@article {pmid41409494,
year = {2025},
author = {Ivanic, S and Vogel, AP and Chatterjee, P and Baird, J and Darby, D and Werden, E and Gao, L and Darzins, P and Patel, SK and Burke, I and Morris, T and Churilov, L and Bice, J and Mielke, MM and Brodtmann, A},
title = {Neurofilament light chain and voice acoustics in dementia diagnosis (NAVAIDD): Protocol for a cohort study assessing the real-world diagnostic utility of blood and digital biomarkers in clinical settings.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251395325},
pmid = {41409494},
issn = {2542-4823},
abstract = {BACKGROUND: The advent of disease modifying therapies for dementia has highlighted the need for simple, accessible and low-cost diagnostic tests. Blood and digital biomarkers increase accuracy in highly selected research populations. However, their real-world applicability for diverse clinical populations remains unknown.

OBJECTIVE: We will investigate the utility of plasma neurofilament light chain (NfL) and voice acoustic analysis in a multi-ethnic and multi-lingual population. We hypothesise that NfL and voice acoustic biomarkers will discriminate between individuals with a neurodegenerative diagnosis and those with non-neurodegenerative causes; abnormal biomarker findings will have high prognostic validity for clinical progression; and shorten the time to diagnosis and reduce costs.

METHODS: All adults presenting with a cognitive concern to outpatient and inpatient settings at a community-based healthcare network in Melbourne, Australia are eligible to participate. Plasma NfL and speech sample recordings are performed at baseline and functional status (modified Rankin Scale) is recorded. Clinical diagnostic consensus meetings are convened wherein baseline diagnostic class (neurodegenerative vs non-neurodegenerative), syndrome (diagnosis), and certainty (low, moderate, high) are confirmed with the clinician prior to and following disclosure of NfL to examine effect on clinical decision-making. Participants complete cognitive, functional and mood screens and speech sampling via 12-month follow-up phone call.

DISCUSSION: Blood and digital biomarkers are transforming the landscape of dementia diagnosis. Our study design allowing inclusion of people from diverse linguistic, cultural and racial backgrounds offers an opportunity to evaluate the utility of NfL and speech markers in real-world clinical settings.

TRIAL REGISTRATION: https//www.clinicaltrials.gov (NCT06339190), Apr 2024.},
}

@article {pmid41409326,
year = {2025},
author = {Ansari, AS and Mohammadi, MS and Cattani, C and Tassaddiq, A},
title = {An advanced multimodal image fusion model for accurate detection of Alzheimer's disease using MRI and PET.},
journal = {Frontiers in medical technology},
volume = {7},
number = {},
pages = {1699821},
pmid = {41409326},
issn = {2673-3129},
abstract = {The accurate detection of Alzheimer's disease (AD), a progressive and irreversible neurodegenerative disorder, remains a critical challenge in clinical neuroscience. The research aims to develop an advanced multimodal image fusion model for the accurate detection of AD using positron emission tomography (PET) and magnetic resonance imaging (MRI) techniques. The proposed method leverages structural MRI and functional 18-fluorodeoxyglucose PET (FDG-PET) information derived from the Alzheimer's Disease Neuroimaging Initiative (ADNI). After preprocessing, including Gaussian filtering, skull stripping, and intensity normalization, voxel-based morphometry (VBM) is applied to extract gray matter (GM) features relevant to AD progression. A GM mask generated from MRI is used to isolate corresponding metabolic activity in the PET scans. These features are then integrated using a mask-coding strategy to construct a unified representation that captures both anatomical and functional characteristics. For classification, the model introduces a Glowworm Swarm-Optimized Spatial Multimodal Attention-Enriched Convolutional Neural Network (GWS-SMAtt-ECNN), where the optimization enhances both feature selection and network parameter tuning. The Python was implemented, and the result demonstrates that the proposed multimodal image fusion strategy outperforms traditional unimodal and basic fusion approaches in terms of F1-score (94.22%), recall (96.73%), and accuracy (98.70%). These results highlight the therapeutic usefulness of the suggested improved fusion architecture in facilitating immediate and accurate AD detection by MRI and PET.},
}

@article {pmid41409156,
year = {2025},
author = {Liu, Y and Zhang, Z and Qiu, M and Wang, S and Salim, FD and Shen, J and Chen, T and Razzak, I and Bian, J},
title = {GatorSC: Multi-Scale Cell and Gene Graphs with Mixture-of-Experts Fusion for Single-Cell Transcriptomics.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2025.12.03.691688},
pmid = {41409156},
issn = {2692-8205},
abstract = {Single-cell RNA sequencing (scRNA-seq) enables high-resolution characterization of cellular heterogeneity, but its rich, complementary structure across cells and genes remains underexploited, especially in the presence of technical noise and sparsity. Effectively leveraging this multi-scale structure is essentially an information fusion problem that requires integrating heterogeneous graph-based views of cells and genes into robust low-dimensional representations. In this paper, we introduce GatorSC , a unified representation learning framework that models scRNA-seq data through multi-scale cell and gene graphs and fuses them with a Mixture-of-Experts architecture. GatorSC constructs a global cell-cell graph, a global gene-gene graph, and a local gene-gene graph derived from neighborhood-specific subgraphs, and learns graph neural network embeddings that are adaptively fused by a gating network. To learn noise-robust and structure-preserving embeddings without labels, we couple graph reconstruction and graph contrastive learning in a unified self-supervised objective applied to both cell- and gene-level graphs. We evaluate GatorSC on 19 publicly available scRNA-seq datasets covering diverse tissues, species, and sequencing platforms. Across 14 benchmark datasets, GatorSC consistently outperforms state-of-the-art deep generative, graph-based, and contrastive methods for cell clustering, gene expression imputation, and cell-type annotation. The learned embeddings are used for accurate trajectory inference, recovery of canonical marker gene programs, and cell-type-specific pathway signatures in an Alzheimer's disease singlenucleus dataset. GatorSC provides a flexible foundation for comprehensive single-cell transcriptomic analysis and can be readily extended to multi-omic and spatial modalities.},
}

@article {pmid41409143,
year = {2025},
author = {Kim, MJ and Blumenfeld, J and Li, Y and Yip, O and Yao, L and Ancheta, S and De Leon, S and Platow, Z and Liang, Z and Shostak, D and Suan, K and Hao, Y and Koutsodendris, N and Ellis, C and Nguyen, J and Huang, Y},
title = {Neuronal APOE4 drives damaging lipid accumulation via contact-dependent neuron-oligodendrocyte-microglia interaction in Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2025.12.04.692390},
pmid = {41409143},
issn = {2692-8205},
abstract = {Apolipoprotein E4 (APOE4) confers the greatest genetic risk for developing Alzheimer's disease (AD). With APOE4 broadly expressed in the brain, its cell-type-specific roles in AD pathogenesis are only beginning to be defined. Here, we show that neuronal APOE4 expression drives damaging lipid accumulation in hippocampal neurons, oligodendrocytes, and microglia, with preferential buildup of peroxidized lipids in microglia in a tauopathy mouse model. Neuron-specific removal of APOE4 abolished this lipid phenotype, whereas neuron-specific expression of APOE4 was sufficient to recapitulate it, demonstrating that neuronal APOE4 is both necessary and sufficient for lipid accumulation. Strikingly, the association between lipid burden, microgliosis, and neurodegeneration was strongest in mice with neuron-specific APOE4 expression. Single-nucleus RNA sequencing revealed neuronal APOE4-vulnerable neuron populations, as well as enrichment of disease-associated microglia and oligodendrocytes, all promoting lipid pathology. Primary mouse co-culture experiments showed that neuronal APOE4 drives microglial lipid accumulation via contact-dependent mechanisms involving uptake of lipids from neurons and oligodendrocytes. These findings establish neuronal APOE4 as a key driver of lipid accumulation via neuron-oligodendrocyte-microglia interactions, providing mechanistic insight into APOE4-driven lipid pathology in AD.},
}

@article {pmid41408986,
year = {2025},
author = {Liu, C and Ene, J and Lu, W and Syed, F and Sun, L and Raulin, AC and Ren, Y and Wang, X and Kanekiyo, T and Li, Y},
title = {Immuno-Regulation of Brain Region-Specific Organoids Containing Isogenic Microglia-Like Cells.},
journal = {Advanced healthcare materials},
volume = {},
number = {},
pages = {e03579},
doi = {10.1002/adhm.202503579},
pmid = {41408986},
issn = {2192-2659},
support = {2017869//NSF/ ; R01NS125016//Foundation for the National Institutes of Health/ ; R21EB033495//Foundation for the National Institutes of Health/ ; },
abstract = {Most brain organoids derived from human induced pluripotent stem cells (iPSCs) lack microglia and thus immune function. Microglia-like cells (MGCs) can be differentiated from iPSCs, while the characteristics of isogenic MGC-containing brain organoids in modeling neurodegeneration and cell-cell communications have not been well investigated. In this study, iPSC-derived MGCs are co-cultured with isogenic forebrain cortical organoids (iFCo), which are stimulated with extracellular vesicles (EVs) of brain organoids differentiated from Alzheimer's disease (AD) patient-derived iPSCs (APOE ε4/ε4 and presenilin 1). The AD EV-stimulated co-culture organoids are treated with EVs from healthy MGCs or co-culture. Differential responses of the co-cultured organoids and the MGCs to AD EVs are demonstrated. The co-cultured organoids mitigated pro-inflammatory gene expressions. EVs from healthy MGCs or co-culture reduced the expression of IL-12β, iNOS, TREM2, and CASS4, which are associated with neural inflammation and degeneration, as well as showed regulation on genes involved in microglial activation and carbon metabolism. AD EV cargo analysis by proteomics and microRNA-sequencing revealed APOE and APP proteins and microRNAs regulated pathways such as mitophagy. This study paves the way for understanding the role of microglia and brain organoids in modeling neural degeneration and the development of EV-based cell-free therapeutics for AD treatment.},
}

@article {pmid41408807,
year = {2025},
author = {Besli, N and Ercin, N and Carmena-Bargueño, M and Pérez-Sánchez, H and Celik, U},
title = {Interpreting the Conformational Dynamics Over Interaction of FAM222A Protein with Amyloid-Beta Peptides.},
journal = {Acta chimica Slovenica},
volume = {72},
number = {4},
pages = {831-845},
doi = {10.17344/acsi.2025.9340},
pmid = {41408807},
issn = {1580-3155},
mesh = {*Amyloid beta-Peptides/chemistry/metabolism ; Molecular Dynamics Simulation ; Protein Binding ; Molecular Docking Simulation ; Humans ; *Peptide Fragments/chemistry/metabolism ; Protein Conformation ; },
abstract = {Alzheimer's disease (AD), a neurological disorder with increasing prevalence worldwide, presents a significant challenge to the medical community. The molecular mechanism underpinning its neuropathology is still wholly unexplained. Recent investigations have focused on the role of the protein aggregatin (AP), encoded by FAM222A, in amyloid-beta (Aβ) aggregation via its N-terminal Aβ binding domain. The current study aims to characterize the interaction mechanisms between the AP and Aβ (1-42 and 1-28) peptides using all-atom molecular dynamics (MD) simulations. The objective is to assess whether AP is a stabilizing scaffold in Aβ peptide aggregation, validate docking outcomes from previous studies, and compare the stability and interaction profiles of different Aβ isoforms. Aβ (1-42, 1-28) peptides were converted from the α-helix to the β-sheet form to inquire better-docked formation with the AP. The selected docking poses from our previous study and the four top scoring from HADDOCK were implemented in MD simulations, resulting in relatively stable complexes as indicated by consistent RMSD/RMSF trends without major structural disruptions. However, no binding free energy or interaction network analysis was conducted, and the conclusions are thus limited to structural stability observations. Our calculations hold accurate points for further experimental AD research on designing and developing the relevant protein-peptide interactions.},
}

*Amyloid beta-Peptides/chemistry/metabolism
Molecular Dynamics Simulation
Protein Binding
Molecular Docking Simulation
Humans
*Peptide Fragments/chemistry/metabolism
Protein Conformation

@article {pmid41408633,
year = {2025},
author = {Lorenzon, G and Marseglia, A and Poulakis, K and Imbimbo, C and Rydén, L and Galaris, E and Lindberg, O and Shams, S and Mohanty, R and Ferreira, D and Kivipelto, M and Eriksdotter, M and Kern, S and Skoog, I and Westman, E},
title = {Risk and protective factors associated with brain grey matter patterns in a population-based cohort of cognitively unimpaired 70 years old.},
journal = {BMC medicine},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12916-025-04583-0},
pmid = {41408633},
issn = {1741-7015},
abstract = {BACKGROUND: Ageing involves heterogeneous brain grey matter (GM) patterns that may overlap with dementia-related changes. We evaluated cognitively unimpaired older adults to identify specific GM patterns, their clinical and cognitive profiles, and longitudinal trajectories.

METHODS: We analysed 746 participants from the Gothenburg H70 study using random forest cross-sectional clustering based on MRI measures of cortical thickness and subcortical volume across 41 regions. Using regression-based models, we examined associations with clinical, MRI variables, biochemical, and CSF Alzheimer biomarkers (n = 286) and assessed 5-year longitudinal cognitive and brain trajectories.

RESULTS: Five clusters emerged, mainly differing in frontoparietal regions. Compared to Cluster 1 (reference), Cluster 2 showed diffuse GM loss, higher odds of diabetes (OR = 2.54, 95% CI [1.27-5.06]) and at-risk alcohol consumption (OR = 1.83, 95% CI [1.13-2.97]), poorer episodic memory (β =  - 0.19, p = 0.014) and visuospatial abilities (β =  - 0.21, p = 0.044), and greater longitudinal decline in MMSE (βslope =  - 0.45, p = 0.035) and increase in white matter hyperintensity volume (βslope = 1.84, p = 0.004). Cluster 3 showed thicker GM and lower BMI (OR = 0.57, 95% CI [0.35-0.94]). Cluster 4 had preserved GM, lower smoking habits (OR = 0.62, 95% CI [0.40-0.95]), triglyceride levels (OR = 0.55, 95% CI [0.32-0.95]) and depression (OR = 0.17, 95% CI [0.05-0.56]), higher education (OR = 2.52, 95% CI [1.08-5.87]), and better cognition in multiple domains. Cluster 5 had a mixed GM pattern and higher odds of heart disease (OR = 3.44, 95% CI [1.48-8.01]).

CONCLUSIONS: Cardiovascular and psychosocial factors influence GM integrity, which in turn relates to cognition. Targeting these risk factors may preserve brain health in late life.},
}

@article {pmid41408566,
year = {2025},
author = {Shabana, S and Hamouda, HI and Shang, A and Shao, S and Zhao, J and Yuan, H and Liu, B},
title = {Recent molecular insights and biosensor-based diagnostic technologies for hyperphosphorylated Tau in Alzheimer's disease.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-025-01932-2},
pmid = {41408566},
issn = {1758-9193},
support = {No. 2023JJ11CG005//Dalian Major Basic Research Projects/ ; },
abstract = {Tau pathology is a defining feature of Alzheimer's disease (AD), with hyperphosphorylated Tau (p‑Tau) emerging as a central biomarker for early diagnosis and disease monitoring. Various p‑Tau epitopes have demonstrated superior diagnostic precision and now form the molecular basis of updated AD diagnostic frameworks. Classical immunoassays such as enzyme-linked immunosorbent assay (ELISA), chemiluminescent enzyme immunoassay (CLEIA), and single molecule array (SIMOA) remain central to fluid based detection, offering high sensitivity and clinical validation. Recent advances in tau biology, especially in post-translational modifications, have driven the development of next generation biosensors. Electrochemical, optical, and nanostructured platforms now enable real-time, label-free, and attomolar level detection of p‑Tau in biofluids and live cell models. These systems are increasingly portable and suitable for point of care or in vivo applications. This review highlights the evolution of p‑Tau detection technologies, from benchmark immunoassays to cutting edge biosensors. Special attention is given to advanced affinity reagents, including aptamers, synthetic peptides, and antibody mimetics, which enhance biosensor specificity, stability, and translational potential. Together, these innovations are redefining AD diagnostics, enabling early intervention and more effective disease monitoring.},
}

@article {pmid41408481,
year = {2025},
author = {Eimer, WA and Rodriguez, AS and DeFao, MT and Ehricke, S and Park, J and Vijaya Kumar, DK and Navalpur Shanmugam, NK and Singh, S and Sawhney, T and Moir, RD and Tanzi, RE},
title = {Phosphorylated tau exhibits antimicrobial activity capable of neutralizing herpes simplex virus 1 infectivity in human neurons.},
journal = {Nature neuroscience},
volume = {},
number = {},
pages = {},
pmid = {41408481},
issn = {1546-1726},
support = {1R01AG061035-01//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; },
abstract = {Tau is a microtubule-associated cytoskeletal protein, which, when hyperphosphorylated and aggregated, can result in a myriad of different tauopathies, including Alzheimer's disease (AD). We previously showed that the principal component of senile plaques, amyloid beta (Aβ), is an antimicrobial peptide capable of binding and entrapping microbial pathogens. Here we show that tau is hyperphosphorylated in neurons in response to viral infection and can neutralize herpes simplex virus 1 (HSV-1) infectivity by directly binding to viral capsids. Our data suggest that the 'pathogenic' characteristics of tau hyperphosphorylation, microtubule destabilization and aggregation are part of an antiviral response, in which tau serves as a host defense protein in the innate immune system of the brain. The combined antimicrobial activities of Aβ and phosphorylated tau resulting in Aβ plaques and neurofibrillary tangles, along with neuroinflammation, suggest that AD neuropathology may have evolved as an orchestrated innate immune host defense response to microbial infection in the brain.},
}

@article {pmid41408378,
year = {2025},
author = {Neuharth, JI and Hernandez, KS and Bernholtz, J and Edwards, H and Stewart, A},
title = {Consideration of sex as a biological variable over the history of the 5xFAD Alzheimer's Disease mouse model.},
journal = {Biology of sex differences},
volume = {16},
number = {1},
pages = {105},
pmid = {41408378},
issn = {2042-6410},
support = {NIH T32NS007421/NH/NIH HHS/United States ; Lulu Merle Johnson Recruitment Fellowship//University of Iowa/ ; },
mesh = {Animals ; *Alzheimer Disease ; Disease Models, Animal ; Male ; Female ; Mice ; Mice, Transgenic ; *Sex Characteristics ; },
abstract = {BACKGROUND: Women are nearly twice as likely to be diagnosed with Alzheimer's Disease (AD) over their lifetime. However, historically, preclinical studies utilizing AD rodent models to define new therapeutic targets in AD treatment have neglected to consider the confounding influence of subject sex leading to a lack of mechanistic insight into the biological underpinnings of sex bias in AD.

METHODS: Here, we tracked choice of subject sex over the twenty-year history of the 5xFAD mouse, one of the most frequently cited pre-clinical AD models. We analyzed 1,330 primary research articles indexed on PubMed and recorded information provided regarding subject sex and/or as a rationale for not including datasets separated by sex, if noted. Trends were then plotted as a function of time ending in December 2024.

RESULTS: In the last 15 years, the number of published manuscripts on the 5xFAD model omitting information on subject sex has progressively declined. However, the proportion of studies utilizing either males only (29%) or combining data from both sexes (24%) far surpasses studies acknowledging sex as a biological variable (SABV) (< 12%) with no significant changes noted over time. On average, the ratio of male only: female only studies of 5xFAD mice hovered around 2:1. The most frequently cited reason for omitting sex-based analyses was either a lack of sex differences found (29%), accelerated development of plaque burden in 5xFAD females (17%), or the possibility of within- or between-sex variability (15%). Mention of SABV has steadily increased in studies utilizing 5xFAD mice peaking at ~ 30% of manuscripts published in 2024. However, two key confounds in the 5xFAD model, including the potential impact of an estrogen response element (ERE) and parental imprinting in the Thy1 promoter driving transgene expression, have been largely ignored.

CONCLUSIONS: The 5xFAD model represents a compelling example of how neglecting to recognize the impact of biological sex on neural function can compromise study design and data interpretation. Given sex-dependent Thy1 promoter regulation may skew phenotypic outcomes, investigators should judiciously interpret sex differences observed in any AD mouse utilizing the Thy1 promoter to drive transgene expression.},
}

Animals
*Alzheimer Disease
Disease Models, Animal
Male
Female
Mice
Mice, Transgenic
*Sex Characteristics

@article {pmid41408128,
year = {2025},
author = {Sharma, R and Acharya, V},
title = {Lightweight Vision Transformer with transfer learning for interpretable Alzheimer's disease severity assessment.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {44028},
pmid = {41408128},
issn = {2045-2322},
mesh = {*Alzheimer Disease/diagnostic imaging/diagnosis/pathology ; Humans ; *Magnetic Resonance Imaging/methods ; *Deep Learning ; Neural Networks, Computer ; Severity of Illness Index ; *Image Interpretation, Computer-Assisted/methods ; },
abstract = {Early and reliable diagnostic tools are critical for slowing the progression of Alzheimer's disease (AD), a neurodegenerative disorder characterized by memory loss and cognitive decline. This study introduces, ViTTL, lightweight deep learning framework for assessing the severity of AD using MRI data. ViTTL integrates Vision Transformers (ViT) with pre-trained convolutional neural networks utilized in transfer learning mode, to extract informative features from 2D MRI slices. Among the evaluated combinations, the ViT-DenseNet201 model integrated with an artificial neural network (ANN) classifier achieved the highest classification accuracy (99.89%) on the OASIS dataset. To ensure interpretability, we incorporated LIME and GRAD-CAM method, which consistently focus on cortical and hippocampal regions known to be associated with Alzheimer's pathology. The average Dice similarity coefficient across runs was 0.85 with a standard deviation of 0.03, indicating high consistency in the model's focus regions against ground truth annotations by expert radiologists. ViTTL also achieved a substantial reduction in model size from 83.0 MB to 6.47 MB enabling deployment in resource-limited environments without compromising performance. Validation on an independent dataset (Kaggle) and comparative performance analysis against state-of-the-art methods further support the robustness and generalizability. These findings demonstrate that ViTTL is a promising tool for accurate, interpretable, and resource-efficient AD diagnosis, with strong potential for clinical translation and patient outcome improvement. The related codes are available at https://github.com/RuhikaSharma/enhanced-alzheimer-risk-assessment .},
}

*Alzheimer Disease/diagnostic imaging/diagnosis/pathology
Humans
*Magnetic Resonance Imaging/methods
*Deep Learning
Neural Networks, Computer
Severity of Illness Index
*Image Interpretation, Computer-Assisted/methods

@article {pmid41408121,
year = {2025},
author = {Lee, JW and Kim, S and Kim, S and Um, YH and Wang, SM and Kim, T and Kim, D and Lim, HK and Lee, CU and Kang, DW},
title = {Alzheimer-related individual factors modulate effects of transcranial direct current stimulation strength on white matter integrity in mild cognitive impairment.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {43985},
pmid = {41408121},
issn = {2045-2322},
support = {HI22C0467//the Korea Health Technology R&D Project through the Korea Health Industry Development Institute/ ; HI22C0467//the Korea Health Technology R&D Project through the Korea Health Industry Development Institute/ ; 2019R1C1C1007608//National Research Foundation of Korea/ ; },
mesh = {Humans ; *Cognitive Dysfunction/therapy/diagnostic imaging/pathology/physiopathology ; *White Matter/diagnostic imaging/pathology/physiopathology ; *Transcranial Direct Current Stimulation/methods ; Male ; Female ; Aged ; *Alzheimer Disease/diagnostic imaging/therapy/pathology/genetics/physiopathology ; Diffusion Tensor Imaging ; Middle Aged ; Prospective Studies ; Apolipoprotein E4/genetics ; Magnetic Resonance Imaging ; Brain-Derived Neurotrophic Factor/genetics ; },
abstract = {Transcranial direct current stimulation (tDCS) is a promising non-invasive intervention for mild cognitive impairment (MCI). This prospective study investigated the relationship between optimized electrical field (EF) strength of tDCS and white matter (WM) microstructural changes in 55 individuals with MCI. Magnetic resonance imaging (MRI)-based computational modeling was used to optimize EF strength targeting the left dorsolateral prefrontal cortex (DLPFC). Diffusion tensor imaging (DTI) assessed WM integrity through fractional anisotropy (FA), mean diffusivity (MD), and radial diffusivity (RD). Higher EF strength was significantly associated with increased FA and reduced MD and RD in specific left-lateralized tracts, including the anterior thalamic radiation, corticospinal tract, inferior fronto-occipital fasciculus, and inferior longitudinal fasciculus. These EF-dependent WM changes were moderated by Alzheimer's disease (AD)-related factors. Greater WM plasticity was observed in Aβ-positive individuals, APOE ε4 non-carriers, and BDNF Met non-carriers. Moreover, APOE ε4 status significantly moderated the relationship between EF strength and executive function; in non-carriers, stronger EF strength was associated with improved Stroop performance, potentially reflecting enhanced WM integrity in the right superior longitudinal fasciculus. However, no significant associations were observed between EF-sensitive tracts and short-term cognitive changes in the full sample, suggesting that structural modifications may precede functional improvements or require longer follow-up. These findings emphasize the importance of individual AD-related factors in shaping neuromodulatory responses. They also support the need for longitudinal, sham-controlled studies to clarify the clinical implications of EF strength in personalized tDCS for MCI.},
}

Humans
*Cognitive Dysfunction/therapy/diagnostic imaging/pathology/physiopathology
*White Matter/diagnostic imaging/pathology/physiopathology
*Transcranial Direct Current Stimulation/methods
Male
Female
Aged
*Alzheimer Disease/diagnostic imaging/therapy/pathology/genetics/physiopathology
Diffusion Tensor Imaging
Middle Aged
Prospective Studies
Apolipoprotein E4/genetics
Magnetic Resonance Imaging
Brain-Derived Neurotrophic Factor/genetics

@article {pmid41408021,
year = {2025},
author = {Kaur, K and Kulkarni, YA and Wairkar, S},
title = {Improved Oral Bioavailability and Brain Distribution of Hesperidin via Cochleate Formulation: Statistical Optimization and Pharmacokinetic Study.},
journal = {AAPS PharmSciTech},
volume = {27},
number = {1},
pages = {59},
pmid = {41408021},
issn = {1530-9932},
mesh = {*Hesperidin/pharmacokinetics/administration & dosage/chemistry ; Animals ; Biological Availability ; Rats, Wistar ; Administration, Oral ; Liposomes/chemistry ; Rats ; *Brain/metabolism ; Male ; Particle Size ; Chemistry, Pharmaceutical/methods ; Solubility ; Tissue Distribution ; Drug Liberation ; },
abstract = {Hesperidin, a flavanone, exhibits antioxidant, anti-inflammatory, and anti-amyloidogenic properties, making it a promising candidate for the treatment of Alzheimer's disease. The hesperidin possesses poor solubility, and its oral bioavailability is < 20%. Therefore, hesperidin cochleates (HC) were prepared using the trapping method of calcium ions into preformed liposomes to improve oral bioavailability. The HC formulation was statistically optimized by applying a 3-level factorial design. Optimum cochleates were observed, with an average particle size of 398.9 nm, a zeta potential of -39.1 mV, and an entrapment efficiency of 92.2%, respectively. The in vitro release of hesperidin from cochleates (Batch 15) was 97% in phosphate buffer at pH 7.4 after 24 h. The HC formulation exhibited a 1% release at a gastric pH of 1.2, indicating its stability in the stomach, allowing the formulation to reach the absorption site. In Wistar rats, a comparative pharmacokinetic study was conducted between hesperidin liposomes and HC. Hesperidin concentration was 2.21-fold higher in plasma and 1.2-fold higher in the brain after cochleates administration than in the liposomal formulation and more than 25-fold greater than plain API. Thus, cochleates may be superior oral carriers for hesperidin, improving its oral bioavailability for the treatment of Alzheimer's disease.},
}

*Hesperidin/pharmacokinetics/administration & dosage/chemistry
Animals
Biological Availability
Rats, Wistar
Administration, Oral
Liposomes/chemistry
Rats
*Brain/metabolism
Male
Particle Size
Chemistry, Pharmaceutical/methods
Solubility
Tissue Distribution
Drug Liberation

@article {pmid41407958,
year = {2025},
author = {Mullard, A},
title = {How common is Alzheimer's? Blood-test study holds surprises.},
journal = {Nature},
volume = {},
number = {},
pages = {},
pmid = {41407958},
issn = {1476-4687},
}

@article {pmid41407938,
year = {2025},
author = {Kalia, V and Reyes-Dumeyer, D and Dubey, S and Udhani, H and Nandakumar, R and Lee, AJ and Lantigua, R and Medrano, M and Rivera, D and Honig, LS and Mayeux, R and Miller, GW and Vardarajan, BN},
title = {Lysophosphatidylcholines are associated with amyloidosis in early stages of Alzheimer's disease.},
journal = {Nature aging},
volume = {},
number = {},
pages = {},
pmid = {41407938},
issn = {2662-8465},
support = {R56AG063908, R01AG067501, RF1AG015473, R01AG072474, R01AG066107//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R56AG063908, R01AG067501, RF1AG015473, R01AG072474, R01AG066107//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG067501//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG067501//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG067501//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG067501//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R56AG063908, R01AG067501, RF1AG015473, R01AG072474, R01AG066107//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R56AG063908, R01AG067501, RF1AG015473, R01AG072474, R01AG066107//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R56AG063908, R01AG067501, RF1AG015473, R01AG072474, R01AG066107//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; 5UL1TR001873//U.S. Department of Health & Human Services | NIH | National Center for Advancing Translational Sciences (NCATS)/ ; 5UL1TR001873//U.S. Department of Health & Human Services | NIH | National Center for Advancing Translational Sciences (NCATS)/ ; 5UL1TR001873//U.S. Department of Health & Human Services | NIH | National Center for Advancing Translational Sciences (NCATS)/ ; 5UL1TR001873//U.S. Department of Health & Human Services | NIH | National Center for Advancing Translational Sciences (NCATS)/ ; 5UL1TR001873//U.S. Department of Health & Human Services | NIH | National Center for Advancing Translational Sciences (NCATS)/ ; },
abstract = {Circulating metabolites can identify biochemical risk factors related to Alzheimer's disease (AD). We measured plasma metabolites in 1,068 participants of Caribbean Hispanic ancestry (250 patients with AD and 818 healthy controls) across 2 cohorts and analyzed their relationship with clinical AD, biomarker-supported AD and plasma biomarkers (P-tau181, P-tau217, P-tau231 and Aβ42:Aβ40). Amino acid metabolism pathways were enriched among metabolites associated with P-tau biomarkers, whereas sialic acid and N-glycan pathways were associated with Aβ42:Aβ40. Through several dimensionality reduction approaches, we identified an APOE-ε4 dependent relationship between lysophosphatidylcholines (lysoPCs) carrying polyunsaturated fatty acids and biomarker-supported AD and P-tau biomarkers. In an independent dataset of 110 postmortem brain tissues from non-Hispanic white participants, lysoPCs in the brain were also associated with AD neuropathological features. Our results show that biomarker-based diagnostic criteria identified an APOE-ε4 dependent association with lysoPCs, which play a critical role in the transport of neuroprotective polyunsaturated fatty acids into the brain, and AD.},
}

@article {pmid41407852,
year = {2025},
author = {Aarsland, D and Sunde, AL and Tovar-Rios, DA and Leuzy, A and Fladby, T and Zetterberg, H and Blennow, K and Tan, K and De Santis, G and Yakoub, Y and Arslan, B and Huber, H and Pola, I and Grötschel, L and Di Molfetta, G and Skjellegrind, HK and Selbaek, G and Ashton, NJ},
title = {Prevalence of Alzheimer's disease pathology in the community.},
journal = {Nature},
volume = {},
number = {},
pages = {},
pmid = {41407852},
issn = {1476-4687},
abstract = {The prevalence of Alzheimer's disease neuropathological changes (ADNCs), the leading cause of cognitive impairment, remains uncertain. Recent blood-based biomarkers enable scalable assessment of ADNCs[1]. Here we measured phosphorylated tau at threonine 217 in 11,486 plasma samples from a Norwegian population-based cohort of individuals over 57 years of age as a surrogate marker for ADNCs. The estimated prevalence of ADNCs increased with age, from less than 8% in people 58-69.9 years of age to 65.2% in those over 90 years of age. Among participants aged 70 years or older, 10% had preclinical Alzheimer's disease, 10.4% had prodromal Alzheimer's disease and 9.8% had Alzheimer's disease dementia. Furthermore, among those 70 years of age or older, ADNCs were present in 60% of people with dementia, in 32.6% of those with mild cognitive impairment and in 23.5% of the cognitively unimpaired group. Our findings suggest a higher prevalence of Alzheimer's disease dementia in older individuals and a lower prevalence of preclinical Alzheimer's disease in younger groups than previously estimated[2].},
}

@article {pmid41407844,
year = {2025},
author = {Rabiei Rad, A and Nadaki, A and Khosravi, F and Nasiri, H and Ghayourvahdat, A and , },
title = {Plasma p-tau217 and p-tau217/Aβ1-42 ratios associate with medial temporal lobe subfield atrophy in normal aging and mild cognitive impairment.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-025-32404-0},
pmid = {41407844},
issn = {2045-2322},
abstract = {Early diagnosis of Alzheimer's disease (AD), particularly during its preclinical and prodromal phases, remains a major challenge. Plasma biomarkers such as phosphorylated tau at threonine 217 (p-tau217), amyloid-β (Aβ) isoforms, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) show promise for early detection; however, their relationships with medial temporal lobe (MTL) subfield atrophy and potential inter-biomarker pathways remain unclear. This study aimed to address this gap by investigating the associations between plasma biomarkers and MTL subfield atrophy, and by assessing potential mediation pathways. We conducted a cross-sectional study using data from 330 participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI), including cognitively normal (CN) and mild cognitive impairment (MCI) groups. High-resolution coronal T2-weighted MRI quantified MTL subfield volumes using the ASHS protocol. Plasma biomarkers were measured using ultrasensitive immunoassays. The cohort included 209 CN participants (mean age [SD] = 69.3 [6.9] years; 64.2% women; 24.4% APOE ε4 carriers) and 121 MCI participants (mean age [SD] = 71.3 [7.3] years; 48.8% women; 27.9% APOE ε4 carriers). MCI individuals showed significantly higher plasma concentrations of p-tau217, p-tau217/Aβ1-42 ratio, NfL, and GFAP, and greater MTL atrophy. Higher plasma p-tau217 and p-tau217/Aβ1-42 were associated with reduced bilateral hippocampal and CA1 volumes in MCI (β = - 0.37 to - 0.28; FDR p < 0.02). In CN, these biomarkers were positively associated with left hippocampal volume (β ≈ 0.19; FDR p = 0.04), and GFAP correlated with larger sulcal volume (FDR p = 0.03). Mediation analysis demonstrated that in CN individuals, the relationship between p-tau217/Aβ1-42 and left sulcal volume was partially mediated by GFAP (indirect β = 0.11; FDR p = 0.048). This study reveals stage-specific plasma biomarker-MTL relationships across the Alzheimer's continuum. In MCI, plasma p-tau217 and its ratio to Aβ1-42 closely track hippocampal subfield atrophy, reflecting tau-related neurodegeneration. In CN individuals, higher p-tau217 and p-tau217/Aβ1-42 levels relate positively to hippocampal integrity, partly mediated by GFAP, suggesting early astroglial activity preceding structural loss. These findings underscore dynamic biomarker interactions and support integrating plasma and imaging markers for early AD characterization.},
}

@article {pmid41407658,
year = {2025},
author = {Xu, YQ and Sun, X and Liao, C and Li, X},
title = {A Framework for Identifying Serum Exosomal Lipid Biomarkers in Alzheimer's Disease.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00947},
pmid = {41407658},
issn = {1948-7193},
abstract = {The escalating global burden of Alzheimer's disease (AD), projected to reach $16.9 trillion by 2050 with disproportionate impacts on low- and middle-income countries and racial minorities, underscores an urgent need for accessible early detection tools. Current therapies offer limited symptomatic relief but fail to halt neurodegeneration. Serum exosomal lipids, which reflect brain pathophysiology through blood-brain barrier crossing vesicles, present promising minimally invasive biomarkers. However, a standardized framework for their systematic development is lacking. We propose a structured three-phase approach comprising discovery, analytical validation, and clinical utility assessment. The discovery phase employs nontargeted lipidomics of serum exosomes from AD patients and controls integrated with machine learning to identify dysregulated pathways and prioritize candidate biomarkers. Analytical validation involves targeted quantification using UPLC-MS/MS to optimize sensitivity and specificity within complex matrices, with rigorous performance evaluation via receiver operating characteristic (ROC) curve analysis and area under the curve (AUC) analysis in independent case-control cohorts establishing preliminary diagnostic cut-offs. Clinical utility assessment requires longitudinal evaluation in treated AD cohorts to correlate biomarker dynamics with disease progression or therapeutic response, refine diagnostic thresholds, and explore presymptomatic risk prediction. Implementing this framework demands multidisciplinary collaboration and strict ethical adherence. This strategy paves the way for clinically validated serum exosomal lipid biomarkers to enable presymptomatic detection and personalized risk stratification, ultimately mitigating AD's devastating socioeconomic impact.},
}

@article {pmid41407593,
year = {2025},
author = {Yan, R and Zhang, W and Wang, W and Wu, J and Zhang, J and Xu, Y and Xu, W and Yang, W},
title = {Deep learning analysis of urine-derived stem cell mitochondrial morphology as a non-invasive Alzheimer's disease biomarker.},
journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics},
volume = {},
number = {},
pages = {e00813},
doi = {10.1016/j.neurot.2025.e00813},
pmid = {41407593},
issn = {1878-7479},
abstract = {Alzheimer's disease (AD), closely associated with mitochondrial dysfunction, currently lacks convenient and non-invasive biomarkers for mitochondrial assessment. In this study, we developed an artificial intelligence framework leveraging live urine-derived stem cell (USC) mitochondrial fluorescence imaging to investigate differences between cognitively impaired individuals (AD and mild cognitive impairment (MCI)) and cognitively normal (CN) subjects. Mitochondrial fluorescence images from living HeLa cells were first segmented, and two binary classification models based on the ResNet-18 convolutional neural network were trained to identify mitochondrial hyperfission and hyperfusion relative to normal morphology. The models demonstrated robust performance in detecting intermediate mitochondrial states during validation. When applied to USCs, the system effectively distinguished mitochondrial patterns associated with cognitive impairment, highlighting its potential for the early detection of Alzheimer's disease and merits further validation in larger, independent cohorts.},
}

@article {pmid41407165,
year = {2025},
author = {Ghosh, N and Ghosh, J and Ghosh, S and Sinha, K and Sil, PC},
title = {Nutraceutical interventions for neuroprotection: a comprehensive review.},
journal = {Biochemical pharmacology},
volume = {},
number = {},
pages = {117637},
doi = {10.1016/j.bcp.2025.117637},
pmid = {41407165},
issn = {1873-2968},
abstract = {Nutraceuticals, bioactive compounds derived from food sources, are emerging as promising agents for neuroprotection, particularly through their modulation of gut health. Unlike conventional single-molecule therapeutics that often target isolated pathways, nutraceuticals offer a multi-targeted approach by influencing the gut-brain axis, a bidirectional communication network linking the gut microbiota and the central nervous system. Key nutraceuticals such as probiotics, prebiotics, polyphenols, omega-3 fatty acids, and vitamins have been shown to beneficially alter microbiota composition, reduce intestinal inflammation, and strengthen gut barrier integrity. These changes can significantly influence brain function by modulating neurotransmitter activity and systemic immune responses. This review compares the holistic action of nutraceuticals with the more focused effects of single-molecules, particularly in the context of neurodegenerative diseases like Alzheimer's, Parkinson's, Huntington's Disease and Motor Neuron Diseases like amyotrophic lateral sclerosis. It discusses how nutraceuticals may mitigate key pathological features of these conditions-including neuroinflammation, oxidative stress, and mitochondrial dysfunction, through gut-mediated pathways. Despite their potential, challenges remain regarding the standardization of formulations, bioavailability, dosage optimization, and long-term safety. Further clinical research is needed to validate the efficacy of nutraceuticals as complementary or alternative strategies to traditional neuroprotective agents.},
}

@article {pmid41407043,
year = {2025},
author = {Fan, B and Liang, Y and Zhi, T and Wu, L and Wu, Y and Yang, Y and Xie, Z and Wu, X},
title = {GPR55 deficiency exacerbates cognitive impairments and Alzheimer's disease-like pathology in mice.},
journal = {Neurochemistry international},
volume = {},
number = {},
pages = {106105},
doi = {10.1016/j.neuint.2025.106105},
pmid = {41407043},
issn = {1872-9754},
abstract = {BACKGROUND: Alzheimer's disease (AD) is the most common type of dementia, characterized by progressive cognitive decline and neuronal damage. Although studies have indicated a link between G-protein coupled receptor 55 (GPR55) and AD-related cognitive impairment, the underlying mechanisms remain unclear. Here, we aim to further investigate the role of GPR55 in the pathogenesis of AD.

METHODS: We used viral vectors to knock down GPR55 expression in the hippocampus of normal mice. We also generated GPR55 knockout in AD mice by crossing GPR55[-/-] mice with APP/PS1 transgenic mice (APP/PS1; GPR55[-/-]). Behavioral tests were conducted to assess spatial memory deficits in 9-month-old APP/PS1; GPR55[-/-] mice. We also assessed the amyloid β (Aβ) deposition, glial cell activation, and synaptic protein expression in the hippocampus. In addition, we used AAV9 viruses to overexpress GPR55 in the hippocampus of APP/PS1; GPR55[-/-] mice to further observe its effect on cognitive function.

RESULTS: Knockdown of GPR55 in the hippocampus induces AD-like pathology, cognitive dysfunction, neuroinflammation, and synaptic plasticity damage in normal mice. This was evidenced by increased hippocampal levels of Aβ and p-Tau, enhanced glial cell activation accompanied by upregulation of proinflammatory cytokines, and aggravated synaptic plasticity damage in the normal mice. Furthermore, knockdown of GPR55 induced the reduction of P-AKT1/2/3/AKT1/2/3 and P-GSK3β/GSK3β, while increasing the expression of P-ERK1/2/ERK1/2 in the hippocampus of normal mice. In addition, GPR55 deficiency exacerbated AD-like pathology and spatial learning and memory deficits in APP/PS1 mice. Conversely, AAV9-mediated overexpression of GPR55 rescued spatial memory impairments in APP/PS1; GPR55[-/-] mice.

CONCLUSIONS: These findings underscore the critical role of GPR55 in AD progression and highlight its potential as a therapeutic target for AD treatment.},
}

@article {pmid41406951,
year = {2025},
author = {Fang, S and Cui, F and Drucker, DJ},
title = {Glucagon-like peptide-1 medicines in neurological and psychiatric disorders.},
journal = {Cell reports. Medicine},
volume = {6},
number = {12},
pages = {102511},
doi = {10.1016/j.xcrm.2025.102511},
pmid = {41406951},
issn = {2666-3791},
mesh = {Humans ; *Glucagon-Like Peptide 1/therapeutic use/metabolism ; *Mental Disorders/drug therapy ; *Nervous System Diseases/drug therapy ; Diabetes Mellitus, Type 2/drug therapy ; },
abstract = {Glucagon-like peptide-1 (GLP-1) medicines are used for the treatment of type 2 diabetes (T2D) and obesity and reduce rates of cardiovascular disease, including stroke, in people with T2D. Substantial evidence from real-world data and clinical trials highlights the therapeutic potential of GLP-1 medicines for the treatment of neurodegenerative disorders such as Parkinson's and Alzheimer's diseases. Similarly, there is growing evidence for the potential utility of using GLP-1 medicines to reduce rates of smoking, or use of alcohol, tobacco, cannabis, or cocaine in individuals with substance use disorders. More limited clinical data suggest utility for GLP-1 medicines in patients with migraine or intracranial hypertension. The available data suggest that the use of GLP-1 medicines exhibits an acceptable safety profile in most individuals with neuropsychiatric disorders. Here, we review recent clinical evidence and ongoing trials exploring the efficacy and safety of GLP-1 medicines across a broad range of neurological conditions.},
}

Humans
*Glucagon-Like Peptide 1/therapeutic use/metabolism
*Mental Disorders/drug therapy
*Nervous System Diseases/drug therapy
Diabetes Mellitus, Type 2/drug therapy

@article {pmid41406948,
year = {2025},
author = {Lan, G and Li, B and Wang, M and Barve, A and Colin, M and Buée, L and Zhang, L and Jiang, M and Yang, J and Li, A and He, Z and Zhou, X and Zhu, Y and Cai, Y and Sun, P and Liu, L and Li, J and Chen, L and Fang, L and Wang, Y and Li, M and Chen, X and Shi, D and Ye, C and Fan, X and Wang, Q and Zhou, L and Liu, Z and Han, Y and Wang, L and Cheng, G and Guan, Y and Ni, R and Richetin, K and Xie, F and Guo, T},
title = {Plasma growth-associated protein 43 correlates with synaptic loss in Alzheimer's disease.},
journal = {Cell reports. Medicine},
volume = {6},
number = {12},
pages = {102508},
doi = {10.1016/j.xcrm.2025.102508},
pmid = {41406948},
issn = {2666-3791},
mesh = {Humans ; *Alzheimer Disease/blood/pathology/metabolism/diagnostic imaging ; Male ; Female ; Aged ; Biomarkers/blood/cerebrospinal fluid ; *Synapses/pathology/metabolism ; *GAP-43 Protein/blood/cerebrospinal fluid/metabolism ; tau Proteins/metabolism ; Positron-Emission Tomography ; Brain/pathology/metabolism/diagnostic imaging ; Aged, 80 and over ; Magnetic Resonance Imaging ; Middle Aged ; Cognitive Dysfunction/blood ; },
abstract = {Synaptic loss is a hallmark of Alzheimer's disease (AD) but lacks robust blood-based biomarkers. We investigate growth-associated protein 43 (GAP-43), previously identified as a synaptic candidate in the cerebrospinal fluid (CSF). Postmortem proteomic profiling of brain-derived extracellular vesicles (n = 21) highlights GAP-43 as a central hub within synaptic protein networks co-depleted in AD and closely linked with proteins enriched in immune-, metabolic-, and synaptic-related modules. In two well-characterized Chinese AD cohorts (n = 785), we measure plasma GAP-43, including subgroups with CSF biomarkers (n = 72), SV2A-PET (positron emission tomography) (n = 85), tau-PET (n = 280), and magnetic resonance imaging (MRI) (n = 595). Plasma GAP-43 correlates with CSF GAP-43, neurofilament light, and both baseline and longitudinal synaptic PET. Elevated plasma GAP-43 is associated with greater tau aggregation, faster brain atrophy, and accelerated cognitive decline, particularly among cognitively unimpaired individuals. These findings support plasma GAP-43 as a promising biomarker of early synaptic degeneration and a potential tool for identifying individuals at risk of AD progression.},
}

Humans
*Alzheimer Disease/blood/pathology/metabolism/diagnostic imaging
Male
Female
Aged
Biomarkers/blood/cerebrospinal fluid
*Synapses/pathology/metabolism
*GAP-43 Protein/blood/cerebrospinal fluid/metabolism
tau Proteins/metabolism
Positron-Emission Tomography
Brain/pathology/metabolism/diagnostic imaging
Aged, 80 and over
Magnetic Resonance Imaging
Middle Aged
Cognitive Dysfunction/blood

@article {pmid41406907,
year = {2025},
author = {Chen, C and Chen, Q and Zou, H and Zhao, C and Wang, X},
title = {Research Trends in Periodontitis and Alzheimer's Disease: A Bibliometric Analysis Based on Web of Science and Scopus.},
journal = {International dental journal},
volume = {76},
number = {1},
pages = {109327},
doi = {10.1016/j.identj.2025.109327},
pmid = {41406907},
issn = {1875-595X},
abstract = {INTRODUCTION AND AIMS: This study aimed to conduct a comprehensive bibliometric analysis to identify global research trends, key contributors and emerging hot spots in the field investigating the association between periodontitis and Alzheimer's disease (AD).

METHODS: Scientific publications from 2002 to 2025 were retrieved from the Web of Science Core Collection (WoSCC) and Scopus databases. The data were analysed using VOSviewer, CiteSpace and the R package 'bibliometrix' to perform co-authorship, co-occurrence and citation analyses.

RESULTS: A total of 262 articles from WoSCC and 272 from Scopus were included in the analysis. China was the leading contributing country, and Shanghai Jiao Tong University was the most productive institution. The Journal of Alzheimer's Disease was identified as the most influential journal in this domain. Keyword co-occurrence analysis identified central research themes, including 'dementia', 'tooth loss', and 'Porphyromonas gingivalis'. Citation burst analysis indicated that 'oral microbiome' and 'oral health' are currently emerging research frontiers.

CONCLUSION: This is the first bibliometric study to systematically map the intellectual structure and evolution of research linking periodontitis and AD. The findings underscore the strengthening link between oral inflammatory conditions and neurodegeneration.

CLINICAL RELEVANCE: The analysis highlights a shifting focus towards mechanisms such as the oral microbiome and systemic inflammation, pointing to promising directions for future research aimed at novel preventive strategies and therapeutic interventions for AD.},
}

@article {pmid41406783,
year = {2025},
author = {Ioannidou, E and Vavilis, T and Bourtzos, Z and Stamoula, E},
title = {Corrigendum to "A review of the TGF-β1 pathway in Alzheimer's disease and depression: Possible restoration potential of antidepressants" [Neuroscience 585 (2025) 429-440].},
journal = {Neuroscience},
volume = {593},
number = {},
pages = {170},
doi = {10.1016/j.neuroscience.2025.12.006},
pmid = {41406783},
issn = {1873-7544},
}

@article {pmid41406583,
year = {2025},
author = {Yıldızbaş, A and Taslimi, P and Tüzün, B and Sadeghian, N and Kurt, R and İstek, A},
title = {Chemical composition and bioactivity of Sideritis taurica Stephan ex Wild. (Lamiaceae) leaves: GC/MS analysis, antioxidant and enzyme inhibition activities, and in silico studies.},
journal = {Journal of chromatography. B, Analytical technologies in the biomedical and life sciences},
volume = {1270},
number = {},
pages = {124894},
doi = {10.1016/j.jchromb.2025.124894},
pmid = {41406583},
issn = {1873-376X},
abstract = {Since ancient times, Sideritis taurica and other Sideritis species have been used in traditional medicine in Türkiye and beyond for treating a variety of ailments, including coughs, sore throats, gastrointestinal, respiratory, and urogenital disorders, as well as wounds, colds, and flu, and are believed to possess numerous therapeutic properties such as antispasmodic, analgesic, antibacterial, anti-inflammatory, and antioxidant effects. This study aimed to evaluate the enzyme inhibition and antioxidant activities of various extracts from S. taurica leaves collected from Kurucaşile, Bartın, Türkiye. The extracts were prepared using ethanol, methanol, and hot/cold water extraction methods from leaves that were dried at room temperature and stored in a freezer. Enzyme inhibition activities were assessed against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), α-glucosidase, and α-amylase, with IC50 values calculated. Antioxidant activities were measured using DPPH, ABTS, and CUPRAC assays. Furthermore, ADME/T (Absorption, Distribution, Metabolism, Excretion, and Toxicity) and molecular docking calculations were performed on the phytochemical components of S. taurica to investigate their effects and interactions with human metabolism. These calculations were performed on a number of proteins, including alpha-amylase protein (PDB ID: 1HNY), AChE protein (PDB ID: 4M0E), and BChE protein (PDB ID: 5NN0). The purpose of these calculations was to investigate the interaction between these substances and human metabolism. The results indicated that the ethanol and methanol extracts exhibited the highest inhibition on AChE and BChE (IC50 values of 73.99 μg/mL and 5.04 μg/mL, respectively). The methanol extracts also demonstrated potent inhibition against α-glucosidase (IC50 value of 25.81 μg/mL) and α-amylase (IC50 value of 70.42 μg/mL). Regarding antioxidant activity, the methanol extracts showed the highest radical scavenging activity in the DPPH (87.88 %) and ABTS (99.97 %) tests. Additionally, the methanol extracts stored in the freezer exhibited the best-reducing power in the CUPRAC assay (2.436 ± 0.1669). These findings underscore the potential of S. taurica as a source of natural antioxidants and enzyme inhibitors, suggesting its applicability in the treatment of neurodegenerative diseases such as Alzheimer's disease. In conclusion, extracts obtained from S. taurica leaves, particularly those derived from room temperature-dried leaves, demonstrate significant enzyme inhibition and antioxidant properties. Also, the findings support the consideration of S. taurica as a natural therapeutic source for neurodegenerative diseases and emphasize for further investigation into its active components and health benefits.},
}

@article {pmid41406575,
year = {2025},
author = {Quadir, A and Tanveer, M},
title = {TRKM: Twin restricted kernel machines for classification and regression.},
journal = {Neural networks : the official journal of the International Neural Network Society},
volume = {197},
number = {},
pages = {108449},
doi = {10.1016/j.neunet.2025.108449},
pmid = {41406575},
issn = {1879-2782},
abstract = {Restricted kernel machines (RKMs) have significantly advanced machine learning by integrating kernel functions with least squares support vector machines (LSSVM), adopting an energy function akin to restricted Boltzmann machines (RBM) to enhance generalization performance. Despite their strengths, RKMs face challenges in handling unevenly distributed or complexly clustered data and incur substantial computational costs when scaling to large datasets due to the management of high-dimensional feature spaces. To address these limitations, we propose the twin restricted kernel machine (TRKM), a novel framework that synergizes the robustness of RKM with the efficiency of twin hyperplane methods, inspired by twin support vector machines (TSVM). TRKM leverages conjugate feature duality based on the Fenchel-Young inequality to reformulate classification and regression problems in terms of dual variables, establishing a bound on the objective function and introducing a new methodology within the RKM framework. By incorporating an RBM-inspired energy function with visible and hidden variables corresponding to both classes, TRKM effectively captures complex data patterns. The kernel trick is employed to project data into a high-dimensional feature space, where an optimal separating hyperplane is identified using a regularized least squares approach, enhancing both performance and computational efficiency. Extensive experiments on 36 diverse datasets from UCI and KEEL repositories demonstrate TRKM's superior accuracy and scalability compared to baseline models. Additionally, TRKM's application to the brain age estimation dataset underscores its efficacy in predicting brain age, a critical biomarker for early Alzheimer's disease detection, highlighting its potential for real-world medical applications. To the best of our knowledge, TRKM is the first twin variant of the RKM framework, offering a robust and efficient solution for complex classification and regression tasks. The source code of the proposed TRKM model is available at https://github.com/mtanveer1/TRKM.},
}

@article {pmid41406552,
year = {2025},
author = {Moazzam, F and Hatamian-Zarmi, A and Sabaghian, M and Khezri, K and Hosseinzadeh, BE and Khodagholi, F and Shahmansouri, MJ and Rashidi, FS},
title = {Frankincense-loaded lactoferrin-conjugated solid lipid nanoparticles for targeted brain delivery and neuroprotection in a scopolamine-induced Alzheimer's model.},
journal = {Colloids and surfaces. B, Biointerfaces},
volume = {260},
number = {},
pages = {115370},
doi = {10.1016/j.colsurfb.2025.115370},
pmid = {41406552},
issn = {1873-4367},
abstract = {Central nervous system (CNS) disorders remain a major field with substantial unmet therapeutic needs. This study aimed to address the critical challenge of brain drug delivery by employing solid lipid nanoparticles (SLNs) surface-functionalized with lactoferrin (Lf) ligands, from the transferrin family, to facilitate transport across the blood-brain barrier. Frankincense (F), a natural compound with well-documented neuroprotective properties and minimal adverse effects, was encapsulated within (SLNs) using a microemulsion approach. The optimal formulation resulted in nanoparticles (NPs) with an average size of 103.1 ± 0.9 nm, an encapsulation efficiency of 95.2 ± 0.8 %, a drug loading capacity of 8.6 ± 0.1 %, a polydispersity index (PDI) of 0.3 ± 0.08, and a zeta potential of -29.2 ± 0.5 mV. The optimized NPs showed a sustained drug release profile, and ATR-FTIR spectra confirmed the conjugation of lactoferrin to the nanoparticles. To establish translational relevance, the neuroprotective effectiveness of (F-Lf-SLNs) was investigated using a scopolamine-induced Alzheimer's disease animal model. Behavioral tests, along with biochemical and histological analyses, were conducted. The findings demonstrated that (F-Lf-SLNs) significantly improved the brain delivery of frankincense, highlighting their promise as a neuroprotective strategy for CNS disorders. They also effectively protected neurons compared to the scopolamine-induced group. Overall, these results emphasize the key role of drug delivery systems and ligand-targeting methods in enhancing the therapeutic effectiveness of drugs.},
}

@article {pmid41406490,
year = {2025},
author = {Shin, J and Kang, HW and Kim, S},
title = {Nanoscale Structural and Immunological Remodeling of the Primo Vascular System in Alzheimer's Disease: Mast Cell Activation Along the Gut-Brain Axis.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00637},
pmid = {41406490},
issn = {1948-7193},
abstract = {The primo vascular system (PVS) is a fine-scale circulatory network composed of nanoscale tissues that are closely associated with biological signal transmission pathways, such as the gut-brain axis, and that harbor immune and regenerative cells. Mast cells (MCs), critical mediators of gut-brain axis communication, have been implicated in the pathogenesis of Alzheimer's disease (AD). Characterized by a high MC density, the PVS is increasingly recognized as a potential modulator of immune responses and tissue regeneration. However, its pathological alterations in neurodegenerative conditions remain poorly understood. This study aimed to investigate the nanoscale structural and immunological characteristics of the organ surface and meningeal PVS (OS-PVS and M-PVS) in APP/PS2 transgenic mice, a well-established model of AD. Behavioral testing in APP/PS2 mice confirmed cognitive impairments characteristic of AD. Atomic force microscopy revealed irregular alignment of primo subvessels and interstitial spaces, along with increased surface roughness and loss of spatial periodicity. Scanning electron microscopy showed a significant increase in the density and diameter of primo pores, as well as reduced fiber structure diameter, suggesting ultrastructural remodeling. Toluidine blue and immunofluorescence staining demonstrated elevated MC density and degranulation ratio within the PVS. These findings suggest that the OS-PVS and M-PVS undergo coordinated nanoscale structural and immunological remodeling in AD, reflecting shared pathological features within the PVS. MC activity within the PVS may contribute to the neuroimmune dysregulation underlying disease progression, supporting its role as an anatomical conduit for immune communication along the gut-brain axis.},
}

@article {pmid41406402,
year = {2026},
author = {Du, Y and Borné, Y and Samuelsson, J and Glans, I and Hu, X and Nägga, K and Palmqvist, S and Hansson, O and Sonestedt, E},
title = {High- and Low-Fat Dairy Consumption and Long-Term Risk of Dementia: Evidence From a 25-Year Prospective Cohort Study.},
journal = {Neurology},
volume = {106},
number = {2},
pages = {e214343},
doi = {10.1212/WNL.0000000000214343},
pmid = {41406402},
issn = {1526-632X},
mesh = {Humans ; Female ; Male ; Middle Aged ; *Dairy Products ; Prospective Studies ; *Dementia/epidemiology ; Sweden/epidemiology ; Aged ; Risk Factors ; Cohort Studies ; *Dietary Fats ; Cheese ; *Diet, High-Fat ; Alzheimer Disease/epidemiology ; },
abstract = {BACKGROUND AND OBJECTIVES: The association between dairy intake and dementia risk remains uncertain, especially for dairy products with varying fat contents. The aim of this study was to investigate the association between high-fat and low-fat dairy intake and dementia risk.

METHODS: This study used data from a prospective cohort in Sweden, the Malmö Diet and Cancer cohort, which consisted of community-based participants who underwent dietary assessment at baseline (1991-1996). Dietary intake was evaluated using a comprehensive diet history method that combined a 7-day food diary, a food frequency questionnaire, and a dietary interview. Dementia cases were identified through the Swedish National Patient Register until December 31, 2020, and cases diagnosed until 2014 were further validated. The primary outcome of the study was all-cause dementia, and the secondary outcomes were Alzheimer disease (AD) and vascular dementia (VaD). Cox proportional hazard regression models were used to estimate hazard ratio (HR) and 95% CI.

RESULTS: This study included 27,670 participants (mean baseline age 58.1 years, SD 7.6; 61% female). During a median of 25 years of follow-up, 3,208 incident dementia cases were recorded. Consumption of ≥50 g/d of high-fat cheese (>20% fat) was associated with a reduced risk of all-cause dementia (HR 0.87; 95% CI, 0.78-0.97) and VaD (HR 0.71, 95% CI 0.52-0.96) compared with lower intake (<15 g/d). An inverse association between high-fat cheese and AD was found among APOE ε4 noncarriers (HR 0.87, 95% CI 0.76-0.99, p-interaction = 0.014). Compared with no consumption, individuals consuming ≥20 g/d of high-fat cream (>30% fat) had a 16% lower risk of all-cause dementia (HR 0.84, 95% CI 0.72-0.98). High-fat cream consumption was inversely associated with the risk of AD and VaD. Consumption of low-fat cheese, low-fat cream, milk (high-fat and low-fat), fermented milk (high-fat and low-fat), and butter showed no association with all-cause dementia.

DISCUSSION: Higher intake of high-fat cheese and high-fat cream was associated with a lower risk of all-cause dementia, whereas low-fat cheese, low-fat cream, and other dairy products showed no significant association. APOE ε4 status modified the association between high-fat cheese and AD. Our study's observational design limits causal inference.},
}

Humans
Female
Male
Middle Aged
*Dairy Products
Prospective Studies
*Dementia/epidemiology
Sweden/epidemiology
Aged
Risk Factors
Cohort Studies
*Dietary Fats
Cheese
*Diet, High-Fat
Alzheimer Disease/epidemiology

@article {pmid41406216,
year = {2025},
author = {Liu, A and Citu, C and Enduru, N and Chen, X and Tung, CH and Sinha, T and Sepulveda, SE and Manuel, AM and Gorski, D and Fernandes, BS and Yu, M and Schulz, PE and Simon, LM and Soto, C and Zhao, Z},
title = {Single-nucleus multiomics reveals the disrupted regulatory programs in three brain regions of sporadic early-onset Alzheimer's disease.},
journal = {Science advances},
volume = {11},
number = {51},
pages = {eadw4917},
pmid = {41406216},
issn = {2375-2548},
mesh = {Humans ; *Alzheimer Disease/genetics/metabolism/pathology ; *Brain/metabolism/pathology ; Male ; Female ; Transcriptome ; Gene Expression Regulation ; Transcription Factors/metabolism/genetics ; Aged ; Hippocampus/metabolism/pathology ; Entorhinal Cortex/metabolism/pathology ; Multiomics ; },
abstract = {Sporadic early-onset Alzheimer's disease (sEOAD) represents a substantial but less-studied subtype of Alzheimer's disease (AD). Here, we generated a single-nucleus multiome atlas derived from the postmortem prefrontal cortex, entorhinal cortex, and hippocampus of nine individuals with or without sEOAD. Comprehensive analyses were conducted to delineate cell type-specific transcriptomic changes and linked candidate cis-regulatory elements (cCREs) across brain regions. We prioritized eight conservative transcription factors in glial cells in multiple brain regions, including RFX4 in astrocytes and IKZF1 in microglia, which are implicated in regulating sEOAD-associated genes. Moreover, we identified the top 25 altered intercellular signaling between glial cells and neurons, highlighting their regulatory potential on gene expression in receiver cells. We reported 33 cCREs linked to sEOAD-associated genes overlapped with late-onset AD risk loci, and found that, in addition, sEOAD cCREs are enriched for neuropsychiatric disorder risk variants. This atlas helps dissect transcriptional and chromatin dynamics in sEOAD, providing a key resource for AD research.},
}

Humans
*Alzheimer Disease/genetics/metabolism/pathology
*Brain/metabolism/pathology
Male
Female
Transcriptome
Gene Expression Regulation
Transcription Factors/metabolism/genetics
Aged
Hippocampus/metabolism/pathology
Entorhinal Cortex/metabolism/pathology
Multiomics

@article {pmid41406173,
year = {2025},
author = {Tanjin, R and Al-Amin, M and Etee, JM and Siddika, A and Siddiki, A and Mahi, SI and Toma, SN and Akter, N and Uddin, MH and Bristy, NA and Mowlee, SI and Rafa, EK and Hossen, MF},
title = {An evaluation of Roluperidone as a promising repurposing candidate for Alzheimer's Disease: A Computational Investigation.},
journal = {PloS one},
volume = {20},
number = {12},
pages = {e0338211},
pmid = {41406173},
issn = {1932-6203},
mesh = {*Alzheimer Disease/drug therapy ; *Drug Repositioning/methods ; Humans ; Molecular Docking Simulation ; Support Vector Machine ; Blood-Brain Barrier/metabolism ; Machine Learning ; Donepezil ; },
abstract = {Alzheimer's disease (AD) is the most dominant and prevalent form of dementia. The therapeutic agents for AD are not sufficient. Drug repurposing (i.e., also called drug repositioning or therapeutic switching of drugs) could contribute to adding novel therapeutic agents in AD discovery pipeline. Blood-brain barrier (BBB) is a crucial factor, for brain's diseases related drug discovery. Since, CNS active compounds have BBB crossing property, in this study this category of compounds was re-evaluated as repurposing potential candidate for AD by integrated machine learning algorithm, cheminformatics analysis, molecular Docking and simulation-based approach. We builded three machine learning model such as Support Vector Machine (SVM), Random Forest (RF), Extreme Gradient Boosting (XGB) for the prediction of AD potential repurposing candidates. The SVM classification model performed better than others. The SVM classification model achieved an Area Under the Curve of the Receiver Operating Characteristics (ROC-AUC) of 0.81, along with higher precision, recall, and F1 scores. The support vector machine (SVM) was implemented to classify 500 CNS active compounds as AD drug potential and non-AD drug potential. Using the SVM model, 60 compounds were predicted as AD repurposing potential from 500 CNS active compounds. Structural similarity analysis of 60 compounds with Donepezil as a reference drug was performed using 5 different types of fingerprints such as 'substructure', 'extended', 'circular', 'EState', 'MACCS'. 9 compounds from them obtained as structurally most similar to the reference drug. After the molecular docking performance of 9 compounds into the active site & peripheral anionic site of human acetylcholinesterase (hAChE), it was revealed that Roluperidone' had binding affinity of -12 kcal/mol, and 'Napitane' had binding affinity of -11.9 kcal/mol whereas the reference drug Donepezil had a binding affinity of -11.8 Kcal/mol. Molecular dynamics simulation revealed that Roluperionde had better binding integrity to hAChE. This study laid out computational reinvestigation of 500 CNS active drugs for therapeutic switching to AD, and 'Roluperidone' is found as an AD repurposing potential candidate. However, in-vitro and in-vivo studies are further needed to fully elucidate the compound's potential as AD repurposing drugs.},
}

*Alzheimer Disease/drug therapy
*Drug Repositioning/methods
Humans
Molecular Docking Simulation
Support Vector Machine
Blood-Brain Barrier/metabolism
Machine Learning
Donepezil

@article {pmid41405898,
year = {2025},
author = {Knopman, DS},
title = {Valacyclovir and Symptomatic Alzheimer Disease-No Evidence for Benefit.},
journal = {JAMA},
volume = {},
number = {},
pages = {},
doi = {10.1001/jama.2025.20795},
pmid = {41405898},
issn = {1538-3598},
}

@article {pmid41405876,
year = {2025},
author = {},
title = {Valacyclovir Treatment of Early Symptomatic Alzheimer Disease: Research Summary.},
journal = {JAMA},
volume = {},
number = {},
pages = {e2522830},
doi = {10.1001/jama.2025.22830},
pmid = {41405876},
issn = {1538-3598},
}

@article {pmid41405855,
year = {2025},
author = {Devanand, DP and Wisniewski, T and Razlighi, Q and Qian, M and Wei, R and Andrews, HF and Acosta, EP and Bell, KL and Pelton, GH and Deliyannides, D and Perrin, AC and Caccappolo, E and Gershon, AA and Prasad, KM and Kreisl, WC and Mintz, A and Huey, ED},
title = {Valacyclovir Treatment of Early Symptomatic Alzheimer Disease: The VALAD Randomized Clinical Trial.},
journal = {JAMA},
volume = {},
number = {},
pages = {},
doi = {10.1001/jama.2025.21738},
pmid = {41405855},
issn = {1538-3598},
abstract = {IMPORTANCE: Neuroscientific, epidemiological, and electronic health record studies implicate herpes simplex virus (HSV) as potentially etiological for Alzheimer disease (AD).

OBJECTIVE: To compare the efficacy and adverse effects of valacyclovir vs placebo in participants with early symptomatic AD and HSV seropositivity (HSV-1 or HSV-2).

This randomized clinical trial included adults with a clinical diagnosis of probable AD or a clinical diagnosis of mild cognitive impairment with positive biomarkers for AD, a positive serum antibody test (IgG or IgM) for HSV-1 or HSV-2, and a Mini-Mental State Examination score of 18 to 28. The trial was conducted at 3 US outpatient clinics specializing in memory disorders. Recruitment occurred from January 2018 to May 2022; the last follow-up occurred in September 2024.

INTERVENTION: Either 4 g/d of valacyclovir (n = 60) or matching placebo (n = 60).

MAIN OUTCOMES AND MEASURES: The primary outcome was least-squares mean (LSM) change at 78 weeks in the 11-item Alzheimer's Disease Assessment Scale Cognitive (ADAS-Cognitive) Subscale score (range, 0-70; higher scores indicate greater impairment). The secondary outcomes were LSM change in the Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) Scale score; LSM change in the 18F-florbetapir amyloid positron emission tomography (PET) standardized uptake value ratio (SUVR; higher scores indicate higher amyloid levels) for 6 brain regions (medial orbitofrontal, anterior cingulate, parietal lobe, posterior cingulate, temporal lobe, and precuneus); and LSM change in 18F-MK-6240 tau PET medial temporal SUVR (higher scores indicate higher tau levels) for 4 brain regions (amygdala, hippocampus, entorhinal, and parahippocampus). The frequency of adverse events was the safety outcome.

RESULTS: Of the 120 participants (mean age, 71.4 [SD, 8.6] years; 55% were female), 93 (77.5%) completed the trial. At 78 weeks, the LSM change in the 11-item ADAS-Cognitive Subscale score was 10.86 (95% CI, 8.80 to 12.91) in the valacyclovir group vs 6.92 (95% CI, 4.88 to 8.97) in the placebo group, indicating greater cognitive worsening with valacyclovir than placebo (between-group difference, 3.93 [95% CI, 1.03 to 6.83]; P = .01). The LSM change in the ADCS-ADL Scale score at 78 weeks was -13.78 (95% CI, -17.00 to -10.56) in the valacyclovir group vs -10.16 (95% CI, -13.37 to -6.96) in the placebo group (between-group difference, -3.62 [95% CI, -8.16 to 0.93]). At 78 weeks, the LSM change in the 18F-florbetapir amyloid PET SUVR was 0.03 (95% CI, -0.04 to 0.10) in the valacyclovir group vs 0.01 (95% CI, -0.06 to 0.08) in the placebo group (between-group difference, 0.02 [95% CI, -0.08 to 0.12]). The LSM change in the 18F-MK-6240 tau PET medial temporal SUVR at 78 weeks was 0.07 (95% CI, -0.06 to 0.19) in the valacyclovir group vs -0.04 (95% CI, -0.15 to 0.07) in the placebo group (between-group difference, 0.11 [95% CI, -0.06 to 0.28]). The most common adverse events were elevated serum creatinine level (5 participants [8.3%] in the valacyclovir group vs 2 participants [3.3%] in the placebo group) and COVID-19 infection (3 [5%] vs 2 [3.3%], respectively).

CONCLUSIONS AND RELEVANCE: Valacyclovir was not efficacious with cognitive worsening for the primary outcome and it is not recommended to treat individuals with early symptomatic AD and HSV seropositivity.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03282916.},
}

@article {pmid41405805,
year = {2025},
author = {Blair, HA},
title = {Sublingual Cyclobenzaprine: First Approval.},
journal = {Clinical drug investigation},
volume = {},
number = {},
pages = {},
pmid = {41405805},
issn = {1179-1918},
abstract = {TONMYA[™] is a sublingual eutectic formulation of cyclobenzaprine being developed by Tonix Pharmaceuticals for the treatment of various conditions, including fibromyalgia, post-traumatic stress disorder (PTSD), acute stress disorder, major depressive disorder, post-acute COVID-19 syndrome, alcohol use disorder, and agitation in Alzheimer's disease. The sublingual formulation was designed for rapid transmucosal absorption to produce diurnal variation in peak-to-trough drug concentrations, making it suitable for long-term bedtime use. On 15 August 2025, sublingual cyclobenzaprine was approved for the treatment of fibromyalgia in adults in the USA. This article summarizes the milestones in the development of sublingual cyclobenzaprine leading to this first approval for fibromyalgia.},
}

@article {pmid41405795,
year = {2025},
author = {Ekström, I and Vetrano, DL and Valletta, M and Ruane, R and Larsson, M and Fredolini, C and Winblad, B and Grande, G and Laukka, EJ},
title = {Blood-based biomarkers of Alzheimer's disease and olfactory decline over 15 years in older adults.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {41405795},
issn = {2509-2723},
support = {2021-00178//Vetenskapsrådet/ ; 2020-01030//Vetenskapsrådet/ ; 2024-00721//Vetenskapsrådet/ ; P22-0785 2023//Riksbankens Jubileumsfond/ ; },
abstract = {Olfactory impairment is common in older age and is a known early feature of several dementia diseases. Blood-based biomarkers of Alzheimer's disease (AD) now offer a scalable method for detecting pathophysiological mechanisms related to olfactory decline in the general population. However, few studies have examined how these biomarkers relate to long-term olfactory trajectories. Most existing work has been limited to cross-sectional settings. In this population-based study, we used biomarker data collected at baseline and followed participants for up to 15 years, enabling us to test whether early biological changes are temporally linked to subsequent olfactory decline. Data came from the ongoing Swedish National Study on Aging and Care in Kungsholmen (SNAC-K), a longitudinal population-based study with baseline assessments from March 21, 2001, through August 30, 2004. We included participants without prevalent neurodegenerative diseases who completed olfactory assessment at baseline. The 15-year follow-up was finished in December 2019. Data were analysed from December 2023 to April 2024. Serum-derived biomarkers of tau phosphorylated at threonine 217 (p-tau217) and at theorine181 (p-tau181), total tau (t-tau), amyloid-β ratio (Aβ42/Aβ40), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) were obtained at baseline. Linear mixed models examined associations between biomarker quartiles and Sniffin' Sticks odor identification performance over 15 years, adjusting for demographics, health conditions, and semantic knowledge. We included 1868 participants (mean [SD] age 71.3 [9.9] years; 1122 females [60.1%]). In fully adjusted models, higher quartiles of p-tau217, p-tau181, NfL, and GFAP, and lower quartiles of Aβ42/Aβ40, were associated with steeper olfactory decline, with the steepest decline among participants in the highest quartiles (β for Q4 vs Q1: -0.20 [95% CI: -0.26 to -0.15] for p-tau217; -0.19 [95% CI: -0.25 to -0.13] for p-tau181; -0.23 [95% CI: -0.29 to -0.17] for NfL; β = -0.17 [95% CI: -0.23 to -0.11] for GFAP. Participants in the lowest Aβ42/Aβ40 quartile declined more steeply than those in the highest (β = -0.09 [95% CI: -0.14 to -0.04]). Associations appeared stronger in the oldest participants, in APOE ε4 carriers for p-tau181, in non-carriers for NfL and GFAP, and among former smokers for NfL. Blood-based biomarkers of AD were consistently associated with faster olfactory decline in older adults, particularly in the highest biomarker quartiles. These results provide large-scale longitudinal evidence, across up to 15 years of follow-up, that olfactory decline in the general population is linked to AD-related blood biomarkers, supporting the hypothesis that common olfactory losses in ageing partly reflect dementia-related processes.},
}

@article {pmid41405782,
year = {2025},
author = {Afifi, I and Elgendy, M and Abdelfatah, M and El-Sappagh, S},
title = {Vision and convolutional transformers for Alzheimer's disease diagnosis: a systematic review of architectures, multimodal fusion and critical gaps.},
journal = {Brain informatics},
volume = {},
number = {},
pages = {},
doi = {10.1186/s40708-025-00286-7},
pmid = {41405782},
issn = {2198-4018},
abstract = {Alzheimer's disease (AD), a significant public health challenge, requires accurate early diagnosis to improve patient outcomes. Vision Transformers (ViTs) and Convolutional Vision Transformers (CViTs) have emerged as powerful Deep Learning architectures for this task. Following PRISMA guidelines, this systematic review analyzes 68 studies selected from 564 publications (2021-2025) across five major databases: Scopus, Web of Science, ScienceDirect, IEEE Xplore, and PubMed. We introduce novel taxonomies to systematically categorize these works by model architecture, data modality, fusion strategy, and diagnostic objective. Our analysis reveals key trends, such as the rise of hybrid CViT frameworks, and critical gaps, including a limited focus on Mild Cognitive Impairment-to-AD progression. Critically, we also assess practical implementation details, revealing widespread challenges in algorithmic reproducibility. The discussion culminates in a forward-looking analysis of Large Vision Models and proposes future directions emphasizing the need for robust multimodal integration, lightweight transformer designs, and Explainable AI to advance AD research and bridge the critical gap between high-performance modeling and clinical applicability.},
}

@article {pmid41405709,
year = {2025},
author = {Duan, X and Wang, F and Liu, W and Xie, Y and Yang, M and Ping, Y and Yu, P and Wei, Z and Li, H and Zhang, Q and Wang, X and Tao, Z},
title = {The diagnostic value of plasma Aβ42 and Aβ40 in Alzheimer's disease: current status, challenges, and impacting variables.},
journal = {Journal of neurology},
volume = {273},
number = {1},
pages = {30},
pmid = {41405709},
issn = {1432-1459},
mesh = {Humans ; *Alzheimer Disease/blood/diagnosis ; *Amyloid beta-Peptides/blood ; *Peptide Fragments/blood ; Biomarkers/blood ; },
abstract = {Alzheimer's disease (AD) is a group of central nervous system degenerative diseases that affect cognitive function. During the diagnosis of AD, the levels of amyloid-β 42 (Aβ42) and amyloid-β 40 (Aβ40) in plasma, as well as their ratio Aβ42/Aβ40, have recently been recommended by the International Association for the Study of Aging and Alzheimer's Disease as biomarkers to assist in clinical decision-making. However, an increasing amount of research data indicates that the effectiveness of these biomarkers is influenced by various factors. The levels of Aβ42 and Aβ40 are not only related to the physiological state of the human body, but also closely associated with the collection and preservation of plasma samples, pre-analytical processing, different detection methodologies, and even the result analysis process. Moreover, the functional status of metabolic organs in the human body, different comorbidities, bacterial or viral infections, and other factors can all affect the true levels of Aβ42 and Aβ40. Therefore, to clearly and comprehensively understand the advantages and limitations of plasma Aβ42 and Aβ40 as diagnostic biomarkers for AD, this article focuses on reviewing and discussing the influencing factors when plasma Aβ42 and Aβ40 are applied to the diagnosis of AD, aiming to help clinicians make better use of these indicators to optimize their diagnostic value.},
}

Humans
*Alzheimer Disease/blood/diagnosis
*Amyloid beta-Peptides/blood
*Peptide Fragments/blood
Biomarkers/blood

@article {pmid41405581,
year = {2025},
author = {Morello-Garcia, F and Corvalan, N and Llibre-Guerra, J and Arruabarrena, M and Clarens, MF and Keller, G and Santos, LL and Martin, ME and Aguzzoli, CS and Allegri, R and Amaral, L and Cristalli, CA and Bellaver, B and Best, MN and Bloomquist, M and Chen, K and Dubey, N and Felix, C and Slezak, DF and Fontana, IC and Garcia-Cordero, I and Hernandez, MA and Ismail, O and Johnson, F and Khan, A and Koerich, S and Moreno, MCL and Ferreira, PL and Guimet, NM and Junior, MO and Pascoal, TA and Povala, G and Rocha, A and Rodrigues, MS and Medeiros, MS and Ruppert, EP and Seibert, K and Sexton, C and Soares, C and Surace, E and Wilks, H and Zimmer, E and Crivelli, L},
title = {Capacity building in dementia research: insights from the World Young Leaders in Dementia.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {12},
pages = {e70667},
doi = {10.1002/alz.70667},
pmid = {41405581},
issn = {1552-5279},
mesh = {Humans ; *Dementia ; *Leadership ; *Capacity Building ; *Biomedical Research ; Surveys and Questionnaires ; *Research Personnel ; Developing Countries ; },
abstract = {Early-career researchers from low- and middle-income countries face systemic barriers to professional development and leadership growth. This article presents results from an initiative led by the World Young Leaders in Dementia (WYLD), including a leadership-focused session at the Alzheimer's Association International Conference 2024 and a global survey completed by 130 dementia researchers from 17 countries. The survey explored five capacity-building domains critical for leadership development. Over half of the survey respondents stated that scientific research in their country was not prioritized in public policy. Additionally, only 39% report holding full-time academic positions. The most cited challenges included lack of funding sources, training opportunities, and physical workspace. These findings highlight the urgent need to invest in research, training, and infrastructure to support future scientific leaders. As dementia incidence rises, prioritizing capacity building is essential to ensure global equity in research. HIGHLIGHTS: Early-career dementia researchers face major barriers, especially in LMICs. A networking session and a global survey explored capacity-building needs in dementia research. Key obstacles: lack of funding, training, workspace, and protected research time. Leadership development is a critical component of sustainable research capacity.},
}

Humans
*Dementia
*Leadership
*Capacity Building
*Biomedical Research
Surveys and Questionnaires
*Research Personnel
Developing Countries

@article {pmid41405543,
year = {2025},
author = {He, K and Zhang, Z and Li, Y and Xiong, W and Xing, Y and Gao, W and Kong, W and Chen, L and Yang, X and Dai, Z},
title = {Sevoflurane Exposure Exacerbates Memory Impairment and Pathological Manifestation by Inhibiting AKT/mTOR-Mediated Autophagy in P301L Tau Transgenic Mice.},
journal = {CNS neuroscience & therapeutics},
volume = {31},
number = {12},
pages = {e70694},
doi = {10.1002/cns.70694},
pmid = {41405543},
issn = {1755-5949},
support = {82471629//National Natural Science Foundation of China/ ; 82301748//National Natural Science Foundation of China/ ; 2022A1515012129//Natural Science Foundation of Guangdong Province/ ; JCYJ20220530152615035//Shenzhen Municipal Science and Technology Foundation/ ; JCYJ20240813103900001//Shenzhen Municipal Science and Technology Foundation/ ; JCYJ20240813104600001//Shenzhen Municipal Science and Technology Foundation/ ; SZSM202211010//Sanming Project of Medicine in Shenzhen/ ; SZXK069//Shenzhen Key Medical Discipline Construction Fund/ ; C2501030//Shenzhen Medical Research Fund/ ; },
mesh = {Animals ; *Sevoflurane/toxicity ; Mice, Transgenic ; Mice ; Male ; *TOR Serine-Threonine Kinases/metabolism/antagonists & inhibitors ; *Memory Disorders/chemically induced/pathology/metabolism/genetics ; *Autophagy/drug effects/physiology ; tau Proteins/genetics/metabolism ; *Proto-Oncogene Proteins c-akt/metabolism/antagonists & inhibitors ; Mice, Inbred C57BL ; *Anesthetics, Inhalation/toxicity ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a global health event with progressive cognitive decline affecting millions of elderly people worldwide. Emerging evidence indicates that sevoflurane may be associated with AD progression. However, the underlying mechanism remains poorly understood. Herein, we explored the potential role of sevoflurane exposure in cognitive ability and the possible mechanisms of action in the early stage of Tg4510 (P301L tau) transgenic mice.

METHODS: Using the novel object recognition test and Y-maze test, we assessed the change in cognitive abilities in 3-month-old male WT mice and Tg4510 mice with or without 3% sevoflurane exposure. By histological analysis and western blot, we determined the effect of sevoflurane exposure on tau pathology, synaptic function, and neuroinflammatory response. TMT-labeled proteomics technique coupled with bioinformatics analysis was performed to identify the potential key pathways or proteins involved in sevoflurane-induced cognitive deterioration.

RESULTS: Behavioral test showed that sevoflurane exposure exacerbated cognitive impairment of young Tg4510 mice. Pathologically, immunofluorescence demonstrated that sevoflurane exposure increased tau phosphorylation, synaptic defects, and neuroinflammatory response, which were further supported by the result of immunoblotting in Tg4510 mice exposed to sevoflurane. Proteomic analysis revealed an obvious decrease in autophagy-related proteins including Sort1, Vps28, and Atg3 in the hippocampus of sevoflurane-exposed Tg4510 mice compared to the nonexposed group. As an upstream signaling of autophagy, the AKT/mTOR pathway was found to be inhibited in sevoflurane-exposed Tg4510 mice. Moreover, our data also validated an inhibition of autophagy signaling associated with sevoflurane exposure in the context of tau pathology, as indicated by the upregulated expression of p62 and the downregulated expression of Sort1, Vps28, and Atg3.

CONCLUSION: These findings suggest that autophagy signaling appears to be a promising target for intervention in sevoflurane-induced cognitive impairment in the early tau pathology, which lays the foundation for further study of the underlying mechanisms.},
}

Animals
*Sevoflurane/toxicity
Mice, Transgenic
Mice
Male
*TOR Serine-Threonine Kinases/metabolism/antagonists & inhibitors
*Memory Disorders/chemically induced/pathology/metabolism/genetics
*Autophagy/drug effects/physiology
tau Proteins/genetics/metabolism
*Proto-Oncogene Proteins c-akt/metabolism/antagonists & inhibitors
Mice, Inbred C57BL
*Anesthetics, Inhalation/toxicity

@article {pmid41405472,
year = {2025},
author = {Verwey, N and Pijnenburg, Y and Duits, F and Van den Elskamp, I and Hempenius, L},
title = {[Frontotemporal dementia in the elderly: Practical tools].},
journal = {Tijdschrift voor gerontologie en geriatrie},
volume = {56},
number = {4},
pages = {46-58},
doi = {10.54195/tgg23650},
pmid = {41405472},
issn = {0167-9228},
mesh = {Humans ; *Frontotemporal Dementia/diagnosis/psychology ; Aged ; Male ; Female ; Aged, 80 and over ; },
abstract = {Frontotemporal dementia (FTD) is known as a form of dementia that generally occurs at a relatively young age. Diagnosing FTD is often complex, particularly due to various clinical symptoms. Often, cognitive impairments and behavioral problems in elderly are attributed to other, more common causes. However, although rare, FTD can also occur in older adults. This article presents two FTD cases in older individuals, raising awareness. Timely and accurate FTD diagnosis can deliver appropriate care and support for both patients and their families.},
}

Humans
*Frontotemporal Dementia/diagnosis/psychology
Aged
Male
Female
Aged, 80 and over

@article {pmid41405443,
year = {2025},
author = {Thompson, LI and Gaster, B and Hammers, DB and Fittipaldi, S and Barrett, AM and Partrick, KA and Scholler, E and Tiede, B and Butler, CR and , },
title = {Acceptable standards for clinic-based digital cognitive assessments: Recommendations from the Global CEO Initiative on Alzheimer's Disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {12},
pages = {e70966},
doi = {10.1002/alz.70966},
pmid = {41405443},
issn = {1552-5279},
support = {//Biogen/ ; //Eisai/ ; //Eli Lilly/ ; },
mesh = {Humans ; *Alzheimer Disease/diagnosis ; *Cognitive Dysfunction/diagnosis ; *Neuropsychological Tests/standards ; },
abstract = {The rising prevalence of mild cognitive impairment (MCI) and dementia, combined with persistent underdiagnosis, is driving an increased need for scalable cognitive assessment tools. Digital cognitive assessments (DCAs) offer a promising solution by addressing longstanding barriers to routine cognitive testing and diagnosis. However, variations in performance and intended use have created confusion about their clinical applications and utility. The Global CEO Initiative on Alzheimer's Disease convened a DCA Workgroup to define the preferred characteristics of DCAs to meet the needs of patients, health care providers, and regulators for three clinical contexts: (1) initial detection of cognitive impairment, (2) diagnostic support for MCI and dementia, and (3) characterization of cognitive profiles to support identifying etiology. In the near term, ensuring that DCAs meet or exceed the performance of non-digital tools is a priority. DCAs must be validated in the intended use population with well-characterized study samples and inclusive designs.},
}

Humans
*Alzheimer Disease/diagnosis
*Cognitive Dysfunction/diagnosis
*Neuropsychological Tests/standards

@article {pmid41405327,
year = {2025},
author = {Tang, C and Zheng, X and Li, H and Wang, B and Zheng, Y and Song, W and Wu, A and Xin, L and Zhang, D and Yang, R and Du, S and He, P and Li, Y and Wu, L and Wang, X and Shi, Q and Bernardes, GJL},
title = {Deep cervical lymphatic-venous anastomosis in dementia: a clinical and mechanistic evaluation.},
journal = {International journal of surgery (London, England)},
volume = {},
number = {},
pages = {},
doi = {10.1097/JS9.0000000000004561},
pmid = {41405327},
issn = {1743-9159},
abstract = {BACKGROUND: Alzheimer's disease (AD) and other dementias are marked by progressive cognitive decline, with few effective treatments available in advanced stages. Impaired clearance of neurotoxic proteins such as amyloid-beta (Aβ) and tau is a central pathological feature. Deep cervical lymphatic-venous anastomosis (dcLVA) is a novel microsurgical approach designed to enhance cerebrospinal fluid (CSF) clearance via extracranial lymphatic pathways, potentially enabling removal of neurotoxic proteins.

OBJECTIVE: To evaluate the clinical effects and potential mechanisms of dcLVA in patients with advanced dementia, focusing on cognitive, functional, and immunopathological outcomes.

METHODS: Twenty-eight patients with advanced dementia underwent dcLVA. Cognitive performance was assessed using the Mini-Mental State Examination (MMSE), alongside evaluations of bowel and bladder control, emotional stability, behavioral responsiveness, and self-care abilities. Biological parameters-including CSF protein, tumor markers, lymphocyte counts, and peripheral blood concentrations of Aβ1-42 and phosphorylated tau-181 (P-tau181)-were measured pre- and postoperatively. Immunohistochemical analysis of resected cervical lymph nodes was performed to detect CNS-derived tau protein.

RESULTS: Within one week after dcLVA, 64.3% of patients demonstrated MMSE improvement, with further functional gains observed in continence, emotional regulation, motor coordination, and feeding independence. Patients with circulatory comorbidities were more likely to show cognitive recovery. Tau protein was detected in all examined cervical lymph nodes, providing direct histopathological evidence of CNS-derived pathological protein transport via the lymphatic system. In a subset of cognitively improved patients, peripheral lymphocyte counts normalized. In contrast, tumor markers and CSF total protein showed no significant correlation with outcomes.

CONCLUSIONS: dcLVA may promote cognitive and functional recovery in patients with dementia by enhancing CNS waste clearance and modulating systemic immune responses. These exploratory findings describe postoperative changes observed in this cohort; however, the single-arm design precludes causal interpretation.},
}

@article {pmid41405261,
year = {2025},
author = {Chang, L and Liu, X and Wu, H and Yan, J and Chen, N and Li, H and Wu, W and Chen, J and Zhang, J},
title = {Alzheimer's and Other Dementias Attributable to Hyperglycaemia and High BMI Worldwide, 1990-2021: GBD 2021 Cross-sectional Analysis and ARIMA Forecasts.},
journal = {International journal of surgery (London, England)},
volume = {},
number = {},
pages = {},
doi = {10.1097/JS9.0000000000004499},
pmid = {41405261},
issn = {1743-9159},
abstract = {BACKGROUND: Against the backdrop of the accelerating global aging population, the burden on society and families caused by Alzheimer's disease, namely AD and non-AD cognitive disorders, is continuously increasing.

METHOD: This article uses the 2021 Global Burden of Disease dataset to comprehensively examine how hyperglycemia and elevated body mass index (BMI) have caused global mortality, disability-adjusted life years(DALYs), years of life lost(YLLs), and years of life with disability(YLDs) related to AD and other types of dementia from 1990 to 2021. For the results obtained from the analysis, this paper classifies them by gender, age and sociodemographic index(SDI), and presents the classified results. Subsequently, this paper also uses the ARIMA model to predict the future development trend of the burden of dementia caused by high blood sugar and high BMI from 2022 to 2050.

RESULTS: From 1990 to 2021, the dementia burden attributable to hyperglycemia increased, with DALYs rising by 3,907,314 (EAPC,2.14), deaths by 218,561 (EAPC,2.31), YLDs by 124,780 (EAPC,2.09), and YLLs by 2,682,533 (EAPC,2.16). High BMI showed similar increases, with DALYs rising by 2,020,996 (EAPC,2.32), deaths by 107,862 (EAPC,2.35), YLDs by 634,949 (EAPC,2.28), and YLLs by 1,386,047 (EAPC,2.34). Growth was greatest among women, among adults aged 80 years and older, and in regions with low and middle SDI. ARIMA forecasts for 2022 to 2050 indicate continued increases, identifying older adults, particularly women, as priority groups for prevention and control.

CONCLUSION: This study shows that the implementation of hierarchical and precise prevention and control strategies for metabolism related dementia, the establishment of a dynamic monitoring system based on age threshold, and the development of a risk prediction model suitable for resource poor areas will effectively delay the growth trend of dementia incidence.},
}

@article {pmid41404739,
year = {2025},
author = {Zhang, CH and Huang, LY and Feng, YG and Tan, CC and Tan, L and Xu, W},
title = {APOE Genotype Modulates the Relationship of Stroke With Dementia Risk: Associations and Peripheral Clues for Biological Mechanisms.},
journal = {Journal of the American Heart Association},
volume = {},
number = {},
pages = {e043446},
doi = {10.1161/JAHA.125.043446},
pmid = {41404739},
issn = {2047-9980},
abstract = {BACKGROUND: Stroke and APOE ε4 are established risk factors of dementia. However, it remains unclear whether stroke interacts with APOE genotypes to influence dementia occurrence. This study aims to investigate the associations of stroke and its interaction by APOE genotypes with incident risk of dementia, with a specific focus on peripheral clues for biological mechanisms.

METHODS: This prospective cohort study included 336 903 participants (mean age: 56.3 years, stroke history: 1.3%, APOE ε4: 28.5%) from the UK Biobank, with a median follow-up of 13 years. Cumulative incidence curves were constructed using Fine-Gray death competing risks analysis. The additive and multiplicative interaction of stroke (including ischemic and hemorrhagic stroke) with APOE genotypes on incident risk of all-cause dementia (ACD) and Alzheimer disease were examined. Blood proteomics combined with bioinformatics analyses were used to explore the peripheral clues for biological mechanisms.

RESULTS: Either ischemic or hemorrhagic stroke was significantly associated with elevated risk of ACD and Alzheimer disease (P<0.001). A significant multiplicative interaction was observed between stroke and APOE ε4 (P<0.001). The association of stroke with increased risk of dementia was stronger in APOE ε4 non-carriers than carriers, for both ACD (hazard ratio [HR], 1.93 for carriers and 3.36 for non-carriers, P<0.001) and AD (HR, 1.14 for carriers and 2.67 for non-carriers, P<0.001). Inflammation-related pathways could be mechanisms underpinning the association of stroke with ACD risk. We identified 191 functionally interconnected (P<1.0×10[-16]) proteins associated with both stroke and ACD only in APOE ε4 non-carriers. CD4-related and TGF-beta (transforming growth factor beta) signaling pathway could mediate the strengthened relationship in APOE ε4 non-carriers.

CONCLUSIONS: Stroke interacts with APOE ε4 to influence dementia, with the association being more pronounced in APOE ε4 non-carriers. Future studies are needed to verify the underpinning mechanisms to guide precise prevention.},
}

@article {pmid41404649,
year = {2025},
author = {Harput, E and Boccalini, C and Mathoux, G and Prior, JO and Testart, N and Jreige, M and Garibotto, V},
title = {Mapping Alzheimer's disease heterogeneity with molecular imaging biomarkers.},
journal = {European journal of clinical investigation},
volume = {},
number = {},
pages = {e70163},
doi = {10.1111/eci.70163},
pmid = {41404649},
issn = {1365-2362},
support = {//Schmidheiny Foundation/ ; //Fondation Privée des HUG/ ; 320030_169876//Fondation Ernst et Lucie Schmidheiny/ ; 320030_185028//Fondation Ernst et Lucie Schmidheiny/ ; 320030_220099//Fondation Ernst et Lucie Schmidheiny/ ; //Velux Fonden/ ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is neuropathologically defined by the buildup of misfolded proteins such as extracellular amyloid-β (Aβ) and intracellular tau neurofibrillary tangles. AD also extends beyond these pathological processes, and additional mechanisms such as synaptic dysfunction, microglial activity, astrocytic neuroinflammation play an important role as biomarkers of AD progression. In vivo evaluation and quantification of these molecular processes are possible with positron emission tomography (PET) imaging. As disease-modifying therapies are entering clinical use, biomarkers' importance for early diagnosis and longitudinal monitoring of the disease increases.

RESULTS: Aβ is the earliest signature of AD which can be measured with PET imaging, followed by tau-PET positivity, which is highly specific and central for staging and longitudinal monitoring. FDG-PET continues to serve as a gold standard for detecting neurodegeneration, challenged by emerging dual-phase PET protocols for amyloid and tau imaging, which integrate perfusion as a measure of neurodegeneration and pathology information in a single session, enhancing diagnostic efficiency. Synaptic density imaging reveals early synaptic loss linked to cognitive performance and decline. Neuroinflammation tracers can visualize microglial and astrocytic activation, contributing to disease onset and progression. Novel PET tracers targeting alpha-synuclein and TDP-43 show great promise for detecting co-pathologies which can contribute to AD clinical heterogeneity.

CONCLUSION: PET imaging has advanced the field by enabling visualization of AD-related changes and providing measurable outcomes for clinical trials and disease-modifying therapies. Imaging of related pathologies can further improve diagnostic accuracy and provide important insights into disease heterogeneity. Moving forward, integrating multiple PET biomarkers into personalized diagnostic approaches will be crucial.},
}

@article {pmid41404527,
year = {2025},
author = {Nestor, PJ and Pelekanos, M and Leinenga, G and Song, J and Lee, W and Richter-Stretton, G and McElligott, C and Fazlollahi, A and Mattingley, JB and Harris, A and Beale, H and Roberts, J and de Las Heras, R and Götz, J},
title = {A pilot safety and tolerability study of scanning ultrasound as a neuromodulation therapy in Alzheimer's disease.},
journal = {Brain communications},
volume = {7},
number = {6},
pages = {fcaf445},
pmid = {41404527},
issn = {2632-1297},
abstract = {Clearing amyloid-β pathology in Alzheimer's disease (AD) has been considered a prerequisite for restoring cognitive functions. Intriguingly, by application of a modality of scanning ultrasound (SUS) to mice that does not remove amyloid-β, we previously achieved significant cognitive improvements. This prompted us to explore SUS as a non-invasive brain stimulation strategy in an open-label safety trial in AD. We conducted a human pilot study in 12 participants with AD with the primary objective of determining feasibility, safety and tolerability. Exploratory secondary end-points were cognitive and behavioural measures, resting-state EEG and functional MRI. A portable device termed UltraThera[Pilot] was built under medical device standard guidelines, integrating a Brainsight image-guided neuronavigation system. A single-element 286-kHz transducer was programmed to deliver non-derated ultrasound doses of 2.6, 1.95 or 1.3 MPa. With four treatment sessions spaced fortnightly, four participants received 30 sonications per session (precuneus, ∼30 cm[3] brain tissue) and the remaining 8 received 100 sonications per session (bilateral precuneus and temporo-parietal association cortex, ∼100 cm[3]). Safety monitoring, EEG, MRI, cognitive and neuropsychiatric evaluations were performed. The treatment was fast, safe and well-tolerated at the 1.95 MPa dose. MRI showed no changes, whereas changes were observed in aperiodic EEG content. Cognitive performance did not change but statistically significant improvements in behavioural and psychological symptoms were found using the Neuropsychiatric Inventory test. In conclusion, this SUS safety trial met its primary and secondary end-points in biomarker-confirmed mild-to-moderate AD. It informs our future work in an upcoming efficacy trial in an AD population.},
}

@article {pmid41404525,
year = {2025},
author = {Parker, CS and Young, C and Magill, N and Lu, K and Crutch, SJ and Fox, NC and Weston, PSJ},
title = {Accelerated forgetting in presymptomatic Alzheimer's: mediation by prefrontal cortical degeneration.},
journal = {Brain communications},
volume = {7},
number = {6},
pages = {fcaf478},
pmid = {41404525},
issn = {2632-1297},
abstract = {In Alzheimer's disease (AD), accelerated long-term forgetting (ALF), where information is retained normally over 10-30 min but lost at an accelerated rate over subsequent days to weeks, develops several years before symptom onset. However, the neuroanatomical changes underpinning ALF remain undetermined. Eighteen presymptomatic autosomal dominant AD mutation carriers and 12 non-carriers underwent ALF assessment with a list, a story, and visual figure, testing 30-min and 7-day recall of each, separately. T1 and diffusion-weighted MRI were acquired. Cortical thickness was estimated for 13 pre-defined grey matter regions, with streamline tractography assessing associated structural connectivity. In mutation carriers, lower verbal ALF performance (list and story) was strongly associated with thinner prefrontal cortex (PFC) across four contiguous regions bilaterally. This association was absent in non-carriers. No associations were found between ALF and the thickness/volume of medial temporal lobe (MTL) structures. The association between ALF and PFC connectivity was weaker than for cortical thickness. Our results suggest that early subtle pathological change in PFC underpins ALF development, highlighting the central role of PFC dysfunction in very early AD-related cognitive decline. ALF may represent a qualitatively different (non-MTL driven) form of forgetting compared with the short interval forgetting that develops at later disease stages.},
}

@article {pmid41404484,
year = {2025},
author = {Huang, X and Xu, Y and Liao, R and Zhao, Q and Lv, X and Liu, Q and Li, L and Ji, Q and Tian, D and Wang, Y and Zhan, Y},
title = {Long-term Alzheimer's disease mortality prediction in adults aged ≥60 years: A prospective cohort study benchmarking survival machine learning algorithms.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {17},
number = {4},
pages = {e70229},
pmid = {41404484},
issn = {2352-8729},
abstract = {INTRODUCTION: Accurate risk stratification for long-term Alzheimer's disease (AD)-specific mortality remains limited.

METHODS: We analyzed data from 5,149 adults aged ≥60 years in NHANES III (1988-1994), with 116 baseline variables and mortality follow-up through 2019 via the National Death Index. Ten survival machine learning (ML) models were benchmarked. Predictive performance was assessed using Harrell's concordance index (C-index).

RESULTS: Over a median follow-up of 12.1 years for survivors and 17.8 years for decedents, Lasso (C-index = 0.76, 95% CI: 0.72-0.80) and Extreme Gradient Boosting (C-index = 0.76, 95% CI: 0.73-0.79) achieved the highest accuracy. Feature importance analyses revealed novel predictors of AD mortality. Models using fewer than 20 variables retained acceptable performance (C-index > 0.70).

CONCLUSION: Survival ML models effectively predict long-term AD-specific mortality using routine clinical data. Their interpretability, scalability, and capacity to identify novel risk factors support integration into geriatric risk assessment frameworks.

HIGHLIGHTS: We benchmarked 10 survival machine learning (ML) algorithms using 116 clinical variables to predict long-term Alzheimer's disease (AD)-specific mortality.Feature importance analysis identified novel non-imaging clinical predictors, including arm circumference, self-rated physical activity, and alcohol consumption.This work highlights the underused potential of routine clinical data for AD mortality prediction and underscores the need for interpretable, population-based ML applications.},
}

@article {pmid41404461,
year = {2025},
author = {Li, W and Liu, X and Gao, C and Li, W and Liao, X},
title = {Network meta-analysis of the efficacy of pharmacological treatments for post-stroke cognitive impairment and vascular cognitive impairment.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1683496},
pmid = {41404461},
issn = {1664-2295},
abstract = {BACKGROUND: Based on recent reviews, vascular cognitive impairment (VCI) encompasses a spectrum of cognitive deficits caused by cerebrovascular disease and its risk factors, ranging from mild cognitive impairment to dementia, and often coexists with neurodegenerative conditions like Alzheimer's disease. VCI is categorized into four clinical-imaging subtypes, including post-stroke cognitive impairment (PSCI)-a common stroke complication and major VCI subtype. Current guidelines recommend cholinesterase inhibitors and NMDA receptor antagonists as first-line treatments for VCI, with expert consensus supporting donepezil and rivastigmine for PSCI. However, existing evidence primarily derives from placebo-controlled or head-to-head drug comparisons, lacking comprehensive evaluations of multiple cognitive enhancers. This study aims to systematically assess the efficacy and safety of cognitive-enhancing drugs in VCI, with a focused analysis on PSCI, to better inform clinical decision-making and improve patient outcomes.

METHODS: We systematically searched four databases using predefined search strategies. Eligible studies were selected based on predetermined criteria. The included studies were analyzed with StataSE 16.0, RevMan 5.3, and Grade software to compare the efficacy and safety of cognitive-enhancing drugs to identify the optimal treatment for VCI and PSCI.

RESULTS: Sixteen studies (5,599 participants) were included. In terms of cognitive outcomes, sailuotong was superior to placebo on the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) (MD = -3.00, 95% CI: -4.50, -1.50) and ranked best (SUCRA 88.5%). Memantine was most effective on the Mini-Mental State Examination (MMSE) (MD = 1.23, 95% CI: 0.23-2.23; SUCRA 80.8%). For the secondary outcome, the MoCA assessment showed that Ginkgo biloba extract significantly improved Montreal Cognitive Assessment (MoCA) scores compared to placebo (MD = 1.29, 95% CI: 1.24, 1.35). Regarding safety, donepezil significantly increased the risk of overall adverse events compared to placebo (OR: 1.57; 95% CI: 1.19-2.06).

CONCLUSION: Our network meta-analysis suggests that memantine might have the best effect for PSCI, with sailuotong potentially serving as a secondary option. However, these estimates are based on a small randomized controlled trial and a sparse network. Therefore, the current evidence is limited, highlighting the need for more high-quality studies to robustly validate the therapeutic potential of these interventions for VCI and PSCI.

https://www.crd.york.ac.uk/PROSPERO/, identifier in PROSPERO (CRD420250627957).},
}

@article {pmid41404293,
year = {2025},
author = {Ray, NR and Kurup, J and Kumar, A and Rajabli, F and Wang, L and Xu, W and Jin, F and Yilmaz, E and Kizil, C and Bertholim-Nasciben, L and Moura, S and Ramirez, AM and Baiyewu, O and Griswold, AJ and Coker, M and Scott, KM and Akinwande, K and Adams, LD and Diala, S and Whitehead, PG and McCauley, JL and Ogunronbi, M and Hamilton-Nelson, KL and Damasceno, A and Zaman, AF and Blanton, SH and Akpalu, A and Cuccaro, ML and Wahab, K and McInerney, KF and Nuytemans, K and Obiako, R and Mena, PR and Okubadejo, N and Martinez, IM and Zewde, YZ and Gugssa, SA and Sarfo, FS and Kalaria, R and Ndetei, DM and Williams, SM and Caban-Holt, A and , and , and Tosto, G and Haines, JL and Akinyemi, RO and Ogunniyi, A and Byrd, GS and Bush, WS and Kunkle, BW and Vance, JM and Pericak-Vance, MA and Reitz, C},
title = {Local genetic correlation analysis of Alzheimer's disease and stroke implicates PHLPP1 as a shared locus in individuals of African ancestry.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2025.12.03.25341552},
pmid = {41404293},
abstract = {BACKGROUND: Neuropathological studies indicate a strong association between Alzheimer's disease (AD) and stroke, yet the molecular mechanisms underlying this association remain unclear.

METHODS: Local genetic correlation analysis was conducted with LAVA using the results from genome-wide association studies on AD and stroke in individuals of African ancestry. Enhanced Hi-C Capture Analysis (eHiCA) examined chromatin interactions using iPSC-derived cells from AD brain autopsy samples.

RESULTS: LAVA identified a region shared between AD and stroke on chromosome 18q21.33(r g = .77, P = 2.41×10 [-6]). eHiCA demonstrated that the AD and stroke loci interact with regulatory elements in PHLPP1 . Variants at PHLPP1 were also associated with AD in an independent set of individuals of African ancestry (P = 4.56 × 10 [-5]).

CONCLUSIONS: This study identified a region on top of PHLPP1 as a locus associated with both AD and stroke. PHLPP1 inhibits protein kinase B, which contributes to both AD and stroke pathophysiology.},
}

@article {pmid41404291,
year = {2025},
author = {Zeng, Y and Cook, N and Yang, C and Sivasankaran, SK and Fujita, M and Gardell, ZA and Le Guen, Y and Shigemizu, D and Ozaki, K and Morizono, T and Hara, N and Miyashita, A and Ikeuchi, T and Pottier, C and Cruchaga, C and Napolioni, V and Corces, MR and Menon, V and Greicius, MD and Belloy, ME},
title = {APOE *4 Risk-Modifying Genes and Drug Targets in Alzheimer's Disease through Cell-Type Specific Genomic Analyses.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2025.12.02.25341367},
pmid = {41404291},
abstract = {IMPORTANCE: APOE *4 is the strongest, common genetic risk factor for late-onset Alzheimer's disease (AD) with widespread and cell-type-specific impact on disease pathogenesis. Genetics and omics studies can help identify genes that counteract the effects of APOE *4, but so far have remained relatively small and crucially did not assess genetic findings through a cell-type-specific framework.

OBJECTIVES: Perform a large-scale APOE *4 stratified genome-wide association study (GWAS) of AD integrated with genetically tethered cell-type-specific multi-omics data.

DESIGN: Meta-analysis of APOE *4 stratified AD GWAS in case-control, family-based, population-based, and longitudinal AD-related cohorts from the Alzheimer's Disease Genetics Consortium, Alzheimer's Disease Sequencing Project, and UK Biobank. Integration of GWAS with brain cell-type-specific genetic regulation of gene expression data, from the Religious Orders Study and Memory and Aging Project, to identify APOE *4 and cell-type-specific AD genes. Cell-type-specific multi-omics gene prioritization followed by compound and drug repurposing. Data analyzed between January 2023 and September 2025.

SETTING: Genetic data available from high-density single-nucleotide polymorphism (SNP) microarrays and whole-genome sequencing (WGS). Single-nucleus (sn) RNA-seq data from dorsolateral prefrontal cortex.

PARTICIPANTS: 567,521 eligible participants for AD genetic association studies were selected from referred and volunteer samples, of which 119,852 were excluded for analysis exclusion criteria.

MAIN OUTCOME AND MEASURES: APOE *4 and cell-type-specific gene Z-scores and FDR-corrected P-values. Gene prioritization scores and APOE *4 stratified enriched compounds.

RESULTS: 67 and 17 significant cell-type-gene pairs were identified in APOE *4 non-carriers (APOE *4-) and carriers (APOE *4+) respectively. Oligodendrocytes displayed the largest proportion of APOE *4+ genes. 46 cell-type-gene pairs were supported by at least half of the gene prioritization analyses. Several prioritized genes were druggable and displayed enrichment of APOE *4 stratified drugs or compounds. Top APOE *4+ genes with connections to enriched drugs or compounds included TNS3 (astrocytes), CISD1 and SLC23A2 (oligodendrocytes), and UBXN4 (excitatory neurons).

CONCLUSION AND RELEVANCE: We identified a set of APOE *4 stratified genes that may be causal for AD through brain cell-type-specific mechanisms and prioritized top genes for further interrogation. We additionally identified compounds that may be repurposed or shed light on therapeutic avenues for treating AD based on an individual's APOE *4 status. Top identified compounds such as Hydrocortisone and Trolox implicate oxidative stress and neuroinflammation as potential biological targets in APOE *4+ individuals.},
}

@article {pmid41404290,
year = {2025},
author = {Rocha, B and Jonaitis, E and Hamwi, A and Engelman, CD},
title = {Longitudinal, intra-individual stability of untargeted plasma and cerebrospinal fluid metabolites.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2025.12.10.25341983},
pmid = {41404290},
abstract = {BACKGROUND/OBJECTIVES: Longitudinal metabolomics analysis offers valuable insight into how metabolic pathways change according to age and health status. However, metabolite levels can fluctuate due to biological factors (ex. age, diet, health-status) and technical factors (ex. sample handling, storage times, instrument performance), with some metabolites exhibiting greater sensitivity to these sources of variability than others. This study aimed to characterize the longitudinal and technical stability of untargeted plasma and cerebrospinal fluid (CSF) metabolites, and to identify a subset that remains reliable over the extended time scales required for epidemiological research.

METHODS: Untargeted ultra-high-performance liquid chromatography-mass spectrometry (LC-MS) metabolomic profiles were available from multiple visits in the Wisconsin Registry for Alzheimer's Prevention (WRAP) and Wisconsin Alzheimer's Disease Research Center (ADRC) studies. For this analysis, we constructed a subset of generally healthy participants with samples drawn at four time points (∼2.5 years apart): two visits analyzed in 2017 and two visits analyzed in 2023, corresponding to two distinct analytical waves. We computed Rothery's intraclass correlation coefficients (ICCs) to quantify intrawave and inter-wave stability, evaluated pooled quality-control (QC) variation, classified metabolite stability by established thresh-olds, and developed a composite score integrating longitudinal stability and susceptibility to technical variance.

RESULTS: Across all metabolites, median stability was classified as fair (Rothery's ρ >0.40 to ≤0.75) for both plasma and CSF. Although analytical batches were bridged using pooled QC samples, inter-wave stability was significantly lower than intra-wave stability, reflecting increased technical variability across waves. Using the composite score, we identified subsets of metabolites with excellent stability and low susceptibility to batch effects in plasma and CSF. Stability patterns varied across biochemical super pathways.

CONCLUSIONS: This work highlights metabolites suitable for long-term epidemiological studies and informs experimental design and analytical strategies for combining data across cohorts and analytical batches.},
}

@article {pmid41404281,
year = {2025},
author = {Barough, SS and Ohno, S and Bilgel, M and Sair, HI and Luciano, MG and Moghekar, A},
title = {Disproportionately Elevated Sulcal Index (DESI): An automatically driven index representing disproportionate subarachnoid space enlargement in brain MRI scans.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2025.12.01.25341388},
pmid = {41404281},
abstract = {BACKGROUND: Idiopathic normal pressure hydrocephalus (iNPH) is a reversible cause of dementia in older adults yet remains underdiagnosed due to nonspecific clinical presentation and reliance on invasive confirmatory tests. Conventional MRI biomarkers, including the Evans index and callosal angle, capture ventricular enlargement but incompletely characterize cerebrospinal fluid (CSF) redistribution. Disproportionately enlarged subarachnoid-space hydrocephalus (DESH) features, tight high-convexity sulci and enlarged Sylvian fissures, are more disease-specific but lack standardized quantitative measures.

METHODS: We developed the Disproportionately Elevated Sulcal Index (DESI), an automated volumetric biomarker quantifying the ratio of Sylvian fissure volume to superior sulcal space volume. T1-weighted MRI scans were acquired from three independent cohorts: the Baltimore Longitudinal Study of Aging (n = 1,032), Johns Hopkins CSF Disorders Clinic (n = 216), and the Placebo-controlled Efficacy of iNPH Shunting trial (n = 94). Preprocessing included N4 bias correction, standard-space registration, and alignment. A U-Net segmentation model with an EfficientNet-B0 encoder delineated Sylvian fissures and sulcal compartments. DESI was computed from 3D reconstructions and evaluated using Dice similarity coefficients, landmark detection error, and classification performance across diagnostic groups.

RESULTS: Segmentation achieved ∼0.80 DICE for Sylvian fissures; ∼0.74 for superior sulci. On external validation, DESI discriminated NPH with DESH from non-DESH NPH with AUC = 0.99, accuracy 97.9%, and from all other groups (healthy controls, Alzheimer's disease, vascular dementia) with perfect classification (AUC = 1.00, 100% sensitivity and specificity at threshold = 4.83). In cognitively normal adults, DESI showed only a modest age-related increase and no sex differences, confirming specificity for hydrocephalic pathology.

CONCLUSION: DESI is a robust, fully automated MRI biomarker that sensitively detects CSF redistribution characteristic of DESH in iNPH. By outperforming traditional indices and achieving near-perfect diagnostic accuracy across independent cohorts, DESI offers a noninvasive tool for early detection, patient selection for shunting, and longitudinal monitoring of disease progression.},
}

@article {pmid41404278,
year = {2025},
author = {Saichandran, KS and Elzokm, K and Guney, OB and Kolachalama, VB},
title = {Agentic AI for automated hypothesis testing in Alzheimer's disease and related dementias.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2025.12.02.25341517},
pmid = {41404278},
abstract = {BACKGROUND: Alzheimer's disease and related dementias (ADRD) are multifactorial disorders driven by genetic, vascular, inflammatory, lifestyle, and biological factors interacting over decades, requiring population-level analyses. However, utilizing multimodal datasets is labor-intensive, impeding discovery and equity. Multi-agentic AI systems promise workflow automation but lack ADRD-specific adaptations.

METHODS: We created a modular AI system with agents for data preparation, planning, analysis, critique, and summarization. Using data from the National Alzheimer's Coordinating Center (NACC) (n=48,876), we tested 100 literature-derived ADRD hypotheses, subsampled cohorts (100-10,000 participants), and 100 non-ADRD controls via iterative loops.

RESULTS: The system verified 42.0±2.8 hypotheses by rejecting the null, found no evidence for 16.6±1.1, and deemed 41.4±2.3 not testable, with consistency in negated versions. Verification rates rose from 10.4 (n=100) to 35.4 (n=10,000); controls showed 85.2±0.6 non-testable.

CONCLUSIONS: Our system illustrates a powerful paradigm in which AI can facilitate automated data analysis, expediting advancements in population-level dementia investigations.},
}

@article {pmid41404160,
year = {2025},
author = {Roche, S and Naran, N and Scholtz, J and Liu, KY and Reeves, S and Howard, R},
title = {Systematic review and meta-analysis of antipsychotic discontinuation in dementia.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {11},
number = {4},
pages = {e70188},
pmid = {41404160},
issn = {2352-8737},
abstract = {INTRODUCTION: Antipsychotics are used to treat behavioral and psychological symptoms of dementia (BPSD). However, treatment is associated with adverse outcomes. A 2018 Cochrane review found low-quality evidence that discontinuation may have little effect on BPSD by primarily comparing the difference in number of study non-completers between treatment groups and did not report a pooled effect size for relapse risk. We performed a meta-analysis of the pooled risk ratio (RR) of relapse of symptoms following antipsychotic medication discontinuation in people with dementia. We hypothesized that trial design (enriched responder samples vs long-term user withdrawal), treatment duration, length of follow-up, withdrawal speed, and sex of participants would affect relapse risk.

METHODS: We systematically searched PsycINFO, EMBASE, PubMed, and ClinicalTrials.gov databases for studies published between January 2018 and June 2024. The eight papers identified in the 2018 Cochrane review were also included in the meta-analysis. The study was registered with PROSPERO (CRD42024570329).

RESULTS: A total of nine studies were included, providing 682 observations with 135 events. Relapse definitions included participant removal due to worsening behavior or starting regular prescription of antipsychotic/rescue medication. A random-effects model found a pooled RR of relapse of 1.52 (95% CI: 1.18 to 1.95, p = 0.005) with stopping antipsychotics. Meta-regressions showed no effect of trial type, withdrawal speed, length of follow-up, or participant sex on RR.

DISCUSSION: While it is important to prescribe cautiously and to reduce and withdraw prescriptions in those who are considered to no longer need antipsychotics, there is a subgroup of patients for whom continuing medication is important. It was particularly surprising that the relative risk of relapse was unaffected by trial design, with similar effect sizes in both trials aiming to reduce prescription and prove efficacy. Further research is needed to identify factors associated with successful antipsychotic withdrawal.

HIGHLIGHTS: An updated meta-analysis of trials of withdrawal of antipsychotics in dementia.Relative risk of symptom relapse increased when stopping antipsychotics.Relapse risk was not affected by trial design or prior length of treatment.Relapse risk was not affected by length of follow-up, withdrawal speed, or sex.},
}

@article {pmid41404120,
year = {2025},
author = {Kim, RY and Kuraji, R and Kapila, YL},
title = {Systemic Health Implications of the Leaky Barriers within the Oral-Gut-Brain Axis and its Pathways of Communication.},
journal = {European Medical Journal (Chelmsford, England)},
volume = {10},
number = {1},
pages = {47-50},
pmid = {41404120},
issn = {2397-6764},
}

@article {pmid41403997,
year = {2025},
author = {Iriepa, I and Contino, M and Abate, C and Marco-Contelles, J},
title = {Zervimesine, a Small Sigma‑2 Receptor Selective Modulator for Alzheimer's Disease.},
journal = {ACS medicinal chemistry letters},
volume = {16},
number = {12},
pages = {2371-2372},
pmid = {41403997},
issn = {1948-5875},
abstract = {Zervimesine is a small molecule, able to cross the blood-brain barrier, readily available by straightforward organic chemistry processes, showing few "off-target" effects, but displays a potent and selective S2R modulator profile. Evidence suggests Zervimesine can protect synapses and neurons by preventing the toxic effects of soluble Aβ oligomers.},
}

@article {pmid41403906,
year = {2025},
author = {Duan, Y and Han, C and Zheng, H and Yu, J and Luo, M},
title = {Global, regional, and national burden of Alzheimer's disease and other dementias from 1990 to 2021: findings from the Global Burden of Disease Study 2021.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1678212},
pmid = {41403906},
issn = {1663-4365},
abstract = {BACKGROUND: As the global population continues to age, the growing number of elderly individuals has contributed to an increase in age-related conditions and illnesses, such as dementia, which places considerable financial and emotional pressure on both families and society. Alzheimer's disease (AD), the most prevalent form of dementia among the elderly, significantly impacts their quality of life and ability to perform daily activities independently. Over the past three decades, the age-standardized mortality rate has declined and life expectancy has steadily increased worldwide. However, this long-term progress was disrupted by the COVID-19 pandemic, which reversed some of the gains made in life expectancy and contributed to a global decline. The pandemic has notably affected global health, exacerbating the prevalence of Alzheimer's disease and other dementias (ADOD).

METHODS: In line with the analytical approach used in the Global Burden of Disease Study (GBD) 2021, we examined the counts and age-standardized rates (ASR) for the prevalence, incidence, mortality, and Disability-Adjusted Life Years (DALYs) associated with ADOD, categorized by region, country, sex, and age from 1990 to 2021. To assess temporal patterns over the study period, we calculated the estimated annual percentage changes (EAPCs).

RESULTS: From 1990 to 2021, both the number and age-standardized rates (ASR) of prevalence, incidence, mortality, and DALYs associated with ADOD showed a significant increase globally. Regionally, high-middle SDI regions had the highest ASPR at 766.2 per 100,000 (95% UI: 659.8, 879.6), with the most considerable rise, reflected in an EAPC of 0.21 (95% CI: 0.17, 0.25). In East Asia, the highest age-standardized incidence rate (ASIR) was reported, at 149.6 (95% UI: 129.6, 171.1) per 100,000 people, along with the greatest increase in ASIR, at 0.4 (95% UI: 0.33, 0.47) among the 21 GBD regions. On a national level, China experienced the greatest burden of ADOD, with the highest ASPR of 900.8 (95% UI: 770.9, 1043.2) and the highest ASIR of 151.5 (95% UI: 131.2, 173.3) per 100,000 people. The 80-84 age group exhibited the highest rates of prevalence, incidence, and DALYs, whereas the number of deaths in the 85-89 age group surpassed those in other age categories. Throughout all age groups, females experienced a higher burden of ADOD than males, regardless of the time or geographical location. The burden of ADOD reached its lowest point in 2019 but has increased steadily since then.

CONCLUSION: In summary, this study highlights the global epidemiological trends of ADOD from 1990 to 2021, including the impact of the COVID-19 pandemic on it. As the population ages, ADOD has emerged as a significant public health concern worldwide. Although some regions have made progress in managing the burden of ADOD, most regions and countries still face a heavy disease burden. More effective prevention and treatment strategies are needed to alleviate the impact of ADOD. In particular, greater focus should be placed on women and the elderly.},
}

@article {pmid41403903,
year = {2025},
author = {Farahani, F and Anaclet, C and Azizi, H and Gompf, HS},
title = {The locus coeruleus, a blue spot for early diagnosis and prognosis of Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1632236},
pmid = {41403903},
issn = {1663-4365},
abstract = {Intact functioning of the locus coeruleus-noradrenergic (LC-NA) system is pivotal in the control of numerous central processes, and damage to these systems leads to a wide range of nervous system disorders. The LC, as the main source of noradrenaline (NA) in the mammalian brain, was the first central nervous system (CNS) modulatory structure to be anatomically and biochemically characterized. LC-NA release exerts both excitatory and inhibitory effects on target areas. Over the past few decades, LC damage has been causatively identified as a common factor in CNS diseases, notably neurodegenerative diseases. Moreover, LC damage is the likely manifestation of common pathophysiological processes, thus elevating the LC as a diagnostic and therapeutic target, especially in Parkinson's and Alzheimer's diseases (PD & AD). This review also addresses why LC neurons, compared to other areas in particular, are highly vulnerable and sensitive to damage-such as specific anatomical features, tau phosphorylation, and high neuronal energy requirements-will be described in this review article. Finally, we explore whether these known LC vulnerabilities might be leveraged towards improved early diagnostic and prognostic biomarkers for AD.},
}

@article {pmid41403902,
year = {2025},
author = {Luo, D and Lian, T and Wei, N and Guo, P and He, M and Zhang, Y and Huang, Y and Liu, G and Li, J and Li, J and Qi, J and Guan, H and Zhang, W and Zhang, W and Zheng, Z and Yue, H and Liu, Z and Zhang, F and Meng, Y and Zhang, W},
title = {An investigation on Alzheimer's disease with obstructive sleep apnea: alterations of cognitive function, roles of cyclin-dependent kinase 5 and changes of brain structure.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1552535},
pmid = {41403902},
issn = {1663-4365},
abstract = {AIMS: To investigate alterations of cognitive function, roles of cyclin-dependent kinase 5 (CDK5) and changes of brain structure in Alzheimer's disease (AD) with obstructive sleep apnea (OSA).

METHODS: Total 94 AD with OSA (AD-OSA) patients were divided into 49 cases of AD with mild OSA (AD-OSA-M) and 45 cases of AD with moderate and severe OSA (AD-OSA-MS). Demographic characteristics, cognitive function, the levels of AD neuropathological proteins, CDK5 and synaptic proteins in cerebrospinal fluid (CSF), and brain volume by magnetic resonance imaging were compared between the two groups. The correlations among OSA and the above variables were analyzed.

RESULTS: Compared with AD-OSA-M group, AD-OSA-MS group had a higher body mass index, lower scores of AVLT N7 and SCWT-C, longer SCWT-C time, higher levels of phosphorylated tau (P-tau) 396 and synaptophysin, lower CDK5 level and smaller volumes of brain gray and white matters in parts of frontal, parietal, temporal and occipital lobes. In AD-OSA patients, the decreased CDK5 level was correlated with the elevated levels of P-tau 396 and synaptophysin in CSF. In AD-OSA-MS group, reductions of gray matter and white matter volumes associated with OSA exacerbation was correlated with memory and executive function impairments. The p-values of above results were <0.05.

CONCLUSION: In AD-OSA, OSA exacerbation is associated with memory impairment and executive dysfunction, P-tau 396 elevation and CDK5 decline in CSF, synaptic disruption, and brain atrophy. Additionally, CDK5 may represent a potential therapeutic target for the individuals with comorbid AD and OSA.},
}

@article {pmid41403678,
year = {2025},
author = {Sinan Tokalı, F and Şenol, H and Demir, Y and Uluçay, O and Ameen, M and Shafiq, Z},
title = {New Mannich-type arylidenerhodanines as potent inhibitors of AChE and BChE: synthesis, biological evaluation, cytotoxicity and molecular modeling.},
journal = {RSC advances},
volume = {15},
number = {58},
pages = {50186-50205},
pmid = {41403678},
issn = {2046-2069},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder with a gradual increase in severity. The underlying cause of the disease is the dysfunction of cholinergic neurotransmission affecting mainly the activity of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Within the context of the present research, a new group of 3,5-disubstituted rhodanine derivatives containing tertiary amine groups has been prepared and their potency in the inhibition of AChE and BChE was assessed. Enzymatic assays demonstrated that compounds 6 and 11 exhibited exceptional inhibitory potency, with K i values of 13.61 nM and 12.70 nM against AChE, and 10.44 nM and 25.11 nM against BChE, respectively, surpassing the reference inhibitors tacrine (145.21 nM for AChE and 169.54 nM for BChE) and donepezil (67.41 nM for AChE and 62.44 nM for BChE). Cytotoxicity studies confirmed minimal toxicity in human umbilical vein endothelial cells (HUVEC) at concentrations several times higher than the effective inhibitory doses (IC50 = 79.13 µM for 6 and 69.14 µM for 11). The results from molecular docking and MM-GBSA calculations supported this presumption by foretelling strong binding affinities, where compound 11 was the one to show a free energy of -103.26 kcal mol[-1] for AChE and compound 6 -86.75 kcal mol[-1] for BChE. Moreover, the 250 ns molecular dynamics simulations gave a confirmation of the structural stability and the prolonged existence of the key interactions in the enzyme active sites during the entire time. The findings of this research emphasize compounds 6 and 11 as potential candidates for the creation of strong cholinesterase inhibitors for the treatment of Alzheimer's disease, thus encouraging additional studies.},
}

@article {pmid41403399,
year = {2026},
author = {Ushkempirova, D and Davis, L and Chalmers, A},
title = {Flavour perception in Alzheimer's disease: A systematic review of olfactory and gustatory assessment methods.},
journal = {JAR life},
volume = {15},
number = {},
pages = {100044},
pmid = {41403399},
issn = {2534-773X},
abstract = {Disruptions in flavour perception, due to olfactory dysfunction and gustatory dysfunction, may serve as early indicators of Alzheimer's disease and contribute to reduced quality of life. Flavour perception is a multisensory process, yet no standardised tools currently exist to assess it comprehensively in Alzheimer's disease. This systematic review examined current olfactory and gustatory assessments used to evaluate flavour function in individuals with Alzheimer's. Six studies met the inclusion criteria, encompassing 471 participants, including 161 with Alzheimer's. Olfactory function was most often assessed with the Sniffin' Sticks test, while gustatory function was typically evaluated using Taste Strips. While olfactory dysfunction was consistently reported across studies, evidence for gustatory impairment was less uniform, reflecting methodological variability in taste assessment procedures. Only one study used a culturally adapted test, and none assessed umami. However, the small number of studies, heterogeneity in methodology, and limited cultural adaptation constrain the generalisability of these findings. These findings highlight the need for a culturally adaptable, combined flavour assessment tool that minimises cognitive and linguistic demands to support early detection and monitoring of Alzheimer's disease.},
}

@article {pmid41403158,
year = {2025},
author = {Bell, SA and Fiffer, M and Martindale, J and Bynum, JPW and Tootoo, J and Zomorrodi, R and Lilienfeld, A and Miranda, ML and Davis, MA},
title = {Variation in One-Year Mortality Following Severe Weather Exposure Among Older Americans by Chronic Health Condition and Sociodemographic Status.},
journal = {Journal of the American Geriatrics Society},
volume = {},
number = {},
pages = {},
doi = {10.1111/jgs.70237},
pmid = {41403158},
issn = {1532-5415},
support = {RF1AG083768/AG/NIA NIH HHS/United States ; },
abstract = {BACKGROUND: While the immediate effect of exposure to severe weather from hurricanes on mortality is well documented, it is unknown whether mortality in the year following exposure to severe weather differs across older Americans with specific vulnerable characteristics. This paper sought to determine whether the association between exposure to high rain and one-year mortality differs across vulnerable subgroups of older adults.

METHODS: This retrospective cohort study used Medicare claims data from fee-for-service beneficiaries aged ≥ 65 in Texas and Louisiana in the year before and after Hurricane Harvey. Historical weather data was used to construct a 4-day measure of cumulative rainfall, the primary severe weather caused by Hurricane Harvey. We identified vulnerable subgroups based on five chronic health conditions requiring regular healthcare access, and sociodemographic factors (e.g., ≥ 85 years, dual eligibility). Cox proportional hazards regression was used to adjust for covariates when estimating the association between high rain exposure and mortality up to 1 year after exposure.

RESULTS: In adjusted models, high rain exposure was significantly associated with greater mortality risk (HR 1.03, 95% CI 1.01-1.05). Among those with chronic health conditions including Alzheimer's disease and related dementias (ADRD) (HR 1.05 [95% CI 1.03, 1.08]), diabetes (HR 1.04 [1.02, 1.07]), and chronic kidney disease (HR 1.04 [1.01, 1.06]) exposed to high rain versus those unexposed to high rain, associations with high rain were found. Higher mortality was also observed among Non-Hispanic Black (HR 1.06 [95% CI 1.01, 1.11]) and Hispanic and Latino populations (HR 1.13 [95% CI 1.08, 1.19]).

CONCLUSION: Exposure to high rain from Hurricane Harvey was associated with higher one-year mortality that varied across vulnerable groups. The largest associations were observed among older adults with health conditions that require regular healthcare (e.g., CKD, ADRD) and minoritized racial and ethnic groups.},
}

@article {pmid41403033,
year = {2025},
author = {Berthier, ML and Sosa-Welford, A and Orozco-Arroyave, JR and López-Barroso, D and Torres-Prioris, MJ and Dávila, G and García, AM},
title = {Speech and language outcome measures in clinical trials of Alzheimer's and Parkinson's diseases.},
journal = {Expert review of neurotherapeutics},
volume = {},
number = {},
pages = {1-20},
doi = {10.1080/14737175.2025.2600616},
pmid = {41403033},
issn = {1744-8360},
abstract = {INTRODUCTION: Alongside core diagnostic symptoms, Alzheimer's disease (AD) and Parkinson's disease (PD) involve early and pervasive speech-language impairments (SLI), often appearing in preclinical stages and capturing disease severity. However, speech language outcome measures are under-represented in clinical trials, missing out on critical clinical outcome assessments (COAs).

AREAS COVERED: The purpose of this review is to survey the findings from classical (analogical) and novel (digital) speech-language measures as pathways toward more precise diagnosis and response to treatment indices in interventional clinical trials. This narrative review covers two main areas; first, it examines the strengths and limitations of SL measures in traditional cognitive testing scales to identify adequate COAs for AD and PD. Second, it overviews findings on classical and digital COAs that hold great promise despite their widespread absence in clinical trials.

EXPERT OPINION: Incorporating strategic SL COAs in clinical trials may identify early, severity-sensitive deficits and enhance the clinical insights thus obtained. The modification of clinical trial designs will nevertheless be required to increase sensitivity to identify meaningful clinical outcomes.},
}

@article {pmid41402904,
year = {2025},
author = {Garg, M and Liu, X and Lin, J and Vassilaki, M and Petersen, RC and St Sauver, J and Kapoor, E and Sohn, S},
title = {Sex differences in cognitive decline and impairment: a scoping review in informatics literature.},
journal = {Biology of sex differences},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13293-025-00804-6},
pmid = {41402904},
issn = {2042-6410},
support = {R01 AG068007 and RF1 AG090341/NH/NIH HHS/United States ; },
abstract = {OBJECTIVES: A scoping review was conducted to investigate knowledge gaps in the informatics research literature regarding sex differences in cognitive decline and impairment, identifying existing studies and areas requiring further exploration.

METHODS AND MATERIALS: Our scoping review follows the Preferred Reporting Items for Systematic reviews and Meta-Analysis Extension for Scoping Reviews (PRISMA - ScR) guidelines. We searched Ovid and other databases (APA PsychInfo, EMB Reviews, and Embase) for studies on sex differences in cognitive decline and impairment, focusing on peer-reviewed informatics journals and conference proceedings from 2000 to 2025. The selected manuscripts were analyzed based on metadata statistics, study attributes, and thematic content.

RESULTS: A total of 17 full articles met the inclusion criteria. Most studies were conducted in North America (n = 7) and the European Union (n = 5). More than half of the studies were published after 2020 (n = 10). Our analyses highlight key aspects of selected studies, including bibliometric metadata, study attributes (e.g., study types, methods, and data sources), and thematic findings. Statistical modeling (n = 8) and machine learning (n = 4) are the most widely used study methods. Majority (n = 11) of the publications are single-site studies, while the other multi-site collaborations (n = 6) have emerged among hospitals, academic institutions, and research institutions.

DISCUSSION: Sex-specific disparities in cognitive decline and impairment remain a critical issue in healthcare. Most informatics research has primarily concentrated on identifying generic sex differences in cognitive decline and impairment progression, rather than exploring the complex underlying mechanisms such as observational studies with causal analysis. While these studies are valuable, they lack a holistic approach to understanding sex-specific disparities.

CONCLUSION: There is a significant gap in using informatics to understand how biological, social, and behavioral factors contribute to sex-specific disparities in cognitive decline and impairment. This limitation underscores the need for more comprehensive informatics research that goes beyond mere identification to find the root cause of these disparities in healthcare.},
}

@article {pmid41402778,
year = {2025},
author = {Myrstad, C and Larssen, M and Engdahl, B and Selbæk, G},
title = {Smoking is associated with increased risk for dementia: the HUNT study, Norway.},
journal = {BMC public health},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12889-025-25813-3},
pmid = {41402778},
issn = {1471-2458},
abstract = {BACKGROUND: Smoking is considered a risk factor for dementia. Nevertheless, uncertainty regarding the associations with dementia subtypes and the effects of quitting remains. In this large longitudinal population-based cohort study, we investigated smoking as an independent risk factor for all-cause dementia. Second, we investigated the associations with dementia subtypes.

METHODS: We included participants from the Trøndelag Health Study (HUNT) and collected their smoking status at baseline (HUNT2, 1995-97). We assessed cognitive status at follow-up two decades later (HUNT4 70+, 2017-19, N = 8,532) and collected pack-years. We handled missing data with multiple imputations and estimated relative risks (RRs) with Poisson regression after adjustment for covariates and stratification by age and sex.

RESULTS: Current smokers had a 31% increased dementia risk (RR 1.31, 95% confidence interval (CI) 1.12-1.52), women <85 at follow-up had a 54% increased risk (RR 1.54, 95% CI 1.20-1.98), and men <85 had a 36% increased risk (RR 1.36, 95% CI 1.01-1.82). We found no associations in persons 85+. Current smokers had an increased risk for vascular dementia but not for Alzheimer's dementia. Pack-years were not associated with increased dementia risk, and former smoking was only associated with vascular dementia in men.

CONCLUSIONS: Current smoking was associated with an increased risk of dementia. Among those 85+ at follow-up, being a smoker 20+ years earlier was not associated with an increased risk of dementia, probably because death was a competing risk. In former smokers, there were no significant associations with dementia. Our results add to the literature an optimism about the effects of changing smoking habits and may encourage smoking cessation.},
}

@article {pmid41402627,
year = {2025},
author = {Guillén, N and Esteller, D and Sarto, J and Perales, I and Ríos-Guillermo, J and Massons, M and Martín-Sobrino, I and Augé, JM and Naranjo, L and Ruiz-García, R and Juncà-Parella, J and Rigol, A and Patricio, V and Tort-Merino, A and Fernandez-Villullas, G and Alcon, D and Comas-Albertí, A and Antonell, A and Borrego-Écija, S and Sánchez, M and Castellví, M and Bosch, B and Sánchez-Valle, R and Balasa, M and Falgàs, N and Lladó, A},
title = {Plasma p-Tau217 and GFAP predict widespread cognitive decline in Alzheimer's disease.},
journal = {Journal of neurology},
volume = {273},
number = {1},
pages = {28},
pmid = {41402627},
issn = {1432-1459},
support = {PI19/00449//Instituto de Salud Carlos III/ ; PI23/00173//Instituto de Salud Carlos III/ ; FI20/00076//Instituto de Salud Carlos III/ ; JR22/00014//Instituto de Salud Carlos III/ ; AACSF_21_723056/ALZ/Alzheimer's Association/United States ; },
mesh = {Humans ; *Alzheimer Disease/blood/diagnosis/complications/cerebrospinal fluid ; *tau Proteins/blood/cerebrospinal fluid ; Male ; Female ; Aged ; Biomarkers/blood/cerebrospinal fluid ; *Glial Fibrillary Acidic Protein/blood ; *Cognitive Dysfunction/blood/diagnosis/etiology ; Middle Aged ; Aged, 80 and over ; Neurofilament Proteins/blood ; Disease Progression ; Longitudinal Studies ; Neuropsychological Tests ; },
abstract = {INTRODUCTION: Progression in Alzheimer's disease (AD) involves three main interrelated biological axes-tau deposition, neurodegeneration, and neuroinflammation-that jointly drive cognitive decline. Although several cerebrospinal fluid (CSF) and plasma biomarkers along these axes are well validated for diagnosis, their value for prognosis remains uncertain. We assessed how baseline markers of each axis predict cognitive trajectories in biomarker-confirmed AD.

METHODS: We included 136 A + T + N + individuals (median follow-up = 24 months [IQR 12-24]; mean = 17.6 months [SD = 12.4]). Tau-deposition markers (CSF p-Tau181; plasma p-Tau181 and p-Tau217), neurodegeneration markers (CSF t-Tau; CSF and plasma neurofilament light chain, NfL) and a neuroinflammation marker (plasma glial fibrillary acidic protein, GFAP) were quantified using CLEIA, ELISA or Simoa, and stratified into tertiles. Participants were classified by age at onset, clinical phenotype, and APOE ε4 status. Cognition was assessed annually with a comprehensive neuropsychological battery. Linear mixed-effects models (MMRM) were used to test biomarker-cognition associations and interactions with clinical variables.

RESULTS: Elevated CSF p-Tau181 and NfL levels were associated with greater decline in memory and executive function. Among plasma biomarkers, p-Tau217 and GFAP showed the strongest associations with widespread cognitive decline, particularly in language, visuospatial, and executive domains. These associations were independent of age at onset, clinical phenotype, and APOE ε4 status.

DISCUSSION/CONCLUSION: Our findings highlight the potential prognostic value of fluid biomarkers in AD, especially CSF p-Tau181 and NfL, and plasma p-Tau217 and GFAP. These results suggest promise for improving disease monitoring, although prognostic utility at the individual level remains uncertain.},
}

Humans
*Alzheimer Disease/blood/diagnosis/complications/cerebrospinal fluid
*tau Proteins/blood/cerebrospinal fluid
Male
Female
Aged
Biomarkers/blood/cerebrospinal fluid
*Glial Fibrillary Acidic Protein/blood
*Cognitive Dysfunction/blood/diagnosis/etiology
Middle Aged
Aged, 80 and over
Neurofilament Proteins/blood
Disease Progression
Longitudinal Studies
Neuropsychological Tests

@article {pmid41402481,
year = {2025},
author = {Cheliadinova, U and Sims, S and Korkmaz, F and Vasilyeva, D and Laurencin, V and Gimenez-Roig, J and Pevnev, G and Burganova, G and Tumoglu, Z and Parte, S and Sultana, F and Pallapati, AR and Rojekar, S and Macdonald, A and Hutchison, S and Soussan, A and Liu, A and Wei, Y and Moldavski, O and Gumerova, A and Zhou, W and Barak, O and Goosens, KA and Ryu, V and Lizneva, D and Rosen, CJ and Yuen, T and Frolinger, T and Zaidi, M},
title = {Fshr gene depletion prevents recognition memory loss, fat accrual and bone loss in Alzheimer's mice.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {41402481},
issn = {1476-5578},
support = {R01 AG074092/AG/NIA NIH HHS/United States ; U01 AG073148/AG/NIA NIH HHS/United States ; U19 AG060917/AG/NIA NIH HHS/United States ; RF1 AG093773/AG/NIA NIH HHS/United States ; R61 AG094602/AG/NIA NIH HHS/United States ; R01 AG071870/AG/NIA NIH HHS/United States ; R61 AG094602/AG/NIA NIH HHS/United States ; RF1 AG093773/AG/NIA NIH HHS/United States ; R61 AG094602/AG/NIA NIH HHS/United States ; R01 AG074092/AG/NIA NIH HHS/United States ; U01 AG073148/AG/NIA NIH HHS/United States ; R01 AG071870/AG/NIA NIH HHS/United States ; R61 AG094602/AG/NIA NIH HHS/United States ; U19 AG060917/AG/NIA NIH HHS/United States ; },
abstract = {Epidemiologic evidence links follicle-stimulating hormone (FSH), a pituitary glycoprotein that rises during menopause, to memory loss, fat accumulation, and bone loss. We and others have shown that the attenuation of FSH signaling, either genetically or pharmacologically, prevents memory loss, fat accrual, and bone loss in multiple mouse models. Here, we investigated whether the genetic depletion of the FSH receptor (Fshr) affects recognition memory, body composition, and bone mineral density (BMD) in two AD mouse models. We generated male and female 3xTg and APP-KI mice carrying the Fshr[+/+], Fshr[+/-], and Fshr[-/-] genotypes. Recognition memory was evaluated using the Novel Object Recognition (NOR) test. Body composition (fat, lean, and total mass) and site-specific bone mineral density (femur, tibia, L3-L5 spine) measurements were made using quantitative nuclear magnetic resonance (qNMR) and dual-energy X-ray absorptiometry (DXA), respectively, at two time points. Given that female Fshr[-/-] genotypes are otherwise hypogonadal, they were implanted with 17β-estradiol pellets at 8-12 weeks of age to normalize serum estrogen. At the early time point, the deficit in recognition memory was rescued in female 3xTg;Fshr[-/-] and APP-KI;Fshr[-/-] mice, but not in male mice. Likewise, female, but not male 3xTg;Fshr[-/-] mice showed reduced fat mass at both the early and later time points, but without changes in total body mass. In contrast, in the APP-KI cohort, both female and male Fshr[-/-] mice showed reduced fat mass at the early, but not the late time point. DXA revealed that female, but not male APP-KI;Fshr[-/-] mice showed progressive increases with time in BMDs in tibiae, femora, and vertebrae, which were either statistically significant or approached significance. This phenotype was not observed on the 3xTg background. These studies constitute the first report for time- and strain-dependent effects of global Fshr depletion in the same mouse, setting the stage for the simultaneous prevention, using a single therapeutic, of three disorders of public health magnitude-Alzheimer's disease, obesity and osteoporosis.},
}

@article {pmid41402464,
year = {2025},
author = {Lin, J and Han, H and Wu, K and Wu, X and Shen, J and Mo, Y and Zhang, Q and Yang, H and Yu, Z},
title = {Hv1 inhibition rescues AD pathology by restoring microglial mitochondrial function and enhancing mitochondrial transfer.},
journal = {Experimental & molecular medicine},
volume = {},
number = {},
pages = {},
pmid = {41402464},
issn = {2092-6413},
support = {82173791//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82273857//National Natural Science Foundation of China (National Science Foundation of China)/ ; 23ZR1436600//Science and Technology Commission of Shanghai Municipality (Shanghai Municipal Science and Technology Commission)/ ; },
abstract = {Hyperphosphorylated tau aggregation and neuroinflammation are hallmark pathologies of Alzheimer's disease (AD), with microglia playing a critical role in modulating these processes through maintaining immune homeostasis and clearing pathological tau, both of which depend on mitochondrial health. However, the mechanisms underlying microglial mitochondrial dysfunction in AD remain poorly understood, limiting therapeutic development. Hydrogen voltage-gated channel 1 (Hv1), expressed in microglia within the central nervous system, regulates intracellular pH and reactive oxygen species generation. Here we observe that Hv1 is upregulated in activated microglia in AD mouse models. Remarkably, Hv1 contributes to electron transport chain abnormalities, leading to mitochondrial oxidative stress, loss of mitochondrial membrane potential, impaired ATP production and deficient mitophagy in tau pathology. These deficits impair tau clearance through phagocytosis and autophagy but can be significantly reversed by the Hv1-specific inhibitor YHV98-4. Furthermore, YHV98-4 enhances microglia-to-neuron mitochondrial transfer, promoting the delivery of functional mitochondria to rescue neuronal damage and improve cognitive function. Collectively, our study underscores the pivotal role of Hv1 in microglial mitochondrial dysfunction in AD and identifies YHV98-4 as a promising therapeutic candidate.},
}

@article {pmid41402453,
year = {2025},
author = {Rasà, DM and Stanga, S and Santonicola, P and Mazzarella, N and Camera, A and Matino, I and Zampi, G and Boido, M and Di Schiavi, E and Vercelli, A},
title = {10H-phenothiazine exerts beneficial effects in spinal muscular atrophy in vitro and in vivo models.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-025-28547-9},
pmid = {41402453},
issn = {2045-2322},
support = {24401//AFM-Telethon/ ; 24401//AFM-Telethon/ ; GGP16203//Italian Telethon Foundation/ ; GGP16203//Italian Telethon Foundation/ ; Mission M4C2I1.3, PRR.AP015.118//National Recovery and Resilience Plan (NRRP)/ ; Department of Excellence//Ministry of University and Research (MUR)/ ; },
abstract = {Spinal Muscular Atrophy (SMA) is a neurodegenerative disorder affecting lower motor neurons (MNs) and leading to muscle atrophy, due to mutation of the SMN1 gene, which encodes SMN protein. Experimental studies also demonstrated the upper MN impairment. The available approved drugs for SMA increase the SMN protein production. Although effective, outcomes are dependent upon treatment timing and disease severity. Drug repositioning may represent a valid strategy to identify new treatments by repurposing FDA/EMA-approved drugs that, combined with the available ones, could delay neurodegeneration. To this aim, for the first time we used primary cortical neurons derived from the SMNΔ7 mice as defective in vitro disease model, to preliminary assess drug efficacy on neuronal survival and morphology. Under basal conditions, SMA cortical neurons showed significantly reduced vitality and altered morphology compared to WT neurons. All the parameters were rescued after treatment with known compounds (Valproic Acid, 4-aminopyridine and N-acetylcysteine), already tested in either preclinical or clinical context for SMA. We then investigated for the first time in SMA pathology the efficacy of 10H-phenothiazine (10H-PTZ), known to exert neuroprotection and to target altered mechanisms in Parkinson's and Alzheimer's disease. Its administration to SMA cortical neurons induced significant protective effects on both neuronal survival and morphology that were further confirmed in vivo, in a C. elegans SMA model. Overall, our results provide valuable insights, both in vitro and in vivo, into the potential of 10 H-PTZ repurposing for SMA, although additional functional studies will be required.},
}

@article {pmid41402425,
year = {2025},
author = {Narayan, S and Mao, K and Williams-Medina, AR and Richmann, T and Gal, M and Engel, M and Zhang, Y and Graff, S and Sidoli, S and Barzilai, N and Huffman, DM},
title = {Reduced IGF-1 signaling fails to limit Alzheimer's disease progression in a novel rat model of IGF-1R haploinsufficiency.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-025-31601-1},
pmid = {41402425},
issn = {2045-2322},
abstract = {The growth hormone/insulin-like growth factor-1 (GH/IGF-1) signaling pathway has been strongly implicated in the aging process. Lifespan is profoundly increased in both male and female dwarf mice, while low IGF-1 signaling per se leads to more modest improvements in female lifespan. However, as opposed to the consistency offered by studies in dwarf mice, nuances in the relationship of this axis with health and disease have also been observed, including in rat models of low GH/IGF-1 signaling. This complexity further extends to cognitive decline and Alzheimer's disease (AD), where this relationship has proven to be nuanced. To help address these gap, we have generated a new rat model of Igf1r[+/-] haploinsufficiency, to assess effects on metabolic health and AD. Similar to mice, we find that constitutively reduced IGF-1R levels leads to ~ 15% reduced adult body size in male and female rats, while not impairing insulin sensitivity. However, when crossed with TgF344-AD rats, lowering IGF-1 signaling per se failed to confer protection against AD-related pathology, including amyloid burden, phosphorylated tau or neuroinflammation in male and female TgF344-AD rats, and even appeared to exacerbate facets of disease in females, including an increase in cortical small amyloid plaques. Moreover, a unique hippocampal proteomic signature emerges in female Het/AD rats, including lower levels of proteins involved in redox balance. Overall, these data suggest a nuanced relationship of IGF-1R tone and AD exists and that better defining a more precise role of growth factor signaling in CNS health and disease throughout the life course is warranted.},
}

@article {pmid41401902,
year = {2025},
author = {Li, HR and Shi, JZ and Zhang, MJ and Yun, LY and Zhou, YF and He, YY and Li, X and Du, GH and Pang, XB and Wang, MW and Xie, XM and Kou, JJ},
title = {Cftr Nominates a Novel Therapeutic Target for Alzheimer's Disease: Evidence from Integrative Omics and In Vitro Validation.},
journal = {Neuropharmacology},
volume = {},
number = {},
pages = {110808},
doi = {10.1016/j.neuropharm.2025.110808},
pmid = {41401902},
issn = {1873-7064},
abstract = {Alzheimer's disease (AD), among the most prevalent neurodegenerative disorders, poses substantial challenges for therapeutic development due to its complex pathophysiology, necessitating novel treatment strategies. This study applied an integrated transcriptomics and untargeted metabolomics approach to hippocampal tissues from wild-type and 3×Tg-AD mice to identify AD-associated molecular alterations and key pathways. KEGG pathway enrichment analysis of significantly differentially expressed genes and metabolites identified several core candidate genes, including C5ar1, Gabrg1, Ptger1, Tac1, Lpar2, Pnp2, Cftr, and Sstr3. PCR-based validation in both in vivo and in vitro models confirmed Cftr as the most promising candidate for further investigation. In Aβ25-35-induced cellular AD models, Cftr knockdown or pharmacological inhibition activated the NLRP3 inflammasome pathway, exacerbating neuroinflammation and oxidative stress, whereas enhancing Cftr activity attenuated these pathological processes. These results establish Cftr as a potential therapeutic target for AD and reveal that its modulation of NLRP3 inflammasome signaling represents a strategic avenue for mitigating neuroinflammation and oxidative stress, suggesting a promising direction for intervening in AD progression.},
}

@article {pmid41401894,
year = {2025},
author = {Mehmood, A and Shahid, F and Khan, R and AlZu'bi, H},
title = {A review of deep learning techniques in Alzheimer's disease with emphasis on data tools and transfer learning.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2025.12.032},
pmid = {41401894},
issn = {1873-7544},
abstract = {Alzheimer's disease (AD) is a significant neurological condition that is marked by the gradual decline of memory and cognitive function, with a higher incidence observed in older individuals. The mental deterioration associated with this condition is irreversible, resulting in substantial consequences for both affected individuals and society as a whole. Despite relentless research efforts, a definitive cure for AD remains elusive. However, interventions targeting the early stages of the disease have shown promise in slowing its progression. Deep learning-based approaches introduced better results for the early identification of AD stages, which can be curable. Due to less annotated data, those models have many problems regarding model over-fitting and class imbalance issues, directly impacting the model's performance. Researchers developed transfer learning-based approaches to overcome those issues, which can produce improved results on fewer annotated data samples. The primary motivation behind this article is to provide a review of the article, which is directly based on the transfer learning techniques for classifying AD stages using MRI and PET modalities. This article also provides a complete review of pre-processing tools for data extraction. It discusses the challenges that affect the performance of the models, as well as generalization challenges and biases in transfer learning.},
}

@article {pmid41401892,
year = {2025},
author = {Jogeshwar, BK and Lu, S and Nephew, BC},
title = {Neuroanatomical-based machine learning prediction of Alzheimer's Disease across sex and age.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2025.12.030},
pmid = {41401892},
issn = {1873-7544},
abstract = {Alzheimer's Disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and memory loss. In 2024 it affected approximately 1 in 9 people aged 65 and older in the U.S., 6.9 million individuals. Early detection and accurate AD diagnosis are crucial for improving patient outcomes. Magnetic resonance imaging (MRI) has emerged as a valuable tool for examining brain structure and identifying potential AD biomarkers. This study performs predictive analyses by employing machine learning techniques to identify key brain regions associated with AD using numerical data derived from anatomical MRI scans, going beyond standard statistical methods. Using the Random Forest Algorithm, we achieved 92.87 % accuracy in detecting AD from Mild Cognitive Impairment and Cognitive Normals. Subgroup analyses across nine sex- and age-based cohorts (69-76 years, 77-84 years, and unified 69-84 years) revealed the hippocampus, amygdala, and entorhinal cortex as con- sistent top-rank predictors. These regions showed distinct volume reductions across age and sex groups, reflecting distinct age- and sex-related neuroanatomical patterns. Younger males and females (aged 69-76) exhibited volume decreases in the right hippocampus, suggesting its importance in the early stages of AD. Older males (77-84) showed substantial volume decreases in the left inferior temporal cortex. The left middle temporal cortex showed decreased volume in females, suggesting a potential female-specific influence, while the right entorhinal cortex may have a male-specific impact. These age-specific sex differences could inform clinical research and treatment strategies, aiding in identifying neuroanatomical markers and therapeutic targets for future clinical interventions.},
}

@article {pmid41401875,
year = {2025},
author = {Aksoz, E and Karabulut, M and Yaranoğlu, MH},
title = {Vitamin D3 supplementation reverses aging-related changes in cholinergic functions and improves spatial memory in aged rats.},
journal = {Behavioural brain research},
volume = {},
number = {},
pages = {115998},
doi = {10.1016/j.bbr.2025.115998},
pmid = {41401875},
issn = {1872-7549},
abstract = {AIM: Dietary intake and synthesis of vitamin D synthesis decline with age, increasing the risk of vitamin D deficiency. Dementia and Alzheimer's disease development are closely linked to vitamin D deficiency. In this study, we investigated whether vitamin D supplementation could attenuate age-related effects on memory and the hippocampal cholinergic system in aged rats.

METHOD: Thirty Wistar albino male rats (young: 4-5 months old, aged: 21-22 months old) were included in this study. Animals were divided into three groups: The Young control and the Aged control groups were administered physiological serum and the Aged + Vitamin D group was administered vitamin D (500 IU/kg/day). Spatial memory was assessed with the Morris Water Maze test. Then, ACh level and ChAT, AChE, and BChE enzyme activities in the hippocampus were examined.

RESULTS: Vitamin D supplementation given to aged rats increased the AchE and BuChE enzyme activities and ACh levels which decreased with aging. The activity of the ChAT enzyme did not change in the aged group, and vitamin D supplementation did not affect it. Increased hippocampal cholinergic transmission improved the spatial memory of aged rats in the MWM test.

CONCLUSION: Vitamin D supplementation improved spatial memory in rats, probably by reversing the aging-related changes in brain cholinergic functions. Vitamin D shows promise in delaying cognitive decline associated with aging and AD.},
}

@article {pmid41401852,
year = {2025},
author = {Huang, YW and Chan, HC and Khoo, JY and Chan, ML and Bender, D and Ponnusamy, VK and Belaidi, AA and Ke, LY},
title = {Assessing the critical role of ceramide in the pathogenesis of Alzheimer's disease and its clinical significance.},
journal = {Neurochemistry international},
volume = {},
number = {},
pages = {106104},
doi = {10.1016/j.neuint.2025.106104},
pmid = {41401852},
issn = {1872-9754},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) deposition, tau hyperphosphorylation, and synaptic loss. Emerging evidence indicates that apolipoprotein E (APOE) polymorphism and dysregulated ceramide metabolism are critical links among these pathogenic processes. Ceramide accumulation in the brain contributes to Aβ generation, tau phosphorylation, and neuronal apoptosis. Elevated ceramide levels have been observed in plasma, cerebrospinal fluid, and peripheral organs such as the liver, reflecting systemic lipid dysregulation. Lipoproteins-particularly low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL)-transport ceramide across the blood-brain barrier, while apoE4 isoforms exacerbate this process by disrupting vascular integrity and lipid homeostasis. In addition, hepatic and gut-derived ceramides may influence neurodegeneration through the liver-gut-brain axis. Therapeutic interventions targeting ceramide synthesis (serine palmitoyltransferase inhibitors), production (neutral sphingomyelinase inhibitors), and the ceramide/sphingosine-1-phosphate (S1P) balance show potential in preclinical models for reducing Aβ pathology, tau aggregation, and neuroinflammation. These findings position ceramide metabolism as a critical mediator of AD pathogenesis and a promising target for diagnosis and treatment. Modulating ceramide and S1P signaling could complement current amyloid- and tau-directed therapies, offering new opportunities for disease modification and early intervention.},
}

@article {pmid41401514,
year = {2025},
author = {Nemzer, B and Al-Taher, F and Abshiru, N and de Mejia, E},
title = {Coffee and Coffee By-Products as Multifunctional Foods and Ingredients.},
journal = {Annual review of food science and technology},
volume = {},
number = {},
pages = {},
doi = {10.1146/annurev-food-052924-114847},
pmid = {41401514},
issn = {1941-1421},
abstract = {Coffee contains various bioactive compounds with potential benefits for human health. Coffee has been shown to, and may, display neuroprotective properties, potentially preventing the onset of neurodegenerative conditions such as Alzheimer's and Parkinson's diseases. Coffee waste and by-products (pulp/husks, silverskin, and spent coffee grounds) exhibit similar phytochemistry and health benefits to coffee. They are also rich in dietary fiber, carbohydrates, phenolic compounds, and caffeine, which vary depending on the beverage processing, roasting, and preparation methods. Coffee and coffee industry by-products are sources of unique functional ingredients that affect gut microbiota. This review aims to summarize the phytochemical and nutritional composition of whole coffee cherries, coffee beans, and coffee by-products as well as their bioavailability, bioactivity, and multifunctionality in supporting human wellness, neuroprotection, and metabolic health. The bioactive compounds of coffee and its by-products suggest their unique applicability as functional food beverages, dietary ingredients, and health supplements.},
}

@article {pmid41401338,
year = {2025},
author = {Polak, A and Kosiń, K and Liszka, W and Malina, M and Kiwior, J},
title = {The impact of intermittent fasting on cognitive function and neuroprotection: A literature review.},
journal = {Wiadomosci lekarskie (Warsaw, Poland : 1960)},
volume = {78},
number = {10},
pages = {2167-2172},
doi = {10.36740/WLek/210261},
pmid = {41401338},
issn = {0043-5147},
mesh = {Humans ; *Fasting/physiology ; *Cognition/physiology ; *Neuroprotection ; *Alzheimer Disease/prevention & control ; *Parkinson Disease ; Circadian Rhythm ; Intermittent Fasting ; },
abstract = {OBJECTIVE: Aim: To summarise current knowledge on the effects of intermittent fasting on cognitive functions and neuroprotective mechanisms, with particular attention to Alzheimer's disease and Parkinson's disease.

PATIENTS AND METHODS: Materials and Methods: A narrative review based on twelve peer-reviewed publications on the effects of intermittent fasting on cognitive function, neuroprotection, and circadian rhythms. Preclinical data and selected clinical studies indicate that intermittent fasting improves memory, attention, and executive functions, which is associated with activation of autophagy, reduction of oxidative stress, improved mitochondrial function, and increased levels of brain-derived neurotrophic factor. In Parkinson's disease, intermittent fasting limits alpha-synuclein aggregation and protects dopaminergic neurons, whereas in Alzheimer's disease it reduces beta-amyloid deposition and enhances synaptic plasticity. Intermittent fasting also influences the gut-brain axis and circadian rhythm alignment, which may further support neuroprotection.

CONCLUSION: Conclusions: Intermittent fasting is a promising adjunct strategy in the management of neurodegenerative diseases. However, well-designed, randomised clinical trials are needed to confirm its effectiveness and safety.},
}

Humans
*Fasting/physiology
*Cognition/physiology
*Neuroprotection
*Alzheimer Disease/prevention & control
*Parkinson Disease
Circadian Rhythm
Intermittent Fasting

@article {pmid41400891,
year = {2025},
author = {Agliardi, C and Guerini, FR and Zanzottera, M and Bolognesi, E and Meloni, M and Saibene, FL and Zangaglia, R and Sturchio, A and Casali, C and Di Lorenzo, C and Navarro, J and Minafra, B and Clerici, M},
title = {Analysis of AQP4 SNPs and Their Association With REM Sleep Behavior Disorder and Hallucinations in Parkinson's Disease.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {302},
pmid = {41400891},
issn = {1559-1182},
support = {National Recovery and Resilience Plan (NRRP), project MNESYS (PE0000006) - A Multiscale integrated approach to the study of the nervous system in health and disease (DN. 1553 11.10.2022)//Ministero dell'Università e della Ricerca/ ; Ricerca corrente 2025 [RC2025]//Ministero della Salute/ ; },
mesh = {Humans ; *Polymorphism, Single Nucleotide/genetics ; *Parkinson Disease/genetics/complications ; *Aquaporin 4/genetics ; Male ; Female ; *Hallucinations/genetics/complications ; *REM Sleep Behavior Disorder/genetics/complications ; Aged ; *Genetic Predisposition to Disease ; Middle Aged ; *Genetic Association Studies ; Case-Control Studies ; },
abstract = {The glymphatic system is a glial-dependent network responsible for the clearance of waste products from the brain through cerebrospinal fluid (CSF) circulation. This process, which involves astrocytes and the water channel AQP4, facilitates the removal of harmful proteins like β-amyloid and tau, making it crucial in neurodegenerative diseases such as Alzheimer's (AD) and Parkinson's disease (PD). AQP4 dysfunction has been linked to the accumulation of these proteins and related pathologies. This study aimed to investigate the association between AQP4 gene polymorphisms (rs2075575, rs162009, and rs335929) and PD in an Italian cohort, consisting of 380 individuals with PD enrolled in a rehabilitation protocol and 461 healthy controls. The analysis found no significant correlation between the selected AQP4 single nucleotide polymorphisms (SNPs) and PD risk. However, the rs162009 AA genotype was associated with a lower risk of developing REM sleep behavior disorder (RBD) symptoms in PD patients, while rs2075575 was linked to hallucinations in these individuals. These findings suggest a potential role for AQP4 polymorphisms in sleep disturbances and psychotic symptoms in PD, but further research is needed to confirm these results and understand the complex interactions between the glymphatic system and PD pathophysiology.},
}

Humans
*Polymorphism, Single Nucleotide/genetics
*Parkinson Disease/genetics/complications
*Aquaporin 4/genetics
Male
Female
*Hallucinations/genetics/complications
*REM Sleep Behavior Disorder/genetics/complications
Aged
*Genetic Predisposition to Disease
Middle Aged
*Genetic Association Studies
Case-Control Studies

@article {pmid41400850,
year = {2025},
author = {Davoody, S and Vakili, K and Jazi, K and Fathi, M and Heidari-Foroozan, M and Mofidi, SA and Taremi, M and Taherkhani, A and Azadnajafabad, S and Pour, FH and Eslami, S and Zangi, M and Mohamadkhani, A},
title = {Alterations of Gut Microbiota and Microbial Metabolites in Parkinson's Disease: A Systematic Review.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {299},
pmid = {41400850},
issn = {1559-1182},
mesh = {*Gastrointestinal Microbiome/physiology ; *Parkinson Disease/microbiology/metabolism ; Humans ; Fatty Acids, Volatile/metabolism ; },
abstract = {Parkinson's disease (PD) is a significant global health issue, ranking as the second most prevalent neurodegenerative disorder after Alzheimer's disease. Research suggests that changes in the gut microbiota may occur before the onset of the motor symptoms of PD. This study seeks to conduct a systematic review (PROSPERO registration ID: CRD420251118297) to explore the mechanistic exploration and biomarker identification of gut microbiota in PD. The research involved a comprehensive literature search across PubMed, Scopus, and Web of Science databases up to August 2022 using a combination of Medical Subject Heading (MeSH) terms for Parkinson's disease, gut microbiota, and metabolites. Eligible studies included in vivo and in vitro investigations focusing on the metabolite levels produced by the gut microbiota in PD patients. Data extraction was performed by two researchers using Microsoft Excel Software. The Newcastle-Ottawa Scale (NOS) was used to assess the risk of bias. The certainty of the evidence was evaluated using the GRADE framework. The review encompassed 39 selected studies, comprising data from over 3000 participants. Approximately two-thirds of the studies reported a reduction in short-chain fatty acids (SCFAs), notably butyrate and acetate, while almost half reported increased trimethylamine N-oxide (TMAO) levels or altered amino acid and bile acid pathways. Key findings emphasized the comparison of microbiomes in PD patients and healthy controls, highlighting metabolic pathway alterations and their implications for PD development. Studies also delved into the role of inflammation in PD progression, exploring the connection between inflammatory factors and the microbiota. Additionally, the present study examined the influence of PD medications on gut microbiota. This systematic review highlights the potential involvement of gut microbiota in modulating the gut-brain axis in PD. Observed associations suggest links between altered metabolite production, pro-inflammatory states, increased gut permeability, and changes in LPS and α-synuclein dynamics. However, these relationships remain largely correlative, and causal mechanisms are yet to be established. Further longitudinal and mechanistic studies are warranted to confirm these observations and explore their clinical relevance.},
}

*Gastrointestinal Microbiome/physiology
*Parkinson Disease/microbiology/metabolism
Humans
Fatty Acids, Volatile/metabolism

@article {pmid41400837,
year = {2025},
author = {Boccardi, V},
title = {From risk to prevention: Clinical and public health strategies to reduce Alzheimer's disease burden.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251407715},
doi = {10.1177/13872877251407715},
pmid = {41400837},
issn = {1875-8908},
abstract = {The growing prevalence of Alzheimer's disease (AD) requires strategies that go beyond risk identification to active prevention. In a recent large cohort study, Lee and colleagues demonstrated a "dose-dependent" relationship between cumulative lifestyle risk and AD incidence, thus underlining the power of modifiable factors in modulating cognitive trajectories. This commentary explores the clinical and public health implications, highlighting how sustained behavioral interventions, early risk assessment, integrated care models, and population-level policies can reduce the burden of AD and improve cognitive health outcomes across aging societies.},
}

@article {pmid41400820,
year = {2025},
author = {Al-Mayahi, S and Andersson, ML and Mo, M and Garcia-Ptacek, S and Xu, H and Wikström, E and Eriksdotter, M},
title = {Increased mortality in dementia patients using inhaled anticholinergics: A nationwide register study from the Swedish registry on dementia/cognitive disorders, SveDem.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251406309},
doi = {10.1177/13872877251406309},
pmid = {41400820},
issn = {1875-8908},
abstract = {BackgroundPatients with chronic obstructive pulmonary disease (COPD) face increased risks of cognitive impairment and mortality compared with the general population. Inhaled anticholinergics (LAMA/SAMA) are central in COPD treatment. The link between COPD and dementia is well studied, while effects of COPD medications on survival in dementia patients, have received limited attention.ObjectiveDescribe dementia patients using LAMA/SAMA in the Swedish Dementia Registry (SveDem) and compare survival between users (exposed) and non-users (unexposed).MethodsThis register-based study used data from SveDem and the Swedish Prescribed Drug Register to identify dementia patients using inhaled anticholinergics. All patients diagnosed with dementia between 2008-01-01 and 2017-12-31 were included. Exposed patients had at least one LAMA/SAMA dispensation per year in the two years prior the index date or more than one in the year before. Standardized-mortality-rates (SMR) were calculated, and survival analysed using Kaplan-Meier and Cox regression.ResultsA total of 74,018 dementia patients were included, of whom 3.5% had used inhaled anticholinergics. Alzheimer's disease was the most common dementia type. SMR was higher in exposed patients across all age groups: 8.21 versus 4.08 (ages 61-75) and 2.94 versus 1.84 (ages 75-90). Exposed had a higher risk of death (crude HR 1.73, 95% CI: 1.62-1.86) compared to unexposed.ConclusionsIn this register-based study we observed an association between inhaled anticholinergic use and reduced survival in dementia patients. This association is thought to be mainly driven by the underlying disease, COPD. Further studies are needed to clarify effects of inhaled anticholinergics on survival.},
}

@article {pmid41400773,
year = {2025},
author = {Kamitaka, Y and Sakata, M and Oda, K and Katsuki, A and Kawakami, H and Wagatsuma, K and Kobayashi, M and Ishii, K},
title = {Quantitative validation of data-driven motion correction for brain PET using phantom with motion generator system.},
journal = {EJNMMI physics},
volume = {},
number = {},
pages = {},
doi = {10.1186/s40658-025-00820-w},
pmid = {41400773},
issn = {2197-7364},
support = {investigator-sponsored research grant//GE Healthcare/ ; },
abstract = {BACKGROUND: Head motion during brain positron emission tomography (PET) degrades image quality and quantitative accuracy. Therefore, a data-driven motion correction (MC) method utilizing ultrafast list-mode reconstruction technology has been proposed and shown to considerably improve image quality. However, reproducing accurate actual motions and motion-free images using clinical data alone remains challenging. This study aimed to quantitatively evaluate data-driven MC using a brain phantom for known tracer distributions and a custom-made motion generator system for variable known motions.

METHODS: Hoffman 3D brain phantom was filled with 20 and 3 MBq of [[18]F]fluoro-2-deoxy-D-glucose (FDG) to simulate high- and low-radioactivity conditions corresponding to brain FDG PET and amyloid PET acquisitions, respectively. Two separate phantom measurements were performed accordingly. Motion simulation was conducted using a custom-designed motion generator, incorporating 15° and 30° rotations about the z-axis, 3° and 6° rotations about the x-axis, and 5 mm and 10 mm translations along the z-axis in the PET image coordinates. The data-driven MC was applied with frame durations of 1, 2, 5, 10, and 20 s for motion estimation. The estimated motions were compared with the motions measured using an external optical tracker system. %contrast and gray matter coefficient of variation (CV%) were calculated from the motion-corrected PET images.

RESULTS: The motion generator system successfully reproduced the designed motions. Motion estimation remained stable under high-radioactivity condition but showed reduced stability under low-radioactivity condition, particularly with shorter frame durations. Under both conditions, longer frame durations led to underestimation of continuous motion. The data-driven MC improved %contrast and gray matter CV% across all conditions, with shorter frame durations providing better correction for quick or continuous motions. However, shorter frame durations increased statistical noise, especially under low-radioactivity condition.

CONCLUSION: The data-driven MC effectively improved the quality of motion-affected PET images under both high- and low-radioactivity conditions, indicating its broad applicability. However, correction accuracy deteriorated under the lower-radioactivity condition.},
}

@article {pmid41400579,
year = {2025},
author = {Islam, MN and Mandal, N and Khanom, NI and Spivey, AL and Patel, AS and Ahmed, T and Islam, R and Bhuiyan, MIH},
title = {Sphingolipid Signaling and Metabolism in Neuronal and Glial Cells: Implications for Cerebrovascular and Neurodegenerative Disorders.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2025.1024},
pmid = {41400579},
issn = {2152-5250},
abstract = {Sphingolipids are essential bioactive lipids that play pivotal roles in maintaining the structural integrity of cellular membranes and regulating key signaling pathways in the central nervous system (CNS). In both neuronal and glial cells, sphingolipid metabolism regulates diverse processes, including cell survival, apoptosis, neuroinflammation, and myelination. Increasing evidence implicates dysregulation of sphingolipid pathways in the pathogenesis of various CNS disorders, notably cerebrovascular diseases such as small vessel disease and stroke, as well as neurodegenerative conditions including Alzheimer's disease, cerebral amyloid angiopathy, Parkinson's disease, and multiple sclerosis. This review summarizes the current advances in sphingolipid metabolism and signaling in the brain, with a focus on the functional interplay between neurons and glia, as well as the mechanisms by which disrupted sphingolipid homeostasis contributes to CNS pathology. Key sphingolipid metabolites such as ceramide, ceramide-1-phosphate, and sphingosine-1-phosphate emerge as critical mediators of neuroinflammation, blood-brain barrier disruption, and cognitive impairment. Furthermore, we explore emerging therapeutic strategies targeting sphingolipid pathways and their potential to slow disease progression and improve neurological outcomes. A deeper understanding of the roles of neuronal and glial sphingolipids in brain health and disease may advance the development of novel diagnostic tools and therapeutic strategies for cerebrovascular and neurodegenerative disorders.},
}

@article {pmid41400571,
year = {2025},
author = {Fiesel, FC and Watzlawik, JO and Heckman, MG and Blumenfeld, SG and Rigby, MJ and Kehili, M and Lohmann, K and Klein, C and Narendra, DP and Scherzer, CR and Ertekin-Taner, N and Graff-Radford, NR and Wszolek, ZK and Ross, OA and Springer, W},
title = {Phosphorylated Ubiquitin as a Clinical Biomarker for Mitochondrial Damage in Neurodegenerative Diseases.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2025.1220},
pmid = {41400571},
issn = {2152-5250},
abstract = {Phosphorylated ubiquitin (pS65-Ub) is generated by the kinase-ligase pair PINK1-Parkin to selectively label damaged mitochondria for degradation via the autophagy-lysosome system (mitophagy). Consistent with increasing mitochondrial and lysosomal dysfunctions, pS65-Ub accumulates with aging in human autopsy brain and in mice. pS65-Ub levels are strongly and independently elevated in brains from subjects with Alzheimer's or Parkinson's disease compared to age-matched, neurologically normal controls. Furthermore, pS65-Ub levels have been used to identify disease risk and potential resilience factors in cells and in human brain. However, it remains unknown whether pS65-Ub measured in biofluids may also be suitable as a clinical biomarker. Here, we used a validated sandwich ELISA based on the Mesoscale discovery platform to assess pS65-Ub levels in over 1500 plasma samples from different cohorts across a spectrum of mild cognitive impairment, Alzheimer's disease, or Parkinson's disease. We further analyzed almost 150 CSF samples from two independent case-control series with Parkinson's disease to determine whether pS65-Ub levels are associated with disease status and other clinical parameters. While pS65-Ub levels are significantly changed with disease compared to controls in certain samples, current measurements in plasma are not sufficiently discriminatory to serve as a robust diagnostic marker. However, in CSF, pS65-Ub levels were decreased in patients with Parkinson's disease compared to controls, and there was better discrimination between these groups. Our data indicate that pS65-Ub shows promise as a biomarker in CSF but will require further replication in larger cohorts and possibly in combination with additional other measures.},
}

@article {pmid41400487,
year = {2025},
author = {Kam, K and Gaggi, NL and Parekh, A and Valencia, DI and Quintana Licona, DA and Hishinuma, SS and Martillo, KR and Chu, SS and Varga Vii, AW and Hwang, J and Williams, MK and Mullins, AE and Tolbert, TM and Balchandani, P and Iosifescu, DV and Blessing, EM and Bubu, OM and Ayappa, I and Rapoport, DM and Morris, LS and Osorio, RS and Varga, AW},
title = {High OSA hypoxic burden associates with reduced locus coeruleus structural integrity on 7T MRI in older adults.},
journal = {Sleep},
volume = {},
number = {},
pages = {},
doi = {10.1093/sleep/zsaf398},
pmid = {41400487},
issn = {1550-9109},
abstract = {The locus coeruleus (LC) plays important roles in sleep/wake regulation and cognitive functions. LC neurons may be particularly sensitive to neural injury and serve as an early site of accumulation pathological tau in Alzheimer's disease. Obstructive sleep apnea (OSA) creates both chronic intermittent hypoxia and sleep fragmentation as potential insults to differentially sensitive neural populations including the locus coeruleus (LC). Using high field 7T imaging in cognitively normal older adults, we demonstrate that time spent with an oxygen saturation below 90% (T90), a measure of OSA's hypoxic burden, inversely correlates with LC structural integrity and explains significant variance in LC structural integrity after controlling for age, sex, and BMI. In contrast, other sleep variables such as the apnea-hypopnea index (AHI), total sleep time, and sleep efficiency did not contribute significant variance in LC structural integrity in this model. Thus, in the diagnosis of OSA, attention to hypoxic burden variables may be important in risk stratification for LC neural injury. This observation may inform future work determining whether mitigation of the hypoxemic burden from OSA can slow deterioration in LC integrity.},
}

@article {pmid41400074,
year = {2025},
author = {Feng, H and Gao, R and Guo, F and Wan, W and Shen, D and Yan, J and Ge, Y and Shen, K and Zhang, X and Liu, Y},
title = {Congo Red Derived Covalent Proteotyping Sensor for Amyloid Deposits in Alzheimer's Disease.},
journal = {ACS sensors},
volume = {},
number = {},
pages = {},
doi = {10.1021/acssensors.5c03211},
pmid = {41400074},
issn = {2379-3694},
abstract = {Congo Red (CR) is the histochemical staining sensor used to diagnose amyloid tissue deposition in current clinical practice. Its characteristic aryl azo linkage is generally considered to be chemically stable. Here, we discovered by serendipity that neutral borate buffer can activate the inert azo bond in CR to covalently modify amyloid proteins at ambient temperature. Such chemistry allowed us to develop a covalent amyloid sensor to image, enrich, and proteotype amyloid deposits in Alzheimer's disease (AD) tissue. We first pinpointed the boronic acid in borate buffer triggers such amyloid bioconjugation and found that ultraviolet-light-induced azo trans-to-cis isomerization further enhanced labeling efficiency. Leveraging this boron-azo bioconjugation chemistry, we developed a covalent sensor based on CR for selective detection and microdissection of amyloid deposits from AD mouse brain tissues. By incorporating an alkyne handle into the CR scaffold, we enabled click-chemistry-assisted enrichment of amyloid aggregates, followed by proteotyping via LC-MS/MS. The covalent amyloid sensor proteotyped a complex network of protein interactors including the AD biomarkers Tau and ApoE within amyloid deposits. Overall, this work establishes a borate-activated azo-based covalent sensor for selective imaging, dissecting and proteotyping of amyloid deposits in AD tissues.},
}

@article {pmid41400007,
year = {2025},
author = {Dori, D and Seixas-Lima, B and Roncero, C and Lahiri, D and Borrie, M and Chertkow, H},
title = {Thyroid function and cognitive health: rethinking the relationship between "suboptimal" TSH/FT4 levels and cognitive decline.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {12},
pages = {e70960},
pmid = {41400007},
issn = {1552-5279},
support = {CNA-137794//the Canadian Institutes of Health Research/ ; CNA-163902//the Canadian Institutes of Health Research/ ; BDO-148341//the Canadian Institutes of Health Research/ ; },
mesh = {Humans ; *Thyrotropin/blood ; *Thyroxine/blood ; Male ; Female ; *Cognitive Dysfunction/blood ; Aged ; Middle Aged ; Aged, 80 and over ; Thyroid Function Tests ; *Cognition/physiology ; Canada ; *Thyroid Gland/physiopathology ; Hypothyroidism/blood ; Cohort Studies ; },
abstract = {INTRODUCTION: Controversial hypotheses suggest that "suboptimal" thyroid function - defined as higher-normal thyroid-stimulating hormone (TSH) (2.0 to 4.5 μIU/mL) or low-normal free thyroxine (FT4) - may increase risk of cognitive decline and dementia in older patients.

METHODS: We examined this claim using data from the Canadian Comprehensive Assessment of Neurodegeneration and Dementia cohort (ages 50 to 91; cognitive statuses from unimpaired to dementia, rarer subtypes of dementia excluded). Thyroid function was categorized as "optimal" (TSH < 2.0 μIU/mL or FT4 ≥ 16.74 pmol/L) or "suboptimal." Six hundred eighty-eight participants had TSH data, and 476 participants had FT4 data.

RESULTS: Chi-squared analyses showed no significant association between "suboptimal" thyroid function and cognitive impairment (TSH: χ[2] = 0.178, p = 0.67; FT4: χ[2] = 0.0027, p = 0.96). True hypothyroidism was rare; 98.6% of those with elevated TSH had normal FT4.

DISCUSSION: These findings do not support claims that higher-normal TSH or low-normal FT4 contribute to cognitive impairment. Caution is warranted against advocating unproven thyroid supplementation for cognitive health.

HIGHLIGHTS: No link was found between "suboptimal" thyroid function and cognitive impairment. Higher-normal TSH levels do not indicate dementia risk or hypothyroidism. Among participants with elevated TSH, 98.6% had normal FT4 levels. Redefining TSH cutoffs to 2.0 μIU/mL lacks clinical justification. Findings question the functional medicine approach of thyroid supplementation for cognitive health.},
}

Humans
*Thyrotropin/blood
*Thyroxine/blood
Male
Female
*Cognitive Dysfunction/blood
Aged
Middle Aged
Aged, 80 and over
Thyroid Function Tests
*Cognition/physiology
Canada
*Thyroid Gland/physiopathology
Hypothyroidism/blood
Cohort Studies

@article {pmid41400005,
year = {2025},
author = {Custodio, N and Brown, G and Custodio, B and Montesinos, R and Nuñez-Huanca, M and Bartolo, P and Yauri, Z and Agüero, K and Verastegui, G and Ibañez, A},
title = {Functional capacity in Peruvian people with Alzheimer's disease and frontotemporal dementia.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {12},
pages = {e70979},
pmid = {41400005},
issn = {1552-5279},
support = {AG057234//National Institutes of Health/ ; R56AG069118-01//National Institutes of Health/ ; SG-21-715176-LATAM FINGERS//National Institutes of Health/ ; 24AARG-D-1246942//National Institutes of Health/ ; D43TW009343//Fogarty International Center of the NIH/ ; },
mesh = {Humans ; *Alzheimer Disease/psychology/physiopathology/epidemiology ; *Frontotemporal Dementia/physiopathology/psychology/epidemiology ; Male ; Female ; Cross-Sectional Studies ; Aged ; Neuropsychological Tests ; Peru/epidemiology ; Middle Aged ; Cognitive Dysfunction/physiopathology/psychology ; Surveys and Questionnaires ; *Activities of Daily Living ; Executive Function ; Aged, 80 and over ; South American People ; },
abstract = {INTRODUCTION: Functional impairment across degenerative dementias remains understudied in Latin American contexts. We aimed to assess total and item-level functional performance, determine specific instrumental activities, and identify differences in functional profiles between groups.

METHODS: In this cross-sectional study, 1445 participants were classified according to the Pfeffer Functional Activities Questionnaire (PFAQ). Statistical comparisons were adjusted for age, sex, and education using linear regression residuals and corrected for multiple comparisons.

RESULTS: Functional impairment increased progressively from normal cognition to dementia. Alzheimer's disease (AD) and frontotemporal dementia (FTD) groups showed significantly greater total PFAQ scores compared to controls and mild cognitive impairment (MCI). Distinct profiles of impairment emerged: AD was more associated with memory-dependent tasks, while FTD showed disproportionate deficits in executive and social activities.

DISCUSSION: Functional abilities are differentially impacted in AD and FTD within the Peruvian population. Our findings highlight the importance of item-level functional evaluation to support early detection and subtype differentiation of dementia in underserved regions.

HIGHLIGHTS: We characterized and compared functional abilities among Peruvian older adults with normal cognition and neurodegenerative disease in different stages. PFAQ scores were analyzed across dementia stages in a Peruvian population. Functional abilities were differentially impacted in Peruvian participants with AD compared to FTD. AD was more associated with memory-dependent tasks, while FTD showed disproportional deficits in executive and social activities.},
}

Humans
*Alzheimer Disease/psychology/physiopathology/epidemiology
*Frontotemporal Dementia/physiopathology/psychology/epidemiology
Male
Female
Cross-Sectional Studies
Aged
Neuropsychological Tests
Peru/epidemiology
Middle Aged
Cognitive Dysfunction/physiopathology/psychology
Surveys and Questionnaires
*Activities of Daily Living
Executive Function
Aged, 80 and over
South American People

@article {pmid41399980,
year = {2025},
author = {Chu, F and Zhou, X and Ma, R and Liu, R and Liu, X and Zhu, K and Wang, Y and Wang, X and Li, Y and Zhang, S and Yin, T and Liu, Z},
title = {Piezo1-Targeted Magnetoacoustic Nanobubbles Rescue Alzheimer's Pathology by Electromechanical Neuromodulation and Amyloid-β Clearance.},
journal = {ACS nano},
volume = {},
number = {},
pages = {},
doi = {10.1021/acsnano.5c13702},
pmid = {41399980},
issn = {1936-086X},
abstract = {Amyloid-β (Aβ) is considered a core pathological feature of Alzheimer's disease (AD), and its clearance efficiency is highly dependent on the function of the Piezo1 channel in microglia. However, the activity of Piezo1 is impaired under the pathological conditions of AD, and existing pharmacological strategies struggle to achieve precise targeted intervention in deep brain regions. To address these concerns, our research proposes a synergistic therapeutic paradigm leveraging transcranial magneto-acoustic stimulation (TMAS) to actuate microglial-Piezo1-targeted magnetic nanobubbles (PT-MNBs) for AD treatment. TMAS noninvasively focuses physical energy into deep brain lesion areas through a magnetoacoustic coupling field and drives PT-MNBs to generate responsive mechanical and electrical stimulation signals. PT-MNBs achieve microglia-specific anchoring through surface-modified phosphatidylserine, while conjugated anti-Piezo1 antibodies precisely deliver mechano-electrical stimulation signals to antibody-functionalized Piezo1 ion channels in microglial populations. This synchronously activates the mechanical- and voltage- sensitive domains of Piezo1 to recruit microglia to areas of inflammation and increase Aβ clearance, ameliorating synaptic plasticity impairment and ultimately reversing the pathological progression of AD. This dual-action mechanism achieves spatially precise manipulation of cellular mechanical and electrical activity in deep brain regions of AD mice and enhances Piezo1 function through precise energy delivery, enhancing their ability to clear Aβ plaques, opening an avenue for a noninvasive, deep-targeted physical stimulation-mediated nanoparticle synergistic therapy for AD.},
}

@article {pmid41399798,
year = {2025},
author = {Ghosh, S and Debnath, I and Bhunia, S and Nandi, S and Ashique, S and Nayak, A and Mallick, S and Basak, S},
title = {Decoding natural products for neuroprotection: Pathway networks and structural insights for drug development.},
journal = {Chinese herbal medicines},
volume = {17},
number = {4},
pages = {643-672},
pmid = {41399798},
issn = {2589-3610},
abstract = {Neurodegenerative diseases (NDs), including Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis, are progressive disorders marked by neuronal dysfunction and death, driven by pathological mechanisms such as oxidative stress, mitochondrial dysfunction, neuroinflammation, apoptosis, and protein misfolding. Despite scientific advances, current treatments remain largely palliative, underscoring the need for multitargeted therapeutic strategies. This narrative review synthesizes preclinical and clinical evidence to explore the neuroprotective potential of natural products, with a focus on their ability to modulate key molecular pathways implicated in NDs. A comprehensive literature search across Scopus, ScienceDirect, PubMed, MDPI, and Web of Science identified relevant studies. Bioactive compounds such as curcumin, resveratrol, ginsenosides, quercetin, and marine-derived molecules like fucoxanthin and phlorotannin demonstrated antioxidant, anti-inflammatory, anti-amyloidogenic, and mitochondrial-protective effects by modulating pathways including PI3K/Akt, NF-κB, and Nrf2/ARE, thereby mitigating neuronal damage and promoting cell survival. Natural products from diverse sources, including honey, ginseng, marine macroalgae, and cyanobacteria, exhibited broad-spectrum neuroprotective properties, with advances in nano-formulations improving bioavailability and brain penetration. Furthermore, emerging approaches such as gene-drug interaction studies and scaffold-based drug design offer promising avenues for enhancing clinical translation. While natural products provide a holistic, multitargeted approach to combat NDs, challenges related to bioavailability and therapeutic translation persist, necessitating future research that integrates advanced drug delivery systems, precision medicine, and synthetic modifications to develop innovative and effective treatment paradigms.},
}

@article {pmid41286027,
year = {2025},
author = {Fawzi, NL},
title = {Solid trouble: tau and TDP-43 interaction in aggregation and pathology.},
journal = {The EMBO journal},
volume = {44},
number = {24},
pages = {7327-7329},
pmid = {41286027},
issn = {1460-2075},
support = {R01GM147677//HHS | NIH | National Institute of General Medical Sciences (NIGMS)/ ; R01NS116176//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; },
abstract = {Both microtubule-binding protein tau and RNA-binding protein TDP-43 have been associated with neurodegenerative diseases, such as Alzheimer’s disease, including in co-pathological deposition with each other, but how they interact biophysically and pathologically has been challenging to evaluate. In this issue of The EMBO Journal, Simonetti and colleagues show how tau and TDP-43 directly interact both in phase separation and pathologically associated seeding, resulting in enhanced TDP-43 aggregation.},
}

@article {pmid41403394,
year = {2024},
author = {Gresenz, CR and Mitchell, JM and Rodriguez, B and Wang, C and Turner, RS and van der Klaauw, W},
title = {The financial consequences of undiagnosed memory disorders.},
journal = {Journal of financial economics},
volume = {172},
number = {},
pages = {},
pmid = {41403394},
issn = {0304-405X},
abstract = {We examine the effect of undiagnosed memory disorders on credit outcomes using individually-matched nationally representative credit reporting and Medicare data. We find effects of early stage disease, years before diagnosis, on a wide range of financial outcomes, including credit card account payment delinquency and amount of delinquent balance, credit utilization among credit card account holders, mortgage delinquency and delinquent balance amount, and credit scores. Effects are pervasive, affecting seniors in single and coupled households, racial/ethnic minorities and non-minorities, and older adults living in areas with higher and lower education levels. Early stage effects are greater among singles and Black individuals.},
}

@article {pmid41403591,
year = {2025},
author = {Batawi, AH},
title = {Implications for the role of natural products in Parkinson disease therapy.},
journal = {Archives of medical science : AMS},
volume = {21},
number = {5},
pages = {2030-2046},
pmid = {41403591},
issn = {1734-1922},
abstract = {Humans still suffer from several nervous system diseases affecting perception and body movement, such as Alzheimer's and Parkinson's diseases. Parkinson's disease is a globally common disease of the nervous system that is characterized by neurodegenerative movement disorders. Patients with Parkinson's disease are characterized by the slow loss of dopaminergic (DA-ergic) neurons, especially in areas of brain tissue called the substantia nigra pars compacta. However, there is still no clear evidence regarding the factors responsible for development of the disease, which remains vague. There are some indications that oxidative stress and mitochondrial dysfunction are among the main causes of the disease. Parkinson's patients are still dependent on taking levodopa as the recommended therapeutic drug. This drug, although it has many side effects, slows down the progression of the disease. Therefore, many scientists and pharmacologists are striving to find a potential drug that can halt the disease while minimizing side effects. Research is underway to find effective natural substances against Parkinson's disease that can renew the vitality of mitochondria and activate their function, as well as diminish the oxidation process in the nerve cells. Therefore, the aim of this review was to highlight the potential role of some natural products from plant sources, such as natural medicinal herbs or marine sources, in protecting neurons and improving their biological functions in order to develop new therapeutic strategies against Parkinson's disease.},
}

@article {pmid41399730,
year = {2025},
author = {Zhang, Y and Chen, S and Yan, G and Zhang, Z and Amina, and Wang, T and Wang, S and Zhang, C and Sun, Y},
title = {MAPT mutation-induced behavioral variant frontotemporal dementia in an Asian patient: a multimodal biomarker case report resolving diagnostic challenges with Alzheimer's disease.},
journal = {Frontiers in genetics},
volume = {16},
number = {},
pages = {1645068},
pmid = {41399730},
issn = {1664-8021},
abstract = {BACKGROUND: The clinical phenotypic overlap between frontotemporal dementia (FTD) and Alzheimer's disease (AD) frequently leads to misdiagnosis, while biomarkers (e.g., Aβ-PET) and genetic testing provide critical differential diagnostic evidence. Although MAPT gene mutations represent common genetic etiologies of FTD, their occurrence in Asian populations remains underreported. Specifically, FTD caused by the MAPT IVS10 + 16C>T mutation shows limited documentation in Asian populations, with its phenotypic heterogeneity and treatment responses remaining poorly characterized.

METHODS: We present a case of FTD manifesting progressive memory decline, compulsive behaviors, and apathy. MRI revealed bilateral frontoparietotemporal atrophy with prominent medial temporal lobe and hippocampal involvement, initially misdiagnosed as AD. Subsequent Aβ-PET negativity emerged as a pivotal diagnostic turning point, and identification of a heterozygous MAPT mutation (IVS10 + 16C>T) confirmed behavioral variant FTD (bvFTD) diagnosis. Partial improvement in compulsive behaviors and verbal fluency was observed following memantine treatment. A literature review summarizes clinical characteristics of FTD associated with IVS10 + 16C>T mutations.

RESULTS: Comprehensive neuropsychological assessment, cranial MRI, and negative Aβ-PET excluded AD pathology. Genetic confirmation of MAPT IVS10 + 16C>T mutation established bvFTD diagnosis. Three-month memantine treatment reduced compulsive behaviors without cognitive improvement. Literature analysis indicates this mutation's rarity in Asian populations, typically presenting with behavioral abnormalities frequently misdiagnosed as AD.

CONCLUSION: This study rectified misdiagnosis of MAPT IVS10 + 16C>T-associated bvFTD through multimodal diagnostics, emphasizing the synergistic value of genetic testing and neuroimaging. Memantine's partial behavioral symptom alleviation suggests potential mutation-specific therapeutic efficacy requiring further validation. Future directions should optimize diagnostic protocols (e.g., cost-effective genetic screening) and address barriers to early diagnosis in Asian populations.},
}

@article {pmid41399728,
year = {2025},
author = {Zhang, Y and Chen, S and Yan, G and Zhang, Z and Amina, and Wang, T and Wang, S and Zhang, C and Sun, Y},
title = {Correction: MAPT mutation-induced behavioral variant frontotemporal dementia in an Asian patient: a multimodal biomarker case report resolving diagnostic challenges with Alzheimer's disease.},
journal = {Frontiers in genetics},
volume = {16},
number = {},
pages = {1749030},
doi = {10.3389/fgene.2025.1749030},
pmid = {41399728},
issn = {1664-8021},
abstract = {[This corrects the article DOI: 10.3389/fgene.2025.1645068.].},
}

@article {pmid41399578,
year = {2025},
author = {Gassull, A},
title = {Ethical Challenges in Managing a Displaced Neer III Humeral Head Fracture in an Undocumented Immigrant With Early Alzheimer's Disease: A Case Report.},
journal = {Cureus},
volume = {17},
number = {11},
pages = {e96805},
pmid = {41399578},
issn = {2168-8184},
abstract = {This report describes an 82-year-old undocumented Peruvian female immigrant presenting to the ED with right elbow pain and limited shoulder mobility, diagnosed with a displaced Neer III right humeral head fracture sustained two days prior. She had not clearly communicated shoulder pain to her family for two days post-injury, possibly due to early Alzheimer's disease, which may have impaired her ability to recognize or articulate the severity of her injury, illustrating the clinical-ethical intersection. Radiographic imaging confirmed the fracture with medial displacement, necessitating surgical intervention. Due to her undocumented status and lack of health insurance, she was required to pay the full cost of a reverse shoulder prosthesis (€24,000), which she could not afford. Her Alzheimer's-related dependency and absence of family support in Peru prevented seeking treatment abroad, resulting in discharge with a sling. Comprehensive blood tests ruled out metabolic contributors to her fall. This case highlights ethical challenges in healthcare access for undocumented immigrants, compounded by Alzheimer's-related communication and dependency issues, underscoring disparities and the need for equitable care. This case exemplifies how clinical vulnerability and legal status can intersect to create barriers in emergency and trauma care.},
}

@article {pmid41399419,
year = {2025},
author = {Chen, HW},
title = {Axial Spinal Traction as a Potential Modulator of Cerebrospinal and Glymphatic Circulation in Neurodegenerative Diseases: A Technical Report and Biomechanical Hypothesis.},
journal = {Cureus},
volume = {17},
number = {12},
pages = {e99153},
pmid = {41399419},
issn = {2168-8184},
abstract = {Impairment of glymphatic function contributes to the accumulation of metabolic and proteinaceous waste products implicated in neurodegenerative diseases such as Alzheimer's disease, frontotemporal dementia, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and certain spinocerebellar ataxias. Pelvis-stabilized axial spinal traction (PSAST) is a biomechanical technique designed to produce brief, controlled cranio-caudal elongation of the vertebral column and spinal dural sac, potentially generating transient pressure gradients capable of influencing cerebrospinal fluid (CSF) dynamics and glymphatic circulation. The technique has been applied in the author's musculoskeletal practice for more than eight years without observed persistent or treatment-related adverse effects, although such practice-based experience does not constitute a formal safety evaluation. Improved sleep quality has been the most consistently reported patient-perceived response to PSAST, a clinically notable observation given the dependence of glymphatic function on consolidated slow-wave sleep. These practice-based observations provide preliminary, hypothesis-generating support for exploring whether controlled axial elongation may modulate cerebrospinal and glymphatic physiology. To the best of the author's knowledge, this report presents the first peer-reviewed technical description of a reproducible, whole-axis axial spinal traction procedure with defined force parameters intended to examine potential modulation of CSF and glymphatic circulation. The report outlines the PSAST protocol and its biomechanical rationale and safety considerations and proposes its potential relevance as a noninvasive, investigational approach for conditions associated with impaired glymphatic function.},
}