@article {pmid41680661,
year = {2026},
author = {Hari, E and Ulasoglu-Yildiz, C and Kurt, E and Kahveci, O and Gurvit, H and Demiralp, T},
title = {Functional connectivity patterns of the cerebellar components of intrinsic connectivity networks in clinically diagnosed probable Alzheimer's disease.},
journal = {BMC medical imaging},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12880-026-02223-4},
pmid = {41680661},
issn = {1471-2342},
abstract = {BACKGROUND: This study investigated the functional connectivity (FC) patterns of cerebellar components of seven intrinsic connectivity networks (ICNs) across different stages of Alzheimer's disease (AD).

METHODS: FC between each cerebellar seed region corresponding to one of the seven ICNs and 91 cerebral regions of interest (ROI) corresponding to the cortical parcels defined by Harvard-Oxford atlas was calculated for individuals with clinically diagnosed probable AD dementia (n = 21), mild cognitive impairment (n = 34), and subjective cognitive decline (n = 33). Group differences were assessed using ANOVA with false discovery rate (FDR) correction for multiple ROIs (pFDR-corr<0.05).

RESULTS: Significant alterations were observed in FC between the frontoparietal network (FPN) and the left superior frontal gyrus (SFG), as well as between the limbic network (LN) and the right superior lateral occipital cortex (sLOC) and temporo-occipital middle temporal gyrus (toMTG). Specifically, FPN-SFG connectivity decreased at the dementia stage, while LN-toMTG and LN-sLOC connectivity decreased during the prodromal stage but increased in the dementia stage.

CONCLUSIONS: These results indicate the presence of both decreases and increases in cerebellar-cortical FC across different stages of AD. A detailed examination of cerebellar involvement, an aspect often underexplored in AD research, may be crucial for understanding the neural mechanisms underlying disease progression.},
}

@article {pmid41680609,
year = {2026},
author = {Pourhossein, S and Mianrood, IB and Khatami, SH and Ehtiati, S and Ghasemian, M and Mokhtari, F and Ahmadzade, R and Goudarzi, M and Hamed, N and Namvarjah, F and Karima, S},
title = {Acetyl-11-keto-β-boswellic acid attenuates tau oligomer-induced neurotoxicity in neuroblastoma cell model.},
journal = {BMC neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12868-026-00996-6},
pmid = {41680609},
issn = {1471-2202},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by microtubule destabilization, neuroinflammation, and tau pathology. Among the proposed therapeutic approaches, acetyl-11-keto-β-boswellic acid (AKBA), a bioactive triterpene from Boswellia serrata, has gained attention due to its multiple neuroprotective mechanisms, including microtubule stabilization, anti-inflammatory activity, antioxidant effects, and promotion of neurogenesis. In this study, we aimed to investigate the neuroprotective effect of AKBA against tau oligomer-induced cytotoxicity in SH-SY5Y neuroblastoma cells.

RESULTS: Recombinant human tau protein was expressed, purified, and oligomerized, and the formation of oligomers was confirmed by thioflavin T fluorescence and dynamic light scattering (DLS). SH-SY5Y cells were then treated with AKBA and exposed to tau oligomers. Cell viability was assessed via MTT assay, and apoptosis was evaluated by flow cytometry. The morphology of tau aggregates was visualized using transmission electron microscopy.

CONCLUSIONS: Our findings demonstrated that AKBA significantly reduced tau oligomer-induced cytotoxicity and enhanced cell viability. These results suggest that AKBA, through its multifaceted protective mechanisms, holds promise as a potential therapeutic agent for the treatment of tauopathies such as Alzheimer's disease.

CLINICAL TRIAL NUMBER: Not applicable.},
}

@article {pmid41680597,
year = {2026},
author = {Roh, HW and Chang, YY and Kim, KY and Jeon, SY and Wang, SM and Kim, E and Bae, JN and Ryu, SH},
title = {Evolving Alzheimer's Disease Clinical Practice: Updated Diagnostic Criteria, Fluid Biomarkers, and Special Considerations for Anti-Amyloid Therapies.},
journal = {Psychiatry investigation},
volume = {23},
number = {2},
pages = {183-200},
doi = {10.30773/pi.2025.0400},
pmid = {41680597},
issn = {1738-3684},
support = {//Korean Association for Geriatric Psychiatry/ ; RS-2024-00450828//National Research Foundation of Korea/ ; //Ministry of Science and ICT/ ; },
abstract = {OBJECTIVE: This review overviewed the recent paradigm shifts in the diagnosis and management of Alzheimer's disease (AD), emphasizing the 2024 Alzheimer's Association (AA) revised criteria, advances in cerebrospinal fluid (CSF) and blood-based biomarkers (BBMs), and practical considerations for anti-amyloid monoclonal antibody therapy.

METHODS: We conducted a narrative appraisal of consensus frameworks (2018 National Institute on Aging-Alzheimer's Association [NIA-AA] amyloid, tau, and neurodegeneration [AT(N)] and the 2024 AA criteria), clinical practice guidance from AA released in 2025, regulatory status of CSF and BBMs. Intended-use settings (triage vs. confirmatory) of BBMs and implementation of anti-amyloid anti-body treatments (lecanemab or donanemab) in real-world practice in Korea were also reviewed.

RESULTS: The 2024 AA criteria define AD biologically and designate A and T as core biomarkers; Core 1 biomarkers can establish AD irrespective of symptoms, whereas Core 2 biomarkers refine staging. A two-cutoff BBM strategy (positive/intermediate/negative) reduces misclassification and guides confirmatory CSF/positron emission tomography (PET) or retesting. BBMs now approach CSF/PET accuracy for amyloid detection, enable triage and, in selected settings, confirmation, and show utility for monitoring treatment response. Integration of clinical stages (1-6) with biological stages (A-D) clarifies syndrome-pathology discordance. Special scenarios-maintenance after induction, APOE ε4 homozygotes, Down syndrome, and serious mental illness-require individualized risk-benefit assessment. In South Korea, constrained access to tau PET and some BBMs necessitates Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision-anchored evaluation with selective biomarker testing.

CONCLUSION: Biomarker-oriented diagnosis and anti-amyloid therapies are reshaping AD care. Priorities include rigorous validation of BBMs across populations, equitable access to core biomarkers, safety strategies, and real-world evidence to implement maintenance and special-population care pathways.},
}

@article {pmid41680169,
year = {2026},
author = {Choi, S and Kim, J and Jeon, H and Lee, Y and Lim, G and Ju, WM and Kim, K and Lee, DS and Lee, YS and Lee, JS and Cheon, GJ and Choi, Y and Kim, C},
title = {Photoacoustic computed tomography monitors cerebrospinal fluid dynamics and glymphatic function.},
journal = {Nature communications},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41467-026-69390-4},
pmid = {41680169},
issn = {2041-1723},
support = {2023R1A2C3004880//National Research Foundation of Korea (NRF)/ ; 2020R1A6A1A03047902//National Research Foundation of Korea (NRF)/ ; 2021M3C1C3097624//National Research Foundation of Korea (NRF)/ ; RS-2022-NR070031//National Research Foundation of Korea (NRF)/ ; },
abstract = {Cerebrospinal fluid (CSF) continuously circulates through the brain and surrounding tissues to remove metabolic waste, a process that becomes less efficient with ageing and in neurodegenerative disease. Visualizing this drainage in living animals has been difficult because existing imaging tools either lack depth, require radioactive tracers, or are too slow to capture dynamic flow. Here, we show that whole-body photoacoustic computed tomography (PACT) enables three-dimensional, real-time tracking of CSF transport in mice using indocyanine green. We visualize CSF movement from the spinal canal into the brain, quantify its efflux under different anesthesia conditions, and detect impaired clearance in a mouse model of Alzheimer's disease. Compared with healthy animals, diseased mice retain the tracer in the brain for several days, indicating reduced waste removal. These results establish PACT as a non-invasive platform for measuring CSF and glymphatic function in vivo, providing a way to study how brain fluid transport is altered in ageing and neurological disorders.},
}

@article {pmid41679926,
year = {2026},
author = {Hernández-Martín, N and Balayeva, T and Naganawa, M and Asch, RH and Huang, Y and Carson, RE and Gallezot, JD and Cai, Z},
title = {Noninvasive Quantification of [[18]F]SynVesT-2 PET in Healthy Human Brains Using Simplified Reference Tissue Models.},
journal = {Journal of nuclear medicine : official publication, Society of Nuclear Medicine},
volume = {},
number = {},
pages = {},
doi = {10.2967/jnumed.125.271207},
pmid = {41679926},
issn = {1535-5667},
abstract = {PET imaging of synaptic vesicle glycoprotein 2A (SV2A) has proven to be a powerful research tool for neurologic disorders. Dynamic SV2A PET scans provide data related to cerebral blood flow and SV2A density, which have been shown to be altered in neurologic disorders such as Alzheimer disease. [[18]F]SynVesT-2, an SV2A PET tracer, has demonstrated fast brain kinetics and high specific binding in human brains. To improve clinical feasibility, we evaluated the performance of 3 simplified reference tissue models (SRTMs) in the quantification of [[18]F]SynVesT-2 PET data and the minimum scan times required for reliable estimation of relative cerebral blood flow and SV2A density. Methods: Data were pooled from 14 [[18]F]SynVesT-2 scans acquired from 9 healthy volunteers. An SRTM, SRTM with a fitted regionally coupled k' 2 (SRTMC), and SRTM with a population-based k' 2 (SRTM2) with the centrum semiovale and cerebellum as reference regions were used to calculate nondisplaceable binding potential (BPND) and distribution volume ratio (DVR), respectively, as well as the relative tracer delivery rate (R 1). Test-retest variability (TRV), absolute TRV, and the minimum scan duration for the reliable estimation of R 1, BPND, and DVR were additionally evaluated. Results: Despite time-activity curves being well-described by all 3 models, SRTM generated unreliable BPND and DVR values in 9% and 12% of the regions of interest, respectively. SRTMC and SRTM2 resulted in BPND and DVR values consistent with those generated from the 1-tissue compartment model. On the basis of the time stability analysis, BPND and DVR estimated using SRTM2 converged after 40 min. Using SRTM2, the TRV and absolute TRV estimated from 40-min dynamic scans were -1.0 ± 11.5% and 9.9 ± 5.8% for BPND and 1.7 ± 4.0% and 3.6 ± 2.5% for DVR. Conclusion: The parameters of relative cerebral blood flow (R 1) and specific binding (BPND and DVR) can be reliably estimated from a 40-min dynamic [[18]F]SynVesT-2 PET scan by SRTM2, which is 30 min shorter than that required for [[11]C]UCB-J and [[18]F]SynVesT-1. The shortened scan time enables the clinical application of dynamic SV2A PET scans to maximize the physiologically relevant information attainable from a single scan.},
}

@article {pmid41679805,
year = {2026},
author = {Sumandar, and Hsu, HT and Hsieh, HF and Chou, PL and Wung, SF and Lin, PC},
title = {Undergraduate nursing students' knowledge and attitudes toward dementia by country income level: A systematic review and meta-analysis.},
journal = {Journal of professional nursing : official journal of the American Association of Colleges of Nursing},
volume = {62},
number = {},
pages = {52-59},
doi = {10.1016/j.profnurs.2025.10.012},
pmid = {41679805},
issn = {1532-8481},
mesh = {*Students, Nursing/psychology ; Humans ; *Dementia/nursing/psychology ; *Health Knowledge, Attitudes, Practice ; Education, Nursing, Baccalaureate ; *Income/statistics & numerical data ; *Attitude of Health Personnel ; },
abstract = {BACKGROUND: It is essential for nursing students to possess a thorough understanding of dementia care and to maintain a positive attitude toward this area of healthcare.

OBJECTIVE: The purpose of this meta-analysis is to examine the knowledge and attitudes of undergraduate nursing students regarding dementia.

METHODS: A comprehensive search was performed in the PubMed, Web of Science, Embase, CINAHL, and ProQuest databases, covering the period from their inception until March 18, 2025. The primary outcome measures included the Alzheimer's Disease Knowledge Scale (ADKS) and the Dementia Attitudes Scale (DAS). Two independent researchers conducted literature searches, screened the studies, extracted relevant data, and performed critical appraisals. The pooled mean sores for knowledge and attitudes toward dementia were analyzed across all studies and subgroups.

RESULTS: A total of 23 studies from 14 countries were included in the analysis. The findings indicate that nursing students demonstrated moderate knowledge (mean score: 19.13, 95 % CI: 17.85-20.42) and moderate positive attitudes (mean score: 95.18, 95 % CI: 94.19-96.17) toward dementia. Subgroup analyses showed that both pooled knowledge and attitudes were significantly higher among students from high-income countries compared to their counterparts from other countries. Sensitivity analyses yielded robust results.

CONCLUSIONS: There is considerable opportunity for improving nursing students' knowledge and attitudes toward dementia care, particularly in developing countries.},
}

*Students, Nursing/psychology
Humans
*Dementia/nursing/psychology
*Health Knowledge, Attitudes, Practice
Education, Nursing, Baccalaureate
*Income/statistics & numerical data
*Attitude of Health Personnel

@article {pmid41679688,
year = {2026},
author = {Tibi, MF and Argote, YM and Walker, AC and Pandey, S and Puente, C and Ellward, GL and Safwat, A and Rincon-Limas, DE and Czyż, DM},
title = {Modulation of Host Proteostasis by Prevotella corporis via Induction of the Heat Shock Response.},
journal = {Cell stress & chaperones},
volume = {},
number = {},
pages = {100150},
doi = {10.1016/j.cstres.2026.100150},
pmid = {41679688},
issn = {1466-1268},
abstract = {Neurodegenerative protein conformational diseases (PCDs) are progressive, currently incurable disorders driven by toxic protein aggregation that leads to neuronal death. Emerging evidence supports a microbial role in PCDs, including the most prevalent: Alzheimer's and Parkinson's disease. While metagenomic studies consistently associate gut dysbiosis with these disorders, the mechanisms by which microbes influence host proteostasis remain poorly understood. In particular, considerable attention has been given to proteotoxic bacteria, but the mechanisms by which commensal microbes confer proteoprotection remain largely unexplored. We have previously employed Caenorhabditis elegans models to characterize the role of over 220 bacterial isolates on host proteostasis. Strikingly, members of the Prevotella genus exhibited proteoprotective effects. Most notably, transient exposure to P. corporis uniquely induced Hsp70, a critical molecular chaperone that maintains proteostasis, and significantly reduced aggregation of polyglutamine (polyQ), Aβ1-42, and α-synuclein. In the present study, we expand on these findings, demonstrating that among 13 Prevotella species tested, P. corporis robustly activates the heat shock response (HSR) and confers conserved aggregate-suppressing activity in Drosophila melanogaster. We further demonstrate that transient exposure to P. corporis results in the activation of protective stress pathways and promotes disaggregation of existing intestinal polyQ aggregates in C. elegans, leading to a general enhancement of global proteostasis. This is supported by significantly improved survival and enhanced thermotolerance. Together, our findings reveal a beneficial niche for P. corporis in activating the HSR to enhance organismal proteostasis and support a microbe-mediated gut-proteostasis axis. This work underscores the therapeutic potential of targeting the gut microbiota for the management of PCDs, highlights the importance of species-level resolution in microbiome studies, and supports the emerging view of the intestine as a proteostasis-modulating organ.},
}

@article {pmid41679672,
year = {2026},
author = {Lin, X and Luo, Y and Zhu, Q},
title = {Postoperative Cognitive Dysfunction and Neurodegeneration: From Inflammation to Precision Medicine.},
journal = {Brain research bulletin},
volume = {},
number = {},
pages = {111776},
doi = {10.1016/j.brainresbull.2026.111776},
pmid = {41679672},
issn = {1873-2747},
abstract = {Postoperative cognitive dysfunction (POCD) is a prevalent neurocognitive complication in elderly surgical patients, marked by memory, attention, and executive function impairments. Its pathophysiology involves neuroinflammation, blood-brain barrier disruption, mitochondrial dysfunction, and Alzheimer's disease (AD)-like pathologies, including amyloid-beta accumulation and tau hyperphosphorylation. Although often reversible, persistent POCD may accelerate neurodegeneration in high-risk individuals, underscoring the need for early biomarkers and targeted therapies. This review synthesizes current evidence on POCD mechanisms, risk factors, and management. Key findings highlight the role of neuroinflammatory mediators (e.g., cytokines, microglial activation) and shared pathways with AD, such as synaptic dysfunction and neurotrophic deficits. Major risk factors include advanced age, genetic susceptibility (e.g., ApoE4), and pre-existing cognitive decline. Emerging interventions-anti-inflammatory agents (minocycline, dexmedetomidine), neuroprotectants (melatonin, IGF-1), and non-pharmacological strategies (BIS-guided anesthesia, exercise)-show promise. Precision medicine approaches, including tailored anesthesia and repurposed AD therapeutics, could further improve outcomes. In conclusion, POCD lies at the intersection of acute perioperative stress and chronic neurodegeneration. Future research should prioritize biomarker validation, individualized prevention, and long-term cognitive monitoring to address the growing burden of POCD in aging populations.},
}

@article {pmid41679671,
year = {2026},
author = {Kokubun, K and Nemoto, K and Kobayashi, S and Yamaguchi, S and Yamakawa, Y},
title = {Apathy mediates the relationship between uncinate fasciculus fractional anisotropy and depression in healthy adults.},
journal = {Brain research bulletin},
volume = {},
number = {},
pages = {111767},
doi = {10.1016/j.brainresbull.2026.111767},
pmid = {41679671},
issn = {1873-2747},
abstract = {Many patients with neurodegenerative and psychiatric diseases, such as Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD), suffer from apathy, which manifests as a lack of emotion, interest, and motivation. Therefore, research on the relationship between apathy and brain structure in patients with the disease is accumulating. However, the relationship between the tendency for apathy and brain structure in healthy people has hardly been clarified. Since changes in the brain's microstructure can occur even in individuals before they develop a specific disease, it is meaningful from the perspective of preventive medicine to clarify the latent apathy and changes in brain structure in healthy people. In addition, it is unclear and worth clarifying how apathy relates to the relationship between depression, which shares some symptoms with apathy, and the brain. Therefore, in this study, using diffusion tensor imaging data collected from 173 participants (69 men and 104 women) aged 23 to 69 years, along with responses to two psychological questionnaires (the Apathy Scale and the Center for Epidemiologic Studies Depression Scale), we analyzed the relationship between apathy and fractional anisotropy (FA) of four fibers, the uncinate fasciculus (UF), corpus callosum (CC), superior longitudinal fasciculus (SLF), and cingulum. As a result, there was a significant negative correlation between UF FA and apathy (p = 0.003), like previous studies in patients with AD and bvFTD. This relationship remained almost unchanged in partial correlation analysis controlling for sex, age, whole brain gray matter volume (GMV), depression, etc. (p = 0.001). Furthermore, the results of path analysis showed that apathy fully mediated the relationship between UF FA and depression (p = 0.001). This is the first study to show that apathy tendency in people who perceive themselves as healthy is associated with UF FA and mediates the relationship between UF FA and depression.},
}

@article {pmid41679590,
year = {2026},
author = {Farkas, S and Jasper, V and Nyers-Marosi, K and Petrovai, B and Szabó, A and Kvak, EE and Sólyomvári, C and Varga, R and Kormos, V and Makkai, G and Ábrahám, IM and Zelena, D and Kovács, T},
title = {Targeting cholinergic cells in a mouse model of Alzheimer's disease: Validating a quadruple transgenic model.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115684},
doi = {10.1016/j.expneurol.2026.115684},
pmid = {41679590},
issn = {1090-2430},
abstract = {Alzheimer's disease (AD) is an increasing health and social problem worldwide with prevalent cholinergic cell involvement. To reveal the details of the exact mechanisms, further preclinical studies in animals are needed. Our aim was to create a mouse model that represents the progression of AD with easy cholinergic manipulation. The 3xTg-AD and ChAT-Cre strains were crossbred. After serial genotyping, a colony, homozygote for all four genes (PSEN1, APPSwe, tauP301L and Cre; 3xAD-ChAT-Cre) was established. The presence of amyloid-β (Aβ) plaques and phosphor-Tau (pTau) aggregates was confirmed by immunohistochemistry. To test the functionality of the Cre enzyme, a stimulating DREADD virus (AAV8-hSyn-DIO-hM3Dq-mCherry) was injected unilaterally into the nucleus basalis magnocellularis, and clozapine-N-oxide-induced c-Fos activation was compared between the two hemispheres. Behavioral characterization was performed using the Y-maze, social discrimination (SDT), single pellet reaching (SPR), fox odor (FOT), and splash tests (ST). Food, water consumption and body weight change were investigated. Immunostaining and RNAscope confirmed the expression of Cre in ChAT-positive cells and the progressive appearance of pathological hallmarks (Aβ and pTau). The c-Fos activity was significantly increased in the virus-injected hemisphere. Compared with control mice, 3xAD-ChAT-Cre mice showed decreased locomotion (Y-maze, SDT, FOT), increased anxiety (FOT, ST) and weaker fine motor skills (SPR). In conclusion, newly created animals have a functional Cre recombinase enzyme in cholinergic cells. Additionally, the animals presented the pathophysiological hallmarks of AD in specific brain areas and maintained the typical behavioral alterations previously reported in 3xTg-AD mice. Thus, this strain seems to be appropriate for further studies.},
}

@article {pmid41679524,
year = {2026},
author = {Chang, J and Liu, T and Cheng, X and Wei, J},
title = {How molecular mechanisms of aging drive Alzheimer's disease pathology.},
journal = {Cellular signalling},
volume = {},
number = {},
pages = {112426},
doi = {10.1016/j.cellsig.2026.112426},
pmid = {41679524},
issn = {1873-3913},
abstract = {Aging is a "multidimensional engine" of biological dysfunction that can fundamentally reshape the pathology of Alzheimer's disease (AD), This review systematically elaborates on how aging synergistically promotes the core pathologies of AD: aging upregulates the activity of β-secretase 1 (BACE1)/γ-secretase, impairs the clearance function of glial cells and meningeal lymphatic drainage, and accelerates Aβ deposition; the imbalance of kinases/phosphatases, dysfunction of molecular chaperones, and aging exosome-mediated propagation of Tau "seeds" facilitate Tau pathology; hyperreactivity of microglia and the transformation of astrocytes to the A1 phenotype form a senescence-associated secretory phenotype (SASP) → neuroinflammation vicious cycle; downregulation of synaptic proteins and disintegration of the default mode network lead to cognitive decline. Recent studies have identified that the impaired transition of aging microglia to the disease-associated microglia (DAM) phenotype, peripheral-central aging signal transmission loops (the gut-brain axis, immune-brain axis, and metabolic-brain axis), as well as circadian rhythm/vascular metabolic dysregulation, have emerged as novel intervention targets. Precision strategies targeting aging mechanisms-such as senescent cell clearance, SASP inhibition, epigenetic reprogramming, and biomarker-guided early intervention-provide a new paradigm for blocking the progression of AD.},
}

@article {pmid41679362,
year = {2026},
author = {Wu, Z and Lv, F and Shao, S and Chen, Y and Weng, N and Xia, Y},
title = {Recent Advances in Traditional Chinese Medicine-Mediated Regulation of Microglial Metabolic Reprogramming in Neurological Disease Therapy.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {121355},
doi = {10.1016/j.jep.2026.121355},
pmid = {41679362},
issn = {1872-7573},
abstract = {Neuroinflammation, driven by microglial metabolic reprogramming, underpins neurological diseases. Contrasting with the limitations of single-target therapies, TCM and acupuncture offer multi-targeted anti-inflammatory and antioxidant effects to modulate microglial activation, with TCM directly regulating microglial energy metabolism.

AIM OF THE STUDY: This review aims to elucidate how TCM and acupuncture regulate microglial energy metabolism in neurological diseases, identify key metabolic enzymes and signaling pathways, and establish a scientific foundation for their translational applications.

MATERIALS AND METHODS: we systematically searched major scientific databases (PubMed, Web of Science, Sinomed, and CNKI) from January 2010 to December 2025 using predefined keywords including "TCM", "acupuncture", "microglia", "glucose/lipid/amino acid metabolism", and "neurological diseases" (e.g., Alzheimer's disease, depression). Our literature review focused on two main aspects: (1) direct mechanistic studies of TCM bioactive compounds and formulas on microglial energy metabolism; (2) related studies on acupuncture's effects on brain or astrocyte metabolism, providing indirect evidence for its potential effects on glial cell metabolism.

RESULTS: TCM bioactive compounds and formulas regulate metabolic enzymes and pathways, correcting microglial metabolic disturbances. These interventions promote microglial polarization toward the anti-inflammatory M2 phenotype, reducing neuroinflammation and improving outcomes in neurological diseases. Acupuncture may modulate metabolic pathways in microglia, supporting its role as an auxiliary therapeutic modality in TCM.

CONCLUSION: TCM restores microglial metabolic homeostasis, enhancing M2 polarization and neuroprotection. These findings highlight TCM's potential for developing metabolism-immunity dual-target interventions for neurological diseases. Further research is needed to elucidate acupuncture's mechanisms and effects on microglial metabolism.},
}

@article {pmid41679193,
year = {2026},
author = {Zhang, J and Yang, C and Tan, Y and Na, M and Shakya, E and Zhang, D and Shi, X and Na, X and Li, Z and Ji, JS and Yang, Y and Zhao, A},
title = {Region-specific brain structural modulation and amyloid-β pathology associated with dietary biotin: insights into dementia neuropathology.},
journal = {EBioMedicine},
volume = {125},
number = {},
pages = {106155},
doi = {10.1016/j.ebiom.2026.106155},
pmid = {41679193},
issn = {2352-3964},
abstract = {BACKGROUND: The association and mechanisms between biotin and dementia remain unclear.

METHODS: We investigated the association through a population and animal study. UK Biobank data were used to evaluate the association of biotin with incident dementia and brain structural alteration. To validate our findings, we established a biotin-deficient mouse model, and performed behavioural tests, immunofluorescence, RT-qPCR, Western blotting, and molecular docking.

FINDINGS: In humans, higher biotin intake was significantly associated with reduced risks of all-cause dementia (moderate: 0.83 [0.74-0.94]; high: 0.78 [0.68-0.89]), Alzheimer's disease (AD, moderate: 0.74 [0.61-0.89]; high: 0.79 [0.64-0.98]), and delayed-onset dementia (DOD, moderate: 0.810 [0.715-0.918]; high: 0.776 [0.672-0.896]), but not vascular dementia (VD) and early-onset dementia (EOD). Neuroimaging results revealed a "pseudo-atrophy" pattern-reduced cortical volume with increased tissue intensity-resembling structural remodelling rather than neurodegeneration. In mice, biotin deficiency triggered region-specific alteration of APP, PSEN1, and APOE in the hippocampus and prefrontal cortex. It was accompanied by elevated Aβ42 levels and an increased Aβ42/40 ratio. Molecular docking suggested that biotin physically interacts with the catalytic pocket of PSEN1 and the receptor-binding domain of APOE.

INTERPRETATION: Dietary biotin is associated with a lower risk of dementia, especially AD, potentially by inhibiting amyloidogenic processing and modulating APOE-mediated clearance. The observed neuroimaging and molecular patterns suggest that maintaining adequate biotin intake is a viable strategy for dementia prevention.

FUNDING: This work was supported by the National Natural Science Foundation of China (No. 82273619).},
}

@article {pmid41679105,
year = {2026},
author = {Wang, C and Xin, T and Zhong, W and Tian, Q and Chen, L},
title = {The growing burden of Alzheimer's Disease and other dementias in China: Lessons for an aging society.},
journal = {Archives of gerontology and geriatrics},
volume = {144},
number = {},
pages = {106165},
doi = {10.1016/j.archger.2026.106165},
pmid = {41679105},
issn = {1872-6976},
abstract = {Alzheimer's disease and other dementias (AD&D) represent an escalating health and social challenge in China's rapidly aging population. Using data from the Global Burden of Disease 2021 study, we observed substantial increases in incidence and prevalence over the past three decades, particularly among women and the oldest age groups. These trends underline the growing strain on family-based care systems and the urgent need for integrated, age-friendly health and social policies to address dementia in aging societies.},
}

@article {pmid41679028,
year = {2026},
author = {Yao, F and Qi, X and Yongli, S and Xiaofen, Z},
title = {Generation of a SV2A knockout human embryonic stem cell line by CRISPR/Cas9 system.},
journal = {Stem cell research},
volume = {91},
number = {},
pages = {103924},
doi = {10.1016/j.scr.2026.103924},
pmid = {41679028},
issn = {1876-7753},
abstract = {Synaptic Vesicle Glycoprotein 2A (SV2A) is a ubiquitously expressed brain glycoprotein, localized to synaptic terminals. It regulates vesicle exocytosis, maintains neurotransmitter release, and serves as a receptor for both botulinum neurotoxins (e.g., BoNT/A) and tetanus neurotoxin (TeNT). It is a target for antiseizure drugs and implicated in epilepsy, Alzheimer's, and Parkinson's diseases. We generated a homozygous SV2A-knockout human embryonic stem cell (hESC) line WAe001-A-3F (H1-SV2A[-/-]), using CRISPR/Cas9 genome editing technology. The SV2A-knockout embryonic stem cell lines provide a precise in vitro model to dissect its roles in synaptic function and disease mechanisms.},
}

@article {pmid41678986,
year = {2026},
author = {Sha, S and Zhang, L and Li, Y and Xing, X and Zhang, C and Guo, Z and Wang, Y and Li, Q and Pang, X and Qu, L},
title = {Global dynamics of blood cadmium in older adults and its association with Alzheimer's disease mortality: A Bayesian hierarchical model-based analysis of 30 countries from 1990 to 2020.},
journal = {Ecotoxicology and environmental safety},
volume = {311},
number = {},
pages = {119864},
doi = {10.1016/j.ecoenv.2026.119864},
pmid = {41678986},
issn = {1090-2414},
abstract = {Cadmium (Cd), a ubiquitous environmental pollutant, exhibits potential neurotoxic risk. While compelling evidence links Cd accumulation to the pathogenesis of Alzheimer's disease (AD), the global impact of blood Cd exposure on AD mortality remains underexplored. We conducted an extensive review of 102 studies from 30 countries and standardized blood Cd concentrations to estimate the geometric mean (GM) and geometric standard deviation (GSD) of Cd exposure. Estimated annual percentage change (EAPC) was calculated to assess the trend in AD mortality, with 1000 Monte Carlo simulations to estimate population attributable fractions (RAF). The augmented human development index (AHDI) was used to analyze correlations with Cd-related mortality. Bayesian hierarchical regression models revealed a 72% reduction in GM in Egypt, contrasted by a 142% increase in Australia. Germany and Brazil demonstrated significant GM reductions along with increased GSD, reflecting regional variability. Conversely, Japan and South Korea exhibited marked rises in the regional variability, while Egypt and France achieved significant reductions in Cd-related AD deaths for both males and females, reaching zero by 2020. The number of deaths related to Cd in Australia and Japan has increased. While countries like Norway, Germany, and Lithuania showed declining mortality trends, others (e.g., Poland and Italy), exhibited rising mortality despite AHDI improvements. This study represents the first comprehensive assessment of the global burden of AD attributable to blood Cd exposure, reveal significant regional disparities. It provides epidemiological references for policymakers to formulate Cd management strategies and guides researchers in selecting impactful study directions.},
}

@article {pmid41678917,
year = {2026},
author = {Xue, D and Hu, X and Li, R and Sun, T and Qian, S and Chu, F and Gao, H and Li, F and Cai, B},
title = {Plant-derived bioactive compounds modulate the gut microbiota in Alzheimer's disease: Metabolite signaling, neuroimmune circuits, and systems-level regulation.},
journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology},
volume = {153},
number = {},
pages = {157919},
doi = {10.1016/j.phymed.2026.157919},
pmid = {41678917},
issn = {1618-095X},
abstract = {BACKGROUND: Alzheimer's disease (AD) is increasingly recognized as a multisystem disorder shaped not only by central neurodegeneration but also by peripheral metabolic and immune dysregulation. Growing evidence highlights the gut microbiota and its metabolites as key modulators of amyloid accumulation, tau phosphorylation, neuroinflammation, and microglial dysfunction.

PURPOSE: This review aims to synthesize current advances on how plant-derived bioactive compounds modulate AD pathophysiology through microbiota-dependent metabolic and neuroimmune mechanisms, and to establish a systems-level framework linking botanical interventions to gut microbiota remodeling and metabolite signaling.

METHODS: A comprehensive literature survey was conducted using PubMed, Web of Science, ScienceDirect, and Google Scholar, covering publications from 2010 to 2026. Studies investigating gut microbiota, microbial metabolites, and plant-derived bioactive compounds in AD-related metabolic, immune, and neurodegenerative pathways were systematically reviewed and integrated.

RESULTS: Plant-derived bioactive compounds, including phytochemicals, polysaccharides, and multi-herb formulations, interact extensively with the gut microbiota, undergoing microbial biotransformation to yield more active metabolites while simultaneously reshaping microbial community structure and metabolite profiles. These bidirectional interactions position the microbiota as a central mediator of plant-derived therapeutic activity. We summarize current evidence on how plant-derived compounds influence AD pathophysiology through microbiota-dependent metabolic and neuroimmune pathways. Major microbial metabolites, including short-chain fatty acids (SCFAs), trimethylamine N-oxide (TMAO), bile acids (BAs), and indole derivatives, are discussed, together with their regulatory roles in signaling networks such as nuclear factor κB (NF-κB), phosphatidylinositol 3-kinase/Akt (PI3K/Akt), cAMP response element-binding protein/brain-derived neurotrophic factor (CREB/BDNF), and triggering receptor expressed on myeloid cells 2 (TREM2)-associated microglial states. We further summarize evidence for synergistic strategies combining plant bioactives with probiotics and highlight advances in microbial biotransformation, precision metabolite modulation, and engineered microbial systems. Finally, future directions integrating multi-omics, personalized microbiota-guided interventions, and synthetic biology are outlined to support the development of targeted, mechanism-based therapies.

CONCLUSION: By framing AD through a gut microbiota-centered perspective, this review provides a unified mechanistic foundation for the development of next-generation interventions based on plant-derived compounds and microbiota regulation.},
}

@article {pmid41678876,
year = {2026},
author = {Shadyab, AH and Zhang, B and LaCroix, AZ and McEvoy, LK},
title = {Randomization to hormone therapy and changes in plasma biomarkers of Alzheimer's pathology: The women's health initiative memory study.},
journal = {Maturitas},
volume = {207},
number = {},
pages = {108873},
doi = {10.1016/j.maturitas.2026.108873},
pmid = {41678876},
issn = {1873-4111},
abstract = {The association of hormone therapy with Alzheimer's pathology among postmenopausal women is not well understood. We examined the association of randomized assignment to hormone therapy with changes in plasma biomarkers of Alzheimer's pathology in the Women's Health Initiative Memory Study. Rates of change in the biomarkers (p-tau217, p-tau181, Aβ42:Aβ40, GFAP, and NfL) over an average 15-year follow-up did not significantly differ for estrogen alone vs placebo or estrogen plus progestin vs placebo. These null associations do not support either a protective or a detrimental association of hormone therapy of the types tested in the Women's Health Initiative with long-term changes in plasma Alzheimer's biomarkers. CLINICALTRIALS.GOV: NCT00685009.},
}

@article {pmid41678838,
year = {2026},
author = {Eltrass, AS and Tageldin, Y and Farag, H},
title = {A new graph-transformer framework for EEG-based differentiation of Alzheimer's disease and frontotemporal dementia.},
journal = {Biomedical physics & engineering express},
volume = {},
number = {},
pages = {},
doi = {10.1088/2057-1976/ae451c},
pmid = {41678838},
issn = {2057-1976},
abstract = {Differentiating between Alzheimer's disease (AD), frontotemporal dementia (FTD), and cognitively normal (CN) subjects remains a significant challenge in clinical neurodiagnosis. This study introduces an automated framework that combines electroencephalography (EEG) signal processing with graphbased deep learning (DL) to improve disease classification. The process begins with artifact suppression and a DL-driven filtering model to enhance EEG signal quality. Once filtered, the signals are segmented, and essential features are extracted to build graph representations that reflect brain connectivity patterns. These graphs are then analyzed utilizing a transformer-based graph neural network, enabling accurate classification of AD, FTD, and CN subjects. Results show that the model achieved highly competitive and well-balanced performance in both binary (AD-CN and FTD-CN) and ternary (AD-CN-FTD) classification tasks, with higher accuracy than existing EEG-based diagnostic methods, demonstrating the benefits of integrating signal filtration, graph representations, and transformer architectures. Overall, the findings suggest that this framework can serve as a reliable tool to support clinical decision-making for the early detection and differentiation of neurodegenerative disorders.},
}

@article {pmid41678156,
year = {2026},
author = {Burks, W},
title = {When Protocol Meets Reality.},
journal = {JAMA},
volume = {},
number = {},
pages = {},
doi = {10.1001/jama.2026.0064},
pmid = {41678156},
issn = {1538-3598},
}

@article {pmid41678108,
year = {2026},
author = {Umesh, SB and Sadanandan, B and Marabanahalli Yogendraiah, K and Vijayalakshmi, V},
title = {The Impact of Zinc on Cellular Dynamics, Brain Function, and its Therapeutic Potential in Neuronal Regeneration.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {436},
pmid = {41678108},
issn = {1559-1182},
mesh = {Humans ; *Zinc/pharmacology/metabolism/therapeutic use ; Animals ; *Nerve Regeneration/drug effects/physiology ; *Brain/physiology/drug effects ; *Neurons/drug effects/metabolism ; Neurogenesis/drug effects ; },
abstract = {Zinc is a vital trace element that plays a central role in maintaining brain function, regulating cellular dynamics, and promoting neuronal repair. As the second most abundant transition metal in the central nervous system, zinc is essential for neurotransmission, synaptic plasticity, and neurogenesis, processes that underlie higher cognitive functions such as learning and memory. Its homeostasis is tightly controlled, as dysregulation contributes to the onset and progression of neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. At the cellular level, zinc serves as a critical regulator of proliferation, differentiation, and survival, influencing the behavior of neural and mesenchymal stem cells. Through modulation of signaling pathways such as PI3K/Akt and MAPK, zinc governs cell growth, maturation, and neuroprotection. Physiological levels support axonal sprouting, neurite extension, and synaptic connectivity, whereas excessive release under pathological conditions exacerbates oxidative stress and excitotoxicity. Emerging evidence highlights zinc's therapeutic role in neuronal regeneration. Controlled supplementation enhances neurogenesis, reduces apoptosis, restores synaptic activity, and improves memory outcomes in experimental models of neural injury. Zinc-enriched biomaterials and scaffolds are also being developed for neural tissue engineering, where the incorporation of zinc enhances neurite outgrowth, cell adhesion, and network repair. Beyond neuroregeneration, zinc-based nanomaterials are gaining biomedical significance. Zinc oxide nanoparticles (ZnO NPs) exhibit potent anticancer activity against human cancer cell lines by inducing reactive oxygen species generation, DNA damage, and apoptosis. Additionally, other zinc nanoparticles, including zinc sulfide and zinc-doped biomaterials, show potential in tissue repair, wound healing, and drug delivery applications. Collectively, these findings underscore zinc's multifaceted role in neural function, regenerative biology, and nanomedicine. Advancing our understanding of zinc-mediated mechanisms may enable the development of novel zinc-targeted therapeutic strategies for treating neurodegenerative diseases and promoting functional recovery after brain injury.},
}

Humans
*Zinc/pharmacology/metabolism/therapeutic use
Animals
*Nerve Regeneration/drug effects/physiology
*Brain/physiology/drug effects
*Neurons/drug effects/metabolism
Neurogenesis/drug effects

@article {pmid41678018,
year = {2026},
author = {Arbaciauskaite, S and Silvestri, S and Luo, P and Krüger, C and Mossmann, ZJ and Allelein, S and Scholz, A and Loeffler, D and Fiorenza, S and Menale, A and Torino, E and Kuhlmeier, D and Peters, O and Lehnardt, S},
title = {Microglia-Derived Extracellular Vesicles from Alzheimer's Disease Patients Carry miRNAs Driving a Neuroinflammatory Response.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {435},
pmid = {41678018},
issn = {1559-1182},
support = {LE 2420/7-1, SFB-TRR167/B03//Deutsche Forschungsgemeinschaft/ ; },
mesh = {*Microglia/metabolism/pathology ; *Alzheimer Disease/genetics/cerebrospinal fluid/pathology/metabolism ; *Extracellular Vesicles/metabolism ; Humans ; *MicroRNAs/metabolism/genetics ; Animals ; Mice ; *Neuroinflammatory Diseases/genetics/pathology/metabolism ; Aged ; Male ; Female ; HEK293 Cells ; Aged, 80 and over ; },
abstract = {Alzheimer's disease (AD) represents the most common cause of dementia and urgently requires sensitive biomarkers and effective therapies. Extracellular vesicles represent membranous nano-sized particles secreted from cells, which serve as intercellular messengers participating in central nervous system (CNS) homeostasis, but also are implicated in AD pathogenesis. In addition, EVs containing disease-specific signatures, such as microRNAs (miRNAs), are considered as potent tools for the diagnosis and treatment of AD and other brain disorders. In this study, we used TMEM119 antibody to immunocapture microglia-derived EVs from cerebrospinal fluid (CSF) of AD patients and control subjects. EVs harvested from these CSF samples contained distinct disease-specific miRNA profiles, as assessed by small RNA sequencing. Using a HEK TLR reporter cell system, we found that these miRNA are potent activators of human TLR8, an established RNA sensor. Out of the miRNAs present in AD-associated EVs, selected oligonucleotides were synthesized and loaded into BV2 microglia-derived EVs. Exposure of primary murine microglia to these miRNA-loaded EVs led to TNF release from these cells, thereby driving a neuroinflammatory response. Taken together, putatively microglia-derived EVs from the CSF of AD patients contain miRNAs, which are capable of activating hTLR8 and inducing an inflammatory response from microglia.},
}

*Microglia/metabolism/pathology
*Alzheimer Disease/genetics/cerebrospinal fluid/pathology/metabolism
*Extracellular Vesicles/metabolism
Humans
*MicroRNAs/metabolism/genetics
Animals
Mice
*Neuroinflammatory Diseases/genetics/pathology/metabolism
Aged
Male
Female
HEK293 Cells
Aged, 80 and over

@article {pmid41677858,
year = {2026},
author = {Zheng, X and Qin, W and Wu, F and Koenig, KL and Afanasyeva, Y and Zeleniuch-Jacquotte, A and Chen, Y},
title = {Association of midlife macronutrient and mineral intake with subjective cognitive complaints in a prospective cohort of women.},
journal = {European journal of nutrition},
volume = {65},
number = {2},
pages = {49},
pmid = {41677858},
issn = {1436-6215},
support = {U01 CA182934/NH/NIH HHS/United States ; },
mesh = {Humans ; Female ; Middle Aged ; Prospective Studies ; *Nutrients/administration & dosage ; *Diet/statistics & numerical data/methods ; *Minerals/administration & dosage ; Dietary Fats/administration & dosage ; Aged ; Dietary Carbohydrates/administration & dosage ; Cohort Studies ; *Cognitive Dysfunction/epidemiology ; Surveys and Questionnaires ; },
abstract = {PURPOSE: Few studies have examined the association between dietary nutrients and subjective cognitive complaints (SCCs), which are potential predictors of Alzheimer's disease-related dementia (ADRD). We aimed to examine the association of midlife intake of macronutrients, as well as of a few other nutrients, with SCC development.

METHODS: We included 5119 participants who responded to the 2018 or 2020 follow-up questionnaire of the New York University Women's Health Study. Dietary data were collected using a validated self-administered Block food frequency questionnaire, and nutrient intake were calculated using food lists and food composition tables. SCCs were assessed using a standardized questionnaire.

RESULTS: Dietary intakes of fiber, carbohydrates, and potassium were inversely associated with having ≥ 2 SCC (p-trend = 0.0047, 0.026, and 0.0015, respectively), whereas higher intakes of total fat and saturated fat, as well as a higher ratio of fat to carbohydrates, were positively associated with ≥ 2 SCCs (p-trend = < 0.0001, 0.0015, and 0.0025, respectively). The positive associations of total fat intake and the log-ratio of fat to carbohydrates with ≥ 2 SCCs remained significant after controlling for other nutrients (p-trend = 0.008 and 0.036, respectively). The association between total fat intake and SCCs was stronger among participants with lower caloric intake (< median = 1430 kcal) compared with those consuming higher intake (≥ 1430 kcal) (p-value for interaction = 0.0049). The associations did not differ appreciably by other factors.

CONCLUSION: We observed a positive association between midlife dietary fat intakes and SCCs in later life in a cohort of women.},
}

Humans
Female
Middle Aged
Prospective Studies
*Nutrients/administration & dosage
*Diet/statistics & numerical data/methods
*Minerals/administration & dosage
Dietary Fats/administration & dosage
Aged
Dietary Carbohydrates/administration & dosage
Cohort Studies
*Cognitive Dysfunction/epidemiology
Surveys and Questionnaires

@article {pmid41677765,
year = {2026},
author = {Kim, H and Hong, JY and Yeo, C and Kim, H and Jeon, WJ and Lee, J and Lee, YJ and Ha, IH},
title = {Neuroprotective Effects of Herbal Formula Yookgong-Dan on Oxidative Stress-Induced Tau Hyperphosphorylation in Rat Primary Hippocampal Neurons.},
journal = {Biology},
volume = {15},
number = {3},
pages = {},
doi = {10.3390/biology15030294},
pmid = {41677765},
issn = {2079-7737},
abstract = {This study sought to evaluate the neuroprotective effects of YGD in an oxidative stress-induced Alzheimer's disease (AD)-like cellular model and to elucidate the underlying molecular pathways, with a focus on tau phosphorylation, Aβ accumulation, and antioxidant defense mechanisms. Rat primary hippocampal neurons were exposed to hydrogen peroxide to induce oxidative stress. The effects of YGD on neuronal viability, neurite outgrowth, and synaptic integrity were assessed using the immunodetection of microtubule-associated protein 2 (MAP2), postsynaptic density protein 95 (PSD-95), and synapsin-1. Levels of phosphorylated tau and Aβ were quantified, and the involvement of extracellular signal-regulated kinase (ERK), glycogen synthase kinase 3β (GSK3β), and nuclear factor-erythroid 2-related factor-2 (Nrf2) pathways was examined. Additionally, in silico molecular docking studies targeting the ATP-binding site of GSK3β were conducted to screen major phytochemicals from the ten medicinal herbs constituting YGD. YGD markedly enhanced neuronal viability under oxidative stress, promoted neurite extension, and increased synaptic marker expression (MAP2, PSD-95, and synapsin-1). Treatment reduced phosphorylated tau by suppressing ERK and GSK3β activation and significantly decreased Aβ accumulation. YGD also upregulated antioxidant defenses via the activation of the Nrf2 pathway. Docking simulations identified oleanolic acid (from Cornus officinalis) as the most potent GSK3β binder (-9.86 ± 0.40 kcal/mol), forming stable interactions with ARG96, ASN95, and GLU97. Additional compounds, including alisol C, drypemolundein B, and friedelin, demonstrated favorable binding energies and engaged key ATP-binding site residues. YGD confers neuroprotection through the integrated modulation of tau phosphorylation, Aβ pathology, and oxidative stress, partly via the multi-target engagement of GSK3β by its constituent phytochemicals. These findings support that YGD attenuates oxidative stress-induced AD-like cellular alterations.},
}

@article {pmid41677754,
year = {2026},
author = {Ang, MY and Feisal, NAS and Ramli, MDC and Hein, ZM},
title = {Environmentally Driven Precision Neurology: A Neurogenomic Perspective.},
journal = {Biology},
volume = {15},
number = {3},
pages = {},
doi = {10.3390/biology15030283},
pmid = {41677754},
issn = {2079-7737},
support = {Ajman University//Ajman University/ ; },
abstract = {The World Health Organization identifies environmental pollution as a primary global health threat, and its role in the onset and progression of neurological diseases is becoming increasingly clear. In the era of precision medicine, understanding the complex interplay between genetic predispositions and environmental factors is particularly important. The global increase in neurological conditions such as Alzheimer's disease, Parkinson's disease, and neurodevelopmental disorders highlights the urgent need for precision neurology. Environmental factors like air pollution, pesticides, and prenatal stress can induce epigenetic changes, including DNA methylation and histone modifications, which alter gene expression and shape disease risk. Advances in neurogenomics, bioinformatics, and artificial intelligence are revolutionizing our ability to decipher these mechanisms, presenting new approaches for personalized diagnostics and interventions. However, significant challenges related to data integration, computational complexity, high implementation costs, and ethical considerations remain. Overcoming these barriers is essential to harness the full potential of environmentally informed precision neurology. This review synthesizes current knowledge on the integration of environmental and genomic data to better predict, prevent, and treat neurological diseases, aiming to alleviate their growing global burden and improve patient outcomes.},
}

@article {pmid41677657,
year = {2026},
author = {Dagla, I and Gkikas, F and Gikas, E and Tsarbopoulos, A},
title = {Targeting Amyloid Beta Aggregation and Neuroinflammation in Alzheimer's Disease: Advances and Future Directions.},
journal = {Cells},
volume = {15},
number = {3},
pages = {},
doi = {10.3390/cells15030295},
pmid = {41677657},
issn = {2073-4409},
mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism/pathology ; *Amyloid beta-Peptides/metabolism ; Animals ; *Neuroinflammatory Diseases/drug therapy ; Blood-Brain Barrier/metabolism ; Drug Delivery Systems ; *Protein Aggregation, Pathological/drug therapy ; Neuroprotective Agents/therapeutic use/pharmacology ; *Protein Aggregates/drug effects ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia in the elderly. Among the diverse pathological features of AD, amyloid beta (Aβ) aggregation and neuroinflammation are recognized as central and interlinked mechanisms driving disease progression. This review focuses specifically on these two processes and highlights current pharmacological limitations in modifying disease pathology. Natural products such as curcumin, resveratrol, Ginkgo biloba, epigallocatechin gallate (EGCG), crocin, ashwagandha, and cannabidiol (CBD) have shown promising activity in modulating Aβ aggregation and neuroinflammatory pathways, offering multi-target neuroprotective effects in preclinical studies. However, their therapeutic application remains hindered by poor solubility, instability, rapid metabolism, and limited blood-brain barrier (BBB) permeability. To overcome these barriers, nanotechnology-based drug delivery systems-including polymeric nanoparticles, niosomes, solid lipid nanoparticles, and chitosan-based carriers-have emerged as effective strategies to enhance brain targeting, bioavailability, and pharmacological efficacy. We summarize the mechanistic insights and nanomedicine approaches related to these bioactives and discuss their potential in developing future disease-modifying therapies. By focusing on Aβ aggregation and neuroinflammation, this review provides a targeted perspective on the evolving role of natural compounds and nanocarriers in AD treatment.},
}

Humans
*Alzheimer Disease/drug therapy/metabolism/pathology
*Amyloid beta-Peptides/metabolism
Animals
*Neuroinflammatory Diseases/drug therapy
Blood-Brain Barrier/metabolism
Drug Delivery Systems
*Protein Aggregation, Pathological/drug therapy
Neuroprotective Agents/therapeutic use/pharmacology
*Protein Aggregates/drug effects

@article {pmid41677635,
year = {2026},
author = {Acquarone, E and Roy, SM and Staniszewski, A and Watterson, DM and Arancio, O},
title = {The Highly Selective 5-HT2B Receptor Antagonist MW073 Mitigates Aggressive Behavior in an Alzheimer's Disease Mouse Model.},
journal = {Cells},
volume = {15},
number = {3},
pages = {},
doi = {10.3390/cells15030273},
pmid = {41677635},
issn = {2073-4409},
support = {AG066722/GF/NIH HHS/United States ; },
mesh = {Animals ; *Alzheimer Disease/drug therapy ; *Aggression/drug effects ; Disease Models, Animal ; Mice ; *Serotonin 5-HT2 Receptor Antagonists/pharmacology/therapeutic use ; Male ; Mice, Transgenic ; *Receptor, Serotonin, 5-HT2B/metabolism ; *Behavior, Animal/drug effects ; *Fluorobenzenes/pharmacology/therapeutic use ; Humans ; Mice, Inbred C57BL ; },
abstract = {Background: Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder and the leading cause of dementia worldwide. Progressive synaptic dysfunction underlies declines in cognition, daily functioning, and the development of neuropsychiatric syndromes. Neuropsychiatric syndromes that include agitation and aggression affect 40-60% of patients and represent a major source of caregiver burden. Serotonin 5-HT2B receptor levels are increased in the AD patient brain, and thus, treatment of AD animal models with the selective 5-HT2B receptor antagonist MW073 in prevention or disease stage paradigms attenuates Aβ- or tau-induced dysfunction. Methods: We investigated the effects of MW073 treatment on the aggressive behavior of Tg2576 mice in a resident-intruder assay. Results: MW073 treatment significantly reduced aggressive behavior in male Tg2576 mice. Conclusions: MW073 efficacy in treating aggression in Tg2576 mice implicates 5-HT2B receptor-mediated signaling in AD neuropsychiatric symptoms as well as cognitive and behavioral dysfunction.},
}

Animals
*Alzheimer Disease/drug therapy
*Aggression/drug effects
Disease Models, Animal
Mice
*Serotonin 5-HT2 Receptor Antagonists/pharmacology/therapeutic use
Male
Mice, Transgenic
*Receptor, Serotonin, 5-HT2B/metabolism
*Behavior, Animal/drug effects
*Fluorobenzenes/pharmacology/therapeutic use
Humans
Mice, Inbred C57BL

@article {pmid41677602,
year = {2026},
author = {Ando, K and Lopez-Gutierrez, L and Mansour, S and Yilmaz, Z and Dauphinot, L and Verheijen, J and Fontaine, G and Quintanilla-Sánchez, C and Aydin, E and Doeraene, E and Nagaraj, S and Kosa, AC and Watanabe, T and Sleegers, K and Potier, MC and Brion, JP and Leroy, K},
title = {PICALM Genetic Variant Alters mRNA Expression Without Affecting Protein Levels or Tau Spreading in Alzheimer's Disease.},
journal = {Cells},
volume = {15},
number = {3},
pages = {},
doi = {10.3390/cells15030235},
pmid = {41677602},
issn = {2073-4409},
support = {T.0023.15//FNRS/ ; NA//the Belgian Fondation Recherche Alzheimer/ Stichting Alzheimer Onderzoek/ ; },
mesh = {*Alzheimer Disease/genetics/metabolism/pathology ; Humans ; *Monomeric Clathrin Assembly Proteins/genetics/metabolism ; *tau Proteins/metabolism ; *RNA, Messenger/genetics/metabolism ; Animals ; Mice ; Male ; Female ; Aged ; Aged, 80 and over ; Brain/metabolism/pathology ; Polymorphism, Single Nucleotide/genetics ; Genetic Predisposition to Disease ; Alleles ; },
abstract = {Phosphatidylinositol-binding clathrin assembly protein (PICALM) is a clathrin adaptor essential for clathrin-mediated endocytosis. Genome-wide association studies (GWAS) have consistently identified PICALM as one of the most significant genetic susceptibility loci for late-onset sporadic Alzheimer's disease (AD). However, the functional impact of the most validated AD-associated variant, rs3851179, remains unclear. Here, we examined PICALM mRNA and protein expression in post-mortem AD brains with reference to rs3851179 genotype. We found that PICALM mRNA levels were significantly increased in AD brains compared with controls, and that the protective rs3851179T allele was associated with reduced PICALM mRNA levels relative to the non-protective rs3851179C allele. In contrast, PICALM levels were significantly reduced in AD brain lysates compared with controls. PICALM expression did not significantly differ between carriers of the protective and non-protective alleles. Analysis of the mRNA-to-protein ratio revealed a significant dissociation between transcript and protein levels, suggesting relatively reduced protein expression efficiency in cases carrying the non-protective CC genotype. To assess whether reduced PICALM levels influence tau pathology, we used Picalm heterozygous knockout (Picalm+/-) mice, which express approximately 50% of the wild-type Picalm protein. Following stereotaxic injection of pathological tau extracted from AD brains, both wild-type and Picalm+/- mice developed tau pathology; however, the extent of tau accumulation did not significantly differ between genotypes. Together, these findings indicate that although PICALM protein level is reduced in AD, this reduction does not appear to affect tau propagation in this model. Therefore, the AD susceptibility associated with PICALM variant likely arises from mechanisms other than tau spread, possibly involving other aspects of autophagy, endocytic or vascular function.},
}

*Alzheimer Disease/genetics/metabolism/pathology
Humans
*Monomeric Clathrin Assembly Proteins/genetics/metabolism
*tau Proteins/metabolism
*RNA, Messenger/genetics/metabolism
Animals
Mice
Male
Female
Aged
Aged, 80 and over
Brain/metabolism/pathology
Polymorphism, Single Nucleotide/genetics
Genetic Predisposition to Disease
Alleles

@article {pmid41677584,
year = {2026},
author = {Minuti, A and Silvestro, S and Muscarà, C and Scuruchi, M and D'Angiolini, S},
title = {PCB 153 Modulates Genes Involved in Proteasome and Neurodegeneration-Related Pathways in Differentiated SH-SY5Y Cells: A Transcriptomic Study.},
journal = {Cells},
volume = {15},
number = {3},
pages = {},
doi = {10.3390/cells15030217},
pmid = {41677584},
issn = {2073-4409},
support = {RRC-2025-23686388//Ministero della Salute/ ; },
mesh = {Humans ; *Polychlorinated Biphenyls/toxicity/pharmacology ; *Proteasome Endopeptidase Complex/metabolism/genetics ; *Transcriptome/drug effects/genetics ; *Cell Differentiation/drug effects/genetics ; Cell Line, Tumor ; Cell Survival/drug effects ; Gene Expression Profiling ; Neurons/drug effects/metabolism ; *Neurodegenerative Diseases/genetics ; },
abstract = {Polychlorinated biphenyls (PCBs) are persistent environmental contaminants associated with neurotoxicity and increased risk of neurodegenerative diseases. PCB 153, a highly abundant non-coplanar congener, bioaccumulates in human tissues and impairs homeostasis. This study investigated the transcriptomic effects of PCB 153 (2,2',4,4',5,5'-Hexachlorobiphenyl) in retinoic acid (RA)-differentiated SH-SY5Y neuronal cells to identify early, sub-cytotoxic molecular alterations. Cell viability was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay after 24 h exposure to increasing PCB 153 concentrations. RNA-Seq was performed on cells treated with 5 μM PCB 153, the highest non-cytotoxic dose. Sequencing reads were quality-filtered, aligned to the human genome, and analyzed with DESeq2. Functional enrichment was conducted using Gene Ontologies and KEGG pathways. Western blot analyses were performed to assess protein level changes in selected targets. RNA-Seq identified 1882 significantly altered genes (q-value < 0.05). Gene Ontology analysis revealed strong enrichment of proteasome-related terms, with most proteasomal subunits displaying coordinated upregulation. KEGG analysis further showed significant enrichment of Alzheimer's (AD), Parkinson's (PD), amyotrophic lateral sclerosis (ALS), and other neurodegenerative disease pathways. These findings indicate that PCB 153 triggers a pronounced proteostatic response in neuron-like cells, suggesting early disruption of protein homeostasis that may contribute to mechanisms associated with neurodegeneration.},
}

Humans
*Polychlorinated Biphenyls/toxicity/pharmacology
*Proteasome Endopeptidase Complex/metabolism/genetics
*Transcriptome/drug effects/genetics
*Cell Differentiation/drug effects/genetics
Cell Line, Tumor
Cell Survival/drug effects
Gene Expression Profiling
Neurons/drug effects/metabolism
*Neurodegenerative Diseases/genetics

@article {pmid41677578,
year = {2026},
author = {Jobson, DD and Hase, Y and Walker, L and Polvikoski, T and Khundakar, AA and Allan, L and Kalaria, RN},
title = {High vulnerability of medial prefrontal pyramidal neurons in post-stroke, vascular, Alzheimer's disease, and aging-related dementias.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {2},
pages = {e71151},
pmid = {41677578},
issn = {1552-5279},
support = {MRC G0500247//UK Medical Research Council/ ; //Newcastle Centre for Brain Ageing and Vitality/ ; //Newcastle Brain Tissue Resource/ ; G0400074//MRC/ ; //Newcastle NIHR Biomedical Research Centre in Ageing/ ; //Tyne Hospitals NHS Foundation Trust/ ; //ARUK/ ; //PhD Studentship Award/ ; 570//DDJ/ ; /ALZS_/Alzheimer's Society/United Kingdom ; //NIHR/ ; //NIHR Applied Research Collaboration/ ; //NIHR Newcastle Biomedical Research Centre/ ; //NIHR Biomedical Research Centre/ ; //Hospitals NHS Foundation Trust/ ; //Newcastle University, and Cumbria/ ; //Northumberland and Tyne and Wear NHS Foundation Trust/ ; },
mesh = {Humans ; *Prefrontal Cortex/pathology/metabolism ; *Pyramidal Cells/pathology/metabolism ; Male ; Female ; Aged ; *Alzheimer Disease/pathology/metabolism ; Aged, 80 and over ; *Aging/pathology ; *Stroke/pathology ; Middle Aged ; *Dementia/pathology ; Electron Transport Complex IV/metabolism ; },
abstract = {INTRODUCTION: The medial prefrontal cortex (mPFC) is critical for executive function, behavioral inhibition, and memory. Its high vulnerability to dementia, compared to other prefrontal regions, remains unclear.

METHODS: We analyzed post mortem brain tissue from 118 older subjects, including post-stroke survivors, Alzheimer's disease; vascular, mixed, and frontotemporal dementia (FTD); and cognitively unimpaired controls. Three-dimensional stereology was used to assess pyramidal neuron densities and volumes in mPFC layers III and V. Immunohistochemistry evaluated metabolic dysfunction via cytochrome c oxidase subunit 1 (COX1), cytochrome c oxidase subunit 4 (COX4), and 78 kDa glucose-regulated protein expression.

RESULTS: Pyramidal neuron densities were lowered by ≈ 45% and volumes by ≈ 37% within all dementia groups relative to controls, except for FTD densities. COX1 and COX4 mitochondrial markers were consistently reduced across dementias. Neuronal densities declined with age, especially in the sixth decade of life. Other prefrontal areas were less affected.

DISCUSSION: The mPFC shows high neuronal vulnerability in dementia, while suggesting a vascular-metabolic mechanism, with implications for targeted therapeutic strategies.

HIGHLIGHTS: Severe pyramidal neuron loss and atrophy arose in the medial prefrontal cortex. Neuronal morphometric changes correlated with cognitive status or aging effects. Metabolic changes decreased by the greatest extent in vascular-associated dementias. Metabolic neuronal markers correlated with aging and frontal vascular pathology.},
}

Humans
*Prefrontal Cortex/pathology/metabolism
*Pyramidal Cells/pathology/metabolism
Male
Female
Aged
*Alzheimer Disease/pathology/metabolism
Aged, 80 and over
*Aging/pathology
*Stroke/pathology
Middle Aged
*Dementia/pathology
Electron Transport Complex IV/metabolism

@article {pmid41677418,
year = {2026},
author = {Kolmans, AAC and Bolt, SR and Leontjevas, R and IJsselsteijn, WA and Gerritsen, DL},
title = {Measuring dementia-related stigma in the Dutch general public: Translation and validation of the dementia public stigma scale.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261419067},
doi = {10.1177/13872877261419067},
pmid = {41677418},
issn = {1875-8908},
abstract = {BackgroundPeople with Alzheimer's disease or other types of dementia may experience stigma, which can influence their quality of life. Valid measurement instruments of public dementia-related stigma are lacking.ObjectiveWe aimed to translate and validate the 16-item Dementia Public Stigma Scale (DePSS) in Dutch.MethodsA survey was conducted among a nationally representative sample of the Dutch population (n = 524). A subset (n = 145) completed the DePSS again after one month. Following validation guidelines, floor and ceiling effects, structural validity, internal consistency, and test-retest reliability were assessed. We used open-ended questions to investigate content validity. The responses provided insights into respondents' perceptions of dementia and their interactions with people with dementia.ResultsForward-backward translation required minor adaptations. No floor or ceiling effects were observed. Confirmatory factor analysis indicated an acceptable fit (CFI = 0.988, RMSEA = 0.073, SRMR = 0.065). Internal consistency (α = 0.82, ω = 0.79) and test-retest reliability (ICC = 0.82, 95%CI 0.76-0.89) were good, with no significant differences between test and retest scores (t(144) = 0.135, p = .893). Responses to open-ended questions were largely clustered under DePSS items, indicating good content validity. Additional themes were disconnection from present reality; feeling pity for people with dementia; and manifestations of negative emotions.ConclusionsThe Dutch DePSS demonstrated good psychometric properties. Together with other versions, these findings enhance the generalizability of the DePSS across diverse populations. Further validation and application of the DePSS will help deepen our understanding of dementia-related stigma and may also inform stigma reduction interventions.},
}

@article {pmid41677387,
year = {2026},
author = {Guidotti, L and Lucchesi, M and Daghini, E and Amato, R and Neri, G and Corsi, F and Marracci, S and Gargini, C and Borello, U and Cammalleri, M and Dal Monte, M and Casini, G},
title = {Morpho-Functional Characterization and miRNA Profiling of the Retina in the 5xFAD Murine Model of Alzheimer's Disease.},
journal = {Investigative ophthalmology & visual science},
volume = {67},
number = {2},
pages = {31},
doi = {10.1167/iovs.67.2.31},
pmid = {41677387},
issn = {1552-5783},
mesh = {Animals ; *Alzheimer Disease/genetics/metabolism/physiopathology/pathology ; *MicroRNAs/genetics ; Disease Models, Animal ; Electroretinography ; Mice ; Tomography, Optical Coherence ; Mice, Transgenic ; Blotting, Western ; *Retina/physiopathology/metabolism/pathology ; Enzyme-Linked Immunosorbent Assay ; Retinal Ganglion Cells/pathology/metabolism ; Immunohistochemistry ; Real-Time Polymerase Chain Reaction ; Visual Acuity/physiology ; *Gene Expression Regulation/physiology ; Gene Expression Profiling ; },
abstract = {PURPOSE: Alzheimer's disease (AD) induces changes in retinal structure/function, making the retina a suitable platform to study the molecular mechanisms of the disease. Dysregulation of some microRNAs (miRNAs) has also been found in AD pathogenesis. Here, we used the 5xFAD mouse to expand our knowledge on structural, functional, and molecular retinal alterations and to elucidate the retinal miRNA profile in this model of AD.

METHODS: The 5xFAD mice at 3, 6, or 9 months of age, were used. Retinal function was evaluated with electroretinogram (ERG) and the Prusky water maze test. Retinal structure was investigated by optical coherence tomography. Molecular analyses included immunohistochemistry, Western blot, and ELISA. Retinal miRNAs were profiled and deregulated miRNAs were validated by qRT-PCR.

RESULTS: Starting from 6 months, the 5xFAD mice showed altered ERG and visual acuity. The inner plexiform layer became thicker whereas the retinal ganglion cell (RGC) layer became thinner. In the RGC layer, the accumulation of amyloid beta was concomitant with RGC apoptosis, whereas tau protein phosphorylation was increased. Inflammatory processes were also activated and microgliosis became apparent. Five deregulated miRNAs were identified, four of which were validated. Two of these miRNAs were related to AD and involved in gene expression relevant to retinal function.

CONCLUSIONS: The present findings confirm and expand our knowledge of the retinal disease in 5xFAD mice, and highlight that neuroinflammation, oxidative stress, and microgliosis participate in AD pathogenesis. The relationship between deregulated miRNAs and AD progression may open the field to miRNA-based strategies to slow down retinal dysfunction in AD.},
}

Animals
*Alzheimer Disease/genetics/metabolism/physiopathology/pathology
*MicroRNAs/genetics
Disease Models, Animal
Electroretinography
Mice
Tomography, Optical Coherence
Mice, Transgenic
Blotting, Western
*Retina/physiopathology/metabolism/pathology
Enzyme-Linked Immunosorbent Assay
Retinal Ganglion Cells/pathology/metabolism
Immunohistochemistry
Real-Time Polymerase Chain Reaction
Visual Acuity/physiology
*Gene Expression Regulation/physiology
Gene Expression Profiling

@article {pmid41677240,
year = {2026},
author = {Dutta, B and Loo, S and Kam, A and Liu, CF and Tam, JP},
title = {Targeted Protein Degrader from Ginkgo to Mitigate Amyloid β-Induced Neurotoxicity.},
journal = {Biochemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.biochem.5c00763},
pmid = {41677240},
issn = {1520-4995},
abstract = {Protein degradation through the autophagy-lysosome process by eukaryotic cells is a major pathway to remove unwanted proteins, organelles, and invading pathogens. It is also an emerging intervention strategy to selectively eliminate inaccessible toxic amyloid proteins to prevent amyloid β (Aβ)-induced neurotoxicity. Currently, there is no natural product-derived peptide that targets amyloid proteins for degradation through the autophagy-lysosome pathway. We recently discovered a new peptide family from Ginkgo biloba nuts, which we termed β-ginkgotides. The prototype β-gB1 is 20-residue in length, cross-braced by three disulfides, and stable to proteolytic degradation. Importantly, it has an LC3-interacting region (LIR) motif, which promotes selective autophagy to degrade harmful proteins and to prevent cell death. Here, we show that β-gB1 is cell-penetrating, primarily entering cells through energy-dependent endocytosis, and protects Aβ-induced neurotoxicity using an SH-SY5Y neuronal cell-based model. Functional studies using synthetic β-gB1 revealed that it impedes Aβ accumulation and reverses the altered gene expression associated with Alzheimer's disease (AD) pathophysiology induced by Aβ. Importantly, β-gB1 maintains cellular homeostasis and enhances the clearance of Aβ aggregates through selective autophagy, thereby safeguarding neurons from Aβ toxicity. Collectively, these results support that β-ginkgotide is a first-in-class cysteine-rich peptide (CRP)-based targeted protein degrader and underscore its potential as a novel and promising neuroprotective therapeutic to manage Aβ-induced neurotoxicity in AD and other neurodegenerative disorders.},
}

@article {pmid41677117,
year = {2026},
author = {Li, Y and Cheng, Q and Tian, S and Li, X and Chen, Y and Guo, Y and Jiang, Y and Tao, Y and Niu, X and Hu, H and Liu, Y and Li, S},
title = {Oridonin Ameliorates Alzheimer's Disease-Like Pathology in Male Mice Through Inhibition of Receptor-Interacting Protein Kinase 1.},
journal = {Phytotherapy research : PTR},
volume = {},
number = {},
pages = {},
doi = {10.1002/ptr.70185},
pmid = {41677117},
issn = {1099-1573},
support = {82404605//National Natural Science Foundation of China/ ; U23A20510//National Natural Science Foundation of China/ ; U24A20806//National Natural Science Foundation of China/ ; 32300318//National Natural Science Foundation of China/ ; BX20220048//National Postdoctoral Program for Innovative Talents/ ; 2022MD723713//China Postdoctoral Science Foundation/ ; 2022NSFSC1362//Natural Science Foundation of Sichuan Province/ ; 2023ZYD0051//Natural Science Foundation of Sichuan Province/ ; 2024NSFSC1324//Natural Science Foundation of Sichuan Province/ ; },
abstract = {Oridonin (Ori) is a bioactive diterpenoid from Rabdosia rubescens that exhibits potent anti-inflammatory and neuroprotective properties. However, its potential role in Alzheimer's disease (AD), especially in modulating receptor-interacting protein kinase 1 (RIPK1)-mediated neuroinflammation and necroptosis, remains unclear. This study aimed to investigate Ori's therapeutic mechanism in AD by targeting RIPK1. We utilized cellular thermal shift assay (CETSA), drug affinity responsive target stability assay (DARTS), and bio-layer interferometry (BLI) to verify the binding of Ori to RIPK1. In vitro, inflammatory and necroptotic responses were assessed in BV2 microglial cells and HT22 neuronal cells using enzyme-linked immunosorbent assay (ELISA), reverse transcription quantitative polymerase chain reaction (RT-qPCR), Western blotting, immunofluorescence, and flow cytometry assays. In vivo, we evaluated Ori's therapeutic efficacy in 5× FAD transgenic mice, a well-established AD model, through behavioral analysis using the Morris water maze, along with histological and biochemical assessments of brain tissues. Ori demonstrated a robust interaction with RIPK1 (KD = 533 nM) and significantly increased its thermal and proteolytic stability. Treatment with Ori markedly suppressed the secretion of pro-inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor alpha (TNFα) in microglia by inhibiting the RIPK1-ERK1/2-NF-κB signaling pathway. In neurons, Ori effectively blocked the activation of the RIPK1-RIPK3-MLKL signaling cascade, prevented necrosome formation, and significantly reduced necroptotic cell death. Importantly, in the 5× FAD mouse model, Ori treatment substantially improved spatial learning and memory performance, decreased amyloid-beta (Aβ) plaque deposition, and attenuated inflammatory and necroptotic markers in both cortical and hippocampal regions. Ori as a natural small-molecule inhibitor of RIPK1, capable of concurrently mitigating neuroinflammation and necroptosis-two critical pathological processes underpinning AD. These findings strongly support Ori's potential as a disease-modifying therapeutic for AD.},
}

@article {pmid41677061,
year = {2026},
author = {Liu, J and Li, Q and Zhu, H and Li, A and Geng, B and Li, ZA and Tian, T},
title = {Suspension Culture With Uniform Shear Stress in Brain Organoids-on-a-Chip for Modelling Alzheimer's Disease.},
journal = {Advanced healthcare materials},
volume = {},
number = {},
pages = {e03966},
doi = {10.1002/adhm.202503966},
pmid = {41677061},
issn = {2192-2659},
support = {CSTB2024NSCQ-MSX0964//Fundamental Research Funds for the National Natural Science Foundation of Chongqing/ ; KJZD-K202303601//Technology Research Program of Chongqing Municipal Education Commission of China/ ; 2025ZYYB007//Chongqing Municipal Health Commission Traditional Chinese Medicine Research Project/ ; YJD201911//Chongqing University-Southeast University Medical Devices Institute graduate Student Joint Education Program/ ; xnykdxcxzx-2024-14//Basic Medicine Research Innovation Center for Cardiometabolic Diseases, Ministry of Education Open Projects Fund/ ; },
abstract = {Research on Alzheimer's disease (AD) has been hindered by the absence of customizable and physiologically relevant in vitro brain models. Although human induced pluripotent stem cell-derived brain organoids (BOs) are beginning to shift the way it is study neurodegenerative disease, BOs notoriously suffer from the limited maturation and 'batch effect'. Due to the lack of vascular systems, suspension cultures often maintained with spinning bioreactors allow for the growth of BOs with large volumes. But spinning bioreactors are limited in size and throughput, as well as in the uneven distribution of shear stress. Here, through computer simulation, suspension culture is achieved by constructing a brain-organoids-on-a-chip (BOoC), which allows adequate oxygenation and nutrient diffusion, facilitating the long-term culture and high maturity of BOs. The uniformly distributed and precisely controllable fluid shear stress in the chip, accompanied by the uniform microstructural units, provided bionic physiological clues for the homogeneous development of organoids. Then the suspension culture design physiologically mimics serum exposure, induced the elevated amyloid β aggregation and tau phosphorylation in BOs, as well as neuronal reduction and synaptic loss, which recapitulate the key pathological features of AD. This BOoC platform provides a microphysiological system for generating highly mature and homogeneous BOs and simulating the pathological process of AD in vitro.},
}

@article {pmid41677026,
year = {2026},
author = {Liu, D and Jiang, Z and Kim, H and Tukker, AM and Dalvi, A and Xie, J and Li, Y and Yuan, C and Bowman, AB and Zhang, D and Zhang, M},
title = {From correlation to causation: cell-type-specific gene regulatory networks in Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {2},
pages = {e71053},
doi = {10.1002/alz.71053},
pmid = {41677026},
issn = {1552-5279},
support = {R01AG080917//National Institute on Aging (NIA) of the National Institutes of Health (NIH)/ ; R01AG080917-02S1//National Institute on Aging (NIA) of the National Institutes of Health (NIH)/ ; K99ES036290//National Institute of Environmental Health Sciences (NIEHS) of the National Institutes of Health (NIH)/ ; R01GM131491//National Institute of General Medical Sciences (NIGMS) of the National Institutes of Health (NIH)/ ; R01GM131491-02S1//National Institute of General Medical Sciences (NIGMS) of the National Institutes of Health (NIH)/ ; P30CA062203//National Cancer Institute (NCI) of the National Institutes of Health (NIH)/ ; //The Anti-Cancer Challenge grant from the Chao Family Comprehensive Cancer Center of the University of California, Irvine/ ; },
mesh = {*Alzheimer Disease/genetics ; Humans ; *Gene Regulatory Networks/genetics ; Transcription Factors/genetics ; *Brain/metabolism ; Male ; Female ; Transcriptome/genetics ; Aged ; Gene Expression Profiling ; },
abstract = {INTRODUCTION: Alzheimer's disease (AD) involves complex regulatory disruptions across multiple brain cell types, yet the comprehensive intracellular causal mechanisms remain poorly understood.

METHODS: We present an integrative analysis framework using single-nucleus transcriptomics with matched subject-level genotype data from 272 AD patients in the Religious Orders Study and Rush Memory and Aging Project (ROSMAP) and construct causality-based, cell-type-specific gene regulatory networks (GRNs).

RESULTS: Our method identifies regulatory genes among transcription factors (TFs) and non-TFs, generating a complete and accurate causal regulatory map across brain cell types. Our analyses reveal both established and novel regulations, pathways, and cell-type-specific hub genes in AD. Beyond constructing transcriptome-wide GRNs, we quantitatively evaluate hub genes and distinguish those with regulatory versus responsive roles.

DISCUSSION: Our study provides a comprehensive map of cell-type-specific causal GRNs in AD, with a methodology applicable to other complex diseases such as cancer, enabling dynamic pathway exploration, hypothesis generation, and functional interpretation.

HIGHLIGHTS: Comprehensive causal regulatory maps across six brain cell types revealed cell-type-specific regulatory mechanisms that move beyond traditional correlation-based and TF-centric model limitations. Novel and established hub genes and functional modules were compared across cell types, providing insights into cellular functions related to AD. Hub gene roles as regulators or targets were quantitatively evaluated within cell-type GRNs. The constructed GRNs show upstream non-TF genes regulating TFs and interconnected TF regulatory modules, highlighting the complexity of AD regulatory mechanisms beyond TF-centric assumptions.},
}

*Alzheimer Disease/genetics
Humans
*Gene Regulatory Networks/genetics
Transcription Factors/genetics
*Brain/metabolism
Male
Female
Transcriptome/genetics
Aged
Gene Expression Profiling

@article {pmid41676992,
year = {2026},
author = {Wang, X and Bakulski, KM and Walker, E and Mukherjee, B and Dodge, H and Albin, RL and Paulson, HL and Park, SK},
title = {Exposure to lead and incidence of Alzheimer's disease and all-cause dementia in the United States.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {2},
pages = {e71075},
doi = {10.1002/alz.71075},
pmid = {41676992},
issn = {1552-5279},
support = {R01 AG070897/AG/NIA NIH HHS/United States ; K01 AG084821/AG/NIA NIH HHS/United States ; P30 AG072931/AG/NIA NIH HHS/United States ; P30 ES017885/ES/NIEHS NIH HHS/United States ; },
mesh = {Humans ; United States/epidemiology ; *Lead/adverse effects/blood ; Female ; Male ; *Alzheimer Disease/epidemiology ; Incidence ; *Dementia/epidemiology ; Aged ; Nutrition Surveys ; *Environmental Exposure/adverse effects ; Prospective Studies ; Risk Factors ; Middle Aged ; Patella/chemistry ; Aged, 80 and over ; },
abstract = {INTRODUCTION: Growing evidence suggests lead exposure may increase dementia risk, but evidence from human studies is limited. We investigated prospective associations between lead exposure and incident Alzheimer's disease (AD) and all-cause dementia in nationally-representative US populations.

METHODS: Baseline measured blood lead and estimated patella and tibia lead from the National Health and Nutrition Examination Survey (NHANES)-III (1988-1994, blood n = 6,217, bone n = 5,865) and continuous NHANES (1999-2016, blood n = 8,038, bone n = 4,824) were linked to Medicare and the National Death Index for incident AD and all-cause dementia, with up to 30 years of follow-up. Survey-weighted Cox regressions estimated hazard ratios (HRs) and 95% confidence intervals (CIs).

RESULTS: In continuous NHANES, estimated patella lead was associated with AD (HR = 2.96, 95% CI:1.37-6.39) and all-cause dementia (HR = 2.15, 95% CI:1.33-3.46), comparing quartile-4 vs. quartile-1. We observed weaker associations in NHANES-III. Blood lead showed no association.

DISCUSSION: These findings suggest cumulative lead as a potential dementia risk factor.

HIGHLIGHTS: We examined Medicare-linked National Health and Nutrition Examination Survey (NHANES) on lead exposure and incident Alzheimer's disease (AD) and dementia. Lead exposure was assessed by blood lead and algorithm-estimated bone lead levels. High estimated patella lead was linked to increased all-cause dementia incidence. Dementia cases drop by 18% if all patella lead levels reduce to the 25[th] percentile. Cumulative lead exposure may raise dementia risk, highlighting its potential impact.},
}

Humans
United States/epidemiology
*Lead/adverse effects/blood
Female
Male
*Alzheimer Disease/epidemiology
Incidence
*Dementia/epidemiology
Aged
Nutrition Surveys
*Environmental Exposure/adverse effects
Prospective Studies
Risk Factors
Middle Aged
Patella/chemistry
Aged, 80 and over

@article {pmid41676923,
year = {2026},
author = {Gupta, J and Le Coq, J and Lietha, D and Izard, T},
title = {Structural insights into SHIP2 reveal its membrane regulatory mechanisms.},
journal = {Protein science : a publication of the Protein Society},
volume = {35},
number = {3},
pages = {e70479},
doi = {10.1002/pro.70479},
pmid = {41676923},
issn = {1469-896X},
mesh = {*Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases/chemistry/metabolism/genetics ; Humans ; Cryoelectron Microscopy ; Models, Molecular ; Phosphatidylinositol Phosphates/metabolism/chemistry ; *Cell Membrane/metabolism/chemistry ; },
abstract = {Src homology 2 domain-containing inositol-5 phosphatase 2 (SHIP2) is a key player in regulating the signaling by phosphoinositides and is involved in the modulation of cellular functions such as proliferation, adhesion, migration, and survival. SHIP2 works by dephosphorylating PIP3 to modulate the PI3K/AKT pathway, which plays a role in different standard and pathological conditions. SHIP2 appears to play a dual part in cancer, serving as a tumor suppressor in some instances and a tumor promoter in others. It is also involved in neurodegenerative diseases, including Alzheimer's disease. To understand the molecular mechanism of SHIP2, we solved its cryogenic electron microscopy (cryoEM) structure. Unexpectedly, the SHIP2 pleckstrin homology-related domain was found to associate with its C2 and phosphatase domains. This arrangement enables the catalytic domain to interact with the substrate, especially at higher concentrations of PIP3 or PI(3,4)P2. Furthermore, SHIP2 forms oligomers on the membrane. Our findings suggest a mechanism by which SHIP2 activity may be regulated through interactions with membrane lipids. This provides structural insights into how domain organization and membrane association regulate its function in various physiological contexts.},
}

*Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases/chemistry/metabolism/genetics
Humans
Cryoelectron Microscopy
Models, Molecular
Phosphatidylinositol Phosphates/metabolism/chemistry
*Cell Membrane/metabolism/chemistry

@article {pmid41676814,
year = {2026},
author = {Kim, SA and Oda, F and Maeda, M and Murata, F and Fukuda, H},
title = {Medical and Long-Term Care Costs of Alzheimer's Disease in Japan According to Clinical Dementia Rating Scores: The LIFE Study.},
journal = {JMA journal},
volume = {9},
number = {1},
pages = {381-384},
pmid = {41676814},
issn = {2433-3298},
}

@article {pmid41676736,
year = {2026},
author = {Doser, RL and LaRocca, TJ},
title = {Mitochondrial double-stranded RNA accumulation in brain aging and Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.02.02.703345},
pmid = {41676736},
issn = {2692-8205},
abstract = {Mitochondria and inflammation are tightly linked in aging and Alzheimer's disease (AD), and recent evidence implicates mitochondrial double-stranded RNA (mt-dsRNA) as a potential trigger of inflammation. We examined mt-dsRNA accumulation and dsRNA signaling in brain aging and AD using human brain tissue and complementary in vitro transcriptomic datasets, quantifying mitochondrial transcripts and dsRNA editing. We found that mt-dsRNA accumulated after midlife and coincided with reduced expression of mitochondrial RNA processing and translation machinery, along with increased expression of dsRNA antiviral signaling proteins, consistent with cytoplasmic mt-dsRNA-driven inflammation. In AD brains, mt-dsRNA accumulation was further increased and correlated with cognitive impairment, neuropathological severity, and AD risk genotypes. Genes associated with these measures reflected altered ubiquitin-dependent regulation of antiviral signaling, potentially indicating altered sensitivity to mt-dsRNA. Together, these findings highlight mitochondrial RNA homeostasis as an unrecognized contributor to age- and AD-related neurodegeneration by identifying mt-dsRNA as a potential driver of chronic inflammation.},
}

@article {pmid41676727,
year = {2026},
author = {Tong, M and Mehfooz, F and Zhang, S and Wang, Y and Fang, S and Saykin, AJ and Wang, X and Yan, J and , },
title = {Learning a Continuous Progression Trajectory of Amyloid in Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.02.03.703568},
pmid = {41676727},
issn = {2692-8205},
abstract = {BACKGROUND: Understanding of Alzheimer progression is critical for timely diagnosis and treatment evaluation, but traditional discrete diagnostic groups often lack sensitivity to subtle early-stage changes.

METHODS: We developed SLOPE, an unsupervised dimensionality reduction method that models the amyloid progression in AD on a continuous scale while preserving the temporal order of longitudinal follow-up visits. Applied to longitudinal amyloid PET data, SLOPE generated a two-dimensional trajectory capturing global amyloid accumulation across the AD continuum.

RESULTS: SLOPE-derived staging scores better preserved temporal progression across diagnostic groups and longitudinal follow-up visits and can be generalized to held-out subjects. The learned trajectory revealed biologically consistent amyloid spreading patterns and greater sensitivity to early progression than global amyloid SUVR.

DISCUSSION: SLOPE provides a continuous staging of amyloid pathology that complements global amyloid measures by capturing early localized progression. These properties highlight its potential in disease modeling and monitoring, particularly in early and preclinical stages of AD.},
}

@article {pmid41676716,
year = {2026},
author = {Rentsendorj, A and Vit, JP and Hutton, A and Koronyo, Y and Shahin, S and Robinson, E and Barron, E and Rodriguez, A and Gaire, BP and Jallow, O and Sheyn, J and Davis, MR and Ljubimov, AV and Graham, SL and Gupta, VK and Mirzaei, M and Hawes, D and Black, KL and Schneider, LS and Sadun, AA and Meyer, JG and Fuchs, DT and Koronyo-Hamaoui, M},
title = {Synergistic retinal UCHL1 dysregulation and synaptic vulnerability reflect Alzheimer's disease severity.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.02.03.703406},
pmid = {41676716},
issn = {2692-8205},
abstract = {Synaptic failure predicts cognitive decline in Alzheimer's disease (AD), yet its impact and molecular drivers in the human retina remain unclear. Leveraging the retina as an accessible central nervous system (CNS) proxy, we integrated spatially resolved histopathology of retinal cross-sections with ultrastructural, proteomic, and biochemical profiling across independent postmortem cohorts spanning normal cognition, mild cognitive impairment due to AD (MCI), and AD dementia. We uncover early, progressive degeneration of excitatory glutamatergic synapses, evidenced by losses of presynaptic vesicular glutamate transporter 1 (VGLUT1) and synaptophysin, and postsynaptic density protein 95 (PSD95) and N-methyl-D-aspartate receptor subunit 2A (NMDAR2A), accompanied by disruption of synaptic ultrastructure. Retinal synaptic loss tightly associates with local accumulation of amyloid-β 42 (Aβ42) and immature tau species, heightened oxidative stress, and upregulation of the Aβ-binding death receptor p75 neurotrophin receptor (p75NTR). Notably, the synapse-enriched deubiquitinase ubiquitin C-terminal hydrolase L1 (UCHL1) is profoundly dysregulated, correlates with synaptic integrity and cognition, and emerges as the strongest retinal predictor of Braak stage and cognitive status in multivariable machine-learning models. Together, these findings position retinal Aβ/p75NTR-mediated UCHL1 imbalance as a proteostasis-synapse mechanistic hub and candidate biomarker reflecting AD severity.},
}

@article {pmid41676677,
year = {2026},
author = {Adler, D and Pinheiro-Rosa, N and Millet, A and Gajic, ZZ and Cheng, E and Gamallo-Lana, B and Morizawa, Y and Klann, E and Gan, WB and Mar, AC and Ledo, JH and Moura Silva, H and Lafaille, JJ},
title = {Functional border-associated macrophages limit Alzheimer's Disease progression.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.31.703045},
pmid = {41676677},
issn = {2692-8205},
abstract = {Brain-resident macrophages are known to play numerous roles in the progression of Alzheimer's Disease (AD). However, the relative contribution of microglia and border-associated macrophages (BAM) to AD pathogenesis has been difficult to disentangle. We recently identified Maf , a newly described AD GWAS gene, as essential for BAM, but not microglial, survival. By crossing BAM depleted mice with the 5xFAD AD model, we found stark evidence of cerebral amyloid angiopathy (CAA), increased overall β-amyloid burden, accelerated markers of neurodegeneration, and early memory deficits. In the healthy brain, BAM take up more β-amyloid per cell than microglia. However, as disease progresses, both in human AD patient samples and model AD mice, BAM number is reduced, and the remaining BAMs display impaired endocytic capacity, and show signs of metabolic exhaustion at an earlier age than microglia. Thus, strategies to preserve or restore BAM function represents a novel therapeutic avenue for AD and CAA.},
}

@article {pmid41676658,
year = {2026},
author = {Zhang, X and Yu, K and Shrestha, HK and Zhou, Y and Yang, J and Wang, Z and Ren, X and Chen, PC and Sun, H and Liu, D and Jiao, Y and Yarbro, JM and Wang, J and Wu, Z and Harper, K and He, L and Yuan, ZF and Wang, X and High, AA and Yu, G and Yu, J and Wen, Z and Peng, J},
title = {Cell type-resolved proteomics reveals intra- and intercellular signaling in Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.02.02.703357},
pmid = {41676658},
issn = {2692-8205},
abstract = {UNLABELLED: Alzheimer's disease (AD) arises from pathological interactions among diverse brain cell types, but cell-specific proteomic changes remain underexplored. Here, we present deep proteomic profiling of sorted or proximity-labeled brain cells from AD mouse models (5xFAD and App [NL-G-F]) at multiple ages, quantifying 13,411 proteins in microglia (three subtypes), astrocytes, oligodendrocyte precursor cells, and neurons. We identified 3,028 differentially abundant proteins across these cell types, the majority of which were not detected in bulk proteomic datasets, and constructed cell type-specific networks to define functional modules and hub proteins. Comparison with transcriptomic data revealed that ∼30% of proteomic changes are RNA-independent. Further analyses uncovered cross-cell type signaling proteins conserved in human AD brains, such as pleiotrophin (Ptn), which is transcriptionally enriched in astrocytes but accumulates in microglia. Importantly, recombinant PTN directly activates induced microglia-like (iMG) human cells. Thus, these findings provide a comprehensive cell type-resolved proteomic atlas of AD models, highlighting novel intra- and intercellular signaling events.

HIGHLIGHTS: A high-resolution cell type-resolved proteomic atlas of Alzheimer's disease mouse models∼3,000 cell type-specific protein alterations identified beyond bulk tissue analysesProteomic profiling of microglial subtypes reveals subtype-specific changes in Alzheimer's diseaseAstrocyte-microglia signaling is highlighted and validated through PTN-mediated interactions.},
}

@article {pmid41676572,
year = {2026},
author = {Chu, M and Wang, J and Yarbro, JM and Chen, PC and Shrestha, HK and Sun, H and Niu, M and Wang, Z and Harvey, S and Wu, Z and Fu, Y and Yuan, ZF and Tan, H and High, AA and Zhang, A and Wang, X and Lu, M and Sheppard, H and Serrano, GE and Beach, TG and Yu, G and Jiao, Y and Peng, J},
title = {Single Plaque Proteomics Reveals the Composition and Dynamics of the Amyloid Microenvironment in Alzheimer's Disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.02.02.703320},
pmid = {41676572},
issn = {2692-8205},
abstract = {Alzheimer's disease (AD) is characterized by amyloid plaques that form complex microenvironments in the brain. However, the molecular composition of these plaques and their temporal regulation are not well defined. Here, we developed a sensitive workflow for quantitative proteomic profiling of single plaques using refined laser capture microdissection and data-independent acquisition mass spectrometry (LCM-DIA-MS). From >200 plaques and control regions in AD mouse models (5xFAD and APP-KI) and human brains, we quantified >7,000 proteins, revealing stage-dependent, cell-type-related remodeling of the amyloid proteome (amyloidome). Temporal profiling uncovered early immune and lysosomal activation followed by engagement of RNA processing and synaptic pathways. Cross-model and cross-species analyses determined a conserved amyloidome including APOE, MDK, PTN, and HTRA1, validated by co-localization in imaging analysis. Network analysis highlighted modules in lipid transport, vesicle organization, and autophagy. These findings establish amyloid plaques as conserved, dynamic multicellular hubs that link amyloid accumulation to downstream cellular events.},
}

@article {pmid41676571,
year = {2026},
author = {Zhu, B and Ghosh, A and Wang, Z and Liao, Z and Appiah, M and Li, J and Zhang, M and Tullio, FD and Kurowski, A and Fullard, J and Wagenblast, E and Walsh, MJ and Goate, A and Roussos, P and Cheung, KL and Yang, N and Ma, S},
title = {Early microglial priming in Alzheimer's disease revealed by ME-seq.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.30.702946},
pmid = {41676571},
issn = {2692-8205},
abstract = {Epigenetic modifications, particularly DNA methylation, change dynamically with aging and are implicated in Alzheimer's Disease (AD), yet how methylation interfaces with transcriptional and chromatin regulation at single-cell resolution remains poorly understood. Progress has been limited by a lack of scalable technologies capable of jointly profiling these regulatory layers. Here, we present ME-seq, a highly scalable technologies capable of simultaneously profiling DNA methylation, gene expression, and chromatin accessibility, while achieving a 100-fold reduction in cost. We generated over 400,000 single-nucleus trimodal profiles from the aging and AD mouse brain across ages, producing the first such atlas of neurodegeneration. We found AD progression triggers pronounced, disease-specific shifts in cellular composition, characterized by accelerated epigenetic aging and the expansion of disease-associated microglia (DAM). Integrative analyses, including aging clocks, revealed that DNA methylation acts as an early priming layer preceding transcriptional activation with IRF1 identified as a methylation-sensitive transcription factor serving as a gatekeeper for DAM activation. Our results establish ME-seq as a transformative tool for large-scale epigenomic dissection, revealing DNA methylation as a primary coordinator of cell-state transitions in the aging brain.},
}

@article {pmid41676557,
year = {2026},
author = {Alipour Pijani, B and Rifat, JM and Bozdag, S and , },
title = {MultiGEOmics: Graph-Based Integration of Multi-Omics via Biological Information Flows.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.29.702593},
pmid = {41676557},
issn = {2692-8205},
abstract = {Multi-omics datasets capture complementary aspects of biological systems and are central to modern machine learning applications in biology and medicine. Existing graph-based integration methods typically construct separate graphs for each omics type and focus primarily on intra-omic relationships. As a result, they often overlook cross-omics regulatory signals-bidirectional interactions across omics layers-that are critical for modeling complex cellular processes. A second major challenge is missing or incomplete omics data; many current approaches degrade substantially in performance or exclude patients lacking one or more omics modalities. To address these limitations, we introduce MultiGEOmics , an intermediate-level graph integration framework that explicitly incorporates regulatory signals across omics types during graph representation learning and models biologically inspired omics-specific and cross-omics dependencies. MultiGEOmics learns robust cross-omics embeddings that remain reliable even when some modalities are partially missing. We evaluated MultiGEOmics across eleven datasets spanning cancer and Alzheimer's disease, under zero, moderate, and high missing-rate scenarios. MultiGEOmics consistently maintains strong predictive performance across all missing-data conditions while offering interpretability by identifying the most influential omics types and features for each prediction task. The source code and the documentation of MultiGEOmics are available at https://github.com/bozdaglab/MultiGEOmics .},
}

@article {pmid41676546,
year = {2026},
author = {West, NR and Lindberg, MF and Dairou, J and MacGregor, S and Puthireddy, S and Meijer, L and Bhattacharyya, A},
title = {Leucettinib-21 decreases dosage effects of DYRK1A in human trisomy 21 iPSC-derived neural cells.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.02.05.704014},
pmid = {41676546},
issn = {2692-8205},
abstract = {UNLABELLED: Dysregulated expression and activity of DYRK1A, dual specificity tyrosine phosphorylation regulated kinase 1A, is a feature of several neurodevelopmental and neurodegenerative diseases, including Down syndrome, DYRK1A syndrome, autism spectrum disorders, Alzheimer's disease, and Parkinson's disease. Thus, manipulating DYRK1A activity in the brain has emerged as a potential therapeutic target for neurological disorders. Several DYRK1A inhibitors have shown promise for improving cognition in rodent models of Down syndrome and Alzheimer's disease, for example, but the ability to affect DYRK1A levels or activity in relevant human cells has not been established. We filled this gap by testing the effects of a new DYRK1A inhibitor on trisomy 21 induced pluripotent stem cell derived neural progenitor cells and neurons, where DYRK1A expression and activity are increased. Our results demonstrate that Leucettinib-21, a potent and selective low-molecular weight pharmacological inhibitor of DYRK1A, decreases DYRK1A activity in human trisomy 21 neural progenitor cells and cortical neurons. We show for the first time that Leucettinib-21 reduces DYRK1A activity in a relevant human disease model, supporting future human trials.

SUMMARY STATEMENT: We show for the first time that Leucettinib-21, a pharmacological inhibitor of DYRK1A, decreases DYRK1A activity in a human iPSC-derived neural cell culture model of Down syndrome.},
}

@article {pmid41676529,
year = {2026},
author = {Kelley, AR and Sackinger, E and Frischman, M and Thomas, N and Kim, KJ and Scuderi, G and Labut, EM and MacMurchy, D and Ikea-Mario, T and Rauenhorst, J and Neitzel, E and Vu, T and Liko, L and Hoff, A and Hoff, A and Wallace, O and Harry, WKE and Hagen, B and Lee, K and Bihun, AZ and Abou-Seada, IA and Butler, JA and Nigussie, F and Ebrahimi, A and Lee, PY and Marney, LC and Maier, CS and Magnusson, KR and Hagen, TM},
title = {Appearance of Amyloid-β Early in Life Initiates Neuronal Hyper-excitability, Mitochondrial Decay, and Loss of Dendritic Complexity in the Hippocampal CA1 Region of 5xFAD Mice.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.02.04.703883},
pmid = {41676529},
issn = {2692-8205},
abstract = {Alzheimer's disease (AD) is characterized by progressive cognitive decline and stereotyped neuropathology, yet the earliest cellular events that precede overt plaque burden and measurable behavioral impairment remain incompletely defined. Here, we tested the hypothesis that synaptic hyperexcitability and subcellular metabolic dysfunction emerge early in the 5xFAD mouse model and contribute to region-specific neuronal vulnerability before substantial amyloid plaque deposition. Using the 5xFAD heterozygous mouse, we first established the onset of transgene expression and the timing of plaque accumulation. Robust transgene expression was detected by postnatal day 15 and significant plaque accumulation by 4 months of age. Ex vivo electrophysiology revealed an early hyperexcitable phenotype at 1 month of age, including both increased AMPA receptor-mediated transmission and N-methyl-D-aspartate receptor signaling associated with the GluN2B subunit. Given the tight coupling between glutamatergic hyperactivity, calcium dysregulation, and mitochondrial health, we assessed mitochondrial structure and function at this pre-plaque stage. Mitochondrial abnormalities consistent with impaired bioenergetic homeostasis were evident. Morphological analyses further demonstrated that these early changes were associated with altered dendritic architecture in the CA1 and dentate gyrus regions, revealing hippocampal subregional susceptibility. Finally, spatial transcriptomics supported this anatomical selectivity by identifying regionally enriched molecular signatures consistent with differential vulnerability. The CA1 region exhibited more reductions in mitochondria-related transcripts than CA3 or dentate gyrus and these reductions were specifically associated with CA1 pyramidal cell neurons. Together, these findings define a pre-plaque window in 5xFAD mice marked by GluN2B-linked glutamatergic hyperexcitability, early mitochondrial disruption, and selective dendritic and transcriptional vulnerability across hippocampal subregions. This integrated timeline suggests that synaptic and metabolic dysfunctions arise before substantial plaque deposition and may represent tractable early targets for intervention aimed at delaying or preventing downstream neurodegeneration in AD.},
}

@article {pmid41676506,
year = {2026},
author = {Guo, Y and Foiret, J and Ajenjo, J and Malek, R and Zhang, N and Seo, JW and Wang, J and Jan, BL and Raie, MN and Tumbale, SK and Beinat, C and Ferrara, KW},
title = {Ultrasound-Mediated Gene Therapy in Alzheimer's Disease Validated through In Vivo PET Imaging.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.02.02.703398},
pmid = {41676506},
issn = {2692-8205},
abstract = {Efficient, spatially selective delivery of adeno-associated virus (AAV) therapeutics to deep brain structures remains a major challenge to gene therapy for Alzheimer's disease (AD), owing to limited transport across the blood-brain barrier (BBB) and poor penetration to target neurons. Here, we establish an integrated, noninvasive imaging and therapy platform that combines microbubble-enhanced focused ultrasound (MB-FUS) with positron emission tomography/computed tomography (PET/CT) to transiently modulate the BBB, enhance region-specific AAV delivery following systemic dosing, and longitudinally track transduction in vivo. Optimized MB-FUS achieved targeted hippocampal delivery of systemically administered AAV9 in healthy mice, resulting in a 10-fold enhancement of neuronal transduction as compared to non-FUS controls. Importantly, longitudinal PET reporter gene imaging in the 5xFAD AD model demonstrated robust brain AAV transduction that remained stable for at least seven months. Finally, to assess therapeutic impact, we used brain-derived neurotrophic factor (BDNF) as a test cargo. MB-FUS-facilitated delivery elevated BDNF expression in targeted regions and produced short-term improvements in synaptic signaling in 5xFAD mice. Collectively, these results highlight MB-FUS as a next-generation delivery platform to overcome barriers to AAV therapeutic delivery in Alzheimer's disease and position longitudinal PET assessment as a critical, translatable tool for monitoring and optimizing gene therapy.},
}

@article {pmid41676499,
year = {2026},
author = {Wang, Y and Chang, Y and Zhang, J and Cai, M and Yan, J and Zhao, H and , },
title = {Geometric Fragility in Alzheimer's Disease: Probing the Loss of Hippocampal Hierarchical Abstraction via Contrastive Point Cloud Modeling.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.31.702997},
pmid = {41676499},
issn = {2692-8205},
abstract = {While human spatial cognition relies on hierarchical abstraction to integrate local features, Alzheimer's disease (AD) pathology is often reduced to local volumetric atrophy. We propose geometric fragility as a distinct failure of global topological integrity within the hippocampus rather than a mere accumulation of local errors. Using a texture-invariant point cloud framework, we contrasted local feature aggregation with global hierarchical attention as computational probes for structural perception. The global paradigm demonstrated enhanced diagnostic sensitivity and exhibited cognitive resilience under simulated neuronal sparsity by maintaining structural recognition where local models suffered pattern collapse. Global modeling effectively unfolded the pathological manifold, revealing a linear trajectory of geometric degradation consistently correlated with clinical cognitive decline. These findings indicate that AD progression may be characterized as a systemic topological dissolution and suggest that effective biomarkers should prioritize hierarchical shape abstraction to accurately map the continuous transition from healthy cognition to dementia.},
}

@article {pmid41676490,
year = {2026},
author = {Itkyal, VS and LaGrow, TJ and Jensen, KM and Iraji, A and Calhoun, V},
title = {Investigating White Matter Functional Network Connectivity Across the Alzheimers Disease Spectrum Using Resting-State fMRI.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.02.04.703913},
pmid = {41676490},
issn = {2692-8205},
abstract = {White matter (WM) has traditionally been considered structurally important but functionally inert in fMRI research. However, growing evidence indicates that WM exhibits meaningful BOLD fluctuations and participates in functional connectivity. Here, we investigate alterations in WM functional network connectivity (FNC) across the Alzheimers disease (AD) spectrum using resting-state fMRI data from the Alzheimers Disease Neuroimaging Initiative (ADNI 415 cognitively normal (CN), 283 mild cognitive impairment (MCI), 91 AD). We applied a guided independent component analysis (ICA) approach based on a combined multiscale template including 202 intrinsic connectivity networks (ICNs; 97 WM, 105 gray matter (GM)) to estimate subject-specific timecourses and compute static FNC (sFNC). Group differences in WMWM, GMGM, and WMGM connectivity (ADCN, ADMCI, MCICN) were assessed using two-sample t-tests with covariates for age, sex, and motion, with false discovery rate correction. Results showed robust alterations in WMWM and WMGM connectivity in AD, particularly involving WM subcortical, frontal, sensorimotor, and occipitotemporal networks. Several WMGM interactions with cerebellar and hippocampal GM networks were also disrupted, including reduced GMcerebellar:WMfrontal coupling and increased GMhippocampal to WMfrontal connectivity. Notably, MCI already showed WMGM dysconnectivity relative to CN, suggesting that functional disruption of WM circuits emerges prior to overt dementia. These findings provide converging evidence that WM functional connectivity is both measurable and selectively altered across the AD continuum. Our findings support WM sFNC as a complementary candidate biomarker to GM-based measures for staging and monitoring AD. This is, to our knowledge, the first large-scale ADNI study to jointly model WM and GM intrinsic connectivity networks and quantify WMGM dysconnectivity across CN, MCI, and AD.},
}

@article {pmid41676487,
year = {2026},
author = {Tagmazian, AA and Schwarz, C and Lange, C and Pitkänen, E and Vuoksimaa, E and , },
title = {petVAE: A Data-Driven Model for Identifying Amyloid PET Subgroups Across the Alzheimer's Disease Continuum.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.02.02.703218},
pmid = {41676487},
issn = {2692-8205},
abstract = {Amyloid-β (Aβ) PET imaging is a core biomarker and is considered sufficient for the biological diagnosis of Alzheimer's disease (AD). However, it is typically reduced to a binary Aβ™/Aβ+ classification. In this study, we aimed to identify subgroups along the continuum of Aβ accumulation including subgroups within Aβ- and Aβ+. We used a total of 3,110 of Aβ PET scans from Alzheimer's Disease Neuroimaging Initiative (ADNI) and Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) datasets to develop petVAE , a 2D variational autoencoder model. The model accurately reconstructed Aβ PET scans without prior labeling or pre-selection based on scanner type or region of interest. Latent representations of scans extracted from the petVAE (11,648 latent features per scan) were used to visualize, analyze, and cluster the AD continuum. We identified the latent features most representative of the continuum, and clustering of PET scans using these features produced four clusters. Post-hoc characterization revealed that two clusters (Aβ-, Aβ-+) were predominantly Aβ negative and two (Aβ+, Aβ++) were predominantly Aβ positive. All clusters differed significantly in standardized uptake value ratio (p < 1.64×10 [-8]) and cerebrospinal fluid (CSF) Aβ (p < 0.02), demonstrating petVAE's ability to assign scans along the Aβ continuum. The clusters at the extremes of the continuum (Aβ-, Aβ++) resembled to the conventional Aβ negative and Aβ positive groups and differed significantly in cognitive performance, Apolipoprotein E (APOE) ε4 prevalence, and Aβ, tau and phosphorylated tau CSF biomarkers (p < 3×10 [-6]). The two intermediate clusters (Aβ-+, Aβ+) showed significantly higher odds of carrying at least one APOE ε4 allele compared with the Aβ-cluster (p < 0.026). Participants in Aβ+ or Aβ++ clusters exhibited a significantly faster rate of progression to AD compared to Aβ-group (Hazard ratio = 2.42 and 9.43 for groups Aβ+ and Aβ++, respectively, p < 1.17×10 [-7]). Thus, petVAE was capable of reconstructing PET scans while also extracting latent features that effectively represented the AD continuum and defined biologically meaningful clusters. By capturing subtle Aβ-related changes in brain PET scans, petVAE -based classification enables the detection of preclinical AD stages and offers a new data-driven framework for studying disease progression.},
}

@article {pmid41676474,
year = {2026},
author = {Rossitto, LM and Foo, J and Di Silvestri, JM and Lehmann, L and Brunelli, M and Nie, Y and Muñoz-Mayorga, D and Xiao, Q and Dai-Liu, AY and Jati, S and Rossi, M and Daneman, R and Kelly, JW and Newman, JC and Myers, SA and Chen, X},
title = {Ketone body β-hydroxybutyrate restores neuronal Tau proteostasis via ketolysis-independent mechanism.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.30.702936},
pmid = {41676474},
issn = {2692-8205},
abstract = {Metabolic interventions that induce ketosis, including ketogenic diets, caloric restriction, intermittent fasting, and exercise, show promise in the treatment of Alzheimer's disease (AD) and related tauopathies. β-hydroxybutyrate (βHB), the primary ketone body produced during ketosis, reproduces key features of these metabolic interventions, but the molecular mechanism underlying its neuroprotective properties is not fully understood. Here, we demonstrate that a βHB precursor diet is sufficient to ameliorate Tau pathophysiology in a tauopathy mouse model. Furthermore, across in vitro , ex vivo , and in vivo models, we find that βHB enhances neuronal Tau proteostasis and reduces Tau aggregation and secretion. Importantly, these effects are independent of βHB's oxidation for ATP production, as its ketolysis-resistant enantiomer reproduces these benefits, indicating that ketolysis is dispensable for these effects. Overall, these data position βHB as a novel therapeutic avenue for AD and tauopathy and elucidate a novel mechanism of action of metabolic interventions in neurodegenerative disease.},
}

@article {pmid41676443,
year = {2025},
author = {Su, FY and Lin, CM and Liu, C and Yao, Y and Wang, H and Zhang, C and Yi, W and Xu, N},
title = {Electroacupuncture reshapes the microbial co-occurrence networks related to the behavioral and psychological symptoms of dementia in Alzheimer's disease.},
journal = {iMetaOmics},
volume = {2},
number = {4},
pages = {e70035},
pmid = {41676443},
issn = {2996-9514},
abstract = {Microbial keystone species and gut microbiota composition are highly variable during the pathological development of the behavioral and psychological symptoms of dementia (BPSD) in Alzheimer's disease (AD). Age stratification reveals stage-specific gut microbial signatures in AD-related BPSD. This study highlights the efficacy of electroacupuncture in regard to altering the intestinal microbial landscape in AD-related BPSD and provides novel insights into the application of phased targeted electroacupuncture interventions in the future.},
}

@article {pmid41676384,
year = {2026},
author = {Ghayourvahdat, A and Azimizonuzi, H and Ahmed, M},
title = {Physical exercise as a non-pharmacological strategy to enhance glymphatic function.},
journal = {IBRO neuroscience reports},
volume = {20},
number = {},
pages = {206-217},
pmid = {41676384},
issn = {2667-2421},
abstract = {The glymphatic system plays a critical role in clearing metabolic waste and neurotoxic proteins from the brain, and its dysfunction is implicated in neurodegenerative diseases such as Alzheimer's disease (AD). Emerging evidence indicates that physical exercise enhances glymphatic function through multiple mechanisms, including increased cerebrospinal fluid (CSF) influx, improved perivascular clearance, astrocytic aquaporin-4 (AQP4) polarization, and modulation of vascular and sleep-dependent processes. Preclinical studies demonstrated that voluntary wheel running and aerobic exercise reduce amyloid-β (Aβ) accumulation, attenuate neuroinflammation, and improve cognitive performance in both aging and AD mouse models, with benefits being highly dependent on AQP4 expression and the timing of intervention. Translational evidence in humans showed that structured aerobic and multicomponent exercise increases glymphatic and meningeal lymphatic activity, enhances vascular dynamics, reduces systemic inflammation, and improves sleep quality, leading to measurable cognitive gains. Despite these promising findings, methodological challenges-such as limitations of non-invasive imaging, difficulty establishing causality, and reliance on short-term interventions-highlight the need for longitudinal, multimodal studies that integrate imaging, cardiovascular, sleep, and cognitive metrics. Collectively, these data suggest that exercise represents a potent non-pharmacological strategy to augment glymphatic clearance, preserve neural homeostasis, and reduce the risk of cognitive decline. This review will summarize evidence on exercise-induced glymphatic enhancement, highlight mechanisms, and identify research gaps for future studies on brain health.},
}

@article {pmid41676359,
year = {2026},
author = {Li, Q and Zhang, D and Quinn, É and Walsh, PK and Hynes, DS},
title = {Online interventions for dementia caregiver burden and self-efficacy: A systematic review and meta-analysis.},
journal = {International journal of nursing studies advances},
volume = {10},
number = {},
pages = {100490},
pmid = {41676359},
issn = {2666-142X},
abstract = {BACKGROUND AND OBJECTIVES: There is growing interest in online psychosocial interventions to address burden and self-efficacy among informal caregivers of people with dementia. However, their effectiveness remains unclear, especially given ongoing debates and limited evidence of online delivery modes. We aimed to synthesize evidence on these online psychosocial interventions, highlight the current state of research, and identify priorities for future studies.

METHODS: A systematic review with meta-analyses was conducted. We included randomized controlled trials comparing online psychosocial interventions to usual care or waitlist control for burden and self-efficacy. Six electronic databases were searched for studies published over the last two decades. Two reviewers evaluated eligibility, extracted data, and assessed risk of bias and quality of evidence. Patient and Public Involvement, as a means to contextualise the results in the lived experience of caregivers, was employed to aid interpretation of the findings. The review protocol was registered in PROSPERO (CRD42023392232).

RESULTS: Nineteen articles involving 2,264 participants were included. Of these, 15 reported caregiver burden, seven reported self-efficacy, and three studies reported both outcomes. Most interventions were multi-component online psychosocial programs delivered via web-based platforms, mobile applications, or videoconferencing tools. They incorporated asynchronous, synchronous, or blended delivery modes and were delivered either individually or in groups. Core components of the psychosocial intervention included information provision and education, caregiving tasks support, and caregiver self-care. Meta-analysis of 13 studies showed no statistically-significant post-intervention effect on reducing burden (Standardized Mean Difference [SMD]: -0.06, 95 % Confidence Interval [CI]: -0.25, 0.12, p =0.50; I² = 47 %), yet analysis of three studies indicated an effect on improving self-efficacy (SMD: 0.20, 95 % CI: 0.03, 0.37, p =0.02; I² = 0 %). The evidence grade for both outcomes was low due to risk of bias, inconsistency, and imprecision of the results.

CONCLUSION: We suggest that online psychosocial interventions have little to no short-term effect on caregiver burden but may enhance self-efficacy, though the evidence grade remains low. Online psychosocial interventions featured diversity in their design, content, and delivery characteristics. From the findings, we have identified key areas for development of future research within this field, with a particular focus on addressing methodological limitations and ensuring rigorous design. Sustained support incorporating interactive and real-time elements, tailored approaches, and the integration of lived experience throughout the research process should be considered to improve both the effectiveness and relevance of these interventions.},
}

@article {pmid41676339,
year = {2025},
author = {Li, Y and Ni, Z and Xia, XY and Cheng, N and Bo, Y and He, J and He, Y and Meng, XY and Wang, X and Xu, X},
title = {Integrating causal human genetics and In vivo transcriptomics to uncover a shared lipid-centric architecture in metabolic and neurocognitive disease.},
journal = {Frontiers in molecular biosciences},
volume = {12},
number = {},
pages = {1712198},
pmid = {41676339},
issn = {2296-889X},
abstract = {BACKGROUND: Metabolic disorders and neurocognitive diseases frequently co-occur, yet the specific mechanisms driving this comorbidity remain elusive. While epidemiological associations are well-documented, the causal links between these conditions are complex and incompletely understood, necessitating a systems-level investigation into their shared biological architecture.

METHODS: This study integrates large-scale human genetics with experimental in vivo transcriptomics and computational chemistry to elucidate these shared pathways. Specifically, an AD-like murine model was used to experimentally prioritize a core network of 13 dysregulated genes within a pathologically relevant context.

RESULTS: Network-informed Mendelian randomization identified bidirectional causalities, including a 14% elevated dementia risk from type 2 diabetes and protective effects of obesity against parental Alzheimer's disease (AD). The study identified a signature encompassing key lipid metabolism hubs APOE, CLU, and LDLR. This signature serves as a critical biological filter, anchoring human genetic associations by providing direct evidence of their dysregulation in a neurodegenerative environment. Subsequent chemical enrichment and molecular docking analyses indicated that these experimentally-prioritized targets are engaged by both therapeutic agents (e.g., valproic acid) and environmental toxins (e.g., benzo[a]pyrene).

CONCLUSION: This multi-modal investigation provides a robust framework that converges on a high-confidence, 13-gene signature of lipid dysregulation as a central mechanistic interface, offering a powerful set of prioritized targets for future functional validation and therapeutic development at the metabolic-neurocognitive nexus.},
}

@article {pmid41676156,
year = {2026},
author = {Weng, Y and He, T and Li, M and Zhou, Q and Xie, J and Wei, L and Wang, X and Wang, JZ and Zhong, M and Li, S},
title = {Microglial histone H3K18 crotonylation promotes STAT1 expression and induces cognitive deficit in Alzheimer disease.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1744375},
pmid = {41676156},
issn = {1664-3224},
mesh = {Animals ; *Alzheimer Disease/metabolism/genetics ; *Histones/metabolism ; Mice ; *Microglia/metabolism ; *STAT1 Transcription Factor/metabolism/genetics ; *Cognitive Dysfunction/metabolism/etiology ; Disease Models, Animal ; Hippocampus/metabolism ; Male ; Protein Processing, Post-Translational ; Mice, Transgenic ; Amyloid beta-Peptides ; Humans ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, yet the epigenetic mechanisms underlying its pathogenesis remain incompletely understood. Histone crotonylation, a novel post-translational modification, has been implicated in neuroinflammation. However, its role in AD-related cognitive impairment has not been elucidated.

METHODS: Histone crotonylation was examined in 5xFAD and Aβ42-injected mice. Crotonic acid was administered intracerebroventricular (ICV) to elevate hippocampal histone crotonylation in wild-type mice. Cognitive function was assessed using behavioral tests. Synaptic integrity was evaluated via western blotting and Golgi staining. Microglial activation and co-localization of H3K18cr were determined by immunofluorescence. Transcriptomic analysis identified differentially expressed genes and enriched pathways. The role of signal transducer and activator of transcription 1 (STAT1) was validated in BV2 microglial cells using the STAT1 inhibitor fludarabine.

RESULTS: Hippocampal pan-histone H3 crotonylation (H3Kcr) and H3K18cr were significantly upregulated in both 5xFAD and Aβ42-injected mice compared to controls. ICV injection of crotonic acid markedly elevated hippocampal H3Kcr and H3K18cr levels and induced significant cognitive deficits, shown by impaired novel object recognition and fear conditioning performance. Crotonic acid treatment resulted in synaptic dysfunction, including reduced synaptic markers (SYN1, SYT, GluA2, GluN2B) and decreased CA1 dendritic spine density. Crotonic acid also induced microgliosis with elevated Iba1 expression. H3K18cr was specifically upregulated in microglia, with no significant changes observed in neurons or astrocytes. Transcriptomic analysis identified 478 differentially expressed genes enriched predominantly in immune-related pathways, with STAT1 highlighted as a key upstream transcription factor. In BV2 cells, crotonic acid significantly increased total and phosphorylated STAT1 (Tyr701) levels via a JAK1-independent mechanism. Treatment with fludarabine effectively suppressed STAT1 expression and attenuated the production of pro-inflammatory cytokines, including TNF-α, IL-6, and IL-1β.

CONCLUSION: This study provides the first evidence that elevated microglial H3K18cr contributes to AD-related cognitive impairment by promoting STAT1 expression and subsequent neuroinflammation. These findings identify microglial histone crotonylation as a novel epigenetic mechanism in AD pathogenesis and suggest that targeting the H3K18cr-STAT1 axis may represent a potential therapeutic strategy for AD.},
}

Animals
*Alzheimer Disease/metabolism/genetics
*Histones/metabolism
Mice
*Microglia/metabolism
*STAT1 Transcription Factor/metabolism/genetics
*Cognitive Dysfunction/metabolism/etiology
Disease Models, Animal
Hippocampus/metabolism
Male
Protein Processing, Post-Translational
Mice, Transgenic
Amyloid beta-Peptides
Humans

@article {pmid41676140,
year = {2026},
author = {Parvez, F and Rahul, },
title = {Immune crosstalk in Alzheimer's and Parkinson's disease: insights from Drosophila models into the brain-peripheral immune axis.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1725046},
pmid = {41676140},
issn = {1664-3224},
mesh = {Animals ; *Parkinson Disease/immunology/metabolism ; Disease Models, Animal ; *Alzheimer Disease/immunology/metabolism ; Drosophila melanogaster/immunology ; *Brain/immunology/metabolism ; Humans ; *Neuroimmunomodulation ; Signal Transduction ; Immunity, Innate ; },
abstract = {BACKGROUND: Neurodegenerative diseases (NDs) such Alzheimer's disease (AD) and Parkinson's disease (PD) are increasingly understood as systemic disorders driven by chronic neuroimmune dysregulation. The bidirectional communication between the central nervous system (CNS) and peripheral immune compartments is termed neuroimmune crosstalk, plays a pivotal role in disease initiation, progression, and therapeutic resistance. However, mammalian models often obscure mechanistic resolution due to immune redundancy and adaptive complexity.

OBJECTIVE: This review highlights Drosophila melanogaster as a genetically tractable and evolutionarily conserved model for dissecting innate immune signaling and inter-organ communication in neurodegeneration. We emphasize its utility in resolving causality, identifying conserved cytokine pathways, and modeling systemic inflammation relevant to Parkinson's and Alzheimer's disease.

KEY FINDINGS: Drosophila possesses a tripartite immune system that is brain-resident glia, circulating hemocytes, and the fat body that coordinates responses via Toll, Immune deficiency (Imd), JAK/STAT, and MAPK pathways. Glial cells engage in Draper-mediated phagocytosis and NF-κB/Relish signaling, while peripheral immune components modulate CNS integrity through cytokines such as Unpaired 3 (Upd3) and Eiger. Furthermore, hyperactivation of the Imd pathway's NF-κB homolog, Relish, within the CNS drives neurodegeneration via the neurotoxic effects of Antimicrobial Peptides (AMPs). These mechanisms mirror mammalian neuroimmune dynamics and reveal conserved therapeutic targets.

CONCLUSION: Drosophila melanogaster offers unparalleled mechanistic clarity in modeling neuroimmune interactions. Its simplified immune architecture, precision genetics, and compatibility with multi-omics and AI-assisted phenotyping position it as a strategic complement to vertebrate models. Insights from Drosophila are redefining neurodegeneration as a multi-organ process and accelerating the development of inflammation-targeted therapies for ND.},
}

Animals
*Parkinson Disease/immunology/metabolism
Disease Models, Animal
*Alzheimer Disease/immunology/metabolism
Drosophila melanogaster/immunology
*Brain/immunology/metabolism
Humans
*Neuroimmunomodulation
Signal Transduction
Immunity, Innate

@article {pmid41676055,
year = {2025},
author = {Kjeldsen, PL and Madsen, LS and Parbo, P and Ismail, R and Aanerud, JFA and Kaasing, M and Damholdt, MF and Eskildsen, SF and Østergaard, L and Brooks, DJ},
title = {Microglial activation is raised in preclinical Alzheimer's disease and associated with covert memory impairment.},
journal = {Frontiers in dementia},
volume = {4},
number = {},
pages = {1745571},
pmid = {41676055},
issn = {2813-3919},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a continuum between normal health and dementia with a long preclinical phase, during which AD pathologies start to emerge, but where there are not yet any overt symptoms. The hallmark pathologies of AD are extracellular β-amyloid (Aβ) plaques and intra-neuronal neurofibrillary tangles (NFTs). Aβ deposition is present at the preclinical stage. Additionally, raised microglial activation is a key factor in AD. However, its exact timing and role is still unclear. This exploratory study investigated the prevalence of microglial activation and its association with Aβ deposition and memory impairment in preclinical AD.

METHODS: A total of 19 preclinical AD subjects with no cognitive complaints but abnormal Aβ deposition present on [11]C-Pittsburgh Compound B ([11]C-PiB PET) and 10 healthy subjects with no cognitive complains or abnormal Aβ deposition on [11]C-PiB PET underwent [11]C-PK11195 PET ([11]C-PK). Additionally, the preclinical AD subjects underwent formal cognitive testing with sensitive memory tests, including the Rey Auditory Verbal Learning Test, the Rey Complex Figure Test, and the Face-Name Associative Memory Exam.

RESULTS: Microglial activation was raised in occipital and parietal cortices in preclinical AD subjects compared to healthy controls (p < 0.01). In the preclinical subjects there were significant positive correlations between Aβ load and microglial activation in parietal areas (p < 0.01). Finally, in the preclinical subjects, there were significant negative correlations between microglial activation and memory test performance in selected cortical areas (p < 0.01).

CONCLUSION: Microglial activation was significantly raised in preclinical AD cases with no cognitive complaints and associated with impaired memory test performance. This suggests that microglial activation is present before overt clinical symptoms emerge and may be detrimental to cognition even at this early stage.},
}

@article {pmid41675964,
year = {2025},
author = {Zhang, P and Gao, T and Guo, J and Duan, J},
title = {Action functional as an early warning indicator in the space of probability measures via Schrödinger bridge.},
journal = {Quantitative biology (Beijing, China)},
volume = {13},
number = {3},
pages = {e86},
pmid = {41675964},
issn = {2095-4697},
abstract = {Critical transitions and tipping phenomena between two meta-stable states in stochastic dynamical systems are a scientific issue. In this work, we expand the methodology of identifying the most probable transition pathway between two meta-stable states with Onsager-Machlup action functional, to investigate the evolutionary transition dynamics between two meta-stable invariant sets with Schrödinger bridge. In contrast to existing methodologies such as statistical analysis, bifurcation theory, information theory, statistical physics, topology, and graph theory for early warning indicators, we introduce a novel framework on Early Warning Signals (EWS) within the realm of probability measures that align with the entropy production rate. To validate our framework, we apply it to the Morris-Lecar model and investigate the transition dynamics between a meta-stable state and a stable invariant set (the limit cycle or homoclinic orbit) under various conditions. Additionally, we analyze real Alzheimer's data from the Alzheimer's Disease Neuroimaging Initiative database to explore EWS indicating the transition from healthy to pre-AD states. This framework not only expands the transition pathway to encompass measures between two specified densities on invariant sets, but also demonstrates the potential of our early warning indicators for complex diseases.},
}

@article {pmid41675961,
year = {2025},
author = {Pal, S and Melnik, R},
title = {Complex non-Markovian dynamics and the dual role of astrocytes in Alzheimer's disease development and propagation.},
journal = {Quantitative biology (Beijing, China)},
volume = {13},
number = {3},
pages = {e70001},
pmid = {41675961},
issn = {2095-4697},
abstract = {Alzheimer's disease (AD) is a common neurodegenerative disorder nowadays. Amyloid-beta (Aβ) and tau proteins are among the main contributors to the AD progression. In AD, Aβ proteins clump together to form plaques and disrupt cell functions. On the other hand, the abnormal chemical change in the brain helps to build sticky tau tangles that block the neuron's transport system. Astrocytes generally maintain a healthy balance in the brain by clearing the Aβ plaques (toxic Aβ). However, overactivated astrocytes release chemokines and cytokines in the presence of Aβ and react to pro-inflammatory cytokines, further increasing the production of Aβ. In this study, we construct a mathematical model that can capture astrocytes' dual behavior. Furthermore, we reveal that the disease progression depends on the current time instance and the disease's earlier status, called the "memory effect," making non-Markovian processes an appropriate approach. We consider a fractional order network mathematical model to capture the influence of such memory effects on AD progression. We have integrated brain connectome data into the model and studied the memory effect, the dual role of astrocytes, and the brain's neuronal damage. Based on the pathology, primary, secondary, and mixed tauopathies parameters are considered in the model. Due to the mixed tauopathy, different brain nodes or regions in the brain connectome accumulate different toxic concentrations of Aβ and tau proteins. Finally, we explain how the memory effect can slow down the propagation of such toxic proteins in the brain, decreasing the rate of neuronal damage.},
}

@article {pmid41675886,
year = {2026},
author = {Suleman, MU and Mursaleen, M and Khalil, U and Khan, SA and Saboor, A and Hussnain, MA and Zahir, M and Khan, UA and Rehman, DU and Tabassum, SN},
title = {Integration of AI diagnostic tools into clinical practice for Alzheimer's disease: barriers and solutions.},
journal = {Annals of medicine and surgery (2012)},
volume = {88},
number = {2},
pages = {1488-1494},
pmid = {41675886},
issn = {2049-0801},
abstract = {Alzheimer's disease is a progressive neurodegenerative disorder that affects millions of people worldwide and remains difficult to diagnose in its earliest stages. This narrative review examines developments in artificial intelligence diagnostic tools designed to support clinicians in the detection of Alzheimer's disease. It evaluates systems that analyze brain imaging scans, genetic information, and cognitive assessments, as well as emerging approaches that monitor speech patterns and data from wearable devices. The review identifies six challenges to clinical adoption: limited and unrepresentative data sets; limited transparency of algorithmic decisions; disruption of established clinical workflows; unclear regulatory frameworks; high implementation costs and infrastructure demands; and the potential to widen health disparities. To address these issues, we propose the creation of large collaborative data repositories, the advancement of transparent model interpretation methods, comprehensive clinician education programs, the establishment of clear regulatory pathways, and strategic investment in scalable infrastructure. By confronting these technical, human, and system-level challenges through coordinated efforts, artificial intelligence diagnostic tools can be incorporated into Alzheimer's disease care to enhance early diagnosis and improve patient outcomes across diverse healthcare settings.},
}

@article {pmid41675875,
year = {2026},
author = {Chen, Q and Zhu, Y and Wang, L and Zhao, M},
title = {Study of the pharmacokinetics of Ginkgolide J in rats by ultra-high-performance liquid chromatography tandem mass spectrometry.},
journal = {Annals of medicine and surgery (2012)},
volume = {88},
number = {2},
pages = {1352-1358},
pmid = {41675875},
issn = {2049-0801},
abstract = {BACKGROUND AND OBJECTIVE: Ginkgolide J is an active ingredient extracted from Ginkgo biloba leaves and has potential therapeutic effects on Alzheimer's disease and rheumatoid arthritis. However, its pharmacokinetic behavior remains unclear. As the efficacy of an active ingredient in natural products is significantly affected by its pharmacokinetic characteristics, the pharmacokinetics of Ginkgolide J needs to be elucidated.

MATERIALS AND METHODS: A rapid and sensitive quantitative method for Ginkgolide J using ultra-high-performance liquid chromatography-tandem mass spectrometry was established and validated. This method was then applied to pharmacokinetic studies in rats after oral and intravenous administration of a Ginkgolide J solution.

RESULTS: The linear range was 2-1000 ng/mL, with a correlation coefficient higher than 0.999. The specificity, precision, accuracy, stability, matrix effect, and recovery rate of this method met the analytical requirements. The pharmacokinetic results showed that the time to maximum plasma concentration (tmax) and half-life (t1/2) after oral administration of Ginkgolide J (10 mg/kg) were 1.50 h and 3.25 h, and t1/2 after intravenous administration (2 mg/kg) was 1.96 h, respectively. The absolute bioavailability of Ginkgolide J was 8.67%. Compared with intravenous medication, the oral bioavailability of Ginkgolide J is very low; therefore, the development of Ginkgolide J as an intravenous injection is more suitable for clinical applications.

CONCLUSION: In this study, we established a method for analyzing Ginkgolide J based on ultra-high-performance liquid chromatography tandem mass spectrometry and measured its pharmacokinetic behavior in rats. The results showed that the oral bioavailability of Ginkgolide J is very low, and intravenous administration may be necessary for drug development.},
}

@article {pmid41675863,
year = {2026},
author = {Ayalew, BD and Alemayehu, ZG and Bonger, TD and Sime, BL and Zewdie, YA and Tewodros, YT and Bano, S},
title = {FDA approval of the Lumipulse G PTau217/β-amyloid 1-42 plasma ratio test: a new era in accessible Alzheimer's diagnosis.},
journal = {Annals of medicine and surgery (2012)},
volume = {88},
number = {2},
pages = {1187-1189},
pmid = {41675863},
issn = {2049-0801},
}

@article {pmid41675725,
year = {2026},
author = {Patel, T and Henna, F and Sharif, I and Javed, I and Mustafa, F and Sharif, H and Nasir, F and Javaid, M and Usman, SF and Hanani, C and Anand, N},
title = {A narrative review on the therapeutic potential of stem cells in neurodegenerative diseases: advances, insights, and challenges.},
journal = {Annals of medicine and surgery (2012)},
volume = {88},
number = {2},
pages = {1441-1453},
pmid = {41675725},
issn = {2049-0801},
abstract = {BACKGROUND: Neurodegenerative diseases (NDs) such as Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD) are set apart by progressive neuronal loss and concomitant functional decline. Traditional therapies are equipped with only symptomatic relief, devoid of neurorestorative properties. Stem-cell-based therapies have the potential to revolutionize neurological care by replenishing lost cells, mitigating inflammation, and fostering a neuroprotective environment.

OBJECTIVES: This narrative review aims to appraise the treatment potential of various stem cell types in managing NDs, highlighting their functional pathways, delivery methods, and current experimental validation.

METHODS: A comprehensive literature search was carried out based on data retrieved from PubMed, The Cochrane Library, and ClinicalTrials.gov. Thirty-one studies that fulfill PICO criteria and only English-language publications are incorporated in this review. No part of the study design, data collection, analysis, or interpretation was conducted using artificial intelligence.

RESULTS: Stem cells, including embryonic stem cells, mesenchymal stem cells (MSCs), induced pluripotent stem cells, and neural stem cells, possess distinctive regenerative properties. MSC-derived exosomes can traverse the blood-brain barrier and improve nerve cell longevity. Administration routes such as intravenous, intranasal, and direct brain transplantation are being studied. Neurodegenerative conditions such as PD, AD, HD, and ALS have been widely studied for therapeutic benefits.

CONCLUSION: Regardless of their potential, stem cell therapies raise health risks, including neoplastic growth and immunological incompatibility, alongside bioethical issues. Developments in genetic modification, nanotechnology, and preconditioning strategies are being analyzed to optimize outcomes. Long-term research, harmonization of protocols, and extended patient follow-up are essential for the safe and effective development of medical applications.},
}

@article {pmid41675591,
year = {2026},
author = {Malliou, G and Reus, LM and Pijnenburg, YAL and van der Flier, WM and de Wit, NM and Chornyi, S and Kooij, G and de Vries, HE and Teunissen, CE and Visser, PJ and Ophoff, RA and Tijms, BM},
title = {Distinct CSF lipidomic profiles are associated with five proteomic subtypes in patients with Alzheimer's disease.},
journal = {Molecular neurodegeneration advances},
volume = {2},
number = {1},
pages = {11},
pmid = {41675591},
issn = {3059-4944},
abstract = {BACKGROUND: Alzheimer's disease (AD) is molecularly heterogeneous. In our previous cerebrospinal fluid (CSF) proteomic study in AD, we identified and validated five distinct molecular subtypes characterized by neuronal hyperplasticity (subtype 1), innate immune activation (subtype 2), RNA dysregulation (subtype 3), choroid plexus dysfunction (subtype 4) and blood-brain barrier impairment (subtype 5). These subtypes also differed in the CSF levels of proteins involved in lipid metabolism, suggesting that lipid dysregulation in AD might be subtype specific.

METHODS: We performed untargeted lipidomics on CSF samples from 601 individuals in the Amsterdam Dementia Cohort who were previously included in our proteomic study (n = 416 AD, 185 controls). Using the CSH-QTOF platform for complex lipids, 3,532 lipids were detected in CSF, 270 of which could be mapped to 13 different lipid classes. Lipid levels were compared between each AD subtype and controls using linear regression models adjusted for age and sex (R v4.2.1). Lipids with significantly different levels (p < 0.05) were included for pathway enrichment analysis with MetaboAnalyst6.0.

RESULTS: We observed alterations in the levels of 1,893 lipids, with the majority associated with a single AD subtype. Subtype 3 (RNA dysregulation) exhibited the most pronounced alterations, with altered CSF levels of 669 lipids, including triglycerides and fatty acids, which were reduced compared to controls. Subtype 4 (choroid plexus dysfunction) and subtype 5 (blood-brain barrier dysfunction) both had alterations in the same set of 150 lipids, but with changes occurring in opposite directions (i.e., decreased in subtype 4, and increased in subtype 5). These lipids were associated with sphingolipid metabolism and lipid transport. Subtype 1 (neuronal hyperplasticity) and subtype 2 (innate immune activation) had less pronounced differences compared to the other subtypes. Subtype 1 had increased levels of several phospholipids, indicating neuronal membrane remodeling, and subtype 2 decreased arachidonic acid levels, a precursor of immunoregulatory oxylipins.

CONCLUSION: Our findings reveal subtype-specific lipid metabolism alterations in AD. Currently, five lipid-targeting drugs are in phase 1 and 2 trials. Our results suggest that treatment efficacy may vary by subtype. Understanding these molecular differences can inform trial design and analysis, advancing the development of tailored therapies for AD.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s44477-026-00018-z.},
}

@article {pmid41675590,
year = {2026},
author = {Ackley, C and Liau, Z and Arya, S and Antee, T and Cheang, E and Knudsen, GM and Lane-Donovan, C and Sampognaro, PJ and Kao, AW},
title = {Lysosomal protease-mediated APP degradation is pH-dependent, mutation-sensitive, and facilitates tau proteolysis.},
journal = {Molecular neurodegeneration advances},
volume = {2},
number = {1},
pages = {10},
pmid = {41675590},
issn = {3059-4944},
abstract = {BACKGROUND: The accumulation and aggregation of amyloid beta (A β)-a peptide fragment derived from the proteolytic processing of amyloid precursor protein (APP)-is a central pathological feature of Alzheimer's disease (AD) and a current target for disease-modifying therapies. Mutations in APP can also drive early-onset AD. While the roles of α -, β -, and γ -secretases and their respective cleavage sites in APP processing are well characterized, much less is understood about the routine degradation of APP within sub-cellular compartments like the lysosome.

METHODS: We applied Multiplexed Substrate Profiling by Mass Spectrometry (MSP-MS) to map cleavage sites within APP that may be targeted by lysosomal proteases, also known as cathepsins. We then employed cell-based and in vitro assays to examine the degradation of both wild-type and mutant APP by these enzymes.

RESULTS: Our findings confirm that APP is enriched in the endo-lysosomal compartment, where it is processed by many cathepsins. Our experiments reveal that cleavages at several mapped APP sites are sensitive to both changes in pH and the presence of pathogenic variants E693G and E693Q. Additionally, we discovered that the large soluble domain of APP (sAPP) enhances tau cleavage by a specific cathepsin, CTSG, in vitro.

CONCLUSIONS: Collectively, these results underscore the importance of lysosomal processing of APP, identify a link between APP and tau, and suggest new avenues for exploring AD pathogenesis. They also highlight potential therapeutic targets related to the lysosomal function of APP and its impact on neurodegenerative diseases.},
}

@article {pmid41675430,
year = {2026},
author = {Wright, LM and De Marco, M and Ferguson, CE},
title = {The effect of Alzheimer's biomarker positivity on neuropsychological networks.},
journal = {Brain communications},
volume = {8},
number = {1},
pages = {fcag015},
pmid = {41675430},
issn = {2632-1297},
abstract = {Although network neuropsychology is a promising approach to the study of clinical profiles, the link between Alzheimer's disease (AD) biomarkers and neuropsychological networks is still undetermined. We hypothesized that network differences would exist between biomarker-positive and biomarker-negative participants, and that these would be driven by network nodes corresponding to performance on tests of episodic memory, as this is the cognitive domain most distinctively affected by AD since the earliest clinical stages. In this case-control study, we investigated sub-cohorts of individuals who had been (i) enrolled in the National Alzheimer's Coordinating Center initiative and (ii) tested with Version 3 of the Uniform Data Set neuropsychological battery (i.e. consisting of 11 tests). These included 1263 'β-amyloid positive' (A+), 1594 'β-amyloid negative' (A-), 442 'β-amyloid and hyperphosphorylated tau positive' (A + T+) and 734 'β-amyloid and hyperphosphorylated tau negative' (A-T-) participants. We first calculated neuropsychological residuals by regressing out age, years of education, sex, Clinical Dementia Rating scores and timepoint distance between neuropsychological and biomarker assessment. Secondly, we used rank-based correlations to define conditional associations across all pairs of test scores (i.e. the nodes of the network). Thirdly, we imposed a penalty (i.e. via the Least Absolute Shrinkage and Selection Operator method) to control for network sparsity. We then tested for differences in global network metrics and node centrality between A+ and A- and between A+T+ and A-T- participants using permutation-based inferential models. Differences were found between biomarker-positive and biomarker-negative sub-cohorts in global network metrics but, contrarily to our hypothesis, no differences were found in relation to episodic memory nodes. A significant node difference, however, was instead found in relation to category fluency (i.e. a test of semantic memory), with increased centrality observed among A+ participants. A similar, yet non-significant trend was also observed between A+T+ and A-T- participants. Network neuropsychology can complement and expand the study of cognitive performance carried out via 'traditional' univariate approaches. While univariate analyses reveal episodic memory decline in people with AD, this is not accompanied by any abnormalities at a neuropsychological network level. Our findings, however, highlight the importance of semantic memory alterations in A+ individuals. The wide set of neural and cognitive resources that sustain semantic memory may play a supportive role in the presence of neuropathology.},
}

@article {pmid41675307,
year = {2025},
author = {Morris, T and Brown, C and Zhao, X and Nichols, L and Martindale-Adams, J and Bowland, S and Zhou, W},
title = {Transforming dementia caregiver support with AI-powered social robotics.},
journal = {Frontiers in robotics and AI},
volume = {12},
number = {},
pages = {1704313},
pmid = {41675307},
issn = {2296-9144},
abstract = {INTRODUCTION: Informal dementia caregivers face significant emotional and physical burdens, yet evidence-based interventions like REACH are often limited by high labor costs and scalability constraints.

METHODS: We design a Robot-based Information and Support to Enhance Alzheimer's Caregiver Health (RISE) system, which uses novel social robotics and generative AI to deliver automated and personalized caregiver training and stress management. RISE uses retrieval-augmented generative AI (RAG-AI) grounded in the verified REACH Caregiver Notebook to ensure content safety and minimize hallucinations. It employs the social robot Pepper to deliver interactive presentations, Q&A sessions, review quizzes, and stress reduction activities. A technical evaluation and a two-phase user evaluation was conducted.

RESULTS: We found that the RISE's RAG-AI backend achieved 87% correctness and 92% relevancy when compared to ground truth. User feedback indicated strong acceptance, with Likert-scale usability scores ranging from 3.6 to 4.6 out of 5 across all components.

DISCUSSION: These results suggest that combining verifiable AI architectures with embodied social robotics offers a feasible, scalable solution for enhancing caregiver support and wellbeing. Future work could include a larger scale user study involving real informal dementia caregivers.},
}

@article {pmid41675131,
year = {2026},
author = {Andrade-Guerrero, J and León-Arcia, K and Aparicio-Trejo, OE and Cuevas-López, B and Arias-Carrión, O and Díaz-Miranda, SY and Soto-Rojas, LO},
title = {Physical exercise mitigates motor and muscular deficits in the 3xTg-AD model of Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1730578},
pmid = {41675131},
issn = {1663-4365},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is the most common neurodegenerative disease worldwide, characterized by progressive cognitive decline and, in advanced stages, marked motor impairments. These motor deficits are associated with muscle atrophy, mitochondrial dysfunction, and amyloid-β (Aβ) pathology affecting both motor brain areas and peripheral tissues, ultimately contributing to disability, fall risk, and reduced quality of life. Although physical exercise has been shown to confer cognitive and functional benefits in AD, to date, no studies have directly examined the relationship between motor performance and the underlying pathological mechanisms. This study introduces a novel approach by simultaneously addressing muscle pathology and mitochondrial alterations associated with motor decline.

METHODS: Twelve-month-old male triple-transgenic (3xTg-AD) and non-transgenic (Non-Tg) mice were assigned to sedentary or exercise groups (n = 16 each group). The exercise protocol combined voluntary wheel running and forced treadmill training, 5 days/week for 4 months. Motor performance was evaluated using open-field, gait analysis, grip strength, and beam walking tests. Post-intervention, histological analyses evaluated Aβ deposition and mitochondrial morphology, biochemical assays assessed mitochondrial function, and ELISA estimated Aβ levels in the brain and muscle.

RESULTS: Physical exercise improved locomotion, balance, and strength in advanced stages of the disease, with modest benefits for memory. Histology showed reduced muscle atrophy and cortical amyloid, but not hippocampal. ELISA detected lower relative levels of Aβ only in the brain. Exercise restored reduced muscle Complex I activity, increased brain Complex IV and ATPase in both tissues, and pronounced changes in mitochondrial morphology in muscle.

CONCLUSION: This study provides the first evidence that physical exercise improves motor function and attenuates muscle and brain pathology in advanced stages of 3xTg-AD, supporting its potential as a complementary therapeutic strategy with translational relevance to humans.},
}

@article {pmid41675130,
year = {2026},
author = {Liu, H and Jiang, Y and Chen, J and Pan, W and Ju, P and Li, L and Zhang, L and Cao, Y and Zhu, Y},
title = {Feasibility randomized controlled trial of a home-based support program for family caregivers of people with Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1744279},
pmid = {41675130},
issn = {1663-4365},
abstract = {OBJECTIVE: This study aimed to develop and preliminarily evaluate the feasibility of a home-based care program for family caregivers of individuals with Alzheimer's disease (AD).

METHODS: We developed a home-based intervention for AD caregivers through systematic literature review and two-round Delphi consensus (18 experts; authority coefficients 0.88-0.91). This feasibility randomized controlled trial enrolled 61 primary caregivers and assigned them to either an experimental group (n=31) receiving a structured, evidence-based, 3-month home-care protocol, or a control group (n=30) receiving conventional nursing guidance.

RESULTS: The Delphi process achieved strong expert consensus. Post-intervention, caregivers in the intervention group demonstrated significant improvements in AD knowledge scores, anxiety reduction, and psychological domain QOL-AD scores compared to baseline (P < 0.05). While total QOL-AD scores increased in the intervention group, between-group differences were not statistically significant.

CONCLUSION: The home-based care program proved feasible and effective in enhancing AD caregiver knowledge and mental health outcomes. These promising findings support the need for larger-scale efficacy trials to further validate clinical utility.},
}

@article {pmid41675129,
year = {2026},
author = {Wang, X and Tang, Y and Zhang, Q and Xiang, B and Zeng, S and Zhang, Q and Gu, M and Zou, L},
title = {An integrated CSF-serum biomarker model for predicting clinical progression in Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1728675},
pmid = {41675129},
issn = {1663-4365},
abstract = {BACKGROUND: The early and accurate identification of Alzheimer's disease (AD) remains a significant clinical challenge. Integrating novel peripheral blood-based biomarkers with established cerebrospinal fluid (CSF) measures may offer a promising strategy to enhance diagnostic accuracy and risk stratification.

METHODS: This study enrolled 91 participants who underwent CSF and serum testing. The cohort was randomly divided into a training set (n = 63) and an internal testing set (n = 28). External validation was performed using matched data (n = 30) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (total n = 639). Data collected included demographics, Mini-Mental State Examination (MMSE) total scores, the Functional Activities Questionnaire (FAQ) total scores, CSF phosphorylated tau (pTau181) and amyloid-β (Aβ42) levels, and serum indices such as the albumin-to-globulin (A/G) ratio and platelet-to-lymphocyte ratio (PLR). Predictor selection was performed via univariate and multivariate logistic regression, and a nomogram was developed from the final model. Model performance was evaluated using the area under the receiver operating characteristic curve (AUC), calibration curves with mean absolute error (MAE), and decision curve analysis (DCA).

RESULTS: The final predictive model incorporated CSF pTau181, A/G ratio, and PLR (using a cut-off ≥113.22). It demonstrated robust discrimination, achieving an AUC of 0.92 in the training set, 0.86 in the testing set, and 0.83 upon external validation. Calibration was excellent (MAE = 0.039). In the testing set, sensitivity was 0.83 and specificity was 0.86. A higher A/G ratio was associated with a reduced risk of AD progression, whereas a higher PLR was associated with an increased risk.

CONCLUSION: The combined CSF-peripheral blood biomarker model demonstrates robust discrimination and calibration for predicting AD progression. By linking central tau pathology with peripheral nutritional and inflammatory status, it may aid clinical risk stratification and guide management strategies focused on nutrition and inflammation. Further large-scale, prospective validation is warranted.},
}

@article {pmid41675007,
year = {2026},
author = {Yang, M and Zou, JQ and Yang, W},
title = {The preliminary study on the effect of PSEN1 on the proliferation and invasion of breast cancer cells.},
journal = {Translational breast cancer research : a journal focusing on translational research in breast cancer},
volume = {7},
number = {},
pages = {6},
pmid = {41675007},
issn = {2218-6778},
abstract = {BACKGROUND: Breast cancer is the most common form of cancer among women, and PSEN1 dysfunction is a primary contributor to the pathogenesis of Alzheimer's disease. However, the involvement of PSEN1 in breast cancer remains unclear. This study was conducted to explore the function and related mechanisms of PSEN1 in breast cancer cells.

METHODS: The correlation between two genes was determined utilizing the R2 platform, and the association between gene expression and prognosis was analyzed employing the Kaplan-Meier plotter. The expression of PSEN1 in breast cancer was assessed by in immunofluorescence. The Transwell assay was employed to detect the migration and invasion capabilities of cells. Colony formation and EdU staining were employed to evaluate the effects of PSEN1 on breast cancer cell proliferation.

RESULTS: We observed a positive correlation between the expression of PSEN1 and the prognosis of breast cancer patients. After manipulated the expression of PSEN1 in breast cancer cell lines Sum159 and BT549, we found that PSEN1 could inhibit cell proliferation and growth in breast cancer through colony formation assays and EdU staining. Meanwhile, we revealed that interference with the cell cycle by PSEN1 was associated with cyclin-dependent kinases (CDKs) and cyclin-dependent kinase inhibitors (CKIs) in breast cancer samples. Furthermore, we observed that an increase in PSEN1 expression inhibited the invasive capabilities of breast cancer cells, while a decrease in PSEN1 expression enhanced invasion in both Sum159 and BT549 cell lines. Lastly, we discovered a negative correlation between PSEN1 and epithelial-to-mesenchymal transition (EMT) transcription factors as well as markers in breast cancer patients.

CONCLUSIONS: Our study demonstrates that PSEN1 inhibits the invasion and proliferation of breast cancer cells, suggesting that PSEN1 could potentially serve as a prognostic biomarker and a novel therapeutic target for patients with breast cancer.},
}

@article {pmid41674830,
year = {2026},
author = {Li, Y and Liu, R and Zhang, Y and Lai, M and Davydzenka, V and Moffitt, C and England, N and Barbera, G and Chen, R and Lin, DT},
title = {Graph Theory Identifies Autistic Patterns in the Prefrontal Circuit of a Mouse Model of Autism.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-8725198/v1},
pmid = {41674830},
issn = {2693-5015},
abstract = {As a well-developed branch of mathematics, graph theory provides unique tools to quantifiably assess various properties of complex networks. Applied to brain circuits, network-level analyses can illustrate disruptions to brain organization that yield both mechanistic and diagnostic insights. Previously, graph theory has been used with functional magnetic resonance imaging datasets to quantify connections among different brain regions, readily capturing the macroscopic-scaled differences in brain networks between healthy and Alzheimer's subjects. Here, we applied graph theory on the microscopic scale, using miniscope-based calcium imaging from the freely behaving wild type (WT) and Shank3 [fx] mice (a mouse model of autism), and compared functional connections among individual neurons in the prefrontal microcircuits during social behavior. We demonstrated that Shank3 [fx] mice displayed reduced neural activity, less-integrated network, and fewer network changes in the prefrontal microcircuits between the presence and absence of social targets. Furthermore, we employed machine learning to test whether graph-theoretic metrics extracted from the prefrontal microcircuits could be predictive of genotype and genotype-associated social behavior difference between Shank3 [fx] and WT mice. Our results indicate a strong link between altered prefrontal microcircuits and social behavior deficits in an autism mouse model, highlighting prefrontal microcircuitry as a potential diagnostic and therapeutic target for autism.},
}

@article {pmid41674829,
year = {2026},
author = {Bu, G and Ning, Z and Lam, JYL and Li, Z and Martens, Y and Doss, SV and Lageman, SB and Vassilaki, M and Petersen, RC and Liu, CC and Heckman, M and Tijms, B and Kanekiyo, T},
title = {Cerebrospinal fluid proteomic signatures reveal APOE genotype-dependent lipid and immune profiles in cognitively unimpaired elderly.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-8605807/v1},
pmid = {41674829},
issn = {2693-5015},
abstract = {Cerebrospinal fluid (CSF) proteomics offers insights into molecular changes in aging and Alzheimer's disease (AD). Key AD biomarkers, in particular amyloid-β (Aβ) and tau, in CSF are strongly associated with APOE genotype, the strongest genetic risk determinant of AD. To investigate how APOE genotype influences CSF proteome across AD pathology and age, we analyzed 362 neurology-related proteins and established AD biomarkers in CSF from 145 cognitively unimpaired participants in the Mayo Clinic Study of Aging. Importantly, our cohort is uniquely balanced across APOE genotypes, with similar representation of APOE2 carriers, APOE3/3 genotype, and APOE4 carriers. We identified several proteins, including lipid metabolism-related Lp-PLA2 and immune-related ITGAM, with strong APOE genotype-specific association. Notably, meta-analysis confirmed that ITGAM levels were consistently higher in APOE4 compared to APOE2 carriers across multiple cohorts and proteomic platforms. In addition, with increasing amyloid deposition, APOE4 carriers exhibited stronger immune responses, reflected by elevated ITGAM, TNF-α receptors, and IL-6, whereas APOE2 carriers showed attenuated responses. We further observed sex-specific effects among APOE2 carriers, characterized by distinct patterns in amyloid and CXCL11 levels. These findings suggest distinct mechanisms underlying APOE2's protective and APOE4's detrimental effects in brain aging and AD, paving for personalized diagnostics and interventions.},
}

@article {pmid41674784,
year = {2025},
author = {Yashooa, RK and Nabi, AQ and Smail, SW and Azeez, SS and Nooh, WA and Mustafa, SA and Al-Farha, AA and Capitanio, N and Shekha, MS},
title = {CRISPR-Cas technologies in neurodegenerative disorders: mechanistic insights, therapeutic potential, and translational challenges.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1737468},
pmid = {41674784},
issn = {1664-2295},
abstract = {CRISPR-Cas genome-editing technologies have emerged as powerful tools for precise DNA and RNA modulation, offering promising therapeutic strategies for neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). This review critically evaluates current CRISPR/Cas applications in neurodegeneration, with emphasis on mechanistic insights, therapeutic outcomes, and translational feasibility. Preclinical and early translational studies demonstrate that CRISPR-Cas platforms can correct pathogenic mutations, suppress toxic gene expression, and restore neuronal function. Advanced modalities, including base and prime editing, CRISPRi/a, and RNA-targeting Cas systems, improve precision and reduce genomic damage, which is particularly advantageous in post-mitotic neurons. Emerging CRISPR-based diagnostics (e.g., SHERLOCK and DETECTR), AI-assisted sgRNA design, and machine-learning approaches for predicting off-target effects further enhance the safety, stratification, and monitoring of CRISPR therapeutics. In parallel, patient-derived brain organoids and assembloids provide scalable human-relevant platforms for mechanistic studies and preclinical validation. Despite this progress, major challenges remain, including efficient delivery across the blood-brain barrier, immune responses, long-term safety, and ethical and regulatory considerations. Overall, CRISPR-Cas technologies hold strong potential as disease-modifying interventions for neurodegenerative disorders, provided that advances in delivery systems, artificial intelligence integration, and regulatory oversight continue to evolve toward clinical translation.},
}

@article {pmid41674646,
year = {2026},
author = {Schultz, AA and Paulsen, AJ and Fredricks, A and Plante, DT and Peppard, PE and Wilson, R},
title = {Feasibility and validity of using self-collected capillary blood using Tasso+ for measuring Alzheimer's Disease plasma-based biomarkers among underrepresented populations.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.02.02.26345372},
pmid = {41674646},
abstract = {BACKGROUND: Blood-based biomarkers offer a scalable alternative to cerebrospinal fluid and PET imaging for Alzheimer's disease (AD) detection, yet traditional venipuncture limits participation among rural and socioeconomically disadvantaged populations. Self-collection using the Tasso+ capillary device could reduce access barriers, but its feasibility and validity for AD plasma biomarkers remain uncertain, particularly with real-world delays prior to processing.

METHODS: Adults aged 45-90 years from the Wisconsin SHOW cohort who were underrepresented in AD research (Black or Hispanic race/ethnicity, rural residence, or
RESULTS: Tasso+ collection was successful for 96% of participants; 64% rated it very easy and 86% reported comfort/no pain, yet 57% preferred future venipuncture-particularly Black, lower-income, and lower-education participants. Agreement varied markedly by biomarker. GFAP and NfL demonstrated excellent concordance (CCC 0.97-0.98) with minimal bias (-6% to -8%). Aβ40 and Aβ42 showed modest correlations (r=0.40-0.47) and substantial underestimation (-60% to -70%). Aβ42/40 and pTau217 exhibited poor correlation and extreme positive bias for pTau217 (∼+2600%). Hemolysis was more frequent in Tasso+ samples and contributed to disagreement for several markers; processing lag and sample volume were not strong predictors.

CONCLUSIONS: Remote capillary self-collection with a 24-hour delay is suitable for measuring GFAP and NfL but not currently reliable for Aβ or pTau217 without improved handling (e.g., temperature control, hemolysis reduction). Although user experience was favorable, trust and logistical concerns limited preference among underrepresented groups. Community-informed strategies and optimized pre-analytics are essential before deploying Tasso+ in large AD studies.},
}

@article {pmid41674644,
year = {2026},
author = {Vlegels, N and de Brito Robalo, BM and de Luca, A and van der Flier, WM and , and Bateman, R and Benzinger, TLS and Cruchaga, C and Cash, DM and Mori, H and Yakushev, I and Duering, M and Finsterwalder, S and Gesierich, B and Kopczak, A and Reijmer, YD and Biessels, GJ},
title = {Critical and non-critical connections not differently associated with either Alzheimer's disease or vascular pathologies.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.02.03.26345446},
pmid = {41674644},
abstract = {Following observations from a pilot study that, contrary to expectations, indicated that critical white matter (WM) connections were not more vulnerable to either SVD or AD pathologies than non-critical connections, we set out to systematically evaluate the relation between these pathologies and both connections types. For patients with CADASIL (n=59), Mixed pathology (n=57) and autosomal dominant AD (ADAD; n=50) we reconstructed WM networks based on diffusion tensor imaging and subsequently defined critical and non-critical connections. Associations between AD markers (CSF Aβ [42] , p-tau levels, estimated years of onset (EYO)) and SVD markers (WM hyperintensity (WMH) volume) and both connection types were tested with linear regression analyses. WMH volume showed equally strong associations to the strength of both critical and non-critical connections. Aβ-positivity, Aβ [42] levels, p-tau levels and EYO, while less strongly related to the strength of the WM connections, did consistently show similar effect sizes for both connection types. Sensitivity analyses using different definitions of connectivity yielded similar results. SVD burden influenced WM integrity more than AD, but we found no support for critical connections being more vulnerable to these disease effects than non-critical connections.},
}

@article {pmid41674627,
year = {2026},
author = {Dolado, AO and Binette, AP and Benedet, AL and Pola, I and Tan, K and Traichel, W and Hristovska, I and Mammana, A and Stomrud, E and Salvadó, G and Janelidze, S and Palmqvist, S and Mattsson-Carlgren, N and Parchi, P and Zetterberg, H and Asthon, NJ and Hansson, O},
title = {Plasma and CSF proteomic signatures related to Alzheimer's, α-synuclein, or vascular pathologies and clinical decline.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.02.04.26345534},
pmid = {41674627},
abstract = {Older individuals frequently harbor multiple brain pathologies, including Alzheimer's disease (AD) related amyloid-β (Aβ) and tau alongside α-synucleinopathy and vascular pathology. Proteomic profiling offers a strategy to better understand common as well as unique features of these different brain pathologies. We analyzed cerebrospinal fluid (CSF) (n=1,658) and plasma (n=749) samples from participants in the BioFINDER cohorts using the automated NULISAseq CNS Disease panel of 125 proteins. Differentially abundant proteins (DAPs) related to AD pathology (based on Aβ- and tau-PET positivity), α-synuclein (based on synuclein amplification assay [SAA] positivity) and vascular pathology (based on white matter lesion [WML] load) were identified with linear models simultaneously including a binary measure for the three pathologies. In the BioFINDER-2 subcohorts, DAPs were further evaluated for associations with continuous baseline (n=1,137) and longitudinal (n=656) Aβ-PET, tau-PET, and WML measures in models accounting for all pathologies. Associations with AD-signature cortical atrophy (n=915) and cognitive decline by the MMSE (n=1054) were also examined. We identified 84 CSF DAPs, with largely distinct protein signatures for each pathology (AD, n=66 DAPs; vascular pathology, n=55; α-synuclein pathology, n=16). 10 DAPs (e.g., FABP3, UCHL1, NPTXR, NPTX2) were altered across all three pathologies, reflecting general neurodegeneration. AD-associated DAPs included glial/inflammatory markers (CHIT1, CX3CL1, CD63) linked to Aβ pathology, and synaptic/neuronal injury markers (VSNL1, NRGN, NEFL) and metabolic enzymes (FABP3, MDH1) linked to tau pathology. Aβ-associated proteomic differences were most evident in CU individuals, while tau-associated differences predominated in MCI. More proteins, particularly neurodegeneration and synaptic markers, were associated with tau change than with Aβ change. Vascular pathology exhibited a distinct profile, enriched for inflammatory, angiogenic and extracellular matrix proteins (PGF, POSTN, TREM1, VCAM1). DDC was the main protein associated with α-synucleinopathy. Only a few proteins, including UCHL1, NPTX2, and NEFL, predicted cognitive decline and cortical atrophy after accounting for all brain pathologies. In plasma, although fewer DAPs were identified (n=20), findings included established AD biomarkers. Only plasma VCAM1 and NEFL were associated with α-synuclein and vascular pathology. NULISA identified stage-dependent, disease-specific CSF biomarker signatures with limited overlap, alongside shared neurodegenerative markers, supporting improved biological interpretation and more refined classification of neurodegenerative pathology.},
}

@article {pmid41674612,
year = {2026},
author = {Lorenzon, G and García-Lluch, G and Coughlan, G and Sindi, S and Maioli, S and Poulakis, K and Najar, J and Mohanty, R and Rydén, L and Shams, S and Kern, S and Buckley, R and Westman, E and Skoog, I and Marseglia, A},
title = {Reproductive lifespan and hormonal therapy in relation to later-life neurovascular health: A population-based study of women in the Gothenburg H70-1944 Birth Cohort.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.02.04.26345605},
pmid = {41674612},
abstract = {BACKGROUND: Women face greater vulnerability to dementia and Alzheimer's disease (AD), potentially due to estrogen fluctuations across the lifespan. However, its role in vascular brain health is unclear. We investigated associations between lifelong estrogen exposure-endogenous (reproductive span) and exogenous (oral contraceptives [OC], menopausal hormone therapy [MHT])-and late-life vascular brain injury, AD-related atrophy, and APOE -ε4 modification.

METHODS AND FINDINGS: We included 352 cognitively unimpaired 70-years-old women from the Gothenburg H70-1944 Birth Cohort with brain MRI and 5-year follow-up. Reproductive lifespan was calculated as age at menopause or oophorectomy minus age at menarche. OC and MHT use were self-reported. Outcomes included cerebral small vessel disease (SVD), AD-related cortical thickness, and white-matter integrity (fractional anisotropy). Linear and multinomial regression and mixed-effects models were adjusted for confounders and stratified by APOE -ε4. Longer reproductive span (OR=0.90 [95%CI 0.83-0.98]) and MHT use (OR=0.43 [95% CI 0.20-0.92]) were linked to lower SVD burden, particularly fewer perivascular spaces and microbleeds. OC and MHT were associated with greater white matter integrity, with additive use throughout life showing the highest fractional anisotropy (OR=0.45 [95% CI 0.12-0.78]). MHT use was associated with greater thickness in areas often affected in AD among APOE -ε4 carriers (β=0.38 [95% CI 0.01-0.76]) but not in non-carriers. Longer estrogen exposure was linked to stable cortical thickness and WMH trajectories over time.

CONCLUSIONS: Extended estrogen exposure throughout life-both endogenous and exogenous-appear to support late-life cerebrovascular health in women, with potential genotype-specific neuroprotective effects. Given the current absence of sex-specific prevention guidelines for cognitive disorders, future research should clarify estrogen's long-term impact on brain health and cognition to inform personalized medicine.},
}

@article {pmid41674604,
year = {2026},
author = {García-González, P and Puerta, R and Dehairs, J and Yang, C and Wang, C and Timsina, J and de Rojas, I and Olivé, C and Valenzuela, A and Bayón-Buján, P and Rovira, M and Montrreal, L and Capdevila, M and Muñoz-Morales, Á and Calm, B and Valero, S and Alegret, M and Marquié, M and , and Morris, JC and Schindler, SE and Holtzman, DM and Sanz, P and Tárraga, L and Khan, A and Sáez, ME and Smets, B and Orellana, A and Montalbán, X and Boada, M and Cano, A and Liu, M and Ali, M and Cruchaga, C and Swinnen, JV and Fernández, V and Cabrera-Socorro, A and Ruiz, A},
title = {CSF turnover reshapes biomarker interpretation in neurodegeneration studies.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.02.02.26345363},
pmid = {41674604},
abstract = {Cerebrospinal fluid (CSF) biomarkers are central to Alzheimer's disease (AD) diagnosis and research. However, CSF composition is shaped not only by neurodegeneration, but also by underlying physiological and pathological processes that remain poorly characterized. By integrating multi-omics data from the deeply characterized memory-clinic ACE CSF cohort (N=1,372), the Global Neurodegeneration Proteomics Consortium (N=1,863), and publicly available quantitative trait loci data, we reveal that 73.2-85.9% of the molecular variance in CSF omics data is driven by two main factors: one reflecting CSF turnover rate, and another representing blood-brain barrier (BBB) integrity. CSF turnover mainly determines brain-derived molecules, while BBB damage leads to increased blood-derived protein abundance. CSF turnover/clearance severely impacted core AD biomarker levels, affecting the classification of subjects in the A/T framework. Adjusting biomarker levels for OPCML, a novel reference marker, improved biomarker-based prediction of AD progression and removed confounded associations, revealing a proteomic signature of sporadic AD pathology that closely resembles that of autosomal dominant AD. Finally, using the ACE CSF cohort as discovery (N=1,221) and Knight ADRC as replication (N=1,073), we report a curated AD signature comprising 446 unique proteins. Our findings identify CSF dynamics as a major source of molecular variation, reshaping the interpretation of CSF biomarkers.},
}

@article {pmid41674602,
year = {2026},
author = {Chea, EF},
title = {Equity and Transportability of Plasma ATN Phenotypes in a Population-Representative U.S. Aging Cohort.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.31.26344775},
pmid = {41674602},
abstract = {Plasma biomarkers are transforming Alzheimer's disease research, yet their performance in diverse, population-representative settings remains largely unknown. Using data from 4,427 adults in the nationally representative Health and Retirement Study, this work evaluates whether amyloid, tau, and neurodegeneration (ATN) biomarkers transport equitably across demographic groups. Population-weighted analyses reveal that tau is the only biomarker showing a stable association with cognition at the population level, whereas amyloid and neurodegeneration markers lose significance after accounting for sampling design. Fairness analyses uncover striking disparities: sensitivity for detecting cognitive impairment is more than twofold higher in White than Black participants, with Black women exhibiting the lowest detection rates. Education further modifies biomarker-cognition relationships, producing paradoxical positive amyloid associations and amplified neurodegeneration effects in structurally disadvantaged groups. These patterns persist after adjustment for vascular comorbidities, indicating that equity gaps arise from more than differential cerebrovascular burden. Together, these findings show that plasma ATN biomarkers do not generalize uniformly across the U.S. population and may systematically underperform in minoritized and socioeconomically disadvantaged groups. The results highlight the need for population-based validation and fairness-aware calibration before deploying blood-based biomarkers in clinical or public health settings.},
}

@article {pmid41674595,
year = {2026},
author = {Liang, N and Mahmoudiandehkordi, S and Heston, MB and Kaushik, P and Powell, WR and Karu, N and Dempsey, DA and Labus, JS and Schimmel, L and Blach, C and Kueider-Paisley, A and Brydges, C and Huynh, K and Mandal, R and Quirke, MV and Brewer, JB and Henderson, VW and Chen, DS and Swerdlow, RH and Taylor, M and Wisniewski, T and Roberson, ED and Craft, S and Miller, JB and Foroud, TM and Faber, KM and Amin, N and Wishart, DS and Saykin, AJ and Bendlin, BB and Brosch, JR and Meikle, PJ and Kind, AJ and Borkowski, K and Kaddurah-Daouk, RF and , and , },
title = {The Metabolome as a Readout for Adverse Social Exposome Influences on Human Health - A Roadmap for Modifiable Factors and Proactive Health.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.02.02.26344798},
pmid = {41674595},
abstract = {The exposome factors, such as diet, lifestyle, microbiome, chemical exposures and social exposome, shapes human health beyond genetic influences, but the mechanisms remain only partially understood. Leveraging the Area Deprivation Index (ADI) of Neighborhood Atlas, a validated measure of the US social exposome, we derive molecular insights on how adverse social exposome (ASE) may impact cardiometabolic and brain health. Using complementary metabolomics platforms, we measured blood metabolome as readouts on net influences of exposome factors. Participants from six Alzheimer's disease research centers (n=449) were studied with generalizability confirmed in the UK Biobank using its harmonizable metric for ASE (n=380,943). Our results suggest that participants living in ASE have metabolic features often shown to predispose individuals to higher risks for cardiovascular diseases and cognitive decline, with impaired mitochondrial energetics, amino acid and lipid metabolism. Diet, microbiome and chemical exposures may contribute to these metabolic features. Molecular insights from metabolic signatures for ASE allows us to map potential modifiable risk factors that can impact and sustain health including brain health.},
}

@article {pmid41674586,
year = {2026},
author = {Scully, J and Dadar, M and Morrison, C},
title = {Associations of amyloid biomarkers with brain and cognitive changes from imaging, spinal fluid, and plasma.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.02.05.26345647},
pmid = {41674586},
abstract = {BACKGROUND: Positron emission tomography (PET), cerebrospinal fluid (CSF), and plasma assessments are used to measure amyloid abnormality in Alzheimer's disease (AD). However, it remains unclear if these three measures are similarly associated with brain structure and cognitive measures.

METHODS: Linear regressions examined the relationship between amyloid levels measured by PET, CSF, and plasma and brain volumes, white matter hyperintensities (WMHs), and cognitive measures.

RESULTS: Moderate correlations were found between PET and CSF amyloid measurements and PET and plasma measurements, while weak correlations were found between CSF and plasma. PET, CSF, and plasma amyloid measurements differed in their associations with brain volume, WMHs, and cognition.

DISCUSSION: Using different measurement methods, amyloid was not consistently associated with volumetric or cognitive measures. Our findings also suggest that plasma markers may not be associated with cognitive and brain changes in the same manner as CSF and PET.},
}

@article {pmid41674583,
year = {2026},
author = {Lin, SS and Milam, A and Kiselica, AM and Aita, SL and Saeed, M and Webber, T and Woods, SP and Borgogna, NC and Walker, KA and Kamath, V and Visscher, K and Murchison, CF and Geldmacher, DS and Roberson, ED and Hill, BD and Del Bene, VA},
title = {Linking Cognitive Variability and Alzheimers Disease Biomarkers by Neurocognitive Status.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.30.26345235},
pmid = {41674583},
abstract = {OBJECTIVE: To assess intra-individual cognitive variability (IICV) in relation to Alzheimer's Disease (AD) biomarkers.

METHODS: The sample included 879 adults from the National Alzheimer's Coordinating Center, aged 50 and above with a complete neuropsychological evaluation and AD biomarker data available (64% cognitively intact; 36% cognitively impaired). We conducted a series of moderated regression models where AD biomarkers, neurocognitive status, and their interaction effects predicted IICV. IICV measures included demographically adjusted normed scores for the intraindividual standard deviation (iSD) and coefficient of variance (CoV). AD biomarkers included cerebrospinal fluid (CSF) measures of Aβ 1-42 , phosphorylated tau 181 (p-Tau 181), and total tau (t-Tau), as well as amyloid positron emission tomography (PET; with both continuous centiloid values and a dichotomous variable).

RESULTS: Increased AD biomarker burden was associated with increased IICV among cognitively impaired individuals (correlational strength ranging from .206 to .391 for iSD and from .149 to .460 for CoV) but not among the cognitively intact group (correlational strength ranging from .008 to .085 for iSD and from .016 to .085 for CoV). The pattern of results held even after controlling for demographic factors and was comparable in magnitude to the association between AD biomarkers and mean cognitive performance.

CONCLUSIONS: Increases in measures of amyloid, soluble tau, and neurodegeneration are associated with increased IICV among cognitively impaired older adults. The findings underscore the potential of IICV as a sensitive outcome measure in the AD clinical disease phase. Future studies should replicate findings longitudinally and in more diverse samples.},
}

@article {pmid41674561,
year = {2025},
author = {Xu, G and An, Y and Du, Y and Cao, Z and Zheng, J and Wang, J and Li, T and Lei, X and Lu, Y},
title = {Alterations and mechanistic insights of gut microbiota and its metabolites in type 2 diabetes mellitus and Alzheimer's disease.},
journal = {iMetaOmics},
volume = {2},
number = {3},
pages = {e70020},
pmid = {41674561},
issn = {2996-9514},
abstract = {Epidemiological studies suggest a link between type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD), possibly due to gut microbiota dysbiosis, although the exact mechanisms are unclear. This narrative review uniquely addresses how gut microbiota-derived metabolites mediate overlapping pathologies of insulin resistance, neuroinflammation, and amyloidogenesis in T2DM and AD, proposing a framework for dual therapeutic targeting. This narrative review provides an in-depth examination of the roles and mechanisms of gut microbiota and their metabolites in the context of T2DM and AD. This study indicates that gut microbiota dysbiosis significantly impacts the pathogenesis and progression of both diseases by modulating metabolic pathways, immune functions, and inflammatory responses. Key bacteria, such as Akkermansia muciniphila (which releases outer membrane vesicles), Lactobacillus, and Bifidobacterium, as well as their metabolites like short-chain fatty acids (SCFAs), bile acids (BAs), lipopolysaccharide (LPS), vitamins, and Trimethylamine N-oxide (TMAO) regulate T2DM and AD through complex mechanisms. Multiple signaling pathways, including G-protein coupled receptor 41/43 (GPR41/43), phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt), Toll-like receptor 4 (TLR4)/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and endoplasmic reticulum (ER) stress-mediated pathways, are also involved. These findings offer insights into the pathogenesis and potential targeted therapies for T2DM and AD.},
}

@article {pmid41674513,
year = {2026},
author = {Urso, D and Giannoni-Luza, S and Alaoui, AA and Ting, J and Jabbour, S and Fuente, A and Logroscino, G},
title = {Impact of dual sensory impairment on dementia: A systematic review and meta-analysis.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {1},
pages = {e70104},
pmid = {41674513},
issn = {2352-8729},
abstract = {UNLABELLED: Hearing and vision loss are considered independent modifiable risk factors for dementia; however, the impact of their dual impairment is not clear and is crucial for preventive strategies. We performed a systematic review and meta-analysis until July 23, 2024, to assess the association of dual sensory impairment (DSI) and dementia. Pooled hazard ratios (HRs) were calculated using random-effects models. Heterogeneity was assessed through subgroup analysis and meta-regression. Population attributable fractions (PAFs) for DSI were calculated. We included 11 studies. DSI was associated with a 52% increased hazard of developing all-cause dementia. Alzheimer's disease (AD) and vascular dementia subtypes showed larger HRs. Heterogeneity was only high for AD. Meta-regressions showed non-significant associations. Overall PAF for DSI was 2.77%. DSI significantly increases the risk of dementia among adults. Comprehensive sensory assessments and interventions targeting both hearing and vision impairments are essential for effective dementia prevention strategies.

HIGHLIGHTS: Dual sensory impairment (hearing and vision) increases dementia risk by 52%.Population attributable fraction of dual sensory impairment for dementia is 2.77%.Sensory assessments are crucial for dementia prevention strategies.},
}

@article {pmid41674512,
year = {2026},
author = {Walsh, C and Fogel, A and Schalkamp, AK and Mabiala, V and Shariati, B and Sandor, C and Ryten, M and Nilforooshan, R and Barnaghi, P},
title = {Temporal comorbidity patterns in Alzheimer's disease and vascular dementia: A population-based observational study in UK Biobank.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {1},
pages = {e70265},
pmid = {41674512},
issn = {2352-8729},
abstract = {INTRODUCTION: In Alzheimer's disease (AD) and vascular dementia (VaD), comorbidities shape disease trajectories and care needs, yet their timing across the lifespan remains poorly understood.

METHODS: We analyzed comorbidities using in-patient hospital International Classification of Diseases 10th Revision codes in 10,730 UK Biobank participants with AD or VaD, spanning 20 years before to 10 years after diagnosis. Logistic regression and Bayesian network analysis identified time- and subtype-specific risk patterns, validated against controls.

RESULTS: Distinct comorbidities emerged decades before diagnosis. In AD, depressive episodes, osteoporosis, and type 1 diabetes appeared up to 20 years pre-diagnosis, while VaD was characterized by early cerebral infarctions, type 1 diabetes, intestinal disorders, and rheumatoid arthritis, absent in controls.

DISCUSSION: Although restricted to severe populations captured in in-patient data, excluding primary care, these findings reveal time-dependent prodromal patterns in AD and VaD, highlighting opportunities for targeted screening, prevention, and early intervention.},
}

@article {pmid41674511,
year = {2026},
author = {Shakeri, A and Farmanbar, M},
title = {Statistical analysis of interpretable linguistic features for MCI detection in bilingual speech.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {1},
pages = {e70246},
pmid = {41674511},
issn = {2352-8729},
abstract = {INTRODUCTION: Early detection of mild cognitive impairment (MCI) is critical for intervention and dementia prevention. Interpretable linguistic features may offer transparent, cross-linguistic markers yet remain underexplored in bilingual dataset contexts.

METHODS: Using the TAUKADIAL Challenge dataset, which includes English and Chinese picture descriptions, we extracted 93 language-specific linguistic features with the Efficient Linguistic Feature Extraction for Natural Language Datasets (ELFEN) package and 141 language-agnostic linguistic features using the Comprehensive Handcrafted Linguistic Features (LFTK) toolkit. One-way ANOVA and Tukey's Honestly Significant Difference tests assessed associations with diagnosis, task, and language.

RESULTS: Seven ELFEN and 33 LFTK features showed significant differences between diagnostic groups. MCI speech exhibited reduced lexical diversity, fewer pronouns, greater use of numerals and participles, and longer sentences across both languages. Task- and language-based analyses revealed structural and lexical variability, with greater variability in Chinese responses.

DISCUSSION: These findings identify statistically significant, interpretable linguistic features associated with MCI, establishing a cross-linguistic foundation for developing transparent, multilingual tools for early cognitive assessment.

HIGHLIGHTS: Nintey-three language-specific and 141 language-agnostic features are analyzed from bilingual speech.Seven ELFEN and 33 LFTK features were identified as significantly linked to MCI diagnosis.MCI speakers used fewer pronouns, showed lower lexical diversity, and produced longer sentences.Findings reveal consistent cross-linguistic markers in English and Chinese picture descriptions.The study offers an interpretable, statistically validated foundation for multilingual MCI screening tools.},
}

@article {pmid41674127,
year = {2026},
author = {Renn, BN and Cross, CL and Zaman, I and Singsank, KT and Cobos, K and John, SE},
title = {Differential item functioning of the Geriatric Depression Scale-short form in the NACC dataset.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {2},
pages = {e71114},
doi = {10.1002/alz.71114},
pmid = {41674127},
issn = {1552-5279},
support = {U24 AG072122/AG/NIA NIH HHS/United States ; P30 AG062429/AG/NIA NIH HHS/United States ; P30 AG066468/AG/NIA NIH HHS/United States ; P30 AG062421/AG/NIA NIH HHS/United States ; P30 AG066509/AG/NIA NIH HHS/United States ; P30 AG066514/AG/NIA NIH HHS/United States ; P30 AG066530/AG/NIA NIH HHS/United States ; P30 AG066507/AG/NIA NIH HHS/United States ; P30 AG066444/AG/NIA NIH HHS/United States ; P30 AG066518/AG/NIA NIH HHS/United States ; P30 AG066512/AG/NIA NIH HHS/United States ; P30 AG066462/AG/NIA NIH HHS/United States ; P30 AG072979/AG/NIA NIH HHS/United States ; P30 AG072972/AG/NIA NIH HHS/United States ; P30 AG072976/AG/NIA NIH HHS/United States ; P30 AG072975/AG/NIA NIH HHS/United States ; P30 AG072978/AG/NIA NIH HHS/United States ; P30 AG072977/AG/NIA NIH HHS/United States ; P30 AG066519/AG/NIA NIH HHS/United States ; P30 AG062677/AG/NIA NIH HHS/United States ; P30 AG079280//the NIA-funded ADRCs/ ; P30 AG062422/AG/NIA NIH HHS/United States ; P30 AG066511/AG/NIA NIH HHS/United States ; P30 AG072946/AG/NIA NIH HHS/United States ; P30 AG062715/AG/NIA NIH HHS/United States ; P30 AG072973/AG/NIA NIH HHS/United States ; P30 AG066506/AG/NIA NIH HHS/United States ; P30 AG066508/AG/NIA NIH HHS/United States ; P30 AG066515/AG/NIA NIH HHS/United States ; P30 AG072947/AG/NIA NIH HHS/United States ; P30 AG072931/AG/NIA NIH HHS/United States ; P30 AG066546/AG/NIA NIH HHS/United States ; P30 AG086401/AG/NIA NIH HHS/United States ; P30 AG086404/AG/NIA NIH HHS/United States ; P20 AG068024/AG/NIA NIH HHS/United States ; P20 AG068053/AG/NIA NIH HHS/United States ; P20 AG068077/AG/NIA NIH HHS/United States ; P20 AG068082/AG/NIA NIH HHS/United States ; P30 AG072958/AG/NIA NIH HHS/United States ; P30 AG072959/AG/NIA NIH HHS/United States ; P20GM109025 (Project R-2)//by NIH/NIGMS/ ; UH2AG083264//and NIH/NIA/ ; },
mesh = {Humans ; Female ; Male ; Aged ; *Depression/diagnosis/psychology ; *Psychiatric Status Rating Scales ; *Geriatric Assessment/methods ; *Cognitive Dysfunction/diagnosis/psychology ; Aged, 80 and over ; },
abstract = {INTRODUCTION: This study examined differential item functioning of the Geriatric Depression Scale - Short Form (GDS-SF) in the National Alzheimer's Coordinating Center (NACC) Uniform Data Set (UDS) to identify potential variables that produce measurement bias.

METHODS: Data from 14077 individuals' first NACC visit were analyzed. Multiple indicator, multiple causes (MIMIC) models assessed differential item functioning (DIF) of the 15-item GDS-SF across race, Hispanic ethnicity, primary language, sex, and cognitive status (Clinical Dementia Rating [CDR] scale scores), while adjusting for educational attainment.

RESULTS: Participants were on average 73 (SD = 9.1) years old and 54.4% women. The majority (13 of 15) of the GDS-SF items demonstrated DIF. For many items, participants with any level of CDR cognitive impairment were more likely to endorse depressive symptoms.

DISCUSSION: Findings indicate the presence of widespread DIF by cognitive impairment severity such that individuals with even mild cognitive impairment may respond differently to certain items on this measure.

HIGHLIGHTS: The Geriatric Depression Scale - Short Form (GDS-SF) showed differential item functioning (DIF) in 13 of 15 items across demographic and cognitive groups. Only two items-hopelessness and worthlessness-were invariant across all groups. Cognitive status (Clinical Dementia Rating [CDR]) most strongly influenced item endorsement patterns. Our study used a large, diverse sample (National Alzheimer's Coordinating Center Uniform Data Set [NACC UDS]) and robust DIF analytic methods. Findings highlight both reliable and problematic GDS-SF items for older adults.},
}

Humans
Female
Male
Aged
*Depression/diagnosis/psychology
*Psychiatric Status Rating Scales
*Geriatric Assessment/methods
*Cognitive Dysfunction/diagnosis/psychology
Aged, 80 and over

@article {pmid41674118,
year = {2026},
author = {Sun, S and Xin, J and Zhang, Y and Yang, B and Su, D and Ni, R and Ma, Q and Li, N and Ma, G and Peng, Q and Chen, S and Prehn, JHM and Tam, KY and Wang, H and Ying, Z},
title = {p62/SQSTM1 Condensation Modulates Mitochondrial Clustering to Participate in Mitochondrial Quality Control.},
journal = {Aging cell},
volume = {25},
number = {2},
pages = {e70402},
doi = {10.1111/acel.70402},
pmid = {41674118},
issn = {1474-9726},
support = {32471048//National Natural Science Foundation of China/ ; 32371018//National Natural Science Foundation of China/ ; 82022022//National Natural Science Foundation of China/ ; 82071274//National Natural Science Foundation of China/ ; BM2013003//Jiangsu Key Laboratory of Drug Discovery and Translational Research for Brain Diseases/ ; 23KJA310005//Natural Science Foundation of Jiangsu Provincial Higher Education Institutions/ ; YXY2301006//Interdisciplinary Basic Frontier Innovation Program of Suzhou Medical College of Soochow University/ ; //Suzhou International Joint Laboratory for Diagnosis and Treatment of Brain Diseases/ ; //Priority Academic Program Development of the Jiangsu Higher Education Institutes (PAPD)/ ; 0062/2021/A//Science and Technology Development Fund/ ; MYRG2022-00171-FHS//the University of Macau/ ; },
mesh = {*Sequestosome-1 Protein/metabolism/genetics ; *Mitochondria/metabolism ; Humans ; Mitophagy ; Ubiquitin-Protein Ligases/metabolism ; },
abstract = {Mitochondrial quality control is tightly associated with aging-related neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD). Previous studies reported that ALS/FTD-associated protein p62 drives "mitochondrial clustering" (perinuclear clustering of fragmented and swollen mitochondria) during PINK1/Parkin-mediated mitophagy, but the underlying molecular mechanism, especially the precise role of p62 in mitochondrial clustering during mitophagy and the potential relationship between the mitochondrial quality control mediated by p62 and disease pathogenesis of ALS/FTD, remains unclear. Here, using cell biology in combination with an optogenetic tool, we show that the phase separation (condensation) of p62 mediates the clustering of damaged mitochondria to form "grape-like" clusters during PINK1/Parkin-mediated mitophagy, which is tightly associated with aging-related neurodegenerative diseases. In addition, our data suggest this mitochondrial clustering process is an arrest mechanism driven by p62 condensation (beyond the function of other autophagy receptors in mitophagy), which acts as a "brake" to reduce the surface area of dysfunctional mitochondria within cytoplasm for minimizing mitochondrial turnover in cells. Moreover, ALS/FTD-related pathological mutations perturb p62 condensation, thereby inhibiting mitochondrial clustering and destroying the "brake" machinery of mitochondrial quality control. Together, our data highlight how p62 condensation modulates organelle quality control in cell biology, and the important role of p62 condensation in both physiology and pathology.},
}

*Sequestosome-1 Protein/metabolism/genetics
*Mitochondria/metabolism
Humans
Mitophagy
Ubiquitin-Protein Ligases/metabolism

@article {pmid41674113,
year = {2026},
author = {Ahmad, MI and Zhou, S and Farooq, S and Ali, U and Li, T and Zhang, H},
title = {Sources, characterization approaches, artificial synthesis, and biological significance of 4,4-dimethylsterols: a review.},
journal = {Journal of the science of food and agriculture},
volume = {},
number = {},
pages = {},
doi = {10.1002/jsfa.70517},
pmid = {41674113},
issn = {1097-0010},
support = {//Talent Introduction Program of Postdoctoral International Exchange Program to Excellent International Young Researchers by the Office of China Postdoc Council (OCPC)/ ; 2023C02044//Pioneer" and "Leading Goose" R&D Program of Zhejiang Province/ ; //Zhejiang University/ ; },
abstract = {4,4-Dimethylsterols constitute a unique class of phytosterols - naturally occurring compounds that have gained significant attention due to their potential health benefits and wide-ranging biological activities. This review explores the diverse sources, chemical structure, synthetic approaches, and identification methods, focusing on the unique properties of 4,4-dimethylsterols that distinguish them within the sterol family. Comparative evaluation of analytical techniques such as solid-phase extraction, thin-layer chromatography, and gas chromatography-mass spectrometry are evaluated for their effectiveness in identifying and quantifying these compounds, which play a crucial role in verifying oil authenticity. Synthetic approaches, such as chemical synthesis and enzymatic transformation are also discussed in the context of 4,4-dimethylsterol production. Beyond methodology, the review examines the emerging trends linking 4,4-dimethylsterols to anti-inflammatory, anti-Alzheimer's, and anti-Parkinsonian properties. Finally, this review addresses prevailing challenges surrounding 4,4-dimethylsterols, including bioavailability, stability, and safety profiles, while offering a glimpse into the future of 4,4-dimethylsterol research. This review produces current knowledge and spotlights overlooked functional attributes, positioning 4,4-dimethylsterols as promising candidates for nutraceutical and therapeutic applications. © 2026 Society of Chemical Industry.},
}

@article {pmid41673920,
year = {2026},
author = {Oeckl, P and Abu-Rumeileh, S and Weise, CM and Otto, M and , },
title = {Longitudinal changes of blood β-synuclein in cognitively unimpaired, mild cognitive impairment and sporadic Alzheimer´s disease.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-01973-1},
pmid = {41673920},
issn = {1758-9193},
}

@article {pmid41673785,
year = {2026},
author = {Li, N and Wen, S and Li, D and Shi, Y and Mei, Z and Liu, D and Yang, H and Wang, Y and Lin, X and Xiang, Y and Wen, H and Meng, P},
title = {Research progress on the Sonic Hedgehog signaling pathway in the central nervous system: Novel insights.},
journal = {Neural regeneration research},
volume = {21},
number = {6},
pages = {2125-2136},
doi = {10.4103/NRR.NRR-D-24-01239},
pmid = {41673785},
issn = {1673-5374},
abstract = {Over the past few decades, the Sonic Hedgehog protein has become a pivotal player in many biological processes, including tumourigenesis, embryonic development, and protective mechanisms after cerebral damage. The Sonic Hedgehog signaling pathway is crucial in the central nervous system, with implications in a diverse range of diseases, including Parkinson's disease, Alzheimer's disease, spinal cord injury, traumatic brain injury, depression, Sonic Hedgehog medulloblastoma, and stroke. In this comprehensive review, we examined Sonic Hedgehog from the perspective of canonical and non-canonical pathways, elucidating their complex connections to the central nervous system. Subsequently, we summarize the latest advancements in drug therapies that offer novel strategies for treating neurological diseases by modulating the Sonic Hedgehog protein. Finally, we summarize and extend the technologies and tools for studying the Sonic Hedgehog signaling field, with the aim of providing new research ideas and methods.},
}

@article {pmid41673769,
year = {2026},
author = {Sharma, S and Vandenakker, A and Cortés-Pérez, C and Milne, S and Douville, RN},
title = {Implications of virus-induced stress granules in tauopathies.},
journal = {Translational neurodegeneration},
volume = {15},
number = {1},
pages = {4},
pmid = {41673769},
issn = {2047-9158},
support = {#2401-3152//St. Boniface Hospital Foundation/ ; RGPIN-2016-05761//Natural Sciences and Engineering Research Council of Canada/ ; },
mesh = {Humans ; *Tauopathies/metabolism/virology/pathology ; *Stress Granules/metabolism/virology ; Animals ; *tau Proteins/metabolism ; *Virus Diseases/metabolism/complications ; },
abstract = {Tauopathies are characterized by aberrant tau structure and function, which is associated with neurodegenerative dementias, such as Alzheimer's disease, Pick's disease, and frontotemporal dementia, as well as the motor neuron disease amyotrophic lateral sclerosis. Consistent association of these neurodegenerative conditions with viruses suggests an interplay between viral activity and the development of tauopathy. In this review, we explore how tau dysregulation may facilitate viral activity, and conversely, how viruses may drive tauopathy. We further discuss how stress granules (SGs) are a likely hub for the interactions between tau and viral components, leading to tau deregulation. Within the network of SG proteins analyzed, 15 proteins were identified to be both tau interactors and implicated in viral processes, having dual functionality. These SG proteins are further discussed in terms of their relationship with tauopathy, viral replication, and neurodegeneration. Concrete examples of synergistic and competing effects between tau and viruses are highlighted, revealing both pathological and protective mechanisms. This dichotomy underscores a complexity that is both disease- and virus-specific, within the context of SG biology and tau pathology. While the viral involvement in tauopathies could be considered detrimental, it may provide insights into antiviral therapeutics to target the accumulation and misfolding of tau in these neurodegenerative diseases.},
}

Humans
*Tauopathies/metabolism/virology/pathology
*Stress Granules/metabolism/virology
Animals
*tau Proteins/metabolism
*Virus Diseases/metabolism/complications

@article {pmid41673758,
year = {2026},
author = {Zheng, D and Gu, J and Nao, J and Sun, M and Dong, X},
title = {APOE4-driven T cell dysregulation in Alzheimer's disease: single-cell genomics and Mendelian randomization reveal novel therapeutic targets.},
journal = {Journal of neuroinflammation},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12974-026-03727-0},
pmid = {41673758},
issn = {1742-2094},
support = {No. 2024-MS-024//Natural Science Foundation of Liaoning Province/ ; },
}

@article {pmid41673732,
year = {2026},
author = {Hok-A-Hin, YS and Bongers, B and Bolsewig, K and Boonkamp, L and Ruiters, DN and Lemstra, AW and van der Flier, WM and Pijnenburg, YAL and Del Campo, M and Teunissen, CE},
title = {Development and validation of a novel panel of CSF biomarkers for Alzheimer's disease.},
journal = {Alzheimer's research & therapy},
volume = {18},
number = {1},
pages = {36},
pmid = {41673732},
issn = {1758-9193},
abstract = {BACKGROUND: Using proximity extension proteomic arrays (PEA), we previously identified a nine-biomarker CSF protein panel reflecting different biological processes dysregulated in Alzheimer´s disease (AD) that discriminated AD from non-AD dementias (i.e., dementia with Lewy bodies (DLB) and Frontotemporal dementia (FTD)). We translated this AD-Differential diagnostic panel into immunoassays for large-scale analysis and validated its discriminative performance in an independent cohort.

METHOD: In-house or commercially available immunoassays for five out of nine proteins (THOP1, ENO2, DDC, MMP7, and ITGB2) were analytically validated on the Ella platform. To verify analytical performance, results in CSF samples (n = 206) were compared between custom-PEA and Ella immunoassays. Clinical validation was performed in patients from the Amsterdam Dementia Cohort, including controls (cognitively unimpaired; n = 55, mean age: 57 ± 4 years, 36% females), amyloid-positive patients with mild cognitive impairment (MCI-Aβ+; n = 39, mean age: 68 ± 4 years, 46% females), AD (n = 47, mean age 66 ± 5 years, 31% females), and a non-AD group including patients with DLB (n = 54, mean age 69 ± 5 years, 17% females) and FTD (n = 50, mean age 64 ± 7 years, 32% females).

RESULTS: Moderate to strong correlations between custom-PEA and Ella immunoassays were observed (Rho’s > 0.646). CSF proteins showed similar though weaker trends compared to custom-PEA results. THOP1 and ENO2 were dysregulated across different AD stages. ENO2 and ITGB2 were increased in AD compared with DLB and FTD, while DDC was specifically increased in DLB. THOP1, ITGB2, and ENO2 correlated strongly with CSF pTau181 and tTau while weak correlations with amyloid were observed. Our CSF panel (THOP1, ENO2, DDC, MMP7, ITGB2) discriminated AD from non-AD dementias with moderate accuracy (AUC = 0.73, 95%CI: 0.64–0.82).

CONCLUSION: We developed immunoassays for novel AD biomarker candidates, which cover relevant biological processes (i.e., cellular remodeling, neuropeptide degradation, energy metabolic processes, the immune system, and neurotransmitter synthesis) underlying AD pathophysiology. CSF patterns were consistent with our discovery study, albeit diagnostic performance was somewhat lower than observed previously. This highlights the need to further evaluate this panel, which monitors a broader spectrum of biological processes, both in clinical practice and within clinical trial settings.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13195-025-01899-0.},
}

@article {pmid41673711,
year = {2026},
author = {Kim, Y and Ha, TY and Kondaurova, O and Lee, MS and Chang, KA},
title = {Microglia TFEB activation attenuates Alzheimer's disease pathology by enhancing autophagy-lysosomal function.},
journal = {Journal of neuroinflammation},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12974-026-03728-z},
pmid = {41673711},
issn = {1742-2094},
support = {GCU-202406100001//Gachon University Research Fund of 2024/ ; RS-2022-NR069987//National Research Foundation of Korea/ ; RS-2024-00338662//Korea Dementia Research Project through the Korea Dementia Research Center/ ; },
abstract = {Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) accumulation, neuroinflammation, synaptic dysfunction, and cognitive decline. Impairment of microglial autophagy-lysosomal pathway (ALP) is increasingly recognized as a key driver of the disease progression. Transcription factor EB (TFEB), a master regulator of ALP, has emerged as a promising therapeutic target; however, its specific role in microglia remains unclear. Here, we aimed to determine the therapeutic effects of microglial TFEB expression in AD pathogenesis. We established a tamoxifen-inducible, microglia-specific TFEB-overexpressing 5xFAD mouse line (5xTFEB) and conducted behavioural testing, histopathology and biochemical analyses, live-cell imaging of Aβ phagocytosis, and bulk RNA sequencing. Differential gene expressions were analysed, and inflammasome activation was evaluated. Microglial TFEB overexpression restored ALP function, promoted phagolysosomal clearance of oligomeric Aβ, and reduced the amyloid burden in the cortex, hippocampus, and entorhinal cortex of the 5xFAD mice. These changes rescued memory deficits in both male and female 5xTFEB mice. Transcriptomic profiling revealed upregulation of ALP and downregulation of inflammatory signalling. Additionally, inflammasome activation was attenuated in 5xTFEB mice. Targeted TFEB activation in microglia reprograms degradative and immune pathways, enhancing Aβ clearance while alleviating neuroinflammation and cognitive impairment in AD. Overall, microglial TFEB modulation is a promising cell-type-specific therapeutic strategy for AD and related neurodegenerative disorders.},
}