@article {pmid41668152,
year = {2026},
author = {Xu, P and Zhang, H and Zhu, S and Kong, Y},
title = {ICE: robust detection of cellular senescence from weak single-cell signatures using imputation-based marker refinement.},
journal = {Genome biology},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13059-026-03997-0},
pmid = {41668152},
issn = {1474-760X},
support = {2024FGC1004//the Interdisciplinary Research Program for Young Scholars from Southeast University/ ; 32570780//National Natural Science Foundation of China/ ; 32470666//National Natural Science Foundation of China/ ; },
abstract = {Detecting senescent cells from single-cell RNA-seq data remains challenging due to the weak and non-specific expression of canonical markers. Here, we demonstrate that simple expansion of these low-signal marker sets does not improve detection accuracy. To address this limitation, we develop ICE (Imputation-based Cell Enrichment), a computational framework that integrates expression imputation with marker refinement. ICE improves the detection of senescent cells in pancreatic β cells and microglia from Alzheimer's disease samples. This tool enables reliable identification of senescence-associated cell populations, facilitating more detailed analyses of their heterogeneity and temporal dynamics across human tissues and disease contexts.},
}

@article {pmid41668150,
year = {2026},
author = {Zilioli, A and Mohanty, R and Rosenberg, A and Matton, A and Granberg, T and Hagman, G and Spallazzi, M and Ferreira, D and Kivipelto, M and Westman, E},
title = {MRI-based atrophy subtypes in a young memory clinic cohort: associations with clinical and biomarker profiles.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-01972-2},
pmid = {41668150},
issn = {1758-9193},
}

@article {pmid41667812,
year = {2026},
author = {Heidt, A},
title = {Coffee linked to slower brain ageing in study of 130,000 people.},
journal = {Nature},
volume = {},
number = {},
pages = {},
pmid = {41667812},
issn = {1476-4687},
}

@article {pmid41667797,
year = {2026},
author = {Darvas, M and Cook, DG and Scimemi, A},
title = {Decoding Alzheimer's Disease One Cell Class at a Time.},
journal = {Cellular and molecular neurobiology},
volume = {},
number = {},
pages = {},
doi = {10.1007/s10571-026-01685-y},
pmid = {41667797},
issn = {1573-6830},
support = {R01AG075338/AG/NIA NIH HHS/United States ; IOS2011998//Division of Integrative Organismal Systems/ ; R56NS14042301/NS/NINDS NIH HHS/United States ; },
abstract = {Multimodal imaging-based on single-cell genomics and spatial transcriptomics has shed new light on the taxonomy of genetically defined cell clusters in the mammalian brain. While transcriptomic approaches have revolutionized our ability to classify brain cells, their true value emerges when they are interpreted in conjunction with anatomical, physiological, and translational frameworks. Accordingly, significant progress has been made to elucidate relationships between gene expression, electrical and morphological properties of some of these clusters. This rapidly growing body of work shows not only that the cell cluster composition varies across brain regions but also evolves over time and changes during the progression of disease states like Alzheimer's disease. Given this complexity, integrating transcriptomic, structural, and functional data is now becoming essential for drawing meaningful comparisons across studies. In this review, we summarize these findings and discuss how this knowledge base is shifting towards more integrative approaches, quickly challenging current ideas regarding the genetic, molecular, and cellular underpinnings of Alzheimer's disease.},
}

@article {pmid41667691,
year = {2026},
author = {Alanís-Bernal, M and Melgarejo, L and Boada-Oller, L and Rios, S and Maisterra, O and Ballvé, A and Buongiorno, M and Giraldo, D and Delgado, P and Gutiérrez, B and Liébana, D and Palasí, A},
title = {Characterization of neuropsychiatric symptoms in patients with early-stage Alzheimer's disease in a specialized outpatient clinic.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {3},
pages = {249},
pmid = {41667691},
issn = {1590-3478},
mesh = {Humans ; Female ; Male ; *Alzheimer Disease/psychology/complications/cerebrospinal fluid/diagnostic imaging/physiopathology ; Aged ; Retrospective Studies ; Aged, 80 and over ; Positron-Emission Tomography ; Ambulatory Care Facilities ; *Psychotic Disorders/etiology ; tau Proteins/cerebrospinal fluid ; },
abstract = {OBJECTIVE: To describe the frequency and temporal onset of neuropsychiatric symptoms (NPS) around the diagnosis of Alzheimer's disease (AD) and to explore their associations with clinical and paraclinical variables.

METHODS: We conducted a retrospective observational study of patients diagnosed with AD between 2020 and 2024, including NPS emerging from six years before to four years after diagnosis. Symptoms were classified by temporal onset as preNPS or postNPS and categorized into affective, psychotic, and behavioral domains. Clinical and demographic data, cerebrospinal fluid (CSF) biomarkers, and FDG-PET imaging findings were collected.

RESULTS: Among 184 patients (mean age 76.7 ± 9.0 years; 68% female), preNPS occurred in 78.2% and postNPS in 53.8%. Psychotic preNPS were associated with older age (81.4 ± 8.6 vs. 76.3 ± 8.9 years; p = 0.049), lower Mini-Mental State Examination scores (19.9 ± 3.7 vs. 22.1 ± 4.1; p = 0.033), and use of benzodiazepines (38.5% vs. 14.0%; p = 0.036) and antipsychotics (61.5% vs. 7.0%; p < 0.001). Affective preNPS were more common in women (71.9% vs. 55.4%; p = 0.029) and were associated with antidepressant use (p < 0.001) and lower alcohol intake (p = 0.018). Behavioral preNPS predominated in men (57.1% vs. 30.1%; p = 0.013) and were associated with a greater preservation of temporal lobe metabolism in FDG-PET imaging (28.0% vs. 76.2%; p = 0.04). PostNPS correlated with disease duration (r = 0.19; p = 0.01) and higher CSF total tau levels (386.9 ± 112.8 vs. 347.1 ± 148.9; p = 0.04).

CONCLUSION: NPS are frequent in early-stage AD, with psychotic preNPS linked to older age and greater cognitive decline, and postNPS correlating with disease duration and CSF tau, indicating an association with neurodegeneration.},
}

Humans
Female
Male
*Alzheimer Disease/psychology/complications/cerebrospinal fluid/diagnostic imaging/physiopathology
Aged
Retrospective Studies
Aged, 80 and over
Positron-Emission Tomography
Ambulatory Care Facilities
*Psychotic Disorders/etiology
tau Proteins/cerebrospinal fluid

@article {pmid41667529,
year = {2026},
author = {Hariharan, J and Jothi, R},
title = {Alzheimer's disease prediction using deep learning and XAI based interpretable feature selection from blood gene expression data.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-35260-8},
pmid = {41667529},
issn = {2045-2322},
abstract = {Alzheimer's disease (AD), a type of neurodegenerative disorder, has seen an increase in cases over the past decade, necessitating the construction of a comprehensive early detection method. Existing methods are typically invasive and costly, so our research concentrates on blood gene expression as a possible biomarker for early diagnosis of AD. Many research directions using machine learning and deep learning techniques exist in the literature for AD diagnosis. However, most of them use MRI scans as the primary data, and very few studies have been carried out on the use of blood gene biomarkers. The analysis of blood gene expression data is complicated by its high dimensionality and limited sample size. In this paper, we attempt to address these issues by applying multiple feature selection methods to identify the critical genes that act as biomarkers for AD diagnosis. To select the genes linked to AD and identify AD patients, we employ four feature selection approaches, including Chi-square, ANOVA, Recursive Feature Elimination (RFE), and ElasticNet, and build two deep learning models for AD classification. The selected genes are assessed with nested five-fold cross-validation to avoid overfitting. Further, we employ SHapley Additive exPlanations (SHAP), an Explainable AI (XAI) model, for ranking the selected genes and explaining why the feature selection algorithms predict a subset of genes as probable biomarkers. Generative Adversarial Network (GAN)-based data augmentation is used to address the issue of small sample size and improve model generalization. We demonstrate the results of feature selection and AD classification on three blood gene expression datasets, namely GSE63060, GSE63061, and ADNI, and their integrated version. Experimental results indicate that the deep neural network classifier achieved an accuracy of 91% and a precision of 95% in identifying AD samples. Feature selection along with data augmentation has significantly enhanced the precision and interpretability of early detection of AD using blood gene expression.},
}

@article {pmid41667435,
year = {2026},
author = {Blackburn, E and Birsa, N and Lopes, AT and Fisher, EMC and Lazo, OM and Schiavo, G},
title = {Impaired BDNF-TrkB trafficking and signalling in Down syndrome basal forebrain neurons.},
journal = {Cell death & disease},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41419-026-08464-z},
pmid = {41667435},
issn = {2041-4889},
support = {107116/Z/15/Z and 223022/Z/21/Z//Wellcome Trust (Wellcome)/ ; },
abstract = {Brain derived neurotrophic factor (BDNF) and its receptor tropomyosin-related kinase B (TrkB) play crucial roles in neuronal development, synaptic transmission, and neuroplasticity. Deficits in BDNF/TrkB signalling and trafficking have been identified in several neurodegenerative diseases, including Alzheimer's disease (AD). Individuals with Down syndrome (DS) are at an increased risk of developing AD compared to the general population. Basal forebrain neurons (BFNs) are among the first to degenerate in AD and DS, but the mechanisms underlying their vulnerability remain unclear. Using BFNs derived from the Dp1Tyb mouse model of DS, we investigated neurotrophic signalling and trafficking deficits in AD-DS. We found enlarged early endosomes and elevated levels of active Rab5, a GTPase critical for early endosome formation, in Dp1Tyb BFNs. These abnormalities were associated with impaired transport of internalised TrkB from axon terminals to the soma. Using microfluidic devices, we demonstrated that axonal BDNF stimulation enhanced signalling endosome dynamics in wild-type but not Dp1Tyb BFNs, which is likely due to impaired axonal ERK1/2 signalling. Our findings establish a link between Rab5 hyperactivation, endosomal dysfunction, and impaired ERK1/2 signalling, highlighting the interplay between trafficking and neurotrophic signalling, and underscore the importance of targeting endolysosomal and signalling pathways to mitigate neuronal dysfunction in AD-DS.},
}

@article {pmid41667430,
year = {2026},
author = {Rossini, PM and Pappalettera, C},
title = {Should all MCI with Alzheimer's biological diagnosis receive anti-amyloid therapy?.},
journal = {Cell death & disease},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41419-026-08456-z},
pmid = {41667430},
issn = {2041-4889},
abstract = {Our perspective addresses one of the most pressing and timely debates in contemporary neurology and health policy: whether the recent approval of anti-amyloid monoclonal antibodies for Alzheimer's disease should extend to all individuals with mild cognitive impairment (MCI; a large population of tens of millions of individuals worldwide mainly represented in Countries with aged population) who test positive for amyloid biomarkers, despite wide variability in prognosis and therapeutic response and the epidemiological demonstration that only about half of them manifest symptoms of dementia. The manuscript highlights three central themes. First, while epidemiological and meta-analytic data confirm that MCI significantly increases the risk of dementia, more than half of affected individuals-many of whom are biomarker-positive for amyloid/tau-do not progress to dementia even over long- term follow-up. Second, recently approved anti-amyloid therapies, although representing a landmark in disease-modifying treatments, carry high costs, non-negligible risks (particularly amyloid-related imaging abnormalities), and uncertain long-term real-world benefits. Third, indiscriminate prescription of these agents risks exposing large numbers of subjects to unnecessary harm while placing unsustainable burdens on healthcare systems. We argue that the field should urgently move to identify and validate accurate and sustainable instruments for risk-stratified treatment pathways, integrating genetic, clinical, neuropsychological, neuroimaging, and fluid biomarker data including risk and resilience factors to refine prognostication. In addition, we call on the scientific community, journals, and policymakers to foster dialog that bridges neurology, geriatrics, bioethics, health economics, and patient advocacy, so that clinical innovation is matched by ethical responsibility and equitable implementation.},
}

@article {pmid41667287,
year = {2026},
author = {Casper, A and Bolin, J},
title = {Alzheimer Disease and the Utility of PET.},
journal = {Journal of nuclear medicine technology},
volume = {},
number = {},
pages = {},
doi = {10.2967/jnmt.125.271758},
pmid = {41667287},
issn = {1535-5675},
abstract = {Alzheimer disease (AD) is the most common cause of dementia and one of the leading causes of death in adults age 65 y or older in the United States. AD presents with symptoms of cognitive impairment that worsen with disease progression, ultimately affecting an individual's functional abilities, independence, and overall health. Historically, treatment has relied on the mitigation of the adverse effects of the disease; however, the recent development of antiamyloid monoclonal antibodies allows for the targeting of pathologic factors that drive the progression of disease. Nuclear medicine has established itself as a useful tool in the evaluation of AD through the use of PET tracers, which target pathologic biomarkers such as amyloid-β and tau proteins, as well as metabolic processes reflective of neurodegenerative damage. Amyloid-β PET imaging and quantification have recently gained interest for their ability to more effectively diagnose AD and identify patients eligible for treatment with new antiamyloid therapies.},
}

@article {pmid41667284,
year = {2026},
author = {Doroudinia, A and York, B and Colletti, PM},
title = {Quantitative Amyloid Brain Imaging: A Literature Review of the Centiloid Scale in Alzheimer Disease Evaluation.},
journal = {Journal of nuclear medicine technology},
volume = {},
number = {},
pages = {},
doi = {10.2967/jnmt.125.271678},
pmid = {41667284},
issn = {1535-5675},
abstract = {Amyloid PET has become a pivotal imaging biomarker for Alzheimer disease (AD), enabling in vivo detection and quantification of β-amyloid deposition. However, variability in quantitative measurements across tracers, scanners, and analysis methods has considerably limited direct comparison of amyloid burden between studies and centers. To address this issue, the Centiloid Project has been developed to provide a standardized quantitative scale for amyloid PET, harmonizing results across tracers and institutions. In this literature review, we aim to summarize current evidence on the development, validation, and clinical application of the Centiloid scale in amyloid PET imaging, emphasizing its methodologic foundations, tracer-specific conversions, and diagnostic thresholds. Methods: A literature review was conducted using PubMed, Scopus, and Embase databases from January 2015 through October 2025. Search terms included "amyloid PET," "Centiloid," "SUVR," and "Alzheimer disease." We reviewed articles with quantitative amyloid PET analyses and Centiloid conversion and studies which compared multiple tracers using MIMneuro software Centiloid calibration. Results: The Centiloid method demonstrates strong intertracer and interscanner harmonization when standardized to the [11]C-Pittsburgh compound B reference, with high correlation (r [2] > 0.9) across [18]F-labeled tracers, including florbetapir, flutemetamol, and florbetaben. Most articles identified a Centiloid threshold between 20 and 25 Centiloids as indicative of significant amyloid pathology. Implementation of the Centiloid framework improved comparability across clinical trials and longitudinal studies, facilitating integration into the AT(N) research framework. Conclusion: The Centiloid scale represents a critical advancement in quantitative amyloid PET imaging, providing a universal reference that enhances data reproducibility, cross-trial comparisons, and clinical decision-making. Continued work is needed to expand standardization for novel tracers and hybrid imaging systems, ensuring full clinical translation of this metric in dementia imaging.},
}

@article {pmid41667283,
year = {2026},
author = {Johnson, SL},
title = {Brain Primer, Part 2: Pathophysiology of Neurodegeneration.},
journal = {Journal of nuclear medicine technology},
volume = {},
number = {},
pages = {},
doi = {10.2967/jnmt.125.271788},
pmid = {41667283},
issn = {1535-5675},
abstract = {Neurodegenerative diseases are characterized by progressive neuronal dysfunction, synaptic loss, and decline in cognitive, behavioral, or motor function. Understanding these disorders requires a foundational knowledge of neuroanatomy and physiology. Although normal aging leads to expected neuronal loss and changes in gray and white matter, neurodegenerative diseases are marked by systematic and progressive destruction of normal anatomy and function. Neurodegenerative diseases involve several key features, such as accumulation of amyloid-β plaques, tau hyperphosphorylation, microtubule destabilization, synaptic degeneration, and widespread neuroinflammatory responses driven by microglia and astrocytes. This article provides an integrated review of neurodegenerative mechanisms and provides a pathophysiologic overview of neurodegenerative diseases relevant to nuclear medicine and molecular imaging.},
}

@article {pmid41667282,
year = {2026},
author = {Grabher, BJ},
title = {Centiloids in Amyloid PET: A Practical Guide to Quantitation Interpretation.},
journal = {Journal of nuclear medicine technology},
volume = {},
number = {},
pages = {},
doi = {10.2967/jnmt.125.271823},
pmid = {41667282},
issn = {1535-5675},
abstract = {The approval of disease-modifying antiamyloid therapies has expanded the clinical role of amyloid PET beyond diagnostic confirmation to include baseline characterization and longitudinal monitoring of treatment response. Although visual interpretation remains the clinical standard for amyloid PET, it may be limited in borderline cases and when assessing subtle changes in amyloid burden over time. Quantitative amyloid PET provides objective measures that complement visual assessment, with z scores, SUV ratios, and Centiloid scaling offering increasing clinical utility. The Centiloid scale standardizes amyloid PET quantification across tracers, scanners, and institutions by anchoring measurements to biologically defined reference points, enabling consistent interpretation and comparison. This article describes the principles of amyloid PET quantification, explains the origin and interpretation of Centiloids, and discusses their role in therapy monitoring and clinical decision-making. Understanding quantitative amyloid PET and its limitations is essential for nuclear medicine professionals in the evolving landscape of Alzheimer disease imaging.},
}

@article {pmid41667280,
year = {2026},
author = {Skyles, T and Bouchal, SM and Giarratana, A and Wengler, J and Hart, I and Greig, E and Singh, H and Huang, SS and Martinez, F and Nguyen, B and Shin, CH and Yang, M and Parent, E and Robb, WH and Franceschi, AM and Burkett, B and Johnson, D and Koran, ME},
title = {PET Imaging in Alzheimer Disease in the Era of Antiamyloid Therapy in the United States: Clinical Utility, Quantification, and Policy Landscape.},
journal = {Journal of nuclear medicine technology},
volume = {},
number = {},
pages = {},
doi = {10.2967/jnmt.125.271835},
pmid = {41667280},
issn = {1535-5675},
abstract = {Alzheimer disease (AD) is increasingly diagnosed using molecular imaging biomarkers. PET imaging provides the opportunity to visualize amyloid and tau aggregates and in vivo neurodegenerative changes. These techniques provide exciting new avenues toward diagnosis, disease staging, and therapeutic monitoring of AD. Methods: This review details recent advances in amyloid PET, tau PET, and [18]F-FDG PET as they relate to the diagnosis, staging, and treatment of AD. The increasing roles of PET in the biologically based diagnosis of AD and antiamyloid immunotherapy response monitoring are addressed. Results: Amyloid PET enables improved detection of amyloid-β plaques within the brain. Amyloid PET is increasingly vital for confirming AD diagnoses given the emergence of antiamyloid immunotherapies, which require biomarker-verified amyloid positivity to initiate treatment. Tau PET provides a direct measure of neurofibrillary tangle pathology and is useful for disease staging, the interpretation of atypical clinical presentations, and treatment decision-making. [18]F-FDG PET plays a vital role in distinguishing AD from other dementia subtypes. Expanded reimbursement policies for amyloid and tau PET have increased accessibility to these modalities. Finally, quantitative methods facilitate interscan reproducibility and permit therapeutic monitoring. Conclusion: Molecular neuroimaging is poised to play a central role in the biologic definition, diagnosis, staging, and management of AD. Integrating amyloid, tau, and FDG PET with clinical assessments and fluid biomarkers provides earlier and more accurate diagnoses, opening the door to personalized treatment.},
}

@article {pmid41667028,
year = {2026},
author = {Fu, W and Ho, PC},
title = {Blood-Based Biomarkers for Alzheimer's Disease: Advances in Early Detection and Monitoring of Age-Related Neurodegeneration.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103058},
doi = {10.1016/j.arr.2026.103058},
pmid = {41667028},
issn = {1872-9649},
abstract = {Alzheimer's disease (AD) presents a critical global challenge, accounting for over 60% of the 57 million current dementia cases worldwide, with prevalence projected to exceed 100 million by 2050. Traditional diagnostic approaches, such as cerebrospinal fluid (CSF) analysis and neuroimaging are constrained by invasiveness, high costs, and limited accessibility, particularly problematic in aging population where early detection is crucial for effective intervention. This review synthesizes recent advances in blood-based biomarkers for AD, specifically phosphorylated tau proteins (p-tau217, p-tau181), neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), and the amyloid-β42/40 ratio. These minimally invasive biomarkers demonstrate exceptional diagnostic accuracy with p-tau217 achieving AUC values greater 0.93 and 91% positive predictive value in detecting AD pathology, Critically, these biomarkers can identify pathological changes 15-20 years before symptom onset, with plasma p-tau217 levels increasing over 8.5% annually during preclinical stages. We propose that dried blood spots (DBS), containing both arterial and venous blood components, offer superior representation of brain-derived substances at their first systematic distribution after cardiac output. Ultrasensitive technologies like Simoa and mass spectrometry now enable femtomolar-level detection, revolutionizing of AD diagnostics. However, challenges persist in assay standardization persist in assay standardization, and population-specific validation. Overcoming these barriers to integrate blood biomarkers with DBS technology represents a transformative shift toward accessible, scalable screening in aging communities, offering a paradigm shift in preventing age-related neurodegeneration through early detection and timely intervention.},
}

@article {pmid41667027,
year = {2026},
author = {Valiantis, S and Perentos, N and Koupparis, AM and Hadjipapas, A and Papacostas, SS and Kousiappa, I},
title = {Fine Motor Function Deficits in the 5xFAD Mouse Model of Alzheimer's Disease.},
journal = {Behavioural brain research},
volume = {},
number = {},
pages = {116097},
doi = {10.1016/j.bbr.2026.116097},
pmid = {41667027},
issn = {1872-7549},
abstract = {Alzheimer's disease (AD) involves not only progressive memory and cognition deficits but also motor impairments, including disturbed balance and activity levels and gait dysfunction. We examined age-related changes in fine motor skills of an Alzheimer's mouse model, the transgenic 5xFAD, from 3 to 9 months of age (3M, 9M), using a battery of behavioral tests including the rotarod for motor coordination and balance, balance beam test for fine motor precision and coordination, and single-pellet reaching test for forelimb dexterity. Rotarod test showed that 9M 5xFAD mice displayed mild motor coordination deficits, spending less time on the rod and falling at lower speeds than 9M WT mice. In the balance beam test, 9M 5xFAD mice exhibited significantly slower traversal times compared to other groups and demonstrated frequent foot slips and dragging behavior with more pronounced effects on the narrower beam. The single-pellet reaching test revealed impaired fine limb movements in 9M 5xFAD mice, with reduced success rates and slower speed than the other groups. This study showed that 9M 5xFAD mice exhibited the most impaired performance at each assay in an age-dependent manner, suggesting that the accumulation of the underlying AD-related pathology affects motor function, extending even to fine motor skills.},
}

@article {pmid41666965,
year = {2026},
author = {Sun, L and Xu, X and Wang, Z and Meng, Y and Li, Y and Hou, Y and Gao, X and Cui, H and Li, Y},
title = {Effects of Different Dietary Restriction Regimens on Cognitive Function and Pathological Markers in Alzheimer's Disease Mouse Models：A Systematic Review and Meta-Analysis.},
journal = {Neuroscience and biobehavioral reviews},
volume = {},
number = {},
pages = {106601},
doi = {10.1016/j.neubiorev.2026.106601},
pmid = {41666965},
issn = {1873-7528},
abstract = {Dietary restriction (DR) has emerged as a promising non-pharmacological intervention for Alzheimer's disease (AD). This systematic review and meta-analysis provides the first comprehensive comparison of five dietary restriction regimens in Alzheimer's disease mouse models. Analysis of 23 studies demonstrates that caloric restriction yields the most consistent benefits. While intermittent fasting exhibits model-dependent efficacy-improving recognition memory but exacerbating neuroinflammation in 5×FAD models. The fasting-mimicking diet showed the largest effect size. From a geroscience perspective, these findings support a precision nutrition framework for Alzheimer's disease, suggesting that future interventions should be tailored to individual pathological profile, inflammatory status, and impaired cognitive subdomains to optimize therapeutic efficacy.},
}

@article {pmid41666775,
year = {2026},
author = {Chaudhari, S and Shinde, A and Salunke, M and Bairagi, S and Dhage, A and Patel, P and Rathod, V and Pathare, S and Altwaijry, N and Khan, MS},
title = {Investigating the anti-Alzheimer potential of biogenic compounds from Zinc15 database as NMDA antagonist: An in-silico approach.},
journal = {Journal of molecular graphics & modelling},
volume = {144},
number = {},
pages = {109277},
doi = {10.1016/j.jmgm.2026.109277},
pmid = {41666775},
issn = {1873-4243},
abstract = {Alzheimer's disease is an unavoidable neurological disorder in which the death of brain cells brings on memory loss, cognitive decline, and eventual dementia. There is no recognized treatment for Alzheimer's illness. By the year 2050, it is expected that the global population will witness approximately 100 million cases of Alzheimer's disease (AD). Despite recognizing AD as a formidable illness for over a century, no effective cure has been discovered thus far. Synaptic dysfunction could result from disturbed synaptic calcium handling caused by excessive activation of glutamate receptors, particularly the N-methyl-D-aspartate receptors (NMDARs). Glutamate serves as the brain's primary excitatory neurotransmitter, acting on ionotropic and metabotropic glutamate receptors. In recent years, several pharmacologically active substances derived from plants, animals, and microbes have shown promise in treating AD by focusing on various pathogenic processes. Initially, we used virtual screening to assess natural product-like compounds against NMDA receptors. In this research study, we have screened a natural compound database derived from zinc15. The best candidate was then validated through molecular dynamics simulation (MDS). The results revealed that out of 4221 compounds tested, only 165 showed superior binding interactions compared to native ligands, making them inhibitors for protein. Further analysis using ADMET indicates favorable drug-like properties, particularly for CNS drug-likeness. The MDS results, including RMSD, RMSF, Rg, and residue interactions, indicated a strong and stable association between top molecules and target protein. This confirms that top molecules can effectively remain within the binding pockets of the target proteins, forming stable protein-ligand complexes.},
}

@article {pmid41666658,
year = {2026},
author = {Grillenberger, AJ and Shenton, N and Lauritzen, M and Benedek, K and Puthusserypady, S},
title = {Exploring the potential of explainable deep learning for EEG-based cognitive decline prediction.},
journal = {Computers in biology and medicine},
volume = {204},
number = {},
pages = {111538},
doi = {10.1016/j.compbiomed.2026.111538},
pmid = {41666658},
issn = {1879-0534},
abstract = {OBJECTIVE: Detecting Alzheimer's disease (AD) at an early stage is essential for administering effective treatments and preventing neuronal damage. Unfortunately, current diagnostic techniques are often invasive and expensive. Our research focuses on creating a cost-effective and non-invasive method for the early detection of cognitive decline.

METHODS: Using a publicly available dataset of resting state electroencephalographic (EEG) data on healthy controls and patients with Mild Cognitive Impairment (MCI), two novel deep learning (DL) algorithms with self-attention mechanisms were developed and evaluated for their performance in predicting MCI and cognitive decline.

RESULTS: Both proposed DL algorithms outperformed a traditional convolutional neural network (CNN) model in predicting MCI, achieving test accuracy improvements of 8.5% and 10%, respectively, while utilizing significantly fewer trainable parameters. An ablation study highlighted the attention layer as a key feature, enhancing model accuracy by 8.5%. Analysis of the attention layers indicated that beta band frequencies (13-30 Hz) were essential for distinguishing MCI from control subjects, highlighting the role of high EEG frequencies in early cognitive deficits. Predicting pre-clinical cognitive decline in healthy subjects proved more challenging than predicting diagnosed MCI. However, using transfer-learning methods, we achieved a test accuracy of 56.08%.

CONCLUSION: Our models achieved state-of-the-art results in the MCI classification task, and demonstrated learning progress in predicting cognitive decline in the preclinical stage. As this is the first time DL models have been evaluated to classify healthy subjects based on cognitive scores, where brain changes are minimal and difficult to detect, this study opens new avenues for discovering biomarkers in early AD diagnosis and facilitating early interventions. Interpretation of the trained DL attention models provided valuable insights that aligned with the existing brain research, serving as a helpful tool for validating AI in healthcare applications.},
}

@article {pmid41666657,
year = {2026},
author = {More, SA and Sikkalgar, A and Chourasiya, N and Agrawal, YO and Goyal, SN and Nakhate, KT and Mohd Siddique, MU and Rathod, SS},
title = {Hentriacontane alleviates streptozotocin-induced Alzheimer's disease-like conditions in rats: In silico and in vivo investigations revealed the unifying principles.},
journal = {Computers in biology and medicine},
volume = {204},
number = {},
pages = {111513},
doi = {10.1016/j.compbiomed.2026.111513},
pmid = {41666657},
issn = {1879-0534},
abstract = {Intracerebroventricular (ICV) streptozotocin (STZ) deveops Alzheimer's disease (AD)-like conditions in rodents, which are characterized by insulin resistance, tau pathology, and neurodegeneration. Hentriacontane, a natural compound found in various sources, including beeswax, possesses anti-inflammatory and antioxidant properties. In the present investigation, we performed in silico molecular docking, molecular dynamics, MMGBSA, PCA, and FEL analysis of hentriacontane and rivastigmine with acetylcholinesterase (AchE). Further, we assessed the in vivo neuroprotective effects of hentriacontane in an ICV-STZ-induced AD-like condition in rats. STZ (3 mg/kg/ICV) was injected into male Sprague-Dawley rats. Cognitive functions were evaluated by Barnes-Maze (BM), novel object recognition test (NORT), and passive avoidance test (PAT). Hentriacontane (3 and 5 mg/kg) and rivastigmine (1 mg/kg) were given intraperitoneally for 14 days. Brain-derived neurotrophic factor (BDNF), AchE, oxidative stress parameters including GSH, MDA, SOD, and CAT, and proinflammatory cytokines including IL-6, TNF-α, IL-1β, and NF-ҡB were measured via ELISA. Further, we have also estimated the BACE1 and NO levels. Histopathological evaluation was conducted using hematoxylin and eosin staining. In silico molecular docking, dynamics, and post-dynamics data revealed promising binding affinities of hentriacontane for AchE. Further, hentriacontane attenuated ICV-STZ-induced cognitive deficit in BM, NORT, and PAT. Additionally, altered oxidative stress, proinflammatory, and cell signalling parameters were restored. Histopathology revealed that the hentriacontane-treated group showed significant restoration of the small pyramidal cells in the CA1 and CA2 regions of the brain. Hentriacontane demonstrated neuroprotective effects by modulation of AchE, leading to improved cognitive functions as evidenced by in silico and in vivo investigations.},
}

@article {pmid41666521,
year = {2026},
author = {Qin, Z and Wang, Z and Gao, C and Yong, X and Hua, Y and Zhou, Y and Xie, J},
title = {Ultrasound-mediated blood-brain barrier opening for targeted neurological drug delivery.},
journal = {Biomaterials advances},
volume = {183},
number = {},
pages = {214754},
doi = {10.1016/j.bioadv.2026.214754},
pmid = {41666521},
issn = {2772-9508},
abstract = {Neurological disorders represent a devastating global health crisis, and the blood-brain barrier (BBB) remains a major obstacle for their treatment. Conventional strategies for BBB opening, including direct intracranial injection, osmotic disruption, receptor-mediated transcytosis, and nanoparticle carriers, often suffers from surgical invasiveness, systemic toxicity, poor biodistribution, and off-target effects. Ultrasound-mediated drug delivery has emerged as a revolutionary non-invasive technology for transient and targeted BBB opening, enabling enhanced penetration of therapeutic agents into the central nervous system. This review comprehensively summarizes the mechanisms underlying ultrasound-based delivery with focus on current delivery platforms including microbubble (MB)-assisted, nanoparticle-based, and MB-nanoparticle composite strategies. Furthermore, we highlight recent advances in the application of focused ultrasound (FUS) combined with MBs for the treatment of Alzheimer's disease, Parkinson's disease, and glioma. Finally, we discuss emerging technologies such as sonodynamic therapy and ultrasound-controlled magnetic nanorobots, while also addressing current challenges in this field. This review underscores the transformative potential of ultrasound-mediated drug delivery as a versatile platform for precision neurology. It also prospects future directions for advancing multidisciplinary research and clinical translation.},
}

@article {pmid41666126,
year = {2026},
author = {Yue, J and Jones, B and Tran, KH and Deen, M and Holicek, V and Cheng, WH and Michalik, M and Power, S and Wellington, CL and Watson, NV and Vocadlo, DJ},
title = {Pharmacological inhibition of O-GlcNAcase reduces pS129-α-synuclein positive aggregates in the substantia nigra of mThy1-hSNCA mice.},
journal = {Journal of Parkinson's disease},
volume = {},
number = {},
pages = {1877718X251410291},
doi = {10.1177/1877718X251410291},
pmid = {41666126},
issn = {1877-718X},
abstract = {BackgroundThe aggregation and spread of α-synuclein within brain are associated with the loss of dopaminergic neurons and the formation of Lewy bodies as seen in Parkinson's disease. Blocking the initiation of α-synuclein aggregation, or the spread of such aggregates, may offer disease-modifying approaches to slow disease progression. Previous studies have demonstrated that modification of aggregation prone proteins, including α-synuclein, with O-linked β-N-acetylglucosamine (O-GlcNAc) reduces their aggregation. Small molecule inhibitors of the enzyme O-GlcNAcase (OGA), which removes O-GlcNAc from proteins, confers neuroprotective benefits in various preclinical disease models of Alzheimer's and Parkinson's diseases.ObjectiveThis study investigates the effects of long-term pharmacological enhancement of O-GlcNAcylation in a transgenic mouse model of Parkinson's disease overexpressing human α-synuclein.MethodsThiamet-G was orally administered to mThy1-hSNCA and wild-type (WT) mice for ten months. Behavioral assessments were conducted to examine changes in locomotion and cognition. Histological analyses were performed to analyze α-synuclein aggregates and dopaminergic neurons in brain sections. Immunoblot and ELISA analyses were performed to analyze O-GlcNAc and soluble α-synuclein using brain lysates, respectively.ResultsThiamet-G increased the level of O-GlcNAc in the brain of both mThy1-hSNCA and WT mice. The levels of total α-synuclein in the brain were unaltered. However, Thiamet-G strongly attenuated the deposition of pS129-immunoreactive α-synuclein aggregates within the substantia nigra, prior to observable neurodegeneration. Thiamet-G also protected against locomotor decline.ConclusionsThese results support OGA inhibition as a therapeutic approach to block the pathological formation of toxic α-synuclein as a disease-modifying treatment against Parkinson's disease.},
}

@article {pmid41666058,
year = {2026},
author = {Zhang, H and Wang, D and Yang, J and Zhao, Y and Liu, Y and Zhu, R and Wang, L and Song, R and Zhang, W},
title = {Unsupervised Disentanglement of Brain Heterogeneity for Identifying Subtypes of Alzheimer's Disease.},
journal = {IEEE transactions on bio-medical engineering},
volume = {PP},
number = {},
pages = {},
doi = {10.1109/TBME.2026.3663181},
pmid = {41666058},
issn = {1558-2531},
abstract = {Neuroanatomical heterogeneity in Alzheimer's disease (AD) hinders precision diagnosis and treatment, as distinct brain phenotypes may correspond to different disease subtypes. However, MRI-based subtype classifications are often confounded by co-occurring pathologies and non-AD factors, such as genetic predisposition and environmental influences, limiting their clinical interpretability. We propose 3D-DisAD, an unsupervised deep learning framework that disentangles AD-specific neuroanatomical variations from unrelated influences and clusters patients into subtypes with homogeneous brain phenotypes. The framework comprises two synergistic networks: (1) Contrastive Disentanglement Network, which separates AD-specific variations from those shared by AD patients and healthy controls; and (2) Transformation Generation Network, which refines these disease-specific variations by transforming healthy brain representations into realistic, pathology-consistent anatomies via diffusion-based generative modeling. Evaluated on four public datasets, 3D-DisAD reveals strong correlations between the disentangled AD-specific variations and diverse clinical and biological profiles, validating their relevance. Using these variations, we identify four AD subtypes with significant differences in biomarkers, cognitive trajectories, and genetic signatures, and uncover distinct longitudinal progression patterns that suggest potential windows for early intervention. By disentangling AD-specific variations, our method enables more precise patient stratification and personalized treatments, particularly in the early stage of AD. Code is available at: https://github.com/cnuzh/3D-DisAD.},
}

@article {pmid41666016,
year = {2026},
author = {Wu, B and Niu, Z and Sui, Y},
title = {LAPTM proteins in neurological disorders - Autophagy-lysosome dysfunction and therapeutic targets: A review.},
journal = {Biomolecules & biomedicine},
volume = {},
number = {},
pages = {},
doi = {10.17305/bb.2026.13624},
pmid = {41666016},
issn = {2831-090X},
abstract = {Lysosomal-associated protein transmembrane (LAPTM) family members-LAPTM4A, LAPTM4B, and LAPTM5-regulate lysosomal integrity, autophagy-lysosome flux, lipid homeostasis, and immune signaling, pathways increasingly implicated in neurological disease. This review synthesizes structure-function evidence for LAPTM proteins and examines how their dysregulation contributes to Alzheimer's and Parkinson's disease, ischemia-reperfusion injury, and gliomas. Based on a targeted narrative analysis of primary and translational studies, we highlight that LAPTM proteins influence lysosomal acidification and membrane stability, endolysosomal trafficking, and ceramide/ion handling, thereby shaping protein aggregate clearance, oxidative stress responses, and microglia/macrophage polarization. Preclinical data link LAPTM5 to stroke outcomes via stress-kinase and lysosomal pathways, while LAPTM4A and LAPTM4B associate with glioma progression, immune evasion, and therapy resistance. Overall, LAPTM proteins represent promising biomarkers and therapeutic targets, warranting cell-type-resolved validation and central nervous system (CNS)-optimized delivery strategies, including gene therapy, small-molecule/degrader approaches, and multi-omics-guided patient stratification.},
}

@article {pmid41665901,
year = {2026},
author = {Halbgebauer, R and Gonzalez-Ortiz, F and Mayer, B and Berger, C and Bergmann, C and Rinderknecht, H and Barth, E and Wohlgemuth, L and Mannes, M and Otto, M and Tumani, H and Relja, B and Gebhard, F and Huber-Lang, M and Zetterberg, H and Halbgebauer, S and Blennow, K},
title = {Blood-Based Analysis of Different Tau Variants in Patients With Multiple Traumatic Injuries.},
journal = {JAMA network open},
volume = {9},
number = {2},
pages = {e2558573},
doi = {10.1001/jamanetworkopen.2025.58573},
pmid = {41665901},
issn = {2574-3805},
mesh = {Humans ; *tau Proteins/blood ; Male ; Female ; Adult ; Middle Aged ; Biomarkers/blood ; *Brain Injuries, Traumatic/blood ; Phosphorylation ; Cohort Studies ; Case-Control Studies ; },
abstract = {IMPORTANCE: With blood-based phosphorylated tau biomarkers soon to be used for diagnosis of Alzheimer disease, analyzing tau levels in other conditions could enhance biomarker interpretability. Moreover, mechanisms of tau release into circulation remain unclear.

OBJECTIVE: To evaluate concentrations of phosphorylated and nonphosphorylated tau variants in the blood of patients with multiple traumatic injuries on days 0, 1, 5, and 10 and investigate biological processes driving tau release.

This multiple-trauma cohort (injury severity score, ≥18) included 45 severely injured patients with (n = 27) and without (n = 18) moderate-to-severe traumatic brain injury on emergency computed tomographic imaging. Controls consisted of 24 healthy volunteers. Participants were recruited from December 1, 2013, to October 31, 2022. Blood samples were analyzed for brain-derived tau (BD-tau), total tau (t-tau), and phosphorylated tau 217 (p-tau217) and 231 (p-tau231) levels. Associations among tau concentrations, clinical data, and outcome (eg, Glasgow Coma Scale [GCS] score) were assessed. Data were analyzed from March 1, 2023, to September 30, 2024.

EXPOSURES: Serum BD-tau, t-tau, p-tau217, and p-tau231 levels.

RESULTS: A total of 214 serum samples were analyzed. Median age of the 45 patients was 48 (IQR, 33-60) years (35 [77.8%] male); median age of the 24 controls, 43 (IQR, 28-50) years (16 [66.7%] male). Median serum levels of tau variants were increased in patients with multiple traumatic injuries at day 0 compared with controls (t-tau: 43 [IQR, 21-95] vs 3 [IQR, 3-5] pg/mL; BD-tau: 78 [IQR, 30-343] vs 2 [IQR, 2-3] pg/mL; p-tau231: 61 [IQR, 21-79] vs 2 [IQR, 1-3] pg/mL; all, P < .001). Only median BD-tau levels remained elevated until day 10 (day 1, 25 [IQR, 14-69] pg/mL; day 5, 9 [IQR, 4-15] pg/mL; day 10, 8 [IQR, 4-18] pg/mL). Median tau levels at admission were higher in patients with lower GCS scores (BD-tau: 107 [ IQR, 59-838] vs 33 [IQR, 24-78] pg/mL [P = .01]; p-tau231: 76 [IQR, 36-114] vs 28 [IQR, 9-63] pg/mL [P = .02]). Elevated median tau levels were also observed in patients with hemorrhagic shock vs those without shock (eg, BD-tau on day 0: 113 [IQR, 78-378] vs 31 [IQR, 24-61] pg/mL; P = .002) and in nonsurvivors vs survivors with uncomplicated courses (eg, BD-tau on day 1: 92 [IQR, 22-527] vs 16 [IQR, 7-23] pg/mL; P = .009).

CONCLUSIONS AND RELEVANCE: In this exploratory study among a cohort of patients with multiple traumatic injuries, levels of tau variants reflected both direct and indirect neurological injury, with BD-tau showing the most persistent elevation in the acute phase.},
}

Humans
*tau Proteins/blood
Male
Female
Adult
Middle Aged
Biomarkers/blood
*Brain Injuries, Traumatic/blood
Phosphorylation
Cohort Studies
Case-Control Studies

@article {pmid41665822,
year = {2026},
author = {Matías-Guiu, JA and Ortega-Madueño, I and Gil-Moreno, MJ and Cárdenas, MC and Abizanda-Saro, P and Alcalá Ramírez Del Puerto, JM and López-Carbonero, JI and Valiente-Gordillo, E and Aguilera, L and Carrillo-Molina, T and García-Rama, M and Matarranz-González, S and Palacios-Sarmiento, M and Matías-Guiu, J and Gómez-Pinedo, U},
title = {Impact of blood p-tau217 testing on diagnosis and diagnostic confidence in cognitive disorders: a real-world clinical study.},
journal = {Journal of neurology},
volume = {273},
number = {2},
pages = {130},
pmid = {41665822},
issn = {1432-1459},
support = {INT20/00079//Instituto de Salud Carlos III/ ; INT23/00017//Instituto de Salud Carlos III/ ; CM23/00094//Instituto de Salud Carlos III/ ; Fondo Estrategia Enfermedades Neurodegenerativas//Ministerio de Sanidad, Consumo y Bienestar Social/ ; },
mesh = {Humans ; Male ; Female ; Aged ; *tau Proteins/blood ; Biomarkers/blood ; *Cognitive Dysfunction/diagnosis/blood ; Aged, 80 and over ; Middle Aged ; Alzheimer Disease/diagnosis/blood ; *Cognition Disorders/diagnosis/blood ; Neuropsychological Tests ; *Dementia/diagnosis/blood ; },
abstract = {BACKGROUND: The blood biomarker p-tau217 has demonstrated high accuracy in predicting underlying Alzheimer's disease (AD) pathology. However, its feasibility and impact on clinician confidence and diagnosis in real-world clinical settings remain underexplored. We aimed to evaluate the effect of implementing blood p-tau217 testing on both diagnosis and diagnostic confidence in patients with cognitive symptoms across two different clinical settings: general neurology consultations referred from primary care and a specialized memory unit.

METHODS: We included 200 consecutive new patients (38.5% with subjective cognitive complaints, 47.5% mild cognitive impairment, and 14% with dementia) evaluated for cognitive symptoms in two distinct clinical settings: general neurology and a memory unit. Attending neurologists were asked to record a pre-biomarker clinical diagnosis and their diagnostic confidence on a scale from 0 to 10. They repeated this assessment after receiving the p-tau217 results.

RESULTS: Across the whole sample, 51/200 patients (25.5%) had a change in their diagnostic category after receiving p-tau217 levels. Furthermore, diagnostic confidence significantly improved from 6.90 ± 1.74 at the first visit to 8.49 ± 1.68 after the test. Changes in diagnosis and confidence were observed in both general neurology and memory unit settings, and across all clinical stages (subjective cognitive complaints, mild cognitive impairment, and dementia). Compared with the final diagnosis, the pre-biomarker diagnosis was maintained in 71/200 cases (75.5%) (Kappa = 0.576), while the post-biomarker diagnosis was maintained in 189/200 cases (94.5%) (Kappa = 0.906).

CONCLUSIONS: Implementing p-tau217 in real-world clinical practice has a strong clinical impact, substantially improving diagnostic accuracy and confidence in both general neurology and memory units across all stages of cognitive decline.},
}

Humans
Male
Female
Aged
*tau Proteins/blood
Biomarkers/blood
*Cognitive Dysfunction/diagnosis/blood
Aged, 80 and over
Middle Aged
Alzheimer Disease/diagnosis/blood
*Cognition Disorders/diagnosis/blood
Neuropsychological Tests
*Dementia/diagnosis/blood

@article {pmid41665770,
year = {2026},
author = {Arora, A and Behl, T and Sehgal, A and Singh, S and Sharma, N and Abdellatif, AAH and Dailah, HG and Bhatia, S and Al-Harrasi, A and Aleya, L and Bungau, S},
title = {Retraction Note: Elucidating the promising role of traditional Chinese medicine in neuroprotection against oxidative stress encompassing Alzheimer's disease.},
journal = {Environmental science and pollution research international},
volume = {},
number = {},
pages = {},
doi = {10.1007/s11356-026-37499-0},
pmid = {41665770},
issn = {1614-7499},
}

@article {pmid41665751,
year = {2026},
author = {Voronova, AD and Karsuntseva, EK and Shishkina, VS and Chadin, AV and Fursa, GA and Gurin, PI and Kuznetsova, TV and Reshetov, IV and Shport, SV and Stepanova, OV and Chekhonin, VP},
title = {Clinical Trials of Cell Products for the Treatment of Alzheimer's Disease (Review).},
journal = {Bulletin of experimental biology and medicine},
volume = {},
number = {},
pages = {},
pmid = {41665751},
issn = {1573-8221},
abstract = {Existing approaches to the treatment of Alzheimer's disease are ineffective because they do not stop neurodegenerative processes in the brain and do not promote the regeneration of the nervous tissue. Cell therapy is a promising strategy for the treatment of this disease. This review discusses clinical studies of cell-based therapies for Alzheimer's disease, evaluates their therapeutic potential, and proposes strategies for developing safe, accessible, and effective cell products.},
}

@article {pmid41665706,
year = {2026},
author = {Giacomini, PS and Voss, P and Devonshire, V and Schneider, R and Macaron, G and Hussein, S and Blanchette, F and de Villers-Sidani, É},
title = {Eye tracking as a digital biomarker in neurodegenerative diseases.},
journal = {Journal of neurology},
volume = {273},
number = {2},
pages = {133},
pmid = {41665706},
issn = {1432-1459},
mesh = {Humans ; *Neurodegenerative Diseases/diagnosis/physiopathology/complications ; Biomarkers ; *Eye-Tracking Technology ; *Eye Movements/physiology ; },
abstract = {Oculomotor abnormalities are a common finding in neurodegenerative diseases due to degeneration of neural pathways and brain regions involved in controlling eye movements. Pathological changes to the dorsolateral prefrontal cortex, basal ganglia, superior colliculus and cerebellum produce subtle changes in eye-movement metrics that may not be detected by clinical examination. The present review addresses the potential use of eye-movement biomarkers in neurodegenerative conditions such as multiple sclerosis, Parkinson's disease, Alzheimer's disease and other dementias, and amyotrophic lateral sclerosis. Eye-movement metrics such as saccades, anti-saccades, fixation and smooth pursuit are prognostic of disease progression, can differentiate pathologic subtypes as an aid to diagnosis, and enable clinicians to evaluate early worsening of motor and cognitive function. The cost of medical technologies limits their optimal use and accessibility in clinical practice. The shortage of subspecialist neurologists further limits access to care. New eye-tracking technologies incorporated into widely-accessible digital devices such as smart phones and tablets now permit detailed assessments with minimal equipment requirements, providing an important non-invasive and potentially cost-effective method for patient evaluation in routine clinical practice and as an aid to treatment decision-making. Digital biomarkers can be readily employed by healthcare professionals such as family physicians, nurses and pharmacists to bridge the care gaps, potentially providing them with powerful tools that can be broadly adopted to improve the delivery of care to patients with neurodegenerative conditions.},
}

Humans
*Neurodegenerative Diseases/diagnosis/physiopathology/complications
Biomarkers
*Eye-Tracking Technology
*Eye Movements/physiology

@article {pmid41665145,
year = {2026},
author = {Baral, R and van Deventer, R and Lyubchenko, YL},
title = {Amyloid β-Cholesterol Interplay: Removal of Cholesterol From the Membranes to Catalyze Aggregation and Amyloid Pathology.},
journal = {Journal of neurochemistry},
volume = {170},
number = {2},
pages = {e70380},
doi = {10.1111/jnc.70380},
pmid = {41665145},
issn = {1471-4159},
support = {GM100156/NH/NIH HHS/United States ; },
mesh = {*Cholesterol/metabolism ; *Amyloid beta-Peptides/metabolism ; Humans ; *Peptide Fragments/metabolism ; *Cell Membrane/metabolism ; *Protein Aggregation, Pathological/metabolism/pathology ; Microscopy, Atomic Force ; Alzheimer Disease/metabolism/pathology ; Animals ; },
abstract = {The interplay between the cholesterol metabolism and assembly of Aβ42 (the 42-residue form of the amyloid-β peptide) peptides in pathological aggregates is considered one of the major molecular mechanisms in the development of Alzheimer's disease (AD). Numerous in vitro studies led to the finding that high cholesterol levels in membranes accelerate the production of Aβ aggregates. The molecular mechanisms explaining how cholesterol localized inside the membrane bilayer catalyzes the assembly of Aβ aggregates above the membrane remain unknown. We addressed this problem by combining different AFM modalities, including imaging and force spectroscopy, with fluorescence spectroscopy. Our combined studies revealed that Aβ42 was capable of removing cholesterol from the membrane. Importantly, physiologically low concentrations of Aβ42 demonstrate such ability. Extracted cholesterol interacts with Aβ42 and accelerates its on-membrane aggregation, which is a molecular mechanism explaining how cholesterol embedded in the membrane accelerates Aβ42 aggregation. The discovered ability of Aβ42 to remove cholesterol from membranes resulted in three major AD-related events. First, free cholesterol catalyzes the assembly of Aβ42 in aggregates, which is the mechanism by which physiologically important Aβ42 monomers are converted into their pathological form. Second, the release of cholesterol from membranes leads to its accumulation in the brain, which is one of the risk factors associated with disease development and progression. Third, cholesterol depletion decreases membrane stiffness, which can result in deterioration of the function of membrane-bound proteins, such as dendritic spine degeneration and, ultimately, synapse loss, a common pathological feature of AD.},
}

*Cholesterol/metabolism
*Amyloid beta-Peptides/metabolism
Humans
*Peptide Fragments/metabolism
*Cell Membrane/metabolism
*Protein Aggregation, Pathological/metabolism/pathology
Microscopy, Atomic Force
Alzheimer Disease/metabolism/pathology
Animals

@article {pmid41665021,
year = {2026},
author = {Elia, A and Parodi-Rullan, R and Vazquez-Torres, R and Carey, A and Zhao, H and Javadov, S and Fossati, S},
title = {Amyloid β Instigates Cardiac Neurotrophic Signaling Impairment, Driving Alzheimer's Associated Heart Disease.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e11924},
doi = {10.1002/advs.202511924},
pmid = {41665021},
issn = {2198-3844},
support = {PACure;CollaborativeResearchonAlzheimer'sDisease//Pennsylvania Department of Health/ ; 24POST1240115//American Heart Association/ ; AARG-20-685663/ALZ/Alzheimer's Association/United States ; R01NS104127//NIH National Institute of Neurological Disorders and Stroke/ ; R01AG062572//NIH National Institute on Aging/ ; SC1GM128210//National Institute of General Medical Sciences (NIGMS)/ ; },
abstract = {While a link between cardiovascular risk factors and increased Alzheimer's disease (AD) risk has been reported, it remains unclear whether AD pathology has a direct effect on cardiac function and myocardial innervation. AD and amyloidosis are known to impair neuronal function and affect brain neurotrophic factors (NGF and BDNF) expression. Amyloid aggregates and neuro-signaling impairments may also expose AD patients to peripheral nervous system deficits, promoting cardiac disorders. Here, we provide novel understanding of cardiac physiological impairment, amyloid pathology, neurotrophic factors loss, and impoverishment of cardiac neuronal fibers in Tg2576-AD mice hearts, human cardiomyocytes in culture, and human AD post-mortem left ventricular (LV) heart tissue. We reveal that Tg2576 animals exhibit increased myocardial fibrosis, amyloid β (Aβ) deposition, and brain/heart-axis neurotrophic deficiencies, resulting in myocardial denervation and cardiac dysfunction. Aβ oligomers challenge reduces BDNF expression in both human immortalized and iPSC-derived cardiomyocytes, by disrupting TrkB/CREB signaling. Analysis of human LV AD post-mortem tissue confirms cell and animal results. Our findings reveal potential pathways by which Aβ pathology may disrupt cardiac neurotrophic signaling and physiology, identifying a possible link between AD and heart degeneration.},
}

@article {pmid41664763,
year = {2026},
author = {Wang, AS and Marino, M and Helson, A and Abbasi, MH and Dally, J and Miulli, DE},
title = {Neuromodulation With Electromagnetic Field Stimulation via Gamma Oscillations Improved Mini-Mental State Examination Scores in Patients With Cognitive Impairment.},
journal = {Cureus},
volume = {18},
number = {1},
pages = {e101122},
pmid = {41664763},
issn = {2168-8184},
abstract = {BACKGROUND: Abnormalities in gamma oscillations have been found in neurological disorders that involve dementia, such as Alzheimer's disease. Neuromodulation via gamma stimulation has shown promising potential to enhance cognitive function in patients with Alzheimer's disease.

OBJECTIVE: In this pilot clinical trial, we describe recording and neuromodulation of brain electromagnetic field (EMF) at gamma oscillations, specifically 70 Hertz (Hz) to 100 Hz, and its effect on brain EMF waves, cognition, and memory as assessed with EMF recordings and Mini-Mental State Examination (MMSE) in patients with cognitive impairment. We hypothesize that EMF stimulation at 70-100 Hz will lead to a statistically significant improvement in MMSE compared with baseline. Additionally, we aim to refine EMF recording and stimulation protocols.  Methods: MMSE was performed before and after EMF recordings. We used a previously developed portable helmet system equipped with Mu-metal (MuMETAL, Magnetic Shield Corporation, Bensenville, IL) and copper shielding, embedded sensors, and EMF generators to record baseline brain EMF of patients with cognitive impairment, identify the sensor of interest and frequency of interest, deliver EMF stimulation at the frequency of interest at 10 Volts over 10 minutes, and record post-stimulation EMF.

RESULTS: Sixteen patients with cognitive impairment were included in this study. EMF recordings from six patients were used to refine analysis protocols, while ten new patients underwent stimulation. The mean pre-stimulation MMSE score was 13.8/30 points, and the mean post-stimulation MMSE score was 17.5/30 points (p=0.170).

CONCLUSIONS: In this pilot study, neuromodulation via EMF stimulation led to improvement in EMF waves and showed a trend toward cognitive and memory improvement without statistical significance in patients with cognitive impairment.},
}

@article {pmid41664707,
year = {2026},
author = {Xiang, Q and Shi, RL and Huang, YX and Liu, LN and Tao, JS and Li, XH and Li, XD},
title = {Oligodendrocyte: Development, Plasticity, Biological Functions, Diseases, and Therapeutic Targets.},
journal = {MedComm},
volume = {7},
number = {2},
pages = {e70618},
pmid = {41664707},
issn = {2688-2663},
abstract = {In the past few years, the incidence rate of central nervous system (CNS) diseases is still growing. Meanwhile, the molecular mechanism on the pathogenesis of neurological diseases remains elusive. Oligodendrocyte progenitor cells (OPCs) are distributed in the whole CNS and represent a population of migrating and proliferating adult progenitor oligodendrocytes that can be differentiated into oligodendrocytes (OLs). The main function of OLs is to produce myelin, the membrane wrapping tightly around the axon, which are associated with the myelination and remyelination. During regeneration, the new OLs from OPCs can regenerate lost myelin, which prevents axonal degeneration and restores its plasticity and function. Considering these energy-consuming processes, the high metabolic turnover OLs are susceptible to neurotoxic factors and its excitatory toxicity. Thus, the pathogenesis of OPC and OL are proven in neurological diseases, such as multiple sclerosis, Alzheimer's disease, major psychiatric diseases, and epilepsy. The current study reviewed the development, plasticity as well as application of OPCs and OLs researches on CNS diseases. Additionally, the effective methods and bioengineering technologies as well as biomaterials relevant to regenerative medicine are also discussed, which could provide the novel insight into the therapeutic treatment of those diseases, exploring new pathological clues, identifying the key molecules and targets as well as the potential biomarkers.},
}

@article {pmid41664541,
year = {2026},
author = {Cánovas, R and Fowler, CJ and Feizpour, A and Dóre, V and Bourgeat, P and Saad, ZS and Triana-Baltzer, G and Kolb, HC and Vandijck, M and Kollmorgen, G and Quijano-Rubio, C and Fripp, J and Laws, S and Bannon, AW and Blennow, K and Zetterberg, H and Rainey-Smith, S and Mathotaarachchi, S and Rowe, CC and Masters, CL and Doecke, JD and , },
title = {Plasma biomarker progression across the Alzheimer's disease amyloid beta and tau positron emission tomography trajectories.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {2},
pages = {e71145},
doi = {10.1002/alz.71145},
pmid = {41664541},
issn = {1552-5279},
support = {//AbbVie/ ; 2023-00356//Swedish Research Council/ ; 2022-01018//Swedish Research Council/ ; 2019-02397//Swedish Research Council/ ; 101053962//European Union's Horizon Europe research and innovation programme/ ; ALFGBG-71320//Swedish State Support for Clinical Research/ ; ADSF-21-831376-C//AD Strategic Fund/ ; ADSF-21-831381-C//AD Strategic Fund/ ; ADSF-21-831377-C//AD Strategic Fund/ ; ADSF-24-1284328-C//AD Strategic Fund/ ; 22HLT07//NEuroBioStand/ ; //Familjen Beiglers Stiftelse/ ; //Stiftelsen för Gamla Tjänarinnor/ ; FO2022-0270//Hjärnfonden/ ; //European Union's Horizon/ ; JPND2021-00694//European Union Joint Programme - Neurodegenerative Disease Research/ ; //National Institute for Health/ ; UKDRI-1003//UK Dementia Research Institute/ ; //Enigma Australia/ ; //Biogen/ ; //Eisai/ ; //Roche/ ; //Johnson and Johnson/ ; },
mesh = {Humans ; *tau Proteins/blood ; Positron-Emission Tomography ; *Amyloid beta-Peptides/blood ; *Alzheimer Disease/diagnostic imaging/blood ; *Biomarkers/blood ; Male ; Female ; Aged ; Disease Progression ; Brain/diagnostic imaging/metabolism ; Aged, 80 and over ; Phosphorylation ; },
abstract = {INTRODUCTION: With increased uptake in disease-modifying treatments for amyloid beta (Aβ) removal, it is important to measure performance of highly sensitive plasma biomarkers to detect the presence of Aβ and tau in cognitively impaired populations.

METHODS: In this study, we investigated a large set of plasma biomarkers for their capability to predict Aβ and tau positron emission tomography (PET) and their association with increasing Aβ and tau burden.

RESULTS: From the biomarkers assessed, tau phosphorylated at threonine 217 (pTau217) showed the largest increases across the full range of Aβ and tau levels. Furthermore, pTau217/Aβ42 had the smallest proportion of participants in the intermediate zone (∼4%) to predict Aβ status using a 90/90% dual cut-off for sensitivity and specificity, with < 20% of participants in the intermediate zone using the 95/95% dual cut-off.

DISCUSSION: While the studied biomarkers proved their utility to predict Aβ and tau PET at their respective thresholds, each has separate quantified responses to Aβ and tau aggregation.},
}

Humans
*tau Proteins/blood
Positron-Emission Tomography
*Amyloid beta-Peptides/blood
*Alzheimer Disease/diagnostic imaging/blood
*Biomarkers/blood
Male
Female
Aged
Disease Progression
Brain/diagnostic imaging/metabolism
Aged, 80 and over
Phosphorylation

@article {pmid41664517,
year = {2026},
author = {Silva Fernandes, A and Barbosa de Souza, Á and Benvindo de Souza, M and Madureira Almeida, L and Luiz Franco, O and Luiz Cardoso Bailão, EF and Borges, LL and Sérgio Nakao de Aguiar, A},
title = {DNA damage induced by fungicides triadimefon, triadimenol, and their mixture in human lymphocytes: cytogenotoxicity and computational analysis of metabolic pathways.},
journal = {Drug and chemical toxicology},
volume = {},
number = {},
pages = {1-9},
doi = {10.1080/01480545.2026.2626753},
pmid = {41664517},
issn = {1525-6014},
abstract = {Triadimefon (TF) and triadimenol (TN) are triazole fungicides widely used to prevent fungal infections in cereals, fruits, and other economically important crops. Their harmful effects on non-target organisms have been reported. This study investigated the cytogenotoxic effects of TF and TN, isolated and combined, at environmentally relevant concentrations (TF: 0.006, 0.012, and 0.024 mg/mL; TN: 1.5, 3.0, and 6.0 mg/mL; and 0.012 mg/mL TF + 3.0 mg/mL TN) on human lymphocytes using the trypan blue exclusion test and the comet assay. Additionally, in silico tools, BioTransformer and DIGEP-Pred, were employed to elucidate metabolic pathways more effectively for detoxifying these xenobiotics and to evaluate their putative effects on gene transcription, respectively. Exposure to TF and TN, either alone or in combination, did not affect lymphocyte viability at the tested concentrations. However, both compounds induced an increase in the percentage of DNA strand breaks after treatment. The in silico predictions suggested that the interaction with the cytochrome P450 isoforms (CYP1A2, CYP2A6, CYP2C9, and CYP2D6) differed for each compound analyzed. Gene expression prediction indicated that TF and TN may up-regulate genes involved with hormonal alterations, Alzheimer's disease risk, and cancer progression (SF1, SPON1, ADGRF5, and RORB). While they may down-regulate a gene involved with changes in heart rhythm and neurotoxicity (HCN1). In conclusion, our findings reinforced that the triazole fungicides TF and TN, while effective in agriculture, may pose risks to genomic stability in humans, highlighting the importance of biomonitoring studies in exposed populations.},
}

@article {pmid41664510,
year = {2026},
author = {Bouwman, MMA and Frigerio, I and Graaf, YG and van de Berg, WDJ and Jonkman, LE},
title = {Distinct regional patterns of synaptic vulnerability across hippocampal and parahippocampal subregions in Alzheimer's disease.},
journal = {Brain pathology (Zurich, Switzerland)},
volume = {},
number = {},
pages = {e70081},
doi = {10.1111/bpa.70081},
pmid = {41664510},
issn = {1750-3639},
support = {WE.03-2020-02//Alzheimer Nederland/ ; S-000438//LSH-TKI PPP/ ; },
abstract = {Synaptic loss in the (para)hippocampus is a major contributor to cognitive decline in Alzheimer's disease (AD), yet its regional specificity and pathological correlates remain poorly understood. Here, we quantified synaptophysin-positive puncta across hippocampal subregions (CA4, CA2, CA1, and subiculum) and parahippocampal cortex (entorhinal cortex, parahippocampal and fusiform gyrus) in postmortem tissue from 28 AD and 17 controls, and assessed relationships to neuropathological severity and cognitive decline. Amyloid-β, phosphorylated tau (p-tau) load and neurofilament light (NfL) immunoreactivity were quantified, and Clinical Dementia Rating scores were collected as a cognitive measure. Group differences were analyzed with linear mixed models; correlations between synaptic puncta, pathology and cognitive scores with linear regressions, corrected for age, sex and multiple comparisons. We found selective synaptic loss in the entorhinal cortex (-14%, p = 0.017) and parahippocampal gyrus (-14%, p = 0.021) in AD versus controls. Hippocampal synaptic density negatively correlated with amyloid-β in controls (r = -0.52, p < 0.001) and positively in AD (r = 0.25, p = 0.007), suggesting a disease-dependent shift. In AD, hippocampal, but not parahippocampal, subregions with higher p-tau burden showed greater synaptic density (r = 0.21, p = 0.003), raising questions about the role of p-tau in synaptic loss at late stages. Axonal damage (i.e., higher NfL load) in the parahippocampal cortex associated with synaptic loss locally and in interconnected subregions. Worse cognitive performance was strongly associated with synaptic loss in the CA1 (r = -0.64, p = 0.003), subiculum (r = -0.62, p = 0.012), entorhinal cortex (r = -0.60, p = 0.008), parahippocampal (r = -0.48, p = 0.041) and fusiform gyrus (r = -0.67, p = 0.002). These findings highlight the vulnerability of the entorhinal cortex and parahippocampal gyrus to synaptic loss in AD. Our results suggest that amyloid-β and p-tau pathology may play a limited role in synaptic loss at end-stage disease, and the strong link between synaptic loss in (para)hippocampal subregions and cognitive decline underscores the need for monitoring synaptic change in light of disease progression and evaluating therapeutic interventions.},
}

@article {pmid41664462,
year = {2026},
author = {Zawadzki, S and Suty, S and Okła, E and Ortega López, P and de la Mata, FJ and Waczulikova, I and Ionov, M and Bryszewska, M and Miłowska, K},
title = {Hemocompatibility of Carbosilane Dendrimers as a Therapeutic siRNA Delivery System across Blood-Brain Barrier.},
journal = {ACS applied materials & interfaces},
volume = {},
number = {},
pages = {},
doi = {10.1021/acsami.5c12952},
pmid = {41664462},
issn = {1944-8252},
abstract = {The development of nanocarriers offers a promising strategy for the delivery of therapeutics to the central nervous system. However, the clinical translation of nanosystems hinges on their interactions with blood components, which not only dictate their biodistribution and therapeutic efficacy but also may pose potential risks to hemostasis. In this study, we assess the hemocompatibility of a novel, third-generation PEGylated carbosilane dendrimer (G3Si PEG6000) and its dendriplex designed for siRNA delivery across the blood-brain barrier pertinent to Alzheimer's disease. Utilizing a comprehensive array of advanced analytical techniques, we assess cellular responses, cytokine expression, hemorheological properties, hematological parameters, and coagulation dynamics within a physiologically relevant environment. Our findings demonstrate that the investigated nanosystem elicits changes in blood rheology, immune recognition, and the intrinsic coagulation cascade, yet these effects remain below thresholds associated with clinically significant adverse outcomes. Hemolysis was ∼8-fold lower for dendriplexes than the dendrimer in PBS at the highest concentration (accordingly 3.5 ± 0.14% vs 27.46 ± 4.66%, 24 h), in 55% plasma, both formulations were nonhemolytic across all concentrations. Whole blood viscosity increased by up to ∼11% (dendrimer) and ∼16% (dendriplex) relative to the control. At 10 μM, the dendrimer approximately doubled the aPTT, whereas the corresponding dendriplex increased the aPTT by ∼30% of the control. Importantly, neither adverse effects on red blood cell and platelet indices nor toxicological responses in white blood cells were observed under the tested conditions. These findings not only support the translational potential of the studied nanosystem for therapy but also emphasize the critical role of the therapeutic cargo and the formation of a biomolecular corona in shaping the nanocarrier's biological identity and its subsequent interactions within the bloodstream. The results provide a compelling scientific basis for advancing this platform in further investigations.},
}

@article {pmid41664377,
year = {2026},
author = {Wen, H and Dong, Y and Wang, R},
title = {Hesperetin Early Intervention Reduces Β-Amyloid Production in APP/PS1 Mice by Decreasing Beta and Gamma-Secretase Enzyme.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273400444251015050402},
pmid = {41664377},
issn = {1996-3181},
abstract = {

Introduction: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by β-amyloid (Aβ) plaque accumulation and cognitive decline. Early intervention targeting Aβ production may mitigate AD progression. This study investigated the neuroprotective effects of hesperetin, a citrus flavonoid, in APPswe/PS1dE9 transgenic mice.

Methods: APPswe/PS1dE9 mice (3 months old) were administered hesperetin (20, 40, and 80 mg/ kg/day) for 6 months. Cognitive function was assessed using the Morris water maze and the Barnes maze. Neuronal morphology in the hippocampal CA1 region was examined using thionin staining. Aβ40, Aβ42, β-secretase, and γ-secretase levels in brain tissue and serum were measured by ELISA, and tau protein expression was analyzed by Western blotting.

Results: Hesperetin-treated mice exhibited improved learning and memory, reduced neuronal degeneration, and lower tau expression. Brain tissue showed decreased Aβ40, Aβ42, and secretase levels, whereas serum Aβ levels increased, suggesting enhanced Aβ clearance.

Discussion: Hesperetin may attenuate AD pathology by inhibiting β- and γ-secretase activity, reducing Aβ production, and promoting Aβ efflux to peripheral circulation.

Conclusion: Early hesperetin intervention demonstrates potential as a therapeutic strategy for AD by modulating Aβ metabolism and preserving cognitive function.

@article {pmid41664344,
year = {2026},
author = {Cao, J and Song, J and Yin, Z and Tang, Z},
title = {Lysine demethylase 1A alleviates Alzheimer disease progression by regulating the leucine carboxyl methyltransferase 1/protein phosphatase 2 catalytic subunit alpha/transcription factor EB pathway via O-GlcNAcase-mediated forkhead box transcription factor A2 O-GlcNAcylation modification.},
journal = {British journal of pharmacology},
volume = {},
number = {},
pages = {},
doi = {10.1111/bph.70289},
pmid = {41664344},
issn = {1476-5381},
support = {21042230044//2023 Postdoctoral Project in Heilongjiang Province/ ; //The Postdoctoral Fellowship Program of CPSF and Innovative Scientific Research Foundation of the First School of Harbin Medical University/ ; GZC20230639//National Postdoctoral Researcher Support Program, Category B/ ; },
abstract = {BACKGROUND AND PURPOSE: Lysine demethylase 1A (KDM1A; LSD1) plays anti-ferroptosis role and has been confirmed to be lowly expressed in Alzheimer disease (AD). This study explores whether LSD1 affects the progression of AD by regulating ferroptosis and related mechanisms involved.

EXPERIMENTAL APPROACH: AD mice (APP/PS1 double transgenic) were injected with adeno-associated virus expressing LSD1 overexpression vector, or siRNA against leucine carboxyl methyltransferase 1 (LCMT1)/transcription factor EB (TFEB). SH-SY5Y cells were treated with Aβ1-42 to establish an AD cell injury model. The levels of lipid peroxidation and ferroptosis-related markers were tested to evaluate ferroptosis. The protein levels of LSD1, O-GlcNAcase (OGA), forkhead box transcription factor A2 (FOXA2), LCMT1, protein phosphatase 2A catalytic subunit alpha (PP2A) and TFEB were detected by western blot. The mRNA levels of LSD1 and OGA were assessed using quantitative real-time PCR. Interactions between targets were measured by ChIP-qPCR, DNA pull down, co-immunoprecipitation and dual-luciferase reporter assay.

KEY RESULTS: LSD1 upregulation suppressed neuronal ferroptosis to attenuate AD progression in mice. Further, LSD1 overexpression alleviated Aβ1-42-induced cell injury by reducing OGA transcription and expression. OGA inhibited FOXA2 O-GlcNAcylation modification to promote its expression and transcriptional activity. Also, FOXA2 repressed LCMT1-mediated the activation of PP2A and TFEB. Furthermore, LSD1 alleviated AD process by inhibiting neuronal ferroptosis through the regulation of OGA/FOXA2/LCMT1/PP2A/TFEB axis.

CONCLUSIONS AND IMPLICATIONS: Overall, LSD1 restrained neuronal ferroptosis to alleviate the progression of AD by regulating LCMT1/PP2A/TFEB pathway via OGA-mediated FOXA2 O-GlcNAcylation modification, providing novel mechanistic insights into the deeper understanding of AD pathogenesis and the development of potential drug targets.},
}

@article {pmid41664331,
year = {2026},
author = {Siddiqui, S and Tufail, P and Khan, F and Khalid, MF and Khalid, F},
title = {Protocatechuic Acid Alleviates Neurodemyelination by Modulating PKCα-p38/MAPK Pathways in an LPC-Induced Model of Neurodegeneration.},
journal = {Current protein & peptide science},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113892037385148251207081917},
pmid = {41664331},
issn = {1875-5550},
abstract = {INTRODUCTION: Neuroinflammation, axonal damage, and alterations in extracellular matrix (ECM) protein expression are hallmarks of neurodegenerative diseases. Therapies that enhance recovery from brain injury are of significant clinical value. Therefore, this study investigated the antiinflammatory properties of protocatechuic acid (PCA).

METHODS: Neuroglial cocultures were prepared from P0-P1 rats. Demyelination was induced using LPC (0.003%). The effects of PCA (10 and 25 μg) on neurite outgrowth were assessed using morphometry software. Expression of COX-2, NF-κβ, PKC-α, and p38/MAPK was examined through immunostaining, SDS-PAGE, and Western blotting. Expression intensities were quantified using ImageJ software. Sustained repetitive neuronal firing was evaluated using the patch-clamp technique.

RESULTS: PCA increased neurite outgrowth in LPC-treated cultures after 72 hours in vitro. LPCinduced upregulation of ECM proteins TN-C, LN, and CSPGs was significantly reduced by PCA treatment compared with LPC controls. Similarly, PCA decreased the expression intensities of the pro-inflammatory markers NF-κβ and COX-2 relative to LPC controls. Furthermore, PCA reversed the sustained neuronal firing pattern observed in untreated LPC-exposed neurons.

DISCUSSION: Purified bioactive compounds commonly present in everyday foods show therapeutic potential for Parkinson's and Alzheimer's diseases due to their lower toxicity compared with conventional drugs. Artificial intelligence tools, such as AlphaFold and RoseTTAFold, further support drug development by predicting PCA binding modes with PKCα and P38/MAPK, thereby contributing to the design of personalized therapeutics and advancing neuroscience research.

CONCLUSION: PCA alleviated neuroinflammation by reducing phosphorylation of PKCα and p38/MAPK.},
}

@article {pmid41664091,
year = {2026},
author = {van der Nulft, V and Stoppelenburg, A and Mahieu, LAI and Hoffstädt, HE and van der Steen, JT and van Vliet, LM and van der Linden, YM},
title = {Factors influencing readiness for advance care planning in dementia: a qualitative interview study.},
journal = {BMC palliative care},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12904-026-02012-4},
pmid = {41664091},
issn = {1472-684X},
support = {10200012110006/ZONMW_/ZonMw/Netherlands ; },
}

@article {pmid41664080,
year = {2026},
author = {García-González, J and Cote, AC and Garcia-Gonzalez, S and Liou, L and O'Reilly, PF},
title = {The gene expression landscape of disease genes.},
journal = {Genome biology},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13059-026-03958-7},
pmid = {41664080},
issn = {1474-760X},
support = {30749//Brain & Behavior Research Foundation/ ; 1K99HG013547-01/HG/NHGRI NIH HHS/United States ; R01MH122866/NH/NIH HHS/United States ; },
abstract = {BACKGROUND: Fine-mapping and gene-prioritisation techniques applied to the latest genome-wide association study (GWAS) results have prioritised hundreds of genes as causally associated with disease. Here we leverage these recently compiled lists of high-confidence causal genes to interrogate where in the body disease genes operate, providing a more direct approach than previous studies, which have primarily relied on the enrichment of GWAS signals among genes with cell- or tissue-specific expression.

RESULTS: By integrating GWAS summary statistics, gene prioritisation results, and RNA-seq data from 46 tissues and 204 cell types, we directly analyse the gene expression of putative disease genes across the body in relation to 11 major diseases and cancers. In tissues and cell types with established disease relevance, disease genes show higher and more specific gene expression compared to control genes. Moreover, we detect elevated expression in tissues and cell types without previous links to the corresponding disease. While some of these results may be explained by cell types that span multiple tissues, such as macrophages in brain, blood, lung and spleen in relation to Alzheimer's disease (P-values < 10[-3]), the cause for others is unclear and warrants further investigation. To support functional follow-up studies of disease genes, we identify technical and biological factors influencing their expression. Finally, we highlight tissue-disease pairs in which significantly elevated expression is associated with increased odds of inclusion in drug development programmes.

CONCLUSIONS: We provide our systematic testing framework as an open-source, publicly available tool that can be utilised to offer novel insights into the genes, tissues and cell types involved in any disease, with the potential for informing drug development and delivery strategies.},
}

@article {pmid41663782,
year = {2026},
author = {Lee, JW and Hasegawa, T and Ikedo, A and Mizuno, K and Amizuka, N and Kong, SW},
title = {Lithium and the Brain-Bone Axis: A Bridge between Osteoporosis and Alzheimer's Disease.},
journal = {Current osteoporosis reports},
volume = {24},
number = {1},
pages = {7},
pmid = {41663782},
issn = {1544-2241},
support = {23K09116//Japan Society for the Promotion of Science/ ; R01NS129188//National Institute of Health/ ; },
mesh = {Humans ; *Alzheimer Disease/metabolism/drug therapy ; *Brain/metabolism/drug effects ; *Osteoporosis/metabolism/prevention & control/drug therapy ; Bone Density/drug effects ; *Bone and Bones/drug effects/metabolism ; Glycogen Synthase Kinase 3 beta/metabolism ; Wnt Signaling Pathway/drug effects ; *Lithium/pharmacology/therapeutic use ; Bipolar Disorder/drug therapy ; beta Catenin/metabolism ; *Lithium Compounds/pharmacology/therapeutic use ; Osteocalcin/metabolism ; },
abstract = {PURPOSE OF REVIEW: We evaluate the converging evidence positioning lithium as a systemic modulator of bone and brain health through shared molecular pathways. This review examines the molecular basis, preclinical data, and clinical observations suggesting that lithium-long established as first-line therapy for bipolar disorder-may simultaneously protect against osteoporosis and neurodegeneration as two clinical conditions increasingly recognized to share biological substrates.

RECENT FINDINGS: Lithium inhibits glycogen synthase kinase-3β (GSK-3β), stabilizes β-catenin, and activates Wnt signaling in neurons and osteoblasts, while also modulating calcium-inositol homeostasis and suppressing NF-κB-mediated inflammation. Large observational studies report lower dementia incidence and reduced fracture risk in long-term lithium users, together with increases in bone mineral density. Declining brain lithium concentrations in patients with Alzheimer's disease raise the hypothesis that lithium may act as an essential micronutrient rather than solely a pharmacological agent. Bidirectional brain-bone crosstalk involving osteocalcin signaling and sclerostin transport across the blood-brain barrier provides a mechanistic basis for these pleiotropic effects. Lithium offers a unique paradigm for understanding and potentially treating age-related decline in multiple organ systems at subclinical dosage and concentration. However, observational study limitations, optimal dose uncertainties, and toxicity related to long-term usage concerns necessitate rigorous randomized controlled trials before broader clinical recommendations can be made. Future research should focus on optimizing formulation and patient selection to realize lithium's dual protective potential for bone and brain while minimizing risk.},
}

Humans
*Alzheimer Disease/metabolism/drug therapy
*Brain/metabolism/drug effects
*Osteoporosis/metabolism/prevention & control/drug therapy
Bone Density/drug effects
*Bone and Bones/drug effects/metabolism
Glycogen Synthase Kinase 3 beta/metabolism
Wnt Signaling Pathway/drug effects
*Lithium/pharmacology/therapeutic use
Bipolar Disorder/drug therapy
beta Catenin/metabolism
*Lithium Compounds/pharmacology/therapeutic use
Osteocalcin/metabolism

@article {pmid41663779,
year = {2026},
author = {Roy, KK and Kumari, R and Upadhyay, AK and Mohanty, S},
title = {Tailoring treatments: pharmacogenomics in the management of neurodegenerative diseases.},
journal = {Acta neurologica Belgica},
volume = {},
number = {},
pages = {},
pmid = {41663779},
issn = {2240-2993},
abstract = {Neurodegenerative diseases like Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis are growing more common worldwide, yet treatment is still poor. Conventional therapies can have unforeseen side effects, produce poor medication reactions, and take longer to work. This persistent treatment gap highlights the need for novel approaches to these disorders' complex distinctions. Pharmacogenomics, which examines how genetic differences affect drug response, is a promising new subject and an urgent solution. Pharmacogenomics tailors medicine selection and administration to each patient's genetic profile, addressing the main causes of poor treatment response and preventable side effects. This research has enabled precision medicine that can improve neurodegenerative disease therapy and reduce harm. In this in-depth research, we examine neurodegenerative disease management issues, pharmacogenomics breakthroughs, and how incorporating genetics to clinical practice can improve outcomes. We examine the latest evidence that genetics affect drug breakdown, efficacy, and toxicity. We also discuss the challenges and opportunities of applying this knowledge. Pharmacogenomic approaches must be widely applied to make medicines for these awful disorders safer, more effective, and really suited to patient needs, according to our compilation.},
}

@article {pmid41663727,
year = {2026},
author = {Pusparani, Y and Lin, CY and Jan, YK and Liau, BY and Lin, FY and Furqon, EN and Talal, M and Pravin, SC and Tsai, ZR and Lung, CW},
title = {Evaluation of deep learning models for segmentation of hippocampus volumes from MRI images in Alzheimer's disease.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-38220-4},
pmid = {41663727},
issn = {2045-2322},
support = {NSTC 114-2923-E-468-001-MY3//National Science and Technology Council of Taiwan/ ; },
}

@article {pmid41663665,
year = {2026},
author = {Kang, IK and Lee, S and Moon, TK and Han, AR and Yu, DB and Jung, M and Kwak, C and Seo, JK and Rhee, HW and Kim, SW and Woo, HN and Mun, JY and Lee, H},
title = {Proximity labeling unveils potential roles of the Miro2-CISD1 network in mitochondrial dynamics and neuronal differentiation.},
journal = {Communications biology},
volume = {9},
number = {1},
pages = {195},
pmid = {41663665},
issn = {2399-3642},
mesh = {*Mitochondrial Dynamics ; Animals ; *Neurogenesis ; *Neural Stem Cells/metabolism/cytology ; *Cell Differentiation ; Humans ; *rho GTP-Binding Proteins/metabolism/genetics ; Mitochondria/metabolism ; *Neurons/metabolism/cytology ; Hippocampus/cytology/metabolism ; Mice ; *Mitochondrial Proteins/metabolism/genetics ; },
abstract = {Adult hippocampal neurogenesis, crucial for maintaining neural homeostasis, is integral to neurodegeneration. We previously identified Miro2 as a key regulator of mitochondrial dynamics and survival in hippocampal neural stem cells with potential relevance to Alzheimer's disease. Here, using TurboID-based proximity labeling, we explore Miro2's interaction networks and identify sixty-six unique interactors specific to hippocampal neural stem cells. Functional enrichment analysis reveals that these proteins are crucial for mitochondrial organization, transport, and neurodegeneration. CISD1 emerges as a significant interaction partner. Knockdown of Miro2 and CISD1 impairs mitochondrial trafficking in adult hippocampal stem cells, disrupted stem cell differentiation with increased cytotoxicity. Rescue experiments partially reverse cell death, and both Miro2 and CISD1 show increased expression and interaction during differentiation. These findings suggest the Miro2-CISD1 axis as a critical regulator of mitochondrial remodeling and neurogenesis, providing a framework for future studies on how mitochondrial dynamics contribute to neurodegenerative disease mechanisms.},
}

*Mitochondrial Dynamics
Animals
*Neurogenesis
*Neural Stem Cells/metabolism/cytology
*Cell Differentiation
Humans
*rho GTP-Binding Proteins/metabolism/genetics
Mitochondria/metabolism
*Neurons/metabolism/cytology
Hippocampus/cytology/metabolism
Mice
*Mitochondrial Proteins/metabolism/genetics

@article {pmid41663048,
year = {2026},
author = {Zhou, J and Lee, DA and Talebi, Y and Wu, G and Wu, H},
title = {Risk of Dementia in Type 2 Diabetes Patients with Open-Angle Glaucoma: Insights from a Nationwide Real-World Cohort Study.},
journal = {American journal of ophthalmology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.ajo.2026.02.003},
pmid = {41663048},
issn = {1879-1891},
abstract = {PURPOSE: To evaluate whether open-angle glaucoma (OAG) serves as a risk marker for subsequent dementia in patients with type 2 diabetes mellitus (T2DM), a population at elevated risk for both conditions.

DESIGN: Retrospective cohort study using longitudinal electronic health record (EHR) data.

PARTICIPANTS: A total of 1,580,368 adults with T2DM from the Merative™ Explorys® Therapeutic Dataset (2010-2022), including 12,405 patients diagnosed with OAG.

METHODS: OAG was treated as a time-dependent exposure in Cox proportional hazards models to account for variable onset timing relative to T2DM diagnosis. The primary outcome was the first recorded diagnosis of all-cause or subtype-specific dementia. Models were adjusted for demographic, clinical, behavioral, and ocular covariates. Kaplan-Meier and subtype-specific time-dependent Cox analyses were performed to evaluate crude and adjusted associations.

MAIN OUTCOME MEASURES: Hazard ratios for incident all-cause and subtype-specific dementia.

RESULTS: Compared to T2DM patients without OAG, those with OAG had significantly reduced dementia-free survival (log-rank p < 0.001). After covariate adjustment, OAG was associated with a 13% increased risk of all-cause dementia (HR = 1.13, 95% CI: 1.09-1.17). Subtype-specific analysis revealed elevated risks for vascular (HR = 1.37, 95% CI: 1.08-1.74) and frontotemporal dementia (HR = 1.39, 95% CI: 1.06-1.82), but no evidence of increased risk for Alzheimer's disease (HR = 0.63, 95% CI: 0.52-0.76). Stroke and depression were also strong independent risk factors.

CONCLUSIONS: In patients with T2DM, OAG was associated with an increased risk of non-Alzheimer's dementia, particularly vascular and frontotemporal types. These findings support the hypothesis of shared neurovascular mechanisms and highlight the potential of ophthalmic assessments for early dementia risk stratification in high-risk populations.},
}

@article {pmid41663025,
year = {2026},
author = {El-Sheekh, MM and Ramadan, NE and Elshikh, FM and R Youssef, F and Salem, JW and Sharaf, MT and Elmor, SH and Ali, SS},
title = {Smart alginate-based biomaterials for neurodegenerative disease therapy: Innovations in delivery, regeneration, and clinical translation.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {150688},
doi = {10.1016/j.ijbiomac.2026.150688},
pmid = {41663025},
issn = {1879-0003},
abstract = {Neurodegenerative diseases and central nervous system (CNS) injuries remain among the most challenging disorders to treat due to their complex pathophysiology, limited regenerative capacity, and the presence of the blood-brain barrier (BBB), which severely restricts therapeutic delivery. Despite extensive research efforts, most current interventions are palliative and fail to modify disease progression. Biomaterial-based strategies have emerged as promising adjuncts to conventional therapies, with alginate-based systems attracting increasing attention due to their biocompatibility, mild aqueous processing, and tunable physicochemical properties. This review critically examines the role of alginate-based biomaterials in CNS drug delivery, tissue engineering, and regenerative medicine, with particular emphasis on their ability to address key translational barriers, including BBB penetration, immune compatibility, and localized, sustained therapeutic release. We discuss how alginate can be engineered into nanoparticles, hydrogels, microspheres, and three-dimensional scaffolds to engage distinct transport mechanisms-such as receptor-mediated transcytosis, adsorptive-mediated uptake, and nose-to-brain delivery-while preserving the stability of labile bioactive cargos. Quantitative design parameters relevant to CNS applications, including stiffness ranges, degradation kinetics, and porosity, are highlighted to support rational material selection. Importantly, this review distinguishes between the structural and delivery functions of alginate as a carrier material and the biological effects mediated by encapsulated therapeutic agents, avoiding overstatement of alginate's intrinsic bioactivity. Disease-specific applications in Alzheimer's disease, Parkinson's disease, spinal cord injury, and brain tumors are discussed in a balanced manner, with clear differentiation between preclinical findings and clinically validated evidence. Current limitations related to mechanical robustness, batch-to-batch variability, and regulatory scalability are critically evaluated, alongside emerging solutions such as surface functionalization, hybrid biomaterials, and advanced fabrication strategies. Overall, this review provides a realistic and integrative framework for understanding the opportunities and constraints of alginate-based systems in CNS therapy, emphasizing that while alginate offers significant preclinical promise, substantial translational challenges remain before widespread clinical adoption can be achieved.},
}

@article {pmid41662806,
year = {2026},
author = {Zhang, H and Zhang, H and Zhao, M and Luo, W and Chen, S and Wang, P and Liu, X and Xu, S},
title = {Da-Bu-Yin-Wan rescues cognitive deficits in aging and Alzheimer's disease models by Wnt/β-catenin-dependent restoration of lysosomal acidification.},
journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology},
volume = {153},
number = {},
pages = {157916},
doi = {10.1016/j.phymed.2026.157916},
pmid = {41662806},
issn = {1618-095X},
abstract = {BACKGROUND: Lysosomal acidification deficits are increasingly recognized as a convergent pathological mechanism driving both age-related cognitive decline (ARCD) and early Alzheimer's disease (AD) progression, creating a self-reinforcing cycle of cellular aging and Aβ dyshomeostasis. Despite demonstrated neuroprotective effects of Da-Bu-Yin-Wan (DBYW) in Parkinson's disease models, its therapeutic potential for lysosomal dysfunction in ARCD and AD remains an uncharted area of investigation.

PURPOSE: This present work aimed to elucidate the mechanistic basis by which DBYW mitigates both ARCD and AD pathology through functionally rescuing impaired lysosomal acidification.

METHODS: Cell-based D-galactose and Aβ-induced in BV2 cells to study lysosomal acidification. Molecular analyses combined immunofluorescence localization studies with quantitative immunoblotting of lysosomal and Wnt signaling proteins. In vivo, DBYW treatment effects were systematically evaluated in both D-gal-induced and APP/PS1 transgenic models using cognitive behavioral followed by immunohistochemical and biochemical assessment of brain tissues lysosomal parameters and Wnt signaling activity.

RESULTS: DBYW attenuated the mechanistic basis of ARCD and AD pathology by functionally rescuing impaired lysosomal acidification. Overexpression of β-catenin could modulate D-galactose or Aβ-induced dysregulation of the Wnt/β-catenin pathway and restore lysosomes with abnormal acidification, while DBYW could regulate lysosomal function by promoting Wnt/β-catenin signaling. In addition, in D-gal-induced aging and AD model mice, DBYW treatment activated Wnt/β-catenin signaling to restore lysosomal acidification, while spatial memory deficits in ARCD and AD models were improved, and pathology in mouse attenuation and APP/PS1 mouse brain tissue was inhibited.

CONCLUSION: DBYW shows a potential dual efficacy in improving cognitive decline in ARCD and AD models. It makes DBYW a promising disease-modifying intervention targeting the shared lysosomal pathophysiology of aging-associated neurodegeneration.},
}

@article {pmid41662789,
year = {2026},
author = {Mayeli, M and Matuskey, D and , },
title = {Social determinants of brain structure and cognition.},
journal = {Social science & medicine (1982)},
volume = {394},
number = {},
pages = {119045},
doi = {10.1016/j.socscimed.2026.119045},
pmid = {41662789},
issn = {1873-5347},
abstract = {BACKGROUND: Socioeconomic disadvantage is recognized as a risk factor for cognitive decline, yet its associated neural pathways remain unclear. We investigated whether neighborhood disadvantage, measured by the Area Deprivation Index (ADI), was associated with cognitive performance in older adults and patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD), and whether structural brain differences explained this relationship.

METHODS: Participants included 822 older adults (478 cognitively unimpaired [CU], 271 with MCI, and 73 with AD). Associations between ADI, cognition, and brain structure were examined using regression models adjusting for age and sex. Mediation analyses tested whether total brain volume accounted for ADI-cognition relationships.

RESULTS: Higher ADI was associated with poorer cognitive performance across all domains in CU individuals (National ADI: memory β = -0.008, p < 0.001; executive function β = -0.005, p < 0.001; language β = -0.005, p < 0.001; visuospatial β = -0.004, p < 0.001) and across multiple domains in MCI (memory β = -0.007, p = 0.002; executive β = -0.007, p < 0.001). ADI was also associated with smaller total cerebral, gray, and white matter volumes in CU (State ADI and gray matter β = -2.37, FDR-p = 0.006) and greater white matter hyperintensity burden (β = 0.152, FDR-p = 0.009). Associations were weaker in MCI and absent in AD. Mediation analyses showed that total brain volume significantly mediated the effect of ADI on language performance (ACME p = 0.024; proportion mediated = 19.7 %, p = 0.036).

CONCLUSIONS: Neighborhood disadvantage is linked to widespread cognitive vulnerability and structural brain differences. However, brain volume explains only a small portion of these associations, suggesting that environmental and contextual factors shape cognitive performance through pathways that extend beyond structural neurodegeneration.},
}

@article {pmid41662521,
year = {2026},
author = {Boskovic, P and Shalita, R and Gao, W and Vernon, H and Deng, YL and Colonna, M and Majzner, RG and Amit, I and Kipnis, J},
title = {Engineering chimeric antigen receptor CD4 T cells for Alzheimer's disease.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {123},
number = {7},
pages = {e2530977123},
doi = {10.1073/pnas.2530977123},
pmid = {41662521},
issn = {1091-6490},
support = {R01AG078667//HHS | NIH | National Institute on Aging (NIA)/ ; R61AG090394//HHS | NIH | National Institute on Aging (NIA)/ ; no number//Carol and Gene Ludwig Family Foundation/ ; no number//Cure Alzheimer's Fund (CAF)/ ; no number//Fred and Ginger Haberle Charitable Fund at East Texas Communities Foundation/ ; },
mesh = {*Alzheimer Disease/therapy/immunology/pathology ; *CD4-Positive T-Lymphocytes/immunology/metabolism/transplantation ; Animals ; *Receptors, Chimeric Antigen/genetics/immunology/metabolism ; Mice ; Humans ; Amyloid beta-Peptides/metabolism/immunology ; *Immunotherapy, Adoptive/methods ; Disease Models, Animal ; Brain/pathology/immunology/metabolism ; },
abstract = {Alzheimer's disease (AD) is the prevailing cause of age-associated dementia worldwide. Current standard of care relies on antibody-based immunotherapy. However, antibody-based approaches carry risks for patients, and their effects on cognition are marginal. Increasing evidence suggests that T cells contribute to AD onset and progression. Unlike the cytotoxic effects of CD8[+] cells, CD4[+] T cells capable of regulating inflammation show promise in reducing pathology and improving cognitive outcomes in mouse models of AD and in aging. Here, we sought to exploit the beneficial properties of CD4[+] T cells while circumventing the need for TCR and peptide-MHC antigen discovery, thereby providing a potential universal therapeutic approach. To achieve this, we engineered CD4[+] T cells with chimeric antigen receptors (CARs) targeting fibrillar forms of aggregated amyloid-β. Our findings demonstrate that optimized CAR-T cells can alter amyloid deposition in the dura and reduce parenchymal pathology in the brain. Furthermore, we observed that CAR-T treatment promotes the expansion and recruitment of endogenous CD4[+] T cells into the brain parenchyma and leptomeninges. In summary, we established the feasibility of amyloid plaque-specific CAR-T cells as a potential therapeutic avenue for AD. These findings highlight the potential of CD4[+] CAR-T therapy not only to modify amyloid pathology but also to reshape the immune landscape of the CNS, paving the way for future development of cellular immunotherapies for neurodegenerative disease.},
}

*Alzheimer Disease/therapy/immunology/pathology
*CD4-Positive T-Lymphocytes/immunology/metabolism/transplantation
Animals
*Receptors, Chimeric Antigen/genetics/immunology/metabolism
Mice
Humans
Amyloid beta-Peptides/metabolism/immunology
*Immunotherapy, Adoptive/methods
Disease Models, Animal
Brain/pathology/immunology/metabolism

@article {pmid41662056,
year = {2025},
author = {Mondragón Bohórquez, SP and Gutiérrez-López, C},
title = {Scope of anti-stigma programs against Alzheimer's disease: A scoping review.},
journal = {PLOS mental health},
volume = {2},
number = {8},
pages = {e0000406},
doi = {10.1371/journal.pmen.0000406},
pmid = {41662056},
issn = {2837-8156},
abstract = {This study identifies and reports evidence related to key guidelines for intervention programs aimed at reducing social stigma associated with Alzheimer's Disease. This scoping review followed the methodology of the Joanna Briggs Institute. The databases searched included: SCOPUS, PubMED, Science Direct, Taylor and Francis, Google Scholar, JBI, Prospero, and Cochrane Library. The STROBE statement was used to organize and draft the protocol. Of the 2275 initial studies, 22 articles were identified for the analysis of emerging categories: social stigma assessment, measurement, and intervention strategies. Of the 2275 initial studies, 22 articles were analysed for the purpose of identifying emerging categories: social stigma assessment, measurement and intervention strategies. Programmes against stigma addressed the following aspects: clinical and epidemiological knowledge and information; emotions, care and impact on patients' lives; general information on the disease; dementia-friendly communities; a multimedia campaign on stigmatising beliefs; digital platforms; support in the arts; knowledge and clinical aspects; bilingual presentations adapted to the culture; and awareness and knowledge about Alzheimer's disease. The most common strategies were: patient and intergenerational contact, life stories [vignettes], theatre, music, art, adapting content for culture, curriculum work, discussion groups and health education. The evidence suggests that the content of educational programs and interventions should focus on promoting understanding of the disease, working with groups or peers with the same condition, and generating intergenerational contact, affectionate bonds, and emotional expression to reduce social stigma.},
}

@article {pmid41661849,
year = {2025},
author = {Braun, LD and Allen, HR and Beyl, RA and Keller, JN},
title = {A case-controlled study investigating gender differences in Face Name Hobby Recall (FNHR) performance in healthy community-dwelling older adults.},
journal = {PLOS mental health},
volume = {2},
number = {3},
pages = {e0000244},
doi = {10.1371/journal.pmen.0000244},
pmid = {41661849},
issn = {2837-8156},
abstract = {Difficulties remembering the faces and the names of individuals are two of the most common memory complaints among older adults (OA's), with impaired performance on face-name recall tests implicated to be one of the earliest changes during the transition to Alzheimer's disease. Studies in children, young-, and middle-aged adults have identified that females generally perform better on face-name association tests than males, although little is known in terms of female versus male performance in OA's. Studies in these same age groups have identified the existence of a "gender bias" whereby face-name recall is improved when facial images are from the same sex as the individual being evaluated. In the current study we employed a case-controlled study design to evaluate 115 OA males and 115 OA females in terms of their performance on the Face Name Hobby Recall (FNHR) test. OA females were observed to have significantly higher levels of both immediate and delayed recall on the FHNR test as compared to males. Improved FNHR test performance by females persisted for up to 12-months in the subset of 21 males and 21 females in the study for whom longitudinal data was available. The rates of learning for names and hobbies did not significantly differ between OA males and females. OA males and females did not exhibit improved FNHR test performance for facial images of their same sex, although OA males did show improved FHNR test performance with female faces as compared to male faces. Data from the current study have implications for future studies that examine the causes and consequences of perturbations in face-name recall in the context of aging and dementia-related research.},
}

@article {pmid41661585,
year = {2026},
author = {Chin, NA and Erickson, CM and Widera, E},
title = {Importance of Function for Alzheimer Diagnosis and Management-More Than Memory.},
journal = {JAMA internal medicine},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamainternmed.2025.7621},
pmid = {41661585},
issn = {2168-6114},
}

@article {pmid41661364,
year = {2026},
author = {Li, L and Kong, J and Fan, R and Yuan, Y and Zhu, L},
title = {Correction: Role of tRNA-Derived Fragments and Their Modifications in the Pathogenesis and Treatment of Alzheimer's Disease.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {429},
doi = {10.1007/s12035-026-05713-2},
pmid = {41661364},
issn = {1559-1182},
}

@article {pmid41661222,
year = {2026},
author = {Daly, T and Imbimbo, BP},
title = {Tau Phosphorylation as an Adaptive Physiological Response: Implications for the Therapy of Tauopathies.},
journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology},
volume = {40},
number = {4},
pages = {e71538},
doi = {10.1096/fj.202503803R},
pmid = {41661222},
issn = {1530-6860},
support = {//N/A./ ; },
mesh = {Humans ; *tau Proteins/metabolism ; *Tauopathies/metabolism/therapy ; Phosphorylation ; Animals ; *Adaptation, Physiological ; Alzheimer Disease/metabolism ; },
abstract = {Recent evidence demonstrates that tau phosphorylation, traditionally viewed as a hallmark of neurodegeneration, also occurs in completely reversible physiological contexts such as mammalian hibernation and human neonatal development. These findings challenge the classical protein-centric "proteinopathy" model of Alzheimer's disease (AD) and other tauopathies. Instead, we propose that phosphorylated tau (p-tau) functions as an adaptive molecular response to metabolic or neuronal activity shifts, and that tauopathies such as AD represent a failure of broader mechanisms that normally restore tau protein homeostasis. Therapeutic strategies should focus on restoring tau protein homeostasis and functionality rather than simply removing phosphorylated species. To achieve this, we discuss one possible therapeutic strategy: dismantling aggregated tau species.},
}

Humans
*tau Proteins/metabolism
*Tauopathies/metabolism/therapy
Phosphorylation
Animals
*Adaptation, Physiological
Alzheimer Disease/metabolism

@article {pmid41661194,
year = {2026},
author = {Talucci, I and Leske, T and Klafki, HW and Hassan, MM and Steiert, A and Morgado, B and Bothe, S and van Werven, L and Liepold, T and Walter, J and Schindelin, H and Wiltfang, J and Wirths, O and Jahn, O and Maric, HM},
title = {Aggregation-dependent epitope sequence and modification fingerprints of anti-Aβ antibodies.},
journal = {eLife},
volume = {14},
number = {},
pages = {},
doi = {10.7554/eLife.106156},
pmid = {41661194},
issn = {2050-084X},
support = {AFN419//Interdisziplinäres Zentrum für Klinische Forschung, Universitätsklinikum Würzburg/ ; MA6957/1-1//Deutsche Forschungsgemeinschaft/ ; IT//Graduate School of Life Sciences, Julius-Maximilians-Universität Würzburg/ ; WI3472/11-1//Deutsche Forschungsgemeinschaft/ ; RTG2824/OW//Deutsche Forschungsgemeinschaft/ ; WA1477/6-6//Deutsche Forschungsgemeinschaft/ ; RTG2824/MMH1//Deutsche Forschungsgemeinschaft/ ; },
mesh = {*Amyloid beta-Peptides/immunology/chemistry/metabolism/genetics ; Humans ; *Epitopes/immunology/chemistry ; *Antibodies, Monoclonal/metabolism ; Alzheimer Disease/drug therapy ; Antibodies, Monoclonal, Humanized/metabolism ; Protein Processing, Post-Translational ; Protein Binding ; },
abstract = {A hallmark of Alzheimer's disease (AD), the most common form of dementia, is the progressive accumulation of amyloid-beta (Aβ) peptides across distinct brain regions. Anti-Aβ antibodies (Aβ-Abs) targeting specific Aβ variants are essential tools for AD research, diagnostics, and therapy. The monoclonal antibodies Aducanumab, Lecanemab, and Donanemab have recently been approved as the first disease-modifying treatments for early AD, highlighting the clinical importance of their exact binding profiles. In this study, we systematically characterized the binding and modification requirements of 20 Aβ-Abs, including biosimilars of Aducanumab, Lecanemab, and Donanemab, across monomeric, oligomeric, and aggregated Aβ forms. Array-based analysis of 20,000 modified Aβ peptides defined binding epitopes at single-residue resolution and revealed the impact of sequence variation, including familial AD mutations, as well as diverse post-translational modifications (PTMs). Notably, genetic variants, such as H6R, impaired binding of therapeutic Aβ-Abs like Aducanumab. Donanemab showed strong preference for pyroglutamate-modified AβpE3-17, while Lecanemab and Aducanumab exhibited aggregation- and sequence-context-dependent binding requirements. Comparison of peptide binding profiles with binding of full-length and aggregated Aβ via immunoprecipitation-mass spectrometry, capillary immunoassays, Western blotting, and immunohistochemistry on AD brain tissue revealed distinct aggregation-dependent binding behaviours. The valency- and context-dependence of Aducanumab binding, together with its preference for Ser8-phosphorylated Aβ, supports a dimerization-mediated binding mechanism. For Lecanemab, our data suggest that additional structural contributions beyond the minimal N-terminal epitope are required for binding to aggregated Aβ, which remain to be fully resolved. Together, this work provides the most comprehensive dataset to date on aggregation-dependent sequence and modification selectivity of Aβ-Abs. By integrating mutational, PTM, and aggregation contexts in a unified experimental framework, we establish a resource that enables rational selection of antibodies for research and diagnostic applications and offers mechanistic insights that may inform the design and optimization of future therapeutic antibodies in AD.},
}

*Amyloid beta-Peptides/immunology/chemistry/metabolism/genetics
Humans
*Epitopes/immunology/chemistry
*Antibodies, Monoclonal/metabolism
Alzheimer Disease/drug therapy
Antibodies, Monoclonal, Humanized/metabolism
Protein Processing, Post-Translational
Protein Binding

@article {pmid41661182,
year = {2026},
author = {Teng, S and Ma, J and Wang, X and Jiang, P and Li, Y},
title = {The clinical significance of miR-484 in depression of older people with Alzheimer's disease and its potential role on depressive behavior.},
journal = {Psychiatric genetics},
volume = {},
number = {},
pages = {},
doi = {10.1097/YPG.0000000000000411},
pmid = {41661182},
issn = {1473-5873},
abstract = {OBJECTIVE: MicroRNAs exhibit remarkable potential as biomarkers due to their multiple advantages in Alzheimer's disease (AD). This study aimed to explore the significance of miR-484 in AD.

METHODS: The study included 216 participants [70 healthy controls (HCs), 77 AD with nondepression, 69 AD with depression (AD-D)]. PCR measured serum and tissue miR-484 levels. Receiver operator characteristic curves evaluated miR-484 diagnostic potential for AD/AD-D. Logistic regression identified AD-D risk factors. Bioinformatics predicted miR-484 targets and functional pathways. Dual-luciferase assay validated the interaction between miR-484 and platelet derived growth factor subunit A (PDGFA). Chronic restraint stress (CRS) induced depression animal model by Kunming mice (20 each group × 6 groups). The effect of miR-484/PDGFA axis on depression-like behaviors was evaluated through behavioral tests (sucrose preference, forced swim, and open field).

RESULTS: Serum miR-484 was downregulated in AD and further decreased in AD-D compared with HCs. MiR-484 downregulation diagnosed AD-D from AD. MiR-484 expression was correlated with amyloid β-protein 1-42 (r = 0.682), total tau (r = -0.575), Mini-Mental State Examination score (r = 0.593), and Hamilton depression rating scale score (r = -0.709). MiR-484 was a risk factor for depression in AD. In the depression mouse model, miR-484 overexpression ameliorated depression-like behaviors (sucrose preference, forced swim immobility time, locomotor activity) by regulating PDGFA.

CONCLUSION: Downregulated miR-484 expression, correlating with cognitive function and depression degree, showed a diagnostic value on AD and AD-D. MiR-484 attenuated the CRS-induced depression-like behavior by regulating PDGFA.},
}

@article {pmid41661021,
year = {2026},
author = {Pervushina, EV and Kutlubaev, MA and Kuznetsova, DR and Karimova, GI and Kachemaeva, OV and Mkhitaryan, EA},
title = {[Combination of amyotrophic lateral sclerosis with Alzheimer's disease].},
journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova},
volume = {126},
number = {1},
pages = {132-136},
doi = {10.17116/jnevro2026126011132},
pmid = {41661021},
issn = {1997-7298},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/diagnosis ; *Alzheimer Disease/complications/diagnosis ; Male ; Aged ; Female ; Middle Aged ; },
abstract = {The combination of amyotrophic lateral sclerosis (ALS) with Alzheimer's disease is rare. Currently, it is unclear whether such comorbidity is an accidental coincidence or a manifestation of a specific pathological process. A case of simultaneous occurrence of classic symptoms of the bulbar form of ALS and Alzheimer's disease is presented. The possible mechanisms of the combination of two diseases are analyzed.},
}

Humans
*Amyotrophic Lateral Sclerosis/complications/diagnosis
*Alzheimer Disease/complications/diagnosis
Male
Aged
Female
Middle Aged

@article {pmid41661003,
year = {2026},
author = {Sayfitdinkhuzhaev, ZF and Zhukova, NG and Nasyrova, RF and Gaponova, OV and Zhukova, IA and Masenko, AY and Baydanova, AN},
title = {[Pathophysiological and neurobiological basis for the development of depression in patients with Parkinson's disease].},
journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova},
volume = {126},
number = {1},
pages = {7-12},
doi = {10.17116/jnevro20261260117},
pmid = {41661003},
issn = {1997-7298},
mesh = {Humans ; *Parkinson Disease/physiopathology/complications/psychology ; *Depression/etiology/physiopathology ; Serotonin/deficiency/metabolism ; Dopamine/deficiency/metabolism ; Substantia Nigra/physiopathology/metabolism ; Locus Coeruleus/physiopathology/metabolism ; Raphe Nuclei/physiopathology/metabolism ; Norepinephrine/deficiency/metabolism ; },
abstract = {Parkinson's disease (PD) is one of the most common neurodegenerative diseases, second only to Alzheimer's disease. PD is characterized by multisystemic lesions and steady progression of the pathological process, which inevitably leads to the occurrence of various symptoms. PD symptoms are divided into motor and non-motor. It is generally accepted that non-motor symptoms precede motor ones and appear several decades before motor symptoms. The most common non-motor symptom of PD is depression, which significantly reduces patients' quality of life. The review addresses recent studies of the pathophysiology of depression in PD patients. The analysis showed the involvement of the substantia nigra, the raphe nuclei, and the locus ceruleus in the development of depression in PD patients. The molecular basis of their dysfunction is a deficiency of dopamine, serotonin, and norepinephrine. A detailed study of the neurobiological mechanisms of the development and progression of depression will create highly effective and pathogenetically based therapeutic areas.},
}

Humans
*Parkinson Disease/physiopathology/complications/psychology
*Depression/etiology/physiopathology
Serotonin/deficiency/metabolism
Dopamine/deficiency/metabolism
Substantia Nigra/physiopathology/metabolism
Locus Coeruleus/physiopathology/metabolism
Raphe Nuclei/physiopathology/metabolism
Norepinephrine/deficiency/metabolism

@article {pmid41660967,
year = {2026},
author = {Elugbadebo, O and Farombi, T and Arulogun, O and Nichols, M and Ogunronbi, M and Olawuyi, C and Simbine, AC and Mkubila, A and Adeleye, O and Olujobi, D and Olorunsogbon, OF and Ojo, O and Adeniyi, S and Moses, A and Oguike, W and Olajire, K and Towolawi, B and Oyinlola, O and Mandy, I and Ogunde, G and Bakor, N and Asibey, SO and Laryea, R and Akinyemi, JO and Rheem, N and Dinku, T and Andrea, D and Njamnshi, K and Akinwande, K and Ogbole, GI and Damasceno, A and Bello, A and Wahab, K and Musyimi, C and Ndetei, D and Nwani, P and Mutiso, V and Njamnshi, WY and Obiako, R and Olowoyo, P and Zewde, YZ and Ayele, BA and Okubadejo, N and Osaigbovo, G and Okereke, C and Sarfo, F and Akpalu, A and Kamada, L and Ogundele, AT and Njamnshi, AK and Iwuozo, E and Adoukonou, T and Paddick, SM and Nwazor, EO and Osemwegie, N and Adebusoye, LA and Olowookere, OO and Ikanga, J and Guerchet, M and Griswold, AJ and Seshadri, S and Caban-Holt, A and Baiyewu, O and Vance, J and Owolabi, M and Byrd, G and Walker, R and Cucarro, M and Kalaria, R and Ogunniyi, A and Pericak-Vance, M and Akinyemi, R},
title = {Recruiting and retaining persons with suspected Alzheimer's disease and related dementias for genetic studies in selected African countries: Lived realities of researchers.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261416066},
doi = {10.1177/13872877261416066},
pmid = {41660967},
issn = {1875-8908},
abstract = {BackgroundGenomic research in dementia in Africa is of utmost importance based on recent reports from studies on African-Americans that the African ancestral gene is associated with a lower risk effect for developing AD. However, dementia-related genetic studies are still evolving in sub-Saharan Africa, with unique challenges influencing participant recruitment.ObjectiveThis study sought to identify key challenges of recruitment and retention how they were mitigated in the READD-ADSP Africa and 'Origins of AD in African ancestry' genetic studies.MethodsA qualitative narrative research design using in-depth interviews explored the challenges of recruiting participants and how these were managed by the nineteen stakeholders involved in the recruitment process from nine African countries participating in the African Dementia Consortium. An inductive thematic analysis was applied to code and analyze the data systematically.ResultsNineteen stakeholders from nine African countries, participating in READD-ADSP and 'Origins' studies were interviewed. Similar challenges were observed across most African countries, including the non-existing national dementia registry. Other challenges include language diversity, myths around blood collection, family dynamics, stigma, logistics, unmet expectations concerning incentives, fewer older controls and data privacy. Leveraging previous research programs, existing community engagement activities and client-doctor relationships were strategies used in addressing these challenges.ConclusionsThere are some unique challenges with recruiting and retaining participants in genetic studies in Africa. Strengthening community engagement and advocacy for genomic research, alongside a well-populated dementia registry in the African Dementia Consortium, could overcome these challenges and improve participant recruitment in genetic studies.},
}

@article {pmid41660965,
year = {2026},
author = {Libon, DJ and Swenson, R and Tobyne, S and Emrani, S and Salciunas, L and Brown, AJ and Ginsberg, T and Kling, M and Overbeck, K and Powell, L and White, C and Okoli-Umeweni, A and Janson, C and Scheinthal, S},
title = {Digital neuropsychological assessment-Part 2: Relations with cardiovascular risk and informant ratings of neurocognitive decline, functional disabilities, and psychiatric symptoms.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261418287},
doi = {10.1177/13872877261418287},
pmid = {41660965},
issn = {1875-8908},
abstract = {BackgroundThe Digital Assessment of Cognition (DAC) is a brief, 7-minute iPad administered-scored neuropsychological protocol.ObjectiveThe current research sought to investigate relationships between DAC test results and family ratings for neurocognitive decline; instrumental activities of daily living (IADL) impairment; psychiatric symptoms, and physician-determined cardiovascular risks.Methods179 memory clinic patients were assessed. Family members rated the severity of neurocognitive impairment, IADL decline, and psychiatric symptoms using the Everyday Cognition Scales (ECog); the Functional Assessment Questionnaire (FAQ); the Instrumental Activities of Daily Living-Compensation Scale (IADL-C); and the Neuropsychiatric Inventory (NPI), respectively. An index measuring cardiovascular risk was extracted from medical records.ResultsPartial correlations controlled for age, education, and sex found that greater functional disability and elevated cardiovascular risks were associated with lower DAC memory and executive index scores. Lower DAC memory scores were seen in relation to family ratings suggesting impaired Ecog Episodic Memory difficulty; relatively intact ECog Executive/Attention ability; and impaired IADL-C Memory/Self-Management difficulty. By contrast, lower DAC executive performance was seen in relation to family ratings suggesting impaired Ecog Executive/Planning difficulty and IADL-C Social Skills difficulty. Lower DAC-executive index scores were also associated with greater informant rated apathy.ConclusionsThe relations between DAC index scores and total informant FAQ and IADL-scores; Ecog and IADL-C subscales; and selected NPI-defined psychiatric problems suggest that the DAC is both sensitive to gross IADL decline, and specific to differing ECog and IADL-C and psychiatric problems. Combining digital assessment with family IADL ratings could help with clinical decision-making.},
}

@article {pmid41660964,
year = {2026},
author = {Aiello, EN and Luca, G and Moreschi, A and Curti, B and Cazzini, F and Cerri, A and Saba, S and Patisso, V and Maranzano, A and Silani, V and Ticozzi, N and Poletti, B and Verde, F},
title = {The yes-no reversal phenomenon: Prevalence and correlates in mild cognitive impairment and dementia due to neurodegenerative, chronic cerebrovascular, and mixed etiologies.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261418686},
doi = {10.1177/13872877261418686},
pmid = {41660964},
issn = {1875-8908},
abstract = {BackgroundThe yes-no reversal (YNR) phenomenon consists in a patient saying "yes" when meaning "no", or vice-versa.ObjectiveTo investigate the prevalence of the YNR phenomenon in mild cognitive impairment (MCI) and dementia across different neurodegenerative, chronic cerebrovascular, or mixed etiologies, and to explore its demographic and clinical correlates.MethodsInformants of N = 267 patients with MCI or dementia due to possible/probable Alzheimer's disease (AD; N = 164), frontotemporal lobar degeneration (N = 25), Lewy body disease (N = 18), mixed-i.e., AD and chronic cerebrovascular-etiologies (N = 37), Aβ-negative degenerative etiologies (N = 6), and chronic cerebrovascular disease (N = 17) were inquired on the occurrence of YNRs in everyday-life conversations. YNR+ and YNR- patients were compared on demographics (i.e., age, sex, education), disease duration (in months), disease severity (i.e., MCI versus dementia), etiology and total and subscale-/item-level Mini-Mental State Examination (MMSE) scores. A multiple logistic model was also run on the presence/absence of YNRs by addressing, as predictors, variables that yielded significance at an univariable level.ResultsThe YNR phenomenon was recorded in 23 patients (8.61%), all of them being demented (i.e., no MCI patient showed YNRs). YNR+ patients were younger and scored lower on Immediate recall and Language subscores of the MMSE. The prevalence of YNRs was higher in non-AD- (∼18%) versus AD-related (∼5%) etiologies. The effects of disease severity and etiology were confirmed by the multiple logistic model, while the others were not.ConclusionsThe YNR phenomenon is a clinical sign possibly associated with dementia due to non-AD etiologies.},
}

@article {pmid41660958,
year = {2026},
author = {Kadamangudi, S and Sanchez-Sanchez, L and Limon, A and Taglialatela, G},
title = {Regional correlates of tau pathology and synaptic function in primary age-related tauopathy.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261416524},
doi = {10.1177/13872877261416524},
pmid = {41660958},
issn = {1875-8908},
abstract = {BackgroundEmerging studies implicate the microtubule-associated protein tau as a key modulator of neuronal excitability and synaptic dysfunction in human tauopathies. How distinct tau forms influence synaptic excitability across brain regions with differing susceptibility to tau accumulation remains unclear. Primary age-related tauopathy (PART), defined by hippocampal-restricted tau pathology in the absence of amyloid-β, offers a tractable model to investigate tau-specific effects on synaptic physiology.ObjectiveTo determine how regionally enriched tau species in PART relate to synaptic excitation-inhibition balance and to identify molecular pathways linking tau oligomers to synaptic dysfunction.MethodsAutopsy-derived hippocampal and superior middle temporal gyrus tissues from neuropathologically validated PART specimens were analyzed. Tau species, including monomers, oligomers, and paired helical filaments (PHFs), were quantified by western blot. Synaptic function was assessed by microtransplantation of synaptosomal membranes into Xenopus laevis oocytes, followed by electrophysiological recordings of glutamatergic (kainate-evoked AMPAR) and GABAergic (GABAAR) currents to calculate the synaptic excitation-to-inhibition (sE/I) ratio. Proteomic and enrichment analyses of brain-derived tau oligomer (BDTO) interactomes from PART hippocampi were performed.ResultsPART specimens showed hippocampal accumulation of aggregation-prone tau assemblies (oligomeric and PHF-tau) that were negatively correlated with sE/I. Proteins within the BDTO interactome linked to reduced sE/I were enriched for pathways related to vesicle-mediated transport, synaptic endocytosis, and neurotransmitter receptor regulation.ConclusionsIn PART, oligomeric and fibrillar tau are associated with shift toward synaptic inhibition, predominantly within the hippocampus. Proteomic correlates implicate vesicle trafficking pathways as mediators of tau oligomer-associated alterations in synaptic function, providing mechanistic insight into early-stage tauopathy.},
}

@article {pmid41660956,
year = {2026},
author = {Cotelli, MS and Bracca, V and Fasolato, D and Geviti, A and Antonella, A and Cagnin, A and Borroni, B},
title = {Repetitive behaviors in syndromes associated with frontotemporal lobar degeneration.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261418302},
doi = {10.1177/13872877261418302},
pmid = {41660956},
issn = {1875-8908},
abstract = {BackgroundRepetitive behaviors (RB) are purposeless movements, speech, or routines performed without self-awareness or conscious intent.ObjectiveThe present study aims to investigate the prevalence and longitudinal changes of RB and to assess these symptoms in a large cohort of patients with frontotemporal lobar degeneration (FTLD)-associated syndromes using a newly developed caregiver-based questionnaire.MethodsThis was a longitudinal cohort study conducted in tertiary frontotemporal dementia research clinics. A total of 210 FTLD patients were included, 68 of whom had follow-up evaluation. RB were assessed through structured caregiver interviews. Compulsive/impulsive behaviors, stereotypies, and ritualistic behaviors were recorded. Univariate and multiple generalized linear models and generalized linear mixed models were used to estimate predictors and longitudinal changes associated with RB.ResultsRB were reported in 71% of patients, showing a progressive increase from the prodromal to moderate dementia stages. Notably, 30% of patients presented RB since the disease onset phase, especially in the form of compulsive/impulsive behaviors. Predictors included male gender, the behavioral variant of frontotemporal dementia and the semantic variant of primary progressive aphasia phenotypes, and higher scores on Frontal Behavioral Inventory scale, part B. A significant increase in total RB was observed in patients reassessed at 8 to 22 months follow-up from baseline (p = 0.0001), especially in the form of stereotypies and ritualistic behaviors.ConclusionsThe questionnaire developed in this study effectively captures the prevalence and progression of RB. It could contribute to the standardization of the behavioral assessment in FTLD clinical trials and, consequently, to a deeper understanding of these syndromes.},
}

@article {pmid41660954,
year = {2026},
author = {Libon, DJ and Drabick, D and Swenson, R and Tobyne, S and Emrani, S and Bezdicek, O and Salciunas, L and Brown, AJ and Ginsberg, T and Kling, M and Overbeck, K and Powell, L and White, C and Okoli-Umeweni, A and Janson, C and Scheinthal, S},
title = {Digital neuropsychological assessment-part 1: Defining mild cognitive impairment subtypes.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261418280},
doi = {10.1177/13872877261418280},
pmid = {41660954},
issn = {1875-8908},
abstract = {BackgroundIn prior research, the Digital Assessment of Cognition (DAC), a brief digitally administered neuropsychological protocol that assesses verbal episodic memory, verbal working memory, and language, has been used to classify a small sample of memory clinic patients (n = 77) into four meaningful clinical groups.ObjectiveThe current research sought to extend these findings with a considerably larger sample.MethodsThe DAC was administered to 179 ambulatory care/memory clinic patients (45.30% female; 91.10% Caucasian). A comprehensive analysis of DAC core outcome measures and behavior reflecting process/errors was undertaken. Traditional paper/pencil assessment was also obtained. Using Jak, Bondi criteria (2009), paper/pencil test results classified patients into five groups: cognitively unimpaired (CU; n = 74), subtle cognitive impairment (SCI; n = 21), amnestic mild cognitive impairment (aMCI; n = 21), combined dysexecutive/mixed MCI (dys/mxMCI; n = 22), and mild dementia (n = 41).ResultsThe aMCI group presented with many of the classic features consistent with amnesia, i.e., rapid forgetting, reduced free recall clustering, and profligate responding to recognition foils. Latency for correct recognition responding was slower for aMCI compared to the CU group and appears to be associated with a neurocognitive network measuring both memory and language-related operations. SCI and dys/mxMCI groups tended to produce more perseverations on working memory test trials; and produced lower scores on DAC executive outcome measures that assessed auditory span and semantic fluency.ConclusionsThese findings support the criterion and construct validity of the DAC. When brought to scale the DAC could be an effective tool to assess for emergent MCI and dementia syndromes.},
}

@article {pmid41660940,
year = {2026},
author = {Dorfsman, DA and Cai, D and Hamilton-Nelson, KL and Adams, LD and Mena, PR and Rodriguez, VC and Sanchez, JJ and Valladares, GS and Lopez, M and Whitehead, PL and Prough, MB and Manrique, P and Martinez, A and Mas, SM and Scaramutti, C and Acosta, H and Silva-Vergara, C and McInerney, K and Griswold, AJ and Feliciano-Astacio, BE and Cuccaro, ML and Kunkle, BW and Reitz, C and Tosto, G and Bush, WS and Haines, JL and Akinyemi, JO and Akinyemi, RO and Ogunniyi, A and Byrd, GS and Vance, JM and Celis, K and Seixas, A and Pericak-Vance, MA and Rajabli, F},
title = {Educational attainment is associated with reduced functional decline in Puerto Ricans with elevated pTau181.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261415933},
doi = {10.1177/13872877261415933},
pmid = {41660940},
issn = {1875-8908},
abstract = {BackgroundEducation promotes cognitive reserve (CR), potentially buffering Alzheimer's disease pathology (ADP). However, the education-CR relationship may differ by population and genetic background.ObjectiveTo examine education, APOE ε4, and functional scores in a Puerto Rican (PR) cohort with varying plasma pTau181, an ADP biomarker.MethodsA subset of 514 PR older adults with "high" (>mean+1SD) or "low" pTau181 ( 0) and (2) severity among impaired participants, adjusting for age and sex.ResultsHigh EA was associated with better CDR-FUNC than low EA within the high pTau181 group (n = 80; MedianLow_EA = 7, MedianHigh_EA = 0; p = 0.011). The hurdle model similarly showed that each additional year of education reduced the odds of any functional impairment in the high-pTau181 group (OR = 0.89, 95% CI [0.79-0.99]). No significant education × APOE ε4 interaction was observed, though a negative trend suggested that increasing education attenuated ε4-related impairment.ConclusionsGreater education is linked to functional preservation in PR older adults, particularly in those with elevated ADP, suggesting potential CR-mediated resilience. APOE ε4 may worsen outcomes with decreasing education, suggesting both educational and genetic factors should inform strategies to mitigate cognitive decline globally.},
}

@article {pmid41660761,
year = {2026},
author = {D'Sa, A and Crutzen, R and Bödenler, M and Diaz, A and Hanke, S and Hilberger, H and Thunborg, C and Mangialasche, F and Bruinsma, J},
title = {Socioeconomic differences in dementia risk, lifestyle, and relevant determinants of behavior.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251414376},
doi = {10.1177/13872877251414376},
pmid = {41660761},
issn = {1875-8908},
abstract = {BackgroundA healthy lifestyle supports cognitive aging while reducing dementia risk. Multidomain interventions promote healthy behavior, but are often unsuccessful in reaching those with a low socio-economic position (SEP), who face additional challenges with changing behavior.ObjectiveThis cross-sectional study explores differences between SEP-groups in dementia risk, lifestyle, and the socio-cognitive determinants of behavior.Methods3,341 Dutch adults (aged 40-79) were divided into low, medium, or high SEP groups. Using Chi-squared tests and ANOVA, SEP-related differences were explored for dementia risk, lifestyle behaviors, and health conditions. SEP-related differences in socio-cognitive determinants were examined using a modified version of Confidence Interval-Based Estimation of Relevance (CIBER).ResultsParticipants in the low SEP group had a significantly higher prevalence of all health conditions and engaged in more unhealthy behaviors, translating into a significantly higher dementia risk score. Many had misperceptions about the room for lifestyle improvement, but those in the low SEP group were slightly more aware of not adhering to lifestyle recommendations. Additionally, they perceived less self-confidence towards engaging in sports, considered healthy food as more expensive, perceived alcohol less pleasurable, experienced habits as less influential on alcohol intake, and had less confidence in their ability to quit smoking while pleasure and habits were strongly associated with smoking.ConclusionsAdults with a low SEP are at higher risk for dementia and have more potential for lifestyle-based risk reduction. Tailored, co-designed interventions that also consider the broader environment are needed to enhance perceived behavioral control, support behavior change, and reduce inequalities in dementia.},
}

@article {pmid41660277,
year = {2026},
author = {Fang, Y and Han, Z and Yang, S and Chen, J and Li, R and Zhang, Z and Song, J and Wang, D and Ban, Y},
title = {Ferroptosis and Alzheimer's disease: unraveling the molecular mechanisms and therapeutic opportunities.},
journal = {Frontiers in cell and developmental biology},
volume = {14},
number = {},
pages = {1758041},
pmid = {41660277},
issn = {2296-634X},
abstract = {Ferroptosis is a novel form of regulated cell death. Compared with other types of cell death, it shows great differences in structure and biochemistry. This type of cell death is receiving increasing attention. For example, studies have found that it plays a key role in the development of neurodegenerative diseases underlying brain atrophy, such as Alzheimer's disease (AD). AD is a chronic and worsening neurodegenerative disease. It poses a serious threat to the health and quality of life of the elderly. The pathology of AD is mainly the presence of extracellular beta-amyloid (Aβ) plaques and intracellular tau-based nerve fiber entanglement (NFTs). Although there are a large number of studies and interventions for AD, so far, no clinical drugs have been found that can stop the pathological progression of AD or cure it. Currently, treatment strategies for this disease only focus on alleviating clinical symptoms and do not achieve slowing disease progression or curing it. Ferroptosis is gradually considered to play a key role in the occurrence and development of AD. Research based on the AD model confirms that neuronal ferroptosis can be inhibited through pharmacology to reverse cognitive disorders. In this review, we first describe the key molecular mechanisms of ferroptosis, and then discuss how these mechanisms operate and develop in AD. Then, we give a detailed introduction to the latest treatments for AD, including iron chelators, antioxidants, and specific ferroptosis inhibitors. What is noteworthy is that this article emphasizes the analysis of the mechanisms of iron metabolism disorders, as well as the introduction of new drugs for the prevention, rather than the alleviation of AD.},
}

@article {pmid41660275,
year = {2026},
author = {Sabbir, MG and Mansouri, B and Ramjiawan, B},
title = {Loss of CAMKK2 and iron-transport proteins-transferrin and its receptor-in the Alzheimer's disease hippocampus: link to tau pathology.},
journal = {Frontiers in cell and developmental biology},
volume = {14},
number = {},
pages = {1716718},
pmid = {41660275},
issn = {2296-634X},
abstract = {INTRODUCTION: Calcium and iron are essential bioelements regulating neuronal function and survival. Dysregulation of calcium signaling and iron homeostasis is implicated in Alzheimer's disease (AD), contributing to oxidative stress, synaptic dysfunction, and neurodegeneration. Previously, using in vitro cell-based models and transgenic mice, we demonstrated that CAMKK2, a calcium/calmodulin-dependent protein kinase, regulates iron transport via transferrin (TF) and transferrin receptor (TFRC). While excessive iron deposition is a hallmark of AD brains, the mechanisms underlying its dysregulation remain poorly understood. In a prior study of postmortem temporal cortex tissues, we showed that CAMKK2/TF/TFRC protein levels were significantly reduced in AD compared to cognitively normal (CN) individuals, and that increased iron accumulation in AD correlated with reduced TF/TFRC levels. This follow-up study aimed to assess CAMKK2/TF/TFRC protein levels in hippocampal tissues - an early site of AD pathology - and examine their relationship with tau (MAPT) aggregation in AD, Parkinson's disease (PD), and frontotemporal dementia (FTD).

METHODS: Postmortem hippocampal tissues from 29 CN individuals and patients diagnosed with AD/FTD/PD (N = 73/7/9 respectively) were analyzed. CAMKK2/TF/TFRC/MAPT levels were quantified using Western blotting. Correlation analyses evaluated associations among these proteins and with age, sex, and postmortem interval (PMI). Isoelectric focusing (IEF) was used to assess post-translational modifications of CAMKK2 and TF.

RESULTS: CAMKK2 and TF levels were significantly reduced in AD, FTD, and PD hippocampi compared to CN controls. TFRC reduction was specific to late onset AD, suggesting a later event. MAPT levels were significantly elevated in AD, with high molecular weight smears indicating tau aggregation. CAMKK2 and MAPT were positively correlated in CN but not in AD, indicating disease-specific disruption. TF and CAMKK2 were also positively correlated in CN but attenuated in AD. No significant changes in CAMKK2 or TF charge states were detected.

DISCUSSION: CAMKK2 downregulation and impaired iron transport appear to be shared features across multiple neurodegenerative diseases, but their decoupling from tau pathology seems specific to AD. These findings position CAMKK2 as a molecular gatekeeper linking calcium signaling, iron metabolism, and tau aggregation. Future studies should focus on elucidating the mechanisms underlying CAMKK2 downregulation to better understand its role in AD pathogenesis.},
}

@article {pmid41660266,
year = {2026},
author = {Rai, A and Damisah, EC and Hill, RA and Tong, L and Grutzendler, J},
title = {TREM2 and APOE are dispensable for microglial clearance of dying neurons revealed by in vivo imaging.},
journal = {iScience},
volume = {29},
number = {2},
pages = {114559},
pmid = {41660266},
issn = {2589-0042},
abstract = {TREM2 and APOE are major Alzheimer's disease (AD) risk genes that may influence microglial pathophysiology by affecting their ability to phagocytose cellular debris and protein aggregates. Here, we investigated the impact of TREM2 and APOE on the removal of dying neurons in the live brain by combining a targeted photochemical method for programmed cell death with high-resolution two-photon imaging in adult mice. We show that deletion of either Trem2 or Apoe does not affect the dynamics of microglia engagement with dying neurons or their efficiency in phagocytosing corpses. Notably, microglia encapsulating amyloid deposits phagocytosed nearby dying cells without disengaging from plaques or moving their cell bodies; however, in the absence of TREM2, microglial cell bodies readily migrated toward dying cells, subsequently disengaging from plaques. These findings indicate TREM2 and APOE variants likely confer AD risk through mechanisms independent of impaired neuronal corpse phagocytosis.},
}

@article {pmid41660240,
year = {2026},
author = {Balzano, E and Twayana, S and Kosiyatrakul, ST and Logsdon, GA and Thakur, BL and Eichler, EE and Bohl, B and Koch, P and Sidoli, S and Kumari, A and Munson, KM and Hoekzema, K and Aladjem, MI and Schildkraut, CL},
title = {Impact of Tau overexpression on DNA replication dynamics in centromeres of human neural progenitor cells.},
journal = {iScience},
volume = {29},
number = {2},
pages = {114707},
pmid = {41660240},
issn = {2589-0042},
abstract = {Aging somatic cells are characterized by specific chromosome aneuploidy, particularly involving chromosome Y (ChrY) and chromosome 21 (Chr21), which are associated with Alzheimer's disease (AD) pathology. This study investigates the role of DNA replication within centromeric regions of these chromosomes using human neural progenitor cells engineered to overexpress either wild-type (wt) or pseudo-hyper-phosphorylated (php) Tau protein. We developed a method to analyze replication dynamics in centromeric DNA. Our findings reveal that replication origins and fork pausing events are mainly located within α-satellite sequences of ChrY and Chr21, where wt and php Tau distinctly modulate origin activation and initiation. Mass spectrometry analysis on immunoprecipitated Tau identified nuclear interactors of Tau, particularly in its php form, which might directly influence the chromatin architecture and gene expression. These studies provide critical insights into the molecular mechanisms of aneuploidy in tauopathies.},
}

@article {pmid41660209,
year = {2026},
author = {Sheng, C and Zheng, W and Yang, H and Chen, X},
title = {Editorial: The role of neuropsychiatry in neurodegenerative disorders.},
journal = {Frontiers in psychiatry},
volume = {17},
number = {},
pages = {1781963},
doi = {10.3389/fpsyt.2026.1781963},
pmid = {41660209},
issn = {1664-0640},
}

@article {pmid41660149,
year = {2025},
author = {Prasher, P and Sharma, M},
title = {O-glycosylation as a potential biomarker in Alzheimer's disease.},
journal = {EXCLI journal},
volume = {24},
number = {},
pages = {1347-1351},
pmid = {41660149},
issn = {1611-2156},
}

@article {pmid41659709,
year = {2025},
author = {Farah, AI and Itoh, SG and Okumura, H},
title = {Molecular dynamics simulations of amyloid-β(29-42) aggregation in bulk water and at the air-water interface.},
journal = {Biophysics and physicobiology},
volume = {22},
number = {4},
pages = {e220033},
pmid = {41659709},
issn = {2189-4779},
abstract = {Oligomers of amyloid-β (Aβ) peptides are related to Alzheimer's disease, and their formation is accelerated at hydrophilic-hydrophobic interfaces. We performed all-atom molecular dynamics simulations of Aβ(29-42) peptides in bulk water and at an air-water interface. In bulk water, the fragments formed stable aggregates, and the secondary structures were hardly changed. At the interface, the peptides were more easily separated from each other due to the low free-energy barrier and changed their secondary structures more frequently. This conformational flexibility is likely to promote amyloid fibril growth, suggesting a key role of interfacial environments in early aggregation processes.},
}

@article {pmid41659668,
year = {2026},
author = {Carroll, T and Pfendler, D and Alhaj Arhayem, H and Thoma, R and Müller-Eigner, A and Straut, A and Johnson, GVW and Nehrke, K},
title = {Tunable Tau Expression in C. elegans Neurons Reveals that Early-AD Tau Phosphorylation Selectively Impacts Behavior and Mitochondrial Quality Control.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.26.701793},
pmid = {41659668},
issn = {2692-8205},
abstract = {UNLABELLED: Tau protein accumulates myriad post-translational modifications as Alzheimer's disease (AD) progresses, and early-disease tau modifications such as phosphorylation at threonine 231 (T231) likely play a key role in AD pathogenesis. Here, a series of "tunable tau" strains was developed in C. elegans to test the relative impact of tau pseudo-phosphorylation of T231 (T231E) compared to protein expression level as a driver of phenotypic penetrance and severity. Multiple copies of a cassette coding for pan-neuronal wildtype tau or T231E were inserted at a genomic safe harbor loci to create a repertoire of strains expressing tau from low to high levels. In stereotypical behavioral assays of locomotory activity, T231E selectively impacted phenotypic severity compared to wild-type human tau controls, which further tracked with age and tau expression level. However, deficits in associative memory were non-selective between tau and T231E. Moreover, genetic, pharmacologic, and molecular approaches indicated that mitophagy modulation could suppress T231E phenotypes. Additionally, a robust mitochondrial unfolded protein response (UPRmt) occurred in T231E, and loss of atfs-1 , a transcription factor central to the UPRmt suppressed T231E toxicity. These results demonstrate that phenotypic severity is invariably associated with tau dosage, while early-AD relevant modifications can be causative drivers of selective deficits. Consistent with recent findings, enhancing mitophagy or suppressing potentially maladaptive consequences of persistent UPRmt induction can be beneficial. This provides a solid foundation for further interrogation into mitochondrial quality control disruption as a potential root cause for AD pathogenesis.

HIGHLIGHTS: Matched sets of pan-neuronal, multi-copy tau strains enhance experimental controlPhosphomimetic tau elicits selective behavioral and neuronal dysfunctionPhosphomimetic tau triggers a unique mitochondrial unfolded responseTau depletion and mitochondrial interventions rescue observed deficits.},
}

@article {pmid41659659,
year = {2026},
author = {Bhandiwad, AA and Kronman, FN and Liwang, J and Gao, P and Ding, SL and Xu, X and Ng, L and Kim, Y and Mollenkopf, T},
title = {A curvilinear coordinate flatmap for visualizing hippocampal structure and development.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.29.702633},
pmid = {41659659},
issn = {2692-8205},
abstract = {The hippocampal formation is a highly curved and topographically complex forebrain structure. This complex geometry presents persistent challenges for analyzing subregional, laminar, and connectivity patterns. Here, we present a computational workflow that generates curvilinear-coordinate flatmaps from Common Coordinate Framework (CCF) registered hippocampal and retrohippocampal regions by solving the Laplacian equation to derive geodesic streamlines. This transformation unfolds the hippocampus into a planar slab, bounded by the meningeal and ventricular surfaces, with the depth defined along the radial axis. We apply this transform to image volumes, single neuron reconstructions, and point data, including spatial transcriptomic and rabies tracing datasets, revealing topographic variations in the dorsoventral and radial axes that are obscured in the CCF coordinate space. As proof of principle, we use flatmaps to show connectivity loss in a mouse model of Alzheimer's disease and track postnatal development of microglial distribution in the hippocampus. This work provides an efficient and accessible resource for visualizing hippocampal organization across development and disease, offering new opportunities to interrogate the structure and function of this important brain region.},
}

@article {pmid41659651,
year = {2026},
author = {Peck, MR and Chapman, JE and Hill, T and Quinn, K and Ikiz, ED and Lopez, A and Hascup, ER and Bae, C and Hascup, KN},
title = {D-Methionine Improves Spatial Navigation and Attenuates Oxidative Stress and Amyloid Pathology in a Sex-Specific Manner.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.27.702104},
pmid = {41659651},
issn = {2692-8205},
abstract = {BACKGROUND: Oxidative stress and maladaptive neuroimmune activation contribute to cognitive decline in Alzheimer's disease (AD) and represent therapeutic targets beyond amyloid-centered approaches.

OBJECTIVE: To determine whether oral D-methionine (D-Met), a redox-active amino acid, reduces amyloid pathology and lipid peroxidation and confers disease-modifying benefits in AD mouse models.

METHODS: Male and female APP/PS1 and APP [NL-F] mice with advanced AD pathology received oral D-Met or vehicle. Behavioral assessments included locomotor activity and hippocampal-dependent spatial learning and memory. Amyloid burden, lipid peroxidation, peripheral metabolic and inflammatory markers, and hippocampal microglial phenotypes were evaluated using biochemical and histological analyses.

RESULTS: D-Met did not alter locomotor or exploratory behavior but improved spatial memory recall in both sexes of APP/PS1 mice and in female APP [NL-F] mice. APP [NL-F] males exhibited improved learning during Morris water maze (MWM) acquisition. Amyloid pathology was modestly and region-specifically reduced, including decreased hippocampal plaque size in male APP [NL-F] mice, reduced cortical plaque size in female APP/PS1 mice, and lower soluble amyloid-β (Aβ) 42 in male APP/PS1 mice. Lipid peroxidation, assessed by malondialdehyde, was reduced only in female APP [NL-F] mice. D-Met induced pronounced sex-dependent peripheral effects, increasing adiposity and pro-inflammatory adipose signaling in males, while reducing perigonadal white adipose tissue (pgWAT) IL-6 expression in female APP [NL-F] mice. In the hippocampus, D-Met remodeled microglial signatures, with female APP [NL-F] mice showing reduced Iba1 and disease-associated microglial (DAM) markers and increased Axl expression.

CONCLUSION: Short-term D-Met acts as a metabolic and redox modulator with modest amyloid-lowering effects mediated by improved microglial function. Therapeutic efficacy is strongly sex- and model-dependent, with the greatest benefit observed in female APP [NL-F] mice.},
}

@article {pmid41659639,
year = {2026},
author = {Khoshkhoo, S and Bae, M and Wang, Y and Tillett, A and Ramirez, RB and Finander, B and Egan, ED and Marx, L and Patel, D and Zhou, Z and Chahine, Y and Chhouk, B and Zoullas, SM and Lai, A and Coras, R and Bielle, F and Navarro, V and Mathon, B and Valiante, TA and Chameh, HM and Gao, AF and Krings, T and Gooley, S and Hildebrand, MS and Bulluss, K and Clark, J and Morokoff, AP and King, JA and Todaro, M and Kwan, P and O'Brien, TJ and Berkovic, SF and Scheffer, IE and Perucca, P and Lapinskas, E and Rolston, JD and Cosgrove, GR and Sarkis, RA and D'Gama, AM and Alexadrescu, S and Yang, E and Poduri, A and Richardson, RM and Erson-Omay, EZ and DeLanerolle, N and Spencer, DD and Brown, KS and Miller, MB and Roberts, AE and Santos, LN and Kontaridis, MI and Bien, CG and Blacklow, SC and Kahle, KT and Blümcke, I and Huang, AY and Lee, EA and Walsh, CA},
title = {Activating Ras-MAPK pathway variants drive hippocampal clonal competition in human epilepsy.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.26.701822},
pmid = {41659639},
issn = {2692-8205},
abstract = {Mesial (a.k.a., medial) temporal lobe epilepsy (MTLE) is the most common focal epilepsy [1,2] and, in drug-resistant cases, is treated by surgical removal of the anterior temporal lobe, which often shows neuronal loss and gliosis consistent with hippocampal sclerosis (HS) [2] . MTLE with HS has minimal contribution from germline genetic variation [3] , and is associated with prior precipitating insults such as prolonged childhood seizures and head trauma [4-6] . Somatic variants in Ras-MAPK pathway genes were recently reported in a few MTLE surgical specimens [7,8] , but their prevalence, clinical relevance, and underlying biological mechanisms remain unknown. Targeted duplex sequencing of hippocampal DNA from 462 surgical resections revealed significant enrichment of deleterious somatic variants in MTLE versus controls, with >40% of MTLE specimens harboring activating Ras-MAPK variants in PTPN11 , NF1 , BRAF , KRAS , and twelve genes not previously associated with focal epilepsy. Eight Ras-MAPK genes showed positive clonal selection in MTLE. Increased somatic variant burden predicted worse surgical outcome. Somatic Ras-MAPK variants at ultra-low (<0.5%) variant allele fractions were associated with older seizure onset and HS pathology, supporting a late prenatal or postnatal origin. Ras-MAPK variants in MTLE were enriched in cells derived from hippocampal progenitors-neurons, astrocytes, oligodendrocytes-in line with the known neuronal hyperexcitability and seizures induced by Ras-MAPK overactivation [9,10] ; in contrast, Alzheimer disease hippocampi exhibited microglial enrichment of Ras-MAPK variants, consistent with prior reports [11] . Single-nucleus RNA sequencing showed increased expression of Ras-MAPK genes in neurons and upregulation of pathways mediating neurogenesis and neural development in MTLE. Functional validation of novel, recurrent PTPN11 variants confirmed gain-of-function, while cellular modeling in induced pluripotent stem cells demonstrated proliferative/survival advantages for mutant cells in mosaic culture. Overall, our data suggest that somatic Ras-MAPK variants and acquired risk factors may converge on clonal competition in the hippocampus to modulate epilepsy risk.},
}

@article {pmid41659595,
year = {2026},
author = {Chaggar, P and Vogel, JW and Thompson, TB and Aldea, R and Strandberg, O and Stomrud, E and Palqmvist, S and Ossenkoppele, R and Jbabdi, S and Magon, S and Klein, G and , and Mattson-Carlgren, N and Hansson, O and Goriely, A},
title = {Dynamical A β -Tau-Neurodegeneration Model Predicts Alzheimer's Disease Mechanisms and Biomarker Progression.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.27.701320},
pmid = {41659595},
issn = {2692-8205},
abstract = {UNLABELLED: Alzheimer's disease is characterised by the pathological interaction of two proteins, amyloid-beta (Aβ) and tau, which collectively drive neurodegeneration and cognitive decline. The progression of Aβ, tau, and neurodegeneration biomarkers is captured by the ATN framework, which is a powerful tool for disease classification. However, since the ATN framework is mainly descriptive, it cannot quantify or predict relationships between biomarkers over time. We address this limitation by introducing a dynamical ATN (dATN) model that mechanistically simulates the spatiotemporal progression of Aβ, tau, and neurodegeneration. The dATN model integrates mechanisms of prion-like protein aggregation of Aβ and tau, network-based tau propagation, Aβ-driven catalysis of tau progression, and tau-driven neurodegeneration. We calibrated the model using multimodal longitudinal imaging data from both the ADNI and BioFINDER-2 cohorts and show that it accurately fits longitudinal regional Aβ, tau, and neurodegeneration data. Using the dATN model, we show that Aβ-induced effects predict Braak-like cortical tau progression, that the spatial colocalisation of Aβ and tau is a crucial biomarker of disease acceleration, and that tau-driven atrophy strongly correlates with observed neurodegeneration. Furthermore, by integrating the disease progression model with pharmacokinetic-pharmacodynamic simulations, we present a powerful tool that facilitates regional evaluation of therapeutic strategies targeting Aβ, identification of critical intervention windows, and prediction of heterogeneous treatment effects across brain regions. This framework unifies mechanistic understanding with clinical imaging biomarkers, offering a quantitative approach for forecasting disease progression, testing mechanistic hypotheses, and optimising personalised treatment strategies in AD.

ONE SENTENCE SUMMARY: Colocalisation of A β and tau predicts regional tau progression and optimal A β -targeted intervention windows, while tau predicts neurodegeneration.},
}

@article {pmid41659563,
year = {2026},
author = {Gelber, A and Romero, H and Burrows, D and Whittaker, DS and Carlin, D and Mukamel, EA and Desplats, P},
title = {Spatial transcriptomics reveals brain-wide circadian disruption in an Alzheimer's disease model.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.26.701799},
pmid = {41659563},
issn = {2692-8205},
abstract = {Diurnal rhythms in brain transcription align neural, immune, and metabolic processes with the light-dark cycle and are profoundly disrupted in Alzheimer's disease (AD). However, the regional organization of diurnal transcription in the healthy and diseased brain remains poorly defined. Using large-scale spatial transcriptomics, we mapped 24-hour rhythmic transcription across cortical and subcortical regions of the mouse brain. We identified marked regional differences in rhythmicity, including distinct oscillatory signatures across cortical areas and along the rostro-caudal axis. In the APP23 mouse model of AD, pathology-vulnerable brain regions exhibited early, region-specific disruption of diurnal transcription prior to substantial amyloid plaque deposition. These findings reveal a spatially organized architecture of brain diurnal rhythms and identify early rhythmic dysregulation as a feature of Alzheimer's disease pathogenesis.},
}

@article {pmid41659516,
year = {2026},
author = {Rifat, JM and Engala, S and Bozdag, S},
title = {scAURA: Alignment- and Uniformity-based Graph Debiased Contrastive Representation Architecture for Self-Supervised Clustering of Single-Cell Transcriptomics.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.25.701579},
pmid = {41659516},
issn = {2692-8205},
abstract = {UNLABELLED: Single-cell RNA sequencing (scRNA-seq) allows transcriptomic profiling at single-cell resolution, providing valuable insights into cellular diversity across tissues, developmental stages, and diseases. However, accurately identifying cell types remains challenging due to the high dimensionality, sparsity, and noise inherent in scRNA-seq data. To address these challenges in cell type identification in scRNA-seq data, we introduce scAURA (single c ell A lignment- and U niformity-based Graph Debiased Contrastive R epresentation A rchitecture), a unified framework that integrates graph debiased contrastive learning with self-supervised clustering. We evaluated scAURA on 18 real single-cell datasets collected from six sequencing platforms spanning diverse tissue and cell types in human and mouse. scAURA outperformed all state-of-the-art (SOTA) methods in nine and eight datasets in Adjusted Rand Index (ARI) and Normalized Mutual Information (NMI), respectively. On average, scAURA obtained average ranks of 2.28 (ARI) and 2.39 (NMI) across all 13 SOTA methods, demonstrating its consistent superiority across datasets. scAURA also exhibited strong robustness to dropout noise by maintaining stable clustering performance even under increasing sparsity levels. Furthermore, in an external single-cell Alzheimer's disease dataset, scAURA accurately clustered different cell types, identified novel cell type-specific marker genes, and inferred their potential transcriptional regulators. The source code and datasets are available at https://github.com/bozdaglab/scAURA .

CONTACT: Serdar.Bozdag@unt.edu.},
}

@article {pmid41659508,
year = {2026},
author = {Georgescauld, F and Okekenwa, S and Boyd, T and Donahue, C and Quittot, N and Dickson, JR and Fan, Z and Brady, S and Blackstone, C and Hyman, B and Song, Y},
title = {Dynamic conformational ensembles of soluble Tau encode neuronal toxicity prior to aggregation.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.26.701882},
pmid = {41659508},
issn = {2692-8205},
abstract = {UNLABELLED: Tau aggregation is a defining feature of Alzheimer's disease and related tauopathies, yet the conformational states of Tau in neurons prior to aggregation remain poorly understood. Existing structural models are derived largely from fibrillar assemblies and provide limited insight into the dynamic, soluble Tau species that initiate pathology. Here, we combine hydrogen-deuterium exchange mass spectrometry with super-resolution imaging and neuronal models to define the conformational ensemble of soluble Tau under physiological and disease-relevant conditions. We show that soluble Tau populates distinct, dynamic conformations characterized by regional stabilization and long-range intramolecular interactions that are invisible to fibril-based structures. Disease-associated perturbations selectively remodel these conformational ensembles, exposing aggregation-prone regions and altering Tau subcellular organization in neurons. Notably, these Tau species inhibit axonal transport, which is essential for neuronal health, linking specific ensemble states to neuronal toxicity. These findings establish soluble Tau conformation as a dynamic, regulatable state that precedes aggregation and encodes disease relevance. By defining the structural logic of Tau before fibril formation, this work provides a framework for understanding early tauopathy mechanisms and for targeting Tau pathology at its earliest stages.

SUMMARY: Tau pathology is a hallmark of Alzheimer's disease (AD) and related dementias (ADRDs). Although Tau is often described as intrinsically disordered, it is a dynamic protein with distinct but poorly defined conformations. Here we conduct a systematic time-resolved structure-function analysis of normal and pathologic Tau, including hyperphosphorylated, mutant Tau, and posttranslational-modification-mimetic Tau. To characterize dynamic conformational changes of Tau, we combined state-of-the-art hydrogen deuterium exchange mass spectrometry with structured illumination microscopy, demonstrating a novel Tau-MT binding mode: "dynamic oscillation". To correlate Tau structure with neuronal function, we evaluated axonal transport as a sensitive readout of neuronal health. Many toxic Tau forms share a common signature of increased exposure of the N-terminal phosphate activating domain (PAD) in vitro and in vivo . Aberrant exposure of PAD correlates with Tau pathology and axonal transport defects. Tau phosphorylation at S262 alone is sufficient to alter Tau-microtubule interactions beyond R1-R4 motifs, globally changing Tau conformation, disrupting "dynamic oscillation" on MTs, and inhibiting axonal transport. Frontotemporal dementia-associated P301L-Tau remains associated with microtubules but also inhibits axonal transport. Our results reveal a well-defined conformation of soluble WT Tau in neurons and its highly dynamic interaction with microtubules, altered by AD/ADRD-Tau forms. Our multidisciplinary approach comprising biochemical manipulations, innovative MS tools, advanced microscopy, cellular assays, and mouse and human data pair Tau conformations with distinct neuronal functions and pathologies in health and disease.},
}

@article {pmid41659445,
year = {2026},
author = {Korukonda, A and Blankenship, HE and Kam, K and Kour, D and Espinosa-Garcia, C and Jang, WE and Srivastava, U and Mulvey, B and Tish, MM and Witztum, R and Ramelow, CC and Pate, BS and Liles, LC and Lu, L and Atallah, J and Guo, E and Martinowich, K and Sharpe, AL and Varga, AW and Rangaraju, S and Beckstead, MJ and Weinshenker, D},
title = {Pathogenic tau in the mouse locus coeruleus produces noradrenergic hyperactivity and neuropsychiatric phenotypes reminiscent of early Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.30.702923},
pmid = {41659445},
issn = {2692-8205},
abstract = {Alzheimer's disease (AD), though defined as a cognitive disorder, often presents neuropsychiatric symptoms such as anxiety, depression, agitation and sleep disruptions years before the onset of frank memory impairment. An early pathological feature is the accumulation of hyperphosphorylated "pretangle" tau (pTau) in the locus coeruleus (LC), the brain's primary source of norepinephrine (NE). While clinical studies link LC pTau burden to behavioral abnormalities, causal mechanisms remain unclear. We developed a translationally-relevant mouse model that recapitulates the 'LC-first' phenomenon using cell type-specific viral expression of pathogenic P364S mutant human tau in LC neurons. Three months post-infusion, pTau accumulation induced anxiety-and compulsive-like behaviors and reduced sleep spindles without altering overall sleep architecture. Consistent with the behavioral phenotypes, electrophysiological recordings revealed significant increases in spontaneous and evoked firing of LC neurons, accompanied by robust astrocytic reactivity with no apparent cell death. Transcriptomic analysis identified upregulation of Hcn2 and downregulation of Clic6 , suggesting changes in neuronal excitability. To further define molecular mechanisms, we developed a cell type-specific proteomics approach, which showed synaptic and metabolic alterations associated with LC-specific tau pathology. Early anxiety-like behaviors observed at 3 months diminished at later timepoints (6-9 months) and were replaced by anxiolytic characteristics. These findings demonstrate that pTau triggers phenotypes reflective of LC-NE hyperactivity in the early stages of AD pathogenesis, laying the foundation for the development of LC-based disease-modifying therapies to address neuropsychiatric manifestations.},
}

@article {pmid41659441,
year = {2026},
author = {Kwon, HC and Eiden, A and Li, J and MacKinnon, M and Garfinkel, JB and Hooper, SM and Liu, Y and Nelson, MT and Koretsky, A and Mughal, A},
title = {Electro-Calcium uncoupling precedes neurodegeneration in Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.26.701803},
pmid = {41659441},
issn = {2692-8205},
abstract = {Alzheimer's disease (AD) is categorized as a neurodegenerative disease, but there is a growing recognition of the vascular components in AD pathophysiology. Reduction in cerebral perfusion is routinely observed in AD patients and preclinical models prior to overt clinical symptoms. However, there is a limited mechanistic understanding of the early neurovascular deficits in AD, and how these may ultimately contribute to pathology. Here, we investigated the mechanisms of early neurovascular dysfunction in AD by using 3-month-old 5xFAD mice, a familial mouse model of AD. Functional hyperemia-the increase in cerebral blood flow (CBF) in response to neuronal activity-is driven by inward rectifier K [+] (K ir 2.1)-mediated hyperpolarizing (electrical) signals and Ca [2+] -dependent nitric oxide production within the capillary endothelial cells (cECs). Electrical and Ca [2+] signals are tightly coupled through cECs membrane potential, referred to as Electro-Calcium (E-Ca) coupling. We hypothesize that E-Ca uncoupling contributes to impaired functional hyperemia in 5xFAD mice and that these neurovascular deficits precede the neurodegeneration and cognitive decline. At three months of age, 5xFAD mice did not exhibit any impairment in spatial learning and memory, or neuronal density. However, whisker stimulation-induced functional hyperemia was significantly reduced in 5xFAD mice compared to controls. Functional hyperemia exhibited a bimodal response in controls-consisting of fast and slow phases-with the slow phase being significantly reduced in 5xFAD mice. To identify mechanisms underlying these deficits, we measured cortical neuronal and endothelial Ca [2+] activity using in-vivo imaging. Neuronal Ca [2+] activity was comparable between controls and 5xFAD mice, while cECs Ca [2+] activity was significantly reduced in 5xFAD mice. Moreover, K ir 2.1 channel blocker, barium (100 μM) significantly suppressed cECs Ca [2+] activity in controls, but not in 5xFAD mice, consistent with crippled E-Ca coupling. Despite these vascular functional impairments, capillary density was preserved in 5xFAD mice. TRPV4 channels are one of the major Ca [2+] entry pathways in cECs and potentiate E-Ca coupling. cECs TRPV4 current density was significantly reduced in 5xFAD mice while K ir 2.1 current density was unchanged, indicating that impaired TRPV4 function underlies the E-Ca uncoupling. In summary, early E-Ca uncoupling leads to impaired functional hyperemia in 5xFAD mice and may contribute to later neuronal and cognitive decline.},
}

@article {pmid41659428,
year = {2026},
author = {Mao, Y and Pan, B and Liu, X and , },
title = {Global brain activity links subcortical degeneration to cortical tau progressively across Braak regions over early Alzheimer's disease stages.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.23.701360},
pmid = {41659428},
issn = {2692-8205},
abstract = {Alzheimer's disease (AD) is characterized by early tau pathology in subcortical neuromodulatory nuclei, followed by progressive cortical tau accumulation; however, the mechanisms linking subcortical dysfunction to cortical tau pathology remain unclear. Using multimodal neuroimaging data from the ADNI cohort, we examined how infra-slow (< 0.1 Hz) global brain (i.e., gBOLD) activity is related to the volume of the nucleus basalis of Meynert (NbM) and cortical tau accumulations in the early stages of AD. NbM degeneration was associated with reduced gBOLD activity and spatially co-localized tau accumulation, appearing in early Braak regions during the preclinical stage, i.e., cognitively unimpaired participants with abnormal CSF markers, and extending to more advanced Braak areas during the prodromal stage, i.e., mild cognitive impairment (MCI) subjects. Our findings suggest that infra-slow gBOLD activity serves as a functional neural mediator linking subcortical degeneration to cortical tau pathology, highlighting a potential functional pathway linking subcortical and cortical pathology in early AD.},
}

@article {pmid41659356,
year = {2026},
author = {Fausto, BA and Akbulut, E and Sheikh, M and Grass, D and Aquino, N and Garza-Martinez, L and Hercules-Tawe, F and Ghaly, S and Codrington, A and Gamil, A and Arshad, I and Napoleon, D and Perna, R and Paruzel, V and Gluck, MA and Fitzgerald-Bocarsly, P},
title = {Lower CD8+ T-cell senescence partially mediates the neuroprotection of higher aerobic fitness.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {1},
pages = {e70202},
pmid = {41659356},
issn = {2352-8737},
abstract = {INTRODUCTION: Immunosenescence - age-related changes in immunity - may exacerbate the pathologic processes of Alzheimer's disease (AD), a condition that disproportionately affects African Americans. Fortunately, a higher level of aerobic fitness is linked to both reduced immunosenescence and lower AD risk. However, it remains unclear whether higher aerobic fitness and decreased AD is mediated by lower proportions of T-cell senescence. In a cohort of older African Americans, we aimed to (1) examine the relationship between aerobic fitness and generalization (a cognitive indicator of AD risk) and (2) investigate whether T-cell senescence mediated this relationship.

METHODS: A total of 231 older African American participants from the Aging & Brain Health Alliance (M age = 70.74 years, SD = 6.40; M education = 14.02 years, SD = 2.25; M MoCA = 23.16, SD = 2.63) responded to demographic, health, and lifestyle questionnaires; completed a cognitive battery including a generalization task (stimulus differentiation and transfer task); underwent anthropometric and physical performance measures; and provided a blood sample for T-cell senescence characterization. Peripheral blood mononuclear cells were isolated and analyzed for senescence-associated beta-galactosidase activity as a measure of proportions of cytotoxic CD8+ T-cell senescence. Aerobic fitness (VO2peak) was estimated from the six-minute walk test. Covariates included age, sex, education, and waist-to-hip ratio.

RESULTS: Higher aerobic fitness was significantly associated with fewer generalization errors. Furthermore, higher aerobic fitness was associated with lower CD8+ T-cell senescence (β = -0.15, p = 0.02), which was associated with fewer generalization errors (β = -0.17, p = 0.01). Overall, 15% of the effect of higher aerobic fitness on fewer generalization errors was mediated by lower CD8+ T-cell senescence.

DISCUSSION: One pathway by which higher aerobic fitness is associated with lower AD risk in older African Americans is through lower proportions of CD8+ T-cell senescence. These results highlight the immune and cognitive function benefits of a physically active lifestyle, particularly in a demographic that faces a higher risk for AD.},
}

@article {pmid41659355,
year = {2026},
author = {Alshahrani, M and Burley, CV and Guan, Z and Brain, J and Dunne, J and Sabatini, S and Tang, EY and Myers, B and Sohrabi, HR and Naheed, A and Tully, PJ and Burton, E and Harrison, F and Siervo, M and Stephan, BC},
title = {Informing depression-specific dementia risk models: An evidence-based analysis of moderators of the depression-dementia association.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {1},
pages = {e70218},
pmid = {41659355},
issn = {2352-8737},
abstract = {Depression is a major modifiable risk factor for dementia, yet most prediction models treat it as a homogeneous exposure, despite evidence that risk varies among people with depression. This study aimed to identify key modifiers of the depression-dementia association to inform the development of tailored prediction models. A narrative synthesis was conducted, incorporating (1) an umbrella review of nine meta-analyses examining the depression-dementia association; (2) a systematic review of depression-related medication use on dementia risk; and (3) findings from three Lancet Commission reports on dementia (2017, 2020, and 2024). Seven key modifiers were identified that influenced the reliability and direction of risk estimates: demographic factors, assessment methods, depression severity, follow-up duration, depression timing and trajectory, the outcome predicted (e.g., all-cause vs dementia subtypes), and antidepressant use. Late-life and severe depression conferred the highest risk, with associations being stronger for vascular dementia than for Alzheimer's disease. Clinical diagnoses yielded higher risk estimates compared to symptomatic rating scales. Duration of follow-up was associated with contradictory directional effects. Antidepressant use was associated with increased dementia risk. However, class-specific analyses were inconclusive due to extreme heterogeneity. The Lancet Commission emphasized late-life and mid-life depression as key modifiable risk factors. Multiple clinical, methodological, and temporal factors influence dementia risk estimates in individuals with depression. The findings support developing depression-specific dementia risk models that prioritize high-risk subgroups. Recommendations include distinguishing between symptom-based and clinical diagnostic approaches, addressing heterogeneity in timing and severity, modeling reverse causation, and validating models across diverse populations.},
}

@article {pmid41659250,
year = {2026},
author = {Farias Quipildor, GE and Belfiore, R and Althobaiti, K and Najarzadeh, Z and Glabe, C and Readhead, BP and Gandy, S and Salton, SRJ and Ehrlich, ME},
title = {Differential downstream signaling in microglia lacking Alzheimer's-related TREM2 or its adaptor TYROBP/DAP12.},
journal = {Molecular neurodegeneration advances},
volume = {2},
number = {1},
pages = {8},
pmid = {41659250},
issn = {3059-4944},
abstract = {UNLABELLED: Microglia, the primary immune cell in the brain, have multiple activation phenotypes involved in broad functions within the brain, playing roles in neurotoxicity/neuroprotection, release of inflammatory and anti-inflammatory cytokines, and in cell survival, proliferation, and phagocytosis. TREM2 and TYROBP form a transmembrane complex in microglia that modulates intracellular signaling networks, and these proteins are essential regulators of the transition from homeostatic to activated microglia. Recent findings support a TREM2-independent molecular signature that is involved in the early transition of homeostatic to disease-associated microglia (DAM), with the next sequential step of DAM activation from stage 1 to stage 2 being TREM2-dependent. However, the underlying mechanisms determining how TREM2 or TYROBP regulate these downstream phenotypes are largely unknown. We isolated primary microglia from C57BL/6 wild-type (WT) controls, Trem2 knock-out (KO), and Tyrobp KO mice at post-natal day 0-3. Cells were treated with Alzheimer's disease (AD)-relevant stimuli, such as amyloid beta (Aβ) oligomers or fibrils, or 'neuroinflammatory-like' stimuli, such as lipopolysaccharide (LPS). We explored protein and gene expression in the presence or absence of inhibitors of the TREM2/TYROBP downstream signaling pathway. We also performed a high-throughput Olink proteomic analysis of conditioned media from WT, Trem2 KO, and Tyrobp KO stimulated with either LPS or Aβ oligomers or fibrils. Our results show that the absence of either TREM2 or TYROBP is associated with increased basal levels of phosphorylated ERK in primary microglia compared to WT controls. In addition, Trem2 KO and Tyrobp KO cells show a less ramified cell morphology at baseline, as compared to WT microglia. Moreover, stimulating primary microglia with either Aβ oligomers or LPS leads to differential protein and gene expression in cells lacking TREM2 or TYROBP. The dysregulated downstream signal transduction and morphology in the absence of TREM2 or TYROBP suggest their essential roles not only in microglial homeostasis but also in their activation in response to different stimuli.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s44477-025-00012-x.},
}

@article {pmid41659206,
year = {2026},
author = {Liu, T and Rong, Z and Li, J and Wu, H and Wei, J},
title = {Three-dimensional interactive network: Mitochondrial-metabolic-calcium homeostasis driving Alzheimer's disease.},
journal = {Genes & diseases},
volume = {13},
number = {3},
pages = {101846},
pmid = {41659206},
issn = {2352-3042},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and neuronal loss, with its pathogenesis tightly linked to a "pathological triad"-mitochondrial dysfunction, metabolic dysregulation, and calcium homeostasis imbalance. This triad forms a mutually reinforcing network that amplifies AD pathology, yet its precise causal relationships and clinical relevance remain incompletely understood. Here, we critically synthesize evidence from human studies, animal models, and in vitro systems to dissect how these dysfunctions interact in vivo: mitochondrial structural damage and bioenergetic failure (e.g., reduced cytochrome c oxidase activity) impair ATP production, triggering metabolic reprogramming (e.g., astrocytic Warburg-like glycolysis, lactate shuttle dysfunction) and disrupting calcium buffering via mitochondrial calcium uniporter (MCU) dysregulation. Conversely, metabolic stress (e.g., hyperglycemia-induced mitochondrial overload) and calcium overload (e.g., NMDA receptor hyperactivation) exacerbate mitochondrial damage through reactive oxygen species (ROS) bursts and mitochondrial permeability transition pore (mPTP) opening. These processes are further amplified by amyloid β-protein (Aβ) and tau pathology: Aβ oligomers directly inhibit mitochondrial respiration and activate calcium channels, while hyperphosphorylated tau disrupts mitochondrial trafficking and exacerbates metabolic enzyme dysfunction. We evaluate the clinical translatability of preclinical findings, highlighting inconsistencies (e.g., conflicting results of CoQ10 trials) and gaps (e.g., human-specific metabolic signatures). Finally, we propose a framework prioritizing multi-target therapies that disrupt the triad's vicious cycle, emphasizing the need for biomarkers to stratify patients based on triad dysregulation patterns.},
}

@article {pmid41659073,
year = {2026},
author = {Pinilla Manriquez, V and Laho, EM and Marvin, SA and Usman, Y and Properzi, MJ and Palmgren, KA and Rao, Y and Yau, WW and Reynolds, G and Johnson, KA and Buckley, R and Rentz, D and Amariglio, R and Redline, S and Purcell, S and Sperling, RA and Djonlagic, I and Chhatwal, JP and Schultz, SA},
title = {REM Sleep is Associated with Cognition and Biomarkers Longitudinally in Older Adults Across the Alzheimer Disease Continuum.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.22.26344642},
pmid = {41659073},
abstract = {UNLABELLED: Sleep disturbances represent a potentially modifiable risk factor for Alzheimer disease (AD). The extent to which changes in rapid eye movement (REM) sleep are related to the accumulation of AD pathology and brain tissue loss is not well understood. In the current study, ninety-four individuals 74 clinically unimpaired [CU] and 20 clinically impaired [CI]) underwent polysomnography (PSG), cognitive assessments, and neuroimaging. Cross-sectional and longitudinal models examined the associations between PSG outcomes of interest (percentage of sleep period spent in REM [%REM] and REM latency) and pre-clinical Alzheimer's cognitive composite-5 (PACC5) scores, entorhinal tau-positron emission tomography (PET; 18F-flortaucipir), cerebral amyloid-PET (11C-Pittsburgh Compound B; PiB), AD signature cortical thickness, and hippocampal volume, after adjusting for covariates. Across CU and CI individuals, less time spent in REM sleep and prolonged REM latency were associated with poorer cognition after adjusting for age, sex, and years of education. Additionally, these factors were associated with a greater AD pathologic burden after adjusting for age and sex. Longitudinal data, spanning up to 16 years, demonstrated that the rate of change in cognition and AD biomarkers in the time preceding PSG assessment was also strongly associated with REM characteristics. Our findings highlight the potentially bidirectional relationship between the accumulation of AD pathology and the disruption of REM sleep. Future studies are needed to better understand the longitudinal relationship between sleep characteristics, AD progression, and cognitive decline, and to assess the potential of sleep-focused interventions to alter the course of AD clinical, cognitive, and pathological progression.

ONE SENTENCE SUMMARY: Cognitive and biomarker data are associated with REM sleep characteristics in unimpaired and impaired individuals cross-sectionally and over time.},
}

@article {pmid41659060,
year = {2026},
author = {Zhou, W and Wang, Y and Wu, Y and Li, X and Liu, H and Wang, H and Zhang, Z and Huang, H},
title = {AI-driven multimodal precision diagnosis and progression prediction of Alzheimer's disease: Data fusion mechanisms, clinical applications, and research trends (2017-2024).},
journal = {Digital health},
volume = {12},
number = {},
pages = {20552076251412649},
pmid = {41659060},
issn = {2055-2076},
abstract = {AIMS: This study combines bibliometric and structured analyses to comprehensively examine the development, methodological characteristics, and application trends of multimodal artificial intelligence (AI) in Alzheimer's disease (AD) diagnosis.

MATERIALS AND METHODS: Literature from January 1, 2017 to December 31, 2024, was retrieved from the Web of Science Core Collection. Retrospective bibliometric and visual analyses were conducted using VOSviewer, CiteSpace, and the Bibliometrix R package.

RESULTS: A total of 234 papers were identified, showing a continuous increase in publication volume, with the United States and China as dominant contributors. The analysis focused on data modalities, fusion architectures, and clinical applications. Data trends highlight the fusion of imaging data with genetics, biomarkers, and clinical data. Methodologically, five fusion approaches were categorized, with intermediate fusion being the most widely used strategy for its ability to balance heterogeneous data integration. In application, multimodal AI demonstrated clear advantages in early diagnosis, disease classification, and progression prediction.

CONCLUSION: Research on multimodal AI for AD has gained global attention and remains a key direction for diagnostic innovation. By synthesizing bibliometric insights with structured analyses of modalities and fusion strategies, this study offers a systematic understanding of current progress and provides valuable guidance for future methodological and translational research.},
}

@article {pmid41659035,
year = {2026},
author = {Hu, C and Zeng, X and Zhang, L and Sehrawat, A and Powell, M and Song, E and Walker, ELS and Watterson, A and Zhu, W and Karikari, TK and Xia, Z},
title = {Plasmaphosphorylated tau as biomarkers for multiple sclerosis diagnosis, subtyping, and prognosis.},
journal = {Brain communications},
volume = {8},
number = {1},
pages = {fcaf510},
pmid = {41659035},
issn = {2632-1297},
abstract = {Blood-based biomarkers are crucial for individualized management of multiple sclerosis (MS). Blood neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) have shown promising clinical utility in MS, but they are insufficient to guide clinical management. Plasma tau proteins remain underexplored despite the growing evidence of shared pathology in Alzheimer's disease and MS. We aimed to: (i) assess the utility of plasma tau biomarkers [phosphorylated tau 181 (p-tau181), p-tau217 and total tau (t-tau)] in MS diagnosis, subtyping and prognosis; and (ii) compare their performance with NfL and GFAP. From a clinic-based prospective cohort, we evaluated 160 people with MS [pwMS; 117 with relapsing-remitting MS, 43 with progressive MS (PMS)] and 20 non-MS controls, all with baseline plasma samples. We measured baseline plasma concentrations of p-tau181, p-tau217, t-tau, NfL and GFAP using ultrasensitive immunoassays. We collected demographics, clinical information, and longitudinal multi-modal outcomes (Patient Determined Disease Steps, normalized age-related MS severity score, walking speed, manual dexterity, cognitive performance, retinal nerve fibre layer thickness, total brain volume and grey matter volume) over a median follow-up of 3.0 years (interquartile range, 3.5). Adjusting for demographic and clinical covariates, we evaluated associations between biomarkers and MS diagnosis, subtypes, and prognosis. We examined the enhanced value of tau markers, in addition to NfL and GFAP, for subtype distinction and outcome prediction. Participants were enrolled between 2017 and 2023. Assays were performed in August 2023. Analyses were conducted in December 2024. Participants (n = 180) had a median age of 51 years and were predominantly women (68%) and non-Hispanic white (91%). Compared with controls, pwMS had higher levels of p-tau217 (1.0 versus 0.7 pg/ml; P = 0.04) and NfL (14.1 versus 9.0 pg/ml; P < 0.01). Among pwMS, higher p-tau181 (adjusted odds ratio (aOR) [95% confidence interval (CI)] = 2.3 [1.4, 4.1]) and p-tau217 (aOR [95% CI] = 3.0 [1.8, 5.7]) were associated with PMS. These markers improved MS subtype classification accuracy beyond clinical features, NfL and GFAP. Higher baseline p-tau181 and p-tau217 predicted worse disability, functional outcomes and imaging outcomes independent of other biomarkers. Plasma p-tau181 and p-tau217 are promising biomarkers for MS subtype classification and disability prediction, providing complementary information to NfL and GFAP. Further studies to validate their potential clinical utility in guiding MS management are warranted.},
}

@article {pmid41658423,
year = {2026},
author = {Nistor, P and Espin-Garcia, O and Merali, Z and Ali, S},
title = {Predicting Dementia Risk: Progress, Pitfalls, and Priorities.},
journal = {International journal of public health},
volume = {71},
number = {},
pages = {1609520},
pmid = {41658423},
issn = {1661-8564},
}

@article {pmid41658395,
year = {2026},
author = {Kaur, B and Zhang, L and Nada, H and Calvo-Barreiro, L and Gabr, MT},
title = {Discovery of a CHI3L1-targeted small molecule modulating neuroinflammation in Alzheimer's disease via DNA-encoded library (DEL) screening.},
journal = {RSC medicinal chemistry},
volume = {},
number = {},
pages = {},
pmid = {41658395},
issn = {2632-8682},
abstract = {Chitinase-3-like protein 1 (CHI3L1, also known as YKL-40) has emerged as a central effector of astrocyte-mediated neuroinflammation and a promising biomarker for Alzheimer's disease (AD). However, small molecule CHI3L1 inhibitors that modulate neuroinflammation are limited. Here, we report the discovery of a CHI3L1-targeted small molecule, DEL-C1, identified through DNA-encoded library (DEL) screening and validated using orthogonal biophysical, computational, and cellular approaches. DEL-C1 demonstrated direct CHI3L1 binding in microscale thermophoresis (MST) and surface plasmon resonance (SPR) assays, with reversible and concentration-dependent association. Molecular docking and 100 ns molecular dynamics simulations revealed a stable binding mode within the CHI3L1 substrate groove, anchored by Tyr206 and flanked by Trp99 and Trp352, supporting a thermodynamically favorable interaction. In vitro ADME profiling indicated a balanced physicochemical profile, permeability, and metabolic stability, consistent with CNS drug-like properties. Functionally, DEL-C1 reversed CHI3L1-induced astrocyte dysfunction by restoring Aβ uptake, lysosomal acidification, and proteolytic activity, while reducing CHI3L1 and IL-6 secretion. DEL-C1 also suppressed CHI3L1-driven NF-κB transcriptional activation, highlighting its anti-inflammatory potential. Collectively, this study establishes DEL-C1 as a promising small molecule modulator of CHI3L1 and a chemical tool to interrogate astrocyte-driven neuroinflammation in AD.},
}

@article {pmid41658393,
year = {2025},
author = {Gohar, N and Saeed, A and Abbas, M and Ayaz, S and Zulfiqar, I and Masaud, SM and Nadeem, H},
title = {Novel isoxazolone derivatives as acetylcholinesterase inhibitors: design, synthesis, in silico and in vitro evaluation.},
journal = {RSC medicinal chemistry},
volume = {},
number = {},
pages = {},
pmid = {41658393},
issn = {2632-8682},
abstract = {Acetylcholinesterase (AChE) plays a pivotal role in Alzheimer's disease by accelerating acetylcholine breakdown, leading to cognitive decline. In this study, a series of novel isoxazolone derivatives were synthesized and structurally characterized using spectroscopic methods. The compounds were evaluated for their AChE inhibitory activity, where several candidates demonstrated stronger inhibition than the standard drug Donepezil. Molecular docking supported these findings, highlighting favorable interactions within the enzyme's active site. Selected compounds also exhibited promising antioxidant properties in the DPPH assay. A developed QSAR model provided insights into structural features contributing to bioactivity. In silico ADMET profiling indicated drug-like behavior, and molecular dynamics simulations confirmed the stability of the top ligand-enzyme complexes. Collectively, the results underscore the potential of isoxazolone-based scaffolds as multifunctional agents for managing Alzheimer's disease. Further biological evaluation is recommended to explore their therapeutic applicability.},
}

@article {pmid41658109,
year = {2026},
author = {Zingales, SK and Gibson, M and Tapia-Hernandez, J and Jenkins, K and Munzing, M and Dickerson, G and Speikers, S and Frazer, DJ and Padgett, CW and Wentzel, MT},
title = {Multicomponent Green Synthesis Involving Aryl Aldehydes and Trapped Enols: Dimerization over Cyclization.},
journal = {ACS omega},
volume = {11},
number = {4},
pages = {5112-5121},
pmid = {41658109},
issn = {2470-1343},
abstract = {This report serves two main purposes: (1) to correct the literature in the area of multicomponent synthesis involving aryl aldehydes and trapped enols 4-hydroxycoumarin 1 or 4-hydroxy-6-methyl-2-pyrone 2 and (2) to fully characterize the dimerization products bis-coumarins 3 and bis-pyrones 4. There have been many reports of cyclizations occurring with these species and various catalysts; however, many products have been mis-characterized and are, in fact, dimers. We successfully synthesized these dimers using a green, one-pot reaction in water that avoids hazardous organic solvents, uses a catalytic amount of acid, does not require chromatography for purification, and has strong green chemistry metrics. Our simplified procedure resulted in high yields of dimers ranging from 24 to 96% including the first report of a meta-substituted bis-pyrone 4i. Herein, we report a green method for their synthesis, along with their photophysical properties, full characterization, and potential as AChE inhibitors for anti-Alzheimer's therapy.},
}

@article {pmid41658012,
year = {2026},
author = {Xu, J and He, Y and Li, Z and Zhou, W and Huang, C and Lu, L and Bajpai, AK and Li, M},
title = {Identification of CTHRC1 as a novel candidate for neurodevelopmental disorders.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1737003},
pmid = {41658012},
issn = {1663-4365},
abstract = {BACKGROUND: Cognitive dysfunction affects over 50 million individuals worldwide, with Alzheimer's disease (AD) representing two-thirds of cases. We identified CTHRC1 (Collagen Triple Helix Repeat Containing 1) as a novel candidate associated with cognitive function and neurodegeneration.

METHODS: Human proteomic analysis revealed CTHRC1 as highly upregulated in AD patients (~5-fold increase, adj. p = 0.05), with corresponding elevation in 5xFAD mice. Single-cell RNA sequencing showed predominant astrocyte and oligodendrocyte progenitor expression. Using BXD mice, systems genetics analysis revealed associations between hippocampal CTHRC1 expression and 22 cognition-related phenotypes. PheWAS, ePheWAS, and GWAS analyses confirmed links to nervous system and AD-related traits.

RESULTS: eQTL mapping identified CTHRC1 as cis-regulated in hippocampus, and correlating with protein transport, transcription, and neurodegeneration pathways. Network analysis revealed 17 direct interactors, including key neurodegeneration genes (BACE1, NEFL, IRS1, VDAC1, SNCAIP) connecting CTHRC1 to core AD pathways (APP, MAPT, APOE, PSEN1/2). CTHRC1 overexpression in SH-SY5Y cells promoted tau degradation and modulated network partner expression.

CONCLUSION: CTHRC1 represents a central hub in cognitive function networks, suggesting therapeutic potential for neurodegenerative disorders.},
}

@article {pmid41658010,
year = {2026},
author = {Rajczyk, JI and Burke, JF and Xu, WY and Wing, JJ},
title = {Broadband Availability and Alzheimer's Disease and Related Dementias Prevalence in Central Appalachia.},
journal = {Journal of social service research},
volume = {},
number = {},
pages = {},
pmid = {41658010},
issn = {0148-8376},
abstract = {Geographical differences in Alzheimer's disease and related dementias (ADRD) prevalence may be driven by under-diagnosis due to insufficient healthcare access. Telehealth may improve ADRD detection in remote regions but relies on broadband service availability. We evaluated the influence of county-level broadband availability on Appalachian and rural variation of ADRD prevalence in six US Central Appalachian states and hypothesized that accounting for broadband access may accentuate Appalachian/non-Appalachian and rural/urban differences. An ecologic analysis evaluated county-level ADRD prevalence among the Medicare fee-for-service population across 591 Central Appalachian counties from 2015 to 2018. ADRD prevalence by Appalachian/non-Appalachian and rural/urban county-designation was estimated using negative binomial regression sequentially adjusting for age/education, diagnostic access, broadband presence/usage, poverty, and internet access/device ownership. Appalachian counties had lower ADRD prevalence than non-Appalachian counties in rural compared to urban counties (βAppXRural = -0.028; 95% Confidence Interval (CI): -0.052, -0.005). This variation attenuated with adjustment for broadband access (βAppXRural = -0.014; 95% CI: -0.038, 0.009). Broadband presence (β= -0.020; 95% CI: -0.032, -0.008) and a higher proportion of households with broadband in a county (β= -0.405; 95% CI: -0.534, -0.277) were negatively associated with ADRD prevalence after adjustment for poverty. Future research should implement alternative study designs to investigate mechanisms linking broadband access to ADRD prevalence.},
}

@article {pmid41657697,
year = {2026},
author = {Gaugler, JE and Johnson, E and Denno, B and Baumgart, M and McGuire, LC},
title = {National and state-level variations in caregiving for persons living with dementia in the US.},
journal = {Frontiers in public health},
volume = {14},
number = {},
pages = {1751603},
pmid = {41657697},
issn = {2296-2565},
mesh = {Humans ; *Caregivers/statistics & numerical data ; *Dementia/nursing ; Cross-Sectional Studies ; Female ; Male ; United States ; Middle Aged ; Aged ; Behavioral Risk Factor Surveillance System ; Adult ; Aged, 80 and over ; },
abstract = {PURPOSE: The objective of this study was to examine variations between dementia caregivers, caregivers of people without dementia, and non-caregivers across a range of sociodemographic and health variables nationally in 47 states and within five specific states representing a region of the U. S. (New York, Arizona, Minnesota, Idaho, Maine).

METHODS: This cross-sectional, observational study utilized 2021-2022 data from the Centers for Disease Control and Prevention (CDC) Behavioral Risk Factor Surveillance System (BRFSS). Bivariate and cross-tabulation analyses were conducted to examine empirical variation.

RESULTS: Although national results remain fairly consistent with prior research on dementia caregivers, heterogeneity emerges when comparing national results with dementia caregiving data across the five selected states.

CONCLUSION: The availability of local data resources on dementia caregiving could help to provide more accurate/relevant estimates of ADRD caregiving prevalence and better deliver home and community-based services where they are most needed.},
}

Humans
*Caregivers/statistics & numerical data
*Dementia/nursing
Cross-Sectional Studies
Female
Male
United States
Middle Aged
Aged
Behavioral Risk Factor Surveillance System
Adult
Aged, 80 and over

@article {pmid41657477,
year = {2026},
author = {Rahi, A and Jafari, E and Azizian, R and Mohammadi, MR and Razmfarsa, A and Shakeri Hosseinabad, S and Hamidi, M},
title = {Exploring the Gut-Brain Connection: The Role of Microbiota in Alzheimer's Disease Pathogenesis.},
journal = {Dementia and neurocognitive disorders},
volume = {25},
number = {1},
pages = {1-12},
pmid = {41657477},
issn = {2384-0757},
abstract = {Alzheimer's disease (AD), the primary cause of dementia accounting for 60% to 70% of cases globally, results in a gradual decline in cognitive abilities, affecting memory, executive function, and daily activities. Recent research highlights the essential involvement of the microbiota-gut-brain axis in AD pathogenesis, characterized by complex bidirectional signaling that modulates neuroinflammation, neurogenesis, neurotransmission, and immune functions. This manuscript extends the discussion beyond the gut alone by emphasizing the significance of the oral-gut microbiota axis as a dynamic and relatively under-investigated factor in AD progression. Microbial populations in both the oral cavity and gastrointestinal tract produce key neurotransmitters, such as gamma-aminobutyric acid, noradrenaline, and dopamine, as well as neuroactive metabolites like short-chain fatty acids, which together impact brain physiology. Disturbances in gut and oral microbial balance can compromise barrier integrity, promoting systemic inflammation and neuroinflammation, and facilitating amyloid-β plaque formation and tau-related changes typical of AD. This review introduces a novel probiotic, prebiotics, synbiotics, and postbiotics (PPSP) therapeutic model designed to modulate both oral and gut microbiota, aiming to restore homeostasis, regulate neuroimmune interactions, and counteract cognitive impairment. We comprehensively assess emerging clinical and translational findings supporting the effectiveness of microbiota-targeted therapies in the scope of this dual-axis framework, addressing both their potential to alter disease course and recognized limitations. By underscoring the importance of the integrated oral-gut microbiota axis alongside targeted PPSP interventions, this manuscript puts forth a paradigm-shifting conceptual strategy that may redefine approaches to AD management and improve cognitive outcomes.},
}