@article {pmid43009035,
year = {2026},
author = {Muskan, A and Khan, AU and Malik, I},
title = {Neuroprotective effects of remdesivir in ICV-STZ induced Alzheimer-like pathology: Potential involvement of ACE2-associated signaling.},
journal = {European journal of pharmacology},
volume = {1040},
number = {},
pages = {179539},
doi = {10.1016/j.ejphar.2026.179539},
pmid = {43009035},
issn = {1879-0712},
abstract = {Alzheimer's disease involves interacting metabolic, oxidative, and inflammatory disturbances, with accumulating evidence implicating dysregulation of the brain renin-angiotensin system in disease-related pathology. This study investigated the neuroprotective effects of remdesivir against intracerebroventricular streptozotocin (ICV-STZ)-induced Alzheimer-like pathology and examined the potential involvement of ACE1/ACE2-associated signaling. Following ICV-STZ administration on Days 1 and 3, remdesivir treatment was initiated on Day 4 and continued once daily through Day 31. Remdesivir was evaluated using molecular docking, molecular dynamics simulation, behavioral testing, cholinesterase inhibition assays, biochemical analyses, ELISA, immunohistochemistry, qRT-PCR, Western blotting, and histopathology. ICV-STZ induced memory-related and affective-like behavioral impairments, altered exploratory activity, reduced ACE2 expression, increased ACE1 expression, oxidative stress, NLRP3/NF-κB-associated neuroinflammation, amyloid/tau-related alterations, and neuronal degeneration. Remdesivir dose-dependently improved behavioral and biochemical outcomes, increased ACE2 expression, reduced ACE1 expression, and attenuated neuroinflammation, oxidative injury, and neurodegeneration, with the most pronounced effects observed at 30 mg/kg. Pharmacological modulation with DX600 and diminazene aceturate altered the protective effects of remdesivir, providing supportive but not definitive evidence for the involvement of ACE2-associated signaling. However, ACE2 enzymatic activity and downstream Ang-(1-7)/Mas receptor signaling were not directly assessed. Remdesivir also inhibited AChE and BChE, with IC50 values of 237.4 μM and 535.7 μM, respectively. These findings demonstrate that early remdesivir intervention attenuates the development of ICV-STZ-induced Alzheimer-like pathology and suggest that modulation of the ACE1/ACE2 expression balance may be associated with its antioxidant, anti-inflammatory, and neuroprotective effects.},
}

@article {pmid43009349,
year = {2026},
author = {Wei, M and Zhang, J and Liu, X and Liu, R and Yao, L and Ni, J and Li, T and Li, F and Shi, J and Tian, J and , },
title = {Plasma p-tau217 as a biomarker mapping cognitive impairment in Alzheimer's disease.},
journal = {International psychogeriatrics},
volume = {},
number = {},
pages = {100311},
doi = {10.1016/j.inpsyc.2026.100311},
pmid = {43009349},
issn = {1741-203X},
abstract = {OBJECTIVE: Plasma p-tau217 is a well-established biomarker of Alzheimer disease (AD) pathology, but its relationship with cognitive status and longitudinal cognitive change remains less well characterized. We investigated the clinical relevance of plasma p-tau217 as a blood-based biological correlate of cognitive status and change in AD.

METHODS: We included 1147 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) with available plasma biomarkers and amyloid-β (Aβ) status determined by amyloid PET or cerebrospinal fluid Aβ42. Cross-sectional associations between plasma p-tau217 and cognitive performance were evaluated across clinical stages and by Aβ status. Longitudinal associations between baseline plasma p-tau217 and subsequent cognitive change, as well as between changes in p-tau217 and changes in cognition, were assessed using linear mixed-effects models and correlation analyses. Baseline to last follow-up change correlations and separated within-person from between-person associations were also analyzed.

RESULTS: Plasma p-tau217 were higher at more advanced clinical stages, particularly among Aβ+ participants. In the Aβ positive group, higher p-tau217 was associated with poorer baseline MMSE, CDR-SB, and ADAS-Cog13 scores (partial ρ = -0.46, 0.52, and 0.55, respectively). Higher baseline p-tau217 was associated with greater subsequent worsening on all three measures at nominal P < 0.05. Increases in p-tau217 were associated with concurrent worsening in ADAS-Cog13 and CDR-SB (P = 0.001 and P = 0.011, respectively, but not MMSE. Exploratory analyses identified a within-person association between p-tau217 increases and ADAS-Cog13 worsening. Associations were less consistent among Aβ- participants.

CONCLUSION: Plasma p-tau217 was associated with cognitive impairment and longitudinal cognitive change, particularly among Aβ+ participants. These findings support plasma p-tau217 as a potential blood-based biological correlate of cognitive status and longitudinal cognitive change in AD.},
}

@article {pmid43009422,
year = {2026},
author = {Zhao, T and Levey, AI and Liang, SH},
title = {[18]F-Florquinitau PET for imaging tau pathology in Alzheimer's disease.},
journal = {Trends in pharmacological sciences},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.tips.2026.10.001},
pmid = {43009422},
issn = {1873-3735},
}

@article {pmid43009438,
year = {2026},
author = {Pourbarkhordar, V and Rahmani, S and Hosseinzadeh, H and Mehri, S},
title = {The Effect of Natural Compounds on Cognitive Impairment Through BDNF/TrkB/CREB Pathway: A Review.},
journal = {Phytotherapy research : PTR},
volume = {},
number = {},
pages = {},
doi = {10.1002/ptr.70517},
pmid = {43009438},
issn = {1099-1573},
abstract = {Considering the global prevalence of Alzheimer's disease (AD) and the restrictions of current treatment procedures, natural compounds (such as curcumin, hesperidin, and rutin) have been evaluated as multifaceted therapeutic agents. This review demonstrated that these compounds employ neuroprotective effects primarily through upregulating the brain-derived neurotrophic factor/tropomyosin receptor kinase B/cAMP response element binding protein (BDNF/TrkB/CREB) pathway. After inducing this pathway, they subsequently decrease apoptosis through the regulation of B-cell lymphoma protein 2-associated X/B-cell lymphoma 2 protein (Bax/Bcl2) ratio and the inhibition of apoptosis signal-regulating kinase 1 (ASK1) (e.g., icariin). They also modulate oxidative stress via increasing superoxide dismutase, catalase, and glutathione peroxidase (e.g., hesperidin), and suppress neuroinflammation through the inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells (Nf-κB) and proinflammatory cytokines (e.g., curcumin). These compounds enhance the level of postsynaptic density protein (PSD-95), a key enhancer of neuronal plasticity, improve synaptic signaling (e.g., oleanolic acid), and reduce cognitive disorders by reducing the formation of amyloid beta (Aβ) plaques (e.g., rutin). The phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling pathway is modulated (e.g., icariin), and cholinergic neurons are restored (e.g., maslinic acid). Despite the beneficial potential of natural compounds, the extrapolation of their findings to clinical application requires more precise preclinical studies and validated biomarkers.},
}

@article {pmid43009540,
year = {2026},
author = {Lee, HJ and Lee, SJ},
title = {The neuro-inflammaging triangle: a self-amplifying circuit of protein pathology, senescence-associated secretory phenotype and innate immunity in neurodegenerative disease.},
journal = {Experimental & molecular medicine},
volume = {},
number = {},
pages = {},
pmid = {43009540},
issn = {2092-6413},
support = {RS-2024-00336045//National Research Foundation of Korea (NRF)/ ; RS-2023-00266536//Ministry of Health and Welfare (Ministry of Health, Welfare and Family Affairs)/ ; },
abstract = {Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, frontotemporal dementia and amyotrophic lateral sclerosis, share common pathological features, including abnormal protein aggregation, chronic neuroinflammation and progressive neuronal loss. Ageing is the strongest risk factor, accompanied by a chronic, mild inflammatory state called 'inflammaging,' partly due to senescent cells producing senescence-associated secretory phenotype (SASP) factors. Innate immune DNA- and danger-sensing pathways, most notably the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway and NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasomes, convert cellular injury into chronic neuroinflammation. Here, we propose that protein pathology, SASP, and innate immune activation form a self-amplifying triangular circuit leading to age-related neurodegeneration. We present the cellular and molecular basis of each part and how microglia, astrocytes, oligodendrocyte precursor cells and neurons contribute. We outline treatment strategies, including senolytics, senomorphics, innate immune pathway inhibitors and metabolic restoration, and identify unresolved questions, including the reversibility of post-mitotic neuronal senescence, the relative contribution of each cell type and the translational challenge of interrupting the cycle. Collectively, the neuro-inflammaging triangle theory shifts focus from individual pathogenic entities to the self-amplifying circuit that sustains them, offering a unified mechanistic model to advance our understanding and treatment of age-related neurodegeneration.},
}

@article {pmid43009562,
year = {2026},
author = {Abbott, A},
title = {Some people are resistant to dementia - here's what their genes can teach us.},
journal = {Nature},
volume = {659},
number = {8140},
pages = {290-292},
pmid = {43009562},
issn = {1476-4687},
}

@article {pmid43009615,
year = {2026},
author = {Li, Y and Xia, X and Sun, Y and Jia, K and Yuan, P and Wei, R and Liang, Z and Shi, M and Li, C and Kleemann, K and Wang, S and Qi, X and Zhang, X and Zhu, J and Zhang, Y and Zhu, B and Liu, J and Wang, Y and Zheng, JC},
title = {Mitochondria-derived extracellular vesicles mediate Alzheimer's disease pathology through transmitting microglial Ggt1.},
journal = {Nature aging},
volume = {},
number = {},
pages = {},
pmid = {43009615},
issn = {2662-8465},
support = {82271477//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82530039//National Natural Science Foundation of China (National Science Foundation of China)/ ; },
abstract = {Extracellular vesicles (EVs) can modify pathological progression in Alzheimer's disease (AD), the most common neurodegenerative disease in older adults, by spreading pathogenic factors. However, the function of mitovesicles (mtVs)-a recently identified subset of EVs-in AD remain unknown. Here we show that release of mtVs is enriched in brain tissue from patients with AD and 5×FAD mice. Administration of 5×FAD mouse brain-derived mtVs (ADmtVs) induced AD-like behavioral and pathological changes in wild-type mice and accelerated disease progression of AD mice. Moreover, the release of mtVs was regulated by mitochondrial respiratory metabolism, and blocking the release of mtVs significantly alleviated AD-like phenotypes. Proteomic analysis identified Ggt1 as a highly enriched protein in ADmtVs. Inhibiting Ggt1 expression and activity mitigated AD-like phenotypes of 5×FAD mice and delayed ADmtV-induced disease progression, suggesting Ggt1 as a pathological cargo of ADmtVs. Our findings highlight the pathological roles of mtVs in AD and highlight mtVs and Ggt1 as potential therapeutic targets.},
}

@article {pmid43009667,
year = {2026},
author = {Chang, J and Dimter, E},
title = {Different Pipelines, Different EEG Microstate Results: Evidence from Dementia Samples.},
journal = {Brain topography},
volume = {40},
number = {1},
pages = {},
pmid = {43009667},
issn = {1573-6792},
mesh = {Humans ; *Electroencephalography/methods ; Female ; Male ; *Alzheimer Disease/physiopathology ; *Brain/physiopathology ; Aged ; *Frontotemporal Dementia/physiopathology ; Middle Aged ; Reproducibility of Results ; Bayes Theorem ; *Dementia/physiopathology ; Signal Processing, Computer-Assisted ; Clustering Algorithms ; Cluster Analysis ; },
abstract = {Electroencephalography (EEG) microstate analysis has been proposed as a potential biomarker for neurological disorders, yet the influence of analytic pipeline choices on clinical findings remains unclear. Resting-state EEG from patients with Alzheimer's disease (n = 36), frontotemporal dementia (n = 23), and healthy controls (n = 29) was analyzed using multiple microstate pipelines combining k-means or atomize-agglomerate hierarchical clustering with different temporal-smoothing conditions. Bayesian ANCOVA showed that evidence for group differences varied substantially across pipelines, particularly as a function of temporal smoothing. Rank-correlation analyses further demonstrated reduced agreement between smoothed and unsmoothed pipelines, indicating that smoothing altered the relative ordering of microstate temporal parameters across participants. To assess methodological stability, intra-subject split-half analyses were performed. Microstate topographies showed > 92% shared variance between independent data halves, whereas the reliability of duration, occurrence, and coverage varied across pipelines. Unsmoothed pipelines generally showed equal or greater split-half reliability for selected microstate B measures, and the reproducibility of clinical effect sizes differed by clustering algorithm and diagnostic contrast. These findings demonstrate that temporal smoothing and clustering choices can substantially influence the reliability and clinical interpretation of EEG microstate measures, underscoring the need for explicit pipeline validation in biomarker studies.},
}

Humans
*Electroencephalography/methods
Female
Male
*Alzheimer Disease/physiopathology
*Brain/physiopathology
Aged
*Frontotemporal Dementia/physiopathology
Middle Aged
Reproducibility of Results
Bayes Theorem
*Dementia/physiopathology
Signal Processing, Computer-Assisted
Clustering Algorithms
Cluster Analysis

@article {pmid43010096,
year = {2026},
author = {Ghazanfarpour, S and Das, RK and Ihnatovych, I and Sule, N and Sharikova, A and Aalinkeel, R and Khmaladze, A and Szigeti, K and Mahajan, SD},
title = {Raman spectroscopic identification of biochemical alterations in Alzheimer's disease brain tissue.},
journal = {Acta neuropathologica communications},
volume = {14},
number = {1},
pages = {},
pmid = {43010096},
issn = {2051-5960},
mesh = {*Alzheimer Disease/pathology/metabolism ; Humans ; *Spectrum Analysis, Raman/methods ; *Brain/metabolism/pathology ; Female ; Aged, 80 and over ; Male ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by chronic inflammation, neuronal loss, and continuous decline in memory and cognitive function. Raman Spectroscopy (RS) offers a powerful, label‑free approach for detecting early biochemical alterations in AD by generating highly sensitive molecular fingerprints, which is valuable for identifying subtle changes associated with protein misfolding, lipid dysregulation, and oxidative stress, key processes underlying AD onset and progression. In our study, full‑spectrum RS revealed clear biochemical distinctions between control and AD brain tissues, as well as between Braak IV and Braak VI AD stages. Multivariate analytical methods, including Singular Value Decomposition (SVD) and Linear Discriminant Analysis (LDA), were applied to manage spectral complexity and highlight the principal biochemical contributors to AD pathology. Multiple Raman bands in the 1200-1800 cm[-1] region showed increased intensity in AD tissue, including 1296 cm[-1] (lipid CH2 deformation), 1440 cm[-1] (lipid/cholesterol deformation), 1554 cm[-1] (Amide II), 1585 cm[-1] (protein‑folding-related vibrations), and 1640-1680 cm[-1] (Amide I). These changes indicate enhanced protein aggregation, loss of ordered secondary structure, and extensive lipid membrane disorganization. Complementary gene‑expression analysis further demonstrated dysregulation of lipid homeostasis in AD, with altered expression of ABCA1, LIPE, CPT1A, PPARA, and SREBP‑1, indicating broad metabolic reprogramming. Together, the coordinated spectral and transcriptional shifts underscore lipid‑metabolic dysfunction as a central feature of AD. By capturing these molecular signatures, RS provides a promising tool for early detection and monitoring of AD progression.},
}

*Alzheimer Disease/pathology/metabolism
Humans
*Spectrum Analysis, Raman/methods
*Brain/metabolism/pathology
Female
Aged, 80 and over
Male

@article {pmid43010103,
year = {2026},
author = {Kano, M and Kimura, T and Yanagisawa, H and Yamashita, K and Tatsumi, L and Sakai, A and Li, X and Saido, TC and Saito, T and Takatori, S and Kikkawa, M and Tomita, T},
title = {Cryo-EM structure of pro-aggregant P301L/S320F double-mutant tau filaments formed in mouse brains following peripheral AAV delivery.},
journal = {Acta neuropathologica communications},
volume = {14},
number = {1},
pages = {},
pmid = {43010103},
issn = {2051-5960},
support = {JP25KJ1009//Japan Society for the Promotion of Science/ ; JP23K06112//Japan Society for the Promotion of Science/ ; JP23H00394//Japan Society for the Promotion of Science/ ; GCL/IIW//University of Tokyo/ ; JP23dm0207073, JP24wm0625303//Japan Agency for Medical Research and Development/ ; JPMJMS2024-1//Moonshot Research and Development Program/ ; },
mesh = {Animals ; *tau Proteins/genetics/ultrastructure/metabolism ; *Brain/metabolism/pathology/ultrastructure ; Dependovirus/genetics ; Humans ; Cryoelectron Microscopy ; Mice ; Mutation ; Mice, Transgenic ; *Tauopathies/pathology/genetics/metabolism ; },
abstract = {Tauopathies are characterized by the accumulation of abnormally phosphorylated tau filaments, with disease-specific folds revealed by cryo-electron microscopy (cryo-EM). Here, we delivered a recombinant human tau carrying the P301L/S320F double mutation into App[NL-G-F]/MAPT double knock-in mice using a blood-brain-barrier-permeable AAV (AAV-PHP.eB), enabling rapid induction of tau aggregation in vivo. The mutant tau was systemically administered via retro-orbital injection, providing a minimally invasive approach for widespread neuronal transduction. Phosphorylated tau aggregation, as well as seeding activity, were observed without the need for exogenous seeds. Our cryo-EM analysis resolved a novel filament fold incorporating residues 279-329, in which the P301L and S320F mutations introduced stabilizing interactions that reinforced filament assembly. This conformation was distinct from previously reported folds, including Alzheimer and Pick tau filaments. Moreover, the filaments adopted a more compact architecture than those observed in patient-derived samples or other model mice. This finding demonstrates that P301L/S320F double-mutant tau adopts a structurally unique, highly aggregation-prone fold, and that this system provides a rapid platform for modeling tau filament formation.},
}

Animals
*tau Proteins/genetics/ultrastructure/metabolism
*Brain/metabolism/pathology/ultrastructure
Dependovirus/genetics
Humans
Cryoelectron Microscopy
Mice
Mutation
Mice, Transgenic
*Tauopathies/pathology/genetics/metabolism

@article {pmid43010123,
year = {2026},
author = {Kim, JS and Han, SS and Yoo, SH and Lee, DH and Jang, J and Lee, HJ and Song, JH and Hoe, HS},
title = {AI-Integrated multimodal neuroimaging in Alzheimer's disease: toward biologically informed precision diagnostics.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {11},
pages = {},
pmid = {43010123},
issn = {1552-5279},
support = {//the KBRI basic research program through KBRI funded by the Ministry of Science/ ; },
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/pathology ; *Artificial Intelligence ; *Neuroimaging/methods ; *Multimodal Imaging/methods ; Brain/diagnostic imaging/pathology ; *Precision Medicine/methods ; Magnetic Resonance Imaging ; Positron-Emission Tomography ; },
abstract = {Alzheimer's disease (AD), which is characterized by the progressive accumulation of amyloid beta plaques and neurofibrillary tangles (NFTs), metabolic dysfunction, and neuroinflammation, is the most prevalent neurodegenerative disorder. The distinct pathological features of AD can be characterized in vivo via neuroimaging: Structural magnetic resonance imaging captures brain atrophy, while positron emission tomography detects Aβ/NFT deposition. The application of artificial intelligence (AI) can enhance the interpretation of neuroimaging data, but single-modality AI provides only limited biological information. This limitation has motivated the development of multimodal approaches that integrate complementary imaging, molecular, and clinical data for diagnosis and prognosis. However, there has been no comprehensive examination of how modality-specific neuroimaging information is incorporated into single-modality AI and subsequently integrated within multimodal frameworks. This review addresses this gap by evaluating conventional neuroimaging, single-modality AI, and multimodal AI as part of a unified framework, with particular emphasis on the added diagnostic and prognostic value of multimodal integration. We further identify key methodological and translational bottlenecks in developing clinically robust multimodal AI, including cross-modal and cross-cohort heterogeneity, model complexity, missing modalities, interpretability, and generalizability. Finally, we propose a translational roadmap emphasizing data harmonization, independent external validation, clinically meaningful explainability, and prospective evaluation. Ultimately, the clinical value of multimodal AI will depend on whether its added predictive value is reproducible across independent populations and translates into meaningful improvements in clinical decision-making and patient outcomes.},
}

Humans
*Alzheimer Disease/diagnostic imaging/pathology
*Artificial Intelligence
*Neuroimaging/methods
*Multimodal Imaging/methods
Brain/diagnostic imaging/pathology
*Precision Medicine/methods
Magnetic Resonance Imaging
Positron-Emission Tomography

@article {pmid43010124,
year = {2026},
author = {Bey, GS and Emrani, S and Kulick, ER and Román, CAF and De Anda-Duran, I and Ashford, MT and Boyle, R and Bubu, OM and Dixon, J and Franzen, S and Gao, PY and George, K and Guest, MA and Heston, MB and Heyn, P and Jackson, D and Krishnamurthy, S and Phillips, JS and Rirash, AF and Viswanathan, J and Zanwar, PP and Zuelsdorff, M and Stites, SD},
title = {Lifestyle interventions on Alzheimer's disease and related dementias: Social and structural determinants of implementation effectiveness and sustainability.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {11},
pages = {},
pmid = {43010124},
issn = {1552-5279},
support = {24PRE1200264//American Heart Association/ ; 3OT2OD032581-0151-184//Artificial Intelligence/Machine Learning Consortium to Advance Health Equity and Researcher Diversity/ ; RF00280-SUB00278-FE//Artificial Intelligence/Machine Learning Consortium to Advance Health Equity and Researcher Diversity/ ; R13AT012585-01A1/AT/NCCIH NIH HHS/United States ; //California Department of Public Health/ ; 10510032120004 NDPI/ZONMW_/ZonMw/Netherlands ; ADR A202033S//BrightFocus Foundation/ ; AARG-22-926144/ALZ/Alzheimer's Association/United States ; AARG-D-21-848397/ALZ/Alzheimer's Association/United States ; AARG-D-1244595/ALZ/Alzheimer's Association/United States ; 45127/PCORI/Patient-Centered Outcomes Research Institute/United States ; L32MD019916/MD/NIMHD NIH HHS/United States ; K23MD019232/MD/NIMHD NIH HHS/United States ; 23AG065442/AG/NIA NIH HHS/United States ; R00AG075327/AG/NIA NIH HHS/United States ; F32 AG072730-02/AG/NIA NIH HHS/United States ; U19AG024904/AG/NIA NIH HHS/United States ; K08AG086588/AG/NIA NIH HHS/United States ; P30AG073105/AG/NIA NIH HHS/United States ; RF1AG083975/AG/NIA NIH HHS/United States ; R01AG082278/AG/NIA NIH HHS/United States ; K23AG0868534A/AG/NIA NIH HHS/United States ; K01AG081499/AG/NIA NIH HHS/United States ; K00AG097172/AG/NIA NIH HHS/United States ; R13AG072884/AG/NIA NIH HHS/United States ; F30AG085932/AG/NIA NIH HHS/United States ; R01AG054519/AG/NIA NIH HHS/United States ; U54AG090792/AG/NIA NIH HHS/United States ; K23AG065442/AG/NIA NIH HHS/United States ; P30AG06619/AG/NIA NIH HHS/United States ; AARFD-23-1150584//Alzheimer's Association Research Fellowship/ ; SCN-25-1474727//Alzheimer's Association/Michael J. Fox Foundation/Cure PSP/ ; },
mesh = {Humans ; *Alzheimer Disease/therapy ; *Life Style ; *Dementia/therapy ; *Social Determinants of Health ; },
abstract = {Alzheimer's disease and related dementias (ADRD) pose a global public health challenge, and epidemiological evidence underscores profound disparities in ADRD risk and outcomes that are rooted in social/structural determinants of health (S/SDOH). Yet, these determinants are seldom integrated into intervention design or implementation strategies. In this review, we identify S/SDOH that influence the equitable implementation of evidence-based ADRD lifestyle interventions across diverse groups and explore implications. Guided by Bronfenbrenner's ecological model, we: (1) examined theoretical foundations, focusing on how macrosystem and microsystem factors modulate implementation effectiveness across multiple intervention modalities; (2) synthesized empirical literature, highlighting successful and suboptimal intervention outcomes in marginalized populations; (3) identified critical gaps, especially where evidence on implementation across socially defined groups is lacking; and (4) discussed implications for enhancing design and policy for equitable ADRD intervention delivery. Our goal is to produce a conceptual and empirical synthesis that offers actionable guidance for clinicians, researchers, and policy makers.},
}

Humans
*Alzheimer Disease/therapy
*Life Style
*Dementia/therapy
*Social Determinants of Health

@article {pmid43010136,
year = {2026},
author = {Wu, M and Luan, Y and Xu, X and Mao, X and Lin, H and He, K and Huang, Q and Zhang, J and Kuang, S and Guan, Y and , and , and O'Bryant, S and Li, B and Guo, Q and Xie, F and Luo, B},
title = {Diabetes mellitus is associated with altered Alzheimer's disease pathology.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {11},
pages = {},
pmid = {43010136},
issn = {1552-5279},
support = {2022ZD0213800//STI2030-Major Projects/ ; 82171473//National Natural Science Foundation of China/ ; 82201583//National Natural Science Foundation of China/ ; 2025ZHYL035//Shanghai Municipal Health Commission/ ; LGL-3142-ADB510100//Lingang Laboratory Grant/ ; 2017QD081//Huashan Hospital/ ; 2022C03064//Key Research and Development Program of Zhejiang Province/ ; },
mesh = {Humans ; *Alzheimer Disease/pathology/diagnostic imaging/metabolism ; Female ; tau Proteins/metabolism/blood ; Positron-Emission Tomography ; Amyloid beta-Peptides/metabolism ; Male ; Aged ; *Brain/pathology/diagnostic imaging/metabolism ; *Diabetes Mellitus/pathology ; Cognitive Dysfunction/pathology ; Aged, 80 and over ; Longitudinal Studies ; },
abstract = {INTRODUCTION: Diabetes mellitus (DM) is a major risk factor for dementia, yet it remains unclear whether DM accelerates cognitive decline through amyloid beta (Aβ) or tau accumulation in Alzheimer's disease (AD).

METHODS: In this study, we included 2784 participants from three independent observational cohorts: the Chinese Preclinical Alzheimer's Disease Study (CPAS), the Alzheimer's Disease Neuroimaging Initiative (ADNI), and Health and Aging Brain Study-Health Disparities (HABS-HD). We examined the associations of DM with Aβ positron emission tomography (PET), tau PET, plasma phosphorylated tau (p-tau)217, and longitudinal cognitive change. We also tested whether DM modified the associations of Aβ and plasma p-tau217 with subsequent tau accumulation and explored the association of metformin use with tau accumulation.

RESULTS: We found that DM was associated with lower global Aβ burden and lower tau accumulation in CPAS and ADNI, in which cognitive impairment was more common than in HABS-HD. The associations of Aβ and plasma p-tau217 with tau accumulation were weaker among individuals with DM. In addition, DM was associated with reduced propagation of tau from early to later stage Braak regions. Longitudinal analyses in ADNI indicated that individuals with DM exhibited slower tau-related cognitive decline. In exploratory analyses, metformin use among individuals with DM was associated with lower tau accumulation compared to individuals without DM.

DISCUSSION: These findings suggest that DM is associated with an attenuation of amyloid- and tau-related processes, particularly in participants with cognitive impairment, and further suggest that diabetes-related mechanisms and its management may modulate the progression of AD pathology.},
}

Humans
*Alzheimer Disease/pathology/diagnostic imaging/metabolism
Female
tau Proteins/metabolism/blood
Positron-Emission Tomography
Amyloid beta-Peptides/metabolism
Male
Aged
*Brain/pathology/diagnostic imaging/metabolism
*Diabetes Mellitus/pathology
Cognitive Dysfunction/pathology
Aged, 80 and over
Longitudinal Studies

@article {pmid43010295,
year = {2024},
author = {Konis, G and Koenig, E and Takahashi, K and Iredale, P and Tugnait, M and Waksman, J and Chang, I and Blackmon, S and Perry, P and Leoni, M and Sanchez, R},
title = {EMPOWERing the Next-Generation: A Phase 2 Program to Evaluate Emraclidine, a Selective M4 Positive Allosteric Modulator (PAM), for the Treatment of Schizophrenia.},
journal = {CNS spectrums},
volume = {29},
number = {5},
pages = {495},
doi = {10.1017/S1092852924001548},
pmid = {43010295},
issn = {2165-6509},
abstract = {BACKGROUND: Emraclidine is a novel, highly selective positive allosteric modulator of M4 muscarinic acetylcholine receptors currently in development for the treatment of schizophrenia and Alzheimer's disease psychosis. By selectively activating M4 receptors, emraclidine may reduce excess dopamine signaling in the striatum, potentially leading to a reduction in psychotic symptoms. Unlike current antipsychotics, emraclidine does not interfere with signaling at dopamine, serotonin, or histamine receptors, which can lead to adverse events. A previous phase 1b study supports further investigation of emraclidine. The phase 2 EMPOWER program will fully evaluate the efficacy, safety, tolerability, and dose-range of once-daily (QD) emraclidine in schizophrenia.

METHODS: EMPOWER-1 and EMPOWER-2 are two adequately powered, multicenter, randomized, double-blind, placebo-controlled, parallel group, 6-week inpatient studies of emraclidine monotherapy (10 mg QD, 15 mg QD, 30 mg QD). The trials are enrolling adult participants with schizophrenia who are experiencing an acute exacerbation of psychosis. Eligible participants will have a Positive and Negative Syndrome Scale (PANSS) Total Score between ≥85 and ≤120 and a Clinical Global Impression - Severity (CGI-S) score ≥4 at baseline. Both de novo participants and those who complete EMPOWER-1 or EMPOWER-2 will be eligible to participate in EMPOWER-3, a 52-week open label extension trial to evaluate the long-term safety and tolerability of emraclidine in adult participants with stable schizophrenia.

RESULTS: Detailed study designs for the EMPOWER program will be presented. Primary outcome measure for EMPOWER 1 and 2 is change from baseline in PANSS total score at week 6. Other outcome measures include change from baseline in CGI-S score at week 6. Data from EMPOWER-3 will contribute to the overall evaluation of safety and tolerability of emraclidine in adult participants with schizophrenia.

CONCLUSIONS: The development of emraclidine is promising, as it selectively activates M4, a novel target that has been implicated in reducing psychotic symptoms while potentially avoiding many of the side effects currently associated with antipsychotics. The EMPOWER program aims to establish the efficacy, safety, tolerability, and appropriate dose-range of emraclidine in the treatment of schizophrenia.

FUNDING: Cerevel Therapeutics.},
}

@article {pmid43010306,
year = {2024},
author = {Brannan, SK and Cutler, AJ and Sawchak, S and Kando, J and Miller, AC and Claxton, A and Paul, SM and Kaul, I},
title = {Safety and Tolerability of KarXT (Xanomeline Trospium): Pooled Results From the Randomized, Double-Blind, Placebo-Controlled EMERGENT Trials.},
journal = {CNS spectrums},
volume = {29},
number = {5},
pages = {515},
doi = {10.1017/S1092852924001901},
pmid = {43010306},
issn = {2165-6509},
abstract = {INTRODUCTION: In prior studies, the dual M1/M4 preferring muscarinic receptor agonist xanomeline demonstrated antipsychotic activity in people with schizophrenia and Alzheimer's disease, but its further clinical development was limited primarily by gastrointestinal side effects. KarXT combines xanomeline and the peripherally restricted muscarinic receptor antagonist trospium chloride. KarXT is designed to preserve xanomeline's beneficial central nervous system effects while mitigating adverse events (AEs) due to peripheral muscarinic receptor activation. The efficacy and safety of KarXT in schizophrenia was demonstrated in the 5-week, randomized, double-blind, placebo-controlled EMERGENT-1 (NCT03697252), EMERGENT-2 (NCT04659161), and EMERGENT-3 (NCT04738123) trials.

METHODS: The EMERGENT trials enrolled people with a recent worsening of positive symptoms warranting hospitalization, Positive and Negative Syndrome Scale total score ≥80, and Clinical Global Impression-Severity score ≥4. Eligible participants were randomized 1:1 to KarXT or placebo. KarXT dosing (xanomeline/trospium) started at 50 mg/20 mg twice daily (BID) and increased to a maximum of 125 mg/30 mg BID. Safety was assessed by monitoring for spontaneous AEs after administration of the first dose of trial drug until the time of discharge on day 35. Data from the EMERGENT trials were pooled, and all safety analyses were conducted in the safety population, defined as all participants who received ≥1 dose of trial drug.

RESULTS: A total of 683 participants (KarXT, n=340; placebo, n=343) were included in the pooled safety analyses. Across the EMERGENT trials, 51.8% of people in the KarXT group compared with 29.4% in the placebo group reported ≥1 treatment-related AE. The most common treatment-relatedAEs occurring in ≥5% of participants receiving KarXT and at a rate at least twice that observed in the placebo group were nausea (17.1% vs 3.2%), constipation (15.0% vs 5.2%), dyspepsia (11.5% vs 2.3%), vomiting (10.9% vs 0.9%), and dry mouth (5.0% vs 1.5%). The most common treatment-related AEs in the KarXT group were all mild or moderate in severity.

CONCLUSIONS: In pooled analyses from the EMERGENT trials, KarXT was generally well tolerated in people with schizophrenia experiencing acute psychosis. These findings, together with the efficacy results showing a clinically meaningful reduction in the symptoms of schizophrenia, support the potential of KarXT to be the first in a new class of antipsychotic medications based on muscarinic receptor agonism and a well-tolerated alternative to currently available antipsychotics.

FUNDING: Karuna Therapeutics.},
}

@article {pmid43010364,
year = {2024},
author = {Kaul, I and Citrome, L and Sawchak, S and Kando, J and Miller, AC and Paul, SM and Brannan, SK},
title = {Efficacy of KarXT (Xanomeline Trospium) in Schizophrenia: Pooled Results From the Randomized, Double-Blind, Placebo-Controlled EMERGENT Trials.},
journal = {CNS spectrums},
volume = {29},
number = {5},
pages = {489-490},
doi = {10.1017/S1092852924001445},
pmid = {43010364},
issn = {2165-6509},
abstract = {INTRODUCTION: Prior studies demonstrated the antipsychotic activity of the dual M1/M4 preferring muscarinic receptor agonist xanomeline in people with schizophrenia and Alzheimer's disease, but its further clinical development was limited primarily by gastrointestinal side effects. KarXT combines xanomeline and the peripherally restricted muscarinic receptor antagonist trospium chloride. KarXT is designed to preserve xanomeline's beneficial central nervous system effects while mitigating side effects due to peripheral muscarinic receptor activation. The efficacy and safety of KarXT in schizophrenia were demonstrated in the 5-week, randomized, double-blind, placebo-controlled EMERGENT-1 (NCT03697252), EMERGENT-2 (NCT04659161), and EMERGENT-3 (NCT04738123) trials.

METHODS: The EMERGENT trials randomized people with a recent worsening of positive symptoms warranting hospitalization, Positive and Negative Syndrome Scale (PANSS) total score ≥80, and Clinical Global Impression-Severity (CGI-S) score ≥4. KarXT dosing (xanomeline/trospium) started at 50 mg/20 mg twice daily (BID) and increased to a maximum of 125 mg/30 mg BID. In each trial, the primary efficacy endpoint was change from baseline to week 5 in PANSS total score. Other efficacy measures included change from baseline to week 5 in PANSS positive subscale, PANSS negative subscale, PANSS Marder negative factor, and CGI-S scores. Data from the EMERGENT trials were pooled, and efficacy analyses were conducted in the modified intent-to-treat population, defined as all randomized participants who received ≥1 trial drug dose and had a baseline and ≥1 postbaseline PANSS assessment.

RESULTS: The pooled analyses included 640 participants (KarXT, n=314; placebo, n=326). Across trials, KarXT was associated with a significantly greater reduction in PANSS total score at week 5 compared with placebo (KarXT, -19.4; placebo, -9.6 [least squares mean (LSM) difference, -9.9; 95% CI, -12.4 to -7.3; P<0.0001; Cohen's d, 0.65]). At week 5, KarXT was also associated with a significantly greater reduction than placebo in PANSS positive subscale (KarXT, -6.3; placebo, -3.1 [LSM difference, -3.2; 95% CI, -4.1 to -2.4; P<0.0001; Cohen's d, 0.67]), PANSS negative subscale (KarXT, -3.0; placebo, -1.3 [LSM difference, -1.7; 95% CI, -2.4 to -1.0; P<0.0001; Cohen's d, 0.40]), PANSS Marder negative factor (KarXT, -3.8; placebo, -1.8 [LSM difference, -2.0; 95% CI, -2.8 to -1.2; P<0.0001; Cohen's d, 0.42]), and CGI-S scores (KarXT, -1.1; placebo, -0.5 [LSM difference, -0.6; 95% CI, -0.8 to -0.4; P<0.0001; Cohen's d, 0.63]).

CONCLUSIONS: In pooled analyses from the EMERGENT trials, KarXT demonstrated statistically significant improvements across efficacy measures with consistent and robust effect sizes. These findings support the potential of KarXT to be first in a new class of medications to treat schizophrenia based on muscarinic receptor agonism and without any direct dopamine D2 receptor blocking activity.

FUNDING: Karuna Therapeutics.},
}

@article {pmid43010397,
year = {2026},
author = {Zhang, Z and Ning, Y and Wu, Z and Sun, J and Gao, F},
title = {A pKa-Guided BBB-Permeable NIR Fluorescent Probe for Tracking Lipid Droplets in Microglia with Neuroinflammation and Alzheimer's Disease.},
journal = {Analytical chemistry},
volume = {98},
number = {44},
pages = {30825-30836},
doi = {10.1021/acs.analchem.6c04279},
pmid = {43010397},
issn = {1520-6882},
support = {22274003, 21874001, 21575004//National Natural Science Foundation of China (NSFC)/ ; },
mesh = {*Alzheimer Disease/diagnostic imaging/metabolism ; *Microglia/metabolism/chemistry ; Animals ; *Fluorescent Dyes/chemistry/chemical synthesis ; *Blood-Brain Barrier/metabolism ; Mice ; *Lipid Droplets/metabolism/chemistry ; *Neuroinflammatory Diseases/diagnostic imaging/metabolism ; Optical Imaging ; Humans ; Infrared Rays ; Fluorescent Chemosensor Compounds ; Thiadiazoles/chemistry/chemical synthesis ; },
abstract = {Abnormal accumulation of lipid droplets (LDs), accompanied by altered microenvironmental polarity within the microglia, is closely associated with neuroinflammation and also has been increasingly recognized as an early and dynamic indicator of Alzheimer's disease (AD). Herein, a LD-targeting polarity-sensitive blood-brain barrier (BBB)-permeable near-infrared (NIR) probe, BTDN, was screened by tuning the electron-donating substituents to modulate the pKa values of benzothiadiazole-based derivatives. Endowed with the donor-acceptor-donor (D1-A-D2) architecture and strong intramolecular charge-transfer (ICT) characteristics, the BTDN probe exhibited high sensitivity to polarity change. The BTDN probe displayed suitable physicochemical properties such as a pKa of 7.47 and lipophilicity with a log P of 3.72 for favorable BBB-penetrating efficiency with a permeability percentage of 24.23%. In addition, the BTDN probe showed advantages for fluorescence imaging including NIR emission from 643 to 770 nm with the increased polarity, Stokes shift larger than 308 nm, comparable two-photon absorption capacity with an absorption cross-section of 10 GM at 870 nm, good biocompatibility, and robust photostability. Using this multifunctional BTDN probe, the dynamic fluorescence imaging of accumulation behaviors of LDs in BV2 microglia with neuroinflammation was performed, demonstrating that LD formation may serve as a potential biomarker for neuroinflammation. Furthermore, overproduced LDs within microglia were directly observed in vivo and in tissue sections from the brains of AD mice. This work not only provides an imaging tool for dynamically characterizing LD accumulation in microglia but also provides insights into the relationship between LD accumulation in microglia and AD pathogenesis.},
}

*Alzheimer Disease/diagnostic imaging/metabolism
*Microglia/metabolism/chemistry
Animals
*Fluorescent Dyes/chemistry/chemical synthesis
*Blood-Brain Barrier/metabolism
Mice
*Lipid Droplets/metabolism/chemistry
*Neuroinflammatory Diseases/diagnostic imaging/metabolism
Optical Imaging
Humans
Infrared Rays
Fluorescent Chemosensor Compounds
Thiadiazoles/chemistry/chemical synthesis

@article {pmid43010452,
year = {2026},
author = {Yin, G and Tan, W and Wang, D and He, Z and Dou, C and Wang, H and Lu, Q and Zhong, G and Du, F and Yin, P},
title = {Simultaneous Visualization of Labile Ferrous Iron Pool and Biothiols Reveals Divergent Pathological Trajectories in Ferroptosis and Alzheimer's Disease.},
journal = {Analytical chemistry},
volume = {98},
number = {44},
pages = {31348-31359},
doi = {10.1021/acs.analchem.6c05055},
pmid = {43010452},
issn = {1520-6882},
support = {2024JJ6088//Natural Science Foundation of Hunan Province/ ; 22277026//National Natural Science Foundation of China (NSFC)/ ; 22407018//National Natural Science Foundation of China (NSFC)/ ; 32303040//National Natural Science Foundation of China (NSFC)/ ; 23B0786//Research Foundation of Education Bureau of Hunan Province/ ; },
mesh = {*Alzheimer Disease/metabolism/pathology ; *Ferroptosis ; Animals ; *Ferrous Compounds/analysis/metabolism ; Humans ; Mice ; *Fluorescent Dyes/chemistry/chemical synthesis ; *Sulfhydryl Compounds/metabolism/analysis ; Fluorescent Chemosensor Compounds ; Glutathione/analysis/metabolism ; *Iron/analysis/metabolism ; Cysteine/analysis/metabolism ; },
abstract = {Alzheimer's disease (AD) and ferroptosis share certain pathobiochemical features, yet the spatiotemporal evolution patterns and metabolic trajectories of their core hallmarks, labile ferrous iron pool and biothiols, and their pathophysiological relationship remain elusive. Herein, we developed a single-molecule dual-site fluorescent probe, FCG, for simultaneous discrimination of Fe2+, Cys/Hcy, and GSH via analyte-specific cascade reaction mechanisms. The probe exhibits rapid kinetics (k = 0.16-1.23 min-1), nanomolar sensitivity (detection limits: 38.8-509.2 nM), and well-separated emission signatures (Δλem ≥ 60 nm), facilitating concurrent visualization of these endogenous species dynamics in living systems. Importantly, application to cellular and mouse models revealed divergent metabolic pathways: ferroptosis displays synchronized labile ferrous iron pool accumulation, catastrophic lipid peroxidation, and global biothiols depletion, whereas AD exhibits modest iron elevation, a unique biothiols profile (elevated total Cys and Hcy but depleted GSH), and protein aggregation that is absent in ferroptosis. Comparative proteomic analysis further elucidated the molecular landscape of these dynamically regulated networks, as well as their distinct pathological metabolic trajectories. This study not only clarifies the mechanistic basis for the fundamentally different pathological trajectories underlying ferroptosis and AD but also provides critical evidence and analytical tools for targeted interventions in neurodegenerative diseases.},
}

*Alzheimer Disease/metabolism/pathology
*Ferroptosis
Animals
*Ferrous Compounds/analysis/metabolism
Humans
Mice
*Fluorescent Dyes/chemistry/chemical synthesis
*Sulfhydryl Compounds/metabolism/analysis
Fluorescent Chemosensor Compounds
Glutathione/analysis/metabolism
*Iron/analysis/metabolism
Cysteine/analysis/metabolism

@article {pmid43010991,
year = {2026},
author = {Lee, H and Ha, SY and An, H and Lee, SE and Oh, M and Kim, JS and Lee, JH and Lim, JS and Jang, H},
title = {CSF Biomarker-Supported Alzheimer's Disease Presenting as Primary Progressive Aphasia With a Negative Amyloid PET: A Case Report.},
journal = {Dementia and neurocognitive disorders},
volume = {25},
number = {4},
pages = {268-272},
pmid = {43010991},
issn = {2384-0757},
}

@article {pmid43010999,
year = {2026},
author = {Park, SH},
title = {Fetal Alcohol Spectrum Disorder as a Potential Early-Life Risk Factor for Dementia: A Life-Course Perspective.},
journal = {Dementia and neurocognitive disorders},
volume = {25},
number = {4},
pages = {195-209},
pmid = {43010999},
issn = {2384-0757},
abstract = {Current models of modifiable dementia risk span the life course but begin with formal education, leaving the prenatal period unexamined. Prenatal alcohol exposure (PAE) is the leading preventable cause of neurodevelopmental disability; its clinical expression is fetal alcohol spectrum disorder (FASD), of which fetal alcohol syndrome is the most severe form. FASD affects about 0.8% of children worldwide and considerably more in residential and foster care, yet its late-life trajectory is unstudied: the first diagnosed cohort is only now in its sixth decade. This review examines whether PAE may be an early-life dementia risk factor. In rodent models, developmental alcohol exposure produces hippocampal, cholinergic, and epigenetic changes demonstrable in adult animals; the report of Alzheimer-type markers in middle-aged exposed animals rests on a single unreplicated study. In humans, FASD is associated with low cognitive reserve, social adversity, and a high prevalence of adult alcohol use disorder, each an established dementia risk factor. Two hypotheses are distinguished: a pathology hypothesis, in which PAE promotes neurodegenerative change, and a reserve hypothesis, in which lower premorbid reserve brings forward clinical expression at comparable pathological burden. The expected phenotype is more likely mixed than purely Alzheimer-type. No human evidence yet links PAE to incident dementia; the proposition remains a hypothesis, not an established association. Given the mechanistic plausibility, examination is warranted through midlife biomarker studies and record linkage in cohorts with documented exposure; recording PAE in memory clinic history taking and at entry into residential and foster care would supply the data required.},
}

@article {pmid43011117,
year = {2026},
author = {Wang, Y and Lin, L and Xu, C and Zheng, Y and Zhu, Q},
title = {Association of systemic inflammation indices with severe cognitive impairment in Chinese Han patients with Alzheimer's disease: a cross-sectional study of NLR, PLR, SII, and SIRI.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1877189},
pmid = {43011117},
issn = {1663-4365},
abstract = {OBJECTIVE: The relationship between systemic inflammatory markers and cognitive impairment severity in Alzheimer's disease (AD) remains unclear. This study aimed to investigate the association of the neutrophil-to-lymphocyte ratio (NLR) and additional composite inflammatory indices-platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII), and systemic inflammation response index (SIRI)-with severe cognitive impairment (SCI) in Chinese Han patients with AD.

METHODS: This cross-sectional study included 282 Chinese Han patients with AD. Sociodemographic characteristics and biochemical indicators were collected, and NLR, PLR, SII, and SIRI were calculated. Cognitive function was assessed using the Montreal Cognitive Assessment (MoCA), and SCI was defined as a MoCA score ≤9. Multivariable logistic regression was used to analyze the associations of the four inflammatory indicators with SCI risk. Smooth curve fitting and piecewise linear regression models were applied, with threshold effect analysis performed. Subgroup analyses were conducted according to sex, age, years of education, disease duration, diabetes, hemoglobin, triglycerides, and free triiodothyronine.

RESULTS: After adjustment for covariates, NLR was linearly and positively associated with SCI risk (OR = 1.17, 95% CI: 1.00-1.37, p = 0.048). Neither PLR nor SIRI showed a significant association with SCI after multivariable adjustment (p > 0.05). In contrast, SII exhibited a non-linear association with SCI risk, with an inflection point at approximately 861.9. Above this threshold, each unit increase in SII was associated with a higher risk of SCI (OR = 1.02, 95% CI: 1.01-1.04, p = 0.01), whereas no significant association was observed below the threshold (p = 0.06).

CONCLUSION: In Chinese Han patients with AD, NLR was independently and linearly associated with a higher risk of SCI, while SII showed a threshold effect; PLR and SIRI exhibited no independent associations after multivariable adjustment. Among the four composite inflammatory indices, NLR and SII may hold potential value for assessing cognitive impairment severity in AD, whereas the negative findings for PLR and SIRI suggest that not all composite inflammatory indices are independently associated with SCI.},
}

@article {pmid43011190,
year = {2026},
author = {Parlak, MM and Bozdağ, Ö and Bizpınar Munis, Ö},
title = {Applicability of the Turkish Version of the Quick Aphasia Battery in Individuals With Alzheimer's Disease.},
journal = {Dementia and neurocognitive disorders},
volume = {25},
number = {4},
pages = {228-242},
pmid = {43011190},
issn = {2384-0757},
abstract = {BACKGROUND AND PURPOSE: Language impairment is a core clinical feature of Alzheimer's disease, emerging early and worsening progressively with disease stage. Although multidimensional language assessment tools are needed in Turkish clinical practice, validated rapid multidimensional batteries for this population remain limited. The Turkish version of the Quick Aphasia Battery (QAB-TR) covers eight language subdomains and can be administered in approximately 15 minutes. This study examined the applicability of QAB-TR in individuals with Alzheimer's disease (IwAD), its correlations with cognitive measures, and its sensitivity to disease stage.

METHODS: This cross-sectional study enrolled 55 IwAD (mild: n=19, moderate: n=18, severe: n=18). Participants underwent the Standardized Mini-Mental State Examination (SMMSE), Addenbrooke's Cognitive Examination III-Turkish Version (ACE-3-TR), and QAB-TR, with language assessments performed by a speech-language pathologist blinded to cognitive results and disease stage.

RESULTS: QAB-TR total scores differed significantly across all stage pairs (p<0.05). Grammatical construction distinguished all three stage pairs, while word comprehension, sentence comprehension, word finding, motor speech programming, and repetition distinguished mild-severe and moderate-severe pairs but not mild-moderate. The reading subtest distinguished only the mild-severe pair. QAB-TR total score correlated strongly with SMMSE (r=0.851, p<0.001) and ACE-3-TR (r=0.852, p<0.001), while motor speech programming showed notably lower correlations (r=0.281-0.338).

CONCLUSIONS: QAB-TR appears to be a clinically sensitive, multidimensional tool for assessing language impairment in IwAD. Its brevity, comprehensive subdomain coverage, and stage sensitivity provide preliminary evidence supporting its applicability in Turkish-speaking clinical settings.},
}

@article {pmid43011204,
year = {2026},
author = {Ashley, CC and Macauley, SL},
title = {The role of lactate in Alzheimer's disease: from controversies to therapeutic opportunities.},
journal = {Molecular neurodegeneration advances},
volume = {2},
number = {1},
pages = {50},
pmid = {43011204},
issn = {3059-4944},
abstract = {Alzheimer's disease (AD) is increasingly recognized as a disorder of disrupted brain metabolism, yet the role of specific metabolic intermediates in disease pathogenesis remains incompletely defined. Lactate, long considered a byproduct of glycolysis, is now understood to function as both an energy substrate and signaling molecule that links neuronal activity, glial biology, and network function. In this review, we synthesize clinical, preclinical, and multi-omic evidence to reframe lactate as a dynamic regulator of AD pathophysiology. Emerging data demonstrate that lactate is differentially regulated across disease stages and cellular compartments, with early increases associated with amyloid pathology, reactive glia, and neuronal hyperexcitability. We highlight evidence that disease reactive microglia undergo glycolytic reprogramming and represent a major and spatially enriched source of lactate in the AD brain, challenging the traditional astrocyte-centric view of lactate metabolism. We further discuss how lactate participates in feed-forward mechanisms linking metabolism to inflammation, neuronal excitability, and protein aggregation, but also through epigenetic modifications such as lactylation. Importantly, we propose a context-dependent framework in which lactate exerts both beneficial and maladaptive effects on disease progression. While transient or well-regulated lactate supports synaptic function and cognitive processes, sustained or dysregulated elevations may contribute to neuroinflammation, network dysfunction, sleep loss, and disease progression. Finally, we evaluate the potential of lactate as both a biomarker and therapeutic target. Together, this perspective integrates metabolism, neuroinflammation, and systems-level dysfunction, positioning lactate as a key therapeutic target in AD.},
}

@article {pmid43011205,
year = {2026},
author = {Lee, S and Heo, M and Kim, Y and Kim, S and Lee, SY and Jang, JW and , },
title = {Mediation of the Association Between APOE Genotype and Cognitive Change Through Alzheimer's Disease Biomarkers in Patients With Mild Cognitive Impairment.},
journal = {Dementia and neurocognitive disorders},
volume = {25},
number = {4},
pages = {243-252},
pmid = {43011205},
issn = {2384-0757},
abstract = {BACKGROUND AND PURPOSE: Apolipoprotein E (APOE) ε4 is associated with Alzheimer's disease risk and amyloid pathology, but whether cerebrospinal fluid (CSF) Alzheimer's disease biomarkers show statistical indirect effects in its association with longitudinal clinical worsening in mild cognitive impairment (MCI) remains unclear.

METHODS: We analyzed 397 participants with MCI from the Alzheimer's Disease Neuroimaging Initiative. The primary analysis used 36-month change in Clinical Dementia Rating-Sum of Boxes (CDR-SB) in the full cohort. APOE ε4 carrier status was the predictor, baseline CSF amyloid beta 1-42 (Aβ42) and phosphorylated tau 181 (p-tau181) were serial mediators, and age, sex, and education were covariates. Secondary analyses were stratified by amyloid status, and 12- and 24-month analyses and APOE ε4 allele-count models were exploratory and sensitivity analyses, respectively. Indirect effects were evaluated using 5,000 percentile bootstrap resamples.

RESULTS: In the full cohort, the total effect of APOE ε4 on 36-month CDR-SB change was significant (estimate, 1.047; 95% bootstrap confidence interval [CI], 0.552 to 1.540), whereas the residual direct effect was not (0.097; 95% CI, -0.447 to 0.636). The Aβ42-specific indirect effect was significant (0.751; 95% CI, 0.474 to 1.035), while the p-tau181-specific (0.068; 95% CI, -0.007 to 0.167) and sequential Aβ42-to-p-tau181 indirect effects (0.131; 95% CI, -0.002 to 0.309) were not. Secondary and allele-count sensitivity analyses were directionally consistent.

CONCLUSIONS: Lower CSF Aβ42 showed a significant statistical indirect association between APOE ε4 carrier status and 36-month clinical worsening in MCI. These observational findings do not establish a causal mediating mechanism.},
}

@article {pmid43011218,
year = {2026},
author = {Gonzalez-Ortiz, F and Kirsebom, BE and Santos, C and Arslan, B and Gundersen, JK and Kvartsberg, H and Sävman, K and Turton, M and Harrison, P and Coley Gleerup, HS and Frederiksen, KS and Hasselbalch, SG and Simonsen, AH and Fladby, T and Barreto Henriksson, H and Frandberg, S and Hellström, A and Groenendaal, F and Nafash, MN and Klaus, EN and Zeng, X and Karikari, TK and Zetterberg, H and Sjöbom, U},
title = {The antagonistic pleiotropy of tau phosphorylation: plasma tau species in newborns and Alzheimer's disease.},
journal = {Brain communications},
volume = {8},
number = {6},
pages = {fcag413},
pmid = {43011218},
issn = {2632-1297},
abstract = {Tau phosphorylation is essential for early brain development but is also central to Alzheimer's disease pathogenesis, suggesting an antagonistic pleiotropy model in which the same biology is beneficial early in life and harmful in ageing. Here, we investigate whether healthy term newborns exhibit higher concentrations of multiple phosphorylated tau species in plasma and compare their profiles against older adults and Alzheimer's disease patients. In this multicentre study, we used the Simoa HD-X platform to measure plasma phospho-tau (p-tau) species (p-tau217 and p-tau205), Glial fibrillary acidic protein (GFAP), Neurofilament light (NfL) and amyloid-β species (Aβ1-40 and Aβ1-42) in healthy term newborns (n = 42), aged controls (n = 41) and patients with Alzheimer's disease (n = 73). Perinatal associations were examined using multivariable regression adjusted for gestational age and birth weight. In an exploratory subset analysis comprising 12 aged controls and 27 term newborns, 220 analytes were measured using the Central Nervous System panel on the NULISA proteomics platform. Group comparisons were performed using either linear regression or Welch t-tests with Benjamini-Hochberg correction for multiple testing. In the Simoa analysis, plasma p-tau217 and p-tau205 showed a stepwise increase from controls to Alzheimer's disease and from Alzheimer's disease to newborns. Mean p-tau217 concentrations were 2.6 pg/mL in controls, 8.6 pg/mL in Alzheimer's disease and 17 pg/mL in newborns; corresponding p-tau205 concentrations were 0.5, 0.7 and 3.3 pg/mL. All pairwise differences for both tau species were significant. Correlations between p-tau markers differed across groups. Newborns showed a strong correlation (r = 0.81, P < 0.001), whereas correlations were weaker in Alzheimer's disease (r = 0.44, P < 0.001). Newborns also had the highest GFAP concentrations, whereas NfL was highest in Alzheimer's disease and lowest in newborns. Mode of delivery affected GFAP and NfL levels, but not p-tau217 or p-tau205, arguing against birth stress as the main driver of neonatal tau phosphorylation. The NULISA analysis independently supported broad neonatal enrichment of tau. Phosphorylated tau species were markedly higher in newborns than controls, and multiple epitopes, including the brain-derived forms of p-tau181, p-tau205, p-tau212, p-tau217 and p-tau231, clustered among proteins with positive newborn-control differences and strong statistical significance. Our findings identify a high early-life phospho-tau state across multiple epitopes that exceeds Alzheimer's disease levels but occurs outside of the amyloid/neurodegenerative biomarker profile. The results support the hypothesis that tau phosphorylation has divergent biological meanings across the lifespan and motivate mechanistic studies of how the developing brain tolerates high phospho-tau without an amyloid/neurodegenerative biomarker profile.},
}

@article {pmid43011223,
year = {2026},
author = {Duran, T and Barcus, RA and Gaussoin, SA and Bacci, JR and Bateman, JR and Hughes, TM and Whitlow, CT and Craft, S and Lockhart, SN},
title = {Diffusion MRI metrics of white matter association tracts are associated with cognitive migration in older adults without dementia.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {4},
pages = {e70520},
pmid = {43011223},
issn = {2352-8729},
abstract = {INTRODUCTION: We analyzed baseline diffusion magnetic resonance imaging (MRI) data including diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) to predict cognitive transitions over a 1-year follow-up in older adults without dementia.

METHODS: A total of 366 participants from the Wake Forest Alzheimer's Disease Research Center (ADRC) Healthy Brain Study (HBS) were included. The outcome was cognitive migration (CM), defined based on Clinical Dementia Rating (CDR) global score transitions: CDR 0 to 0 (CDR-0 Stable), CDR 0 to 0.5 (Migrant[-]), CDR 0.5 to 0.5 (CDR-0.5 Stable), and CDR 0.5 to 0 (Reverter[+]). NODDI free water (FW) and DTI metrics (fractional anisotropy [FA] and mean diffusivity [MD]) from whole brain and white matter (WM) association tracts were examined for their association with 1-year CM status.

RESULTS: CM transition rates were: 46% CDR-0 Stable, 29% CDR-0.5 Stable, 16% Reverter[+], and 9% Migrant[-]. In WM association tracts, the Reverter[+] group had higher DTI FA and lower MD than the CDR-0.5 Stable group.

DISCUSSION: FA and MD (not FW) may be sensitive markers for reversion during early transitions in WM association tracts.},
}

@article {pmid43011234,
year = {2026},
author = {Zhang, S and Hu, H and Wang, X and Xiong, C and Kanekiyo, T and Asmann, YW and Ren, Y},
title = {scMINA: an interpretable workflow for paired scRNA-scATAC multiome integration and regulatory prioritization.},
journal = {NAR genomics and bioinformatics},
volume = {8},
number = {4},
pages = {lqag140},
pmid = {43011234},
issn = {2631-9268},
mesh = {Humans ; Multiomics ; *Single-Cell Analysis/methods ; Single-Cell Gene Expression Analysis ; Workflow ; Alzheimer Disease/genetics/pathology/metabolism ; *Software ; *RNA-Seq/methods ; Gene Regulatory Networks ; Chromatin/genetics/metabolism ; *RNA, Small Cytoplasmic/genetics ; },
abstract = {Single-cell multiomic technologies that jointly profile transcriptomic and epigenomic states provide unprecedented opportunities to investigate cellular heterogeneity and gene regulatory mechanisms in complex diseases. However, analysis of paired single-cell RNA-seq (scRNA-seq) and chromatin accessibility (scATAC-seq) data remains computationally challenging due to modality-specific technical variation, integration complexity, and limited interpretability of downstream regulatory inference. Here, we present scMINA (single-cell Multimodal Integration and Network Attribution), a modular and interpretable analytical workflow for the analysis of paired single-cell multiome datasets. scMINA comprises coordinated modules for multimodal integration, technical covariate correction, and regulatory feature prioritization, enabling systematic characterization of cellular states across transcriptomic and epigenomic modalities. In addition, scMINA incorporates explainable artificial intelligence-based attribution strategies to prioritize candidate genes and transcription factors associated with cell-state heterogeneity and disease-related regulatory alterations. We applied scMINA to the single-cell multiome data from the Seattle Alzheimer's Disease Brain Cell Atlas, where the workflow robustly resolved major glial cell populations and identified regulatory features associated with Alzheimer's disease pathology. By coupling multimodal integration with interpretable regulatory prioritization, scMINA provides a practical workflow for systematic analysis and biological interpretation of paired scRNA-seq and scATAC-seq datasets.},
}

Humans
Multiomics
*Single-Cell Analysis/methods
Single-Cell Gene Expression Analysis
Workflow
Alzheimer Disease/genetics/pathology/metabolism
*Software
*RNA-Seq/methods
Gene Regulatory Networks
Chromatin/genetics/metabolism
*RNA, Small Cytoplasmic/genetics

@article {pmid43011405,
year = {2026},
author = {Lamola, II and Veliotes, DGA and Mochan, A},
title = {The profile of patients diagnosed with Parkinson's disease at the Charlotte Maxeke Johannesburg Academic Hospital.},
journal = {Journal of the colleges of medicine of South Africa},
volume = {4},
number = {1},
pages = {425},
pmid = {43011405},
issn = {2960-110X},
abstract = {BACKGROUND: Idiopathic Parkinson's disease (IPD) is the second most common neurodegenerative disorder after Alzheimer's disease, but data from Sub-Saharan Africa are scarce. This study describes the demographic and clinical characteristics of IPD patients at the Charlotte Maxeke Johannesburg Academic Hospital movement disorder clinic and evaluates disease severity with the Unified Parkinson's Disease Rating Scale (UPDRS-III) and the Hoehn and Yahr staging scales.

METHODS: A prospective cohort study was conducted from May 2024 to May 2025, enrolling adult patients (≥ 18 years) with a diagnosis of IPD.

RESULTS: Eighty-two patients were included (mean age 68.2 years, s.d. 10.9; 59.8% male; 52.4% Black African). Median disease duration was 3 years (interquartile range [IQR] 1-6). Levodopa monotherapy was the most common treatment (42.7%), followed by combinations with amantadine or pramipexole. The median UPDRS-III score was 60 (IQR 48-76), with 73.2% classified as having severe disease. The Hoehn and Yahr staging revealed that 39% of patients were at Stage 4 and 11% at Stage 5.

CONCLUSION: Most patients in this cohort had advanced disease at presentation, underscoring the need for earlier diagnosis and timely referral to specialist clinics.

CONTRIBUTION: These findings highlight the importance of strengthening movement disorder services in South Africa and suggest that delayed presentation may contribute to the high burden of severe disease in this population.},
}

@article {pmid43011462,
year = {2026},
author = {Ashish, RM and Turner, JA},
title = {Evaluating the Accuracy of Remote Questionnaire and Speech Measures in Detecting Cognitive Impairment in the ADNI4 Remote Digital Cohort: Cross-Sectional Study.},
journal = {JMIR neurotechnology},
volume = {5},
number = {},
pages = {e108372},
pmid = {43011462},
issn = {2817-092X},
abstract = {BACKGROUND: Scalable remote approaches are increasingly needed to identify cognitive impairment in clinical research. The Everyday Cognition (ECog) scale and its short form (12-item Everyday Cognition [ECog12]) capture subjective cognitive and functional decline, whereas automated speech-based story recall provides an objective measure of cognitive performance. Whether speech recall contributes information beyond remote questionnaire assessment remains unclear.

OBJECTIVE: This study aimed to determine whether automated speech-based story recall measures provide incremental discrimination of cognitive impairment diagnoses beyond the self-reported ECog12 (Self-ECog12) scale and demographics, both without and with 2 additional subjective memory measures that assess current memory/thinking concerns and perceived recent decline.

METHODS: This cross-sectional study included 7268 individuals from the Alzheimer's Disease Neuroimaging Initiative 4 (ADNI4) Remote Digital cohort with complete baseline questionnaire, demographic, and Storyteller speech-recall data. The outcome was defined as a participant report of a prior diagnosis of mild cognitive impairment or memory problem, Alzheimer disease, or dementia (n=574, 7.9%). Participants completed a smartphone-based Storyteller assessment involving immediate and delayed spoken recall of standardized stories; recordings were automatically analyzed to derive 5 prespecified recall and language measures. Participants were stratified into training and independent natural-prevalence test cohorts. Logistic regression models evaluated Self-ECog12 alone; Self-ECog12 plus demographics; Storyteller added to that model; the 2 additional subjective memory measures; and the full model incorporating Storyteller. Model development and threshold selection were confined to training data. Discrimination, calibration, and threshold-dependent performance were evaluated in the held-out test cohort. Area under the receiver operating characteristic curve (AUC) comparisons used paired DeLong tests.

RESULTS: The test cohort included 1817 participants, of whom 143 (7.9%) reported a prior diagnosis. Self-ECog12 alone achieved an AUC of 0.792 (95% CI 0.755-0.828), increasing to 0.827 (95% CI 0.792-0.859) with demographics. Adding Storyteller increased AUC to 0.853 (95% CI 0.821-0.883; ΔAUC 0.026, 95% CI 0.009-0.043; paired DeLong P=.002). With the 2 subjective memory measures included, AUC was 0.857 (95% CI 0.830-0.882) and increased to 0.875 (95% CI 0.851-0.899) after adding Storyteller (ΔAUC 0.019, 95% CI 0.008-0.030; P<.001). At the frozen threshold, the full model achieved sensitivity of 0.874 (95% CI 0.818-0.930), specificity of 0.746 (95% CI 0.725-0.767), positive predictive value of 0.227 (95% CI 0.210-0.246), and negative predictive value of 0.986 (95% CI 0.980-0.992). The Brier score was 0.060, with a calibration intercept of 0.023 and a slope of 0.870, suggesting acceptable calibration with overfitting.

CONCLUSIONS: Speech measures provided incremental information beyond Self-ECog12 and demographics, with and without additional subjective memory measures. These findings support further evaluation of multimodal remote assessment as a scalable screening or enrichment approach for identifying individuals who may benefit from clinical evaluation. Because the outcome was a participant-reported prior diagnosis rather than an independently adjudicated current diagnosis, validation against clinically adjudicated outcomes is necessary before diagnostic use.},
}

@article {pmid43011480,
year = {2026},
author = {Vesque, C and Segobin, S and Coppalle, R and Colas, A and Naveau, M and Mauger, C and Hommet, M and de la Sayette, V and Eustache, F and Platel, H and Groussard, M},
title = {Newly learned items form long-term memory in severe Alzheimer's disease despite hippocampal atrophy.},
journal = {Brain communications},
volume = {8},
number = {6},
pages = {fcag399},
pmid = {43011480},
issn = {2632-1297},
abstract = {Alzheimer's disease is a neurodegenerative disorder marked by a progressive decline in episodic memory and impaired encoding of new information. While hippocampal atrophy is a hallmark of the disease, several observations suggest that some mechanisms may remain preserved, including familiarity-based recognition. Artistic items, such as music and paintings, are particularly suitable to elicit these spared processes, as they engage reward, emotional, and implicit learning networks that remain intact in this condition. However, the extent to which patients with moderate to severe Alzheimer's disease can learn new information in these domains remains unclear. Thirty-three patients with Alzheimer's disease (79.30 ± 5.82 years; mean Mini-Mental State Examination [MMSE] score = 14.76 ± 5.42) and 24 healthy control participants (77.17 ± 4.62 years; mean MMSE score = 28.83 ± 0.92) were included in the protocol. A data-driven stratification based on neuropsychological scores identified two subgroups of patients, classified as moderate and severe cognitive impairments. Participants first completed repeated exposure sessions to unknown musical and pictorial items until they reported a sense of familiarity, assessed by a six-point scale designed for this population. One to two days later, a recognition session during which target items and distractor items were presented was conducted; participants' performance was also evaluated using the familiarity scale. Structural MRI was acquired to quantify hippocampal atrophy and examine the relationship between grey matter volume and recognition performance. Despite significantly different learning rates across clinical groups (cumulative link mixed model, all pairwise comparisons P < 0.001), 31 patients out of 33 reached the learning criterion for at least one of the two artistic materials. In the recognition session, pairwise comparisons confirmed that all clinical groups significantly discriminated target from distractor items (cumulative link mixed model, all pairwise comparisons P < 0.001), with a gradient of discrimination consistent with disease severity, indicating preserved but modulated familiarity-based recognition. Structural imaging confirmed substantial hippocampal atrophy in both patient subgroups relative to healthy controls (P < 0.001). Multiple regression revealed that higher familiarity scores in recognition session were associated with greater grey matter volume in the right caudate nucleus (cluster-level, P FWE < 0.05). These findings demonstrate that patients with moderate to severe Alzheimer's disease retain the ability to encode new musical and pictorial information despite pronounced hippocampal atrophy. Familiarity-based mechanisms, supported by subcortical regions, appear to underpin this preserved learning and may offer promising perspectives for care in patients with Alzheimer's disease.},
}

@article {pmid43011630,
year = {2026},
author = {Vahid, A and Faghihzadeh, S and Hubert, J and Hosseini, SMH},
title = {Choroid plexus biomarkers capture neuroinflammatory processes associated with amyloid and neurodegeneration in Alzheimer's disease.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {4},
pages = {e70491},
pmid = {43011630},
issn = {2352-8729},
abstract = {INTRODUCTION: The amyloid/tau/neurodegeneration (ATN) framework characterizes Alzheimer's disease (AD) biomarkers but does not fully capture neuroinflammation. The choroid plexus (CP), a critical blood-cerebrospinal fluid (CSF) barrier component, has emerged as a neuroinflammatory imaging marker whose relationship to established AD biomarkers remains unclear.

METHODS: We analyzed multimodal data from 641 Alzheimer's Disease Neuroimaging Initiative participants using magnetic resonance imaging, amyloid/tau positron emission tomography, CSF/plasma biomarkers, and cognitive measures. Associations were examined via correlations, amyloid-stratified analyses, and structural equation modeling (SEM).

RESULTS: CP volume was consistently associated with hippocampal atrophy but did not differentiate amyloid-positive from amyloid-negative individuals. Plasma glial fibrillary acidic protein showed the strongest association with CP volume, particularly in amyloid-positive participants. SEM linked CP volume and entorhinal tau to hippocampal atrophy, with amyloid contributing indirectly through tau.

DISCUSSION: CP volume reflects neuroinflammatory processes more closely tied to neurodegeneration than to amyloid or tau pathology, supporting its role as a complementary biomarker within the ATN framework.},
}

@article {pmid43011645,
year = {2026},
author = {Luo, Y and Yu, H and Zhang, J and Wu, Z and Zhang, H},
title = {Deciphering the effects of aging on Alzheimer's disease based on mitochondrial dysfunction and neuroinflammation.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1991837},
pmid = {43011645},
issn = {1663-4365},
abstract = {Alzheimer's disease (AD), a neurological disorder characterized by progressive deterioration of cognitive function, has complex pathogenic mechanisms and lacks curative therapies with proven efficacy. Aging and inflammatory responses, which play indispensable roles in the onset and progression of AD, are closely intertwined with mitochondrial dysfunction. During aging, a series of degenerative alterations, including accumulated mitochondrial DNA (mtDNA) mutations, excessive mitochondrial reactive oxygen species (ROS) accumulation, disrupted mitochondrial quality control (MQC) and disturbed energy metabolism, further induce structural mitochondrial damage. This damage causes the leakage of damage-associated molecular patterns (DAMPs) and activates numerous downstream inflammatory signaling pathways. In brain tissue, inflammatory cytokines, which continuously facilitate blood-brain barrier (BBB) disruption, aberrant activation of microglial cells, tau protein hyperphosphorylation, as well as Aβ accumulation, drive an endlessly amplified neuroinflammatory cascade that leads to irreversible neuronal damage and fuels the initiation and progression of AD. In this review, we clarify the regulatory effects of aging on AD pathogenesis through the mitochondrial dysfunction-chronic inflammation axis and ultimately focus on mitochondrial-targeted therapies, with future outlooks for AD treatment provided.},
}

@article {pmid43011657,
year = {2026},
author = {Wang, J and Wu, J and Liang, F and Huang, S and Liu, L and Huang, Y and Wang, Y},
title = {Gastrodin combined with donepezil alleviates cognitive dysfunction in Alzheimer's disease mice by improving mitochondrial function through AMPK/PGC-1α/SIRT3 axis.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1978729},
pmid = {43011657},
issn = {1663-4365},
abstract = {OBJECTIVE: This study aims to explore whether gastrodin (Gas) combined with donepezil (Don) has a neuroprotective effect on Alzheimer's disease (AD) mice by regulating the AMPK/PGC-1α/SIRT3 signaling axis.

METHODS: HT22 cells were transfected with SIRT3 siRNA or control siRNA. Cells were then treated with the AMPK inhibitor, Don, Gas, or their combination. Subsequently, HT22 cells were treated with Amyloid beta 1-42 (Aβ 1-42) to induce an in vitro AD model. Cell viability was detected by CCK8 assay. DCFH-DA fluorescent probe was used to evaluate cell reactive oxygen species (ROS). Adenosine triphosphate (ATP) content was detected by luciferase chemiluminescence method. Cell membrane potential was measured by flow cytometry. For in vivo experiments, WT mice and APP/PS1 mice were treated with Don, Gas or a combination of drugs. Morris water maze test, Y-maze test and novel object recognition test were used to evaluate the cognitive impairment of mice. The pathological changes of hippocampus were detected by HE staining, and the expression of Aβ protein in hippocampus and cortex was detected by IHC. In addition, the protein and mRNA expressions of APP, Tau, and AMPK/PGC-1α/SIRT3 signaling axis were determined by Western blot and RT-QPCR.

RESULTS: Gas combined with Don significantly improved cognitive dysfunction, reduced Aβ plaque deposition in the cortex and hippocampus, up-regulated AMPK/PGC-1α/SIRT3 axis, and inhibited the abnormal phosphorylation of Tau and APP in APP/PS1 mice compared with the model group and the Don group (p < 0.05). In vitro cell experiments confirmed that the combination of the two drugs could improve cell viability, inhibit cell apoptosis, restore ATP level, reduce ROS accumulation, stabilize mitochondrial membrane potential, and improve mitochondrial function (p < 0.05). Molecular experiments and complementary experiments showed that Gas combined with Don activated AMPK/PGC-1α/SIRT3 signaling axis (p < 0.05). Silencing SIRT3 or inhibiting AMPK could reverse the protective effect of the combined regimen (p < 0.05).

CONCLUSION: Gas combined with Don can maintain mitochondrial homeostasis through AMPK/PGC-1α/SIRT3 pathway, alleviate AD-relaated pathological damage, and exert neuroprotection.},
}

@article {pmid43011830,
year = {2026},
author = {Lin, J and Zou, X},
title = {From intestinal barrier sensing to glial immune programming: a barrier-immune-glia relay in microbiota-associated neurodegeneration.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1956619},
pmid = {43011830},
issn = {1664-3224},
mesh = {Humans ; Intestinal Barrier Function ; Animals ; *Neurodegenerative Diseases/immunology/metabolism/microbiology/etiology ; *Neuroglia/immunology/metabolism ; *Gastrointestinal Microbiome/immunology ; Blood-Brain Barrier/immunology/metabolism ; *Intestinal Mucosa/immunology/metabolism/microbiology ; },
abstract = {The gut microbiota contributes to host homeostasis through metabolic, immunological, neural, and barrier-related pathways, and its role in the onset and progression of neurodegenerative diseases has received increasing attention. Patients with Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis often exhibit alterations in gut microbial composition, microbial metabolic function, and peripheral inflammatory phenotypes. However, existing clinical evidence is derived predominantly from cross-sectional studies, and the direction of causality between microbiota alterations and disease pathology remains to be established. This review uses a "barrier-immune-glial relay" framework to systematically summarize the potential mechanisms through which gut microbiota-associated signals influence immune homeostasis in the central nervous system. First, alterations in microbial composition, short-chain fatty acids, bile acids, tryptophan derivatives, and lipopolysaccharide may act on the intestinal epithelial barrier, enteric nervous system, and intestinal mucosal immune cells, thereby affecting local immune tolerance and inflammatory responses. Second, intestinal macrophages, dendritic cells, innate lymphoid cells, T cells, and B cells may translate local microbial signals into circulating metabolites, inflammatory mediators, and immune cell-associated signals, which may in turn influence blood-brain barrier function and the central immune microenvironment. Furthermore, microglia and astrocytes, as key integrators within the central nervous system, can respond to gut-derived metabolites and peripheral immune signals. Their interaction network may determine whether neuroinflammation, synaptic injury, and neurodegenerative pathology are amplified or constrained. This review also evaluates the levels of evidence supporting these mechanisms in Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and multiple sclerosis. Although these disorders may share mechanistic nodes, including barrier impairment, immunometabolic dysregulation, and glial responses, their core pathologies, immune contexts, and temporal disease trajectories differ substantially. Finally, we propose that establishing a verifiable causal chain linking "microbial functional genes-metabolites-barrier and immune remodeling-glial cell states-neuropathology-clinical phenotypes" will provide a basis for biomarker development and precision interventions in neurodegenerative diseases.},
}

Humans
Intestinal Barrier Function
Animals
*Neurodegenerative Diseases/immunology/metabolism/microbiology/etiology
*Neuroglia/immunology/metabolism
*Gastrointestinal Microbiome/immunology
Blood-Brain Barrier/immunology/metabolism
*Intestinal Mucosa/immunology/metabolism/microbiology

@article {pmid43011839,
year = {2026},
author = {Ramineni, V and Khan, FF and Kim, JH and Kwon, GR},
title = {Speech and sMRI as multimodal biomarkers for early detection of Alzheimer's disease using machine learning, deep learning, and transformer-based models.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1975870},
pmid = {43011839},
issn = {1663-4365},
abstract = {Alzheimer's disease (AD) and its prodromal stage, MCI are typically diagnosed using cerebrospinal fluid analysis and amyloid positron emission tomography procedures that are invasive, costly, and poorly suited to population-scale screening. Speech and structural magnetic resonance imaging (sMRI) have emerged as complementary non-invasive alternatives: speech captures the real-time functional consequences of neurodegeneration on lexical retrieval, semantic organization, and prosody, while structural MRI reveals the anatomical substrate of cortical and subcortical atrophy that underlies these impairments. This Mini Review examines how machine learning, deep learning, graph based and transformer based models have been applied to these two modalities, individually and in combination, for classifying cognitively normal individuals and those with MCI or AD. We trace the progression from classical machine learning on hand-engineered acoustic and lexical features, through convolutional and recurrent neural networks that learn volumetric atrophy patterns and discourse-level speech representations, to vision transformers and graph neural networks that capture long-range spatial and connectomic dependencies in brain structure. We then examine multimodal fusion strategies early, late, intermediate and the cross-modal attention architectures that link speech and MRI within a single, interpretable framework. While intermediate fusion shows the strongest diagnostic performance in early evidence, this advantage narrows in the three-way classification task most relevant to clinical screening. We close by identifying dataset diversity, language dependency, and the lack of longitudinal multimodal studies as the principal barriers to clinical translation.},
}

@article {pmid43011928,
year = {2026},
author = {Blanton, C and Hines, J and Ginsburg, J and Parnell, S},
title = {Acute Neurologic Decline in the ED: A Case Report on Recognizing ARIA in the Age of Anti-Amyloid Therapy.},
journal = {Journal of education & teaching in emergency medicine},
volume = {11},
number = {4},
pages = {V37-V43},
pmid = {43011928},
issn = {2474-1949},
abstract = {UNLABELLED: Anti-amyloid beta (Aβ) immunotherapies are an emerging treatment for Alzheimer's disease (AD) with a rare but significant risk of amyloid-related imaging abnormalities (ARIA). This visual case report describes a patient with lecanemab-induced ARIA to familiarize emergency providers with this critical adverse effect of novel anti-amyloid therapies. An 85-year-old female receiving lecanemab infusions presented to the emergency department (ED) with abruptly worsening confusion, an unsteady gait, and new left-sided deficits, including homonymous hemianopia and hemineglect. A non-contrast head computed tomography (CT) revealed extensive right parieto-occipital vasogenic edema, prompting magnetic resonance imaging (MRI), which confirmed extensive ARIA with edema (ARIA-E) on fluid-attenuated inversion recovery (FLAIR) sequences and microhemorrhages (ARIA-H) on T2-weighted sequences. Lecanemab was discontinued, and the patient experienced partial neurologic recovery after a four-day admission. However, she was discharged with persistent functional limitations, including an inability to drive and a need for caregiver assistance. This case underscores the need for emergency physicians to maintain a high index of suspicion for ARIA in patients on anti-Aβ immunotherapies who present with new neurologic symptoms. Definitive diagnosis requires MRI, and management warrants prompt neurologic consultation.

TOPICS: Alzheimer's, dementia, neurology, medication adverse effects, ARIA.},
}

@article {pmid43012281,
year = {2026},
author = {Mohammed, SI and Taha, MA and Allami, AJ and Mohammed, EA and Ibrahim, RO},
title = {Artificial Intelligence for Brain MRI Diagnosis: A Scoping Review and Evidence-Gap Map Across Neurological Diseases.},
journal = {Current medical imaging},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115734056523075261026051524},
pmid = {43012281},
issn = {1573-4056},
abstract = {INTRODUCTION/OBJECTIVE: Artificial Intelligence (AI), including machine learning and deep learning, is increasingly applied to brain Magnetic Resonance Imaging (MRI) for disease detection, classification, segmentation, and clinically relevant prediction. This review aimed to map the evidence on AI-assisted brain MRI diagnosis, identify methodological and clinical translation gaps, and propose priorities for future research.

METHODS: This scoping review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews. PubMed/MEDLINE, Scopus, IEEE Xplore, and Web of Science were searched for peer-reviewed English-language publications from January 2018 to April 2026. Data were charted according to disease domain, study design, AI method, dataset, validation strategy, performance metrics, explainability, and key limitations.

RESULTS: The search identified 1,020 records. After duplicate removal and screening, 61 publications were included, comprising 24 original studies used for the primary evidence map and 37 reviews or commentaries used for contextual synthesis. Evidence was strongest for brain tumor imaging and Alzheimer's disease, whereas stroke, multiple sclerosis, pediatric neuroimaging, and rare neurological conditions were underrepresented. Most studies relied on public benchmark datasets and retrospective validation, whereas external validation, prospective clinical evaluation, subgroup analysis, explainability, and workflow integration were inconsistently reported.

DISCUSSION: The findings indicate that AI-assisted brain MRI research remains unevenly developed and is constrained by dataset dependence, limited external validation, limited prospective clinical evaluation, and inconsistent reporting of explainability, subgroup performance, and workflow integration.

CONCLUSION: AI shows promising research-stage potential for brain MRI-based diagnosis, particularly in brain tumor analysis and Alzheimer's disease classification. Future research should prioritize multicenter validation, diverse and disease-specific datasets, explainable and equitable AI design, transparent reporting, and prospective evaluation within real clinical workflows.},
}

@article {pmid43012292,
year = {2026},
author = {Eng, JH and Chong, AEY and Koh, RY and Ling, APK},
title = {Ferroptosis as a Therapeutic Target in Neurological Disorders: Pharmacological Advances and Translational Challenges.},
journal = {Current pharmaceutical biotechnology},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113892010520055261019113815},
pmid = {43012292},
issn = {1873-4316},
abstract = {Ferroptosis is an iron-mediated form of programmed cell death characterised by distinct features, including excessive iron accumulation, lipid peroxidation, and impaired antioxidant mechanisms. The susceptibility of the Central Nervous System (CNS) to ferroptosis has been reported, along with evidence that ferroptosis is associated with neurological disorders such as Alzheimer's Disease (AD), Parkinson's Disease (PD), Amyotrophic Lateral Sclerosis (ALS), stroke, and Multiple Sclerosis (MS). To date, major ferroptosis inhibitors encompass iron chelators, lipid-trapping antioxidants, and antioxidant modulators. Translational challenges in drug toxicity, selectivity, and delivery promote drug development in terms of improving pharmacokinetics through structural modification, alternative routes of administration, and nanoparticle encapsulation. In addition, research on identifying novel and promising ferroptosis inhibitors from natural products and known drug compounds is continuous, accompanied by ongoing drug optimisation and modification. Biomarkers of ferroptosis have been discussed given the emerging clinical interest in them for disease diagnosis or prognosis and patient stratification. Standalone anti-ferroptotic treatments for CNS disorders have been found to be difficult to achieve favourable clinical outcomes, thereby suggesting combination therapies that not only harness ferroptosis but also address diverse pathological pathways in the respective diseases as a prospect for managing CNS disorders. Thus, this article aims to review recent updates on clinically approved ferroptosis inhibitors as well as summarise the current drug development landscape and outline future directions to provide a better understanding of the contemporary development of ferroptosis inhibitors for neurological disorders.},
}

@article {pmid43012625,
year = {2026},
author = {Chen, L and Wei, M and Zhang, Q and Jia, L and Zheng, Z and Tan, R},
title = {Natural Glycosides in Neurodegenerative Diseases: Multi-Target Mechanisms via the Gut-Brain Axis.},
journal = {Phytotherapy research : PTR},
volume = {},
number = {},
pages = {},
doi = {10.1002/ptr.70521},
pmid = {43012625},
issn = {1099-1573},
support = {2024zd021//Sichuan Provincial Administration of Traditional Chinese Medicine/ ; 25ZDAZX012//Sichuan Provincial Administration of Traditional Chinese Medicine/ ; 2024zd033//Sichuan Provincial Administration of Traditional Chinese Medicine/ ; },
abstract = {The multifactorial complexity of neurodegenerative diseases (NDs), including Alzheimer's and Parkinson's disease, limits the efficacy of single-target therapies. Natural glycosides exhibit promising neuroprotective potential, but their clinical translation is hindered by poor oral bioavailability and limited blood-brain barrier (BBB) penetration. The gut-brain axis offers a framework for understanding their potential biological effects beyond direct central exposure. This review explores the multi-target mechanisms of natural glycosides in NDs, focusing on their interactions with the gut-brain axis. A narrative literature search was conducted in PubMed, Web of Science, and ScienceDirect for studies published up to June 2026. Relevant literature on glycosides, NDs, gut microbiota, microbial biotransformation, pharmacokinetics, and neuroprotective mechanisms was critically reviewed. Natural glycosides may affect ND-related processes through gut-mediated and systemic/central mechanisms. Poorly absorbed glycosides can interact with intestinal microbiota, potentially modulating microbial composition, intestinal barrier integrity, and short-chain fatty acids (SCFAs) production. Microbial biotransformation may generate metabolites with altered physicochemical properties and systemic exposure, potentially enhancing central nervous system accessibility in a compound-specific manner. Experimental evidence also suggests effects on neuroinflammation, mitochondrial homeostasis, autophagy, and synaptic function. However, most findings remain preclinical, with limited direct human evidence. The gut-brain axis provides a valuable perspective for understanding the biological activities of natural glycosides despite their limited oral bioavailability and BBB penetration. Further pharmacokinetic studies, causal investigations of microbiota-mediated effects, and controlled clinical trials are needed to establish their therapeutic potential in NDs.},
}

@article {pmid43012695,
year = {2026},
author = {Hao, M and Wu, D and Sun, L and Lai, X and Chen, R and Zhang, Z and Li, Q and Zhang, S and Zheng, X and Li, D and Sun, S},
title = {Isovitexin Attenuates Aβ-Induced Neurotoxicity by Activating SKN-1/Nrf2 Signaling and Suppressing Ferroptosis in Caenorhabditis elegans Models of Alzheimer's Disease.},
journal = {Journal of agricultural and food chemistry},
volume = {74},
number = {44},
pages = {34867-34884},
doi = {10.1021/acs.jafc.6c10083},
pmid = {43012695},
issn = {1520-5118},
support = {R2026PY-TJ027//Guangdong Academy of Agricultural Sciences/ ; XT202506//Guangdong Academy of Agricultural Sciences/ ; 2022A1515110190//Basic and Applied Basic Research Foundation of Guangdong Province/ ; 2023A1515010264//Basic and Applied Basic Research Foundation of Guangdong Province/ ; 2024A1515010696//Basic and Applied Basic Research Foundation of Guangdong Province/ ; 2021ZDZX002//Guangdong Provincial Science and Technology Achievements Reach Townships Special Project/ ; R2021YJ-YB3014//Guangdong Academy of Agricultural Sciences Special Fund Project to Introduce Science and Technology Talent/ ; R2024YJ-YB3005//Guangdong Academy of Agricultural Sciences Special Fund Project to Introduce Science and Technology Talent/ ; SKXRC2025483//Guangdong Provincial Association for Science and Technology/ ; },
mesh = {Animals ; *Caenorhabditis elegans/metabolism/genetics/drug effects ; *Amyloid beta-Peptides/metabolism/toxicity/genetics ; *Alzheimer Disease/metabolism/drug therapy/genetics/physiopathology ; *Caenorhabditis elegans Proteins/metabolism/genetics ; Signal Transduction/drug effects ; *Ferroptosis/drug effects ; *Transcription Factors/metabolism/genetics ; *NF-E2-Related Factor 2/metabolism/genetics ; *Apigenin/administration & dosage ; *DNA-Binding Proteins/metabolism/genetics ; Humans ; Disease Models, Animal ; Mitochondria/metabolism/drug effects ; Neuroprotective Agents/administration & dosage ; Oxidative Stress/drug effects ; Tea/chemistry ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by β-amyloid (Aβ) deposition, oxidative stress, ferroptosis, and mitochondrial dysfunction, while effective therapeutic interventions remain limited. Epidemiological evidence indicates that tea and flavonoids with antiaging properties lower AD risk. In this study, untargeted metabolomic profiling identified isovitexin as a differentially abundant flavonoid in postfermented dark tea (DT), and Caenorhabditis elegans (C. elegans) AD models were employed to evaluate its anti-AD potential and elucidate the underlying molecular mechanisms. The results showed that isovitexin significantly extended lifespan, reduced Aβ accumulation, and improved neuromuscular function, demonstrating marked neuroprotective effects. Mechanistically, isovitexin mitigated Aβ-triggered toxicity through SKN-1 signaling, accompanied by the attenuation of Aβ-evoked ferroptosis and mitochondrial dysfunction. Collectively, these results broaden the therapeutic potential of dark tea flavonoids and support further investigation of isovitexin as a candidate for mitigating Aβ-induced neurodegeneration.},
}

Animals
*Caenorhabditis elegans/metabolism/genetics/drug effects
*Amyloid beta-Peptides/metabolism/toxicity/genetics
*Alzheimer Disease/metabolism/drug therapy/genetics/physiopathology
*Caenorhabditis elegans Proteins/metabolism/genetics
Signal Transduction/drug effects
*Ferroptosis/drug effects
*Transcription Factors/metabolism/genetics
*NF-E2-Related Factor 2/metabolism/genetics
*Apigenin/administration & dosage
*DNA-Binding Proteins/metabolism/genetics
Humans
Disease Models, Animal
Mitochondria/metabolism/drug effects
Neuroprotective Agents/administration & dosage
Oxidative Stress/drug effects
Tea/chemistry

@article {pmid43012735,
year = {2026},
author = {Tuncgovde, E and Kemiklioglu, E and Kocabiyik, M and Erac, Y and Ozsarlak-Sozer, G},
title = {A unique liquid crystal-based biosensor for label-free detection of amyloid beta-42 peptide using gelsolin protein.},
journal = {Analytical methods : advancing methods and applications},
volume = {},
number = {},
pages = {},
doi = {10.1039/d6ay01961g},
pmid = {43012735},
issn = {1759-9679},
abstract = {In this study, we report the development of a liquid crystal (LC)-based biosensor functionalized with gelsolin protein for the detection of Alzheimer's disease (AD)-related amyloid beta-42 (Aβ42). The gelsolin-modified glass substrate induced a robust homeotropic alignment of the LC molecules. Binding between gelsolin and Aβ42 disrupted this ordered orientation and produced a shift from a dark to a bright optical response under polarized optical microscopy (POM), enabling straightforward visual detection. The biosensor demonstrated a wide detection range of 1-1000 pg mL[-1] and an exceptionally low detection limit of 1 pg mL[-1] for Aβ42. In addition, apolipoprotein E4 (ApoE4), a major genetic risk factor for AD, was detected in the range of 0.1-30 nM. The interaction between Aβ42 and ApoE4 induced measurable changes in LC orientation, confirming the sensor's capability to transduce biomolecular interactions. Moreover, this LC-based biosensor was used for the detection of the Aβ42 peptide in cell culture samples. The obtained results demonstrate that with further optimization, the developed biosensor could pave the way for practical applications in real clinical samples.},
}

@article {pmid43012927,
year = {2026},
author = {Gupta, PR and Shahapure, P and Sarkar, N and Venu, G and Krishnan, D and Ramasamy, S and Justin, A},
title = {Death-Associated Protein Kinase 1 (DAPK1) Signalling at the Crossroads of Apoptosis, Autophagy, and Post-transcriptional Cascades in Neurodegenerative Diseases.},
journal = {Cellular and molecular neurobiology},
volume = {46},
number = {1},
pages = {},
pmid = {43012927},
issn = {1573-6830},
mesh = {Humans ; *Death-Associated Protein Kinases/metabolism/genetics ; *Neurodegenerative Diseases/genetics/pathology/metabolism/enzymology ; *Signal Transduction/physiology ; Animals ; *Autophagy/physiology ; *Apoptosis/physiology ; *RNA Processing, Post-Transcriptional ; },
abstract = {Death-associated Protein Kinase-1 is a Ca2+/calmodulin- dependent serine/threonine protein kinase which controls various cellular processes and functions, including apoptosis, autophagy, and post-transcriptional processes, through multiple microRNAs. Increasing evidence suggests that, aberrant increase in the level of DAPK1 may result in neuronal injury and neurodegeneration by integration of multiple pathological processes such as excitotoxicity, neuroinflammation, and protein aggregation. DAPK1 contributes to disease progression through mechanisms such as NMDA receptor-mediated excitotoxicity, tau and α-synuclein hyperphosphorylation, apoptotic signaling, autophagic dysregulation, and synaptic loss. This review overviews the structural organization, regulatory mechanisms and role of DAPK1 in various cellular processes involved in neurodegeneration. This review discusses the complex transcriptional, post-transcriptional, and post-translational mechanisms governing DAPK1 activity, including regulation by transcription factors, microRNAs, phosphorylation events, and protein degradation pathways. Particular highlighting is given to the involvement of DAPK1 in both chronic and acute neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, diabetic encephalopathy, traumatic brain injury, and cerebral ischemic stroke. Finally, current therapeutic approaches based on the modulation of DAPK1 activity, including kinase inhibitors, competitive peptides, and gene-regulatory approaches, are reviewed, along with the challenges associated with target selectivity, blood-brain barrier penetration, and clinical translation. Collectively, this review emphasizes the therapeutic potential and discusses future directions for the development of disease-modifying interventions targeting DAPK1 in neurodegenerative diseases.},
}

Humans
*Death-Associated Protein Kinases/metabolism/genetics
*Neurodegenerative Diseases/genetics/pathology/metabolism/enzymology
*Signal Transduction/physiology
Animals
*Autophagy/physiology
*Apoptosis/physiology
*RNA Processing, Post-Transcriptional

@article {pmid43013102,
year = {2026},
author = {Rapant, S and Beňová, N and Cvečková, V and Stehlíková, B and Hunarova, N and Ižarik-Verešpejová, A and Kolísek, M},
title = {Drinking water hardness and nervous system mortality: a 15 year ecological study of calcium and magnesium content in the Slovak Republic.},
journal = {Environmental geochemistry and health},
volume = {48},
number = {17},
pages = {},
pmid = {43013102},
issn = {1573-2983},
support = {LIFE17 ENV/SK/000036//LifeScan/ ; },
mesh = {*Magnesium/analysis ; Slovakia/epidemiology ; Humans ; *Calcium/analysis ; *Drinking Water/chemistry/analysis ; *Nervous System Diseases/mortality/epidemiology ; },
abstract = {The chemical composition of the natural physical environment significantly impacts human health, yet the specific influence of drinking water minerals on nervous system disorders remains largely unexamined. This study investigated the relationship between drinking water hardness, specifically calcium and magnesium concentrations, and nervous system disease mortality across populations in the Slovak Republic. Two size wise comparable groups of rural municipalities supplied exclusively by public water systems were monitored over a 15 year period (1994-2008), totaling 1.58 million person-years. The soft water cohort comprised 34 municipalities (Ca ≤ 25 mg L[-1]; Mg ≤ 10 mg L[-1]), and the hard water cohort comprised 21 municipalities (Ca ≥ 50 mg L[-1]; Mg ≥ 20 mg L[-1]). Relative mortality rates and indirectly age-standardized mortality ratios were calculated using national registry data for 99 specific nervous system diagnoses (ICD-10 codes G00-G99). Total nervous system mortality was approximately 2.5 times higher in the soft water regions than in the hard water regions. Highly significant statistical associations were discovered for epilepsy and cerebral palsy, with relative mortality rates expanding 4.25 and 16.41 times higher in the soft water group, respectively. No statistically significant differences were observed for neurodegenerative conditions like Alzheimer's or Parkinson's diseases. Low levels of calcium and magnesium in public drinking water are associated with increased population-level mortality from epilepsy and cerebral palsy. However, due to the ecological design of this study, these findings represent geographical correlations and cannot establish a direct causal relationship. Controlled individual-level epidemiological studies or clinical trials are required to determine whether targeted mineral interventions would successfully reduce mortality in high-risk demographics.},
}

*Magnesium/analysis
Slovakia/epidemiology
Humans
*Calcium/analysis
*Drinking Water/chemistry/analysis
*Nervous System Diseases/mortality/epidemiology

@article {pmid43013131,
year = {2026},
author = {Vorberg, IM and Priola, SA},
title = {The evolution of prion cell biology: from viruses to prions to prion-like proteins.},
journal = {Acta neuropathologica},
volume = {152},
number = {1},
pages = {},
pmid = {43013131},
issn = {1432-0533},
mesh = {Humans ; Animals ; *Prions/metabolism ; *Prion Diseases/metabolism/pathology ; },
abstract = {Prion diseases are inevitably fatal, rare, and infectious neurodegenerative diseases of humans and animals. Initially, they were thought to be caused by unconventional slow viruses, and early research therefore relied heavily on experimental approaches used in virology. This view changed with the discovery that the causative agent of these diseases is not a virus but a conformational variant of a host-encoded protein. The conversion of the normally soluble host prion protein into an insoluble, infectious form enables the spread of pathology between cells and throughout the host. Over the past two decades, it has become clear that similar prion-like mechanisms of protein misfolding and templated self-propagation also underlie more common, non-infectious neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Thus, just as the cell biology of viruses provided important insights into the first studies of prion cell biology, discoveries in prion research have profoundly influenced our understanding of the cell biology of other amyloid-forming proteins. In this review, we discuss common principles and differences in the cell biology of prions and prion-like particles. We also highlight the seminal contributions of the late Dr. Byron Caughey and his laboratory, whose pioneering work has helped to shape our current understanding of how pathogenic protein aggregates form, propagate, and ultimately cause devastating neurological diseases.},
}

Humans
Animals
*Prions/metabolism
*Prion Diseases/metabolism/pathology

@article {pmid43013143,
year = {2026},
author = {Vu, NH and Esper, GW and Pettit, C and Ganta, A and Egol, KA and Konda, SR},
title = {Association between Alzheimer's disease and related dementias and postoperative outcomes after geriatric hip fracture surgery.},
journal = {European journal of orthopaedic surgery & traumatology : orthopedie traumatologie},
volume = {37},
number = {1},
pages = {},
pmid = {43013143},
issn = {1432-1068},
mesh = {Humans ; Female ; Retrospective Studies ; Male ; *Postoperative Complications/epidemiology/etiology ; *Hip Fractures/surgery/complications ; Aged, 80 and over ; Aged ; *Alzheimer Disease/complications/epidemiology ; *Dementia/complications/epidemiology ; Patient Readmission/statistics & numerical data ; Comorbidity ; Treatment Outcome ; Proximal Femoral Fractures ; Length of Stay/statistics & numerical data ; },
abstract = {BACKGROUND: Patients with Alzheimer's Disease and Related Dementias (ADRD) represent a vulnerable subset of geriatric hip fracture patients, yet the extent to which ADRD influences postoperative outcomes remains incompletely characterized. The purpose of this study was to examine the association between Alzheimer's Disease and Related Dementias (ADRD) and outcomes.

METHODS: A retrospective cohort analysis was conducted of patients 65 years or older undergoing operative management for hip fractures at a multi-site urban academic medical center. Patients were stratified by ADRD status as documented in the electronic medical record. Univariate analyses compared demographic characteristics, injury and surgical variables, hospital quality metrics, and mortality using chi-square and Student's t-tests, as appropriate. Multivariable regression models controlling for age, sex, BMI, ASA class, Charlson Comorbidity Index, baseline functional status, and fracture classification evaluated the association between ADRD and study outcomes.

RESULTS: A total of 3,312 patients were included: 829 (25.0%) ADRD vs. 2483 (75.0%) control. ADRD patients were older, had greater comorbidity burden, and had worse baseline functional status. ADRD patients had increased minor and major complications, ICU admissions, readmissions, 1-year mortality, and longer hospitalization (all p < 0.001). Variance inflation factor analysis confirmed no meaningful multicollinearity among covariates (VIF range 1.04-1.34). On multivariable analysis, ADRD was independently associated with major complications (OR 1.372, 95% CI 1.066-1.760), ICU admission (OR 1.581, 95% CI 1.231-2.025), length of stay (β 0.958, 95% CI 0.624-1.292), 30-day (OR 1.994, 95% CI 1.521-2.608) and 31- to 90-day readmission (OR 1.956, 95% CI 1.453-2.625), and mortality between 31 days and 1 year (HR 1.54, 95% CI 1.18-2.01).

CONCLUSION: ADRD is independently associated with worse postoperative outcomes after geriatric hip fracture. These associations persisted after adjustment for baseline comorbidity, functional status, and fracture classification, though residual confounding by unmeasured frailty domains cannot be excluded. Orthogeriatric co-management should be directed toward this vulnerable population to optimize outcomes.},
}

Humans
Female
Retrospective Studies
Male
*Postoperative Complications/epidemiology/etiology
*Hip Fractures/surgery/complications
Aged, 80 and over
Aged
*Alzheimer Disease/complications/epidemiology
*Dementia/complications/epidemiology
Patient Readmission/statistics & numerical data
Comorbidity
Treatment Outcome
Proximal Femoral Fractures
Length of Stay/statistics & numerical data

@article {pmid43013230,
year = {2026},
author = {Kan, CN and Chew, J and Lim, WS and Tan, CH},
title = {Neural correlates of frailty and the development of a cerebral frailty risk score for dementia.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {43013230},
issn = {2509-2723},
support = {RG58/23//Ministry of Education - Singapore/ ; SSRC2023-SSHR-003//Ministry of Education - Singapore/ ; },
abstract = {Frailty is a multisystem clinical syndrome closely linked to cognitive aging, yet its relationship with brain pathology and contribution to neurological outcomes remain unclear. We examined neuroimaging correlates of frailty and evaluated their integrative impact on incident dementia within a cerebral frailty risk score (CFRS) framework. In a population-based UK Biobank cohort, we analyzed neuroimaging-derived phenotypes, including cerebral volumetrics and thickness, white matter hyperintensities (WMH), cerebral blood flow (CBF), and diffusion metrics. Associations between global neuroimaging markers and frailty index (FI), and their joint effects on incident dementia over 10 years were analyzed using regression models. Long-term dementia risk was modelled using extreme gradient boosting with accelerated failure time, integrating FI and multimodal neuroimaging features. A total of 63,509 dementia-free participants (mean age = 65.02 years, 52.3% female) were included. Higher FI values were associated with greater WMH volume, lower CBF, reduced hippocampal volume, greater cortical thinning, and impaired diffusion metrics. Higher FI and neuroimaging markers independently increased dementia and mortality risks. The cerebral frailty model outperformed FI-only model (nested C-index = 0.825, iAUC = 0.759), driven by higher FI, WMH burden, and key Alzheimer's disease-related brain regions and circuits. Integrating the top 10 predictors into an integer-based CFRS achieved strong discriminatory performance (C-index = 0.843, iAUC = 0.808) and was robust to competing mortality risk. Our findings suggest that systemic frailty is associated with mixed cerebral pathologies. Both frailty and cerebral pathological burden may represent parallel but distinct pathways contributing to dementia. With external validation and recalibration, the CFRS framework integrating these vulnerabilities demonstrates potential for dementia risk profiling.},
}

@article {pmid43013232,
year = {2026},
author = {Cai, Y and Miao, J and Gogniat, MA and Snitz, BE and Cohen, AD},
title = {Multidimensional 24-h activity patterns in relation to cognition and Alzheimer's disease plasma biomarkers: a cross-sectional study.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {43013232},
issn = {2509-2723},
support = {R03AG088612/AG/NIA NIH HHS/United States ; UF1AG051197/AG/NIA NIH HHS/United States ; },
abstract = {Beyond total volume, how physical activity is distributed, timed, and structured across the 24-h cycle may reflect aspects of brain aging missed by conventional measures. We examined how these activity dimensions relate to cognitive status, cognitive performance, and Alzheimer's disease (AD)-related plasma biomarkers. In this cross-sectional analysis of 164 adults aged 50-89 from the Human Connectome Project-Connectomics in Brain Aging and Dementia study, 7-day wrist actigraphy measured activity volume, fragmentation, complexity, and rest-activity rhythms. Outcomes were adjudicated: mild cognitive impairment (MCI)/AD diagnosis, cognitive performance, and plasma amyloid-β 42/40 ratio, phosphorylated tau217 (p-tau217), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL). Logistic and linear regression models were adjusted for age, sex, race, education, and comorbidities; cognitive and biomarker models were additionally adjusted for MCI/AD diagnosis. Benjamini-Hochberg false discovery rate (FDR) correction was applied. Forty-four participants had MCI/AD. In fully adjusted models, higher interdaily stability (IS) and most-active-10-h activity (M10) were associated with lower odds of MCI/AD (IS: odds ratio (OR) = 0.65, 95% confidence interval (CI) 0.44-0.95, FDR-p = 0.212; M10: OR = 0.57, 95% CI 0.38-0.82, FDR-p = 0.053). Higher IS, M10, and relative amplitude (RA) were associated with better verbal memory, language, and executive function, respectively. Higher RA was associated with lower GFAP and NfL, whereas higher IS and M10 were associated with higher p-tau217. These associations did not remain significant after FDR correction. Multiple 24-h activity dimensions, particularly rest-activity rhythm stability and amplitude, were associated with cognition and AD-related plasma biomarkers, supporting further study of these measures as accessible indicators of brain aging and AD-related biology.},
}

@article {pmid43013309,
year = {2026},
author = {Bokor, L and Yu, MKL and Carter, B and Chauhan, U and Sheehan, R and Strydom, A},
title = {Avoidable Mortality in Adults With Down Syndrome or With Other Intellectual Disabilities.},
journal = {JAMA network open},
volume = {9},
number = {11},
pages = {e2643229},
doi = {10.1001/jamanetworkopen.2026.43229},
pmid = {43013309},
issn = {2574-3805},
mesh = {Humans ; *Down Syndrome/mortality ; *Intellectual Disability/mortality ; Male ; Female ; England/epidemiology ; Adult ; Retrospective Studies ; Middle Aged ; Cause of Death ; Aged ; },
abstract = {IMPORTANCE: Down syndrome is the most common genetic cause of Alzheimer disease. Adults with Down syndrome experience higher mortality than the general population. However, the avoidable causes and their associated factors remain unclear.

OBJECTIVE: To compare the proportion and causes of avoidable mortality in adults with Down syndrome, adults with other intellectual disabilities, and the general population, and to identify factors associated with avoidable death.

This population-based retrospective cohort study used data from the Learning From Lives and Deaths mortality review and the Office for National Statistics in England from 2016 to 2023. It included adults with Down syndrome (n = 3381), other adults with intellectual disabilities (n = 15 347), and the general population (n = 4 163 160).

EXPOSURES: Down syndrome status, ethnicity, socioeconomic deprivation, co-occurring health conditions, COVID-19 pandemic period.

MAIN OUTCOMES AND MEASURES: Proportion and causes of avoidable, treatable, and preventable deaths according to Organisation for Economic Co-operation and Development/Eurostat criteria; odds of avoidable death estimated using logistic regression; and age at avoidable death using Cox regression. Factors associated with avoidable death and age at death were also evaluated.

RESULTS: Among 3381 adults with Down syndrome (1892 male [56.0%]; median [IQR] age at death, 59.5 [54.3-64.2] years), 1589 (47.0%) died from avoidable causes. Among 15 347 adults with other intellectual disabilities (8675 male [56.5%]; median [IQR] age at death, 63.8 [51.7-73.4] years), 6885 (44.9%) died from avoidable causes. Both proportions were substantially higher than in the general population (22.0%) (both P < .001). Treatable deaths were more common (972 [28.7%] vs 3847 [25.1%] vs 317 968 [7.6%]), with epilepsy and pneumonia as the leading treatable causes. Down syndrome was independently associated with higher odds of avoidable death (aOR, 1.15; 95% CI, 1.06-1.25) and earlier age at avoidable death (aHR, 1.49; 95% CI, 1.40-1.58). Minoritized ethnic background, asthma, diabetes, and osteoporosis were each independently associated with higher odds of avoidable death, and minoritized ethnic background and greater socioeconomic deprivation with earlier age at avoidable death.

CONCLUSIONS AND RELEVANCE: In this cohort study of adults with Down syndrome and other adults with intellectual disabilities in England, avoidable mortality exceeded that of the general population. For the adults with Down syndrome, epilepsy and pneumonia were the dominant treatable causes. These findings support proactive integrated neurological care, including epilepsy review with dementia monitoring, pneumonia prevention, and respiratory vaccination, alongside targeted interventions for minoritized ethnic groups and socioeconomically deprived groups.},
}

Humans
*Down Syndrome/mortality
*Intellectual Disability/mortality
Male
Female
England/epidemiology
Adult
Retrospective Studies
Middle Aged
Cause of Death
Aged

@article {pmid43013411,
year = {2026},
author = {Gedankien, T and Kriegel, J and Zabeh, E and McDonagh, D and Lega, BC and Jacobs, J},
title = {Cholinergic blockade reveals a role for human hippocampal theta in memory encoding but not retrieval.},
journal = {eLife},
volume = {14},
number = {},
pages = {},
pmid = {43013411},
issn = {2050-084X},
support = {R01-MH104606/NH/NIH HHS/United States ; R01-NS125250/NH/NIH HHS/United States ; R01-NS107357/NH/NIH HHS/United States ; },
mesh = {Humans ; *Hippocampus/physiology/drug effects ; Scopolamine/administration & dosage/pharmacology ; *Theta Rhythm/drug effects ; Male ; Female ; *Memory/drug effects/physiology ; *Mental Recall/drug effects ; Middle Aged ; Muscarinic Antagonists/administration & dosage/pharmacology ; Adult ; },
abstract = {Cholinergic dysfunction is a hallmark of Alzheimer's disease and other memory disorders. Yet, the neurophysiological mechanisms linking cholinergic signaling to memory remain poorly understood. In this study, we administered scopolamine, a muscarinic cholinergic antagonist, to neurosurgical patients with intracranial electrodes as they performed an associative recognition memory task. When scopolamine was present at encoding, we observed disruptions to hippocampal slow theta oscillations (2-4 Hz), with selective impairments to recollection-based memory. However, when scopolamine was present during retrieval alone, we observed disruptions to slow theta without impaired memory performance. These disruptions included dose-dependent reductions in theta power, theta phase reset, and encoding-retrieval pattern reinstatement. Together, our results challenge the notion that theta oscillations are necessary for memory retrieval, and instead suggest that theta universally reflects an encoding-related neural state. These findings motivate updates to current models of acetylcholine's role in memory and may inform future therapies targeting rhythmic biomarkers of memory dysfunction.},
}

Humans
*Hippocampus/physiology/drug effects
Scopolamine/administration & dosage/pharmacology
*Theta Rhythm/drug effects
Male
Female
*Memory/drug effects/physiology
*Mental Recall/drug effects
Middle Aged
Muscarinic Antagonists/administration & dosage/pharmacology
Adult

@article {pmid43013556,
year = {2026},
author = {Cheng, C and He, Y and Cao, X and Xiang, S and Fang, Y and Wang, M and Shao, Z and Yao, Y and Huang, H and Xu, S and Luo, X and Zong, X and Wang, W and Hao, X and Wang, M},
title = {Multi-omics characterization of white matter free water reveals genetic and vascular determinants of neurological disorders.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {123},
number = {46},
pages = {e2611353123},
doi = {10.1073/pnas.2611353123},
pmid = {43013556},
issn = {1091-6490},
support = {82271355//MOST | National Natural Science Foundation of China (NSFC)/ ; 32470658//MOST | National Natural Science Foundation of China (NSFC)/ ; 2022CFA097//| Natural Science Foundation of Hubei Province ()/ ; 2024ZD0526603//National Science and Technology Major Project ()/ ; },
mesh = {Humans ; *White Matter/metabolism/diagnostic imaging ; Multiomics ; Genome-Wide Association Study ; Genetic Predisposition to Disease ; *Nervous System Diseases/genetics/metabolism/diagnostic imaging ; Proteomics ; Female ; Male ; *Water/metabolism ; Diffusion Magnetic Resonance Imaging ; },
abstract = {White matter free water (FW-WM), quantified using diffusion MRI, reflects extracellular water content and microstructural alterations within water matter, but its genetic architecture and clinical relevance remain largely uncharted. We conducted a multi-omics study integrating 42,039 individuals from the UK Biobank and Alzheimer's Disease Neuroimaging Initiative cohorts to characterize tract-specific FW-WM across genetic, phenotypic, and proteomic dimensions. Genome-wide association analyses identified 27 independent loci and prioritized 88 genes, which were enriched in the genomic functional elements of vascular endothelial cells, pericytes, and astrocytes. Notably, 20 loci (74%) were novel compared to conventional white matter metrics. Both genetic predisposition to higher FW-WM and imaging-derived FW-WM were associated with a spectrum of neurological disorders. Specifically, imaging-derived FW-WM showed strong associations with stroke (OR = 3.14) and dementia (OR = 4.15), while higher baseline FW-WM predicted progression from MCI to AD (HR = 2.58). Bidirectional Mendelian randomization analyses further supported genetically predicted associations between hypertension and FW-WM, which were together associated with increased risks of stroke and cognitive impairment. Integrative proteomic analyses further nominated PEAR1 and ANGL3 as candidate proteins potentially linking hypertension-related vascular processes to FW-WM variation. Together, these findings provide a multi-omics characterization of FW-WM that connects genetic susceptibility, vascular factors, and neurological outcomes, supporting FW-WM as a tract-specific imaging phenotype with potential utility for neurological risk stratification.},
}

Humans
*White Matter/metabolism/diagnostic imaging
Multiomics
Genome-Wide Association Study
Genetic Predisposition to Disease
*Nervous System Diseases/genetics/metabolism/diagnostic imaging
Proteomics
Female
Male
*Water/metabolism
Diffusion Magnetic Resonance Imaging

@article {pmid43013788,
year = {2026},
author = {Lorkiewicz, SA and Abdelnour, C and Bolen, ML and Smith, AM and Shahid-Besanti, M and Hemachandra, D and Müller-Oehring, EM and Siddiqui, N and Montoliu-Gaya, L and Arslan, B and Ashton, NJ and Wilson, EN and Tian, L and Andreasson, K and Mormino, E and Henderson, VW and Zetterberg, H and Poston, KL},
title = {Plasma P-Tau217 as a Prognostic, Monitoring, and Risk-Stratification Biomarker of Clinical Progression in Lewy Body Disease.},
journal = {Neurology},
volume = {107},
number = {11},
pages = {e218686},
doi = {10.1212/WNL.0000000000218686},
pmid = {43013788},
issn = {1526-632X},
mesh = {Humans ; Female ; *Lewy Body Disease/blood/diagnosis ; *tau Proteins/blood ; Biomarkers/blood ; Male ; Disease Progression ; Prognosis ; Longitudinal Studies ; Aged ; Prospective Studies ; Aged, 80 and over ; Alzheimer Disease/blood ; Cognitive Dysfunction/blood ; Risk Assessment ; Phosphorylation ; },
abstract = {BACKGROUND AND OBJECTIVES: Although plasma phosphorylated tau-217 (pTau217) detects co-occurring Alzheimer disease (AD) neuropathologic change in Lewy body disease (LBD), relationships with long-term clinical outcomes remain unclear. Our aim was to evaluate plasma pTau217 as a prognostic, risk-stratification, and monitoring biomarker of cognitive and functional decline in LBD.

METHODS: This prospective longitudinal study included Stanford AD Research Center participants enrolled from 2015 to 2023 with plasma pTau217 data and clinical diagnoses of LBD spectrum, AD spectrum, or healthy control (HC). To evaluate prognostic and monitoring utility, respectively, linear mixed-effect models tested whether baseline level and longitudinal change (2-5 years) in plasma pTau217 were associated with longitudinal changes (2-8 years) in daily functioning (Clinical Dementia Rating-Sum of Boxes [CDR-SB]), global cognition (Montreal Cognitive Assessment [MoCA]), and 5 domain-specific cognitive indices. For risk stratification, baseline plasma pTau217 status was defined using an amyloid PET-derived, LBD-specific cut-point to examine whether participants with abnormal levels demonstrated faster clinical progression in separate linear-mixed effects and survival models.

RESULTS: A total of 501 participants (mean[SD] age = 71.1[8.5]; 51.5% female) were included across LBD (n = 131), AD (n = 133), and HC (n = 237) groups. In LBD, higher baseline plasma pTau217 was associated with faster CDR-SB increase (β = 0.30; 95% CI [0.14, 0.45]; p < 0.001), MoCA decline (β = -0.35; 95% CI [-0.57, -0.13]; p = 0.002), and cognitive index decline (all p ≤ 0.028). Participants with abnormal baseline pTau217 had a 0.85 points/year faster CDR-SB increase (95% CI [0.56, 1.15]; p < 0.001), 0.87 points/year faster MoCA decline (95% CI [-1.38, -0.37]; p = 0.001), faster decline on cognitive indices (all p ≤ 0.018), and a three-fold higher risk of diagnostically progressing to mild cognitive impairment or dementia (HR = 3.41; 95% CI [1.60, 7.28]; p = 0.002) compared to participants with normal pTau217. Faster longitudinal pTau217 increase was associated with faster CDR-SB increase (β = 0.24; 95% CI [0.10, 0.38]; p = 0.003).

DISCUSSION: Plasma pTau217 is a promising prognostic, risk-stratification, and monitoring biomarker of clinical progression in LBD, underscoring its utility for clinical practice and trials in mixed pathology groups.},
}

Humans
Female
*Lewy Body Disease/blood/diagnosis
*tau Proteins/blood
Biomarkers/blood
Male
Disease Progression
Prognosis
Longitudinal Studies
Aged
Prospective Studies
Aged, 80 and over
Alzheimer Disease/blood
Cognitive Dysfunction/blood
Risk Assessment
Phosphorylation

@article {pmid43013867,
year = {2026},
author = {Hosoda, C and Adachi, F and Tamura, Y and Takashio, O},
title = {Utilizing Voxel-Based Specific Regional Analysis as a Noninvasive Examination of a Rare Case of Very-Late-Onset Schizophrenia-Like Psychosis.},
journal = {Journal of psychiatric practice},
volume = {32},
number = {6},
pages = {369-373},
doi = {10.1097/PRA.0000000000000964},
pmid = {43013867},
issn = {1538-1145},
mesh = {Humans ; Male ; Aged ; *Magnetic Resonance Imaging/methods ; *Schizophrenia/diagnostic imaging/pathology/drug therapy ; *Psychotic Disorders/diagnostic imaging/drug therapy/pathology ; *Temporal Lobe/pathology/diagnostic imaging ; *Prodromal Symptoms ; Antipsychotic Agents/therapeutic use ; },
abstract = {We present a rare, atypical case of very-late-onset schizophrenia-like psychosis (VLOSLP) in a 78-year-old male patient with a family history of schizophrenia and thought withdrawal. Although the patient showed no clinically significant cognitive impairment, we evaluated the medial temporal lobes of the brain for prodromal changes using the voxel-based specific regional analysis system for Alzheimer disease (VSRAD), a magnetic resonance imaging-based volumetric software program. The patient had gradually developed psychosis, including experiencing thought withdrawal, over almost 1 year before admission. His daughter had been diagnosed with schizophrenia at the age of 20 years. After careful examination, the patient was diagnosed with VLOSLP. We analyzed the target volume of interest for disease-specific atrophy obtained from VSRAD. The Z score for the target volume of interest was 1.42, which was too low for a diagnosis of Alzheimer disease. These results suggest that the patient's psychosis in this case might not have been due to the prodrome of Alzheimer disease. The patient responded well to treatment with a low dose of a single atypical antipsychotic. The use of noninvasive procedures such as VSRAD for the evaluation of prodrome in dementia in patients with VLOSLP is expected to become routine in the future.},
}

Humans
Male
Aged
*Magnetic Resonance Imaging/methods
*Schizophrenia/diagnostic imaging/pathology/drug therapy
*Psychotic Disorders/diagnostic imaging/drug therapy/pathology
*Temporal Lobe/pathology/diagnostic imaging
*Prodromal Symptoms
Antipsychotic Agents/therapeutic use

@article {pmid43014307,
year = {2026},
author = {Zhou, H and Maynard, JC and Pennacchio, AJ and Apolonio, A and Liu, X and Yao, L and Negahban, M and Zhang, Z and Ding, B and Oberhauser, J and Wen, X and Yang, MJ and Huang, F and Chayama, Y and Doddipalli, S and Bernardi, M and Domke, L and Lo, I and Simms, J and Pan, A and Du, S and To, NS and Wong, PS and Duong, D and Fox, E and Seyfried, NT and Cheung, TH and Tracy, TE and Burlingame, AL and Yang, AC},
title = {The blood-brain barrier imports diverse neuroprotective proteins through pathways impaired early in Alzheimer's disease models.},
journal = {Cell},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.cell.2026.10.039},
pmid = {43014307},
issn = {1097-4172},
abstract = {The blood-brain barrier (BBB) has been defined primarily by what it excludes, yet the scale and function of physiological blood-to-brain protein transport remain largely unknown. Using bioorthogonal proteomics, we find that the healthy BBB samples 191 plasma proteins and permits 92 into the brain parenchyma. Enriched for carrier and metabolic functions, these proteins home to distinct brain cell types, such as apolipoprotein A1 (APOA1) to astrocytes and alpha-1 antitrypsin (SERPINA1) to microglia. This cell-type tropism relies on a BBB-parenchyma receptor hand-off: APOA1 crosses the BBB via SR-B1 and engages astrocytic ATP-binding cassette transporter A1 (ABCA1), a key Alzheimer's risk gene, driving cholesterol efflux that supports synapse integrity. Unlike LPS-induced nonspecific leakage, early-stage 5xFAD mice show selective BBB transport remodeling, with reduced APOA1 and increased SERPINA1 uptake. Hepatic APOA1 overexpression restores APOA1 in the 5xFAD brain, rescuing astrocytic, synaptic, and behavioral deficits. These findings recast the BBB as a selective interface that recruits neuroprotective circulatory proteins for brain health.},
}

@article {pmid43014439,
year = {2026},
author = {Sharma, C and Basak, M and Dhungel, A and Hazam, PK and Deka, T},
title = {From insulin resistance to neurovascular breakdown: mTOR signaling as a convergence point in Alzheimer's disease.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2026.11.018},
pmid = {43014439},
issn = {1873-7544},
abstract = {Alzheimer's disease (AD), the leading cause of dementia, is increasingly recognized as a metabolic disorder characterized by disrupted insulin and insulin-like growth factor-1 signaling in the brain, a concept now referred to as type 3 diabetes. Central to this perspective is the insulin receptor substrate-1/phosphoinositide 3-kinase/protein kinase B/mechanistic target of rapamycin (IRS-1/PI3K/Akt/mTOR) cascade, which acts as the primary convergence point linking systemic insulin resistance to neurodegeneration. Impaired insulin signaling in astrocytes, neurons, microglia, and cerebral endothelial cells disrupts glucose metabolism, energy production, and amyloid-β (Aβ) clearance, while promoting tau hyperphosphorylation through glycogen synthase kinase-3β activation. Chronic mTOR hyperactivation exacerbates these dysfunctions by suppressing autophagy, impairing insulin sensitivity, and compromising blood-brain barrier (BBB) integrity through tight junction disassembly, pericyte loss, and endothelial senescence. These processes collectively establish a self-perpetuating cycle of metabolic dysfunction, protein aggregation, neuroinflammation, and vascular breakdown. Neuron-derived extracellular vesicles have emerged as a promising non-invasive biomarker platform for monitoring central insulin resistance and therapeutic response in real time. Metabolically targeted interventions, including intranasal insulin, glucagon-like peptide-1 receptor agonists, and mTOR inhibitors such as rapamycin, demonstrate encouraging preclinical and early clinical efficacy in restoring insulin sensitivity, reducing tau and Aβ pathology, and preserving BBB function. However, challenges related to delivery and dosing remain significant barriers to clinical translation. Continued investigation into neurovascular unit and multi-target combination therapies may facilitate the development of effective, biomarker-guided treatments for AD.},
}

@article {pmid43014489,
year = {2026},
author = {Xie, W and Pan, X and Zhan, Y and Wu, X and Zhang, W and Pei, Y and Zhang, G and Wang, Z},
title = {Deep learning-based estimation of multi-tracer PET phenotypes from structural MRI for A/T/N-related analysis and progression prediction in Alzheimer's disease.},
journal = {NeuroImage},
volume = {},
number = {},
pages = {122345},
doi = {10.1016/j.neuroimage.2026.122345},
pmid = {43014489},
issn = {1095-9572},
abstract = {Early identification and staging of Alzheimer's disease (AD) require integrated assessment of amyloid deposition, tau pathology, and neurodegeneration. PET provides spatially resolved in vivo imaging biomarkers, but its routine use is constrained by cost, tracer availability, and radiation exposure, limiting access to complete A/T/N imaging profiles. We propose a conditional flow matching-based framework that estimates SUV-space PET-derived phenotypes related to [18]F-FDG, [18]F-florbetapir and [18]F-flortaucipir from a single T1-weighted MRI scan. To address limitations in SUV-level quantitative fidelity, single-tracer applicability, and external generalization, the framework combines a PET prior network with a time-conditioned velocity network and uses multi-constraint losses to preserve SUV accuracy, regional uptake consistency, and anatomical boundaries. The model was developed using 1,978 paired ADNI MRI-PET records from 991 participants and evaluated in a predefined ADNI test set and an independent hospital PET/MR cohort of 514 participants. In ADNI, voxel-level MAEs were 0.012, 0.034, and 0.021 SUV, with representative ROI Pearson correlations of 0.978, 0.842, and 0.781. In the hospital cohort, corresponding MAEs were 0.014, 0.037, and 0.024 SUV, with ROI correlations of 0.952, 0.803, and 0.834. In OASIS, generated PET-derived features improved CDR stratification and future cognitive decline prediction, increasing AUCs from 0.662 to 0.739 and from 0.569 to 0.643. These findings suggest that the method can provide PET-derived phenotypes related to A/T/N analysis from structural MRI when PET is unavailable, but should not be interpreted as a replacement for molecular PET assessment.},
}

@article {pmid43014684,
year = {2026},
author = {Adeboye, OC and Kavehmoghaddam, S and Zarate, JG and Khatri, KK and McNally, D and Siner, A and Stellwag, A and Solesio, ME and Da Costa, RT},
title = {Could pharmacological modulation of Cu homeostasis be a valid approach against increased reactive oxygen generation and associated oxidative stress in neurodegenerative disorders?.},
journal = {Pharmacological research},
volume = {},
number = {},
pages = {109752},
doi = {10.1016/j.phrs.2026.109752},
pmid = {43014684},
issn = {1096-1186},
abstract = {Our society is aging. Accordingly, the incidence and prevalence of age-associated diseases are exponentially increasing. Among these diseases, neurodegenerative disorders emerge as major contributors to decreased health span. The molecular mechanisms underlying these disorders are complex and multifaceted. However, increased generation of reactive oxygen species (ROS) and associated oxidative stress have emerged as a potent contributor to the etiopathology of many of these disorders, including Alzheimer's Disease and Parkinson's Disease (AD and PD, respectively). In this context, changes in copper homeostasis have been described as important contributors to increased ROS generation and associated oxidative stress, and targeting Cu homeostasis has been explored as a promising pharmacological approach. In this bibliographical review, we comprehensively discuss the most relevant pharmacological approaches in the field. Most of the research articles discussed here used AD and PD models, but some studies also employed models of less common neurodegenerative disorders. The literature presented here demonstrates the promising effects of targeting Cu homeostasis to halt increased ROS generation and associated oxidative stress in neurodegenerative disorders. However, many of these studies were conducted in vitro, with only a small portion in murine models of the diseases. Consequently, further research is needed to determine whether the promising results are, in fact, translatable to human therapeutics. The urgency for these studies is real, considering the high incidence and prevalence of neurodegenerative disorders and the limited therapeutics in the field.},
}

@article {pmid43014720,
year = {2026},
author = {Matsushita, S},
title = {[Effects of Alcohol on the Central Nervous System].},
journal = {Brain and nerve = Shinkei kenkyu no shinpo},
volume = {78},
number = {11},
pages = {1165-1173},
doi = {10.11477/mf.188160960780111165},
pmid = {43014720},
issn = {1881-6096},
mesh = {Humans ; *Ethanol/adverse effects ; *Central Nervous System/drug effects ; *Alcoholism/complications ; },
abstract = {Alcohol affects the central nervous system through acute and chronic mechanisms. The acute effects include intoxication and blackouts, whereas abrupt cessation or reduction in alcohol intake after chronic excessive consumption may result in alcohol-withdrawal syndrome, seizures, and alcohol-induced psychotic symptoms. Chronic excessive alcohol consumption may cause cognitive impairment and structural changes in the brain through direct neurotoxicity, nutritional deficiency, neuroinflammation, and oxidative stress. Neuroimaging studies have shown that alcohol use disorder is associated with reduced brain volume, and it may accelerate age-related brain changes, particularly in the frontal regions. Alcohol use disorder is also associated with an increased risk of dementia, particularly early-onset dementia. In contrast to progressive neurodegenerative disorders, such as Alzheimer's disease, alcohol-related cognitive impairment can partially improve with sustained abstinence or reduced alcohol consumption. Alcohol-related dementia is a clinically important but incompletely defined condition, and its diagnostic criteria, underlying pathophysiology, relationship to Wernicke-Korsakoff syndrome, and nosological status, are subject to ongoing debate.},
}

Humans
*Ethanol/adverse effects
*Central Nervous System/drug effects
*Alcoholism/complications

@article {pmid43014749,
year = {2026},
author = {Hu, X and Ma, YN and Wang, Z and Xia, Y},
title = {From postoperative improvement to disease modification: Interpreting cervical lymphatic surgery in Alzheimer's disease.},
journal = {Drug discoveries & therapeutics},
volume = {},
number = {},
pages = {},
doi = {10.5582/ddt.2026.01089},
pmid = {43014749},
issn = {1881-784X},
abstract = {Deep cervical lymphaticovenous anastomosis (dcLVA) has been proposed as a means of enhancing brain clearance in Alzheimer's disease. Reports of postoperative cognitive and functional improvement have renewed interest in the procedure, but their interpretation is limited by uncontrolled study designs, incomplete follow-up, and the potential influence of perioperative care. This editorial distinguishes four claims that require different evidence: technical success, engagement of the intended drainage pathway, symptomatic benefit, and disease modification. Changes in cerebrospinal fluid biomarkers and positron emission tomography findings do not, by themselves, establish enhanced cerebral clearance or disease modification. Controlled trials with blinded assessment, mechanistic measures of drainage pathway engagement, clinically meaningful functional outcomes, and longitudinal safety monitoring are needed to determine whether dcLVA provides symptomatic benefit and whether it alters the course of the disease.},
}

@article {pmid43014781,
year = {2026},
author = {Inoue, K and Saito, T and Fujimura, H and Yamadera, M and Mori, C and Toyooka, K and Sudo, M and Oeda, T and Kageyama, Y and Izumi, Y},
title = {Relationship between age-related factors and Lewy body scores in Parkinson's disease.},
journal = {The journal of medical investigation : JMI},
volume = {73},
number = {3.4},
pages = {474-481},
doi = {10.2152/jmi.73.474},
pmid = {43014781},
issn = {1349-6867},
mesh = {Humans ; *Parkinson Disease/pathology ; Female ; Male ; *Lewy Bodies/pathology ; Aged ; Middle Aged ; Aged, 80 and over ; Age Factors ; Age of Onset ; Brain/pathology ; },
abstract = {BACKGROUND: In Japan, the number of patients with late-onset Parkinson's disease (PD) is increasing (1). These patients tend to exhibit a wider range of motor and non-motor symptoms as well as cognitive impairment compared to middle-aged onset cases (2, 3).

OBJECTIVE: The aim of this study is to determine whether neuropathological changes consistent with the clinical characteristics of late-onset PD patients differ across brain regions.

METHODS: A consecutive autopsy series of 38 patients, at Osaka Toneyama Medical Center (from the years 2005-2024), with clinically and pathologically confirmed sporadic PD, who were aged 50 years or older at the time of onset, were studied. The age of onset, sex, age at death, disease duration, Lewy body (LB) score and Alzheimer's disease (AD) pathology were analyzed.

RESULTS: The correlations between age at onset and limbic LB score, age at death and both the limbic and total LB scores were found to be significant, with Spearman's correlation coefficients of 0.363, 0.430 and 0.339, and p-values of 0.025, 0.007 and 0.037, respectively.

CONCLUSION: The late-onset PD patients have more LBs, especially in the limbic system, than the younger-onset PD patients at the end stage of their clinical course. J. Med. Invest. 73 : 474-481, August, 2026.},
}

Humans
*Parkinson Disease/pathology
Female
Male
*Lewy Bodies/pathology
Aged
Middle Aged
Aged, 80 and over
Age Factors
Age of Onset
Brain/pathology

@article {pmid43014972,
year = {2026},
author = {eBioMedicine, },
title = {Clonal haematopoiesis: a major link in the cancer-Alzheimer's disease inverse correlation.},
journal = {EBioMedicine},
volume = {133},
number = {},
pages = {106566},
doi = {10.1016/j.ebiom.2026.106566},
pmid = {43014972},
issn = {2352-3964},
}

@article {pmid43003089,
year = {2026},
author = {Sokolova, D and Puletti, F and Addington Ghansah, S and Georgiades, T and Zheng, Y and Wu, L and De Schepper, S and Lange, J and Ferreira, LSS and Sierksma, A and Rebejac, J and Crowley, G and Rueda-Carrasco, J and Geary, B and Nirujogi, R and Koutsiouroumpa, A and Muckett, P and Kittler, J and Gentry, M and Bourdenx, M and Freeman, OJ and Burden, JJ and Khakh, BS and Hong, S},
title = {An astrocyte-microglia MFG-E8 axis promotes synapse engulfment in early amyloid pathology.},
journal = {Neuron},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuron.2026.10.011},
pmid = {43003089},
issn = {1097-4199},
abstract = {Region-specific synapse loss is an early hallmark of Alzheimer's disease, yet the upstream signals that render synapses vulnerable remain unclear. In a mouse model of amyloidosis, we identify an early astrocyte state that emerges in vulnerable brain regions before widespread plaque deposition and overt gliosis. These astrocytes exhibit bulbous-looking perisynaptic processes enriched in p62 and glycogen, impaired autophagic flux and calcium signaling, and diminished astrocyte-synapse coverage. Rather than exhibiting increased synapse engulfment, bulbous astrocytes show elevated milk fat globule-epidermal growth factor 8 (MFG-E8) and are associated with increased local microglial synapse engulfment. Astrocyte-specific gain- and loss-of-function experiments demonstrate that astrocyte-derived MFG-E8 is required for microglial synapse engulfment and acts through microglial β3 integrin signaling. Astrocytic Mfge8 deletion reduces microglial engulfment and synapse loss across amyloidosis models and is associated with reduced amyloid pathology, gliosis, and cognitive impairment. Together, these findings define an astrocyte-microglia MFG-E8 signaling axis that contributes to region-specific synaptic vulnerability during early amyloid pathology.},
}

@article {pmid43003143,
year = {2026},
author = {Zhang, M and Zhang, H and Fu, B and Xu, D},
title = {Effects of Probiotics/Synbiotic Interventions on Cognitive Dysfunction in Alzheimer's or MCI: A Systematic Review and Meta‑Analysis of randomized controlled trials.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103442},
doi = {10.1016/j.arr.2026.103442},
pmid = {43003143},
issn = {1872-9649},
abstract = {OBJECTIVE: To systematically evaluate the effects of probiotics or synbiotics on cognitive function in individuals with mild cognitive impairment, Alzheimer's disease, and related cognitive decline.

METHODS: PubMed, Embase, Web of Science, and the Cochrane Library were searched from inception to 20 September 2026. Randomized controlled trials comparing viable probiotics or synbiotics with placebo or usual care were included. Cognitive changes were pooled as standardized mean differences (SMDs) using a random-effects model. Subgroup, sensitivity, RoB 2, Egger, and GRADE assessments were conducted.

RESULTS: Ten trials involving 739 participants were included. Probiotics or synbiotics were associated with a possible improvement in cognitive function (SMD = 0.50, 95% CI: 0.19, 0.81; P = 0.002; Ι[2] = 76%). The approximate 95% prediction interval was -0.57 to 1.57. No statistically significant differences in treatment effects were detected between subgroups defined by disease category, intervention duration, intervention type, study-level mean age, strain composition, dosage, or cognitive instrument. The effect was numerically larger in studies with a mean age ≤ 70 years, but this difference was not significant (P = 0.17) and was sensitive to individual studies. Sensitivity analyses maintained the direction and statistical significance of the pooled effect. Egger's test showed no significant small-study effects (Z = 1.00, P = 0.318). The certainty of evidence was very low.

CONCLUSION: Probiotics or synbiotics may improve cognitive test performance, but the certainty of evidence is very low because of risk of bias, substantial heterogeneity, and imprecision. Exploratory subgroup analyses did not provide clear evidence that disease category, intervention duration, intervention type, study-level mean age, strain composition, dosage, or cognitive assessment instrument modified the treatment effect. Larger, well-designed randomized trials are needed.},
}

@article {pmid43003335,
year = {2026},
author = {Wang, C and Zhang, R and Lo, H and Wu, J and Song, L and Qu, L and Wang, H and Liu, M and Yun, X and Chen, X and Qu, Y and Tang, Y and Zhuang, G and Xiang, X and Ye, Z and Zhang, H and Ng, JPL and Wong, VKW and Tang, Y and Law, BYK},
title = {Tectoridin Attenuates Alzheimer's Pathology by Inhibiting Aβ Aggregation in 3xTg-AD Mice.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {179540},
doi = {10.1016/j.ejphar.2026.179540},
pmid = {43003335},
issn = {1879-0712},
abstract = {BACKGROUND: Alzheimer's disease (AD) remains a major neurodegenerative challenge, necessitating the development of innovative, mechanism-targeted therapies.

PURPOSE: Tectoridin (Tec), an isoflavone from Belamcanda chinensis (L.) DC., was systematically investigated for its novel neuroprotective effects in AD to elucidate its therapeutic potential and molecular mechanisms.

METHODS: In vitro, western blotting, calcium assays, and flow cytometry were used to characterize Tec's impact on neuronal homeostasis. In vivo, the therapeutic efficacy of Tec was assessed in 3xTg-AD mice. Cognitive performance was evaluated via the Morris Water Maze, while pathological changes were analyzed through immunohistochemistry. RNA sequencing and experimental validation were performed to delineate regulatory pathways.

RESULT: Tec effectively inhibited Aβ aggregation and exhibited potent antioxidant activity. It maintained cellular homeostasis by mitigating Aβ-induced calcium overload, restoring ATP levels, and stabilizing mitochondrial membrane potential, ultimately preventing neuronal apoptosis. Furthermore, Tec treatment significantly ameliorated cognitive impairments in 3xTg-AD mice and markedly reduced cerebral Aβ plaque deposition. Mechanistic analysis revealed that Tec improves AD pathology by upregulating LRP1, thereby promoting the transmembrane transport and systemic clearance of Aβ.

CONCLUSION: This study confirms that Tec exerts significant neuroprotective effects in AD by inhibiting Aβ aggregation, reducing neuronal apoptosis and upregulating the expression of LRP1. The upregulation of LRP1 by Tec may enhance Aβ efflux from the brain, thereby contributing to the reduced Aβ pathology and subsequent neuroprotection observed in this study. In summary, tectoridin is a promising natural therapeutic for AD due to its high safety and multi-target mechanisms.},
}

@article {pmid43003587,
year = {2026},
author = {Pan, Z and Wang, Q and Feng, Q and Xu, H and Liu, W and Wang, P and Chen, G},
title = {Mn-doped dual-emission CdZnSe/Mn:ZnS quantum dots for self-calibrated ratiometric sensing of Alzheimer's disease biomarker.},
journal = {Analytica chimica acta},
volume = {1427},
number = {},
pages = {346394},
doi = {10.1016/j.aca.2026.346394},
pmid = {43003587},
issn = {1873-4324},
mesh = {*Quantum Dots/chemistry ; *Alzheimer Disease/diagnosis ; Zinc Compounds/chemistry ; Humans ; Sulfides/chemistry ; Manganese/chemistry ; *Amyloid beta-Peptides/analysis ; Biomarkers/analysis/blood ; *Biosensing Techniques/methods ; Cadmium/chemistry ; Selenium Compounds/chemistry ; Spectrometry, Fluorescence ; Aptamers, Nucleotide/chemistry ; Calibration ; Limit of Detection ; Fluorescent Chemosensor Compounds ; },
abstract = {BACKGROUND: Accurate detection of Alzheimer's disease (AD) biomarkers is critical for early identification, precise diagnosis, and timely therapeutic intervention. Nevertheless, conventional detection techniques rely on single-signal readout, which is susceptible to environmental interference and yields unreliable results in complex biological matrices. Therefore, developing reliable, sensitive and selective sensing platforms for AD biomarkers are highly desirable.

RESULTS: Herein, a self-calibrated ratiometric fluorescence aptasensor based on Mn-doped dual-emission CdZnSe/Mn:ZnS quantum dots (QDs) is constructed for detecting AD biomarker amyloid-β oligomers (AβO). Possessing two characteristic fluorescence peaks at 425 nm and 628 nm, CdZnSe/Mn:ZnS QDs act as dual self-calibrating references. CdZnSe/Mn:ZnS QDs and Ag NPs are modified at two termini of hairpin H1 (CdZnSe/Mn:ZnS QDs-H1-Ag NPs), quenching the 425 nm fluorescence (FL425 off and FL628 on). Upon AβO recognition, aptamer-functionalized magnetic beads convert AβO into released DNA strands (S). These S strands react with CdZnSe/Mn:ZnS QDs-H1-Ag NPs and black hole quencher 3-labeled H2 (H2-BHQ3) to trigger catalytic hairpin assembly (CHA) for signal amplification, quenching Mn-doped FL628 while restoring core FL425 and yielding an AβO-dependent FL425/FL628 ratiometric response. The aptasensor achieves a 5.2 fM detection limit and effectively distinguishes AD patients from healthy subjects, with results well consistent with standard diagnostic methods.

SIGNIFICANCE: This study demonstrates the great potential of intrinsic dual-emission Mn-doped QDs for self-calibrated ratiometric biosensing. By integrating magnetic beads-mediated signal transduction and CHA amplification, the aptasensor achieves high sensitivity and robust anti-interference performance toward AβO in clinical samples, providing a reliable analytical tool for early auxiliary diagnosis of AD.},
}

*Quantum Dots/chemistry
*Alzheimer Disease/diagnosis
Zinc Compounds/chemistry
Humans
Sulfides/chemistry
Manganese/chemistry
*Amyloid beta-Peptides/analysis
Biomarkers/analysis/blood
*Biosensing Techniques/methods
Cadmium/chemistry
Selenium Compounds/chemistry
Spectrometry, Fluorescence
Aptamers, Nucleotide/chemistry
Calibration
Limit of Detection
Fluorescent Chemosensor Compounds

@article {pmid43003805,
year = {2026},
author = {Leslie, S and Hicks, C and Norman, M and Zummach, D and McAiney, C},
title = {"I have Alzheimer's disease, it doesn't have me". Words of Wisdom From People Living With Dementia: A Secondary Qualitative Analysis.},
journal = {Dementia (London, England)},
volume = {},
number = {},
pages = {14713012261507124},
doi = {10.1177/14713012261507124},
pmid = {43003805},
issn = {1741-2684},
abstract = {Receiving a diagnosis of dementia can be an unsettling experience, often complicated by a lack of hope when seeking resources and support. While clinical guidance is important, peer-to-peer knowledge shared among people living with dementia can provide meaningful insight into ways to support one's well-being. The Wisdom Series was a three-part webinar series designed and offered by people living with dementia for people living with dementia. Led by a dementia advocate who lives with dementia, the series provided a platform for 17 individuals living with dementia across Canada to share their experiences and strategies for living well with dementia with others. A secondary qualitative data analysis was conducted with transcripts of the Wisdom Series webinars to understand participants' perspectives on well-being. Using thematic analysis, six themes were identified: (1) Knowing Yourself: Recognizing Abilities and Limits, highlighting the importance of adaptation and self-awareness; (2) Connecting with Meaningful Supports, focusing on relationships with peers, family, and animals; (3) Keeping your Mind and Body Nourished and Active, emphasizing cognitive, physical, and holistic approaches to health; (4) Finding Joy in Nature, illustrating emotional benefits of engaging with the natural environment; (5) Supporting Self and Others through Advocacy, describing participants' efforts to improve accessibility and awareness in their communities; and (6) Planning for the Future, encompassing advance care planning, medical assistance in dying, autonomy, and burden. In sharing their experiences and perspectives, the webinar panellists not only shared their wisdom but challenged deficit-based assumptions about dementia by demonstrating the agency, citizenship, and personhood of people living with dementia.},
}

@article {pmid43003833,
year = {2026},
author = {Madduri, AV and Ellis, RJ and Lakhani, CM and Bennett, DA and Patel, CJ},
title = {Single-cell machine learning uncovers genetically anchored, cell-type specific programs of Alzheimer's disease.},
journal = {Nature communications},
volume = {17},
number = {1},
pages = {},
pmid = {43003833},
issn = {2041-1723},
support = {R01AG074372//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01ES032470//U.S. Department of Health & Human Services | NIH | National Institute of Environmental Health Sciences (NIEHS)/ ; R01DK137993//U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (National Institute of Diabetes & Digestive & Kidney Diseases)/ ; },
mesh = {*Alzheimer Disease/genetics/pathology/metabolism ; Humans ; *Single-Cell Analysis/methods ; *Machine Learning ; Single-Cell Gene Expression Analysis ; Genome-Wide Association Study ; Quantitative Trait Loci ; Brain/metabolism/pathology ; Transcriptome ; Gene Expression Profiling ; Genetic Predisposition to Disease ; },
abstract = {Univariate differential expression analysis dominates single-cell transcriptomic studies of Alzheimer's disease, yet marginal testing alone cannot resolve multivariate disease-associated structure or distinguish clinical from neuropathological signatures. Here we introduce TriSCOPE, a framework integrating multivariate predictive modeling, donor-aware differential expression, and pseudotime inference, applied to six Alzheimer's disease snRNA-seq datasets comprising ~4.2 million nuclei from 627 donors. Across six major brain cell types and 41 subclusters, we identify cell-type-specific predictively expressed genes that are largely non-overlapping with differentially expressed genes, revealing disease-relevant signals invisible to univariate approaches. Conditional GWAS-eQTL colocalization anchors a subset of these predictively expressed genes to inherited Alzheimer's disease risk loci, including 27 genetically supported gene-cell type pairs (among them ARL17B, JAZF1) with no significant differential expression. Integration across all three analytical branches nominates high-confidence convergent programs including astrocytic stress markers (such as GFAP, MT2A), neuronal signaling genes (like RASGEF1B, LINGO1, NRG1), and microglial and oligodendrocyte regulators (including SYTL3, SPP1, APOD). Comparison of clinical and neuropathological models reveals cell-type-specific divergence between cognitive and pathological Alzheimer's disease signatures. Key predictively expressed genes including ARL17B, LINGO1, and APOE replicate across independent cohorts, with cross-cohort generalizability confirmed across all three analytical branches of TriSCOPE.},
}

*Alzheimer Disease/genetics/pathology/metabolism
Humans
*Single-Cell Analysis/methods
*Machine Learning
Single-Cell Gene Expression Analysis
Genome-Wide Association Study
Quantitative Trait Loci
Brain/metabolism/pathology
Transcriptome
Gene Expression Profiling
Genetic Predisposition to Disease

@article {pmid43003834,
year = {2026},
author = {Yan, T and Hou, X and Watzlawik, JO and Dickson, DW and Fiesel, FC and Springer, W},
title = {Serine-65 phosphorylated ubiquitin associates with soluble tau and seeding activity in Alzheimer's disease.},
journal = {Nature communications},
volume = {17},
number = {1},
pages = {},
pmid = {43003834},
issn = {2041-1723},
support = {R56AG062556//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; U54NS110435//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; RF1NS085070//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; 9AZ10//Florida Department of Health/ ; 25A11//Florida Department of Health/ ; 22A07//Florida Department of Health/ ; 26A09//Florida Department of Health/ ; P30AG062677//Mayo Clinic/ ; AARF-22-974258/ALZ/Alzheimer's Association/United States ; NIAP25-1446587/ALZ/Alzheimer's Association/United States ; AARF-22-973152/ALZ/Alzheimer's Association/United States ; NIAP25-1445722/ALZ/Alzheimer's Association/United States ; },
mesh = {*Alzheimer Disease/metabolism/pathology ; *tau Proteins/metabolism ; Humans ; Phosphorylation ; Female ; *Brain/metabolism/pathology ; Male ; *Ubiquitin/metabolism ; *Serine/metabolism ; Aged, 80 and over ; Aged ; Solubility ; },
abstract = {Tau propagation is a key driver of Alzheimer's disease (AD), yet selective markers of seeding-competent tau remain elusive. Ubiquitin phosphorylated at Serine-65 (pS65-Ub) is a PINK1-derived cellular stress signal that accumulates in AD with elevated tau pathology, but its relationship to tau seeding is unknown. Here, using postmortem brain tissue from female and male donors, we show that a subset of tau is covalently modified by pS65-Ub in AD brain. The pS65-Ub-associated tau population is elevated in AD and is enriched in soluble, high-molecular-weight, oligomeric, and hyperphosphorylated tau species. Across AD cases, soluble pS65-Ub-associated tau levels strongly correlate with tau seeding activity. Tau species isolated with pS65-Ub antibodies exhibit seeding activity, whereas removal of pS65-Ub-associated material markedly reduces seeding from AD brain extracts. Together, these findings identify pS65-Ub as a disease-enriched molecular feature of a seed-competent tau population and link cellular stress signaling with pathological tau propagation in AD.},
}

*Alzheimer Disease/metabolism/pathology
*tau Proteins/metabolism
Humans
Phosphorylation
Female
*Brain/metabolism/pathology
Male
*Ubiquitin/metabolism
*Serine/metabolism
Aged, 80 and over
Aged
Solubility

@article {pmid43003846,
year = {2026},
author = {Urbanek, A and Dear, AJ and Rhodes, DP and Garland, EF and Wareing, HE and Baker, HJ and Molenkamp, W and Zhang, R and Chen, G and Abelein, A and Bell, SM and Varela, JA and Michaels, TCT and Highley, JR and Meisl, G and Johansson, J and De, S},
title = {Two functionally distinct amyloid-β intermediates link aggregation pathways to pathology in Alzheimer's disease.},
journal = {Nature communications},
volume = {17},
number = {1},
pages = {},
pmid = {43003846},
issn = {2041-1723},
support = {MR/V023861/1//RCUK | Medical Research Council (MRC)/ ; MR/N013840/1//RCUK | Medical Research Council (MRC)/ ; 2594676//RCUK | Engineering and Physical Sciences Research Council (EPSRC)/ ; ARUK-PhD2024-010//Alzheimer's Research UK (ARUK)/ ; },
mesh = {*Alzheimer Disease/pathology/metabolism ; Animals ; *Amyloid beta-Peptides/metabolism/genetics ; Humans ; Brain/pathology/metabolism ; Mice ; Plaque, Amyloid/pathology/metabolism ; Neurons/metabolism/pathology ; Disease Models, Animal ; Mice, Transgenic ; *Protein Aggregation, Pathological/metabolism/pathology ; *Peptide Fragments/metabolism/genetics ; Neuroglia/metabolism/pathology ; Female ; },
abstract = {Neurotoxic intermediates formed during amyloid-β (Aβ) aggregation are thought to drive Alzheimer's disease, yet their rarity and transient nature have obscured their identity and formation pathways in the human brain. Here, we combine super-resolution microscopy and single-molecule functional imaging with kinetic modelling to classify Aβ intermediates according to their membrane-disrupting activity and connect their damaging effects to the aggregation pathways that generate them. Applying this framework to recombinant Aβ42, an Alzheimer's knock-in mouse model and human Alzheimer's brain tissue, we find two functionally distinct intermediate populations present across all systems. They form through separate aggregation routes and differ in their neurotoxicity, abundance and susceptibility to inhibition. Both damage neurons and glia, but only one converts into plaques. Suppressing these intermediates pharmacologically in mice reduces plaque burden, attenuates astrogliosis and improves cognition. Our findings connect model systems with human pathology and identify intermediate formation pathways as actionable therapeutic targets across protein-misfolding disorders.},
}

*Alzheimer Disease/pathology/metabolism
Animals
*Amyloid beta-Peptides/metabolism/genetics
Humans
Brain/pathology/metabolism
Mice
Plaque, Amyloid/pathology/metabolism
Neurons/metabolism/pathology
Disease Models, Animal
Mice, Transgenic
*Protein Aggregation, Pathological/metabolism/pathology
*Peptide Fragments/metabolism/genetics
Neuroglia/metabolism/pathology
Female

@article {pmid43004046,
year = {2026},
author = {Rempe, MP and Voller, ME and Garrison, GM and Glesinger, RJ and Horne, LK and Hall, MC and Petts, AJ and Kress, KA and Carusi, OR and Volberding, LD and DeLuca, KR and John, JA and Springer, SD and Embury, CM and Johnson, CM and May-Weeks, PE and Spooner, RK and Wilson, TW},
title = {Glycemic control is differentially related to spontaneous cortical activity in patients on the Alzheimer's disease spectrum.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {43004046},
issn = {2509-2723},
support = {R01-NS141729/NS/NINDS NIH HHS/United States ; R01-MH116782/MH/NIMH NIH HHS/United States ; S10-OD028751//NIH Office of the Director/ ; P20-GM144641/GM/NIGMS NIH HHS/United States ; },
abstract = {Diabetes is a major risk factor for developing cognitive impairment and studies have shown that poor glycemic control can increase this risk, but the neural mechanisms are poorly understood. Many studies have linked altered spontaneous cortical activity during the resting-state to Alzheimer's disease and other neurological conditions associated with cognitive impairment. Herein, we examine whether the strength of spontaneous activity during the resting-state is differentially related to glycemic control in 37 biomarker-positive participants on the Alzheimer's disease spectrum (ADS) and 43 cognitively normal aging adults. All participants completed resting-state magnetoencephalography (MEG), a blood draw to derive their level of glycemic control (i.e., A1C), and comprehensive neuropsychological assessment. Spontaneous activity was imaged in each of the canonical frequency bands (e.g., alpha) and probed for group differences in the relationship between neural activity and glycemic control. We found significant interactions between A1C and disease status (ADS vs. control) in the delta and alpha bands (p < 0.001). Specifically, delta power decreased with increasing A1C in the ADS group across a broad area of frontotemporal and inferior parietal cortices, while spontaneous alpha decreased with higher A1C in the control group across inferior frontal and temporal cortex. Importantly, delta activity in the superior frontal cortices mediated the effect of A1C on attention performance in the ADS group. In sum, these data suggest that the impact of glycemic dysregulation on spontaneous cortical activity may differ in those on the ADS compared with cognitively normal controls and that spontaneous delta may be critical for attention function.},
}

@article {pmid43004192,
year = {2026},
author = {Jian, Y and Shi, H and Hu, T and Zhou, S and He, X and Tao, D and Du, H and Zhou, J and Yao, Y and Shu, Z},
title = {Interpretable radiomics signature of the basal ganglia-thalamic circuitry for predicting PD-MCI: a multi-center study with external validation.},
journal = {BMC medical imaging},
volume = {26},
number = {1},
pages = {},
pmid = {43004192},
issn = {1471-2342},
support = {S2024018//the Medical Research Project of Sichuan Medical Association/ ; WJKY2024018//the Research Project of Health System of Longquanyi District/ ; },
mesh = {Humans ; Radiomics ; *Magnetic Resonance Imaging/methods ; *Cognitive Dysfunction/diagnostic imaging/etiology ; *Basal Ganglia/diagnostic imaging ; *Thalamus/diagnostic imaging ; Female ; *Parkinson Disease/diagnostic imaging/complications ; Retrospective Studies ; Male ; Aged ; Disease Progression ; ROC Curve ; },
abstract = {BACKGROUND: To develop and validate a T1-weighted imaging (T1WI)-based radiomic signature and integrate it with clinical features to construct a combined model for the early identification of cognitive decline in Parkinson's disease (PD).

METHODS: We retrospectively analyzed data from 233 PD patients, including 182 from the Parkinson's Progression Markers Initiative (PPMI) and 51 from the National Alzheimer's Coordinating Center (NACC). Based on baseline Montreal Cognitive Assessment (MoCA) scores, patients were classified into those with normal cognition (PD-NC) and those with mild cognitive impairment (PD-MCI). The PPMI cohort was randomly divided into training (n = 127) and test (n = 55) sets at a 7:3 ratio, while the NACC cohort served as an external validation set (n = 51). Radiomic features were extracted from T1WI of the bilateral basal ganglia (globus pallidus, putamen) and bilateral thalamus. After dimensionality reduction, a radiomic model was constructed. Independent clinical predictors were identified and integrated with the radiomic signature to establish a combined model. Model performance was evaluated using receiver operating characteristic (ROC) curves, confusion matrices, and F1-scores. SHapley Additive exPlanations (SHAP) was employed to interpret model outputs.

RESULTS: The radiomic model achieved area under the curve (AUC) values of 0.809, 0.777, and 0.776 in the training, test, and external validation sets, respectively. Multivariable regression identified the Geriatric Depression Scale (GDS) score (odds ratio [OR] = 1.41, P = 0.005) and resting tremor (OR = 4.11, P = 0.036) as independent predictors. The combined model incorporating these clinical factors with the radiomic signature yielded significantly improved AUCs of 0.848 (95% CI: 0.774-0.906), 0.796 (95% CI: 0.666-0.893), and 0.812 (95% CI: 0.628-0.925) across the three datasets, outperforming either model alone. Among the 13 retained radiomic features, texture features were predominant (69.2%). SHAP analysis confirmed that the Rad-score was the most influential predictor.

CONCLUSION: The combined model integrating T1WI-based radiomic features from the bilateral basal ganglia (globus pallidus, putamen)-thalamus with clinical characteristics demonstrates robust predictive capability for cognitive decline in PD. This approach offers valuable support for early intervention and precision management in clinical practice.},
}

Humans
Radiomics
*Magnetic Resonance Imaging/methods
*Cognitive Dysfunction/diagnostic imaging/etiology
*Basal Ganglia/diagnostic imaging
*Thalamus/diagnostic imaging
Female
*Parkinson Disease/diagnostic imaging/complications
Retrospective Studies
Male
Aged
Disease Progression
ROC Curve

@article {pmid43004376,
year = {2026},
author = {Zha, L and Xu, J and Zhu, X and Tu, Q and Zhong, C and Zhan, L and Zhang, M and Zhou, D and Wang, X and Wu, J and Hua, F and Guan, X},
title = {Rab GTPases and the Rabopathy framework: from synaptic trafficking to neurodegeneration via LRRK2-driven pathology.},
journal = {Translational neurodegeneration},
volume = {15},
number = {1},
pages = {},
pmid = {43004376},
issn = {2047-9158},
mesh = {Humans ; *Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/metabolism ; *rab GTP-Binding Proteins/metabolism ; *Neurodegenerative Diseases/metabolism/pathology ; Animals ; Protein Transport/physiology ; *Synapses/metabolism/pathology ; },
abstract = {Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD) show significant differences in their clinical manifestations, but they all seem to share a common upstream problem: malfunction in the membrane transport controlled by Rab GTPases. This review introduces the concept of Rabopathy, a framework that connects developmental synaptic maturation defects with late-onset protein aggregation. The LRRK2-Rab phosphorylation axis is emerging as a potential common amplifying mechanism across these disorders, with the strongest mechanistic support in PD and growing implications in AD and HD. When Rab substrates are excessively phosphorylated at specific sites, vesicular transport is impaired or arrested, leading to progressive depletion of the reserve pool of synaptic vesicles and the surface pool of receptors, and severe compromise of the autophagy-lysosome flux. The failure of distinct Rab sub-networks also produces disease-specific signatures, including Rab5-driven endosomal congestion in AD, Rab35-mediated α-synuclein secretion in PD, and Rab11/Rab7 trafficking collapse in HD. Restoration of Rab flux may be a therapeutic strategy for neurodegenerative diseases, which can be achieved through calibration of LRRK2 activity, modulation of selective Rab subtypes, and rescue of the trafficking network at the systems level.},
}

Humans
*Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/metabolism
*rab GTP-Binding Proteins/metabolism
*Neurodegenerative Diseases/metabolism/pathology
Animals
Protein Transport/physiology
*Synapses/metabolism/pathology

@article {pmid43004385,
year = {2026},
author = {Schöll, M},
title = {A pain in the Aß: a typographical plea to the amyloid community.},
journal = {Alzheimer's research & therapy},
volume = {18},
number = {1},
pages = {},
pmid = {43004385},
issn = {1758-9193},
}

@article {pmid43004463,
year = {2026},
author = {Christensen, A and Valencia-Olvera, AC and Xeros, H and Nguyen, ET and Lopez, M and Javaheri, R and Tai, LM and LaDu, MJ and Pike, CJ},
title = {Effects of sexual differentiation and APOE genotype on the development of Alzheimer-related pathology in female EFAD mice.},
journal = {Biology of sex differences},
volume = {17},
number = {1},
pages = {},
pmid = {43004463},
issn = {2042-6410},
support = {AG052374/NH/NIH HHS/United States ; AG069711/NH/NIH HHS/United States ; AG058068/NH/NIH HHS/United States ; AG058068/NH/NIH HHS/United States ; },
mesh = {Animals ; Female ; *Alzheimer Disease/genetics/pathology ; *Sex Differentiation ; Mice, Transgenic ; Genotype ; Male ; Mice ; *Apolipoprotein E4/genetics ; Sex Characteristics ; Brain/pathology/metabolism ; *Apolipoprotein E3/genetics ; Humans ; Amyloid beta-Peptides/metabolism ; },
abstract = {Apolipoprotein E ε4 genotype (APOE4), the most significant genetic risk factor for late-onset Alzheimer's disease (AD), is associated with sexually dimorphic effects whereby higher risks are generally observed in women. Sex differences can arise in part from developmental processes of sexual differentiation, which yield permanent sex-specific phenotypes that can impact adult trajectories and vulnerabilities to various conditions. We investigated the potential contributions of sexual differentiation to the female bias of APOE4 in driving AD pathogenesis. Specifically, using the EFAD transgenic mouse model of AD that includes knock-in of human APOE3 or APOE4, we examined the effects of experimental masculinization in perinatal female mice on adult patterns of AD-related pathology relative to control male and female mice. Both female sex and APOE4 genotype were associated with increased levels of β-amyloid pathologies. Masculinization resulted in expected systemic and neural phenotypes in adult animals. The effects of masculinization differed depending upon both outcome measure and APOE genotype. Intermediate phenotypes were the most common response to masculinization, though select aspects of AD-related endpoints, including the numbers of mature amyloid plaques, were reduced by masculinization of APOE4 female mice. These findings suggest that sexual differentiation in early life has modest effects on adult development of AD in females, a relationship that appeared stronger in the context of APOE4. The results complement prior work establishing roles of sex chromosomes and age-related depletion of sex hormones in the sexual dimorphisms characteristic of AD and provide new insights into the organizational actions of sex hormones and how these interact with APOE genotype.},
}

Animals
Female
*Alzheimer Disease/genetics/pathology
*Sex Differentiation
Mice, Transgenic
Genotype
Male
Mice
*Apolipoprotein E4/genetics
Sex Characteristics
Brain/pathology/metabolism
*Apolipoprotein E3/genetics
Humans
Amyloid beta-Peptides/metabolism

@article {pmid43004564,
year = {2026},
author = {Medina, G and MacKenzie, AE},
title = {The Role of DHA in PSD-95 Regulation and Postsynaptic Organization: Implications for Synaptic Function and Neurological Disorders.},
journal = {Journal of neurochemistry},
volume = {170},
number = {11},
pages = {},
doi = {10.1111/jnc.70571},
pmid = {43004564},
issn = {1471-4159},
support = {CFREF-2022-00007//Canada First Research Excellence Fund for the Brain (CFREF)/ ; },
mesh = {*Docosahexaenoic Acids/metabolism/pharmacology ; Humans ; Animals ; *Disks Large Homolog 4 Protein/metabolism ; *Synapses/metabolism/drug effects ; *Nervous System Diseases/metabolism/drug therapy ; *Neuronal Plasticity/physiology/drug effects ; *Post-Synaptic Density/metabolism/drug effects ; },
abstract = {Docosahexaenoic acid (DHA), a long-chain omega-3 fatty acid, plays a critical role in synaptic function by regulating membrane biophysical properties, neurotransmitter dynamics, and synaptic protein organization; as such, its therapeutic potential for synaptic disorders is an area of considerable research. Among DHA's effects on synapses is its modulation of postsynaptic density protein-95 (PSD-95), a key scaffolding protein essential for synaptic stability and plasticity. This review integrates current evidence linking DHA to changes in PSD-95 expression, synaptic localization, and interactions with glutamate receptors. Specifically, DHA incorporation into neuronal membranes alters lipid packing and membrane microdomain organization, which can influence receptor mobility and clustering. In parallel, DHA also engages intracellular signaling pathways, including protein kinase B (Akt)- and cAMP response element-binding protein (CREB)-associated signaling, which may contribute to PSD-95 synthesis, synaptic retention, and postsynaptic stabilization. Bioactive DHA metabolites, such as neuroprotectin D1 (NPD1) and N-docosahexaenoyl ethanolamide (DHEA; synaptamide), further influence synaptic function via receptor-mediated signaling at nanomolar concentrations. DHA deficiency disrupts synaptic architecture, impairing long-term potentiation (LTP) and cognitive function, while DHA repletion following deficiency can restore PSD-95 levels and selected measures of synaptic function. From a clinical perspective, DHA has shown potential to mitigate synaptic and behavioral deficits in neurodevelopmental disorders such as autism spectrum disorder (ASD) and Fragile X syndrome (FXS) and preserve synaptic integrity in neurodegenerative diseases, including Alzheimer's and Huntington's. However, clinical trials reveal variable outcomes, influenced by factors such as apolipoprotein E (APOE) genotype, dosing regimen, and baseline DHA status. Continued efforts to optimize bioavailability, incorporate genotype-stratified designs, and evaluate DHA metabolites are essential to advancing its translation from a nutritional supplement to a targeted neuromodulatory therapy for disorders characterized by postsynaptic dysfunction.},
}

*Docosahexaenoic Acids/metabolism/pharmacology
Humans
Animals
*Disks Large Homolog 4 Protein/metabolism
*Synapses/metabolism/drug effects
*Nervous System Diseases/metabolism/drug therapy
*Neuronal Plasticity/physiology/drug effects
*Post-Synaptic Density/metabolism/drug effects

@article {pmid43004651,
year = {2026},
author = {Shetty, S and Suvarna, V},
title = {Functionalized nanocarrier-based intranasal drug delivery of rivastigmine tartrate for enhanced brain exposure: a pharmacokinetic and biodistribution evaluation.},
journal = {Therapeutic delivery},
volume = {},
number = {},
pages = {1-16},
doi = {10.1080/20415990.2026.2760224},
pmid = {43004651},
issn = {2041-6008},
abstract = {AIMS: To develop and evaluate a polyethylene glycol (PEG)-functionalized multi-walled carbon nanotube (MWCNT)-based intranasal delivery system for rivastigmine tartrate (RT) to improve systemic exposure and brain delivery for Alzheimer's disease (AD).

MATERIALS AND METHODS: RT-loaded PEGylated MWCNTs were prepared, optimized using a 3[2] factorial design, and characterized for particle size, zeta potential, entrapment efficiency, morphology, in vitro release, ex vivo nasal permeation, pharmacokinetics, brain biodistribution, cytocompatibility, and neuroprotective activity.

RESULTS: The optimized formulation showed an entrapment efficiency of 90.92%, particle size of 176.7 nm, and zeta potential of -24.1 mV. Sustained drug release and efficient permeation across goat nasal mucosa were observed. Intranasal administration increased plasma exposure, producing approximately 5-fold higher relative bioavailability and a 4.1-fold increase in brain exposure compared with oral administration. In SH-SY5Y cells, the formulation reduced rotenone-induced oxidative stress and improved cell viability, indicating neuroprotective potential.

CONCLUSIONS: PEGylated MWCNT-mediated intranasal delivery enhanced rivastigmine bioavailability and brain exposure while demonstrating neuroprotective activity in vitro. These findings support further investigation of this nanocarrier platform as a strategy for brain-targeted delivery of rivastigmine.},
}

@article {pmid43004772,
year = {2026},
author = {Soni, J and Capucciati, A and Uttarkar, M and Monzani, E and Pezzoli, G and Cassidy, CM and Sulzer, D and Khairnar, A and Zecca, L and Zucca, FA},
title = {Neuromelanins: a link between brain aging and neurodegenerative diseases.},
journal = {Physiological reviews},
volume = {},
number = {},
pages = {},
doi = {10.1152/physrev.00036.2025},
pmid = {43004772},
issn = {1522-1210},
abstract = {Neuromelanins (NMs) accumulate in large amounts in catecholaminergic neurons of the substantia nigra (SN) and locus coeruleus (LC), which selectively degenerate in Parkinson's disease (PD) and Alzheimer's disease (AD). Lower amounts of NMs are also present in other human brain regions. NMs are contained in specialized autolysosomes with lipid bodies, proteins, and metals. Their structure, synthesis, functions, and cellular localization differ from those of melanins in non-nervous tissues. Purified NMs have a complex structure, are composed of melanic moieties, lipids, proteins, and inorganic components, and are insoluble. NMs can exert either a protective or toxic role depending on cellular context. NMs synthesis is driven by cytosolic catecholamines and is a protective process, as it removes excess cytosolic catechols that would otherwise trigger neurotoxicity. NMs can bind reactive/toxic metals, forming stable and non-toxic complexes, thereby playing a neuroprotective role. However, NMs released from degenerating neurons in PD and AD activate microglia, which release reactive species and proinflammatory factors, thereby exacerbating neuroinflammation and neurodegeneration. The major histocompatibility complex class I is present within NM-containing organelles of SN and LC neurons and can bind antigens, presenting them on the neuronal membrane. Subsequently, CD8[+] T-cells may target catecholaminergic NM-containing neurons, contributing to neurodegeneration. The loss of NM-containing neurons in PD and AD causes a decrease of NMs concentration within the SN and LC, which can be visualized using magnetic resonance imaging (MRI). NM-sensitive MRI of the SN and LC is increasingly being used for the diagnosis and treatment monitoring of neurodegenerative and psychiatric disorders.},
}

@article {pmid43004896,
year = {2026},
author = {Li, C and Leitner, D and Liang, Z and Yakovishina, V and Ibrahim, M and Faustin, A and Wisniewski, T and Wadghiri, YZ and Ge, Y and Zhang, J},
title = {Short T1 Fraction as a Marker of Myelin Content: Evidence From Postmortem MRI and Histology.},
journal = {Magnetic resonance in medicine},
volume = {},
number = {},
pages = {},
doi = {10.1002/mrm.70656},
pmid = {43004896},
issn = {1522-2594},
support = {P30 AG066512//National institutes of Health in the United States/ ; R01 AG077422//National institutes of Health in the United States/ ; R01 HD074593//National institutes of Health in the United States/ ; R01 NS108491//National institutes of Health in the United States/ ; R13 AG067684//National institutes of Health in the United States/ ; RF1 NS11041//National institutes of Health in the United States/ ; U24 NS135568//National institutes of Health in the United States/ ; U24 NS141774//National institutes of Health in the United States/ ; RRID_SCR_017937//Preclinical Imaging Laboratory/ ; NIH/SIG 1S10OD018337-01//NYU Langone Health/NYU Grossman School of Medicine/ ; NIH/NCI 5P30CA016087//Laura and Isaac Perlmutter Cancer Center Support/ ; NIH P41 EB017183//NIBIB Biomedical Technology Resource Center/ ; },
abstract = {PURPOSE: To investigate the short-T1 fraction as a potential biomarker of white matter myelin integrity, using myelin histology as ground truth.

METHODS: Multi-inversion-time MRI data were acquired from four postmortem brain specimens from donors with Alzheimer's disease on a clinical 3T scanner, and from five dissected tissue blocks containing white matter hyperintensities (WMHs) on a preclinical 3T system. Short-T1 fraction maps were generated using inverse Laplace transform to isolate short-T1 components and were compared with T2-based myelin water imaging metrics through joint T1-T2 correlation analysis. Short-T1 fraction maps from the tissue blocks were further compared with myelin histology. In addition, in vivo short-T1 fraction data were acquired from five participants, including four healthy male volunteers (35.4 ± 12.1 years) and one 71-year-old female participant with moderate white matter microangiopathy and WMHs, to demonstrate translational feasibility.

RESULTS: Postmortem MRI revealed reduced short-T1 fractions in WMHs. T1-T2 correlation analysis suggested that the short-T1 fraction was closely associated with the short-T2 (myelin water) component. Strong correlations were observed between short-T1 fractions and optical densities from both Luxol Fast Blue- and Myelin Basic Protein-stained histological sections, supporting the link between the short-T1 signal and myelin content. Preliminary in vivo findings also showed reduced short-T1 fraction within WMHs, consistent with the ex vivo observations.

CONCLUSION: The short-T1 fraction correlated with myelin content in postmortem brain white matter, supporting its potential as a biomarker of myelin integrity.},
}

@article {pmid43004989,
year = {2026},
author = {Sharma, R and Niranjan, N and Long, A and Sharma, R and Safieh, F and Kumar, P and Sund, P and Sellami, Z},
title = {Genome Editing of Mitochondrial Dysfunction in Neurological Disease: Progress and Translational Barriers.},
journal = {The Yale journal of biology and medicine},
volume = {99},
number = {3},
pages = {521-539},
pmid = {43004989},
issn = {1551-4056},
mesh = {Humans ; Animals ; *Gene Editing/methods ; *Mitochondria/genetics/metabolism/pathology ; *Nervous System Diseases/genetics/therapy ; *Mitochondrial Diseases/genetics/therapy ; DNA, Mitochondrial/genetics ; Neurodegenerative Diseases/genetics ; Translational Research, Biomedical ; },
abstract = {Mitochondrial dysfunction is increasingly recognized as a shared mechanism across neurological disease. Specifically, impaired oxidative phosphorylation, oxidative stress, and mitochondrial DNA damage are factors in primary mitochondrial disorders and major neurodegenerative diseases such as Parkinson, Alzheimer, and Huntington diseases, and amyotrophic lateral sclerosis. This review surveys the mechanisms driving mitochondrial dysfunction and evaluates the current landscape of gene-editing technologies developed to address them. We examine mitochondria-targeted editors and nuclear-targeted editors, examining the editing capability, delivery constraints, and off-target risk of each. Heteroplasmy-shifting nucleases currently offer the strongest in vivo evidence for mtDNA-directed therapy, while base editors extend correction to homoplasmic mutations at the cost of a narrower editing scope and off-target editing. Nuclear editing platforms avoid the mitochondrial gRNA import barrier entirely, allowing current technologies to achieve the most progress toward functional, behavioral rescue in animal models. Across all platforms, delivery efficiency, off-target specificity, and translation from rodent to primate models remain unresolved barriers to clinical application. Gene editing for mitochondrial dysfunction is highly creditable as a precision therapy for genetically defined disease subsets, including primary mitochondrial disease and other neurodegenerative disorders with a known nuclear driver, rather than as a universal strategy for sporadic neurodegeneration, where mitochondrial dysfunction arises from multifactorial and poorly localized causes.},
}

Humans
Animals
*Gene Editing/methods
*Mitochondria/genetics/metabolism/pathology
*Nervous System Diseases/genetics/therapy
*Mitochondrial Diseases/genetics/therapy
DNA, Mitochondrial/genetics
Neurodegenerative Diseases/genetics
Translational Research, Biomedical

@article {pmid43005006,
year = {2026},
author = {Uzakov, U and Anvarkhonov, A and Azizakhon, A},
title = {Mechanisms of Mitochondrial DNA Leakage as Primary Upstream Catalysts for NLRP3 Inflammasome Activation in Neurodegenerative Pathology: A Systematic Review.},
journal = {The Yale journal of biology and medicine},
volume = {99},
number = {3},
pages = {600-616},
pmid = {43005006},
issn = {1551-4056},
mesh = {*NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *DNA, Mitochondrial/metabolism/genetics ; *Inflammasomes/metabolism ; Humans ; *Neurodegenerative Diseases/metabolism/pathology/genetics ; Animals ; Mitochondria/metabolism ; },
abstract = {Chronic neuroinflammation drives progressive neurodegenerative pathology, including Alzheimer and Parkinson diseases. While the NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome is a central mediator of this response, its upstream, nonlinear activation mechanics remain poorly defined. Recent studies suggest that the translocation of damaged mitochondrial DNA (mtDNA) into the cytosol serves as a critical immunogenic catalyst bridging metabolic stress with inflammatory cascades. Following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 2020 guidelines, a systematic review was conducted across PubMed, Embase, and Scopus for primary experimental studies. Eligibility focused on quantitative metrics of cytosolic mtDNA leakage and subsequent NLRP3 conformational assembly kinetics in neurodegenerative models. The data demonstrate that chronic oxidative stress and toxic protein aggregation induce mitochondrial outer membrane permeabilization via BCL2-associated X protein/BCL2 antagonist/killer 1 (BAX/BAK) macropores. The resulting efflux of oxidized mtDNA (8-OHdG) escapes cytoplasmic exonuclease degradation, binding directly to the leucine-rich repeat domain of NLRP3 to trigger enzymatic activation. This synthesis establishes that mtDNA leakage acts as a distinct, cooperative biochemical switch rather than a linear cascade. Characterizing these nonlinear threshold dynamics bridges clinical pathology with predictive systems biology, providing the quantitative parameters necessary to constrain advanced computational models of early-stage neurodegeneration.},
}

*NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
*DNA, Mitochondrial/metabolism/genetics
*Inflammasomes/metabolism
Humans
*Neurodegenerative Diseases/metabolism/pathology/genetics
Animals
Mitochondria/metabolism

@article {pmid43005040,
year = {2026},
author = {Somaa, F and Khan, A and Kiyani, MM},
title = {Mitochondrial Dysfunction and Bioenergetic Failure at the Amyloid-Tau-Metal Interface: An Integrative Model of Alzheimer Disease Pathogenesis.},
journal = {The Yale journal of biology and medicine},
volume = {99},
number = {3},
pages = {405-425},
pmid = {43005040},
issn = {1551-4056},
mesh = {Humans ; *Alzheimer Disease/metabolism/pathology ; *Mitochondria/metabolism/pathology ; *Energy Metabolism ; *Amyloid beta-Peptides/metabolism ; *tau Proteins/metabolism ; *Metals/metabolism ; Animals ; },
abstract = {Background Alzheimer disease (AD) is a multifactorial neurodegenerative disorder characterized by amyloid-β (Aβ) accumulation, tau hyperphosphorylation, and metal dyshomeostasis. Emerging evidence suggests that mitochondrial dysfunction is a pivotal convergent event linking these hallmark pathologies, with bioenergetic failure emerging as a pivotal convergent driver of neurodegeneration rather than a downstream epiphenomenon. Objective This narrative review examines the mechanistic interplay between Aβ, tau, and transition metal ions in mediating mitochondrial dysfunction. We introduce the amyloid-tau-metal-mitochondria (ATMM) axis as a conceptual framework for understanding bioenergetic failure in AD and evaluate emerging therapeutic strategies targeting this integrative pathway. Key Findings Transition metals (copper, iron, zinc) catalyze Aβ aggregation and promote reactive oxygen species generation, damaging the mitochondrial membrane and impairing electron transport chain function. Aβ-heme complexes acquire peroxidase-like activity that sequesters heme from cytochrome c oxidase (Complex IV), amplifying respiratory failure. Tau hyperphosphorylation exacerbates energy deficits by disrupting axonal mitochondrial trafficking and promoting dynamin-related protein 1-mediated fragmentation. These constitute a self-reinforcing feedback loop-the ATMM cycle-culminating in a neuronal energy crisis and apoptosis. Conclusion Mitochondrial impairment represents a mechanistic hub in AD pathogenesis, integrating protein aggregation, metal dyshomeostasis, and oxidative stress into a unified neurodegenerative model. Mitochondria-targeted antioxidants, metal redistributing agents, and modulators of fission-fusion dynamics offer rational therapeutic avenues. Future efforts should prioritize validating mitochondria-centered biomarkers to facilitate early intervention and disease modification.},
}

Humans
*Alzheimer Disease/metabolism/pathology
*Mitochondria/metabolism/pathology
*Energy Metabolism
*Amyloid beta-Peptides/metabolism
*tau Proteins/metabolism
*Metals/metabolism
Animals

@article {pmid43005121,
year = {2026},
author = {Ghiamaty, Z and Akhlaghi, M and Jokar, S and Hafezi, H and Bavi, O and Sharifzadeh, M and Sabzevari, O and Shafiee Ardestani, M and Ghorbandaeipour, T and Asadi, M and Kiani, M and Roustaei, S and Ebrahimi, F and Beiki, D},
title = {Design and Evaluation of a Chalcone-Based Dimeric Scaffold Targeting Amyloid-Beta Plaques for Early Detection of Alzheimer's Disease: Synthesis, Radiolabeling, In Vivo Studies, and Integrated Molecular Docking and Dynamics Simulation.},
journal = {Advanced pharmaceutical bulletin},
volume = {16},
number = {2},
pages = {416-431},
pmid = {43005121},
issn = {2228-5881},
abstract = {PURPOSE: Amyloid-Beta (Aβ) plaque imaging can serve as a desirable tool for early detection of Alzheimer's disease (AD). This study presents a new dimer of a chalcone-based scaffold, [68Ga]Ga-DTPA[Ch-DE]2, as a potential radiotracer for Aβ plaques imaging.

METHODS: The synthesis of DTPA[Ch-DE]2 and its radiolabeling with gallium-68 were characterized using techniques such as 1H-NMR, mass spectrometry, HPLC, and instant thin-layer chromatography. Neurotoxicity of DTPA[Ch-DE]2 was evaluated using the MTT assay. The stability of radiotracer was tested in various buffer systems and human serum albumin (HSA). The binding affinity of the radiotracer to Aβ aggregations was evaluted on the brain sections from both normal and AD rat models. Positron emission tomography-computed tomography (PET/CT) of brain imaging and Thioflavin S staining characterized the AD model. Biodistribution studies and PET/CT scans were performed on normal and AD rats. Computational studies also were conducted.

RESULTS: [68Ga]Ga-DTPA[Ch-DE]2 was synthesized with over 93% radiochemical purity. It showed high stability in various buffer systems and HSA after 2 hours. The binding assay revealed strong affinity to Aβ42 aggregations. Biodistribution studies and PET/CT imaging indicated favorable brain uptake: 0.54% ID/g and 0.59% ID/g at 2 minutes in normal and AD rats, respectively. Computational studies indicated that DTPA[Ch-DE]2 binds specifically to the Aβ fibrils while maintaining the receptor's architectural integrity. In vivo studies show that [68Ga] Ga-DTPA[Ch-DE]2 has good brain uptake and retention in AD rats compared with normal.

CONCLUSION: Thus, results suggest that [68Ga]Ga-DTPA[Ch-DE]2 could be a promising radiotracer for Aβ targeting and early diagnosis of AD.},
}

@article {pmid43005271,
year = {2026},
author = {Wang, X and Zhang, BW},
title = {Extracellular vesicles and Alzheimer's disease: hotspots, trends, and future directions-a tri-database bibliometric analysis.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1951959},
pmid = {43005271},
issn = {1663-4365},
abstract = {BACKGROUND: Alzheimer's disease is a neurodegenerative disorder marked by progressive cognitive decline. The pathogenesis of AD is complex, and effective methods for early diagnosis and treatment are currently lacking. Extracellular vesicles, which are key mediators of intercellular communication, significantly influence the onset and progression of AD. Consequently, a systematic review of this field is essential.

METHODS: This study utilized the WoSCC and Scopus databases to gather English "Articles" and "Reviews." Following duplicate removal via Python, bibliometric methods systematically analyzed research hotspots and frontiers concerning extracellular vesicles in Alzheimer's disease. The analysis encompassed publication trends, countries, institutions, authors, journals, keywords, and references. Concurrently, the PubMed database was searched to verify the robustness and consistency of the analysis results.

RESULTS: This study conducted a bibliometric analysis of 2,626 articles, with 1,614 articles from PubMed used for consistency verification. The findings indicate a continuous rise in research interest in this field. Key areas of focus include emerging pathological mechanisms, peripheral blood biomarkers, targeted drug delivery, miRNA, and clinical trials. Cross-database verification confirmed a strong consistency in publication trends, countries, institutions, and authors, with a significant overlap of keywords and prominent research hot spots.

CONCLUSION: This study demonstrates a shift in the research focus on Extracellular vesicles within Alzheimer's disease from single-pathology investigations to exploring multiple mechanisms. Their significance in precise diagnosis and targeted therapy is increasingly evident. However, clinical trials remain limited. Future efforts should prioritize enhancing clinical validation and standardizing isolation techniques.},
}

@article {pmid43005312,
year = {2026},
author = {Chu, YY and Wang, BY and Qu, CY and Lan, Y and Wang, LY and Mao, M},
title = {Gastrodia elata in neurological disorders: a systematic review of anti-inflammatory mechanisms and cross-disease therapeutic potential.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1967946},
pmid = {43005312},
issn = {1663-4365},
abstract = {BACKGROUND: Neuroinflammation serves as a common pathological substrate across various neurological disorders, including neurodegenerative diseases, cerebrovascular diseases, and neuroimmune conditions. Key pathogenic mechanisms underlying these disorders include aberrant microglial activation, sustained release of pro-inflammatory cytokines, and dysregulation of critical signaling cascades, particularly the NLRP3 inflammasome, NF-κB, and Nrf2/HO-1 pathways, all of which collectively contribute to progressive neuronal damage and functional decline.

OBJECTIVES: This review aims to systematically evaluate the preclinical evidence for the neuroprotective effects of Gastrodia elata Blume and its major bioactive constituents-gastrodin, parishin, p-hydroxybenzyl alcohol, and G. elata polysaccharides-in the treatment of Parkinson's disease, Alzheimer's disease, acute ischemic stroke, vascular dementia, and epilepsy, with a particular focus on their modulation of inflammation-related signaling pathways.

METHODS: A comprehensive literature search was performed in PubMed, Web of Science, ScienceDirect, China National Knowledge Infrastructure (CNKI), and Wanfang databases from inception to May 2026. Original studies investigating G. elata or its components in animal or cellular models of the aforementioned diseases and reporting inflammatory mechanisms were included.

RESULTS: G. elata and its active constituents regulate multiple neuroinflammation-associated signaling pathways, including Nrf2/HO-1, NF-κB/NLRP3, JAK2/STAT3, and MAPK, thereby suppressing inflammatory responses. Mechanistically, these effects are primarily manifested as: (1) inhibition of microglial M1 polarization and consequent reduction of pro-inflammatory cytokine release; (2) blockade of inflammation-induced neuronal death through suppression of ferroptosis, pyroptosis, and apoptosis; (3) enhancement of Nrf2 nuclear translocation, leading to upregulation of antioxidant enzymes and attenuation of oxidative stress-mediated inflammation (e.g., ROS-driven cascades); and (4) modulation of the gut microbiota-brain axis to reduce both peripheral and central low-grade chronic inflammation.

CONCLUSION: Despite certain limitations in the existing evidence, this review clearly identifies future research priorities, including investigation of non-gastrodin active components, causal validation using gene-knockout models, and development of brain-targeted delivery strategies. These findings provide a valuable reference for the mechanism-guided development of neuroprotective agents derived from G. elata.},
}

@article {pmid43005395,
year = {2026},
author = {Jiang, C and Krivinko, J and Sweet, RA and Deng, Y and Ezigbo, U and Huang, R and Kofler, J and Wang, L},
title = {Comparative functional and cognitive trajectories following second-generation antipsychotic initiation among long-term care residents with Alzheimer disease: A target trial emulation study.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {4},
pages = {e70347},
pmid = {43005395},
issn = {2352-8737},
abstract = {INTRODUCTION: Real-world evidence comparing the functional and cognitive outcomes associated with commonly prescribed second-generation antipsychotics (SGAs) in long-term care (LTC) residents with Alzheimer disease (AD) is limited.

METHODS: We emulated target trials using linked LTC Data Cooperative and Medicare data. A total of 17,766 eligible new users initiating risperidone, quetiapine, olanzapine, or aripiprazole were compared under an intention-to-treat framework using inverse probability of treatment weighting and weighted generalized estimating equations. Outcomes were 12-month trajectories of Activities of Daily Living (ADL) and Brief Interview for Mental Status (BIMS).

RESULTS: ADL trajectories were similar across SGAs. In BIMS trajectory, quetiapine was associated with a modestly greater decline (β = -0.203, 95% confidence interval [CI] -0.380 to -0.027) compared with aripiprazole. Age modified several comparative treatment effects, particularly for BIMS. Findings were consistent across sensitivity analyses.

DISCUSSION: Long-term functional and cognitive outcomes were broadly comparable across commonly prescribed SGAs. Age-related heterogeneity in comparative treatment effects warrants further investigation.},
}

@article {pmid43005418,
year = {2026},
author = {Zhao, Y and Liu, M and Zhou, Y and Cui, M and Cai, N and Wang, H and Liu, G and Sun, H and Kong, X and Zhao, P},
title = {Chronic neuropeptide S treatment improves sleep architecture and reduces Aβ-related pathology in APP/PS1 mice.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1825666},
pmid = {43005418},
issn = {1664-2295},
mesh = {Animals ; *Neuropeptides/pharmacology/administration & dosage ; *Amyloid beta-Peptides/metabolism ; Mice, Transgenic ; *Alzheimer Disease/pathology/metabolism/complications/drug therapy/genetics ; Mice ; Amyloid beta-Protein Precursor/genetics ; Presenilin-1/genetics ; Male ; Hippocampus/metabolism/drug effects ; Disease Models, Animal ; *Sleep Wake Disorders/drug therapy/etiology ; *Sleep/drug effects ; Hypothalamus/metabolism/drug effects ; Peptide Fragments ; Wakefulness/drug effects ; },
abstract = {BACKGROUND: Sleep disturbances frequently occur in Alzheimer's disease (AD). Although neuropeptide S (NPS) promotes wakefulness through the widely expressed NPS receptor (NPSR), its role in AD-related sleep dysregulation is unclear.

AIMS: To investigate the effects of chronic NPS administration on AD-related sleep disturbances beyond its acute wake-promoting effects.

METHODS: NPSR expression was examined in the hypothalamus and hippocampus of APPswe/PS1dE9 (APP/PS1) mice, a double-transgenic mouse model of AD. Mice received intracerebroventricular NPS (1 nmol/day) for 14 days. Sleep-wake states were classified as wakefulness, non-rapid eye movement (NREM) sleep, and rapid eye movement (REM) sleep. Sleep architecture and amyloid-β (Aβ)-related pathology were assessed in mice. Cell-associated Aβ levels, extracellular signal-regulated kinase (ERK) phosphorylation, and autophagy-related proteins were examined in BV2 cells. Sleep responses to subsequent intracerebroventricular Aβ₁-₄₂ administration were examined in NPS-treated APP/PS1 mice.

RESULTS: APP/PS1 mice had lower NPSR protein levels in the hypothalamus and hippocampus than wild-type (WT) controls. Compared with saline-treated APP/PS1 mice, NPS-treated mice showed increased NREM sleep, reduced wakefulness, and lower Aβ-related pathology. Changes in sleep amounts were most evident during the light phase. Subsequent Aβ₁-₄₂ administration increased wakefulness and reduced NREM sleep mainly during the dark phase. It also shortened NREM episodes during the light phase. In BV2 cells, NPS altered cell-associated Aβ levels and increased ERK phosphorylation. NPS treatment was also associated with higher LC3B-II and lower p62 levels. SCH772984 attenuated the NPS-associated changes in autophagy-related proteins and cell-associated Aβ.

CONCLUSION: Chronic NPS administration improved sleep architecture and reduced Aβ-related pathology in APP/PS1 mice. The BV2 findings suggest possible involvement of ERK signaling and autophagy-related processes in cellular Aβ handling.},
}

Animals
*Neuropeptides/pharmacology/administration & dosage
*Amyloid beta-Peptides/metabolism
Mice, Transgenic
*Alzheimer Disease/pathology/metabolism/complications/drug therapy/genetics
Mice
Amyloid beta-Protein Precursor/genetics
Presenilin-1/genetics
Male
Hippocampus/metabolism/drug effects
Disease Models, Animal
*Sleep Wake Disorders/drug therapy/etiology
*Sleep/drug effects
Hypothalamus/metabolism/drug effects
Peptide Fragments
Wakefulness/drug effects

@article {pmid43005441,
year = {2026},
author = {Amon, KK and Huang, C and Fleischmann, HH and Correia, S and Kiselica, AM},
title = {Comparing criteria for objective cognitive staging in preclinical Alzheimer's disease.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {4},
pages = {e70527},
pmid = {43005441},
issn = {2352-8729},
abstract = {INTRODUCTION: Individuals with preclinical Alzheimer's disease may develop objective subtle cognitive decline (OSCD) as they transition between the cognitively unimpaired and mild cognitive impairment stages. Selection of individuals with OSCD into clinical trials may provide enrichment for participants likely to benefit from treatment. We examined how choice of operational criteria for OSCD impacted clinical staging.

METHODS: We analyzed data from 6154 older adults in the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease clinical trial to evaluate differences in clinical categorization rates by operational approach, as well as interactions with sex, race, and ethnicity.

RESULTS: Multinomial generalized estimating equation models yielded significant differences in clinical categorization rates: Interview-based methods led to the lowest proportion of individuals categorized with OSCD, cognitive screeners yielded the highest proportion, and multi-test neuropsychological methods provided a balance. These main effects were moderated by significant interactions with sex and race/ethnicity.

DISCUSSION: Choice of OSCD criteria will have significant impacts on trial sample makeup.},
}

@article {pmid43005453,
year = {2026},
author = {Duehring, JA and Feldman, HH and Salmon, DP and Edland, SD},
title = {Statistical efficiency of outcome measures for secondary prevention trials in Alzheimer's disease: Evidence from the A4 trial.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {4},
pages = {e70344},
pmid = {43005453},
issn = {2352-8737},
abstract = {INTRODUCTION: Secondary prevention trials targeting preclinical Alzheimer's disease (AD) require clinical outcome assessments (COAs) that are sensitive to subtle decline that might be found in the cognitively unimpaired population typically enrolled in these trials. The recently completed Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) trial is an opportunity to explore the performance of commonly applied COAs in the preclinical AD population.

METHODS: The performance of COAs was compared using power calculations informed by data from the placebo arm of the A4 trial alone (N = 583), and through a cross-cohort analysis incorporating data from participants in the companion observational Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) study (N = 538). Outcomes included the Preclinical Alzheimer's Cognitive Composite (PACC), the Clinical Dementia Rating Sum of Boxes (CDR-SB), the Alzheimer's Disease Cooperative Study Activities of Daily Living Prevention Instrument (ADL-PI), and the Cognitive Function Instrument (CFI).

RESULTS: The PACC and its component neuropsychological tests did not meaningfully decline over the first 168 weeks of the trial, compromising their utility as trial endpoints. In contrast, the CDR-SB and the ADL-PI declined monotonically. Based on the progression observed in A4 alone, a trial using the CDR-SB endpoint would require a fraction of the participants required for a commonly used neuropsychological endpoint.

DISCUSSION: These findings help inform the selection of clinical endpoints for secondary prevention trials, and highlight potential limitations of cognitive performance tests in the earliest stages of AD. We found that practice effects on the PACC and its component tests were present despite the use of alternating test forms, reducing the effectiveness of these instruments in this population and motivating future exploration of the effectiveness of alternate clinical endpoints.},
}

@article {pmid43005456,
year = {2026},
author = {de Oliveira, RM and Nalvarte, I and González, A},
title = {Editorial: Glucose metabolism in brain and neurodegenerative diseases: multifactorial effects.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1991548},
pmid = {43005456},
issn = {1663-4365},
}

@article {pmid43005510,
year = {2026},
author = {Ali, AE and Otranen, HM and Lehtonen, JV and Courtney, MJ and Pentikäinen, OT and Postila, PA},
title = {In Silico Assessment of SYNGAP1 Missense Variant Pathogenicity.},
journal = {Human mutation},
volume = {2026},
number = {},
pages = {8234670},
pmid = {43005510},
issn = {1098-1004},
mesh = {Humans ; *Mutation, Missense ; *ras GTPase-Activating Proteins/genetics/chemistry ; *Computational Biology/methods ; Computer Simulation ; Machine Learning ; Models, Molecular ; Protein Conformation ; },
abstract = {SynGAP, a critical regulator at the postsynaptic density, is associated with Alzheimer's disease, tumorigenesis, and most notably, SYNGAP1-related disorders (SRD), which manifests as autism, epilepsy, and cognitive impairment. SRD is likely primarily caused by SynGAP missense (SGM) variants, whose pathogenicity is difficult to confirm experimentally. To address this issue, a wide range of structure- and/or sequence-based as well as machine learning- and deep learning-based in silico predictors were benchmarked against clinically annotated SRD data. Folding stability calculations (e.g., Foldetta) and deep learning methods ESM1b and AlphaMissense showed the highest prediction accuracy under default settings. Applying optimized nondefault thresholds, especially with AlphaMissense, could further improve predictor performance. The predictions exhibited a strong structural pattern: Pathogenic variants were highly enriched within defined structural domains, particularly the GAP and PH domains, whereas variants located in nondomain and nonmotif regions were predominantly predicted to be benign. The verified phosphosites and predicted phase separation impacting variants occupy matching sections, including the protein's N-terminal region and the vicinity of putative SH3-binding motif in the disordered regions. Thus, these regions collectively could act as phase separation-promoting segments, complementing the protein's trimerization-coupled coiled-coil domain. Finally, the SynGAP Missense (SGM) server was presented to support SynGAP variant assessment. The SGM server integrates a Data Table with top-performing predictors, a 3D Viewer for structure-level assessment and AI-generated lay summaries for all variants arising from single-base substitutions, including those not yet observed in public databases.},
}

Humans
*Mutation, Missense
*ras GTPase-Activating Proteins/genetics/chemistry
*Computational Biology/methods
Computer Simulation
Machine Learning
Models, Molecular
Protein Conformation

@article {pmid43005539,
year = {2026},
author = {Jiang, S and Kong, L and Bai, X and Yang, M and Ding, J and Wang, Y and Fan, W and Yan, Y and Pu, C and Zhang, N},
title = {Apigenin promotes neuronal norepinephrine release via GPR30/PLCβ1-Ca[2+]-Syt1 signaling to enhance astrocytic lactate and exert neuroprotection in D-galactose-induced cognitive impairment.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1979963},
pmid = {43005539},
issn = {1663-9812},
abstract = {OBJECTIVE: AD, a prevalent neurodegenerative disorder clinically defined by progressive cognitive impairment, is pathologically featured by early dysfunction of the locus coeruleus, depletion of noradrenergic (NE) neurons, and dysregulated astrocytic glycogen metabolism, which collectively compromise patients' daily functioning. Although Api, a common phytoestrogen, has shown therapeutic efficacy in diverse diseases, its role and mechanism in AD remain unexplored.

METHODS: To address this gap, we evaluated the protective effects of Api against D-gal-induced cognitive deficits through behavioral and histomorphological assessments. Untargeted metabolomics was performed to profile metabolic alterations in the locus coeruleus (LC), complemented by targeted metabolomics focusing on specific pathways. Putative targets were predicted by molecular docking and verified via cellular thermal shift assay (CETSA), while molecular biology approaches were adopted to elucidate the underlying signaling cascades.

RESULTS: Api significantly ameliorated D-gal-induced cognitive impairment and increased hippocampal NE and lactate levels with enhanced neuronal activity. Metabolomics indicated that Api regulates energy metabolism pathways including TCA cycle, amino acid metabolism, glycolysis/gluconeogenesis, and glutathione metabolism. Specifically, Api elevated NE and lactate in the LC. GPR30 was identified and validated as the key target via molecular docking and CETSA, showing strong binding affinity. Mechanistically, Api activates GPR30 on noradrenergic neurons to regulate PLCβ1-Ca[2+]-Syt1 signaling, promoting NE release, which in turn drives astrocytic glycogenolysis and lactate production, thereby relieving neuronal energy deficits.

CONCLUSION: Collectively, this study not only clarifies the PLCβ1-Ca[2+]-Syt1-dependent mechanism of Api in aging-related cognitive impairment, but also highlights NE and lactate elevation as a promising therapeutic approach.},
}

@article {pmid43005561,
year = {2026},
author = {Tang, L and Li, XY and Ran, Z and Qin, ZZ and Chen, SY and Zhang, MM and Zhou, LY and Wang, WJ and Chen, L},
title = {Microglia in Alzheimer's disease: from pathogenic mechanisms to therapeutic targeting.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1952810},
pmid = {43005561},
issn = {1664-3224},
mesh = {Humans ; *Alzheimer Disease/metabolism/pathology/immunology/therapy/etiology ; *Microglia/immunology/metabolism/pathology/drug effects ; Animals ; Amyloid beta-Peptides/metabolism ; Inflammasomes/metabolism ; Molecular Targeted Therapy ; },
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder driven by β-amyloid (Aβ) deposition, tau hyperphosphorylation, synaptic dysfunction, neuroinflammation, vascular injury, and metabolic dysregulation. Recent advances in single-cell, spatial, and multi-omics transcriptomics have substantially reshaped our understanding of microglia, shifting the field from the classical M1/M2-like polarization dichotomy toward a model of state-dependent functional heterogeneity. Distinct subpopulations-including disease-associated microglia, lipid-associated microglia, interferon-responsive microglia, and senescence-associated microglia are now mechanistically linked to Aβ clearance, tau propagation, complement-mediated synaptic pruning, NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation, and immunometabolic reprogramming. Central to this regulatory network are the TREM2-ApoE axis, complement cascades, NLRP3 inflammasome, mitochondrial dysfunction, and aberrant lipid/iron metabolism, which largely contribute to AD progression. In parallel, the clinical deployment of anti-Aβ monoclonal antibodies such as lecanemab has ushered in the era of disease-modifying therapy; however, limited efficacy and the occurrence of amyloid-related imaging abnormalities underscore that Aβ removal alone is insufficient to halt disease evolution completely. In this review, we systematically synthesize the evolving landscape of microglial states and their pathogenic contributions, and we further evaluate current therapeutic avenues, including microglia-targeted strategies, anti-Aβ antibody combination regimens, non-pharmacological interventions, and peripheral immunomodulation. We also compare these microglial mechanisms with those in multiple sclerosis to highlight shared neuroimmune modules and disease-specific features. Our goal is to provide a valuable updated reference for accurate molecular subtyping and multi-target combination therapy in AD.},
}

Humans
*Alzheimer Disease/metabolism/pathology/immunology/therapy/etiology
*Microglia/immunology/metabolism/pathology/drug effects
Animals
Amyloid beta-Peptides/metabolism
Inflammasomes/metabolism
Molecular Targeted Therapy

@article {pmid43005575,
year = {2026},
author = {Liu, X and Zhang, X and Su, Y and Guan, G and Luo, X and Zhang, P},
title = {Brain insulin resistance and microglial immunometabolic dysregulation in neurodegenerative diseases.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {2002283},
pmid = {43005575},
issn = {1663-4365},
abstract = {Brain insulin resistance (BIR) is increasingly recognized as a contributor to the development and progression of neurodegenerative diseases rather than simply a metabolic abnormality. In the central nervous system, insulin signaling is involved in neuronal survival, synaptic plasticity, energy metabolism, and protein homeostasis. Increasing evidence suggests that impaired brain insulin signaling is associated with Alzheimer disease (AD), Parkinson disease (PD), and other neurodegenerative conditions, although the mechanisms linking BIR to persistent inflammation and neuronal injury remain incompletely understood. Microglia, the principal innate immune cells of the central nervous system, integrate metabolic and immune signals and may therefore provide an important link between impaired insulin signaling and chronic inflammation. BIR may disrupt insulin receptor substrate (IRS), phosphoinositide 3-kinase (PI3K), and protein kinase B (Akt) signaling and promote nuclear factor-kappa B (NF-κB) activation, mitochondrial dysfunction, oxidative stress, impaired mitophagy, and lysosomal and lipid metabolic disturbances. These changes may promote activation of the NLR family pyrin domain-containing 3 (NLRP3) inflammasome, inflammatory mediator release, excessive phagocytosis, and synaptic dysfunction. In turn, persistent microglial inflammation may further impair insulin signaling, forming a reciprocal feedback loop that sustains pathological changes. This review summarizes the mechanisms linking BIR to microglial immunometabolic dysfunction and discusses potential therapeutic strategies targeting metabolic and inflammatory pathways in neurodegenerative diseases.},
}

@article {pmid43005605,
year = {2026},
author = {Hu, M and Esmaeeli, S and Stolzenburg, L and Milkovich, B and Jouni, M and Nyamugenda, E and Hammond, RK and Reinhardt, P and Bahnassawy, L and Gasparini, L and Waring, JF and Vasanthakumar, A},
title = {New insights on bridging integrator 1 protein isoforms as a risk increasing gene in Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1937726},
pmid = {43005605},
issn = {1663-4365},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a multifactorial, age-associated neurodegenerative disorder that leads to progressive declines in cognition, memory, and the capacity for independent daily living. Genome-wide association studies (GWAS) have identified Bridging Integrator 1 (BIN1) as one of the strongest and most reproducible genetic risk factor for AD, which we replicated in our GWAS by proxy (GWAX) analysis on UKBiobank data. However, the mechanism by which BIN1 impacts AD risk is largely unknown and our work aims to uncover the underlying mechanism.

METHODS: We generated human induced pluripotent stem cell (hiPSC)-derived neuronal and microglia cell models to evaluate cell-type specific BIN1 isoform expression using droplet digital polymerase chain reaction (ddPCR). We then extended our analysis to a Phase 2 AD clinical trial in which we evaluated the association of BIN1 isoform expression with the BIN1 genotype status.

RESULTS: Our data indicated that BIN1 isoform expression patterns shifted with the differentiation of hiPSC into neurons or microglia. We also found that the SNP rs35103166 is associated with the expression of the microglia-specific BIN1 isoforms.

CONCLUSION: We demonstrate that BIN1 genotype is associated with isoform expression, which differs between neurons and microglia, enabling evaluation of disease-specific isoform effects. Given the strong association of BIN1 with susceptibility to AD, exploring the mechanisms of BIN1 genetic variants and their impacts on cell-type specific expression could serve as a valuable resource for novel drug discovery.},
}

@article {pmid43005608,
year = {2026},
author = {Wang, J and Chen, W and Zhang, Z},
title = {Comparative efficacy and safety of quetiapine versus other atypical antipsychotics for behavioral and psychological symptoms in Alzheimer's disease: a systematic review and meta-analysis.},
journal = {Frontiers in psychiatry},
volume = {17},
number = {},
pages = {1887284},
pmid = {43005608},
issn = {1664-0640},
abstract = {BACKGROUND: The management of behavioral and psychological symptoms of dementia (BPSD) in Alzheimer's disease (AD) remains a significant challenge. While atypical antipsychotics are used, their comparative efficacy and safety, particularly for quetiapine, are not well-established within a homogeneous AD population. This meta-analysis aimed to directly compare the efficacy and safety of quetiapine versus other active pharmacological agents (primarily risperidone and olanzapine) for BPSD specifically in patients with AD.

METHODS: A systematic search of PubMed, Embase, Cochrane Library, Web of Science, CNKI, and WanFang databases was conducted up to March 15, 2024, for randomized controlled trials (RCTs). The primary efficacy outcome was treatment failure (lack of clinical improvement). Safety outcomes included specific adverse events. Data were pooled using random-effects models to calculate odds ratios (ORs) with 95% confidence intervals (CIs).

RESULTS: Twenty-five RCTs involving 2143 participants were included. The pooled analysis of 16 studies (n=1384) demonstrated that quetiapine was associated with significantly lower odds of treatment failure compared to other atypical antipsychotics (OR 0.66, 95% CI 0.49 to 0.89, P = 0.006). In pre-specified subgroup analyses, quetiapine showed significant superiority over risperidone (OR 0.50, 95% CI 0.33 to 0.75, P = 0.0009) and a non-significant trend favoring quetiapine over olanzapine (OR 0.90, 95% CI 0.58 to 1.38, P = 0.62). Regarding safety, quetiapine was associated with a substantially and significantly lower risk of extrapyramidal symptoms (EPS) (OR 0.17, 95% CI 0.09 to 0.33, P<0.00001). No significant differences were found for other common adverse events such as somnolence, dizziness, or constipation.

CONCLUSION: This meta-analysis suggests that quetiapine may offer a potential efficacy advantage for alleviating BPSD in patients with AD, particularly when compared to risperidone, while demonstrating comparable overall effectiveness to other atypicals. Its most distinguishing feature is a substantially lower risk of extrapyramidal symptoms. Interpretation of these findings must be tempered by the moderate risk of bias in constituent trials, the necessary harmonization of disparate efficacy metrics, and the scarcity of long-term safety data. Quetiapine may serve as a neurologically better-tolerated option when non-pharmacological strategies are insufficient, pending careful, time-limited use.},
}

@article {pmid43005718,
year = {2026},
author = {Kaufman, EJ and Smukowski, SN and Gudsnuk, K and Course, MM and Valdmanis, PN},
title = {Alzheimer Disease Risk Variants at ABCA7 Tag Tandem Repeat Length.},
journal = {Neurology. Genetics},
volume = {12},
number = {6},
pages = {e200456},
pmid = {43005718},
issn = {2376-7839},
abstract = {BACKGROUND AND OBJECTIVES: ATP-binding cassette subfamily A member 7 (ABCA7) variants are a well-established genetic risk factor for Alzheimer disease (AD). This risk includes increased length of a variable number tandem repeat (VNTR) with a ∼25bp repeat motif in intron 18 of ABCA7. We sought to examine VNTR length, exact internal sequence composition, and correlation with genome-wide association study (GWAS) single nucleotide polymorphisms (SNPs) in AD.

METHODS: Three hundred and seven ABCA7 alleles based on long-read sequencing were evaluated from the 1000 Genomes Project. Short read sequences from 7,968 cases and 6,792 controls were evaluated from the AD Sequencing Project (ADSP). RNA sequencing data from 130 cases and 253 controls from the Religious Orders Study/Memory and Aging Project were used to identify alternative splicing at ABCA7.

RESULTS: We found that the top AD GWAS SNPs at ABCA7 tag tandem repeat length in an allele-specific manner. Homozygous carriers of the rs3764650 risk allele average 87 copies of the ABCA7 VNTR compared with 65 repeat copies in heterozygous individuals and 53 copies in individuals homozygous for the reference allele. This effect was specific to samples of European descent because rs3764650 had no correlation with repeat length in samples of African ancestry in 1000 Genomes Project samples. Nevertheless, an African-specific sentinel GWAS variant (rs115550680) is adjacent to the 25bp VNTR. In ADSP samples, we found that tandem repeat length was significantly associated with rs3764650, rs78117248, and rs4147929 regardless of affection status. ABCA7 repeat length was associated with aberrant splicing leading to mRNAs with premature termination codons.

DISCUSSION: Converging lines of genetic and functional evidence implicate ABCA7 VNTR length as a potential risk factor for AD.},
}

@article {pmid43005833,
year = {2026},
author = {Mohammadi, S and Sharbafshaaer, M and Pirozzi, MA and Trojsi, F and Ghaderi, S and Iturria-Medina, Y and Fereshtehnejad, SM},
title = {White matter hyperintensities and amyloid pathology in cognitively unimpaired aging: topographical, microstructural, and network-level evidence.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {2005174},
pmid = {43005833},
issn = {1663-4365},
abstract = {The frequent coexistence of white matter hyperintensities (WMHs) and β-amyloid (Aβ) pathology in cognitively unimpaired older adults complicates interpretation of vascular and neurodegenerative imaging findings. This narrative review synthesizes topographical, microstructural, and network-level evidence in cognitively unimpaired aging, distinguishing biomarker-characterized samples from supportive mixed or symptomatic cohorts. WMHs have heterogeneous etiologies. Posterior and some periventricular patterns are associated with cerebral Aβ in several cohorts, but lobar location and distance from the ventricles are overlapping classifications, and vascular associations are not confined to frontal or deep lesions. Independent and additive cognitive associations are more consistently reported than interactions. Longitudinal executive-function interactions reported in a dissertation and related abstract remain preliminary and non-independent. Some longitudinal studies associate baseline Aβ with subsequent WMH accrual, but findings are not uniform and do not establish causation. APOE-related findings vary with age, population, and amyloid burden. Diffusion MRI detects tissue abnormalities beyond visible lesions, although microstructural and disconnectome measures require prospective validation before they can improve individual prognosis. Anti-amyloid trial evidence identifies MRI safety considerations; effects on chronic WMH progression remain uncertain.},
}

@article {pmid43005927,
year = {2026},
author = {Adnan Azeez Aboomaima, W and Hasan Burhan, A and Aziz Abu Omaima, HA and Mahmoudi, A},
title = {Isoform-Selective and Context-Dependent Modulation of Nitric Oxide Synthase by Cannabidiol: A Mechanistic Review of Preclinical Evidence in Neurological and Neuropathic Disorders.},
journal = {Journal of inflammation research},
volume = {19},
number = {},
pages = {650304},
pmid = {43005927},
issn = {1178-7031},
abstract = {Nitric oxide (NO), produced by nitric oxide synthase (NOS) isoforms, plays a dual role in the central nervous system. Cannabidiol (CBD), a non-psychoactive phytocannabinoid, has shown promise as a neuroprotective and anti-inflammatory agent. This narrative review examines the complex interactions between CBD and NOS isoforms, including neuronal (nNOS), inducible (iNOS), and endothelial (eNOS) variants, and discusses how these may contribute to its neuroprotective and analgesic properties. Preclinical evidence, primarily from cellular and animal models, indicates that CBD can reduce excessive NO production, particularly by inhibiting iNOS in neuroinflammatory conditions. However, the effects of CBD on nNOS are context-dependent and cannot be characterized simply as inhibitory: while CBD may attenuate pathological nNOS-mediated excitotoxicity in some models, nNOS-derived NO is also required for CBD-induced analgesia in certain neuropathic pain models, where nNOS activation and downstream NO signaling contribute to antinociception. The strongest preclinical evidence supports CBD-mediated suppression of pathological iNOS expression and NO production in neuroinflammatory conditions. The effects of CBD on nNOS are context-dependent and cannot be characterized simply as inhibitory: while CBD may attenuate pathological nNOS-mediated excitotoxicity in some models, nNOS-derived NO is also required for CBD-induced analgesia in certain neuropathic pain models, where nNOS activation and downstream NO signaling contribute to antinociception. Similarly, evidence for eNOS-mediated vascular benefits in the CNS remains preliminary and largely derived from peripheral studies, and cerebrovascular eNOS effects require further investigation. We review the potential therapeutic implications of these interactions in neurological conditions such as Alzheimer's disease, multiple sclerosis, depression, and neuropathic pain. The review also addresses antioxidant and anti-nitrosative benefits of CBD, pharmacokinetic challenges, and research gaps, including the need for clinical trials with biomarkers to validate NOS-related findings. By integrating molecular, preclinical, and translational perspectives, this review provides insights into the context-dependent and isoform-selective modulation of NOS by CBD, emphasizing that the strength of evidence varies by isoform, with iNOS and nNOS modulation being better established than eNOS-related effects.},
}

@article {pmid43006157,
year = {2026},
author = {Xiao, S and Wu, L and Qiao, W and Yue, R and Guo, X and Li, C and Tang, Y and Ye, J},
title = {HDAC7 Scaffolds GSK3β-Tau Interaction to Drive GSK3β Activation and Tau Pathology.},
journal = {Aging cell},
volume = {25},
number = {11},
pages = {},
pmid = {43006157},
issn = {1474-9726},
support = {82101493//National Natural Science Foundation of China/ ; 2025A1515012551//Basic and Applied Basic Research Foundation of Guangdong Province/ ; 2023SHIBS0003//Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions/ ; },
mesh = {Animals ; *Glycogen Synthase Kinase 3 beta/metabolism ; *Histone Deacetylases/metabolism/genetics ; *tau Proteins/metabolism ; Humans ; Mice ; Phosphorylation ; *Tauopathies/metabolism/pathology ; Neurons/metabolism ; Acetylation ; Alzheimer Disease ; },
abstract = {Intraneuronal accumulation of hyperphosphorylated tau is a pathological hallmark of Alzheimer's disease (AD) and related tauopathies. Although dysregulation of both histone deacetylases (HDACs) and glycogen synthase kinase 3β (GSK-3β) has been implicated in tau pathogenesis, whether and how they functionally interact to drive tau pathology remains unclear. Here, we identify HDAC7 as a critical scaffold that promotes GSK-3β-tau complex formation, leading to GSK-3β activation and tau hyperphosphorylation in a tauopathy mouse model. HDAC7 is selectively upregulated in human tau-bearing neurons. Neuronal overexpression of HDAC7 exacerbates tau hyperphosphorylation and cognitive deficits, accompanied by increased GSK-3β kinase activity and protein levels both in vivo and in vitro. Mechanistically, HDAC7 scaffolds the direct interaction between GSK-3β and tau independently of its deacetylase activity. Formation of the HDAC7-GSK3β-tau complex enables tau to promote GSK-3β acetylation at lysine 15, which in turn stabilizes GSK-3β protein and enhances its kinase activity. Conversely, neuronal deletion of HDAC7 reduces GSK-3β protein levels and kinase activity, attenuates tau hyperphosphorylation, restores synaptic integrity, and rescues cognitive deficits in hTau-expressing mice. Together, our findings propose a novel mechanism by which HDAC7 scaffolds GSK3β-tau interaction to drive sustained GSK-3β activation and tau pathology, highlighting reducing HDAC7 as a potential therapeutic strategy for AD and other tauopathies.},
}

Animals
*Glycogen Synthase Kinase 3 beta/metabolism
*Histone Deacetylases/metabolism/genetics
*tau Proteins/metabolism
Humans
Mice
Phosphorylation
*Tauopathies/metabolism/pathology
Neurons/metabolism
Acetylation
Alzheimer Disease

@article {pmid43006195,
year = {2026},
author = {Berruga, Y and Nanjundan, R and van Baelen, AC and Panek, S and Tonali, N and Dodero, VI and Garcia, AM},
title = {Peptide Self-Assembly: Insights From Functional Short Peptides, Amyloid-β, and Gluten Peptides.},
journal = {Journal of peptide science : an official publication of the European Peptide Society},
volume = {32},
number = {12},
pages = {},
doi = {10.1002/psc.70148},
pmid = {43006195},
issn = {1099-1387},
support = {RYC2023-042600-I//Agencia Estatal de Investigación/ ; PID2024-160195NA-I00//Agencia Estatal de Investigación/ ; PID2023-152323NB-I00//Agencia Estatal de Investigación/ ; SBPLY/24/180225/000086//Junta de Comunidades de Castilla-La Mancha/ ; 2025-GRIN-38471//Universidad de Castilla-La Mancha/ ; 2024_UNIVERS_12844//Universidad de Castilla-La Mancha/ ; ANR-22-CE92-0076-01//Agence Nationale de la Recherche/ ; DFG SE 609/20-1//Deutsche Forschungsgemeinschaft/ ; 43057848//Deutsche Forschungsgemeinschaft/ ; ANR-11-IDEX-003//PASREL (Université Paris-Saclay), France 2030 Programme/ ; COST Action CA23111 - SNOOPY//European Cooperation in Science and Technology/ ; },
mesh = {*Amyloid beta-Peptides/chemistry/metabolism ; Humans ; *Glutens/chemistry/metabolism ; *Peptides/chemistry ; Peptide Fragments/chemistry ; Amino Acid Sequence ; Alzheimer Disease/metabolism ; },
abstract = {In this perspective, we discuss how short peptides can be programmed through sequence design, stereochemistry, terminal modification, and external stimuli to form diverse supramolecular architectures. We then examine how similar molecular principles underlie disease-associated aggregation, focusing on early Aβ(1-42) assemblies in Alzheimer's disease and proteolysis-resistant gluten peptide nanostructures in gluten-related disorders. Attention is given to the detection, stabilization, and modulation of transient oligomeric species, which remain challenging but highly relevant to therapeutic and diagnostic targets. We further highlight how short functional peptides can be engineered to interfere with aggregation pathways in amyloid and nonamyloid aggregopathies, including diabetes-related amyloids, α-synuclein, and phenylalanine assemblies. Together, these examples illustrate the cross-applicability of concepts from supramolecular materials chemistry to molecular pathology. This perspective emphasizes that understanding peptide self-assembly at the molecular level is key to both exploiting and controlling its biological consequences.},
}

*Amyloid beta-Peptides/chemistry/metabolism
Humans
*Glutens/chemistry/metabolism
*Peptides/chemistry
Peptide Fragments/chemistry
Amino Acid Sequence
Alzheimer Disease/metabolism

@article {pmid43006698,
year = {2026},
author = {Liang, EX and Li, QW and Liang, H},
title = {Chinese herbal medicine formulas for Alzheimer's disease: Evidence, mechanisms, and translational standards.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261505070},
doi = {10.1177/13872877261505070},
pmid = {43006698},
issn = {1875-8908},
abstract = {Alzheimer's disease (AD) is defined biologically by amyloid and tau pathology. The emergence of biomarker-based diagnostic criteria, blood-based assays, and anti-amyloid therapeutic trials has substantially raised the evidentiary standard for all candidate AD interventions, including Chinese herbal medicine (CHM) formulas. However, CHM formula evidence for AD lacks critical appraisal and methodological standards. Thus, this review aims to: (1) critically evaluate the clinical, mechanistic, and translational evidence for oral or topical CHM formulas used in AD, specifically those selected according to Traditional Chinese Medicine (TCM) diagnostic; and (2) assess the methodological requirements necessary for credible development of such formulas in AD research. Preclinical studies suggest plausible effects of CHM formulas on amyloid-related pathways, tau phosphorylation, neuroinflammation, oxidative stress, and energy metabolism, but these findings remain hypothesis-generating rather than clinically validated. Most included studies relied on clinical diagnoses, likely encompassing mixed pathologies (e.g., vascular dementia, dementia with Lewy bodies, or depression-related cognitive impairment), rendering their results preliminary rather than confirmatory for biologically defined AD. Current evidence does not support CHM formulas as established therapies for AD. Future studies will require biomarker-confirmed diagnosis, rigorous formula quality control, prespecified TCM pattern stratification, clinically meaningful cognitive and functional endpoints, mechanistic target-engagement measures, and prospective safety and herb-drug interaction monitoring.},
}