprehensive characterization of the RNA editing landscape in the human aging brains with Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {7},
pages = {e70452},
doi = {10.1002/alz.70452},
pmid = {40631452},
issn = {1552-5279},
support = {U01AG073323//National Institute on Aging (NIA)/ ; R01AG066707//National Institute on Aging (NIA)/ ; R01AG076448//National Institute on Aging (NIA)/ ; R01AG082118//National Institute on Aging (NIA)/ ; R01AG084250//National Institute on Aging (NIA)/ ; R01AG092462//National Institute on Aging (NIA)/ ; R01AG092591//National Institute on Aging (NIA)/ ; RF1AG082211//National Institute on Aging (NIA)/ ; R21AG083003//National Institute on Aging (NIA)/ ; RF1NS133812//National Institute of Neurological Disorders and Stroke (NINDS)/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics/pathology ; *RNA Editing/genetics ; Male ; *Brain/metabolism/pathology ; Female ; Genome-Wide Association Study ; *Aging/genetics ; Aged ; Aged, 80 and over ; },
abstract = {INTRODUCTION: While RNA editing has been linked to Alzheimer's disease (AD), its specific impact on the transcriptomic landscape in human AD brains remains under explored.

METHODS: We conducted a comprehensive analysis of RNA editing across nine human brain regions affected by AD, utilizing RNA-seq data and matched whole-genome sequencing data from three human brain biobanks, adjusting for age, post mortem interval, sex, and apolipoprotein E4 (APOE4) status.

RESULTS: RNA-editing events were identified in both AD and healthy control aging brains, highlighting 127 genes with significant RNA editing loci. AD exhibited elevated RNA editing in the parahippocampal gyrus and cerebellar cortex. We also discovered 147 colocalized genome-wide association studies (GWAS) and cis-edQTL (± 1 MB) signals in 48 likely causal genes encompassing CLU, BIN1, and GRIN3B, primarily allied to amyloid and tau pathology, and neuroinflammation.

DISCUSSION: Our findings delineate RNA editing regulatory signatures in human AD, providing novel insights into AD pathophysiology and potential biomarkers and therapeutic targets.

HIGHLIGHTS: ·We discovered genome-wide landscape of RNA editing signals from 4208 (1364 Alzheimer's disease [AD] cases vs. 742 healthy controls) RNA-seq data across nine human brain regions from three large brain biobanks (Mount Sinai Brain Bank [MSBB], Mayo Clinic [MAYO] Religious Order Study and Memory and Aging Project [ROSMAP]) tied with AD, including in sex-specific and apolipoprotein E4 (APOE4) -specific manner adjusting for age, post mortem interval (PMI), sex, and APOE4 status. ·We emphasize 127 genes, including SYT11, KCNIP4, NRG3, ANKS1B, and RALYL, exhibiting significant RNA editing loci shared by multiple brain tissues, mainly implicated in synaptic plasticity, signaling and transmission, neuronal development, and morphogenesis. ·Brain-wide tissue-specific cis-regulatory variants (cis-edQTLs) were inspected using matched genotyping data from 3627 samples from all brain biobanks. We revealed 147 colocalized AD-GWAS and cis-edQTLs signals pertaining to 48 likely causal genes comprising CLU (rs7982, rs1532278), BIN1 (rs2276582, rs3768863), GRIN3B (rs10417824, rs1058603), NYAP1 (rs12539172), DGKQ (rs4690197, rs3733347), CLPTM1 (rs204468), etc. ·Colocalized signals show affiliations to tau protein binding, amyloid-β regulation, cellular morphogenesis, and immune response pathway suggesting possible roles of epitranscriptomic mechanisms in shaping the AD risk.},
}

Humans
*Alzheimer Disease/genetics/pathology
*RNA Editing/genetics
Male
*Brain/metabolism/pathology
Female
Genome-Wide Association Study
*Aging/genetics
Aged
Aged, 80 and over

@article {pmid40631443,
year = {2025},
author = {Daskoulidou, N and Shaw, B and Zelek, WM and Morgan, BP},
title = {The Alzheimer's disease-associated complement receptor 1 variant confers risk by impacting glial phagocytosis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {7},
pages = {e70458},
doi = {10.1002/alz.70458},
pmid = {40631443},
issn = {1552-5279},
support = {DRI-3002//UK Dementia Research Institute/ ; },
mesh = {*Phagocytosis/genetics/physiology ; Humans ; *Alzheimer Disease/genetics ; *Receptors, Complement 3b/genetics/metabolism ; Induced Pluripotent Stem Cells ; *Microglia/metabolism ; *Neuroglia/metabolism ; *Astrocytes/metabolism ; Genetic Predisposition to Disease ; Amyloid beta-Peptides/metabolism ; },
abstract = {INTRODUCTION: Genome-wide association studies have implicated complement in Alzheimer's disease (AD). The CR1*2 variant of complement receptor 1 (CR1; CD35), confers increased AD risk. We confirmed CR1 expression on glial cells; however, how CR1 variants influence AD risk remains unclear.

METHODS: Induced pluripotent stem cell-derived microglia and astrocytes were generated from donors homozygous for the common CR1 variants (CR1*1/CR1*1;CR1*2/CR1*2). CR1 expression was quantified and phagocytic activity assessed using diverse targets (Escherichia coli bioparticles, amyloid β aggregates, and synaptoneurosomes), with or without serum opsonization.

RESULTS: Expression of CR1*1 was significantly higher than CR1*2 on glial lines. Phagocytosis for all targets was markedly enhanced following serum opsonization, attenuated by Factor I-depletion, demonstrating CR1 requirement for C3b processing. CR1*2-expressing glia showed significantly enhanced phagocytosis of all opsonized targets compared to CR1*1-expressing cells.

DISCUSSION: CR1 is critical for glial phagocytosis of opsonized targets. CR1*2, despite lower expression, enhances glial phagocytosis, providing mechanistic explanation of increased AD risk.

HIGHLIGHTS: Induced pluripotent stem cell (iPSC)-derived glia from individuals expressing the Alzheimer's disease (AD) risk variant complement receptor (CR) 1*2 exhibit lower CR1 expression compared to those from donors expressing the non-risk form CR1*1. The iPSC-derived glia from individuals expressing the AD risk variant CR1*2 exhibit enhanced phagocytic activity for opsonized bacterial particles, amyloid-β aggregates and human synaptoneurosomes compared to those from donors expressing the non-risk form CR1*1. We suggest that expression of the CR1*2 variant confers risk of AD by enhancing the phagocytic capacity of glia for opsonized targets.},
}

*Phagocytosis/genetics/physiology
Humans
*Alzheimer Disease/genetics
*Receptors, Complement 3b/genetics/metabolism
Induced Pluripotent Stem Cells
*Microglia/metabolism
*Neuroglia/metabolism
*Astrocytes/metabolism
Genetic Predisposition to Disease
Amyloid beta-Peptides/metabolism

@article {pmid40631440,
year = {2025},
author = {Gogola, A and Zeng, X and Williams, LA and Chapple-McGruder, T and Saeed, A and Lopresti, BJ and Snitz, B and Tudorascu, D and Minhas, D and Ikonomovic, MD and Kofler, J and Matan, C and Pascoal, TA and Aizenstein, H and Zetterberg, H and Blennow, K and Lopez, O and Villemagne, VL and Karikari, TK and Cohen, AD},
title = {Impact of racialization on neuroimaging and plasma biomarkers of Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {7},
pages = {e70463},
doi = {10.1002/alz.70463},
pmid = {40631440},
issn = {1552-5279},
support = {P30 AG066468/AG/NIA NIH HHS/United States ; P50 AG005133/AG/NIA NIH HHS/United States ; RF1 AG025516/AG/NIA NIH HHS/United States ; R01 AG052446/AG/NIA NIH HHS/United States ; R01 AG052521/AG/NIA NIH HHS/United States ; P01 AG025204/AG/NIA NIH HHS/United States ; R01 AG063752/AG/NIA NIH HHS/United States ; R01 AG083874/AG/NIA NIH HHS/United States ; R01AG083874/NH/NIH HHS/United States ; U24AG082930/NH/NIH HHS/United States ; P30AG066468/NH/NIH HHS/United States ; RF1AG052525/NH/NIH HHS/United States ; R01AG053952/NH/NIH HHS/United States ; R37AG023651/NH/NIH HHS/United States ; RF1AG025516/NH/NIH HHS/United States ; R01AG073267/NH/NIH HHS/United States ; R01AG075336/NH/NIH HHS/United States ; R01AG072641/NH/NIH HHS/United States ; P01AG025204/NH/NIH HHS/United States ; #2023-00356//Swedish Research Council/ ; #2022-01018//Swedish Research Council/ ; and #2019-02397//Swedish Research Council/ ; 101053962//the European Union's Horizon Europe research and innovation programme/ ; #ALFGBG-71320//Swedish State/ ; #AF-930351//the Swedish Alzheimer Foundation/ ; #AF-939721//the Swedish Alzheimer Foundation/ ; #AF-968270//the Swedish Alzheimer Foundation/ ; and #AF-994551//the Swedish Alzheimer Foundation/ ; #ALZ2022-0006//Hjärnfonden, Sweden/ ; #FO2024-0048-TK-130//Hjärnfonden, Sweden/ ; and FO2024-0048-HK-24//Hjärnfonden, Sweden/ ; #ALFGBG-965240//Swedish government and the County Councils/ ; #ALFGBG-1006418//Swedish government and the County Councils/ ; JPND2019-466-236//the European Union Joint Program for Neurodegenerative Disorders/ ; ZEN-21-848495//Alzheimer's Association 2021 Zenith Award/ ; SG-23-1038904 QC//Alzheimer's Association 2022-2025 Grant/ ; },
mesh = {Humans ; *Alzheimer Disease/blood/diagnostic imaging/ethnology ; *Biomarkers/blood ; Male ; Aged ; Female ; Amyloid beta-Peptides/blood ; tau Proteins/blood ; Positron-Emission Tomography ; Magnetic Resonance Imaging ; *Neuroimaging ; Middle Aged ; Black or African American ; Aged, 80 and over ; White People ; Neurofilament Proteins/blood ; Brain/diagnostic imaging ; White ; },
abstract = {INTRODUCTION: Given the predominance of imaging and plasma biomarkers in Alzheimer's disease observational studies and clinical trials, it is critical to understand the differences between these biomarkers across racialized groups.

METHODS: A total of 260 older adults without dementia racialized as Black and/or African American (AA) and non-Hispanic white (NHW), ranging in age from 50 to 90 years (68.8 ± 9.1 years), were evaluated for differences in plasma amyloid-β (Aβ) 42/Aβ40, p-tau181, p-tau217, p-tau231, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) as well as Aβ positron emission tomography (PET) and magnetic resonance (MR) imaging-derived cortical thickness using Mann-Whitney U tests and analysis of covariance (ANCOVA).

RESULTS: Both Mann-Whitney tests and ANCOVA found significant differences between groups racialized as AA or NWH with respect to global [11][C]-Pittsburgh Compound B (PiB) standardized uptake value ratio (SUVR), cortical thickness values, p-tau181, and p-tau231 values (p < 0.05).

DISCUSSION: Racialization should be given more consideration in AD clinical research, particularly when biomarker results are used for inclusion or exclusion criteria for clinical trials and qualification in clinical practice.

HIGHLIGHTS: Global [11][C]-Pittsburgh compound B (PiB) standardized uptake value ratio (SUVR), cortical thickness, p-tau181, and p-tau231 differed between groups Differences were unaffected by age, sex, apolipoprotein E *4 (APOE*4), education, and Mini-Mental State Examination (MMSE) score Racialization needs more consideration in Alzheimer's disease clinical research Additional work is needed to understand the sources of biomarker differences.},
}

Humans
*Alzheimer Disease/blood/diagnostic imaging/ethnology
*Biomarkers/blood
Male
Aged
Female
Amyloid beta-Peptides/blood
tau Proteins/blood
Positron-Emission Tomography
Magnetic Resonance Imaging
*Neuroimaging
Middle Aged
Black or African American
Aged, 80 and over
White People
Neurofilament Proteins/blood
Brain/diagnostic imaging
White

@article {pmid40631430,
year = {2025},
author = {Knopman, DS and Weigand, SD and Wiste, HJ and Graff-Radford, J and Graff-Radford, NR and Petersen, RC and Boeve, BF and Jr, CRJ and Lowe, VJ and Machulda, MM and Fields, JA and Ramanan, VK and Botha, H and McCarter, SJ and Jones, DT and Neth, BJ and Day, GS and Kantarci, K and Algeciras-Schimnich, A and Bornhorst, JA and Johnson, DR and , },
title = {Discrepancies between CSF biomarker and PET determinations of elevated brain amyloid and their prognostic significance.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {7},
pages = {e70468},
doi = {10.1002/alz.70468},
pmid = {40631430},
issn = {1552-5279},
support = {U19AG024904/NH/NIH HHS/United States ; U01 AG006786/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Positron-Emission Tomography ; Male ; Female ; *Cognitive Dysfunction/cerebrospinal fluid/diagnostic imaging ; Biomarkers/cerebrospinal fluid ; *Amyloid beta-Peptides/cerebrospinal fluid/metabolism ; Aged ; *Brain/diagnostic imaging/metabolism ; Prognosis ; *Alzheimer Disease/cerebrospinal fluid/diagnostic imaging ; Longitudinal Studies ; Aged, 80 and over ; },
abstract = {INTRODUCTION: When cerebrospinal fluid (CSF) and positron emission tomography (PET) measurements for amyloid-beta-peptide (Aβ) related pathology are discordant, therapeutic decision-making becomes uncertain.

METHODS: Using data from patients with mild cognitive impairment (n = 541) from the Alzheimer's Disease Neuroimaging Initiative, we examined baseline characteristics and longitudinal clinical outcomes in persons grouped according to normal/abnormal Aβ via concurrent CSF and PET determinations using standard cutpoints.

RESULTS: Discordant groups for brain Aβ status (CSF+/PET- and CSF-/PET+) each represented about 5% of the mild cognitive impairment (MCI) population. Longitudinally, neither discordant group declined more than the CSF-/PET- group on either a memory measure or the Clinical Dementia Rating Sum of Boxes scores over a median 4 years of observation, while the CSF+/PET+ group exhibited worsening on both measures.

DISCUSSION: In contrast to the clinical decline observed in the CSF+/PET+ group, persons with MCI and CSF+/PET- or CSF-/PET+ brain amyloid patterns did not exhibit incipient decline.

HIGHLIGHTS: Discrepant abnormal cerebrospinal fluid (CSF) and positron emission tomography (PET) brain amyloid indicators are uncommon in mild cognitive impairment (MCI). CSF-PET discrepant persons with MCI tend to have less abnormal values initially. CSF-PET discrepant persons with MCI have a benign prognosis at 4 years.},
}

Humans
*Positron-Emission Tomography
Male
Female
*Cognitive Dysfunction/cerebrospinal fluid/diagnostic imaging
Biomarkers/cerebrospinal fluid
*Amyloid beta-Peptides/cerebrospinal fluid/metabolism
Aged
*Brain/diagnostic imaging/metabolism
Prognosis
*Alzheimer Disease/cerebrospinal fluid/diagnostic imaging
Longitudinal Studies
Aged, 80 and over

@article {pmid40631427,
year = {2025},
author = {Hu, S and Zhu, P and Gao, S and Wu, S and He, Y and Liu, F and Wang, K and Liu, G},
title = {Self-Report Alzheimer's Disease Statuses in UK Biobank Distort Downstream Analyses.},
journal = {Journal of neurochemistry},
volume = {169},
number = {7},
pages = {e70151},
doi = {10.1111/jnc.70151},
pmid = {40631427},
issn = {1471-4159},
support = {JQ21022//Beijing Municipal Natural Science Foundation/ ; 82471449//National Natural Science Foundation of China/ ; 2023YFC3605200//National Key Research and Development Program of China/ ; 2023YFC3605202//National Key Research and Development Program of China/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics/diagnosis/epidemiology ; United Kingdom/epidemiology ; Genome-Wide Association Study/methods ; *Biological Specimen Banks ; Mendelian Randomization Analysis/methods ; Male ; *Self Report/standards ; Female ; Aged ; Middle Aged ; Polymorphism, Single Nucleotide ; UK Biobank ; },
abstract = {Genetic studies have identified Alzheimer's disease (AD)-linked variants through genome-wide association studies (GWAS) and proxy-based GWAS (GWAX), yet inconsistent causal inferences still persist. Here, we systematically evaluated how self-reported AD diagnoses in the UK Biobank (UKB) distort Mendelian randomization (MR) analyses. Using seven AD datasets (four GWAS and three GWAX, including IGAP, N = 63 926; FinnGen R10, N = 191 061; UKB G30, N = 420 531; UKB2024, N = 434 286, and GWAX2017, N = 74 366; GWAX2018, N = 548 955; GWAX2021, N = 408 691) and six education subtypes (including years of schooling, N = 1 131 881; hardest math class completed, N = 430 445; self-reported math ability, N = 564 698; college completion, N = 280 007; cognition test performance, N = 257 841; and non-cognitive skills, N = 257 841). We also assessed the heterogeneity and pleiotropy across these datasets. We found opposing causal directions between GWAS and GWAX cohorts. In GWAS datasets, genetic variations related to education were causally linked to a lower risk of AD (OR < 1, p < 0.05), with years of schooling showing the strongest protective effects (OR = 0.71 in IGAP, p < 0.05). Conversely, UKB-based GWAX analyses paradoxically linked education-related traits to increased AD risk (OR > 1, p < 0.05), directly conflicting with the protective associations in clinical AD GWAS results. Genetic heterogeneity was observed in both AD GWAS and GWAX datasets. Pleiotropy was noted in AD outcomes, but MR estimates remained stable after outlier adjustments. Our findings reveal that self-reported AD statuses in UKB distorted genetic effect estimates, particularly for education subtypes requiring validation. The research urges caution in interpreting MR results from GWAX studies that use self-reported endpoints and highlights the need for rigorous phenotyping in biobank studies.},
}

Humans
*Alzheimer Disease/genetics/diagnosis/epidemiology
United Kingdom/epidemiology
Genome-Wide Association Study/methods
*Biological Specimen Banks
Mendelian Randomization Analysis/methods
Male
*Self Report/standards
Female
Aged
Middle Aged
Polymorphism, Single Nucleotide
UK Biobank

@article {pmid40631426,
year = {2025},
author = {Behera, DK and Rahut, DB and Tripathy, S},
title = {Alzheimer's disease and dementia in Japan: Epidemiological trends, regional disparities, and future projections.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {7},
pages = {e70444},
doi = {10.1002/alz.70444},
pmid = {40631426},
issn = {1552-5279},
mesh = {Humans ; Japan/epidemiology ; *Alzheimer Disease/epidemiology ; Risk Factors ; Aged ; *Dementia/epidemiology ; Prevalence ; Female ; Forecasting ; Incidence ; Male ; Aged, 80 and over ; Disability-Adjusted Life Years ; Global Burden of Disease/trends ; Life Expectancy ; },
abstract = {INTRODUCTION: Alzheimer's disease and other dementias (ADOD) are a growing public health concern in Japan. This study examines historical ADOD burden trends, identifies contributing risk factors, and forecasts future projections using time-series modeling.

METHODS: This study uses the Global Burden of Disease (GBD) study 2021 data to analyze ADOD trends in Japan, and assess incidence, mortality, and Disability-adjusted life years (DALYs). Regression analysis identifies risk factors, and an Autoregressive Integrated Moving Average (ARIMA) model is employed to forecasts the burden from 2021 to 2030.

RESULTS: ADOD cases have steadily increased, with projections indicating continued growth by 2030. Aging and life expectancy are major contributors, with urban areas like Kantō and Kansai region experiencing higher prevalence than Tōhoku and Kyūshū. High fasting plasma glucose, obesity, and smoking are significant modifiable risk factors. The ARIMA model forecasts an ongoing upward trend, highlighting a rising public health challenge.

DISCUSSION: Targeted policies, early interventions, and equitable health care access are vital to mitigating Japan's growing ADOD burden.

HIGHLIGHTS: Alzheimer's disease and other dementias (ADOD) are rising in Japan due to an aging population. Key risk factors include high fasting plasma glucose, obesity, and smoking. Kantō and Kansai region have higher ADOD prevalence than other region ARIMA modeling predicts a continuous increase in ADOD cases through 2030. Targeted health care policies and preventive measures are crucial to mitigate the burden.},
}

Humans
Japan/epidemiology
*Alzheimer Disease/epidemiology
Risk Factors
Aged
*Dementia/epidemiology
Prevalence
Female
Forecasting
Incidence
Male
Aged, 80 and over
Disability-Adjusted Life Years
Global Burden of Disease/trends
Life Expectancy

@article {pmid40631359,
year = {2025},
author = {Omole, JG and Okon, IA and Udom, GJ and Aziakpono, OM and Agbana, RD and Aturamu, A and Niwamanya, N and Oritsemuelebi, B and Etukudo, EM and Yemitan, OK},
title = {Neurophysiological mechanisms underlying cardiovascular adaptations to exercise: A narrative review.},
journal = {Physiological reports},
volume = {13},
number = {13},
pages = {e70439},
doi = {10.14814/phy2.70439},
pmid = {40631359},
issn = {2051-817X},
mesh = {Humans ; *Exercise/physiology ; *Adaptation, Physiological/physiology ; *Brain/physiology/metabolism ; Animals ; *Cardiovascular System/metabolism ; Neuronal Plasticity ; Brain-Derived Neurotrophic Factor/metabolism ; Neurovascular Coupling ; *Cardiovascular Physiological Phenomena ; *Heart/physiology ; },
abstract = {The brain-heart connection, particularly during physical activity, plays a crucial role in health and disease management. This review examined the neurophysiological mechanisms driving cardiovascular adaptations to exercise, focusing on the bidirectional relationship between the brain and heart. Key mediators such as central autonomic networks, brain-derived neurotrophic factors (BDNF), and vascular endothelial growth factor (VEGF) enhance neural plasticity and vascular health. Regular structured exercise (e.g., high-intensity interval training, moderate and resistance exercise) moderates autonomic responses, increases BDNF, and supports neurovascular coupling, improving both cognitive and cardiovascular resilience through molecular pathways such as PGC-1α and TrkB signaling. Exercise enhances cerebral perfusion, reduces oxidative stress, and protects brain-heart health. It mitigates risks linked to neurodegenerative diseases, such as Alzheimer's and Parkinson's, by promoting neuroplasticity and vascular integrity. This review highlights the importance of incorporating exercise-based interventions in clinical practice and public health policies to optimize cognitive and cardiovascular health. Future studies should explore exercise-induced neurovascular coupling to further elucidate the mechanisms connecting brain and cardiovascular health.},
}

Humans
*Exercise/physiology
*Adaptation, Physiological/physiology
*Brain/physiology/metabolism
Animals
*Cardiovascular System/metabolism
Neuronal Plasticity
Brain-Derived Neurotrophic Factor/metabolism
Neurovascular Coupling
*Cardiovascular Physiological Phenomena
*Heart/physiology

@article {pmid40631275,
year = {2025},
author = {Tutrow, KD and Harkin, J and Varghese, L and Hernandez, M and Huang, KC and Fang, Y and Wilcox, P and Bedford, L and Lin, TY and Zhang, C and Gomes, C and Puntambekar, S and Bissel, S and Lamb, BT and Meyer, JS},
title = {Human induced pluripotent stem cell-derived microglia with a CX3CR1-V249I genetic variant exhibit dysfunctional phenotypes and modulate neuronal growth and function.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.07.01.662163},
pmid = {40631275},
issn = {2692-8205},
abstract = {The involvement of microglia in neurodegenerative diseases has drawn increasing attention, as many genetic risk factors are preferentially expressed in microglia. Microglial fractalkine receptor (CX3CR1) signaling regulates many key microglial functions, and the CX3CR1-V249I single nucleotide polymorphism (SNP) has been associated with increased risk for multiple neurodegenerative conditions, including Alzheimer's disease, yet its functional consequences in human microglia remain unexplored. In this study, we generated iPSC-derived human microglia-like cells (hMGLs) and found that the CX3CR1-V249I variant increased susceptibility to starvation-induced cell death, reduced amyloid-beta uptake, altered microglial morphology, and impaired migration, with more pronounced effects in homozygous cells. Co-culture with neurons demonstrated that hMGLs with the CX3CR1-V249I variant misregulated neuronal properties, including abnormal neuronal growth as well as an induction of neuronal hyperexcitability. These findings highlight the critical role of CX3CR1 in regulating microglial function and implicate the V249I variant in driving pathogenic microglial states relevant to neurodegeneration.},
}

@article {pmid40631238,
year = {2025},
author = {Brisendine, MH and Nieves-Esparcia, DQ and Willoughby, OS and Brown, JR and Braxton, DS and Henry, SN and McCoin, C and Thyfault, JP and Morris, JK and Poelzing, S and Grange, RW and Najt, CP and Drake, JC},
title = {Age-dependent remodeling of the sciatic proteome in 5xFAD mice can be attenuated by exercise or donepezil treatment to maintain neuromuscular function.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.07.01.662603},
pmid = {40631238},
issn = {2692-8205},
abstract = {UNLABELLED: Background: Alzheimer's disease (AD) progresses along a continuum for years to possibly decades prior to cognitive decline and clinical diagnosis. Preclinical AD is associated with neuromuscular dysfunction. We previously characterized early neuromuscular impairment prior to cognitive decline at 4 months of age in the 5xFAD mouse model of AD. However, the underlying cause(s) for peripheral nerve dysfunction leading to impaired skeletal muscle torque production are not understood, therefore limiting interventional capacity. We hypothesized that either voluntary wheel running or donepezil treatment, begun prior to neuromuscular decline, would delay manifestation of neuromuscular impairment in 5xFAD mice. Methods: Sciatic nerves from 5xFAD and wild-type (WT) mice were analyzed by tandem mass tag (TMT)-labeled proteomics at 3, 4, and 7 months to investigate proteome remodeling. Separate cohorts, using 3-month-old 5xFAD mice and WT littermates given voluntary wheel access for 4 weeks or treated with the acetylcholinesterase inhibitor donepezil to test if neuromuscular dysfunction could be attenuated. Afterwards, we assessed tibial nerve stimulated plantar flexion torque and sciatic nerve compound (motor) neuron action potential (CNAP) in-vivo at 4 months. Additionally, we performed TMT-labeled proteomics to ascertain the effect of exercise and donepezil treatments on sciatic proteome. Results: Sciatic nerves in 5xFAD mice exhibited proteomic remodeling from 3 to 4 months, particularly in pathways linked to mitochondrial turnover, calcium handling, lipid metabolism, and inflammation, coinciding with onset of neuromuscular dysfunction. Both exercise and donepezil attenuated in nerve-stimulated muscle torque and CNAP dysfunction. Both exercise and donepezil attenuated proteomic remodeling of the sciatic nerve involving mitochondrial-centric processes through both shared and independent mechanisms. Conclusions: Declines in neuromuscular function may be pre-clinical identifiers for AD that share pathway similarities with noted central effects of the pathology on the brain. Our findings highlight the importance of a systemic approach to AD pathology and importance of disease state in interventional efficacy.

GRAPHICAL ABSTRACT: Created in Biorender.},
}

@article {pmid40631232,
year = {2025},
author = {Yousofvand, R and Handy, G and Tithof, J},
title = {Boundary Homogenization and Numerical Modeling of Solute Transport Across the Blood-Brain Barrier.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.07.01.662658},
pmid = {40631232},
issn = {2692-8205},
abstract = {Effective clearance of amyloid-β (Aβ) from the brain is essential for preventing neurodegenerative diseases such as Alzheimer's. A significant portion of this clearance occurs through the blood-brain barrier (BBB) via receptor-mediated transport. However, current models fail to capture the complex kinetics and spatial heterogeneity of receptors at the BBB. In this study, we derive a novel boundary condition that accounts for finite receptor kinetics, receptor density, and bidirectional transport across the BBB. Specifically, we develop a nonlinear homogenized boundary condition that ensures mass conservation and incorporates receptor-mediated Michaelis-Menten kinetics. We then implement this boundary condition in a cylindrical geometry representing a capillary surrounded by brain tissue. After verifying that the model matches an analytical steady state solution that we derive and that it yields realistic blood Aβ concentrations, we explore how realistic variations in parameter values drive changes in both steady state Aβ concentration and transient dynamics. Simulations and analytical results reveal that Aβ concentrations in the brain are sensitive to receptor number ratios, while concentrations in the blood are primarily affected by the blood clearance rate. Additionally, we use the model to investigate Aβ clearance during sequential sleep cycles and due to a pathological phenomenon, spreading depolarization. This work presents the first biophysically consistent boundary condition for Aβ transport across the BBB, offering a powerful tool for studying brain waste clearance under both physiological and pathological conditions.},
}

@article {pmid40631204,
year = {2025},
author = {O'Toole, HJ and James, A and Nasim, N and Hadley, DJ and Hale, EJ and He, Q and Bein, KJ and Valenzuela, AE and Rojalin, T and Dugger, BN and Wexler, AS and Lein, PJ and Carney, RP},
title = {Spatial and spectral mapping of traffic-related air pollution (TRAP) nanoparticles in relation to plaques and inflammatory markers in an Alzheimer disease model.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.07.01.662638},
pmid = {40631204},
issn = {2692-8205},
abstract = {Chronic exposure to traffic-related air pollution (TRAP) is linked to increased risk of neurodegenerative diseases, including Alzheimer disease (AD). Ultrafine particulate matter (UFPM) is a suspected driver of TRAP neurotoxicity, but its spatial interactions with AD pathology remain poorly defined. We investigated the distribution, composition, and pathological context of TRAP-derived UFPM in the hippocampus of TgF344-AD rats chronically exposed to TRAP or filtered air (FA) for 14 months. Using a multimodal imaging workflow that combines enhanced darkfield hyperspectral imaging (EDF-HSI) with confocal immunofluorescence for microglia (CD68/Iba1) and amyloid beta (Aβ) plaques (Thioflavin S), we mapped the localization and spectral properties of UFPM in situ. UFPM accumulation was elevated in TRAP-exposed females, suggesting sex-specific vulnerability in blood-brain barrier (BBB) permeability or particle retention. Particles near plaques showed red-shifted spectral signatures, consistent with biochemical transformation. Dimension reduction revealed clustering of particle spectra by TRAP exposure and plaque proximity. However, UFPM was rarely found within plaques or microglia, implying indirect neuroimmune modulation. These findings highlight a novel spatial and spectral imaging approach for characterizing environmental nanoparticle interactions in the brain and suggest that chronic TRAP exposure may influence AD-related inflammation and pathology in a sex- and region-dependent manner.},
}

@article {pmid40631171,
year = {2025},
author = {Genner, RM and Meredith, M and Moller, A and Weller, C and Daida, K and Ayuketah, A and Jerez, PA and Akeson, S and Malik, L and Baker, B and Kouam, C and Paquette, K and Marenco, S and Auluck, P and Mandal, A and Paten, B and Reed, X and Jain, M and Cookson, MR and Singleton, AB and Nalls, M and Blauwendraat, C and Billingsley, KJ},
title = {Haplotype-Resolved DNA Methylation at the APOE Locus identifies Allele-Specific Epigenetic Signatures Relevant to Alzheimer's Disease Risk.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.07.01.662592},
pmid = {40631171},
issn = {2692-8205},
abstract = {The APOE gene encodes a key lipid transport protein and plays a central role in Alzheimer's disease (AD) pathogenesis. Three common APOE alleles, ε2 (rs7412(C>T), ε3 (reference), and ε4 (rs429358(T>C)), arise from two coding variants in exon 4 and confer distinct AD risk profiles, with ε4 increasing risk and ε2 providing protection. The ε3-linked APOE variant rs769455[T] has also been associated with elevated AD risk in individuals of African ancestry carrying both rs769455[T] and ε4 alleles. These single nucleotide variants (SNVs) reside in a cytosine-phosphate-guanine (CpG) island, which is a region with a higher frequency of CpG sites compared to the rest of the genome. CpG sites are subject to 5-methylcytosine (5mC) methylation by DNA methyltransferases which add a methyl group to the fifth carbon on the cytosine residue of a CpG site. The presence of SNVs can disrupt this process, making these regions prime targets for differential methylation; however, allele-specific methylation patterns in APOE remain poorly resolved due to technical limitations of conventional bisulfite and methylation array based methods, including degraded DNA quality, sparse CpG coverage, and lack of haplotype phasing. Here, we leverage high-accuracy long-read sequencing data to generate haplotype-resolved methylation profiles of the APOE locus in 332 postmortem brain samples from two ancestrally different cohorts. This includes 201 individuals of European ancestry from the North American Brain Expression Consortium (NABEC), comprising 402 haplotypes (48 ε2 and 58 ε4 alleles), and 131 individuals of African and African admixed ancestry from the Human Brain Core Collection (HBCC), comprising 262 haplotypes (25 ε2, 64 ε4, and 7 rs769455 alleles). A linear regression analysis identified 18 novel differentially methylated CpG sites (DMCs) associated with APOE ε2, ε4, and rs769455 within a gene cluster spanning TOMM40, APOE, APOC1, and APOC4-APOC2 . This represents the most comprehensive haplotype-resolved methylation study of APOE in human brain tissue to date. Our results uncover distinct allele-specific methylation signatures and demonstrate the power of long-read sequencing for resolving epigenetic variation relevant to AD risk.},
}

@article {pmid40630924,
year = {2025},
author = {Li, J and Xu, Y and Balboni, G and Xia, Y},
title = {A new pathway for neuroprotection against tau hyperphosphorylation via δ-opioid receptor initiated inhibition of CDK5 and AMPK signaling.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1587219},
pmid = {40630924},
issn = {1663-4365},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by decreased memory and cognitive impairment. Abnormal tau hyperphosphorylation ultimately forms neurofibrillary tangles, which is one of the most important pathological features of AD. Since we have previously shown that the δ-opioid receptor (DOR) is neuroprotective in the brain, we asked if DOR plays any role in the control of tauopathy.

METHODS: In the PC12 cell model with okadaic acid-induced tau hyperphosphorylation, cell viability and cytotoxicity were evaluated by using CCK8 assay kit and lactate dehydrogenase cytotoxicity assay kit. The techniques of western blot and immunofluorescence were used to investigate the effect of DOR on tau hyperphosphorylation.

RESULTS: We found that DOR activation inhibited okadaic acid-induced tau hyperphosphorylation in PC12 cells and attenuated the cell cycle reactivation and apoptosis. The DOR effect was blocked by Naltrindole, a DOR antagonist. Furthermore, the mechanistic studies showed that the DOR displayed its effect by reducing the expression of cyclin-dependent kinase (CDK) 5 and AMP-activated protein kinase (AMPK) in the model of tauopathy.

DISCUSSION: Our novel findings suggest that DOR signaling may protect neurons from AD injury by inhibiting tau hyperphosphorylation.},
}

@article {pmid40630923,
year = {2025},
author = {Pascuzzo, R and Palesi, F and Wan, YM and Cazzaniga, FA},
title = {Editorial: A comprehensive look at biomarkers in neurodegenerative diseases: from early diagnosis to treatment response assessment.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1642793},
pmid = {40630923},
issn = {1663-4365},
}