@article {pmid42103282,
year = {2026},
author = {Cissé, M and Moullé, V and Brossaud, R and Oullier, T and Neunlist, M},
title = {Microbiota-Gut-Brain Axis in Neurodegenerative Diseases: The Role of Bacterial Amyloids.},
journal = {Cellular and molecular gastroenterology and hepatology},
volume = {20},
number = {8},
pages = {101802},
doi = {10.1016/j.jcmgh.2026.101802},
pmid = {42103282},
issn = {2352-345X},
abstract = {Neurodegenerative diseases are proteinopathies, characterized by misfolded protein aggregation in the brain that drives neuronal dysfunctions. Neurodegenerative diseases are also increasingly recognized as multi-organ disorders in which the gut plays a pivotal role. Indeed, recent advances in the research field of neurodegenerative diseases suggest that the gut is not merely a passive bystander, given the high prevalence of gastrointestinal symptoms, but a critical contributor to disease etiology, with evidence supporting a direct role in initiating and driving disease progression. Among environmental factors increasingly recognized as modulators of neurodegenerative disease progression, the gut microbiota has gained prominence. Beyond the impact of altered bacterial metabolites, growing evidence indicate a potential role of gut microbiota-derived amyloids in neurodegenerative diseases. For instance, gut microbial amyloids such as curli can cross-seed host proteins like α-synuclein and β-amyloid promoting aggregation, gut-to-brain propagation, and exacerbating neurodegeneration, revealing a novel mechanism linking the microbiome to neurodegenerative diseases. This conceptual shift opens promising avenues for strategies targeting the gut microbiota, including therapeutic and preventive interventions aimed at reshaping microbial communities or limiting exposure to pathogenic amyloids to reduce risk of neurodegenerative diseases. Here, we review recent discoveries to elucidate the complex interplay between gut microbiota and host amyloids, offering insights for enhancing gut and brain health and potentially preventing or reversing neurodegenerative disease progression.},
}

@article {pmid42330851,
year = {2026},
author = {Mlakić, M and Talić, S and Odak, I and Roca, S and Šagud, I and Barić, D and Škorić, I},
title = {Novel resveratrol-inspired thieno-benzimidazoles and thieno-oxazoles - Synthesis, selective butyrylcholinesterase inhibition and molecular modeling.},
journal = {Bioorganic chemistry},
volume = {180},
number = {},
pages = {110096},
doi = {10.1016/j.bioorg.2026.110096},
pmid = {42330851},
issn = {1090-2120},
abstract = {This study reports the design, synthesis, and biological evaluation of novel resveratrol-inspired thieno-benzimidazole and thieno-oxazole derivatives as potential therapeutics for Alzheimer's disease. The research is grounded in the cholinergic hypothesis, which links cognitive decline to reduced acetylcholine levels due to enzymatic degradation by acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Given the increasing relevance of BChE in later disease stages, the focus was placed on developing selective BChE inhibitors. A series of 14 compounds was synthesized using multi-step organic reactions, including Wittig reactions, Vilsmeier formylation, and cyclization strategies. Structural confirmation was achieved through NMR and mass spectrometry. The studied acetylated derivatives exhibit photochemical instability due to efficient trans-cis isomerization and subsequent secondary processes under UV irradiation, necessitating strict light protection during handling, storage, and application. Biological evaluation revealed that all compounds selectively inhibited BChE, with no significant AChE inhibition observed. Among them, carbamate-oxazole derivative 14 exhibited the highest potency (IC50 = 0.248 μM), outperforming the reference drug rivastigmine. Several other derivatives showed moderate to strong activity, with oxazole-based compounds generally outperforming benzimidazole analogs. In addition to enzyme inhibition, antioxidant activity was assessed using the DPPH and CUPRAC assays. Compound 8 exhibited the strongest radical-scavenging activity, comparable to that of Trolox. Molecular docking and dynamics simulations provided insight into binding interactions, highlighting key π-π stacking and hydrogen bonding within the BChE active site. Furthermore, in silico genotoxicity analysis indicated that the most active compounds lack mutagenic potential. Overall, the study identifies promising multifunctional candidates combining selective BChE inhibition, antioxidant properties, and favorable safety profiles, supporting their potential as lead compounds for Alzheimer's disease therapy.},
}

@article {pmid42330959,
year = {2026},
author = {Du, Y and Sun, C and Wu, L and Wu, Z and Tong, Y and Tian, H and Mao, Y and Shi, X and Ding, H and Xie, W and Yao, W and Chen, S and Gao, X},
title = {Oral GLP-1 receptor agonist promotes astrocyte-neuron lactate and lipid transfer with neuroprotective effects.},
journal = {Cell metabolism},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.cmet.2026.05.014},
pmid = {42330959},
issn = {1932-7420},
abstract = {Glucagon-like peptide-1 receptor (GLP-1R) activation is widely assumed to regulate the metabolic disorder in Alzheimer's disease (AD). However, direct evidence for this hypothesis is lacking, and currently, there is no oral GLP-1R agonist with effective blood-brain barrier-penetrating ability. Here, we show that a candidate peptide, OHP2, an oral GLP-1R agonist with blood-brain barrier permeability, exhibits promising therapeutic potential for AD. OHP2 primarily activates GLP-1R on astrocytes, leading to increased aerobic glycolysis and driving lactate release. Astrocyte-derived lactate is taken up by neurons and elevates histone H3 lysine 9 lactylation (H3K9la), which in turn facilitates lipid transport from neurons back to astrocytes. This astrocyte-neuron metabolic coupling sustains continuous aerobic glycolysis and offers a potential treatment strategy for AD. The H3K9la derived from OHP2 links glucose and lipid metabolic cycle and facilitates metabolic coupling between astrocytes and neurons, which leads to remission of metabolic disturbances in AD. Thus, our study provides a new candidate molecule for drug research in treating AD and illustrates that intracerebral GLP-1R activation, which facilitates astrocyte-neuron metabolic coupling, may be a potential approach for the treatment of AD.},
}

@article {pmid42331016,
year = {2026},
author = {Steinhorst, K and Lakatos, P and Hohberger, B},
title = {Imbalanced Trace Elements as Risk Factors in the Pathogenesis of Glaucoma.},
journal = {Klinische Monatsblatter fur Augenheilkunde},
volume = {},
number = {},
pages = {},
doi = {10.1055/a-2805-1399},
pmid = {42331016},
issn = {1439-3999},
support = {01EP2108A//German Federal Ministry of Education and Research/ ; 01EP2108A//German Federal Ministry of Education and Research/ ; },
abstract = {Glaucoma, a neurodegenerative disease, is characterised by ocular pathogenic patterns, yet also by cerebral pathologies, particularly within the visual pathway. Oxidative stress is involved in glaucoma pathogenesis, similar to other neurodegenerative diseases, such as Alzheimer's disease. Trace elements can intervene within these molecular processes (e. g., via enzymes) and in the event of imbalances, also cause pathological changes. This review aims to provide an overview of the common features of glaucoma and other neurodegenerative diseases, focusing on the influence of imbalanced trace elements such as zinc, copper, iron and selenium, and oxidative stress.},
}

@article {pmid42331020,
year = {2026},
author = {Feng, H and Hao, Y and Li, Y and Chen, J and Zhao, R and Huang, Y},
title = {Targeting Membrane Lipid and Curvature Signatures for Neuronal Exosome Capture and Protein Profiling as a Liquid Biopsy for Cognitive Impairment.},
journal = {Analytical chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.analchem.6c00397},
pmid = {42331020},
issn = {1520-6882},
abstract = {Selective isolation and analysis of brain-derived exosomes are essential for understanding and clinical management of neurodegeneration diseases. Herein, inspired by the unique lipidomic features of the central nervous system and lipid packing signature of exosomal membranes, we report a high-performance exosome capture platform, Exo-RTrap, developed through screening of the molecular interactions between an arginine-rich peptide (R9) and main lipids. Different from conventional view of nonspecific electrostatic association, we demonstrate highly selective and high-affinity binding of R9 toward phosphatidylserine (PS) over other anionic lipids, accompanied by spontaneous assembly into nanoscale vesicular complexes. Notably, R9 exhibits 370-fold stronger affinity for PS-containing liposomes than PS-free ones and recognizes membrane curvature in a PS-dependent manner, with sensitivity regulated by PS lateral density. Guided by these mechanistic insights, Exo-RTrap with dual-mode recognition coupling PS targeting with curvature responsiveness enabled rapid and selective isolation of exosomes from complex medium and biofluids, with purity and antifouling ability exceeding ultracentrifugation and precipitation methods. The capability of Exo-RTrap to selectively enrich disease-relevant neuronal exosomes was demonstrated by its accurate discrimination of serum samples from patients with Alzheimer's disease and mild cognitive impairment, whereas exosomes isolated by ultracentrifugation failed to achieve comparable performance. Moreover, integration with mass spectrometry-based proteomics further identified differentially expressed proteins as potential biomarkers for staging cognitive impairment. By defining the molecular rules governing R9-lipid interactions, this work presents a promising peptide-based exosome isolation platform for early detection and monitoring of neurodegenerative disorders.},
}

@article {pmid42331203,
year = {2026},
author = {Li, D and Zhang, Z and Lu, L and Liu, J and Cai, W and Hou, J and Lu, Y and Yu, G},
title = {Neuroinflammation-centered pathophysiology and therapeutic strategy design in Alzheimer's disease: Cutting-edge developments.},
journal = {Cellular signalling},
volume = {},
number = {},
pages = {112689},
doi = {10.1016/j.cellsig.2026.112689},
pmid = {42331203},
issn = {1873-3913},
abstract = {Alzheimer's disease (AD) is a multifactorial and progressive neurodegenerative disorder characterized by complex interactions among amyloid-β (Aβ) deposition, tau protein hyperphosphorylation, neuroinflammation, oxidative stress, metal dyshomeostasis, and impaired autophagy. Increasing evidence positions neuroinflammation not merely as a secondary response but as a central driver of disease progression, dynamically interacting with amyloid and tau protein pathology and contributing to synaptic dysfunction and neuronal loss. Among inflammatory mechanisms, microglial activation pathways-particularly TREM2 signaling, NLRP3 inflammasome activation, and complement cascade dysregulation-are currently the most clinically actionable targets, supported by genetic, biomarker, and therapeutic evidence. Emerging data suggest that modulation of innate immune pathways is most likely to confer benefit during the prodromal and early symptomatic stages of AD, when neuroinflammatory responses remain partially adaptive and neuronal networks retain functional reserve. Despite decades of drug development, many candidates have failed due to limited efficacy or safety concerns. Recent FDA approvals of anti-amyloid monoclonal antibodies, including aducanumab and lecanemab, represent important advances toward disease-modifying therapy, although their long-term clinical impact and safety profiles remain under evaluation. These developments underscore the importance of biomarker-guided patient selection, disease-stage stratification, and vigilant safety monitoring, particularly regarding amyloid-related imaging abnormalities. Therapeutic strategies are increasingly shifting toward multi-target approaches that integrate amyloid modulation, tau protein-directed interventions, and attenuation of maladaptive neuroinflammatory responses. Concurrently, inflammatory mediators and peripheral metabolic biomarkers are gaining recognition as tools for early detection, risk stratification, and therapeutic response monitoring, potentially enabling precision-based intervention. This review synthesizes current understanding of AD pathogenesis through an inflammation-centered framework, highlighting clinically actionable immune pathways and stage-specific therapeutic windows. By integrating mechanistic insights with biomarker-driven strategies, we aim to delineate translational paths toward more precise, safe, and clinically meaningful disease modification.},
}

@article {pmid42331250,
year = {2026},
author = {Fahmy, MI and Rizk, NI and Eitah, HE and Arab, HH and Alsufyani, SE and Arafa, EA and Azzam, HN},
title = {Resveratrol alleviates neurological disorders and motor dysfunction in 3-NP induced- Huntington Disease in rats: Role of activating AMPK/SIRT1/ULK1 autophagy pathway.},
journal = {Neuropharmacology},
volume = {},
number = {},
pages = {111084},
doi = {10.1016/j.neuropharm.2026.111084},
pmid = {42331250},
issn = {1873-7064},
abstract = {Huntington's disease (HD) is a genetic neurodegenerative disease characterized by striatum damage, which results in a number of uncontrollable muscle movements alongside intellectual and cognitive impairment. The progression of HD is accompanied by neuroinflammation, oxidative stress, and neuronal apoptosis. Resveratrol (RESV) is a naturally occurring compound known for its potent antioxidant and anti-inflammatory effects. RESV showed promising neuroprotective effects against Alzheimer's and Parkinson's disease. The current research aims to study the neuroprotective effects of RESV against 3-nitropropionic acid (3-NP)-induced HD. Forty adult male rats were divided equally into four groups as follows: Group 1- normal control group. Group 2- RESV (25 mg/kg/day, p.o) - treated rats. Group 3- rats treated with 3-NP (10 mg/kg/day, i.p). Group 4- rats treated with 3-NP (10 mg/kg/day, i.p) +RESV (25 mg/kg/day, p.o). The results showed that RESV alleviated the behavioral deficits observed in 3-NP treated rats. In addition, the histopathological images showed obvious improvement in RESV-treated rats. RESV activated the AMP-activated protein kinase (AMPK)-related autophagy pathway that resulted in neuroprotection and cell survival. Moreover, RESV showed anti-inflammatory and antioxidant effects by decreasing levels of inflammatory biomarkers including tumor necrosis factor (TNF)-α, nuclear factor kappa (NF-κ)-B, and interleukin (IL)-1β, alongside increasing neuronal antioxidant capacity by stimulating reduced glutathione (GSH), superoxide dismutase (SOD), and preventing lipid peroxidation. In conclusion, our study showed that RESV has a potent neuroprotective effect as evidenced by its ability to significantly alleviate biochemical and behavioral hallmarks of HD.},
}

@article {pmid42331352,
year = {2026},
author = {Salgado, KDCB and de Albuquerque, ALS and Pedrosa, TCF and Cota, AAB and Talvani, A and Oliveira, LAM and Nogueira, KOPC},
title = {Cannabidiol Limits Early Aβ-Induced Glial Activation and Preserves Synaptic Integrity in Primary Mouse Hippocampal Neuron-Glia Cultures.},
journal = {The European journal of neuroscience},
volume = {63},
number = {12},
pages = {e70588},
doi = {10.1111/ejn.70588},
pmid = {42331352},
issn = {1460-9568},
mesh = {Animals ; *Cannabidiol/pharmacology ; *Hippocampus/drug effects/cytology/metabolism ; *Neurons/drug effects/metabolism ; *Amyloid beta-Peptides/toxicity ; Mice ; *Neuroglia/drug effects/metabolism ; *Synapses/drug effects/metabolism ; Cells, Cultured ; Mice, Inbred C57BL ; Oxidative Stress/drug effects ; Coculture Techniques ; },
abstract = {Alzheimer's disease (AD) initiates with subtle neuroimmune alterations that precede overt synaptic loss and neuronal death, yet the early sequence linking Aβ exposure to glial activation remains incompletely understood. To capture early neuroimmune dynamics with greater physiological relevance, we employed primary mixed neuron-glia cultures derived from the hippocampi of postnatal day 1 (P1) mice. Unlike conventional coculture systems, these hippocampal mixed cultures preserve intrinsic neuron-astrocyte-microglia communication and recapitulate key features of the in vivo hippocampal microenvironment. Using this model, we investigated whether cannabidiol (CBD) modulates the initial pathogenic events triggered by Aβ25-35 during a 24h simultaneous cotreatment in cell culture. Aβ exposure induced robust hippocampal glial activation, oxidative stress, and elevated levels of proinflammatory mediators, particularly IL-1β, IL-6, and TNF-α. Notably, hippocampal synaptic and neurogenic markers (5HT1A, Gria1, GRIN1, DCX, PSD-95) remained largely unaltered at this early stage, revealing a temporal dissociation in which glial-driven inflammation precedes synaptic dysfunction. CBD significantly attenuated inflammatory and oxidative responses and prevented Aβ-induced cellular damage, indicating engagement of endocannabinoid-related mechanisms that constrain early hippocampal glial reactivity. Although CBD did not fully normalize all glial alterations, it preserved hippocampal synaptic integrity and halted progression toward neuronal dysfunction. Together, these findings identify early hippocampal glial inflammation as a primary target of CBD and provide mechanistic insight into the temporal sequence linking Aβ exposure to neuroimmune activation. These results highlight early glial responses as a critical window for therapeutic intervention and support cannabinoid-based strategies to modulate the initial stages of Alzheimer's disease pathogenesis.},
}

Animals
*Cannabidiol/pharmacology
*Hippocampus/drug effects/cytology/metabolism
*Neurons/drug effects/metabolism
*Amyloid beta-Peptides/toxicity
Mice
*Neuroglia/drug effects/metabolism
*Synapses/drug effects/metabolism
Cells, Cultured
Mice, Inbred C57BL
Oxidative Stress/drug effects
Coculture Techniques

@article {pmid42331506,
year = {2026},
author = {Hu, J and Lu, S and Zhang, Q and Qian, K and Rehman, H and Zhu, C and Farrell, J and Castrillon-Candas, JE and Au, R and Farrer, LA and Qiu, WQ and Chen, J and Zhang, X},
title = {Alzheimer's disease risk prediction from clinical and social determinants of health: a machine learning cohort study in UK Biobank.},
journal = {BMJ health & care informatics},
volume = {33},
number = {1},
pages = {},
doi = {10.1136/bmjhci-2025-101803},
pmid = {42331506},
issn = {2632-1009},
mesh = {Humans ; *Social Determinants of Health/statistics & numerical data ; United Kingdom/epidemiology ; Female ; *Alzheimer Disease/epidemiology/diagnosis ; Male ; Aged ; *Machine Learning ; UK Biobank ; Risk Assessment/methods ; Predictive Learning Models ; Risk Factors ; Cohort Studies ; Classification Algorithms ; Middle Aged ; Prediction Algorithms ; Biological Specimen Banks ; },
abstract = {OBJECTIVES: Social determinants of health (SDOH) may improve Alzheimer's disease (AD) risk prediction by capturing upstream contextual risk beyond routinely measured clinical variables. We aimed to develop and validate an accurate, interpretable machine-learning pipeline for AD risk prediction in UK Biobank using routinely collected data.

METHODS: Using data from 13 076 participants in the UK Biobank, we developed an automated machine-learning pipeline for AD risk prediction with feature selection and a C5.0 boosted-tree classifier. Data were split into training, development and test sets (7:2:1); missing values were imputed in the training data only, and feature selection, tuning and threshold calibration were performed using the training/development data, with final evaluation on the independent test set. Internal validation used repeated subsampling without replacement.

RESULTS: During up to 16 years of follow-up, 927 participants developed AD. Feature selection reduced 3590 variables to 26 predictors spanning age, APOE4, SDOH, medical history and routine clinical measures. The final model showed good discrimination (area under the precision-recall curve 0.89) and adequate calibration (Hosmer-Lemeshow p=0.71), with stable performance under repeated subsampling. Sex-stratified models showed similar patterns.

DISCUSSION: SDOH contributed useful predictive information, but their associations should be interpreted as predictive rather than causal and may reflect socioeconomic confounding and healthcare access.

CONCLUSIONS: This model could support scalable AD risk screening using routinely collected data, but external validation and recalibration in non-UK populations are needed before broader application.},
}

Humans
*Social Determinants of Health/statistics & numerical data
United Kingdom/epidemiology
Female
*Alzheimer Disease/epidemiology/diagnosis
Male
Aged
*Machine Learning
UK Biobank
Risk Assessment/methods
Predictive Learning Models
Risk Factors
Cohort Studies
Classification Algorithms
Middle Aged
Prediction Algorithms
Biological Specimen Banks

@article {pmid42331512,
year = {2026},
author = {Si, S and Deng, S and Zhang, Y and Wang, X and Yue, G and Sun, Y and Lu, H and Li, J and Tao, F and Lin, M and Dong, Z and Zhuo, B and Li, L and Pang, B and Jin, X and Meng, Z and Shi, J},
title = {Impact of ambient fine particulate matter (PM2.5) pollution on disease burden in BRICS from 1990 to 2023: evidence from the Global Burden of Disease Study 2023.},
journal = {BMJ global health},
volume = {11},
number = {6},
pages = {},
doi = {10.1136/bmjgh-2026-023674},
pmid = {42331512},
issn = {2059-7908},
mesh = {Humans ; *Global Burden of Disease/trends ; *Particulate Matter/adverse effects ; India/epidemiology ; China/epidemiology ; Brazil/epidemiology ; Russia/epidemiology ; Disability-Adjusted Life Years ; South Africa/epidemiology ; *Air Pollution/adverse effects ; *Environmental Exposure/adverse effects ; },
abstract = {BACKGROUND: Ambient fine particulate matter (PM2.5) pollution (APMP) is a leading global mortality risk factor. Its long-term trends, drivers and future burden trajectories in emerging economies remain inadequately understood. This study provides the first systematic assessment of spatiotemporal patterns, key drivers and projections to 2050 of APMP-attributable health loss in BRICS countries (Brazil, Russia, India, China and South Africa) from 1990 to 2023, benchmarked against global and Group of Seven (G7) trends.

METHODS: Using Global Burden of Disease 2023 data, this study analysed APMP-attributable deaths and disability-adjusted life years (DALYs) via absolute numbers and age-standardised rates. The multidimensional framework included joinpoint regression, age-period-cohort (APC) modelling, Das Gupta decomposition, disease spectrum ranking and Bayesian-APC projection.

RESULTS: In 2023, APMP caused 2.955 million deaths in BRICS (59% of the global total). Age-standardised mortality and DALY rates remained higher than global averages and increased since 1990, contrasting with sustained declines in the G7. Substantial heterogeneity existed: India's burden was heaviest and growing, China's remained high but stabilised, while Brazil and Russia achieved marked reductions. APC modelling revealed pronounced mortality increases in older ages (especially 95+ years in China and India). Decomposition identified population ageing as the key driver in BRICS, especially China; population growth and deteriorating epidemiological conditions under high exposure drove increases in India and South Africa. Leading APMP-attributable burdens in BRICS were ischaemic heart disease, chronic obstructive pulmonary disease and intracerebral haemorrhage, unlike in the G7 where Alzheimer's disease and other dementias ranked first. Projections indicate the BRICS burden will remain above the global average by 2050, with China and India continuing to bear severe burdens.

CONCLUSION: BRICS is the epicentre of global APMP-attributable burden. The widening gap with the G7 underscores divergent environmental health governance paradigms. Findings call for differentiated strategies within BRICS and enhanced transnational collaboration to curb APMP burden rises and bridge global environmental health equity gaps.},
}

Humans
*Global Burden of Disease/trends
*Particulate Matter/adverse effects
India/epidemiology
China/epidemiology
Brazil/epidemiology
Russia/epidemiology
Disability-Adjusted Life Years
South Africa/epidemiology
*Air Pollution/adverse effects
*Environmental Exposure/adverse effects

@article {pmid42331642,
year = {2026},
author = {Guedj, E and Verger, A and Horowitz, T},
title = {Brain [18F]FDG PET in Subjective Cognitive Complaints: From Diagnostic Gap to Neurobiological Insight.},
journal = {PET clinics},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.cpet.2026.05.004},
pmid = {42331642},
issn = {1879-9809},
abstract = {Subjective cognitive complaints are heterogeneous and may occur with normal, subtle, or objectively abnormal cognitive testing. Fluorodeoxyglucose (FDG) PET can help explore their metabolic substrate, particularly in subjective cognitive decline within the Alzheimer's disease continuum. In mild traumatic brain injury and long coronavirus disease (COVID), available studies suggest possible metabolic-network abnormalities but involve more heterogeneous populations and should be interpreted cautiously within multimodal, clinically characterized frameworks.},
}

@article {pmid42331677,
year = {2026},
author = {Gildengers, A and Wang, Y and Hughes, TF and Jacobsen, E and Karikari, TK and Snitz, B and Zeng, X and Chang, CH and Ganguli, M},
title = {Loneliness and Plasma Biomarkers of Neurodegeneration in Community-Dwelling Older Adults: Cross-Sectional and Longitudinal Analyses.},
journal = {The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jagp.2026.05.012},
pmid = {42331677},
issn = {1545-7214},
abstract = {BACKGROUND/OBJECTIVE: Loneliness has been linked with cognitive decline and dementia. Studies show relationships between loneliness and neurodegeneration, amyloid, and tau burden. We investigated whether loneliness relates to plasma biomarkers of neurodegenerative processes among cognitively normal or mildly impaired older adults at the population level.

SETTING/PARTICIPANTS: A population-based cohort (n = 884) in southwestern Pennsylvania.

MEASUREMENTS: Demographics; loneliness and social isolation composite scores, depression symptoms, Clinical Dementia Rating, plasma amyloid beta (Aβ) 42, Aβ40, p-tau181, p-tau217, NfL, GFAP.

DESIGN: We examined the associations of loneliness with plasma biomarkers using regression analyses in both cross-sectional and longitudinal models. For cross-sectional analysis, we used data from 884 dementia-free participants at the closest wave to biomarker testing (within 180 days). For longitudinal analysis, we first derived loneliness trajectories from 514 participants with repeated annual loneliness measurements for up to 15 years prior to biomarker testing, then used these trajectories as predictors in regression models examining their associations with plasma biomarkers.

RESULTS: Compared with the stable loneliness trajectory, the increasing loneliness trajectory showed nominally higher p-tau181 levels (β = 0.305 log-transformed, 95% CI: 0.022, 0.587; t_476 = 2.112; p = 0.035, uncorrected; multiple comparison-adjusted p = 0.211), adjusting for age, sex, education, social isolation, and depression symptoms.

CONCLUSIONS: This exploratory analysis found a nominal association between increasing loneliness and p-tau181 that did not survive correction for multiple comparisons. Findings should be considered hypothesis-generating. If confirmed through replication in larger samples, associations between loneliness patterns and tau pathology could inform understanding of psychosocial contributions to neurodegeneration.},
}

@article {pmid42331740,
year = {2026},
author = {Xu, K and Salaiza, JA and Adeoye, H and Bhowmik, S and El Sayed, T and Rana, M and Mirica, LM},
title = {Pharmacokinetic Studies of Amyloid-Targeting Bis(styryl)benzene Agents for Alzheimer's Disease.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.6c00361},
pmid = {42331740},
issn = {1948-7193},
abstract = {The pharmacokinetics (PK) and biodistribution of radiolabeled amyloid-β (Aβ)-targeting probes have been extensively characterized in the context of Alzheimer's disease (AD), whereas the corresponding nonradiolabeled scaffolds remain largely unexplored in vivo. Herein, we report in vivo PK studies of the widely used amyloid probe methoxy-X04 (MeX04) in transgenic 5xFAD and wild-type (WT) mice. In plasma, MeX04 shows comparable exposure between 5xFAD and WT mice, indicating no major genotype-dependent differences in systemic clearance. In contrast, brain exposure was markedly increased in 5xFAD mice, with higher brain Cmax and AUC parameters and slower washout, consistent with Aβ-dependent sequestration and retention in the AD brain tissue. Notably, fluorescence microscopy revealed that the fluorescence intensity of amyloid plaque-bound MeX04 closely mirrored the total brain concentration, and we employed ex vivo fluorescence intensity quantification to evaluate the PK of a related bis(styryl)benzene compound, LS-4, which is proposed to exhibit increased affinity for soluble Aβ aggregates. We then performed age-dependent ex vivo staining of compound-bound Aβ aggregates in 5xFAD brains, and LS-4 exhibits appreciable amyloid-bound fluorescence intensity in younger 5xFAD mice, consistent with its higher affinity for Aβ oligomers, whereas MeX04 exhibited stronger fluorescence intensity in older mice. Consequently, we propose an efficient approach to track temporal changes in the PK of Aβ-binding compounds by ex vivo evaluation of their amyloid-bound fluorescence intensity, providing a rapid assessment of the general PK trends of newly developed amyloid-binding probes.},
}

@article {pmid42331779,
year = {2026},
author = {Gao, TL and Geng, S and Chen, J and Yang, L and Nie, YJ and Yu, H and Chai, GS},
title = {Immune cell-specific genetic architecture of Alzheimer's disease revealed by multi-omics analysis for therapeutic target discovery and prioritization.},
journal = {Translational psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41398-026-04199-9},
pmid = {42331779},
issn = {2158-3188},
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative condition in which accumulating genetic and molecular evidence implicates dysregulation of peripheral immune processes in disease pathogenesis. Nevertheless, the contribution of distinct peripheral immune cell subsets and associated gene regulatory landscapes to AD risk remains incompletely defined. To address this gap, we integrated single-cell expression quantitative trait loci (sc‑eQTL) data from the OneK1K cohort with AD GWAS summary statistics. We systematically interrogated immune cell-specific genes for their contributions to AD risk by integrating genetic causal inference with Bayesian colocalization analyses, and identified 24 eGenes that passed both the MR significance threshold (P < 0.05) and the criterion for strong shared genetic signals (PP.H4 > 0.8). Notable candidates included GATS, HLA-DOB, HLA-DQA1, PM20D1, and others, with each gene demonstrating a cell-type-specific association restricted to its corresponding immune cell type, such as monocytes, CD8[ + ]T cells, or B cells. Independent peripheral blood single-cell transcriptomic data further supported disease-associated shifts in cell-type-specific expression patterns in AD. Phenome-wide association studies (PheWAS) indicated limited associations with off-target traits, indicating a favorable safety profile for therapeutic intervention, with the exceptions of B4GALNT3, PM20D1, and CNN2. Integration of immune gene targets with pharmacological databases yielded three candidate compound, including NSC321521 (targeting HLA-DQA1), phenoxybenzamine (targeting GSTP1), and rimexolone (targeting BIN1). Among these compounds, Predicted blood-brain barrier permeability was observed only for phenoxybenzamine and rimexolone, with docking studies indicating stable interactions, such as those between NSC321521 and HLA-DQA1, phenoxybenzamine and GSTP1, and rimexolone and BIN1. This integrative approach highlights key immune‑cell‑specific genes involved in AD and proposes repurposable drugs with central nervous system potential, paving the way for more targeted immunomodulatory strategies in AD.},
}

@article {pmid42331820,
year = {2026},
author = {Gonzalez-Kozlova, E and Tichkule, S and Nose, Y and Chen, TY and Reznik, E and Santiago, JV and Korrapati, A and Soleymani, T and Kosoy, R and Figueiredo, I and Lee, D and Hoffman, GE and Kyprianou, N and Gordon, RE and Cordon-Cardo, C and Rangaraju, S and Seyfried, NT and Haroutunian, V and Fullard, JF and Roussos, P and Dogra, N},
title = {SECmeres outperform extracellular vesicles as potential blood RNA biomarkers for Alzheimer's disease.},
journal = {Nature communications},
volume = {17},
number = {1},
pages = {},
pmid = {42331820},
issn = {2041-1723},
support = {NIH R21 AGO78848//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; },
mesh = {Humans ; *Alzheimer Disease/blood/genetics/diagnosis ; *Biomarkers/blood ; *Extracellular Vesicles/metabolism/genetics ; *RNA/blood ; Brain/metabolism/pathology ; Female ; Male ; Blood-Brain Barrier/metabolism ; Aged, 80 and over ; Aged ; },
abstract = {Cells release heterogeneous extracellular vesicles and particles (EVPs) into circulation, carrying RNA and proteins that reflect their origin. Recently, brain-derived EVs have gained significant attention as non-invasive biomarkers for Alzheimer's disease (AD). Here, we identified sub-50nm extracellular nanoparticles in human brain and blood that lack the hallmarks of small EVs, exosomes, exomeres, and supermeres but are enriched for brain-specific markers, hereafter termed small EPs or 'SECmeres'. We discovered that RNAs associated with SECmeres discriminated AD cases from controls with higher significance than small EVs, large EVs showed no differences. Discriminating RNAs were enriched in small EVs (Synaptotagmin, Alpha-synuclein, MAPT) or SECmeres (L1CAM, Syntaxin, Neurogranin), indicating distinct brain-derived signatures. Single-cell RNAseq deconvolution shows small EVs contain RNAs from diverse brain cells, whereas SECmeres enrich brain endothelial transcripts, lining cerebral blood vessels and forming the blood-brain barrier (BBB). These findings challenge the prevailing view that small EVs are the primary carriers of biomarkers. Collectively, our study shows that blood EVPs carry brain-specific information for liquid biopsy, pending validation in larger blinded clinical trials.},
}

Humans
*Alzheimer Disease/blood/genetics/diagnosis
*Biomarkers/blood
*Extracellular Vesicles/metabolism/genetics
*RNA/blood
Brain/metabolism/pathology
Female
Male
Blood-Brain Barrier/metabolism
Aged, 80 and over
Aged

@article {pmid42332025,
year = {2026},
author = {Korukonda, A and Weinshenker, D},
title = {A new hope: locus coeruleus-norepinephrine system at the nexus of neuropsychiatric symptoms.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {42332025},
issn = {1476-5578},
support = {AG079199//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; AG062581//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; AG081046//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; AG066511//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; },
abstract = {The earliest stages of Alzheimer's disease (AD) are frequently characterized by neuropsychiatric symptoms (NPS) such as anxiety, agitation, depression, compulsivity, appetite dysregulation, and sleep disturbances, often preceding measurable cognitive decline. Evidence from clinical and animal studies implicates hyperactivity of the locus coeruleus-norepinephrine (LC-NE) system as a mechanistic driver of these behaviors. Here, we review noradrenergic circuits that can potentially underlie psychiatric disturbances to identify therapeutic targets for preventing and delaying onset of AD. Given that this system influences attention, arousal, mood, and stress responses, LC-NE hyperactivity across circuitry involving amygdala, thalamus, hypothalamus, anterior cingulate cortex, prefrontal cortex, and olfactory areas can contribute to NPS features in early AD. Advances in neuroimaging and physiological measures of noradrenergic function have enabled in vivo tracking of LC integrity and NE transmission, offering the opportunity to detect LC-NE dysfunction early in disease progression and potentially implement targeted pharmacologic and neuromodulatory interventions to restore optimal LC-NE tone. Overall, dissection of LC-NE circuitry and its clinical translation hold promise for developing biomarker-driven, stage-specific interventions to reduce NPS burden and enhance the efficacy of disease-modifying therapies in AD.},
}

@article {pmid42332177,
year = {2026},
author = {Tang, M and Fleming, E and Gu, J and Shi, H and Xu, Y and Gong, X},
title = {Trace Elements Dyshomeostasis and Toxic Metals Neurotoxicity in Neurodegenerative Diseases.},
journal = {Biological trace element research},
volume = {},
number = {},
pages = {},
pmid = {42332177},
issn = {1559-0720},
support = {Grant No. SH2023078//the Zhenjiang Science and Technology Plan Project/ ; Grant No. JDYY2023009//the Medical Education Collaborative Innovation Fund of Jiangsu University/ ; Grant No. 32002235//the National Natural Science Foundation of China/ ; },
abstract = {Neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, are defined by the progressive loss of neurons through interconnected pathological mechanisms, including oxidative stress, mitochondrial dysfunction, protein aggregation, and neuroinflammation. Accumulating evidence implicates metal dyshomeostasis as a central and multifaceted contributor to these mechanisms, with roles ranging from a primary pathogenic driver in AD and PD, to a secondary amplifier of genetic pathology in HD and ALS, and as a contextual risk modifier in the presence of toxic metals. Essential trace metals such as iron, zinc, copper, manganese, selenium, iodine, and molybdenum are vital for neurotransmission, antioxidant defense, and cellular metabolism. Dysregulation of these metals disrupts redox balance, impairs proteostasis, and activates regulated cell death pathways, including ferroptosis and cuproptosis. Toxic metals, such as lead, cadmium, and mercury, exacerbate neurodegeneration by displacing essential metals, inducing oxidative injury, and promoting protein misfolding and neuroinflammation. This narrative review synthesizes mechanistic, experimental, genetic epidemiological, and clinical evidence to critically evaluate the contributions of both essential and toxic metals to neurodegeneration in AD, PD, HD, and ALS. We examine the genetic, environmental, and physiological determinants of metal homeostasis; the analytical techniques for quantifying metals in clinical samples; and clinical trial data on metal-targeted therapeutic strategies. Notably, iron chelation with deferiprone consistently reduces brain iron on neuroimaging but worsens clinical outcomes in both PD and AD, presenting a translational paradox that requires mechanistic re-evaluation. We also provide methodological recommendations for interpreting Mendelian randomization studies of metal exposures and propose translational priorities to advance metal-targeted diagnostics and therapeutics for neurodegenerative diseases.},
}

@article {pmid42332290,
year = {2026},
author = {Zheng, M and Fang, Y and Na, L and Zhao, Q},
title = {Predicting piRNA-Disease Associations Based on Dual-View Learning and Multi-head Self-Attention Mechanism Fusion.},
journal = {Interdisciplinary sciences, computational life sciences},
volume = {},
number = {},
pages = {},
pmid = {42332290},
issn = {1867-1462},
support = {2025-MSLH-351//Science and Technology Plan Project of Liaoning Province/ ; LJ212410146026//Fundamental Research Funds for the Liaoning Universities/ ; },
abstract = {PIWI-interacting RNAs (piRNAs) are an important class of non-coding RNA molecules in epigenetic regulation. It plays a crucial role in maintaining genomic stability and inhibiting transposable elements, and have been proven to participate in various diseases by regulating gene expression and influencing signaling pathways. Traditional biological experimental methods have limitations such as low throughput, long cycles, and high costs, making them difficult to meet the requirements of large-scale systematic screening. In this study, we develop a predictive framework named PiDA-DVLSA. We integrate autoencoder, dual graph transformer, and multi-head self-attention mechanisms, and construct an end-to-end multimodal deep learning system. We use autoencoder to perform nonlinear dimensionality reduction and denoising on piRNA sequence features and disease phenotype semantic features, and extract potential representations with strong discriminative ability. Then, we use graph transformers to model the high-order topological relationships between nodes in isomorphic similar graphs, and input heterogeneous graph transformers to learn complex cross-entity interaction patterns in heterogeneous networks. Finally, we achieve adaptive fusion of multi-source information through multi-head self-attention mechanisms. PiDA-DVLSA performs excellently on the benchmark dataset, with AUC and AUPR reach 0.9437 and 0.9195, respectively, significantly outperform eight mainstream algorithms. In independent case validations for breast cancer, clioblastoma, and Alzheimer disease, our model successfully predicts multiple biologically significant potential associations, further confirming its practicality and effectiveness in real scientific research scenarios and providing a solid computational basis for future precision diagnostic and therapeutic applications. PiDA-DVLSA is freely available at https://github.com/zhaoqi106/PiDA-DVLSA .},
}

@article {pmid42332435,
year = {2026},
author = {He, W and Zhang, K and Jia, X and Lv, Y and Cheng, T and Han, L and Xia, Y and Zhang, X and Zhai, W and Yang, F and Wang, S and Jin, L},
title = {Design, Biological Characterization, and Discovery of the Brain-Penetrant NLRP3 Inhibitor Based on a [1,2,4]Triazolo[1,5-a]pyrimidine Scaffold for the Treatment of Central Nervous System Diseases.},
journal = {Journal of medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jmedchem.6c00839},
pmid = {42332435},
issn = {1520-4804},
abstract = {NLRP3 inflammasome is a critical cytosolic multiprotein complex central to the innate immune response. Upon activation, NLRP3 oligomerizes and recruits the adapter protein ASC; this scaffold recruits and activates pro-caspase-1. Active caspase-1 catalyzes the proteolytic maturation and secretion of the potent pro-inflammatory cytokines IL-1β and IL-18, and induces a programmed cell death called pyroptosis. Dysregulated or chronic NLRP3 inflammasome activation is a major driver of pathogenesis in a wide spectrum of peripheral inflammatory diseases, including gout, pericarditis, atherosclerosis, nonalcoholic steatohepatitis, and NLRP3 gain-of-function autoinflammatory disorders known as CAPS, as well as neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis. Herein we described the discovery of NLRP3 inhibitors based on the [1,2,4]triazolo[1,5-a]pyrimidine scaffold. Represented by compound 25, this scaffold exhibited exceptional potency, favorable physicochemical properties, and desirable pharmacokinetic profiles, including good brain penetration. Compound 25 showed potential as a candidate for the treatment of Parkinson's disease.},
}

@article {pmid42332490,
year = {2026},
author = {Wei, Y and Yang, B and Wang, J and Zhao, W and Dai, W and Xie, R and Zhang, L},
title = {Optimizing cardiovascular health to mitigate cognitive decline: Physical activity as a primary modifiable target.},
journal = {Medicine},
volume = {105},
number = {25},
pages = {e49246},
doi = {10.1097/MD.0000000000049246},
pmid = {42332490},
issn = {1536-5964},
support = {JSDW202233//Jiangsu Provincial Medical Key Discipline Cultivation Unit/ ; LKM2023044//Elderly Health Foundation of Jiangsu Province/ ; },
mesh = {Humans ; Female ; Male ; Cross-Sectional Studies ; Aged ; *Exercise/physiology ; *Cardiovascular Diseases/complications/epidemiology/prevention & control ; Nutrition Surveys ; United States/epidemiology ; Neuropsychological Tests ; *Cognitive Dysfunction/prevention & control ; Cognition/physiology ; Middle Aged ; },
abstract = {Cardiovascular disease has been consistently associated with cognitive impairment; however, the relationship between Life's Essential 8 (LE8), a novel composite metric of cardiovascular health (CVH), and cognitive function in older adults remains inadequately characterized. This study aimed to investigate the cross-sectional association between LE8 scores and cognitive function among United States older adults and identify the relative contributions of individual LE8 components. We conducted a cross-sectional analysis using data from the National Health and Nutrition Examination Survey 2011 to 2014 cycles. A total of 2108 participants aged ≥ 60 years with complete cognitive assessment and LE8 data were included. Cognitive function was evaluated using 4 validated neuropsychological tests: Consortium to Establish a Registry for Alzheimer Disease Word Learning and Delayed Recall, animal fluency test, and Digit Symbol Substitution Test. Composite and domain-specific z-scores were computed. Weighted multiple linear regression models were employed to examine LE8-cognition associations, adjusting for demographic and clinical covariates. Weighted quantile sum regression was applied to determine the relative contribution weights of individual LE8 components. In fully adjusted models, each 10-point increment in LE8 score was associated with a 0.09-unit increase in composite cognitive z-score (95% confidence intervals: 0.04-0.14, P < .001). Compared with low CVH (LE8 < 50), high CVH (LE8 ≥ 80) demonstrated significantly higher cognitive z-scores (β = 0.41, 95% confidence intervals: 0.25-0.57, P < .001). Weighted quantile sum regression identified moderate physical activity as the predominant contributor (weight = 0.56) to cognitive performance, followed by blood glucose (0.19) and blood pressure (0.14). Higher LE8 scores are significantly associated with better cognitive function in older adults, with moderate physical activity emerging as the most influential modifiable factor. These findings underscore the potential of integrated CVH optimization as a strategy for cognitive preservation in aging populations.},
}

Humans
Female
Male
Cross-Sectional Studies
Aged
*Exercise/physiology
*Cardiovascular Diseases/complications/epidemiology/prevention & control
Nutrition Surveys
United States/epidemiology
Neuropsychological Tests
*Cognitive Dysfunction/prevention & control
Cognition/physiology
Middle Aged

@article {pmid42332537,
year = {2026},
author = {Ni, P and Zhao, B and Xv, H},
title = {Study on diagnostic genes and immune microenvironment disorder in comorbid atherosclerosis and Alzheimer disease.},
journal = {Medicine},
volume = {105},
number = {25},
pages = {e49470},
doi = {10.1097/MD.0000000000049470},
pmid = {42332537},
issn = {1536-5964},
mesh = {Humans ; *Alzheimer Disease/genetics/immunology/diagnosis/epidemiology ; *Atherosclerosis/genetics/immunology/diagnosis/epidemiology ; Biomarkers ; Mendelian Randomization Analysis ; Early Growth Response Protein 2/genetics ; Machine Learning ; Protein Interaction Maps/genetics ; MicroRNAs/genetics ; Computational Biology ; Gene Expression Profiling ; Membrane Proteins/genetics ; },
abstract = {Atherosclerosis (AS) and Alzheimer disease (AD) are globally prevalent chronic diseases with challenges of difficult early diagnosis and a lack of effective combined therapies. This study explored their shared molecular mechanisms, potential diagnostic biomarkers, and immune microenvironment disorders. Using AS dataset GSE100927 and AD dataset GSE97760, key differentially expressed genes (key DEGs) were identified via bioinformatics (differential expression analysis, protein-protein interaction network, machine learning). A risk prediction model was built and validated with receiver operating characteristic/area under the curve. Immune infiltration was compared between patient and control groups; miRNA-transcription factor-mRNA and key DEGs-chemical networks were predicted, and key DEGs-AS/AD causal relationships verified by Mendelian randomization. Venn analysis found 89 common DEGs (enriched in lipid metabolism, Wnt pathway, etc). Four key DEGs (early growth response 2 [EGR2], leukocyte-specific transcript 1 [LST1], membrane-spanning 4-domains subfamily A member 7 [MS4A7], and 2'-5'-oligoadenylate synthetase like [OASL]) were confirmed. The model had high accuracy (C-index = 0.982, area under the curve > 0.9). Mendelian randomization showed EGR2 was an AS risk/AD protective factor; LST1 an AS risk factor; MS4A7 an AD risk factor; no clear OASL-AD causality. EGR2, LST1, MS4A7, and OASL are novel diagnostic biomarkers and potential therapeutic targets for comorbid AS and AD.},
}

Humans
*Alzheimer Disease/genetics/immunology/diagnosis/epidemiology
*Atherosclerosis/genetics/immunology/diagnosis/epidemiology
Biomarkers
Mendelian Randomization Analysis
Early Growth Response Protein 2/genetics
Machine Learning
Protein Interaction Maps/genetics
MicroRNAs/genetics
Computational Biology
Gene Expression Profiling
Membrane Proteins/genetics

@article {pmid42332710,
year = {2026},
author = {Liu, Y and Dai, Y and Pan, Y and Yang, X and Zhu, M and Diao, X and Ma, J and Huang, X and Zheng, F},
title = {Dynamic dementia risk before and after incident diabetes mellitus: a combined case-control and cohort study.},
journal = {BMC public health},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12889-026-28216-0},
pmid = {42332710},
issn = {1471-2458},
support = {82373665//National Natural Science Foundation of China/ ; 2021-RC330-001//Non-profit Central Research Institute Fund of the Chinese Academy of Medical Sciences/ ; },
abstract = {BACKGROUND: Evidence on the temporal dynamics of dementia risk before incident diabetes remains limited. We aimed to investigate the temporal pattern of dementia risk before and after incident diabetes, compared with matched controls.

METHODS: Case-control and cohort analyses were conducted by using data from the UK Biobank. Propensity score matching was performed to match participants with and without diabetes. Conditional logistic regression was adopted in case-control analysis to estimate dementia risk before incident diabetes. Cox proportional-hazard regression models were adopted in cohort analysis to estimate dementia risk following a diabetes diagnosis.

RESULTS: A total of 44,166 participants with diabetes and 132,498 matched diabetes-free participants were included. During the 10-year period before diabetes, dementia occurred in 344 (0.78%) participants who later had diabetes and 530 (0.40%) diabetes-free participants. Compared to participants without diabetes, the dementia risk was significantly higher in participants with diabetes (Odds Ratio [OR]: 2.14, 95% Confidence Interval [CI]: 1.83-2.50), with the ORs gradually increasing as the time approached the diagnosis date. The adjusted OR was 3.86 (95% CI: 3.11-4.80) for dementia in the 2 years before diabetes. After a diabetes diagnosis, a higher risk for dementia remained in participants with incident diabetes (Hazard Ratio [HR]: 1.82, 95%CI: 1.68-1.97). Similar results were found for Alzheimer's disease and vascular dementia (VD), with VD showing a risk of over 6-fold.

CONCLUSIONS: Dementia risk starts to increase 10 years before diabetes, and the 2-year period preceding diagnosis might represent a high-risk period that calls for closer cognitive monitoring for vulnerable individuals.},
}

@article {pmid42332766,
year = {2026},
author = {Bodde, HE and Poos, JM and Kolman, GHPR and Bosman, A and Willemsen, SP and Peetoom, K and Pijnenburg, YAL and Koopmans, R and Verhey, FRJ and de Vugt, ME and Bakker, C and , and Papma, JM},
title = {The prevalence and incidence of young onset dementia in the Netherlands: a prospective study in two catchment areas.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02120-6},
pmid = {42332766},
issn = {1758-9193},
support = {WE.09-2017-09//Gieskes-Strijbis Foundation/ ; WE.09-2017-09//Alzheimer Netherlands/ ; WE.09-2017-09//Dutch Young‑Onset Dementia Knowledge Centre/ ; 10510032120002/ZONMW_/ZonMw/Netherlands ; },
abstract = {BACKGROUND: Young-onset dementia (YOD), defined as dementia with symptom onset before the age of 65, is associated with distinct and often complex care needs that differ from those with late-onset dementia. Current national data on YOD incidence, prevalence, and demographic characteristics are limited, underscoring the importance of prospective studies to inform policy and tailored care services.

METHODS: We conducted two prospective one-year prevalence and incidence studies using active case-finding in two Dutch catchment areas, one urban and one more rural region, between 2020 and 2022. Individuals with YOD making use of care services were registered in an online database. Data on dementia subtype, living situation, and migration background were collected to explore regional variation.

RESULTS: We identified 372 individuals with YOD in the urban Rotterdam area, and 209 in the more rural Eindhoven-De Kempen area. Age-standardized prevalence per 100,000 individuals, standardized to the Dutch population, was 77.3 in the Rotterdam region, and 66.1 in the Eindhoven-De Kempen region for ages 30-69 years, and 46.3 and 36,9, respectively, for ages 30-64 years. Corresponding age-standardized incidence rates were 24.2 and 23.5 for ages 30-69 years, and 13.9 in both regions for ages 30-64 years. Alzheimer's disease was the most common diagnosis in both areas. Compared with Eindhoven-De Kempen, the Rotterdam region had significantly more vascular dementia cases (p < 0.05 for incidence, and p < 0.001 for prevalence) and longer diagnostic delays (2.2 vs. 1.3 years between first GP consultation and diagnosis). Most individuals lived at home (76.4% and 85.4% resp. in Rotterdam and Eindhoven-De Kempen) and 30.8% in Rotterdam and 12.5% in Eindhoven-De Kempen had a migration background. Extrapolation of incidence figures suggests that between 14,655 and 20,340 individuals were living with YOD in the Netherlands in 2021.

CONCLUSIONS: This study estimates the number of people living with YOD in the Netherlands. In addition, our findings show regional variation in dementia subtypes, a high proportion of people with YOD living at home, and a substantial proportion of people with YOD with a migration background. These insights underline the importance of region‑specific, person‑centered, culture sensitive YOD care at home.},
}

@article {pmid42332767,
year = {2026},
author = {Ye, J and Deng, Y and Zhang, B and Li, C and Guo, X and Yue, R and Wan, H and Hao, Y and Xiao, S},
title = {HDAC7 acts as an astrocytic mediator of Aβ pathology that directly engages IKK to drive astrocyte neurotoxicity and neurodegeneration in Alzheimer's disease.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02121-5},
pmid = {42332767},
issn = {1758-9193},
support = {82101493//National Natural Science Foundation of China/ ; 82474227//National Natural Science Foundation of China/ ; 2025A1515012551//Basic and Applied Basic Research Foundation of Guangdong Province/ ; JCYJ20240813141825034//Shenzhen science and technology research and development funds/ ; 20231121103959001//Shenzhen Science and Technology Innovation Commission/ ; 2023SHIBS0003//Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions/ ; },
abstract = {BACKGROUND: Astrocytes undergo reactive transformations in response to pathological stimuli and play a critical role in neuronal loss associated with Alzheimer's disease (AD). However, the intrinsic mechanisms through which astrocytes detect amyloid-β (Aβ) pathology and develop neurotoxic properties remain inadequately understood. The dysregulation of class IIa Histone deacetylases (HDACs) has been implicated in astrocyte dysfunction under pathological conditions. This study aims to elucidate the role of HDAC7 as an astrocytic mediator of Aβ that drives the formation of neurotoxic reactive astrocytes, and to propose HDAC7 as a potential therapeutic target for mitigating neuronal loss and cognitive deficits in AD.

METHODS: We examined HDAC7 expression in APP/PS1 mice of varying ages using RT-qPCR, Western blotting, and immunostaining analysis. Astrocyte-specific HDAC7 overexpression and knockdown were achieved through adeno-associated virus (AAV) delivery (GfaABC1D promoter) in wild-type (WT) and APP/PS1 mice, followed by behavioral tests, immunostaining, RT-qPCR, and RNA-seq. Mechanistic studies were conducted using primary astrocytes derived from WT and Hdac7[flx/flx] mice, employing co-immunoprecipitation, Western blotting, and neuron viability assays. Pharmacological inhibition of HDAC7 in APP/PS1 mice was performed via intraperitoneal injection of TMP195, and the effects on neurotoxic reactive astrocytes, neuronal and synaptic loss, and behavioral performance were measured.

RESULTS: HDAC7 was selectively upregulated in plaque-adjacent astrocytes in APP/PS1 mice. Overexpression of HDAC7 specifically in astrocytes was sufficient to induce a neurotoxic transcriptional profile, neuronal loss, and cognitive deficits in both WT and young APP/PS1 mice. Mechanistically, upon Aβ stimulation, the upregulated HDAC7 directly interacted with and deacetylated IKKα and IKKβ, resulting in the activation of IKK, translocation of NF-κB to the nucleus, and subsequent expression of neurotoxic genes. This neurotoxic conversion was dependent on IKK activity, as IKK inhibition nullified the effects in astrocytes overexpressing HDAC7. Conversely, astrocytic HDAC7 knockdown or treatment with TMP195 attenuated IKK-NF-κB signaling, reduced the presence of neurotoxic reactive astrocytes, and rescued neurodegeneration and cognitive deficits in APP/PS1 mice.

CONCLUSIONS: HDAC7 acts as an intrinsic effector within astrocytes, responding to Aβ pathology and converting astrocytes into a neurotoxic state through direct interaction with IKK. Targeting HDAC7 presents a promising strategy for astrocyte-directed therapeutic interventions in Alzheimer's disease.},
}

@article {pmid42332768,
year = {2026},
author = {Lee, CY and Hsu, CW and Tseng, PT and Fang, YY and Stubbs, B and Thompson, T and Carvalho, AF and Lin, YH and Kao, YC and Yang, FC and Hsu, TW and Liang, CS},
title = {Real-world effectiveness of monoclonal antibody lecanemab versus acetylcholinesterase inhibitors in Alzheimer's disease: a target trial emulation.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02095-4},
pmid = {42332768},
issn = {1758-9193},
abstract = {BACKGROUND: Acetylcholinesterase inhibitors (AChEIs) provide symptomatic relief in Alzheimer's disease (AD), whereas lecanemab may modify disease progression; however, real-world evidence on its safety and clinical impact remains limited. Therefore, this study aimed to compare the safety and effectiveness of initiating lecanemab versus AChEIs in patients with mild cognitive impairment (MCI) or AD.

METHODS: Using the TriNetX US electronic health record network, we conducted a retrospective cohort study including individuals diagnosed with MCI or AD between July 2023 and September 2025. A target trial emulation with 1:1 propensity score matching and Cox models estimated comparative risks.

RESULTS: Lecanemab was associated with a fivefold higher incidence of neuroimaging abnormalities than AChEIs, while 1-year treatment persistence was similar (53.4% vs 52.5%). After matching, 589 patients were included in each cohort. Compared with AChEIs, lecanemab was associated with significantly lower risks of behavioral and psychological symptoms of dementia (BPSD) (HR, 0.52; 95% CI, 0.36-0.77) and emergency visits (HR, 0.66; 95% CI, 0.51-0.85), but a higher risk of hospitalization (HR, 1.31; 95% CI, 1.03-1.67). Lecanemab was also associated with lower use of antipsychotics (HR, 0.47; 95% CI, 0.32-0.70), antidepressants (HR, 0.60; 95% CI, 0.43-0.85), melatonin/orexin antagonists (HR, 0.61; 95% CI, 0.42-0.88), antibiotics (HR, 0.61; 95% CI, 0.44-0.86), and antifungals (HR, 0.57; 95% CI, 0.37-0.88), whereas steroid use was higher among lecanemab users (HR, 2.19; 95% CI, 1.55-3.10).

CONCLUSIONS: Compared with an AChEI-based conventional care strategy, lecanemab initiation was associated with comparable treatment persistence and lower observed risks of BPSD, emergency visit as well as reduced use of psychotropic and infection-related medications in exploratory analyses. However, the higher incidence of neuroimaging abnormalities associated with lecanemab, along with increased risks of hospitalization and corticosteroid use, likely reflects proactive clinical monitoring and management of amyloid-related imaging abnormalities (ARIA). While residual confounding cannot be excluded and results warrant cautious interpretation, these exploratory findings warrant further validation in biomarker-confirmed cohorts and head-to-head randomized trials.},
}

@article {pmid42332793,
year = {2026},
author = {Mari, E and Aventaggiato, M and Paldino, E and Ceccarelli, S and Mucci, N and Bellomo, G and Mantuano, E and Dugheri, S and Martellucci, S and Mattei, V},
title = {Cellular prion protein and its derived peptides: multifaceted roles in neurodegenerative diseases and potential as biomarkers.},
journal = {Cell & bioscience},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13578-026-01609-9},
pmid = {42332793},
issn = {2045-3701},
abstract = {Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and transmissible spongiform encephalopathies (TSEs), share fundamental mechanisms of protein misfolding, synaptic dysfunction, and progressive neuronal loss. The cellular prion protein (PrP[C]), long viewed through the lens of prion biology, is now recognized as a pleiotropic modulator of neuronal physiology and a central interaction hub for amyloidogenic proteins. PrP[C] undergoes tightly regulated proteolytic processing (α-, β-, γ-cleavage, and ectodomain shedding), generating soluble fragments and peptides with distinct and sometimes opposing biological activities. These derivatives modulate neurotrophic signaling, oxidative stress responses, and the uptake/toxicity of Alzheimer's disease-relevant soluble amyloid-β (Aβ), α‑synuclein, and tau. Recent work highlights PrP[C] as a ligand for low-density lipoprotein receptor‑related protein‑1 (LRP1) and the NMDA receptor (NMDAR), with shed PrP[C] and PrP‑derived peptides capable of initiating cell signaling and attenuating inflammatory responses, including when PrP[C] is delivered via extracellular vesicles. In parallel, ultrasensitive seed amplification assays (SAA; RT‑QuIC/PMCA) have transformed prion diagnostics and underscore the biomarker potential of both full-length PrP[C] and of its proteolytic fragments. Here, we synthesize current knowledge on PrP[C] structure-function relationships, proteolytic processing, and crosstalk with disease‑ associated protein aggregates. We also outline emerging translational opportunities, ranging from PrP‑derived peptide therapeutics to fluid-based biomarkers that track disease onset and progression.},
}

@article {pmid42332816,
year = {2026},
author = {Ni, D and Feng, Z and Liang, D and Qi, Z and Lu, Y and Zhu, L and Li, G},
title = {PCSK9 inhibitors do not increase cognitive risk.},
journal = {Biology direct},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13062-026-00865-6},
pmid = {42332816},
issn = {1745-6150},
abstract = {BACKGROUND: Proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors are potent lipid-lowering therapies, however, concerns regarding their neurocognitive safety persist because of conflicting evidence.

METHODS: We applied an integrated approach combining real-world pharmacovigilance, genetic epidemiology, and preclinical models. Disproportionality analysis was performed using the FDA Adverse Event Reporting System (FAERS) data to assess cognitive adverse events. Two-sample Mendelian randomization (MR) was used to assess the causal effects of apolipoprotein B (ApoB) lowering and PCSK9 inhibition on Alzheimer's disease (AD) using UK Biobank and FinnGen data, with a factorial MR design to evaluate interactions stratified by ApoB and PCSK9 polygenic risk. Preclinically, hepatocyte-specific knockout and pharmacological inhibition of PCSK9 in AD-transgenic mice were assessed through cognitive testing and neuropathological assessment.

RESULTS: FAERS analysis showed no increased reporting signal for cognitive adverse events with PCSK9 inhibitors. For AD, the ROR was below unity (ROR = 0.62, 95% CI 0.45-0.87), whereas no statistically significant signal was observed for dementia (ROR = 0.92, 95% CI 0.79-1.08). In contrast, statins showed significant disproportionality signals for AD (ROR = 2.86, 95% CI 2.51-3.26) and dementia (ROR = 1.51, 95% CI 1.36-1.67). MR analysis revealed no causal association between genetically proxied PCSK9 inhibition and AD risk (OR = 1.00, 95% CI 0.93-1.07), or between ApoB and AD risk (OR = 0.79, 95% CI 0.56-1.11). In AD-transgenic mice, PCSK9 knockout reduced low-density lipoprotein-cholesterol by 54% without impairing cognition or neuronal integrity, or increasing amyloid-β plaques and astrocytes. Pharmacological inhibition of PCSK9 similarly showed no cognitive deficits.

CONCLUSIONS: Integrated evidence from pharmacovigilance, genetic epidemiology, and preclinical models robustly supports the neurocognitive safety of PCSK9 inhibitors, including in individuals with high ApoB levels. These findings affirm their long-term neurocognitive safety profile in the management of atherosclerotic cardiovascular disease.},
}

@article {pmid42332831,
year = {2026},
author = {Rådman, G and Denning, AE and Ravikumar, S and Spotorno, N and Ittyerah, R and Levorse, LM and Robinson, JL and Schuck, T and Lim, SA and Chung, E and Bedard, M and Trotman, W and Bahena, A and Del Mar Arroyo-Jiménez, M and Vela, A and Buendia, E and de Onzoño Martin, MMI and Rabal, MPM and Muñoz-López, M and Olsen, RK and Detre, JA and Lee, EB and Wolk, DA and Ohm, DT and McMillan, CT and Insausti, R and Irwin, DJ and Yushkevich, PA and Wisse, LEM and , },
title = {Characterizing the MRI signature of hippocampal sclerosis of aging.},
journal = {Alzheimer's research & therapy},
volume = {18},
number = {1},
pages = {},
pmid = {42332831},
issn = {1758-9193},
mesh = {*Hippocampal Sclerosis/diagnostic imaging/pathology ; Humans ; *Magnetic Resonance Imaging/methods ; *Aging/pathology ; Male ; *Hippocampus/pathology/diagnostic imaging ; Female ; Aged, 80 and over ; *Alzheimer Disease/diagnostic imaging/pathology ; Aged ; Sclerosis ; },
abstract = {BACKGROUND: Hippocampal sclerosis of aging (HS-A), a common cause of dementia, can currently only be diagnosed at autopsy. We aimed to identify and evaluate MRI metrics to distinguish HS-A from Alzheimer's Disease neuropathologic change (ADNC) and cases with limited/no pathology.

METHODS: HS-A (N = 5), ADNC (N = 10), and limited/no pathology (N = 12) cases were compared on postmortem MRI signatures: manually measured cornu ammonis (CA)1/subiculum thickness, grey matter signal intensity, and automated hippocampal subfield thickness metrics. Similar metrics were obtained in T1-weighted antemortem MRI in an initial dataset (HS-A = 4, ADNC = 7, limited/no pathology = 25) for group differences and discrimination (HS-A vs ADNC). T1-weighted metrics were then evaluated in a second dataset (HS-A = 6, ADNC = 18) and in a pooled post-hoc analysis combining HS-A and ADNC cases from both datasets (NHS-A = 10, NADNC = 25).

RESULTS: Postmortem MRI showed hippocampal thinning and grey matter hypointensity in HS-A at the CA1-subiculum junction more severe than in ADNC and limited/no pathology cases. In antemortem MRI, differentiating HS-A and ADNC based on anterior/posterior manual measures of CA1/subiculum thickness and hippocampal volumes displayed good discrimination in dataset 1, but lower discriminative performance in dataset 2. In complementary analyses pooling both datasets and adjusting for age, manual thickness achieved good performance (area under the curve (AUC) = 0.80-0.87), while anterior, posterior, and whole hippocampal volumes showed excellent discrimination (AUC = 0.94-0.98).

LIMITATIONS: The study included a relatively small and neuropathologically heterogeneous sample. The final antemortem analyses were exploratory, reflecting challenges in replicating findings across independent datasets. Classification was limited to HS-A and ADNC, leaving it uncertain how the metrics perform when comparing HS-A with other diagnostic groups. HS-A diagnoses were determined postmortem, often several years after MRI, and most measures relied on standard imaging sequences with limited resolution to assess fine-grained hippocampal subfields.

CONCLUSIONS: HS-A displays distinct changes in the hippocampus that are detectable through structural MRI. Associated quantifiable MRI metrics may serve as promising tools in aiding antemortem HS-A diagnosis but require further validation in larger cohorts and against other dementia-related diseases.},
}

*Hippocampal Sclerosis/diagnostic imaging/pathology
Humans
*Magnetic Resonance Imaging/methods
*Aging/pathology
Male
*Hippocampus/pathology/diagnostic imaging
Female
Aged, 80 and over
*Alzheimer Disease/diagnostic imaging/pathology
Aged
Sclerosis

@article {pmid42332867,
year = {2026},
author = {Barash, JA and Madden, J and Kofke, WA},
title = {Opioid-Associated Hippocampal Injury: Past, Present, and Future Directions.},
journal = {Hippocampus},
volume = {36},
number = {4},
pages = {e70111},
doi = {10.1002/hipo.70111},
pmid = {42332867},
issn = {1098-1063},
support = {1R21DA051737-01A1//National Institute on Drug Abuse/ ; },
mesh = {Humans ; *Hippocampus/drug effects/pathology/injuries ; Animals ; *Analgesics, Opioid/adverse effects ; *Opioid-Related Disorders/complications/pathology/epidemiology ; Amnesia/chemically induced ; },
abstract = {Three of the great public health challenges of our time converge at the hippocampus. The first, dementia, most commonly in the form of Alzheimer's disease, is well known to cause progressive hippocampal damage, resulting in the memory loss associated with the illness. The second, COVID-19 infection, has thus far been linked to hippocampal alterations across multiple studies. Lastly, the third, opioids-especially in the setting of misuse-have been associated with acute and persistent hippocampal injury; this review focuses on the collection of pre-clinical, clinical, and epidemiologic observations supporting this final relationship. Basic science work dating back decades has demonstrated a hypermetabolic response to opioids and associated damage to the hippocampus. The earliest cases recognized as opioid-associated amnestic syndrome (OAS) were subsequently identified in 2012 and reported as part of larger case series several years later. In 2019, a related but more fulminant syndrome involving cerebellar, hippocampal, and basal nuclei transient edema with restricted diffusion (CHANTER) was first described. From these investigations, a growing body of data has since emerged to suggest that regular opioid use, particularly at higher doses or potency, may be connected to a reduction in hippocampal volume and greater risk of dementia. This review begins with a synthesis of data supporting the underlying pathological mechanisms of opioid-associated hippocampal injury (OAHI), then covers the clinical spectrum of this phenomenon. Lastly, we will close with implications of OAHI that warrant further study, including the future epidemiologic impact on related cognitive disorders in the wake of the opioid epidemic and potential therapeutic applications of opioid antagonism for mild cognitive impairment.},
}

Humans
*Hippocampus/drug effects/pathology/injuries
Animals
*Analgesics, Opioid/adverse effects
*Opioid-Related Disorders/complications/pathology/epidemiology
Amnesia/chemically induced

@article {pmid42332917,
year = {2026},
author = {Lee, YS and Roh, S and Moon, H and Steele, JS and Yoon, DP and Warne, DK},
title = {If a Family Member Develops Alzheimer's Disease: Gender Differences in Help-Seeking Intentions Among American Indians.},
journal = {Journal of applied gerontology : the official journal of the Southern Gerontological Society},
volume = {},
number = {},
pages = {7334648261459708},
doi = {10.1177/07334648261459708},
pmid = {42332917},
issn = {1552-4523},
abstract = {This study examined psychosocial factors associated with help-seeking intentions if and when a family member developed Alzheimer's disease (AD) among American Indian populations, focusing on gender differences. Guided by Andersen's behavioral model of health service use, predisposing, enabling, and need factors were considered as potential sources for AD help-seeking intentions. Multivariate regression analyses were conducted on a sample of 226 American Indian adults residing in South Dakota. Subjective norms and family support were positively associated with help-seeking intentions for both men and women. Gender differences emerged. American Indian women were more likely than men to intend to seek help for a family member with AD if the need arose, while self-confidence in completing medical forms was positively associated with help-seeking intentions among American Indian men only. Identifying common and gender-specific AD intervention strategies can promote timely help-seeking and improve treatment outcomes in American Indian communities.},
}

@article {pmid42333003,
year = {2026},
author = {Onur, S and Çeşme, M and Tümer, F},
title = {Biological and In Silico Evaluation of Novel Methoxyphenol-1,2,3-Triazole Hybrids as Multifunctional Anti-Alzheimer's and Anticancer Agents.},
journal = {Chemical biology & drug design},
volume = {107},
number = {6},
pages = {e70343},
doi = {10.1111/cbdd.70343},
pmid = {42333003},
issn = {1747-0285},
support = {BAP-2022/3-25M//Kahramanmaraş Sütçü İmam University/ ; },
mesh = {Humans ; *Triazoles/chemistry/pharmacology ; *Antineoplastic Agents/pharmacology/chemistry/metabolism ; *Cholinesterase Inhibitors/chemistry/pharmacology/metabolism ; Acetylcholinesterase/metabolism/chemistry ; Molecular Docking Simulation ; Alzheimer Disease/drug therapy ; Butyrylcholinesterase/metabolism/chemistry ; Antioxidants/chemistry/pharmacology ; Cell Proliferation/drug effects ; Structure-Activity Relationship ; Cell Line, Tumor ; Catalytic Domain ; PC-3 Cells ; },
abstract = {The development of multifunctional small molecules capable of simultaneously modulating multiple pathological pathways represents a rational strategy in medicinal chemistry for complex disorders such as Alzheimer's disease (AD) and cancer. Herein, a novel series of methoxyphenol-based 1,2,3-triazole hybrids (5a-h) was designed and synthesized via Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC). All derivatives were fully characterized by FT-IR, [1]H/[13]C NMR spectroscopy, and elemental analysis. Biological evaluation encompassed in vitro antioxidant screening (DPPH•, ABTS•[+], and CUPRAC), acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibition (modified Ellman method), and antiproliferative activity against the PC3 prostate cancer cell line using HDF-1 healthy fibroblasts as a selectivity control. Compound 5c proved the most potent AChE inhibitor (IC50 = 1.44 ± 0.33 μM; SI = 16.77), while 5h exhibited preferential BuChE inhibition (IC50 = 11.40 ± 1.25 μM). Enzyme kinetic studies confirmed a mixed-type inhibition mechanism for both lead compounds, suggesting dual-site engagement within the cholinesterase gorge. In the antiproliferative assay, 5e and 5c surpassed the reference drug methotrexate (IC50 = 4.42 ± 0.15 μM) with IC50 values of 3.57 ± 0.11 μM and 3.89 ± 0.20 μM, respectively, alongside favorable selectivity over healthy fibroblasts. In silico ADMET profiling confirmed drug-likeness for all derivatives, and DFT calculations at the B3LYP/6-311++G(d,p) level provided electronic rationale for observed reactivity trends. Molecular docking against human AChE (PDB: 4EY7) and BuChE (PDB: 4BDS) rationalized key stabilizing interactions including π-π stacking with Trp86/Trp286 and hydrogen bonding with active-site residues. Collectively, these findings identify the methoxyphenol-triazole scaffold as a promising lead platform warranting further optimization for multitarget therapeutic applications in neurodegenerative and oncological disorders.},
}

Humans
*Triazoles/chemistry/pharmacology
*Antineoplastic Agents/pharmacology/chemistry/metabolism
*Cholinesterase Inhibitors/chemistry/pharmacology/metabolism
Acetylcholinesterase/metabolism/chemistry
Molecular Docking Simulation
Alzheimer Disease/drug therapy
Butyrylcholinesterase/metabolism/chemistry
Antioxidants/chemistry/pharmacology
Cell Proliferation/drug effects
Structure-Activity Relationship
Cell Line, Tumor
Catalytic Domain
PC-3 Cells

@article {pmid42333278,
year = {2026},
author = {Ravella, B and Theli, A and Gadde, EC and Ravipati, H},
title = {Jejunal Diverticulitis With Contained Perforation and Abscess Successfully Managed With Conservative Therapy: A Case Report and Review of the Literature.},
journal = {Cureus},
volume = {18},
number = {6},
pages = {e111181},
pmid = {42333278},
issn = {2168-8184},
abstract = {Jejunal diverticulosis is a rare condition that predominantly affects elderly individuals and is often asymptomatic. However, complications such as diverticulitis, perforation, and abscess formation can result in significant morbidity. Perforated jejunal diverticulitis has traditionally been managed surgically, although increasing evidence supports conservative treatment in selected patients. We report a case of a 74-year-old female with hypothyroidism, hyperlipidemia, and Alzheimer's dementia who presented with acute bilateral lower abdominal pain and nausea. Laboratory evaluation demonstrated leukocytosis, elevated inflammatory markers, and lactic acidosis. CT of the abdomen and pelvis revealed jejunal diverticulitis with focal perforation and an adjacent 2.4 × 3.6 cm gas-containing abscess. Given her hemodynamic stability and absence of generalized peritonitis, she was managed nonoperatively with bowel rest, IV fluids, ceftriaxone, and metronidazole. The patient improved clinically with normalization of inflammatory markers and was discharged on oral antibiotics. Follow-up imaging demonstrated complete resolution of the abscess and eventual resolution of inflammatory changes without surgical intervention. This case contributes to the growing body of evidence supporting conservative management of contained perforated jejunal diverticulitis and highlights the importance of careful patient selection and longitudinal radiographic follow-up.},
}

@article {pmid42333303,
year = {2026},
author = {Bélik, J and Silvestre, F},
title = {Epigenetic Aging in Brain Tissue of the Self-Fertilizing Vertebrate, Kryptolebias marmoratus.},
journal = {Ecology and evolution},
volume = {16},
number = {6},
pages = {e73881},
pmid = {42333303},
issn = {2045-7758},
abstract = {DNA methylation changes predictably with age across taxa, but in most species, these patterns are confounded by genetic variation. As a result, age-predictive methylation models have mostly been developed in genetically heterogeneous, cross-fertilizing organisms, limiting inference about epigenetic aging per se. Disentangling epigenetic and genetic effects is therefore essential for understanding aging, adaptation, and evolution. Here, we exploit the mangrove rivulus (Kryptolebias marmoratus), one of only two known self-fertilizing vertebrates (together with K. hermaphroditus), to examine epigenetic aging in a system of naturally occurring near-isogenic individuals. Using reduced-representation bisulfite sequencing of 89 brain samples spanning 60-1100 days of age, we identified 40 CpG sites whose methylation levels predict chronological age with high accuracy (R [2] > 0.96, Median Absolute Error of 28.7 days). These 40 age-associated CpG sites were linked to nearby genes with known roles in cellular maintenance and neurodegeneration. These include genes implicated in aging and neurodegenerative processes across vertebrates, such as lamin-A, the aryl hydrocarbon receptor, and genes associated with Alzheimer's disease in humans. By leveraging a self-fertilizing vertebrate, this study demonstrates that DNA methylation undergoes consistent, age-associated changes across the lifespan in the near absence of genetic variation. Our results establish self-fertilizing vertebrates as powerful models for disentangling epigenetic aging from genetic effects and provide a foundation for comparative and evolutionary studies of aging.},
}

@article {pmid42333360,
year = {2026},
author = {Spantidakis, N and Zisis, V and Charisi, C and Fytros, F and Poulopoulos, K and Chontos, T and Yiannouras, A and Papadopoulos, P and Katsagkolis, A and Arsoudi, V and Thomaidi, ZM and Poulopoulos, A and Diamanti, S},
title = {Oral-Systemic Links: A Narrative Review of the Role of Periodontitis in Alzheimer's Disease Development.},
journal = {Cureus},
volume = {18},
number = {5},
pages = {e109402},
pmid = {42333360},
issn = {2168-8184},
abstract = {Alzheimer's disease (AD) and periodontitis are prevalent chronic conditions that disproportionately affect aging populations and pose substantial public health challenges worldwide. Increasing evidence suggests a potential association between these two diseases, with chronic oral infection and systemic inflammation emerging as key linking mechanisms. Periodontitis is characterized by a dysbiotic oral microbiome and persistent inflammatory responses that can lead to the dissemination of periodontal pathogens and their virulence factors into the systemic circulation. Notably, some studies have reported the detection of pathogens such as Porphyromonas gingivalis and their toxic products in the brains of individuals with AD, implicating a possible role in neuroinflammation and neurodegeneration. However, it should be clarified that detection does not establish causation. This narrative review aims to synthesize the existing evidence from animal studies exploring the link between periodontitis and AD and its related mechanisms, including neuroinflammation, amyloid and tau pathology, blood-brain barrier dysfunction, and systemic interactions. The electronic search in PubMed yielded 585 results. We focused on the past 10 years, thus removing 114 results. A total of 471 studies remained. Of the 471 articles reviewed, 239 studies were excluded based on their titles, abstracts, publication types, and topics because of inappropriate study designs (i.e., designs other than cross-sectional or animal studies). A total of 232 studies were further investigated. In this review, the analysis focused exclusively on animal studies, and the full texts were assessed against predefined eligibility criteria focusing on study design, animal model, periodontal exposure, and AD-related outcomes. Studies that met all inclusion criteria were included, whereas articles with inappropriate study designs or irrelevant outcomes were excluded. After full-text screening, 101 studies remained. Preclinical (animal) evidence supported plausible mechanistic links between periodontitis and AD. Furthermore, oral pathogens appear to mediate this ongoing neuroinflammation.},
}

@article {pmid42333463,
year = {2026},
author = {Lee, N and Youn, K and Moon, M and Lee, DS and Kim, DH and Ho, CT and Jun, M},
title = {Fucoxanthin enhances AMPK/mTOR-dependent autophagic flux and attenuates ferroptosis in Alzheimer's disease models.},
journal = {Food & function},
volume = {},
number = {},
pages = {},
doi = {10.1039/d6fo01264g},
pmid = {42333463},
issn = {2042-650X},
abstract = {Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) accumulation, impaired proteostatic clearance, and oxidative damage, all of which contribute to neuronal dysfunction and disease progression. Fucoxanthin (FX), a marine-derived carotenoid abundant in brown algae, has shown antioxidant and neuroprotective potential. However, its role in autophagy-lysosome dysfunction and ferroptosis-associated oxidative injury under amyloidogenic conditions remains unclear. In this study, the effects of FX were investigated in APP Swedish mutant-expressing Neuro2a (SweAPP N2a) cells treated with 0.1-5 μM FX and in 5XFAD transgenic mice orally administered FX at 200 mg kg[-1]. FX treatment increased LC3-II expression and reduced p62 accumulation in SweAPP N2a cells, indicating enhanced autophagic degradation. FX also increased the expression of the lysosomal markers LAMP1 and cathepsin D (CTSD), suggesting enhanced lysosome-associated degradative capacity. These responses were accompanied by AMPK activation and suppression of mTOR signaling, together with increased autophagic flux as confirmed by bafilomycin A1-based analysis. Moreover, FX significantly reduced intracellular ROS levels and lipid peroxidation marker 4-hydroxynonenal (4-HNE), while modulating ferroptosis-associated proteins, including GPX4 and FTH1. Consistent with the cellular findings, FX administration in 5XFAD mice modulated autophagy-lysosome-related and ferroptosis-associated proteins in the brain and significantly reduced ThS-positive amyloid plaque burden. Collectively, these findings demonstrate that FX enhances autophagy-lysosome-associated proteostatic regulation through AMPK/mTOR signaling and attenuates ferroptosis-linked oxidative injury under amyloidogenic conditions. These results provide mechanistic evidence supporting the role of FX as a marine-derived bioactive compound for modulating AD-related pathological processes.},
}

@article {pmid42333503,
year = {2026},
author = {Rotonen, S and Auvinen, J and Bloigu, A and Härkönen, P and Jokelainen, J and Timonen, M and Keinänen-Kiukaanniemi, S},
title = {Association of insulin resistance and health-related quality of life with mild cognitive impairment during aging.},
journal = {Scandinavian journal of primary health care},
volume = {44},
number = {1},
pages = {2686715},
doi = {10.1080/02813432.2026.2686715},
pmid = {42333503},
issn = {1502-7724},
mesh = {Humans ; *Quality of Life ; *Insulin Resistance ; *Cognitive Dysfunction/epidemiology/etiology ; Aged ; Female ; Male ; Middle Aged ; Risk Factors ; *Aging ; Depression/complications ; Insulin/blood ; },
abstract = {BACKGROUND: Previous studies have shown an association between dementia and diabetes. This study focused on examining whether insulin resistance is a risk factor for mild cognitive impairment (MCI). We also evaluated whether common cardiovascular risk factors or depressive symptoms modify the risk of MCI along with insulin resistance and compared the health-related quality of life (HRQoL) with or without MCI.

METHODS: The participants were followed from 57 to 69 years of age and divided into two groups, MCI and non-MCI, according to their Consortium to Establish a Registry for Alzheimer's Disease (CERAD) total score at the follow-up. The changes in Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) and fasting insulin level during the follow-up were determined. Smoking, alcohol consumption, physical activity, depressive symptoms, and HRQoL were obtained by questionnaire. Body weight, height, blood pressure, and low-density lipoprotein (LDL) cholesterol were measured at baseline and follow-up. Adjustments were made for baseline cognitive performance, professional education and physical activity.

RESULTS: Greater increases in HOMA-IR (OR 2.20, 95% CI 1.05-4.62) and fasting insulin (OR 3.49, 95% CI 1.48-8.23) increased the risk of MCI. Lower cognitive performance at baseline (OR 6.33; 95% CI 3.27-12.29), lower level of education (OR 3.94, 95% CI 1.76-8.81) and lower level of physical activity (OR 2.44, 95% CI 1.06-5.65) also increased the risk of MCI at follow-up. There was a greater decline in health-related quality of life among the MCI group.

CONCLUSION: Insulin resistance is a risk factor for MCI and MCI causes worsening of HRQoL during aging.},
}

Humans
*Quality of Life
*Insulin Resistance
*Cognitive Dysfunction/epidemiology/etiology
Aged
Female
Male
Middle Aged
Risk Factors
*Aging
Depression/complications
Insulin/blood

@article {pmid42333549,
year = {2026},
author = {Rishika, C},
title = {Apolipoprotein E Mimetics in Targeted Drug Delivery: Advances and Therapeutic Potential for Neurodegenerative and Cardiovascular Diseases.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050464479260610102042},
pmid = {42333549},
issn = {1875-5828},
abstract = {The need to improve the delivery of therapeutic compounds that require effective intracranial delivery across the Blood-Brain Barrier (BBB) has generated significant interest in apolipoprotein E (ApoE) mimetic peptides. These synthetic equivalents of the lipid-binding receptorsinteracting domains of natural ApoE are frequently reproducible when incorporated into nanocarriers or nano platforms, including reconstituted low-high density lipoproteins, polymeric nanoparticles, and liposomal systems. The progress in formulation science has led to the development of ApoE- functionalized nanoparticles and multifunctional liposomes with improved BBB translocation, cellular internalization, and Amyloid-beta (Aβ) affinity compared to conventional delivery vehicles. This review provides a comprehensive discussion of the process by which ApoE mimetics can be used to deliver therapeutic drugs and evaluates the different nanocarrier designs adapted to deliver drugs into the nervous system. Emphasis is also placed on new multifunctional systems in which ApoE mimetics are conjugated to therapeutic or diagnostic molecules, enabling imaging of the targeted area, delivery to the disease site, and disease-specific activity. Although the right direction has been taken, several issues still need to be addressed before ApoE-based strategies can be implemented in clinical practice. The problems that continue to limit larger use include formulation stability, unintended off-target interactions, pharmacokinetics, and scalability of complex nanocarrier systems. This review identifies key concerns needed to move ApoE-mimetic technologies toward effective, clinically viable therapies for central nervous system diseases, identifies the issues that inhibit progress, and analyzes possible methods for their management.},
}

@article {pmid42333562,
year = {2026},
author = {Srivastava, V and Chakraborty, S and Srivastava, R},
title = {Toll-Like Receptor-Mediated Neuroinflammation and Its Role in Neurocognitive Functions.},
journal = {Current reviews in clinical and experimental pharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/0127724328415188260605204430},
pmid = {42333562},
issn = {2772-4336},
abstract = {Toll-like receptors (TLRs) are a family of pattern recognition receptors that recognise both pathogen-associated and damage-associated molecular patterns. While their expression was initially believed to be restricted to immune cells, accumulating evidence now demonstrates their presence across multiple neural cell types. Due to their significant involvement in neuroinflammatory and neurodegenerative processes, TLRs have garnered growing attention for their potential contributions to neurocognitive disorders, including Alzheimer's disease, Parkinson's disease, stroke, amyotrophic lateral sclerosis, and other forms of dementia. Potential treatment targets for lowering neuroinflammation and slowing the evolution of neurocognitive diseases include TLR signalling pathways, namely the MYD88-dependent and TRIF-dependent cascades. To initiate signalling, Toll-like receptors (TLRs) recruit specific adaptor molecules that activate the transcription factors NF-κB and IRFs, which regulate the induction of innate immune responses. Over the past decade, a combination of genetic, biochemical, structural, cellular, and bioinformatics approaches has been utilised to elucidate the detailed molecular mechanisms underlying TLR signalling. These studies have clarified how TLRs interact with cytosolic innate immune sensors to orchestrate effective immunological reactions. The function of different TLRs expressed in various brain immune cells and their contribution to the pathophysiology of neuroinflammation are described. This paper discusses the involvement of TLRs in autoimmune and neuroinflammatory circumstances like multiple sclerosis (MS), bacterial meningitis, viral encephalitis, stroke, Alzheimer's disease, and Parkinson's disease. It is intended for TLR biologists and immunologists studying neuroinflammation, as well as neuroscientists delving into central nervous system processes mediated by TLRs.},
}

@article {pmid42333570,
year = {2026},
author = {Abubakar, MD and Gupta, J and Daksh, R and Chavan, PR and Alom, S and Mondal, A and Azizuddin, S and Pal, B and Murti, K and Kumar, D and Kumar, N},
title = {Neurodegenerative Disease Molecular Therapeutics based on Structural Activity Connections of Microglia Activation and Priming: A Comprehensive Review.},
journal = {Current topics in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115680266405995260414053514},
pmid = {42333570},
issn = {1873-4294},
abstract = {INTRODUCTION: In neurodegenerative diseases (NDDs) such as Alzheimer's (AD) and Parkinson's (PD), neuroinflammation plays a crucial role in the development and advancement of these disorders by contributing to the buildup of defective protein folding. Native immune response cells, known as microglial cells, enhance neuroinflammation by altering their shape and producing cytokines that promote inflammation. Inflammation in NDDs causes synapse pathology and dysfunction, although microglia-synapse relationships are unclear. Microglial structural activity alters physiology and architecture, causing functional changes and degeneration. Neurodegeneration and protein accumulation trigger microglial priming, which activates and regenerates microglia, resulting in heightened inflammatory responses. The biological activities and structural activation of microglia are studied to improve NDD therapy.

METHODS: An exhaustive search was conducted using the internet databases of PubMed, ScienceDirect, Google Scholar, DOAJ, and Wiley to identify any papers that discussed microglial activation, priming of this process, and molecular intervention in NDDs. First, molecular, preclinical, and clinical data were carefully reviewed for extraneous or redundant references, then narratively merged to offer a conceptual overlay.

RESULTS: This review examines the role of microglial cells in NDDs, highlighting potential interventions such as peptide- and RNA-based therapies, NF-κB, TLR4, JAK inhibitors, antibodies, and biologics.

DISCUSSION: The results suggest that stimulating microglial cells and enhancing neuron connections may improve treatment outcomes. The review indicates that translational research should be conducted to connect molecular pathways with clinically effective medicines.

CONCLUSION: Targeting microglia- and astrocyte-driven molecular markers could help resolve neuroinflammation and facilitate reliable therapeutic interventions in the progression of NDDs.},
}

@article {pmid42333847,
year = {2026},
author = {Song, T and Shang, Y},
title = {Inhibitory Effects of Flavonoids from the Stems and Leaves of Scutellaria baicalensis Georgi on Oligodendrocyte Pyroptosis Induced by Aβ1-42.},
journal = {Current topics in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115680266471937260616073434},
pmid = {42333847},
issn = {1873-4294},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is characterized not only by gray matter lesions but also by significant white matter damage and oligodendrocyte dysfunction. This study elucidates the pyroptosis-suppressive potential of Scutellaria baicalensis Georgi stem-leaf flavonoids (SSFs) in oligodendroglial lineage cells.

METHODS: We co-treated rat oligodendrocytes (OLN-93 cell line) with 7.5 μmol/L Aβ₁₋₄₂ to simultaneously induce pyroptosis and SSFs. We observed cell morphology via microscopy, measured cell viability with the MTT assay, and assessed membrane damage using the LDH release assay. We then used qPCR to measure the mRNA levels of myelin-related genes (MBP, MAG, MOG) and pyroptosis-related genes (NLRP3, Caspase-1, GSDMD). We employed Western blotting to quantify the expression of pyroptosis-related proteins.Immunofluorescence was. used to localize myelin proteins whereas pyroptosis indicators and applied PI/Hoechst staining was used to evaluate cell membrane permeability within cells.

RESULTS: SSFs at concentrations of 15-60 mg/L significantly improved cell morphology, increased cell survival, reduced LDH release, modulated the expression of relevant genes and proteins, decreased the proportion of cells with impaired membrane integrity, and reduced the fluorescence signal of the pyroptotic execution protein GSDMD. These effects were comparable to those of the commonly used positive control, 60 mg/L Ginkgo biloba extract (GBE).

DISCUSSION: This study found that SSFs can alleviate Aβ-induced oligodendrocyte pyroptosis by inhibiting the NLRP3 inflammasome pathway, thereby preserving myelin function. The limitations of this study include the exclusive use of cell line models, the unclear identity of the specific active ingredients in SSFs, and the lack of verification of their blood-brain barrier penetration. Further studies, including in vivo animal experiments, active component isolation, and pharmacokinetic research, are required to evaluate its therapeutic potential for AD fully.

CONCLUSION: SSFs protect oligodendrocytes against Aβ-induced injury by inhibiting the NLRP3 inflammasome pathway.},
}

@article {pmid42334012,
year = {2026},
author = {Stratton, L and Moczygemba, W and Zimmerman, S and Cattell, M and Eichenberger, L and Griff, M and Fazio, S},
title = {Provider Perspectives on the Design, Implementation, and Impact of Technology on Person-Centered Dementia Care: Insights From the Alzheimer's Association Dementia Care Provider Roundtable.},
journal = {Journal of applied gerontology : the official journal of the Southern Gerontological Society},
volume = {},
number = {},
pages = {7334648261453115},
doi = {10.1177/07334648261453115},
pmid = {42334012},
issn = {1552-4523},
abstract = {BackgroundThere has been a rapid growth of technologies designed for people living with dementia and their care-partners. However, despite the proliferation of dementia care technologies, their person-centeredness is not guaranteed, and successful integration into care settings is inconsistent.ObjectiveTo better understand the relationship between technology and person-centered dementia care.MethodsThis article draws on discussions from two Alzheimer's Association Dementia Care Provider Roundtable meetings to understand key issues related to technology and person-centered dementia care.ResultsFindings relate primarily to long-term care settings and suggest that technologies hold promise to facilitate engagement and improve care efficiency. However, concerns include the lack of person-centered design, potential for depersonalization of care, and challenges related to implementation. Drawing on provider recommendations, the Modified Hexagon Tool for Designing and Implementing Person-Centered Dementia Care Technologies is introduced as a practical framework for person-centered dementia care technologies in long-term and other care settings.},
}

@article {pmid42334062,
year = {2026},
author = {Corriveau-Lecavalier, N and Falgàs, N and Putcha, D and Graff-Radford, J and Yong, KXX and Boon, BDC and Mohanty, R and Westman, E and Groot, C and Jones, DT and Grinberg, LT and Rabinovici, GD and Whitwell, JL and Apostolova, LG and Murray, ME and Hammers, DB and Schindler, SE and Atonsdottir, I and Rhodus, EK and Schott, JM and Illán-Gala, I and Chukwuanugo, O and Guerra, JJL and Peters, R and Abner, EL and Abdelnour, C and Lladó, A and La Joie, R and de Souza, LC and Rezaii, N and Shir, D and Pijenburg, YAL and Carrillo, MC and Dickerson, BC and Aisen, P and Ossenkoppele, R and Raman, R},
title = {Improving the clinical trial landscape for patients with atypical variants of Alzheimer's disease: a call to action.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {6},
pages = {e71521},
doi = {10.1002/alz.71521},
pmid = {42334062},
issn = {1552-5279},
support = {JR22/00014//Instituto de Salud Carlos III/ ; R01-AG50603/GF/NIH HHS/United States ; R01-AG075802/GF/NIH HHS/United States ; P30 AG 062677/GF/NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/therapy/diagnosis ; *Clinical Trials as Topic ; Disease Progression ; },
abstract = {Patients with atypical variants of Alzheimer's disease (AD) often present at a younger age with predominantly non-amnestic impairments and a more aggressive disease course. Historically, individuals with atypical presentations have not been included in large-scale clinical trials, which typically focus on late-onset, sporadic amnestic-predominant AD. Consequently, treatment options and research efforts specific to atypical AD remain limited. The emergence of amyloid-targeting therapies that slow disease progression underscores these challenges, as evidence supporting their efficacy in early-onset amnestic and non-amnestic AD variants is scarce. This perspective article argues that atypical AD represents an excellent disease model for clinical trials and proposes strategies to address critical gaps in clinical trial design for this population. Key considerations include optimizing participant selection approaches, establishing syndrome-specific or surrogate biological and clinical endpoints, and fostering advocacy to enhance early and accurate diagnosis, equitable representation, and outcomes for these populations.},
}

Humans
*Alzheimer Disease/therapy/diagnosis
*Clinical Trials as Topic
Disease Progression

@article {pmid42334086,
year = {2026},
author = {Xue, D and Blue, EE and Sofer, T and Hughes, TM and Rotter, JI and Post, WS and Fohner, AE},
title = {Polygenic Risk Scores for Incident Dementia in the Multi-Ethnic Study of Atherosclerosis.},
journal = {Genetic epidemiology},
volume = {50},
number = {5},
pages = {e70046},
doi = {10.1002/gepi.70046},
pmid = {42334086},
issn = {1098-2272},
support = {F99AG07979//National Institute on Aging/ ; K01AG071689//National Institute on Aging/ ; //National Heart, Lung, and Blood Institute/ ; },
mesh = {Humans ; Genetic Risk Score ; *Dementia/genetics/epidemiology/ethnology ; Polymorphism, Single Nucleotide ; Bayes Theorem ; Female ; Aged ; Genome-Wide Association Study ; *Atherosclerosis/genetics ; Male ; *Multifactorial Inheritance ; Ethnicity/genetics ; White People/genetics ; Alzheimer Disease/genetics ; Genetic Predisposition to Disease ; Incidence ; Black or African American/genetics ; Aged, 80 and over ; Hispanic or Latino/genetics ; },
abstract = {Over 75 Alzheimer's disease (AD) and dementia-associated variants have been identified through genome-wide association studies, but the utility of polygenic risk scores (PRS) for predicting AD and dementia in diverse and admixed populations remains unclear. We compared how PRS approaches differing in p-value thresholds, variant weights, and source ancestry perform in predicting dementia in 6338 African American, Chinese, Hispanic, and White individuals from the Multi-Ethnic Study of Atherosclerosis. We tested clumping and thresholding (C+T) methods with varying parameters against Bayesian approaches (PRS-CS, PRS-CSx). We compared the ability of each method to predict incident dementia in all participants and in groups stratified by self-reported race/ethnicity. We additionally analyzed performance across groups stratified by estimated proportion of non-Finnish European (NFE)-like ancestry. Including more variants does not improve performance. We found comparable associations between dementia and PRS when comparing a C+T method with only 15 SNPs and PRS derived from Bayesian models that include > 800,000 SNPs (HR5e-08 = 1.18, 95% CI: 1.08-1.28; HRCSx = 1.17, 95% CI: 1.07-1.27). The p < 5e-08 C+T method was more strongly associated with incident dementia in populations genetically dissimilar from the source data (HRlowNFE_5e-08 = 1.27, 95% CI: 1.08-1.50; HRlowNFE_CSx = 1.12, 95% CI: 0.94-1.33). More selective PRS models using genome-wide significant SNPs may be preferable for dementia prediction in diverse populations.},
}

Humans
Genetic Risk Score
*Dementia/genetics/epidemiology/ethnology
Polymorphism, Single Nucleotide
Bayes Theorem
Female
Aged
Genome-Wide Association Study
*Atherosclerosis/genetics
Male
*Multifactorial Inheritance
Ethnicity/genetics
White People/genetics
Alzheimer Disease/genetics
Genetic Predisposition to Disease
Incidence
Black or African American/genetics
Aged, 80 and over
Hispanic or Latino/genetics

@article {pmid42334143,
year = {2026},
author = {},
title = {Corrigendum to "Aluminum involvement in the progression of Alzheimer's Disease".},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261458196},
doi = {10.1177/13872877261458196},
pmid = {42334143},
issn = {1875-8908},
}

@article {pmid42334154,
year = {2026},
author = {Choi, BK and Park, JA and Kim, TH and Kim, HC and Ko, IO and Oh, TI and Kim, JW and Kim, HJ},
title = {Monitoring Alzheimer's disease-related fluid microenvironment changes using magnetic resonance-based electrical conductivity imaging.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261461256},
doi = {10.1177/13872877261461256},
pmid = {42334154},
issn = {1875-8908},
abstract = {Cerebrospinal fluid (CSF) status is an indicator of pathological feature associated with metabolic waste clearance dysfunction in Alzheimer's disease (AD) progression. Magnetic resonance-based conductivity imaging provides novel contrast sensitive to ion concentration, mobility, and microstructural changes. We applied conductivity imaging to 5xFAD mice and age-matched wild-type controls using 9.4 T MRI, measuring regional conductivity in ventricular CSF, caudate putamen, cerebral cortex, thalamus, and hippocampus. AD mice showed ventricular enlargement with significantly elevated CSF conductivity, and increased hippocampal conductivity consistent with AD involvement, but no changes in other regions. These findings suggest conductivity imaging as a marker of fluid microenvironmental changes in AD.},
}

@article {pmid42334173,
year = {2026},
author = {Sulatsky, MI and Stepanenko, OV and Stepanenko, OV and Mikhailova, EV and Sulatskaya, AI},
title = {Macromolecular crowding inhibits degradation of alpha-synuclein amyloid fibrils induced by cathepsins and MMP9.},
journal = {Protein science : a publication of the Protein Society},
volume = {35},
number = {7},
pages = {e70707},
doi = {10.1002/pro.70707},
pmid = {42334173},
issn = {1469-896X},
support = {23-74-10092//Russian Science Foundation/ ; },
mesh = {*alpha-Synuclein/metabolism/chemistry ; Humans ; *Amyloid/metabolism/chemistry ; *Matrix Metalloproteinase 9/metabolism/chemistry ; Proteolysis ; *Cathepsin D/metabolism/chemistry ; *Cathepsin B/metabolism/chemistry ; },
abstract = {The accumulation of amyloid fibrils in the brain leads to cognitive and motor impairment in incurable neurodegenerative disorders, particularly in Alzheimer's and Parkinson's diseases. Emerging anti-amyloid immunotherapies rely on recruiting immune proteases to clear these pathological aggregates, yet a stark disconnect remains between the high proteolytic efficiency observed in dilute in vitro assays and the limited efficacy of these treatments in vivo. This discrepancy likely arises because standard models neglect the dense macromolecular crowding characteristic of the cellular milieu. Here, we address this gap by investigating the degradation of alpha-synuclein amyloids by key immune proteases (cathepsin B, cathepsin D, and matrix metalloproteinase-9) in the presence of synthetic crowding agents at physiological densities. We found that macromolecular crowding in a crowding agent- and dose-dependent manner inhibits protease-induced amyloid declusterization, cluster size reduction, fibril fragmentation, and structural disorganization. We propose that the observed inhibition arises from the excluded volume effect, which stabilizes fibril structure and restricts both enzyme mobility and steric access to the fibril surface rather than suppressing catalytic activity. By restricting the extent of enzymatic amyloid degradation, this "crowding shield" modulated the cytotoxic consequences of enzymatic processing in human cell lines, attenuating enzyme-induced shifts in fibril toxicity in a condition-dependent manner. These findings identify the crowded cellular environment as a critical stabilizer of pathogenic protein aggregates, explaining their persistence in vivo.},
}

*alpha-Synuclein/metabolism/chemistry
Humans
*Amyloid/metabolism/chemistry
*Matrix Metalloproteinase 9/metabolism/chemistry
Proteolysis
*Cathepsin D/metabolism/chemistry
*Cathepsin B/metabolism/chemistry

@article {pmid42334176,
year = {2026},
author = {Freire-Flores, D and Ramos, M and Burgos, H and Carvallo, C},
title = {Prevalence and determinants of polypharmacy and its association with cognitive and functional performance in community-dwelling older adults: A population-based study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261462138},
doi = {10.1177/13872877261462138},
pmid = {42334176},
issn = {1875-8908},
abstract = {BackgroundPopulation aging is accompanied by increasing multimorbidity and medication exposure, raising concerns regarding the role of polypharmacy as a potential modifiable risk factor for cognitive decline and Alzheimer's disease. However, polypharmacy is a heterogeneous construct, and its cognitive impact may depend more on regimen complexity and pharmacological burden than on medication count alone.ObjectiveTo estimate the prevalence and determinants of polypharmacy and to examine its association with functional status and cognitive performance in community-dwelling older adults from southern Chile.MethodsA cross-sectional study was conducted between 2023 and 2025 including 848 adults aged ≥60 years from four provinces in the Los Lagos Region. Sociodemographic, clinical, and psychosocial data were collected through structured interviews and standardized assessments. Functional status was evaluated using EFAM-Chile, Barthel, and Pfeffer scales, and Cognitive performance and functional status were assessed using the Preventive Medicine Examination for Older Adults (EFAM-Chile). Polypharmacy was defined as the concurrent use of ≥5 medications, including prescribed and over-the-counter drugs. Regimen complexity and anticholinergic/sedative burden were quantified using the Medication Regimen Complexity Index (MRCI) and the Drug Burden Index (DBI).ResultsPolypharmacy was associated with better functional and cognitive scores in unadjusted analyses (p < 0.05), although these associations were not independent after adjustment. Multimorbidity was the strongest predictor of medication count. Despite greater medication exposure, MRCI and DBI values remained within low-to-moderate ranges, indicating limited pharmacological burden relevant to cognitive vulnerability. These findings may be explained by reverse causation or by confounding related to health statusConclusionsIn this population, polypharmacy was not associated with cognitive screening outcomes, although the absence of detailed neuropsychological assessment limits conclusions regarding cognitive impairment or dementia risk and may reflect optimized management of chronic conditions. Qualitative pharmacological indices may improve the identification of medication-related cognitive risk in aging populations.},
}

@article {pmid42334178,
year = {2026},
author = {Kashif, M and Ho, MH and Pandurangan, AK and Waseem, M and Majumder, D and Chou, SY},
title = {Vitamin D in Alzheimer's disease: Neuroinflammatory, metabolic, and clinical implications.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261460850},
doi = {10.1177/13872877261460850},
pmid = {42334178},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia worldwide. Beyond amyloid-β and tau pathology, accumulating evidence indicates that chronic neuroinflammation, oxidative stress, mitochondrial dysfunction, disrupted calcium homeostasis, and diabetes are critically contributing to disease onset and progression, underscoring the need to identify modulatory factors that influence multiple pathogenic pathways.ObjectiveThis review evaluates the role of vitamin D in modulating cognitive function and its association with the pathophysiology of AD.MethodsThis narrative review examines the connection between vitamin D and cognitive and neurological outcomes by integrating findings from preclinical and clinical studies. Relevant literature was identified through a PubMed search, restricted to English language publications available up to 2025.ResultsVitamin D, a secosteroid hormone traditionally associated with bone metabolism, has emerged as a potential neuroprotective factor in the aging brain. Vitamin D receptors are widely expressed in neurons and glial cells, and vitamin D readily crosses the blood-brain barrier. Despite increasing evidence linking vitamin D deficiency to AD, its mechanistic roles in neuroinflammation and metabolic dysfunction, as well as its translational relevance, remain incompletely understood. Experimental and clinical studies suggest that vitamin D modulates amyloid metabolism, microglial activation, inflammatory signaling, redox balance, mitochondrial function, synaptic integrity, and regulates insulin resistance.ConclusionsIn this review, we integrate evidence from molecular, cellular, animal, and human studies to examine the role of vitamin D in AD. Finally, we highlight current limitations and knowledge gaps and outline future directions for clinical and translational research.},
}

@article {pmid42334274,
year = {2026},
author = {Akgün, E and Minoshima, S},
title = {Pearls and Pitfalls of [18]F-FDG PET/CT for Suspected Alzheimer's Disease in Patient with Down Syndrome.},
journal = {Molecular imaging and radionuclide therapy},
volume = {},
number = {},
pages = {},
doi = {10.4274/mirt.galenos.2026.13285},
pmid = {42334274},
issn = {2146-1414},
abstract = {Dementia in individuals with Down syndrome (DS) is the leading cause of early-onset cognitive decline occurring before the age of 50. However, establishing an accurate diagnosis remains particularly challenging due to pre-existing intellectual disability, variability in baseline cognitive function, and the limited reliability of standard neuropsychological assessments. [18]F-fluorodeoxyglucose positron emission tomography ([18]F-FDG PET) plays a critical role in identifying underlying neurodegenerative processes and supporting the diagnosis. We present a case of DS with multiple known and unknown pathologies identified on brain [18]F-FDG PET and a confirmed diagnosis of early-onset mild Alzheimer's disease.},
}

@article {pmid42334485,
year = {2026},
author = {Coleman, JS and Capstick, RA and Chang, S and Rios, DJ and Bubser, M and Thompson Gray, AD and Zagol-Ikapitte, I and Krishnan, S and Cho, HP and Rodriguez, AL and Niswender, CM and Boutaud, O and Garcia, GP and Elder, GA and Engers, DW and Jones, CK and Lindsley, CW},
title = {Discovery of VU6066098: A Selective and CNS-Penetrant mGlu2 NAM with Robust Antidepressant-, Antipsychotic-, and Procognitive-like Activity in Rodents.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.6c00324},
pmid = {42334485},
issn = {1948-7193},
abstract = {Herein, we report the discovery and development of an optimized mGlu2 Negative Allosteric Modulator (NAM) in vivo tool compound, VU6066098, based on a novel, structurally distinct chemotype. VU6066098 is a potent, selective, and CNS-penetrant mGlu2 NAM with excellent rat PK (CLp = 23.9 mL/min/kg, t1/2 = 2.2 h, %F = 100, Kp = 1.28, Kp,uu = 0.25), making it ideal to explore the therapeutic potential of selective mGlu2 inhibition in preclinical rat models. In a rat forced swim test, VU6066098 displayed an oral minimum effective dose (MED) of 1 mg/kg and was equi-efficacious to ketamine. In amphetamine-induced hyperlocomotion, VU6066098 displayed an oral minimum effective dose (MED) of 30 mg/kg. While in the preclinical cognitive tasks of rat novel object recognition and acquisition of contextual fear conditioning, VU6066098 produced robust dose-dependent effects at oral minimum effective doses (MED) of 3 mg/kg and 0.3 mg/kg, respectively. In a blast-related traumatic brain injury (TBI) model, administration of VU6066098 at a dose of 10 mg/kg IP was effective acutely, and the effect on NOR memory was sustained up to 30 days postdose. Thus, mGlu2 NAMs show therapeutic potential for the treatment of a broad range of affective and cognitive symptoms associated with Major Depressive Disorder, Alzheimer's disease, TBI, and acute psychosis; moreover, these data strongly support further optimization of mGlu2 NAMs for future clinical development.},
}

@article {pmid42334543,
year = {2026},
author = {Träger, TK and Kyrilis, FL and Kafetzopoulos, G and Tüting, C and Kastritis, PL},
title = {The Pyruvate Dehydrogenase Complex: A 90-Year-Old Enigma Shaping the Future of Structural Enzymology.},
journal = {Advances in experimental medicine and biology},
volume = {1514},
number = {},
pages = {207-253},
pmid = {42334543},
issn = {0065-2598},
mesh = {Humans ; *Pyruvate Dehydrogenase Complex/chemistry/metabolism/genetics ; Animals ; Protein Conformation ; Cryoelectron Microscopy ; Models, Molecular ; },
abstract = {The ancient pyruvate dehydrogenase complex (PDHc) performs the "link reaction" of cellular respiration-a discovery from the 1930s that was central in the award of the 1953 Nobel Prize in Physiology and Medicine to Krebs and Lipmann. Fast forward to 2024, PDHc emerges with roles in Alzheimer's, cancer, and neurodegeneration, as well as in obesity and aging processes. Due to these recent reports, structural analysis of PDHc, a 10-megadalton enzymatic complex, comes into focus-only now this analysis begins to unveil an enormous and challenging molecular complexity. Cutting-edge techniques and methods, such as cryo-electron microscopy (cryo-EM), cross-linking (XL) and mass spectrometry (MS), advanced molecular and biochemical analysis, and computational structural biology, powered by artificial intelligence (AI), converge to systematically probe the mechanistic details governing PDHc function. This chapter collects and updates the knowledge in PDHc structure and function and pinpoints unresolved questions, with the hope of not waiting another 90 years for their answer.},
}

Humans
*Pyruvate Dehydrogenase Complex/chemistry/metabolism/genetics
Animals
Protein Conformation
Cryoelectron Microscopy
Models, Molecular

@article {pmid42334663,
year = {2026},
author = {Siddiqui, F and Khanam, S and Faruqui, T and Mishra, P and Mahmood, S and Mir, SS and Khan, S},
title = {Amino Acid-Driven Gold Nanochaperone Platforms for Alzheimer's Therapy: A Mechanistic and Design Framework for Protein Misfolding Modulation.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42334663},
issn = {1559-1182},
mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism/therapy ; *Metal Nanoparticles/chemistry ; *Gold/chemistry ; Animals ; *Amino Acids/chemistry ; *Protein Folding/drug effects ; Amyloid beta-Peptides/metabolism ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the misfolding and aggregation of amyloid-β (Aβ) peptides and tau proteins, leading to synaptic dysfunction and neuronal degeneration. Despite decades of therapeutic development, currently available treatments provide limited disease modification, largely due to the structural heterogeneity of Aβ aggregates, poor blood-brain barrier penetration and insufficient targeting of toxic oligomeric intermediates. Recently, nanotechnology-based strategies have emerged as promising approaches to modulate pathological protein aggregation. Among these, gold nanoparticle (AuNP)-based nanochaperones have attracted considerable attention due to their tunable physicochemical properties, multivalent binding capabilities and high biocompatibility. In particular, amino acid-functionalized AuNPs provide a biologically inspired platform capable of mimicking molecular chaperone interactions with misfolded proteins. These systems can modulate Aβ aggregation through electrostatic interactions, hydrophobic effects, π-π stacking, hydrogen bonding and metal-ligand coordination, enabling selective targeting of monomers, oligomers and fibrillar aggregates. In this review, we synthesize current advances in amino acid-engineered gold nanochaperones and analyze their mechanisms of interaction with Aβ species. This review integrates mechanistic insights and design considerations to highlight how amino acid-functionalized gold nanoparticles can be optimized for modulating amyloid-β aggregation. In addition, we critically evaluate key translational challenges such as blood-brain barrier delivery, biodistribution, nanotoxicology, protein corona formation and clinical development considerations. By bridging molecular mechanisms with engineering design principles, this review provides a strategic roadmap for the development of next-generation nanochaperone therapeutics targeting protein misfolding in Alzheimer's disease. Overall, amino acid-engineered gold nanochaperones represent a promising frontier in nanomedicine for selectively modulating pathological protein aggregation and developing disease-modifying therapies for Alzheimer's disease.},
}

Humans
*Alzheimer Disease/drug therapy/metabolism/therapy
*Metal Nanoparticles/chemistry
*Gold/chemistry
Animals
*Amino Acids/chemistry
*Protein Folding/drug effects
Amyloid beta-Peptides/metabolism

@article {pmid42334726,
year = {2026},
author = {Dai, L and Lv, S and Guo, H and Li, Z and Li, J and Wang, Y and Du, M and Wu, D and Ma, K and Wu, N and Zhang, J and Chen, B},
title = {A Humanized Knock-in Mouse Model of the PSEN1 V97L Mutation from a Major Chinese Alzheimer's Disease Pedigree Reveals Early Neuroinflammation.},
journal = {Neuroscience bulletin},
volume = {},
number = {},
pages = {},
pmid = {42334726},
issn = {1995-8218},
abstract = {Mutations in the presenilin-1 (PSEN1) gene cause familial Alzheimer's disease (FAD). The PSEN1 V97L mutation is prevalent in Chinese FAD families. Previous studies using a transgenic model that overexpresses PSEN1 V97L have substantially contributed to understanding FAD pathogenesis. However, these models have limitations, including random genetic integration of the transgene, supra-physiological protein expression levels, and retention of endogenous mouse PSEN1 genes. The genetic engineering of novel mouse models carrying human mutant PSEN1 using knock-in methods addresses many of these issues. Here, we generated a humanized PSEN1 V97L knock-in (hV97L) mouse model. At 4 months of age, hV97L mice exhibited early neuroinflammation characterized by microglial activation and M1-like polarization, without Aβ pathology. By 8 months, cognitive deficits, dendritic loss, and myelin damage emerged, still in the absence of amyloid pathology. Our findings demonstrate that the PSEN1 V97L mutation triggers neuroinflammation before cognitive onset, providing a clinically relevant model for early therapeutic targeting.},
}

@article {pmid42334768,
year = {2026},
author = {Zainuddin, MS and Bai Magalingam, K and Pamidi, N and Azman, AS and Bhuvanendran, S},
title = {In-vitro modelling of Alzheimer's disease using cholinergic neurons derived from human neuroblastoma (SH-SY5Y) retinoic acid-induced differentiation.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42334768},
issn = {1573-4978},
mesh = {Humans ; *Tretinoin/pharmacology/metabolism ; Cell Differentiation/drug effects ; *Alzheimer Disease/metabolism/pathology ; *Cholinergic Neurons/metabolism/drug effects/pathology ; Neuroblastoma/metabolism/pathology ; Cell Line, Tumor ; Choline O-Acetyltransferase/metabolism ; Acetylcholinesterase/metabolism ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is characterised by severe degeneration of cholinergic neurons within the basal forebrain complex (FBC) which is a key regulator of cognitive function. Cholinergic loss represents a central pathological hallmark of AD; however, the underlying molecular mechanisms remain incompletely understood. Although various in-vitro models are available, many are limited by species-specific differences, high cost, and technical complexity. Human neuroblastoma (SH-SY5Y) cells can be differentiated into neuron-like cells and represent a practical alternative for AD research. This study aimed to optimise retinoic acid (RA)-based differentiation conditions to enhance cholinergic characteristics in SH-SY5Y cells and evaluate their susceptibility to AD-related stressors as a simplified, cost-effective model for preliminary high-throughput AD studies.

METHODS: A structured literature search (2000-2025) was conducted using PubMed and ScienceDirect. After screening based on predefined criteria, 23 relevant studies were analysed for differentiation inducers, serum concentration, duration, neuronal markers, and cholinergic markers. Here, a simplified RA-only protocol was evaluated using 10µM RA with 1% or 3% heat-inactivated foetal bovine serum (1% or 3% HI-FBS) over 3, 5, and 7 days. Neuronal differentiation was assessed by morphological analysis, neurite length measurement, choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) gene expressions, acetylcholinesterase (AChE) activity. Additionally, model relevance was further evaluated using AD-associated stressors such as streptozotocin (STZ), hydrogen peroxide (H₂O₂), lipopolysaccharide (LPS), and aluminium chloride (AlCl₃).

RESULTS: Although most protocols generated mature neuron-like cells, only ~ 30% reported cholinergic marker expression, with retinoic acid (RA) and brain-derived neurotrophic factor (BDNF) as the most common inducers. This study reports that differentiation with 1% HI-FBS with 10µM RA for 7 days produced pronounced neuronal morphology, significant neurite extension, and extensive branching. These cells demonstrated a cholinergic-like phenotype, with significant upregulation of ChAT and AChE gene expressions, accompanied by increased AChE enzymatic activity. These neuron-like cells also showed dose-dependent responses to STZ, H₂O₂, and AlCl₃, with time-dependent effects observed for H₂O₂ and AlCl₃. Notably, cells were resistant to LPS-induced cytotoxicity.

CONCLUSION: These findings support the utility of this RA-differentiated SH-SY5Y for neuronal-like cells for cholinergic-like model (1% HI-FBS, 10µM RA) as a practical and cost-effective platform for high-throughput AD drug screening.},
}

Humans
*Tretinoin/pharmacology/metabolism
Cell Differentiation/drug effects
*Alzheimer Disease/metabolism/pathology
*Cholinergic Neurons/metabolism/drug effects/pathology
Neuroblastoma/metabolism/pathology
Cell Line, Tumor
Choline O-Acetyltransferase/metabolism
Acetylcholinesterase/metabolism

@article {pmid42334823,
year = {2026},
author = {da Silva, AMP and Tudella, GCN and Gonçalves, OR and Ribeiro, FV and Pereira, MAOM and do Nascimento, MDVS and Nogueira, BV and Santos, DH and de Gobbi Porto, FH and Høilund-Carlsen, PF and Duarte, FS and Perry, G and de Souza Franco, E and de Sousa Maia, MB},
title = {Use of Sedative-Hypnotic Drugs and the Risk of Developing Alzheimer's Disease: A Systematic Review, Meta-Analysis and Meta-Regression.},
journal = {Drugs},
volume = {86},
number = {7},
pages = {1103-1119},
pmid = {42334823},
issn = {1179-1950},
mesh = {Humans ; *Alzheimer Disease/chemically induced/epidemiology ; *Hypnotics and Sedatives/adverse effects ; *Benzodiazepines/adverse effects ; Risk Factors ; Sleep Initiation and Maintenance Disorders/drug therapy ; },
abstract = {BACKGROUND: Sedative-hypnotics, including benzodiazepines (BZDs) and non-benzodiazepine hypnotics (Z-drugs), are widely prescribed for insomnia and anxiety, particularly in older adults. Their long-term cognitive safety and potential association with Alzheimer's disease (AD) remain uncertain. We examined whether use of BZDs and Z-drugs is associated with incident AD and assessed variation by drug class, pharmacokinetics, and methodological factors.

METHODS: PubMed, Embase, and the Cochrane Central Register of Controlled Trials were searched from inception to 16 August 2025 without language restrictions. Reference lists of eligible articles and reviews were screened. We included observational cohort and nested case-control studies enrolling adults without dementia at baseline that compared BZD or Z-drug users with non-users and reported incident AD diagnosed using validated clinical or administrative criteria (e.g., ICD-9/10, NINCDS-ADRDA, or NIA-AA). We excluded reviews, case reports, conference abstracts, studies with overlapping populations, and studies without extractable effect estimates. Two reviewers independently screened studies, extracted data, and assessed risk of bias using ROBINS-E. Random-effects meta-analyses were performed separately for odds ratios (ORs) and hazard ratios (HRs). Heterogeneity was quantified with I[2]. Publication bias was evaluated with funnel plots and Egger test when applicable. Subgroup and meta-regression analyses assessed clinical and methodological modifiers. Certainty of evidence was rated using GRADE. The protocol was prospectively registered (PROSPERO CRD420251141623).

RESULTS: Thirteen studies (N = 721,354 subjects) were included. Overall sedative-hypnotic use was associated with higher odds of AD (OR 1.29; 95% CI, 1.10-1.53; I[2] = 86.5%). Estimates restricted to HRs were attenuated and not statistically significant (HR 1.17; 95% CI, 0.87-1.58; I[2] = 73.1%). In subgroup analyses, BZDs overall (OR 1.21; 95% CI 1.07-1.36), Z-drugs (OR 1.14; 95% CI 1.10-1.18; I[2] = 0%), and short-acting agents (OR 1.19; 95% CI 1.04-1.36) were associated with higher odds of AD, whereas broad-acting BZDs were not (OR 1.01; 95% CI 0.98-1.05). Long-acting agents showed a borderline estimate (OR 1.44; 95% CI 0.99-2.09). Age-stratified analyses showed higher odds in individuals aged <75 years (OR 1.36; 95% CI 1.24-1.49), but not in those aged ≥75 years (OR 1.14; 95% CI 0.61-2.11). Estimates were also higher in studies using ICD-based definitions (OR 1.47; 95% CI 1.16-1.86) than in those using clinical criteria (OR 1.13; 95% CI 0.84-1.52). Meta-regression identified drug class and publication year as significant moderators. Risk of bias was rated moderate to serious in several studies, mainly due to residual confounding and exposure misclassification. Certainty of evidence ranged from very low to moderate.

CONCLUSIONS: Use of BZDs and Z-drugs was associated with increased odds of AD, with variation across drug classes and pharmacokinetic profiles. Short-acting agents, BZDs overall, and Z-drugs were associated with higher risk, whereas broad-acting BZDs were not; this finding should be interpreted with caution given subgroup heterogeneity and limited statistical power. Residual confounding and reverse causation limit causal inference. These results support careful prescribing and the need for prospective studies with detailed characterization of exposure, dose, duration, and clinical indication to clarify whether observed associations reflect drug-related effects or underlying disease processes.

TRIAL REGISTRATION: PROSPERO protocol number: CRD420251141623.},
}

Humans
*Alzheimer Disease/chemically induced/epidemiology
*Hypnotics and Sedatives/adverse effects
*Benzodiazepines/adverse effects
Risk Factors
Sleep Initiation and Maintenance Disorders/drug therapy

@article {pmid42334840,
year = {2026},
author = {Ramasinghe, C and Xu, B},
title = {Unhealthy dietary patterns and Alzheimer's disease: associations and underlying mechanistic pathways.},
journal = {Critical reviews in food science and nutrition},
volume = {},
number = {},
pages = {1-22},
doi = {10.1080/10408398.2026.2691237},
pmid = {42334840},
issn = {1549-7852},
abstract = {Unhealthy dietary patterns are increasingly recognized as important modifiable factors associated with cognitive decline and Alzheimer's disease (AD). Diets characterized by high intake of saturated fats, refined sugars, and ultra-processed foods are consistently linked to metabolic dysfunction, systemic inflammation, and impaired brain health. Epidemiological and interventional studies suggest that these dietary patterns are associated with poorer cognitive outcomes, whereas adherence to nutrient-rich dietary patterns such as the Mediterranean, MIND, and DASH diets is linked to improved metabolic profiles and slower cognitive decline. Several biological mechanisms have been proposed to explain these associations, including insulin resistance, oxidative stress, neuroinflammation, vascular dysfunction, and alterations in gut-brain axis signaling; however, much of the current human evidence remains observational, limiting definitive causal inference. Emerging research also indicates that individual susceptibility to diet-related AD risk may be modified by genetic background, metabolic status, and sex-specific biological factors. Despite variability in study findings, the overall body of evidence supports a biologically plausible relationship between dietary quality and key processes implicated in AD pathogenesis. Future research should prioritize long-term, biomarker-driven randomized controlled trials, alongside life-course approaches that consider early- and mid-life dietary exposures, to better clarify causal pathways and inform targeted nutritional strategies for AD risk reduction.},
}

@article {pmid42334856,
year = {2026},
author = {Abdallah, M and Keddis, PM and Keddis, TM and El-Gamil, DS and Abadi, AH and Kii, I and Engel, M and Abdel-Halim, M},
title = {An updated patent review of dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) inhibitors (2020-present).},
journal = {Expert opinion on therapeutic patents},
volume = {},
number = {},
pages = {},
doi = {10.1080/13543776.2026.2694586},
pmid = {42334856},
issn = {1744-7674},
abstract = {INTRODUCTION: Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is a conserved CMGC serine/threonine kinase with an autophosphorylation-dependent activation mechanism. As a dosage-sensitive regulator of transcription, RNA splicing, cell-cycle progression, and signaling, DYRK1A is implicated in neurological, oncological, cardiovascular, metabolic, immune, and infectious diseases. These roles have driven drug discovery, from early probes to advanced clinical-stage inhibitors.

AREAS COVERED: This review covers patent literature related to the discovery of DYRK1A inhibitors and degraders published from January 2020 to the review cutoff date. The literature search was conducted in WIPO, Reaxys, SciFinder, Lens.org, Espacenet, USPTO, and Google Patents.

EXPERT OPINION: Recent patents indicate that DYRK1A inhibition is no longer a single pharmacological concept but an indication-driven strategy shaped by tissue access, delivery, and mechanistic pharmacodynamic biomarkers. The most credible programs prioritize functional pathway modulation and meaningful target engagement at therapeutically achievable exposure rather than maximal biochemical potency alone, with selectivity defined by disease biology rather than as an absolute requirement. Delivery-advantaged indications such as osteoarthritis and peripheral inflammatory disorders may provide the earliest clinical validation, whereas CNS programs will require brain-penetrant compounds with controlled, likely partial, target modulation. Degraders and macrocycles broaden the toolbox, but biomarker-guided translation remains the key determinant of success.},
}

@article {pmid42334898,
year = {2026},
author = {Wang, TC and Archer, DB and Ali, M and Wu, Y and Mormino, E and Buckley, RF and Lee, AJ and Saykin, AJ and De Jager, PL and Schneider, JA and Bennett, DA and Barnes, LL and Vardarajan, B and Mayeux, R and Kunkle, BW and Bush, WS and Dirk Keene, C and Seshadri, S and Sperling, RA and Vemuri, P and Ramanan, VK and Ilyas Kamboh, M and Harrison, TM and Jagust, WJ and Laws, SM and Schellenberg, GD and Huentelman, M and Hamilton-Nelson, K and Pericak-Vance, MA and Goate, AM and Haines, JL and Montine, TJ and Beecham, G and Below, JE and Cruchaga, C and Hohman, TJ and Dumitrescu, L},
title = {Combining post-mortem and neuroimaging measures of brain amyloidosis to accelerate genomic discovery.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag216},
pmid = {42334898},
issn = {1460-2156},
abstract = {Histopathological assessment has served as the gold standard for diagnosing Alzheimer's disease (AD). Emerging technological advancements, including the development of amyloid positron emission tomography (PET), have enabled early detection of amyloid pathology, one of the neuropathological hallmarks of AD. Genome-wide association study (GWAS) across cohorts of aging and AD, leveraging different measurements of amyloid burden, may facilitate the identification of novel genetic variants that drive the earliest neuropathological changes in AD. This study presents the largest GWAS of brain amyloidosis to date, leveraging amyloid β (Aβ) measured by in vivo amyloid PET and postmortem histopathology from 13,555 individuals of European ancestry. Amyloid positivity was defined as moderate or frequent neuritic plaques according to the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) staging scores for each postmortem cohort. A Gaussian mixture model (GMM) was applied to each amyloid PET cohort to identify the cohort and tracer-specific cut-offs that differentiate amyloid positive and negative populations. In silico and ex vivo analyses further characterized implicated loci, including interrogating the association between bulk and single-nucleus gene expression profiles and AD-related traits. Genetic covariance analysis assessed the extent amyloid PET and postmortem measures reflect the shared genetic architecture of brain amyloidosis. Our combined amyloidosis GWAS identified three established AD risk loci: BIN1 (rs6733839, OR = 1.20, 95% CI 1.14-1.26, P = 1.32 × 10-11), CR1 (rs4844610, OR = 1.24, 95% CI = 1.16-1.32, P = 4.21 × 10-10), APOE (rs429358, OR = 4.01, 95% CI = 3.66-4.38, P = 4.54 × 10-201), and a newly identified brain amyloidosis-associated variant on chromosome 17 (rs35635959, OR = 1.18, 95% CI = 1.12-1.25, P = 1.47 × 10-8). SuSiE fine-mapping identified a single credible set of 15 putative causal variants with rs35635959 as the lead variant. Subsequent eQTL and SuSiE-based colocalization analyses prioritized rs35635959 as a strong eQTL for TUBG2, encoding tubulin gamma 2, which is involved in microtubule organization and synaptic plasticity. Further cell-type-specific characterization of this gene in neurons from dorsolateral prefrontal cortex tissue indicated that decreased TUBG2 expression was associated with increased Aβ burden and AD case status (PFDR < 0.045). Furthermore, our study is the first to report a modest genetic covariance (covariance=0.17, P < 6.54 × 10-8) between the genetic architecture of amyloid burden captured by different modalities. While APOE showed a strong association with both amyloid endophenotypes, the observed genetic covariance was not substantially attenuated after excluding variants within the APOE region (covariance=0.16, P < 1.32 × 10-7). Our results highlight the benefits of leveraging compatible, harmonized AD endophenotypes to increase power to uncover new molecular insights into the etiology of AD neuropathology. Wang et al. present the largest GWAS of brain amyloidosis to date, analysing 13,555 individuals using amyloid PET and postmortem Aβ measures. They identify a novel amyloidosis-associated variant on chromosome 17, demonstrate genetic covariance between modalities, and highlight complex traits sharing genetic architecture with Aβ burden.},
}

@article {pmid42335249,
year = {2026},
author = {Wang, Y and Aguilar, BJ and Li, M and Morin, P and Reisman, J and Hu, W and Lee, JS and Berlowitz, D and Li, Q and Zhang, R and Tahami Monfared, AA and Zhang, Q and Xia, W},
title = {Health care utilization in veterans with Alzheimer disease.},
journal = {The American journal of managed care},
volume = {32},
number = {6},
pages = {e185-e191},
doi = {10.37765/ajmc.2026.89959},
pmid = {42335249},
issn = {1936-2692},
mesh = {Humans ; *Alzheimer Disease/therapy/epidemiology ; Male ; United States ; Aged ; Retrospective Studies ; *Veterans/statistics & numerical data ; United States Department of Veterans Affairs/statistics & numerical data ; *Patient Acceptance of Health Care/statistics & numerical data ; Female ; Hospitalization/statistics & numerical data ; Aged, 80 and over ; },
abstract = {OBJECTIVE: To evaluate health care utilization in veterans with Alzheimer disease (AD) in the Veterans Affairs health system (VAHS).

STUDY DESIGN: This retrospective analysis identified veterans with AD using clinical notes extracted from the VAHS electronic health record from fiscal years 2010 to 2019.

METHODS: The first note identifying AD was the index date. Health care utilization in veterans with AD and a 1:1 matched comparison group without AD was evaluated at 2 years preindex, 1 year preindex, 1 year post index, and 2 years post index.

RESULTS: From clinical notes, we identified 571,671 veterans with AD and 571,671 for the comparison group (overall: mean age, 74 years; 96% male; 75% White). In those with AD, outpatient visits per patient per year peaked 1 year post index at 67 and remained elevated 2 years post index at 57; without AD, the rate was approximately 19 at all time points. Hospitalization rates peaked at 1 year post index with AD but were lower and generally stable without AD. Nursing home utilization was relatively low overall. Veterans meeting the 2-code criteria (n = 56,305), defined as having 2 diagnostic codes for AD recorded at least 30 days apart, had consistently higher utilization than veterans without AD (especially post index).

CONCLUSION: Veterans with AD have higher health care utilization than veterans without AD, especially around the time of AD diagnosis.},
}

Humans
*Alzheimer Disease/therapy/epidemiology
Male
United States
Aged
Retrospective Studies
*Veterans/statistics & numerical data
United States Department of Veterans Affairs/statistics & numerical data
*Patient Acceptance of Health Care/statistics & numerical data
Female
Hospitalization/statistics & numerical data
Aged, 80 and over

@article {pmid42335281,
year = {2026},
author = {Yu, C and Tong, M and Zhao, W and Zou, Y and Zhao, J and Sun, Y and He, M and Cui, M and Cui, Q and Liu, H and Li, D},
title = {Instantaneous Lipid Profiling in Rat Cerebrospinal Fluid via a Nanoconfined Sampling Extraction and Grouping Separation Integrated System: Overcoming Ex Vivo Degradation.},
journal = {Analytical chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.analchem.6c01453},
pmid = {42335281},
issn = {1520-6882},
abstract = {Monitoring lipid dynamics in cerebrospinal fluid (CSF) is critical for understanding central nervous system disorders. However, rapid ex vivo lipid degradation under the effect of enzymes in CSF during in vitro analysis compromises accuracy. To address this, we developed an integrated nanoconfined sampling extraction and grouping separation system using carbon nanofibers (CNFs) and tandem carbon fibers (TCFs). The system achieves rapid in situ sampling and extraction of various lipids in rat CSF within 80 s through nanoconfinement of methyl tert-butyl ether on the surface of CNFs, concurrently separating enzymes (including other proteins) and salts. Coupled with an activated carbon fiber/carbon fiber tandem system, it achieves online grouping and separation of multiple polar lipids within 5 min. Integrated with mass spectrometry, the platform enables the determination and identification of 176 lipids that cover a broad polarity spectrum of lipid metabolites in CSF, offering a sensitive and efficient strategy for authentic lipid analysis in vivo. Notably, the detected lipids include four key classes, namely, fatty acyls, glycerophospholipids, sphingolipids, and sterols, which have been closely associated with Alzheimer's disease pathology. This advancement enhances early diagnosis accuracy and mechanistic insights into brain disorders.},
}

@article {pmid42322668,
year = {2026},
author = {Tremblay, SA and Tulsi, J and Yang, D and Alsibai, Z and McDonald, I and Aladeeb, R and Novielli, A and Wong, TYM and Freitas, JG and Miller, M and Dhir, V and Natasha Rajah, M and Godard-Sebillotte, C and Altuntur, S and Karunananthan, S and Geddes, MR},
title = {Review of current research practices in social and structural determinants of health data collection in Canadian longitudinal cohorts of aging and dementia.},
journal = {Neurobiology of aging},
volume = {167},
number = {},
pages = {53-75},
doi = {10.1016/j.neurobiolaging.2026.06.005},
pmid = {42322668},
issn = {1558-1497},
abstract = {BACKGROUND: Social and structural determinants of health (SSDH) are key drivers of disparities in cognitive aging and dementia risk, yet their collection in aging and dementia research remains inconsistent. We examined SSDH data collection practices across Canadian longitudinal cohorts of aging and dementia, aiming to identify which SSDH are collected and how they are operationalized.

METHODS: We conducted an environmental scan using three sources: (1) literature databases (Cochrane, Embase, Medline, PubMed, and Web of Science), 2) grey literature (e.g., Alzheimer Society of Canada's website), and 3) key informants. We included Canadian longitudinal cohorts of community-dwelling older adults that assessed at least one cognitive or dementia-related outcome, including seven key cohorts previously identified by our group. For each study, we extracted information from data collection instruments on whether specific SSDH were assessed, and which tools were used.

RESULTS: From 1043 non-duplicated articles identified through database searches, fourteen unique cohorts met inclusion criteria, eleven of which provided data collection instruments. Five additional cohorts were identified from other sources, and together with 7 pre-identified key cohorts, yielded 23 included cohorts. Disability-related measures and ethnicity- and culture-related constructs were among the most comprehensively assessed domains, whereas literacy, environmental context, and economic conditions were among the least frequently assessed.

CONCLUSION: SSDH that shape dementia risk and brain resilience, many modifiable at the community and policy levels, remain unevenly collected in Canadian aging and dementia cohorts. Strengthening and harmonizing SSDH measurement is a critical step toward equitable dementia prevention and reducing health disparities.},
}

@article {pmid42322864,
year = {2026},
author = {Li, L and Gu, Y and Luo, X and Wang, J and Jia, Y and Yan, T},
title = {Chrysin reprograms microglial metabolism and function via targeting SYK to alleviate the symptoms of Alzheimer's disease.},
journal = {Journal of ethnopharmacology},
volume = {370},
number = {},
pages = {122056},
doi = {10.1016/j.jep.2026.122056},
pmid = {42322864},
issn = {1872-7573},
abstract = {Alpiniae Oxyphyllae Fructus, first documented in Bencao Shiyi, is a classical traditional Chinese herb traditionally used to warm the kidney, invigorate the spleen, consolidate essence and relieve chronic diarrhea. Guided by the TCM theory that kidney essence nourishes brain marrow, modern studies have confirmed its notable neuroprotective and anti-neuroinflammatory activities.

BACKGROUND: Neuroinflammation is a key pathological hallmark of Alzheimer's disease (AD), and spleen tyrosine kinase (SYK) serves as a critical signaling regulator. Our previous work confirmed that Alpiniae Oxyphyllae Fructus extract (AE) exerts notable neuroprotection; nevertheless, its blood-brain barrier-permeable components and detailed mechanisms remain poorly clarified.

OBJECTIVE: The purpose of this study is to identify the main active components in AE and clarify its mechanism of improving AD pathology by regulating the SYK signaling pathway.

METHODS: A preliminary dose-finding study with two AE doses (180 mg/kg, 360 mg/kg) was performed via open field test and inflammatory indexes to select the optimal dose for subsequent experiments. Behavioral assays assessed AE-related neurobehavioral improvements. LC-QTOF-MS/MS identified brain-permeable components, while network pharmacology combined with GEO database analysis screened potential targets and underlying mechanisms. Molecular docking was applied to filter SYK-binding candidates, further validated by molecular dynamics simulation and Cellular thermal shift assay (CETSA). In vivo, a piceatannol-induced SYK inhibition model was established to verify whether the candidate component alleviated LPS-triggered behavioral deficits in mice in a SYK-dependent manner. In vitro, BV2 microglia were used to detect microglial polarization, Aβ phagocytosis and migration through qRT-PCR, glucose/ATP/lactate measurement, wound healing assay and immunofluorescence staining.

RESULTS: Chrysin was identified as the primary brain-permeable constituents targeting SYK. In AD mice, it significantly ameliorated cognitive deficits and reduced Aβ accumulation. Mechanistically, Chrysin modulated the SYK/BTK/PLCγ2 and NF-κB axes to trigger a microglial M1-to-M2 phenotypic shift. This phenotypic transition is accompanied by metabolic reprogramming-shifting from glycolysis to oxidative phosphorylation, thereby notably enhancing microglial migration capacity and Aβ phagocytosis. These neuroprotective effects were confirmed to be SYK-dependent.

CONCLUSION: Chrysin is the primary brain-permeable constituent of AE. that targets SYK to restore microglial metabolic homeostasis, offering a promising therapeutic strategy for AD.},
}

@article {pmid42322910,
year = {2026},
author = {Liu, R and Wei, M and Xu, L and Qu, Z and Yu, JQ and Liu, Y and Zhang, WN and Zhang, D and Zhuang, C},
title = {A Keap1-Nrf2 protein-protein interaction inhibitor 4-95 ameliorates cognitive dysfunction by suppressing neuronal ferroptosis.},
journal = {Bioorganic chemistry},
volume = {180},
number = {},
pages = {110134},
doi = {10.1016/j.bioorg.2026.110134},
pmid = {42322910},
issn = {1090-2120},
abstract = {Alzheimer's disease (AD) is a severe neurodegenerative disorder. With current therapies failing to halt clinical progression, identifying novel disease-modifying therapeutics is of paramount urgency. Although ferroptosis has emerged as a crucial driver of AD pathogenesis, effective pharmacological strategies targeting this pathway remain limited. Bioinformatic analysis revealed close associations among ferroptosis, oxidative stress, the Keap1-Nrf2 pathway, and AD. Compound 4-95, a selective Keap1-Nrf2 protein-protein interaction (PPI) inhibitor, significantly alleviated Erastin and RSL-3-induced ferroptosis in SH-SY5Y and HT-22 cells. In Aβ1-42-treated cell models, 4-95 dose-dependently decreased Aβ and p-Tau expression, while increasing the anti-ferroptotic proteins GPX4 and SLC7A11. Keap1 and GPX4 knockdown verified that 4-95 inhibits ferroptosis via the Keap1-Nrf2-GPX4 axis. In vivo, 4-95 markedly improved cognitive and spatial memory deficits in Aβ1-42-induced AD mice, promoted Nrf2 nuclear translocation, upregulated the downstream antioxidant targets HO-1 and NQO1, and attenuated neuronal injury. Collectively, the study reveals a new mechanism of a Keap1-Nrf2 PPI inhibitor that mitigates AD pathogenesis by directly inhibiting ferroptosis. This novel mechanism underscores a new class of disease-modifying candidates for AD treatment, representing a new therapeutic strategy for this devastating disorder.},
}

@article {pmid42322996,
year = {2026},
author = {Hamm, MJ and McNaught, K and Janus, C and Gazarov, EA and Strickland, Z and Shubin, J and Reinhardt, J and Park, J and Rayaprolu, S and Antropov, WV and Miller, DM and Hotop, A and Patel, S and Yuksel, IS and Howard, J and Fromholt, S and Xu, G and Bird, JE and Moehle, M and Borchelt, DR and Lewis, J},
title = {Robust tauopathy and memory deficits in a mouse model constitutively overexpressing human P301L MAPT.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107496},
doi = {10.1016/j.nbd.2026.107496},
pmid = {42322996},
issn = {1095-953X},
abstract = {Mutations in the MAPT gene encoding tau protein can be causative for frontotemporal lobar degeneration, FTLD-tau. Preclinical mouse models expressing these disease-causing MAPT alleles have successfully modeled biochemical and neuropathological phenomena similar to those seen in human FTLD-tau. One such model, rTg4510, features P301L human tau primarily expressed in the forebrain under the control of a Tet-off system, using the CaMKII promoter to drive transgene expression. While this model allows temporal manipulation of the transgenic tau, many experiments do not require such manipulation, and the bigenic tet-off system adds to the costs of simple transgenics, introduces additional genetic variation, and increases animal usage. Here, we have generated and characterized mice that constitutively overexpress P301L human tau under the CaMKII promoter. The initial founder and offspring were produced in the FVB/N background where we identified a line of constitutive "cTau[P301L]" mice that stably expresses the 0N4R isoform of P301L human tau at levels comparable to the rTg4510 mouse. The cTau[P301L] line features a relatively small deletion at the transgene insertion site and demonstrates no overt motor phenotype. There was, however, unexpectedly high early lethality on the FVB background that was mitigated after just one crossing to C57BL/6 mice. In both backgrounds, Tau[P301L] expression resulted in an age-dependent accumulation of tau and gliosis that occur prominently in the forebrain and hippocampus. In transgenic F1 B6/FVB mice, spatial memory deficits were detected by 6 months of age. Overall, this new cTau[P301L] model recapitulates disease-associated pathology and memory deficits, with limited disruption of the murine genome and a lack of longevity-restricting motor phenotypes. The cTau[P301L] mouse is a robust, new alternative to existing mouse models of tauopathy.},
}

@article {pmid42323146,
year = {2026},
author = {Puranik, K and Ranpise, N and Khot, S and Negi, P},
title = {Nose-to-Brain delivery of empagliflozin-loaded nanostructured lipid carriers incorporated In-situ gel: Biopharmaceutical evaluation for Alzheimer's disease.},
journal = {European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V},
volume = {},
number = {},
pages = {115161},
doi = {10.1016/j.ejpb.2026.115161},
pmid = {42323146},
issn = {1873-3441},
abstract = {Alzheimer's therapy remains limited by poor drug targeting and multifactorial pathology. The therapeutic potential of SGLT-2 inhibitors like empagliflozin (EGZ) is constrained by poor brain bioavailability. Current study investigates the potential of EGZ-nanostructured lipid carrier (ENLC) for brain delivery via nasal route. The ENLC were prepared using hot melt emulsification technique followed by probe sonication and optimized using Box-Behnken design. ENLC were incorporated into poloxamer 407-chitosan in situ gel (ENPCG) to improve nasal retention, controlled release, and direct brain transport via olfactory and trigeminal uptake. ENPCG demonstrated a sustained drug release of 56.36 ± 3.37 % and enhanced nasal permeation. Nasal kinetics revealed high Cmax[mucosa] (48.2 ± 1.42 µg/cm[2]) relative to plain EGZ-suspension (15.9 ± 0.7 µg/cm[2]) in goat nasal mucosa. ENPCG significantly improved cognitive memory in sporadic AD model, as confirmed by behavioural, biochemical, and histopathological assessments in Wistar rats. Pharmacokinetic study in Sprague Dawley rats revealed a 4.5-fold increase in AUC0-t of intranasal ENPCG (30.56 ± 0.45 μg/mL*h) relative to intravenous ENLC (6.73 ± 0.15 μg/mL*h). ENPCG showed 95.31 ± 3.89 % drug targeting potential. Furthermore, a strong point-to-point ex vivo-in vivo correlation (R[2] = 0.9952) was observed, suggesting a non-invasive potential of ENPCG for translating AD interventions.},
}

@article {pmid42323193,
year = {2026},
author = {Chang, M and Hong, B and Barense, MD},
title = {Improving autobiographical episodic memory, quality of life, and sense of self with a smartphone intervention in early dementia: A case study.},
journal = {Neuropsychological rehabilitation},
volume = {},
number = {},
pages = {1-37},
doi = {10.1080/09602011.2026.2689541},
pmid = {42323193},
issn = {1464-0694},
abstract = {In memory disorders such as Alzheimer's disease, recent autobiographical memories are disproportionately vulnerable to loss, yet most traditional reminiscence therapies focus on remote past events. We present a case study examining whether a digital reminiscence intervention designed to support memory for recent experiences can improve episodic recall and psychosocial outcomes in neurodegenerative memory impairment. G.F., a 79-year-old man with early-stage dementia, completed an 11-week personalized intervention using HippoCamera, a neuroscience-based smartphone application that helps users generate and review multimodal memory cues from everyday events. Events that G.F. reviewed using HippoCamera were recalled with greater episodic detail than events that were recorded but not reviewed. Post-intervention, G.F. reported improvements in quality of life, life satisfaction, self-concept, and perceived episodic and spatial memory abilities, along with reduced depressive symptoms. Qualitative feedback revealed that the intervention helped G.F. regain confidence, re-engage socially, and feel more optimistic about the future. These findings suggest that digital interventions targeting memory for recent experiences - a domain often overlooked in traditional reminiscence therapy - may provide benefits to cognition and quality of life in the early stages of dementia. This work highlights the promise of HippoCamera as an accessible, neuroscience-informed tool to support memory and well-being in those experiencing memory loss.},
}

@article {pmid42323462,
year = {2026},
author = {Chen, Y and Wang, Z and Chen, H and Li, H and Zhang, Z and Cui, H and Li, S and , },
title = {Plasma p-Tau217 and Aβ42/Aβ40 mediate the association between minimal depressive symptoms and cognitive impairment.},
journal = {Journal of neurology},
volume = {273},
number = {7},
pages = {},
pmid = {42323462},
issn = {1432-1459},
support = {82471199//National Natural Science Foundation of China/ ; 82171582//National Natural Science Foundation of China/ ; },
mesh = {Humans ; *Amyloid beta-Peptides/blood ; *tau Proteins/blood ; *Cognitive Dysfunction/blood ; *Peptide Fragments/blood ; Female ; Male ; Biomarkers/blood ; *Depression/blood ; Aged ; Aged, 80 and over ; Glial Fibrillary Acidic Protein/blood ; Phosphorylation ; Neurofilament Proteins/blood ; Alzheimer Disease/blood ; },
abstract = {Depression is a recognized risk factor and potential prodromal feature of Alzheimer's disease (AD). While associations between depressive symptoms and AD pathology have been observed using cerebrospinal fluid (CSF) and PET imaging, it remains unclear whether these relationships can be captured by accessible plasma biomarkers, particularly the highly specific phosphorylated tau-217 (p-Tau217). We analyzed 615 participants from Alzheimer's disease Neuroimaging Initiative (ADNI) cohort, of whom 374 had minimal depressive symptoms (MDS). Plasma biomarkers included phosphorylated tau-217 (p-Tau217), amyloid-β 42/40 ratio (Aβ42/Aβ40), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP). Linear regression models and mediation analyses were employed to examine associations between MDS, plasma biomarkers (p-Tau217, Aβ42/Aβ40, NfL, and GFAP), and cognitive impairment, with adjustments for age, sex, and APOE ε4 carrier status. Participants with MDS demonstrated significantly elevated plasma p-Tau217 levels (mean difference = 0.105, 95% CI [0.046, 0.163]; P < 0.001) and reduced Aβ42/Aβ40 (mean difference = -0.024, 95% CI [-0.041, -0.006]; P = 0.007) compared with those without MDS. These associations were primarily observed in non-demented individuals and influenced by age, sex, and APOE ε4 status. In mediation analyses, plasma p-Tau217 accounted for 41.57%-42.18% of the association between MDS and cognitive impairment, while Aβ42/Aβ40 mediated 7.13%-8.45% of this relationship. Plasma biomarkers of p-Tau217 and Aβ42/Aβ40 were associated with early depressive symptoms and mediate their associations with cognitive impairment. These findings identify plasma p-Tau217 as a key mediator linking MDS to cognitive impairment, extending evidence from CSF to accessible blood-based biomarkers. This highlights the value of monitoring plasma p-Tau217 and Aβ42/Aβ40 to unravel the pathological basis of depressive symptoms in early AD.},
}

Humans
*Amyloid beta-Peptides/blood
*tau Proteins/blood
*Cognitive Dysfunction/blood
*Peptide Fragments/blood
Female
Male
Biomarkers/blood
*Depression/blood
Aged
Aged, 80 and over
Glial Fibrillary Acidic Protein/blood
Phosphorylation
Neurofilament Proteins/blood
Alzheimer Disease/blood

@article {pmid42323643,
year = {2026},
author = {Bouveret, Z and Pruvost, L and Trédan, O and Le Romancer, M and Poulard, C},
title = {How post-translational modifications impact glucocorticoid receptor function in human pathologies.},
journal = {Cell communication and signaling : CCS},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12964-026-03015-7},
pmid = {42323643},
issn = {1478-811X},
support = {ANR-22-CE13-0001-01//Agence Nationale de la Recherche/ ; },
abstract = {Glucocorticoid receptor (GR) is a member of the nuclear hormone receptor family, which acts as a transcription factor when bound by glucocorticoid (GC) ligands. GR is expressed in nearly all tissue types and regulates essential processes such as inflammation, immune regulation and metabolism. Given its ubiquitous role, GR has frequently been associated with a wide range of illnesses, particularly in the fields of allergy, pulmonary, dermatology, rheumatology, or ophthalmology. It was reported that GCs either contribute to their development or serve as part of their treatment, making them the most prescribed drugs worldwide. GR activity and signaling is finely regulated by a network of post-translational modifications (PTMs). Indeed, PTMs can alter GR behavior and function by modifying its localization, stability, interaction with other proteins and transcriptional activity. Aside from the well-characterized phosphorylation events, additional PTMs are implicated in GR activity and their dysregulation has been described in various diseases. This review provides an integrated overview of current knowledge on GR PTMs, highlighting both mechanistic insights and their relevance in disease. We will present how aberrant PTMs contribute to extremely prevalent diseases, such as cancer, chronic inflammatory diseases, Alzheimer's disease and other neurological diseases. Special attention will be given to the specific readers of these PTMs and to the enzymes catalyzing these modifications, as they represent promising therapeutic targets.},
}

@article {pmid42323655,
year = {2026},
author = {Monteverdi, A and Cotta Ramusino, M and Conca, F and Augello, A and Totaro, C and Grasso, PA and Castelnovo, A and Lorenzi, RM and Terzaghi, M and Farina, LM and Costa, A and Pichiecchio, A and Cappa, SF and Gandini Wheeler-Kingshott, C and Palesi, F and D'Angelo, E},
title = {Virtual brain and electroencephalography explain the variance of memory alterations in mild cognitive impairment.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02114-4},
pmid = {42323655},
issn = {1758-9193},
abstract = {BACKGROUND: Mild Cognitive Impairment (MCI) is a heterogeneous clinical condition characterized by a wide spectrum of cognitive and behavioural manifestations. Despite numerous studies, the link between neuropsychological performance and pathophysiological signatures of the disease-including Aβ and tau accumulation along with altered excitation/inhibition (E/I) balance and brain rhythms-remains elusive.

METHODS: Here Aβ/tau biomarkers were used to distinguish positive (MCI[+]- prodromal Alzheimer's disease) and negative (MCI[-]) subjects in a cohort of 30 MCI patients (18 MCI[+] and 12 MCI[-]). Virtual brain models based on high-field magnetic resonance imaging data were then developed to determine the inter-node coupling and E/I profile in resting-state networks, while node spectral information was obtained from source analysis of high-density electroencephalography (HD-EEG). Finally, virtual brains and HD-EEG parameters, creating brain digital twins of individual subjects, were correlated with cognitive performance.

RESULTS: While virtual brain simulations did not reveal E/I differences between MCI[+] and MCI[-], a positive correlation emerged between synaptic parameters of the limbic network and verbal episodic memory for both groups. EEG power spectral density revealed a lower high-frequency/low-frequency ratio in MCI[+] largely due to a reduced alpha band in the default mode, limbic, attention, frontoparietal, visual and somatomotor networks. A strong correlation emerged between multimodal parameters and memory functions, supporting that brain digital twin simulations can effectively explain the variability of neuropsychological performance in MCI patients beyond the sensitivity of individual techniques alone. In particular, the combination of HD-EEG and virtual brain parameters explained more than 90% of variance for episodic memory patients' scores, confirming the compound origin of memory performance involving network specific E/I levels and electroencephalographic activity acting in concert.

CONCLUSIONS: This multimodal and multiparametric analysis combining virtual brain modelling with HD-EEG and molecular data enhances the stratification of MCI patients and could be used to develop digital biomarkers of progression to dementia, opening new perspectives for personalized prognosis and treatment.},
}

@article {pmid42323731,
year = {2026},
author = {Domingo, J and Alves, A and Sanders, J},
title = {Evaluating the Use of Anxiety Patient-Reported Outcome Measures (PROMs) in Dementia Clinical Trials: A Systematic Review.},
journal = {Health expectations : an international journal of public participation in health care and health policy},
volume = {29},
number = {3},
pages = {e70736},
pmid = {42323731},
issn = {1369-7625},
mesh = {Humans ; *Patient Reported Outcome Measures ; *Dementia/psychology ; *Anxiety/diagnosis ; Randomized Controlled Trials as Topic ; Quality of Life ; *Clinical Trials as Topic ; Female ; },
abstract = {UNLABELLED: Anxiety is a common but underdetected or underdiagnosed symptom in dementia, affecting quality of life and care outcomes. Clinical trials are essential for informing effective management, yet the use of patient-reported outcome measures (PROMs) in dementia trials remains unclear. This review examined how validated PROMs are used to assess anxiety in dementia trials, including measurement tools, methods, demographic representation and evidence gaps.

METHODS: A systematic review was conducted following PRISMA and Cochrane Handbook guidance, with protocol registration on PROSPERO (CRD42025649920). Randomised controlled trials published between January 2015 and February 2025 were included if they assessed anxiety in mild to moderate dementia using validated PROMs within pharmacological or non-pharmacological interventions. Searches were conducted across MEDLINE, Embase, PsycINFO, Cochrane Library and ClinicalTrials.gov, supplemented by citation tracking. Two reviewers independently undertook study selection, data extraction and risk of bias assessment. Due to heterogeneity, findings were narratively synthesised.

RESULTS: Of 2328 records screened, 29 trials (n = 5697) met inclusion criteria. While 93.1% used validated anxiety measurement tools, only 44.4% employed PROMs, most frequently the Hospital Anxiety and Depression Scale, mainly in non-pharmacological trials. Women and individuals of White ethnicity were overrepresented, and no studies examined PROM effectiveness by sex and ethnicity. Most trials showed moderate to high risk of bias, and evidence was confined to high-income countries.

CONCLUSIONS: Anxiety outcomes in dementia trials remain largely proxy-reported. Existing anxiety PROMs are generic and unvalidated for dementia populations. There is a critical need for dementia-specific, culturally sensitive anxiety PROMs, improved demographic reporting and integration of anxiety assessment within dementia core outcome sets.

Feedback from research participants in dementia studies, who reported experiencing anxiety, motivated this systematic review. Patient and public involvement was examined across all included studies. The lack of validated dementia-specific anxiety PROMs identified in this review highlights a broader gap in co-produced outcome development within dementia research. These findings emphasise the need for meaningful involvement of people living with dementia and care partners in the development, validation and cultural adaptation of anxiety PROMs to ensure that trial outcomes are relevant, acceptable and representative.},
}

Humans
*Patient Reported Outcome Measures
*Dementia/psychology
*Anxiety/diagnosis
Randomized Controlled Trials as Topic
Quality of Life
*Clinical Trials as Topic
Female

@article {pmid42323822,
year = {2026},
author = {Pan, JP and Zhang, J and Wang, PJ and Chen, G and Fang, EF},
title = {Mitophagy mitigates tau acetylation via the ULK1-NAD[+]/SIRT1 axis in Alzheimer's disease.},
journal = {Autophagy},
volume = {},
number = {},
pages = {1-3},
doi = {10.1080/15548627.2026.2689031},
pmid = {42323822},
issn = {1554-8635},
abstract = {Autophagy preserves neuronal integrity by clearing damaged proteins and other subcellular components, yet it declines with age and exacerbates in Alzheimer's disease (AD). Although autophagy reduces tauopathy, whether it can proactively restrict early tau pathology via post-translational modifications (PTMs) has remained unclear. In a recent paper, we have identified a mitophagy-based metabolic signaling mechanism linking the autophagy-initiating kinase Unc-51-like autophagy activating kinase 1 (ULK1) to the inhibition of pathogenic tau acetylation via the ULK1-NAD[+]/SIRT1 axis. Analyses of human biofluidic to postmortem and transcriptomic data reveal an age-associated decline of ULK1; this situation gets worse in AD with the extent of ULK1 reduction positively correlates with Tau-based Braak stage progression, consistent with a bidirectional vicious cycle in which pathological tau disrupts mitochondrial homeostasis and impairs autophagy. Restoring ULK1-dependent mitophagy breaks this cycle in the upstream: in the hTau.P301S mice, ULK1 overexpression reduces ac‑tauK174 leading to reduced tau pathology and improved cognition. Mechanistically, ULK1 activates PINK1- and FUNDC1- as well as AMBRA1-dependent mitophagy to eliminate damaged mitochondria, restore bioenergetics, and elevate intracellular NAD[+], which activates the deacetylase SIRT1 to directly deacetylate tau at Lys174. Pharmacological ULK1 activation with a small molecule Rac‑BL‑918 phenocopies these protective effects in a mitophagy- and SIRT1-dependent manner. Collectively, our recent findings position mitophagy as a metabolic signaling hub that couples mitochondrial turnover to NAD[+]/SIRT1 activity to shape neuronal tau PTMs, supporting ULK1-mitophagy activation as an upstream strategy to limit tauopathy before overt aggregation.},
}

@article {pmid42324021,
year = {2026},
author = {Yang, LL and Luo, YX and Song, D and Liu, N and Gong, LH and Heng, T and Zhou, XH and Li, YX and Chen, JH and Song, ZX and Li, Y and Wang, YL and Bai, CC and He, R and Hu, P and Zhou, Y and Jia, GW and Yao, XQ},
title = {Physical exercise mitigates amyloid beta-driven muscle degeneration in Alzheimer's disease.},
journal = {Journal of advanced research},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jare.2026.06.018},
pmid = {42324021},
issn = {2090-1224},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is increasingly recognized as a systemic disorder, with skeletal muscle dysfunction contributing substantially to frailty and functional decline. Although amyloid-β (Aβ) has been detected in peripheral tissues, including skeletal muscle, how it drives muscle degeneration and whether exercise can counteract this process remain to be elucidated.

OBJECTIVES: This study aimed to define the molecular mechanisms underlying Aβ-induced skeletal muscle degeneration in AD and assess the potential of high-intensity interval training (HIIT) to alleviate muscle dysfunction and related pathology.

METHODS: We combined a small-scale exploratory clinical cohort with the 5 × FAD mouse model, integrating transcriptomic and metabolomic profiling with in vitro and in vivo functional assays to dissect Aβ-induced muscle pathology and the protective mechanisms of HIIT.

RESULTS: AD patients in the exploratory cohort showed a trend toward reduced handgrip strength, mirroring the progressive muscle weakness, myofiber atrophy, and intramuscular Aβ accumulation observed in 5 × FAD mice. Mechanistically, Aβ activated RAGE/NF-κB signaling, driving inflammation and oxidative stress in myofibers. HIIT reversed these pathological changes and concomitantly lowered Aβ levels. Transcriptomic profiling identified fibroblast growth factor 10 (FGF10) as a key exercise-induced mediator: FGF10 activated the FGFR2-AKT-ADAM10 axis to promote RAGE ectodomain shedding, generating soluble RAGE that suppressed Aβ-mediated inflammatory and injury signaling.

CONCLUSION: Our findings define an Aβ-RAGE axis driving AD-associated muscle degeneration and reveal an exercise-responsive FGF10-RAGE protective pathway, reframing AD as a brain-muscle axis disorder and highlighting FGF10 as a promising target for systemic therapeutic intervention.},
}

@article {pmid42324031,
year = {2026},
author = {Donepudi, K and Eadha, S and Rodarte, D and Sharma, B and Kumar, S},
title = {Cell-Specific MicroRNA Networks Orchestrate the Pathogenesis of Alzheimer's Disease.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103211},
doi = {10.1016/j.arr.2026.103211},
pmid = {42324031},
issn = {1872-9649},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by extracellular amyloid-β (Aβ) plaques, intracellular neurofibrillary tangles of hyperphosphorylated tau, synaptic dysfunction, and chronic neuroinflammation. AD pathogenesis involves multiple central nervous system (CNS) cell types-including neurons, astrocytes, microglia, and oligodendrocytes, and, less prominently, neural stem cells (NSCs), ependymal cells, and endothelial cells-which undergo coordinated but cell-type-specific pathological changes. These include neuronal loss, reactive gliosis, impaired myelin maintenance, reduced neurogenesis, and blood-brain barrier (BBB) dysfunction. MicroRNAs (miRNAs), the small non-coding RNAs that regulate post-transcriptional gene expression, have emerged as key modulators of these cell-specific processes and are consistently dysregulated in AD. Across AD-vulnerable brain regions and CNS cell types, miRNAs influence amyloid and tau biology, synaptic resilience, glial activation states, myelin structure, neurogenic potential, and vascular homeostasis. Dysregulated miRNAs also act across cell types through extracellular vesicle (EV) transfer, amplifying or mitigating amyloidogenesis, tauopathy, neuroinflammation, and white-matter injury. This review provides a comprehensive, cell-type-specific analysis of miRNAs involved in AD, detailing their roles in neurons, astrocytes, microglia, oligodendrocytes, NSCs, ependymal cells, and endothelial cells. We highlight common miRNAs that function across multiple CNS cell types and examine the potential of circulating and cerebrospinal fluid (CSF) miRNAs as minimally invasive biomarkers. Finally, we discuss therapeutic strategies aimed at restoring protective miRNAs or inhibiting pathogenic miRNAs, emphasizing the need for targeted interventions. By integrating pathways of miRNA dysregulation across CNS cell types, this review underscores the central role of miRNA networks in AD pathogenesis and the promise of precise, cell-specific miRNA modulation.},
}

@article {pmid42324052,
year = {2026},
author = {Tomyshev, A and Cherkasov, N and Panikratova, Y and Bozhko, O and Kolykhalov, I and Lebedeva, I},
title = {Structural MRI and mild behavioral impairment as complementary predictors of conversion from amnestic MCI to Alzheimer's disease.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2026.06.025},
pmid = {42324052},
issn = {1873-7544},
abstract = {Mild Behavioral Impairment (MBI) and amnestic Mild Cognitive Impairment (aMCI) are complementary early markers of Alzheimer's disease (AD), yet their combined neuroanatomical correlates and predictive value for conversion remain underexplored. In this study of 72 community-dwelling older adults (49 aMCI, 23 healthy controls), we retrospectively classified aMCI participants into non-converters (aMCI-NC, n = 31) and converters (aMCI-C, n = 18) based on longitudinal follow-up. Baseline structural MRI revealed that aMCI-C patients exhibited bilateral atrophy in the hippocampus, amygdala, and nucleus accumbens, alongside cortical thinning in temporal-limbic and parietal regions compared to both aMCI-NC and controls. Notably, in the non-converter group, MBI-Checklist scores correlated negatively with temporal-parietal cortical thickness, while Montreal Cognitive Assessment scores correlated positively with subcortical volumes. Cox proportional-hazards regression with supervised principal component analysis revealed that while MBI symptoms alone did not independently predict conversion, they demonstrated significant conditional predictive value when combined with structural MRI markers. Model robustness was confirmed via rigorous internal validation using nested leave-one-out cross-validation with bootstrap aggregation. Furthermore, time-varying analysis indicated that the protective effect of larger medial temporal-limbic subcortical volumes was strong initially but attenuated over follow-up, consistent with a depletable brain reserve. Given the limited conversion events, which constrained statistical power for smaller independent effects and restricted model complexity, replication in larger prospective cohorts is warranted. Despite this limitation, our results underscore the conditional utility of integrating MBI assessment with structural MRI to enhance early detection and risk stratification in memory clinic settings.},
}

@article {pmid42324246,
year = {2026},
author = {Zammit, AR and Yu, L and Poole, VN and Tasaki, S and Vialle, R and Arfanakis, K and Schneider, JA and Petyuk, VA and De Jager, PL and Kaddurah-Daouk, R and Iturria-Medina, Y and Bennett, DA},
title = {Associations of stable psychological traits with multi-omic subtypes of Alzheimer's dementia.},
journal = {Translational psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41398-026-04195-z},
pmid = {42324246},
issn = {2158-3188},
support = {R01AG17917//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG015819//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG17917//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; P30AG10161//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01 AG064233/AG/NIA NIH HHS/United States ; RF1 NS139975/NS/NINDS NIH HHS/United States ; P30 AG072975/AG/NIA NIH HHS/United States ; R01AG17917//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; P30AG10161//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG015819//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; U01AG61356//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG17917//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; P30AG10161//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; P30AG72975//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG015819//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; U01AG61356//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG17917//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; P30AG10161//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; P30AG72975//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG015819//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; U01AG61356//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; },
abstract = {Psychological traits reflecting neuroticism, depressive symptoms, loneliness, and purpose in life are risk factors of AD dementia; however, the underlying biological mechanisms remain largely unknown. Using multi-omic data from the dorsolateral prefrontal cortex of 822 decedents in the Religious Orders Study and Rush Memory and Aging Project, we utilized a previously derived multi-omic brain molecular pseudotime representing molecular distance from no cognitive impairment (NCI) to AD dementia, and three distinct multi-omic brain molecular subtypes of AD dementia. We first confirmed generalizability of pseudotime and subtypes in two independent samples. We then annotated the subtypes, and explored whether they differed by neuropathologic burden, brain morphology or genetic risk, and found that while these indices differentiated all subtypes from NCI they did not differentiate amongst them. Finally, we tested for differential associations between the psychological traits and the subtypes, adjusting first for age, sex, education, and time to death, and then additionally for 9 common AD and Related Dementias pathologies. We found that in fully adjusted models, neuroticism, loneliness and purpose in life remained differentially associated with some AD subtypes relative to NCI. Our results are consistent with a two-stage model in which (i) upstream genetic risk influences overall disease liability, while (ii) intermediary psychological predispositions align more directly with subtype differentiation capturing AD-related heterogeneity not explained by neuropathology or brain atrophy. These results indicate that psychological risk factors may be associated with AD dementia via multi-omic molecular pathways, predominantly informed by metabolomic dysregulation, capturing heterogeneity not explained by neuropathology.},
}

@article {pmid42324333,
year = {2026},
author = {Lu, Y and Hammonds, SK and Fernandez-Quilez, A},
title = {Clinical pathways matter for multimodal deep learning in early Alzheimer's disease detection.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-57861-z},
pmid = {42324333},
issn = {2045-2322},
abstract = {Identifying individuals at risk of Alzheimer's disease (AD), particularly in the preclinical and early stages, remains challenging. Although deep learning approaches based on structural MRI show promise as a non-invasive biomarker, existing multimodal models require task-specific training and depend on biomarkers that are not routinely available in clinical practice. Here, we propose a zero-shot multimodal feature extraction framework based on SigLIP that combines structural MRI embeddings with text embeddings of routinely collected clinical variables for early AD risk stratification in individuals at preclinical or mild cognitive impairment (MCI) stages. We evaluated the approach in 416 individuals from the ADNI cohort (age: 72.73 ± 6.7). SigLIP was used without fine-tuning to extract MRI and clinical text embeddings, which were combined into multimodal representations for individual-level AD risk prediction within 4 years. We further compared the model performance in a single-visit and two-visit settings to assess the value of longitudinal information and framework scalability. In the 1-visit setting, combining MRI embeddings with MMSE, age, and sex achieved an AUC of 0.91 ± 0.02, showing higher performance than the CSF Aβ42-based model (AUC 0.73 ± 0.08) and MMSE-based model (AUC 0.85 ± 0.22). In the 2-visit setting, performance was maintained or improved, supporting the scalability of the approach to longitudinal data. These findings suggest that multimodal fusion of SigLIP-derived MRI features and routinely collected clinical variables may provide a practical and scalable strategy for early AD risk progression prediction without task-specific training.},
}

@article {pmid42324487,
year = {2026},
author = {Buée, L and Wildsmith, KR and Alladi, S and Bertucci, T and Boche, D and Bowles, KR and Boxer, A and Brummet, J and DeVos, SL and Diaz, K and Dreyer, AJ and Duff, K and Duran-Aniotz, C and Durrant, CS and Farrell, K and Fontana, IC and Franzmeier, N and Frost, B and Horie, K and Kaňovský, P and Kao, AW and Mahinrad, S and Malpetti, M and Morris, HR and Palleis, C and Petrucelli, L and Rexach, J and Reyderman, L and Rommel, A and Rowe, JB and Sanabria Bohórquez, SM and Sato, C and Schöll, M and Schneider, A and de Silva, R and Snyder, HM and VandeVrede, L and Varga, AW and Vogel, JW and Yeh, FL and Yoo, AS and Carrillo, MC},
title = {Emerging directions in tauopathy research.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {6},
pages = {e71431},
doi = {10.1002/alz.71431},
pmid = {42324487},
issn = {1552-5279},
support = {RT/ESG2005C//Alzheimer's Research UK/ ; ART/PG2006/4//Alzheimer's Research UK/ ; ARTEXT2010-1//Alzheimer's Research UK/ ; ARUK-EG2015A-4//Alzheimer's Research UK/ ; ARUK-PG2018A-012//Alzheimer's Research UK/ ; ARUK-RADF2021A-010//Alzheimer's Research UK/ ; MC_UU_00030/14//Medical Research Council UK/ ; MR/T033371/1//Medical Research Council UK/ ; G0501033//Medical Research Council UK/ ; UK DRI-4211//UK Dementia Research Institute/ ; //NIHR Applied Research Collaboration East of England/ ; AS-PG-21-006/ALZS_/Alzheimer's Society/United Kingdom ; //Fogarty International Center (FIC)/ ; R01AG057234//National Institutes of Health (NIH), National Institute on Aging (NIA)/ ; R01AG075775//National Institutes of Health (NIH), National Institute on Aging (NIA)/ ; R01AG21051//National Institutes of Health (NIH), National Institute on Aging (NIA)/ ; R01AG083799//National Institutes of Health (NIH), National Institute on Aging (NIA)/ ; R21AG081961//National Institutes of Health (NIH), National Institute on Aging (NIA)/ ; R01AG081394-01//National Institutes of Health (NIH), National Institute on Aging (NIA)/ ; R01AG078964//National Institutes of Health (NIH), National Institute on Aging (NIA)/ ; U01AG072464//National Institutes of Health (NIH), National Institute on Aging (NIA)/ ; K01AG070326//National Institutes of Health (NIH), National Institute on Aging (NIA)/ ; R01AG075802//National Institutes of Health (NIH), National Institute on Aging (NIA)/ ; R21AG091113//National Institutes of Health (NIH), National Institute on Aging (NIA)/ ; R01AG080609//National Institutes of Health (NIH), National Institute on Aging (NIA)/ ; R01AG066870//National Institutes of Health (NIH), National Institute on Aging (NIA)/ ; R01AG056682//National Institutes of Health (NIH), National Institute on Aging (NIA)/ ; R21AG088736//National Institutes of Health (NIH), National Institute on Aging (NIA)/ ; //Rainwater Charitable Foundation/ ; //Global Brain Health Institute/ ; 1210622//ANID/FONDECYT Regular/ ; 1250091//ANID/FONDECYT Regular/ ; 240065//ANID/FOVI/ ; 13240170//ANID/Proyecto Exploracion/ ; CARE-2025-0883490149//Wellcome Leap CARE Program/ ; 101236426//European Union / Horizon Europe/ ; A2026019S//BrightFocus Foundation/ ; 685-2023-06-Pathway//CurePSP/ ; //Eisai, Inc./ ; NW25-04-00194//AZV CR/ ; FNOL 0098892//Czech Republic for the Conceptual Development of a Research Organization/ ; NIHR 203312//National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre/ ; //PSP Association/ ; //Michael J Fox Foundation/ ; //CBD Solutions/ ; //Drake Foundation/ ; /PUK_/Parkinson's UK/United Kingdom ; //Cure Parkinson's Trust/ ; EXC2145SyNergy//Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)/ ; ID390857198//Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)/ ; //Thiemann Stiftung/ ; RF1NS144499//National Institutes of Health (NIH), National Institute of Neurological Disorders and Stroke (NINDS)/ ; RF1NS139972//National Institutes of Health (NIH), National Institute of Neurological Disorders and Stroke (NINDS)/ ; RF1NS128800//National Institutes of Health (NIH), National Institute of Neurological Disorders and Stroke (NINDS)/ ; 220258/WT_/Wellcome Trust/United Kingdom ; //Cambridge Centre for Parkinson-Plus/ ; KAW2014.0363//Wallenberg Centre for Molecular and Translational Medicine/ ; KAW2023.0371//Wallenberg Centre for Molecular and Translational Medicine/ ; 2017-02869//the Swedish Research Council/ ; 2021-02678//the Swedish Research Council/ ; 2021-06545//the Swedish Research Council/ ; 2023-06188//the Swedish Research Council/ ; 101132933//European Union's Horizon Europe research and innovation program/ ; 101112145//European Union's Horizon Europe research and innovation program/ ; RS-2023-00263612//National Research Foundation of Korea/ ; ALFGBG-813971//Swedish government and the County Councils/ ; ALFGBG-965326//Swedish government and the County Councils/ ; FO2021-0311//the Swedish Brain Foundation/ ; FO2024-0372//the Swedish Brain Foundation/ ; AF-1011738//Swedish Alzheimer Foundation/ ; //JM Dahl Foundation/ ; //Familjen Rönström's Foundation/ ; //Sahlgrenska Academy/ ; VGFOUREG-995510//Västra Götaland Region R&D/ ; //National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre/ ; FZK01EK2102A//German Federal Ministry of Education and Research/ ; PREPARE//German Federal Ministry of Education and Research/ ; FZK01GP2213A//German Federal Ministry of Education and Research/ ; EXC2151-39087304//Cluster of Excellence ImmunoSensation/ ; //Reta Lila Weston Trust for Medical Research/ ; //Merck Investigator Studies Program/ ; //Cure Alzheimer's Fund/ ; //Eisai WashU Research Exchange Program/ ; SG-20-725707/ALZ/Alzheimer's Association/United States ; AARGD-24-1310017;AARG-1027406/ALZ/Alzheimer's Association/United States ; 2018-AARG-589632/ALZ/Alzheimer's Association/United States ; //Innovation platforms, Sahlgrenska Science Park/ ; //Alzheimerfonden/ ; //Swedish government/ ; //Vetenskapsrådet/ ; //Knut och Alice Wallenbergs Stiftelse/ ; //Else Kröner-Fresenius-Stiftung/ ; //National Institute for Health and Care Research/ ; //Ministerstvo Zdravotnictví Ceské Republiky/ ; //Agentura Pro Zdravotnický Výzkum České Republiky/ ; //James Dyson Foundation/ ; //Tau Consortuim/Rainwater Charitable Trust/ ; //Eli Lilly and Company/ ; //PSPA/ ; //UCB/ ; },
mesh = {*Tauopathies/therapy/diagnosis/metabolism ; Humans ; *tau Proteins/metabolism ; Biomarkers ; *Biomedical Research/trends ; Animals ; },
abstract = {The Tau Global Conference 2025, hosted by the Alzheimer's Association, CurePSP, and the Rainwater Charitable Foundation, convened international experts from academia, industry, government, and philanthropy to explore advances and challenges in tauopathy research. The meeting highlighted progress across tau biology, including emerging models of tau regulation, degradation, and propagation; advances in biomarker development for the diagnosis and staging of tauopathies; and evolving therapeutic strategies targeting diverse aspects of tau pathophysiology. Discussions also emphasized the importance of cross-sector collaboration, and global initiatives to address disparities in tau research. This report synthesizes key insights from the conference and underscores the critical role of interdisciplinary, biomarker-driven, and globally inclusive approaches in accelerating the translation of tau research into effective clinical applications.},
}

*Tauopathies/therapy/diagnosis/metabolism
Humans
*tau Proteins/metabolism
Biomarkers
*Biomedical Research/trends
Animals

@article {pmid42324743,
year = {2026},
author = {Sakagami, S and Yoshida, Y and Uemura, S and Kumamoto, T and Tsukamoto, R and Nishi, T and Kawano, S and Fukuoka, K and Ino, H and Hamamura, K and Ohdo, S and Matsunaga, N},
title = {Benzbromarone as a Novel Candidate for Preventing Alzheimer's Disease: Evidence From Real-World Data Screening and in Vitro Validation.},
journal = {Clinical and translational science},
volume = {19},
number = {7},
pages = {e70650},
doi = {10.1111/cts.70650},
pmid = {42324743},
issn = {1752-8062},
mesh = {Humans ; *Benzbromarone/therapeutic use/pharmacology ; *Alzheimer Disease/prevention & control/epidemiology ; *Drug Repositioning ; Female ; Male ; Japan/epidemiology ; *Uricosuric Agents/pharmacology/therapeutic use ; Aged ; Amyloid beta-Peptides/metabolism ; Aged, 80 and over ; Incidence ; Cell Line, Tumor ; },
abstract = {Drug development for Alzheimer's disease (AD) remains challenging, with only a 0.4% success rate from Phase I trials to regulatory approval. Drug repositioning leverages existing approved drugs to identify promising drug alternatives, particularly when combined with real-world data (RWD) and target trial emulation. In this study, we comprehensively screened 1,241 approved drugs using a large-scale Japanese claims database (n = 2,090,465; 2005-2023). We identified patients newly prescribed a study drug and applied an active-comparator, new-user design. We used propensity score-based inverse probability of treatment weighting (IPTW) to balance the covariates. The primary outcome was incident AD, defined using ICD-10 codes (F00 and G30). We estimated cumulative incidence using IPTW-adjusted Kaplan-Meier analysis and Cox proportional hazards models and conducted sensitivity analyses using Fine-Gray competing risk models, empirical calibration with negative control outcomes, and E-value estimation. We performed in vitro validation using Aβ-Tet-ON SH-SY5Y cells and quantified Aβ expression using western blotting. Benzbromarone, a uricosuric agent, was associated with a decreased risk of AD onset (adjusted HR: 0.54, 95% CI: 0.41-0.71, p < 0.05 post-FDR correction); this association remained robust across sensitivity analyses. In vitro, benzbromarone reduced Aβ protein expression in SH-SY5Y cells in a dose-dependent manner, even following transcriptional blockade, suggesting a posttranscriptional regulatory mechanism. In conclusion, using a combined approach of RWD-based pharmacoepidemiology and in vitro validation, we identified benzbromarone as a novel candidate potentially associated with reduced AD risk. Our findings highlight the potential of drug repositioning strategies to accelerate AD drug discovery, promoting further mechanistic and clinical investigations.},
}

Humans
*Benzbromarone/therapeutic use/pharmacology
*Alzheimer Disease/prevention & control/epidemiology
*Drug Repositioning
Female
Male
Japan/epidemiology
*Uricosuric Agents/pharmacology/therapeutic use
Aged
Amyloid beta-Peptides/metabolism
Aged, 80 and over
Incidence
Cell Line, Tumor

@article {pmid42324842,
year = {2026},
author = {Ugale, V and Sharon, N and Salunkhe, C and Salunkhe, J and Lokwani, D and Patil, K and Reddy, PN and Kulkarni, P},
title = {Naphthalene-4H-Chromene Molecular Hybrids as Dual Cholinesterase Inhibitors for the Treatment of Alzheimer's Disease.},
journal = {Drug development research},
volume = {87},
number = {5},
pages = {e70338},
doi = {10.1002/ddr.70338},
pmid = {42324842},
issn = {1098-2299},
support = {RGSTC/File-2024/DPP-309/CR-20/332//Rajiv Gandhi Science and Technology Commission/ ; TAR/2021/000140//Department of Science and Technology (DST)-Science and Engineering Research Board (SERB)/ ; CRG/2022/004365//Department of Science and Technology (DST)-Science and Engineering Research Board (SERB)/ ; KBCNMU/RGSTC/Sanction Order/199//Kavayitri Bahinabai Chaudhari North Maharashtra University (KBCNMU)/ ; },
mesh = {*Cholinesterase Inhibitors/pharmacology/chemistry/therapeutic use/chemical synthesis ; Animals ; *Alzheimer Disease/drug therapy ; Mice ; *Naphthalenes/chemistry/pharmacology ; *Benzopyrans/chemistry/pharmacology ; Acetylcholinesterase/metabolism ; Butyrylcholinesterase/metabolism ; Molecular Docking Simulation ; Male ; Humans ; Scopolamine ; Cell Line ; Structure-Activity Relationship ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline associated with cholinergic dysfunction. Herein, we have designed and synthesized series of 4-(naphthalen-1-yl)-4H-chromene derivatives 4(a-n) by a one-pot three-component reaction with adequate synthetic yield and purity. Naphthalene-chromene hybrids were synthesized by formation of two C─C bonds and one C─O bond in a single synthetic step. All synthesized compounds were tested for safety and efficacy using in vitro and in vivo studies. Compounds were found devoid of cytotoxicity in BV-2 cells. Most of the synthesized compounds have shown moderate to good inhibitory activity against cholinesterase enzymes. These compounds were found to be more selective towards acetylcholinesterase (AChE) compared to butyrylcholinesterase (BuChE). Compound 4 m has shown highest inhibitory potency against AChE (AChE, IC50 = 1.08 µM; BuChE, IC50 = 82.59 µM). The prototype compound (4 m) from in-vitro screening was found to be safe in acute oral toxicity followed by histopathological analysis. Compound 4 m was evaluated for in vivo efficacy in scopolamine-induced cognitive impairment model in mice. It significantly reversed the cognitive deficit in neurobehavioral tests. Pre-treatment with 4 m have balanced key biochemical markers involved in the oxidative stress and cognitive functions. The compound 4 m alleviated neuronal tissue damage caused by scopolamine as indicated in the histological study. Molecular docking analysis also reconfirmed the binding affinity of 4 m at cholinesterase enzymes. Taken together, these findings supported the emergence of 4 m as a potential cholinesterase inhibitor for the treatment of AD.},
}

*Cholinesterase Inhibitors/pharmacology/chemistry/therapeutic use/chemical synthesis
Animals
*Alzheimer Disease/drug therapy
Mice
*Naphthalenes/chemistry/pharmacology
*Benzopyrans/chemistry/pharmacology
Acetylcholinesterase/metabolism
Butyrylcholinesterase/metabolism
Molecular Docking Simulation
Male
Humans
Scopolamine
Cell Line
Structure-Activity Relationship

@article {pmid42324916,
year = {2026},
author = {Yin, J and Srivastava, S and Tang, X and Galbraith, C and Uchenunu, O and Miller, J and Liu, Y and Crescenzi, I and Kiyota, T and Kurinov, I and Costa-Mattioli, M and Laufer, R and Aman, A and Rottapel, R and Ramnauth, J and Haakonsen, DL and Uehling, DE and Sicheri, F},
title = {Structural Transformation of a BRAF Inhibitor into a Selective PKR Inhibitor.},
journal = {Journal of medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jmedchem.5c03664},
pmid = {42324916},
issn = {1520-4804},
abstract = {The RNA-dependent protein kinase PKR regulates responses to viral infection and has emerging roles in memory formation. Inhibition of PKR enhances long-term memory in mice and reverses cognitive decline in models of aging and Alzheimer's disease. However, existing PKR inhibitors have poor selectivity and pharmacokinetic properties, limiting therapeutic development. Here, we describe the transformation of dabrafenib, an FDA-approved oncogenic BRAF inhibitor, into a selective PKR inhibitor. Dabrafenib was identified by screening as a promising PKR lead with similar potency against BRAF and PKR. Guided by X-ray cocrystal structures, we introduced modifications that removed BRAF while retaining PKR inhibition. This optimization yielded OICR-403184, which shows markedly reduced BRAF activity, improved PKR selectivity (IC50 > 10,000 nM against BRAF vs IC50 = 263 nM against PKR in vitro), and minimal activity against related eIF2α kinases in cells. These findings establish OICR-403184 as a promising chemical starting point for further PKR inhibitor optimization.},
}

@article {pmid42324989,
year = {2026},
author = {Carriere, L and Minyo, M and Bass, D and Possin, KL and Samper-Ternent, R and Salinas, J and Deaner, N},
title = {Bridging the diagnostic gap: Expanding dementia care navigation for timely diagnosis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {6},
pages = {e71619},
doi = {10.1002/alz.71619},
pmid = {42324989},
issn = {1552-5279},
support = {/ALZ/Alzheimer's Association/United States ; },
mesh = {Humans ; *Dementia/diagnosis/therapy ; *Patient Navigation ; *Delayed Diagnosis/prevention & control ; Treatment Delay ; },
abstract = {Over half of dementia cases remain undiagnosed, with persistent disparities across racial, ethnic, and socioeconomic groups. Dementia care navigation (DCN) has demonstrated value in post-diagnosis settings. If implemented earlier, DCN could address diagnostic delays and care gaps. We define the diagnostic window as the period from initial symptom awareness through diagnosis and early care planning. Drawing on deliberations from the Alzheimer's Association Dementia Care Navigation Roundtable, we present a pre-diagnosis DCN framework organized across six domains and describe navigator roles across three phases: pre-evaluation, diagnostic assessment, and immediate post-diagnosis and transition. We address special considerations, including people without a care partner and those with unmet care needs. The framework complements federal initiatives such as the Guiding an Improved Dementia Experience (GUIDE) Model and the National Alzheimer's Project Act and identifies existing reimbursement pathways for pre-diagnostic navigation activities. Generating evidence to refine these models across diverse settings will be essential to inform policy action and system-level integration.},
}

Humans
*Dementia/diagnosis/therapy
*Patient Navigation
*Delayed Diagnosis/prevention & control
Treatment Delay

@article {pmid42325000,
year = {2026},
author = {Chen, Y and Duggan, MR and Timsina, J and Xu, Y and Western, D and Gong, K and Liu, M and Budde, J and Schindler, SE and Morris, JC and Holtzman, DM and Benzinger, TLS and Gordon, BA and Moqri, M and , and Ibanez, L and Walker, KA and Cruchaga, C and Ali, M},
title = {Blood-based proteomic signature of amyloidosis: identification of novel regulators of amyloid load.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {6},
pages = {e71611},
doi = {10.1002/alz.71611},
pmid = {42325000},
issn = {1552-5279},
support = {ZEN-22-848604/ALZ/Alzheimer's Association/United States ; R01AG044546//Foundation for the National Institutes of Health/ ; },
mesh = {Humans ; *Proteomics/methods ; *Amyloidosis/blood/diagnostic imaging ; *Alzheimer Disease/blood ; Biomarkers/blood ; Positron-Emission Tomography ; *Amyloid beta-Peptides/metabolism ; Female ; Male ; Aged ; Brain/diagnostic imaging/metabolism ; },
abstract = {INTRODUCTION: Cerebral amyloidosis is a defining feature of Alzheimer's disease (AD), yet the molecular heterogeneity among amyloidbeta-positive (Aβ+) individuals remains poorly defined. We aimed to map the proteomic correlates of cerebral amyloidosis and link them to clinical variability within Aβ+ individuals.

METHODS: We integrated quantitative amyloid PET with large-scale plasma proteomics (∼7000 proteins; SomaScan version 4.1) in Knight Alzheimer's Disease Research Center and Bio-Hermes cohorts (n = 1429). Proteome-wide association analyses identified proteins associated with amyloid load, followed by unsupervised clustering and pathway enrichment analyses.

RESULTS: We identified 454 amyloid-associated proteins, of which 54 replicated cross-cohort. A derived 54-protein proteomic score correlated with amyloid burden, AD biomarkers, and clinical severity. Pathway analyses of clinically distinct protein clusters revealed coordinated enrichment of intracellular signaling, immune, and proteostasis modules.

DISCUSSION: These findings delineate the circulating proteomic signature of cerebral amyloidosis and support plasma proteomics as a complementary approach to phosphorylated tau at threonine 217 and amyloid PET for biological stratification and characterization of disease heterogeneity in AD.},
}

Humans
*Proteomics/methods
*Amyloidosis/blood/diagnostic imaging
*Alzheimer Disease/blood
Biomarkers/blood
Positron-Emission Tomography
*Amyloid beta-Peptides/metabolism
Female
Male
Aged
Brain/diagnostic imaging/metabolism

@article {pmid42325001,
year = {2026},
author = {Yin, H and Deng, Y and Lu, Z and Jiang, Y and Zuo, C and Li, J and Guo, L and Ying, B and Battaglia, G and Tian, X and Gong, Q and , },
title = {Choroid plexus remodeling linked to impaired CSF-mediated clearance and Alzheimer's disease progression.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {6},
pages = {e71606},
doi = {10.1002/alz.71606},
pmid = {42325001},
issn = {1552-5279},
support = {ZYGD23007//1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University/ ; ZYYC24011//1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University/ ; },
mesh = {*Alzheimer Disease/cerebrospinal fluid/pathology/diagnostic imaging ; *Choroid Plexus/pathology/diagnostic imaging ; Animals ; Humans ; Disease Progression ; Positron-Emission Tomography ; Mice, Transgenic ; Mice ; Magnetic Resonance Imaging ; Male ; Female ; Aged ; Amyloid beta-Peptides/cerebrospinal fluid/metabolism ; Aged, 80 and over ; Diffusion Tensor Imaging ; tau Proteins/cerebrospinal fluid/metabolism ; Amyloid beta-Protein Precursor/genetics ; Biomarkers/cerebrospinal fluid ; Disease Models, Animal ; },
abstract = {INTRODUCTION: Impaired cerebrospinal fluid (CSF) -mediated clearance has been implicated in Alzheimer's disease (AD), but how choroid plexus (ChP) remodeling relates to these processes in vivo remains incompletely understood.

METHODS: In a large ADNI cohort, we integrated structural magnetic resonance imaging (MRI), amyloid/tau positron emission tomography (PET), and diffusion tensor imaging (DTI) -derived analysis along the perivascular space (ALPS) to characterize ChP changes and their associations with ventricular measures, glymphatic marker, CSF biomarkers, and cognition across diagnostic stages. Our experiments in APP/PS1 mice complemented human analyses.

RESULTS: ChP volume increased with disease stage, while PET signal decreased. Larger ChP volume was associated with ventricular enlargement, a lower ALPS index, higher cortical amyloid/tau burden, and worse cognitive performance. Glymphatic impairment partially mediated ChP effects on cognition and pathology. APP/PS1 mice recapitulated the key ChP and glymphatic MRI phenotypes observed in humans, alongside altered expression and localization of key proteins.

DISCUSSION: ChP remodeling linked to impaired CSF-mediated clearance, highlighting its role as an early diagnostic and therapeutic target.},
}

*Alzheimer Disease/cerebrospinal fluid/pathology/diagnostic imaging
*Choroid Plexus/pathology/diagnostic imaging
Animals
Humans
Disease Progression
Positron-Emission Tomography
Mice, Transgenic
Mice
Magnetic Resonance Imaging
Male
Female
Aged
Amyloid beta-Peptides/cerebrospinal fluid/metabolism
Aged, 80 and over
Diffusion Tensor Imaging
tau Proteins/cerebrospinal fluid/metabolism
Amyloid beta-Protein Precursor/genetics
Biomarkers/cerebrospinal fluid
Disease Models, Animal

@article {pmid42325010,
year = {2026},
author = {Perović, M and Phillips, NA and Einstein, G},
title = {Sex differences in the association of adverse childhood experiences with brain and cognition along a continuum of risk for Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {6},
pages = {e71612},
doi = {10.1002/alz.71612},
pmid = {42325010},
issn = {1552-5279},
support = {MFE-201012//Canadian Institutes of Health Research Postdoctoral Fellowship/ ; //Jacqueline Ford Gender and Health Fund/ ; //Wilfred and Joyce Posluns Chair in Women's Brain Health and Aging/ ; //Alzheimer's Society of Canada/ ; //Ontario Graduate Scholarship - International/ ; WJP-150643//Ontario Brain Institute/ ; CCNA 049-04//Consortium canadien en neurodégénérescence associée au vieillissement/ ; CNA-163902//Consortium canadien en neurodégénérescence associée au vieillissement/ ; },
mesh = {Humans ; Female ; *Alzheimer Disease/psychology/pathology/diagnostic imaging ; Male ; *Adverse Childhood Experiences ; *Sex Characteristics ; *Cognitive Dysfunction/psychology/pathology ; Aged ; *Brain/pathology/diagnostic imaging ; Magnetic Resonance Imaging ; *Cognition/physiology ; Risk Factors ; Aged, 80 and over ; Neuropsychological Tests ; Canada ; Prefrontal Cortex/pathology ; },
abstract = {INTRODUCTION: Women make up two-thirds of people with Alzheimer's disease (AD). Research has focused on biological explanations for this sex difference, while contributions of psychosocial risk factors are less well understood.

METHODS: We examined sex differences in the effects of adverse childhood experiences (ACEs) on late-life cognition in groups along a continuum of AD risk: cognitively unimpaired controls (CU; n = 128), subjective cognitive decline (SCD; n = 113), mild cognitive impairment (MCI; n = 241), and AD (n = 77), from the Canadian Consortium on Neurodegeneration in Aging Comprehensive Assessment of Neurodegeneration and Dementia (COMPASS-ND) study.

RESULTS: Women reported more ACEs than men. There were negative associations between ACEs and hippocampal and prefrontal cortical volumes in CU men and prefrontal volumes in men with SCD. In MCI, ACEs were linked to poorer executive function and associative memory in women. No ACE-related effects were found in AD.

DISCUSSION: ACEs may have enduring effects on late-life cognition that differ between men and women and vary by cognitive status.},
}

Humans
Female
*Alzheimer Disease/psychology/pathology/diagnostic imaging
Male
*Adverse Childhood Experiences
*Sex Characteristics
*Cognitive Dysfunction/psychology/pathology
Aged
*Brain/pathology/diagnostic imaging
Magnetic Resonance Imaging
*Cognition/physiology
Risk Factors
Aged, 80 and over
Neuropsychological Tests
Canada
Prefrontal Cortex/pathology

@article {pmid42325211,
year = {2026},
author = {Laham, MS and Ackerman-Berrier, MS and Alam, F and Turner, S and Velma, GR and Penton, C and Musku, SR and Rana, M and Thulasingam, S and Annadurai, A and Sulaiman, MI and Ma, N and Thatcher, GRJ},
title = {Exploration of precision coregulator TR-FRET identifies diverse signatures for LXR ligands relevant to discovery of nonlipogenic ABCA1 inducers.},
journal = {eLife},
volume = {14},
number = {},
pages = {},
doi = {10.7554/eLife.109146},
pmid = {42325211},
issn = {2050-084X},
support = {T32GM008804/NH/NIH HHS/United States ; U01AG076450/NH/NIH HHS/United States ; },
mesh = {*Liver X Receptors/metabolism/agonists ; Humans ; *ATP Binding Cassette Transporter 1/metabolism ; Ligands ; Fluorescence Resonance Energy Transfer/methods ; },
abstract = {APOE4, the major genetic risk factor for Alzheimer's disease (AD), and ATP-binding cassette-A1 (ABCA1), required for lipidation of APOE are gene products of the liver X receptor (LXR) receptor. LXR agonists have been validated in animal models as therapeutics for AD, atherosclerosis, and many other diseases. Clinical progress has been thwarted by unwanted hepatic lipogenesis. Structurally diverse LXR ligands were profiled in coregulator TR-FRET (CRT) assays analyzing ligand-induced coactivator recruitment, coactivator selectivity, corepressor dissociation, and LXR isoform selectivity. A multiplex CRT assay was developed to measure synchronous ligand-induced displacement of corepressor by coactivator. Potency for coactivator recruitment to LXRβ correlated with induction of ABCA1 in human astrocytoma cells. Correlation with lipogenic activation of sterol response element (SRE) in hepatocarcinoma cells, was more complex. CRT response was diverse revealing ligands with theoretical full agonist, partial agonist, antagonist, inverse agonist, and other signatures within the same chemical series, suggesting the scope for precision CRT to guide nonlipogenic LXR agonist design.},
}

*Liver X Receptors/metabolism/agonists
Humans
*ATP Binding Cassette Transporter 1/metabolism
Ligands
Fluorescence Resonance Energy Transfer/methods

@article {pmid42325223,
year = {2026},
author = {Thia, BWQ and Tan, DYZ and Wong, BWX and Shen, L and Gong, L and Ling, LH and Chen, CL and Yong, EL},
title = {Indices of Arterial Stiffness and the Alzheimer's Disease Biomarker, p-tau217, in Non-Demented Midlife Women.},
journal = {Pulse (Basel, Switzerland)},
volume = {14},
number = {1},
pages = {78-92},
pmid = {42325223},
issn = {2235-8676},
abstract = {INTRODUCTION: The association between indices of arterial stiffness and/or pressure wave reflection with Alzheimer disease amyloid-β accumulation and tau pathology in the brain is unclear. Deficiency of estrogen post-menopause may be an important contributor to changes in these indices to affect Alzheimer's disease progression. We aimed to assess the associations between indices of arterial stiffness and/or pressure wave reflection and the Alzheimer's disease blood biomarker, p-tau217, in midlife women without dementia.

METHODS: This cross-sectional analysis of participants from the Integrated Women's Health Program (IWHP) enrolled community-dwelling midlife women without dementia attending routine health screening at the National University Hospital in Singapore. Fasted blood p-tau217 was measured using the Simoa® ALZpath p-tau217 Advantage PLUS (Quanterix, MA, USA). Aortic augmentation index (AIx) and reflection index (RI) were obtained from peripheral arterial pressure waveforms and cardio-ankle vascular index (CAVI) measured using pressure cuffs on the extremities and a phonocardiogram. Multivariable linear regression was used to examine the independent associations between indices of arterial stiffness and serum levels of p-tau217.

RESULTS: Among 871 participants (mean age: 62.80 ± 6.02 years), every SD increase in AIx and RI scores was both associated with 0.010 pg/mL (95% CI: 0.003-0.017, p = 0.004) higher blood p-tau217 levels after adjustment for age, employment status, BMI, mild cognitive impairment, hypertension, cholesterol-HDL ratio, renal function, and ApoE4 carrier status. With natural logarithmic transformed p-tau217, RI remained significantly associated with ln(p-tau217), β = 0.026 (0.007, 0.045), p = 0.007, after covariate adjustment. For AIx, the association was attenuated but remained directionally consistent. Trends for the association between CAVI and blood p-tau217 level were not statistically significant after adjustment for covariates.

CONCLUSION: Increases in indices of arterial stiffness and pressure wave reflection were associated with higher blood p-tau217 levels in community-dwelling midlife women without dementia. These indices may be markers of risk for tau-related pathologies in the brain.},
}

@article {pmid42325225,
year = {2026},
author = {Mukherjee, D and Raghul Kannan, S and Tamizhselvi, R},
title = {N-terminal modifications as fate switches in neurodegeneration: a mechanistic review.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1809812},
pmid = {42325225},
issn = {1663-4365},
abstract = {The accumulation of aberrant proteins or their impaired clearance leads to neurodegenerative diseases (NDs). The protein amino terminus (Nt) and its modifications determine the fate of proteins and their cellular effects. Nt acetylation, Nt methylation, and Nt myristoylation are protein Nt modifications implicated in the pathogenesis of proteinopathies like Alzheimer's, Parkinson's, and Huntington's diseases by regulating the protein lifespan, folding, and interaction with protein/DNA. In particular, Nt acetylation shields proteins from degradation or targets them for the same, thereby affecting their fate. Distinct enzymes catalyze Nt acetylation, Nt methylation, and Nt myristoylation, and these modifications compete for the nascent polypeptide at the ribosomal exit tunnel. Dysregulation of Nt modifications initiates the protein aggregation cascade and could potentially induce neuroinflammation and neurodegeneration. Here, we review Nt modifications and their emerging roles in the pathogenesis of NDs. Further, we highlight the crosstalk among distinct Nt modifications and explore how their convergence may shape disease vulnerability and progression.},
}

@article {pmid42325226,
year = {2026},
author = {Alhowail, AH and Al Mouslem, AK and Almatrafi, MA and Aldubayan, MA},
title = {Semaglutide in cognitive dysfunction: neuroprotective potential, clinical trial limitations, and a prevention-focused framework.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1851072},
pmid = {42325226},
issn = {1663-4365},
abstract = {Metabolic dysfunction is increasingly recognized as a pivotal factor in cognitive decline and neurodegenerative diseases, such as Alzheimer's disease (AD). Glucagon-like peptide-1 receptor agonists (GLP-1RAs), notably the long-acting agonist semaglutide, exhibit significant metabolic efficacy and pronounced neuroprotective effects across a broad spectrum of preclinical models. This is corroborated by extensive epidemiological studies that consistently link GLP-1RA use with a decreased incidence of dementia. Nevertheless, promising preclinical and observational findings have not been mirrored in clinical success for the treatment of established AD. Recent negative outcomes from the pivotal phase 3 EVOKE and EVOKE+ trials, which demonstrated no clinical benefit of oral semaglutide in patients with early AD, have resulted in a notable translational paradox. This review critically examines the mechanistic, preclinical, epidemiological, and clinical evidence concerning the impact of semaglutide on cognitive function to reconcile these conflicting findings. Preclinical studies have revealed complex neuroprotective mechanisms, including suppression of neuroinflammation, restoration of metabolic function, and activation of pro-survival pathways. Conversely, clinical trials in symptomatic AD have been unsuccessful, although modest and clinically insignificant changes in cerebrospinal fluid biomarker levels have been observed. We propose the hypothesis that the current body of evidence is consistent with a prevention-focused model, wherein semaglutide's primary value may lie in modifying the upstream metabolic and inflammatory drivers of neurodegeneration, such as those prevalent in vascular and metabolic cognitive impairment, rather than reversing established amyloid-driven AD pathology. This hypothesis, however, remains speculative and requires prospective validation in appropriately designed trials. This review seeks to resolve the apparent contradictions in the literature and propose future research directions centered on appropriate patient populations and therapeutic windows.},
}

@article {pmid42325271,
year = {2026},
author = {Liang, C and Jiang, W and Chen, J and Turner, JA and Calhoun, VD and Abbott, CC and Jiang, R and Fu, Z and Wu, L and Wang, X and Qi, S and Yuan, Y},
title = {Longitudinally altered default mode network and insula multimodal brain pattern in end-stage renal disease during sustained hemodialysis treatment.},
journal = {iScience},
volume = {29},
number = {6},
pages = {116008},
pmid = {42325271},
issn = {2589-0042},
abstract = {Hemodialysis (HD) is the predominant treatment for end-stage renal disease (ESRD). Despite the efficacy of HD, the neurobiological underpinnings underlying high-risk complications remain unclear. In this study, using unsupervised fusion of functional and structural MRI, we identified a longitudinally altered default mode network (DMN)-insula pattern in ESRD receiving HD over 1-year follow-up (n = 39). This pattern was associated with cognition, and its related genes were enriched in biological processes involving DNA damage and repair, energy metabolism, and cellular activation. The baseline DMN-insula pattern demonstrated potential predictive value for follow-up cognition in ESRD. More importantly, these brain-cognition associations were validated in independent high-risk complications cohorts, including major depressive disorder (n = 60), mild cognitive impairment (n = 291), and Alzheimer's disease (n = 77) by extracting the corresponding brain features and assessing their correlations with cognition. Collectively, this study may help researchers better understand the underlying mechanisms of ESRD receiving HD from a multimodal neuroimaging and molecular perspective.},
}

@article {pmid42325273,
year = {2026},
author = {Hao, W and Yu, X and Zhou, Q and Jia, Y and Su, X and Yu, Y and Wang, Y and Wang, J and Liu, C},
title = {Different modulation patterns of theta and gamma dual-site HD-tACS on cognitive impairment.},
journal = {iScience},
volume = {29},
number = {6},
pages = {116138},
pmid = {42325273},
issn = {2589-0042},
abstract = {Alzheimer's disease (AD) is characterized by impaired local network integration and long-range connections. Theta and gamma oscillations are critical for cognitive function, so this study used dual-site fronto-temporoparietal junction (TPJ) high-density transcranial alternating current stimulation (HD-tACS) to explore its frequency-specific effects on brain networks and cognition. Thirty-six AD patients were randomized 1:1:1 to 6Hz-tACS, 40Hz-tACS and sham stimulation targeting bilateral fronto-TPJ cortex for four weeks. Cognitive functions were assessed at baseline, post-treatment and 8-week follow-up. TMS-EEG and voxel-based distance-related functional connectivity analysis evaluated network changes. Both active stimulation groups showed sustained cognitive improvements for eight weeks compared to the sham stimulation group (all p < 0.017). 40Hz-tACS also enhanced language function (p < 0.025). 6Hz-tACS increased anterior functional connections and anterior-to-posterior information flow, while 40Hz-tACS increased posterior connections and posterior-to-anterior flow, closely linked to cognitive improvements. These effects are oscillation frequency-dependent, supporting cognitive improvement in AD.},
}

@article {pmid42325435,
year = {2026},
author = {Liu, C and Zhu, Z and Lin, H and Bush, WS and Jenq, RR and Cominelli, F and Pillai, JA and Haines, JL and Zhu, X and Xu, R and Williams, SM and Cheng, F and Zhang, L},
title = {The gut-brain axis in Alzheimer's disease: early detection, microbial metabolites, mechanisms, and therapeutic opportunities.},
journal = {Frontiers in molecular biosciences},
volume = {13},
number = {},
pages = {1735332},
pmid = {42325435},
issn = {2296-889X},
abstract = {Alzheimer's disease (AD), the leading cause of dementia worldwide, imposes a growing clinical and societal burden, yet no therapies have been proven to alter its progression despite decades of intensive research. As traditional targets have yielded limited success, attention has shifted to modifiable upstream pathways, notably the gut-brain axis, a bidirectional system linking gut microbiota with CNS function. Emerging evidence indicates that microbial dysbiosis may influence key processes leading to AD, including neuroinflammation, amyloid and tau pathology, and cognitive decline. While microbiome composition is associated with AD, it remains unclear at which stage-preclinical, mild cognitive impairment (MCI), or AD dementia-these differences first arise, or how specific risk bacteria and metabolites contribute to progression. The precise roles of these microbes and metabolites in AD pathology or brain resilience also remain poorly understood, and few microbiome-targeted treatments have been validated in humans. Existing reviews often overlook host-specific factors that influence microbiome composition and confound associations with AD. To bridge these gaps, we summarize human studies published in the past 5 years. The literature suggests that gut microbial changes may precede clinical symptoms, with consistent dysbiosis observed in AD patients. We adopt a microbiome-centered perspective emphasizing bacteria-driven and metabolite-driven mechanisms, each playing distinct yet complementary roles in neural and bloodstream pathways. These pathways offer potential targets for microbiome-based prevention and treatment but require more human validation. Future studies should leverage longitudinal, multi-omics approaches and artificial intelligence (AI) tools while rigorously accounting for confounders to improve early detection and develop personalized therapies for AD.},
}

@article {pmid42325550,
year = {2026},
author = {Li, X and Chen, H and Xu, P and Guo, X and Gao, J and Yao, D and Wang, Y and Wang, T and Liu, B and Yuan, J},
title = {Exosomes: A new frontier in the treatment of neurological diseases.},
journal = {iScience},
volume = {29},
number = {7},
pages = {116331},
pmid = {42325550},
issn = {2589-0042},
abstract = {Exosomes (Exos) are an essential class of extracellular vesicles enriched with a wide range of biologically active molecules, which gives them a unique advantage in participating in intercellular signaling and communication and serving as carriers for drug delivery. Exo-based diagnostic and therapeutic strategies are currently hot topics in disease research. Owing to their naturally low immunogenicity, good biocompatibility, ability to penetrate the blood‒brain barrier (BBB), and engineered modifications, exos have significant advantages and possible applications in the treatment of nervous system diseases. Due to the serious harm of neurological diseases to human health, they have been widely studied by researchers. Exos can be administered in a variety of ways, including intranasal administration, intracranial administration, local stereotactic injection, and encapsulation in biomaterials, each of which has its own advantages and disadvantages. However, several requirements need to be met before exo-based therapies can be implemented, such as the standardization of isolation and purification techniques, an in-depth understanding of the mechanism of action, and safety assessments and regulation for clinical translation. The aim of this review is to provide a comprehensive overview of the biogenesis, molecular composition, function, and delivery modes of exos and their therapeutic roles and mechanisms in neurological diseases (e.g., multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD), and stroke) and to discuss the current challenges and future perspectives to support ongoing research and clinical applications.},
}

@article {pmid42325556,
year = {2026},
author = {Xiong, D and Liu, M and Xie, J and Liu, Z and Wang, J},
title = {A dual space MRI radiomic network signature for risk stratification and subtyping of mild cognitive impairment.},
journal = {iScience},
volume = {29},
number = {7},
pages = {116394},
pmid = {42325556},
issn = {2589-0042},
abstract = {Mild cognitive impairment (MCI) is a clinically heterogeneous prodromal stage of Alzheimer's disease (AD) in which accurate risk stratification could support earlier intervention and more efficient trial design. Using baseline T1-weighted MRI from the Alzheimer's Disease Neuroimaging Initiative and the National Alzheimer's Coordinating Center cohorts, we developed a dual-space anatomical radiomic-network signature that integrates regional radiomic features and radiomics similarity network metrics extracted in standard and native spaces. The signature improved prediction of MCI-to-AD conversion relative to regional volumetric and clinical models, achieved consistent external validation performance, and separated participants into high- and low-risk groups. The same feature set identified five imaging-defined MCI subtypes with distinct anatomical patterns, conversion risks, and clinical, APOE ε4, and cerebrospinal fluid biomarker profiles; fronto-parietal and parahippocampal-temporal subtypes showed the highest risk. These findings support structural MRI radiomic-network profiling as a complementary framework for individualized prognosis and cohort stratification in AD research.},
}

@article {pmid42325559,
year = {2026},
author = {Wei, Z and Yang, J and Qiao, Y and Wang, S and Cai, Y and Gao, L},
title = {Sleeve gastrectomy improves cognition by enhancing central ERK/CREB/BDNF pathway through increased GIP secretion.},
journal = {iScience},
volume = {29},
number = {7},
pages = {116292},
pmid = {42325559},
issn = {2589-0042},
abstract = {Sleeve gastrectomy (SG) was used to probe the gut-brain axis in Alzheimer's disease (AD). In APP/PS1/Tau triple transgenic mice, SG improved glucose tolerance and insulin sensitivity without lasting effects on body weight or food intake. SG significantly improved cognitive performance and reduced anxiety-like behavior, attenuated neuronal damage and pTau accumulation in the hippocampal CA3 region, and increased both peripheral levels and hippocampal immunoreactivity of GIP and GLP-1 along with ERK/CREB/BDNF pathway activity. In HT22 cells, GIP receptor knockdown exacerbated Aβ-induced pTau and suppressed this pathway, whereas GLP-1 acted synergistically. These findings indicate that SG could improve cognition in non-obese AD mice largely through GIP/GLP-1 signaling rather than metabolic changes, supporting dual incretin targeting as a therapeutic strategy for AD.},
}

@article {pmid42325569,
year = {2026},
author = {Sebastian, RM and Kupp, R and Nanavati, D and Parfentev, I and Krzystek, TJ and Romanul, N and Yanamandra, K and Preiss, CN and Manos, JD and Wu, HY and Volkova, A and Crescenti, S and Titterton, K and Welker, AM and Townsend, M and Karran, E and Langlois, X and Wu, JW},
title = {SynCAR platform for capturing neuronal synaptic proteopathic seeds.},
journal = {iScience},
volume = {29},
number = {7},
pages = {116362},
pmid = {42325569},
issn = {2589-0042},
abstract = {Synaptic proteins are critical for maintaining healthy neuronal transmission but can also drive prion-like trans-synaptic spreading of pathological aggregated proteins found in many neurodegenerative diseases, including Alzheimer's disease. Recognizing technological limitations for in situ identification of synaptic proteins, we built a modular synaptic chimeric antigen receptor (synCAR) for capture of synaptic proteins by fusing a single-chain antibody fragment with the post-synaptic protein neurolignin-1 (NLGN1). Using our synCAR platform, we show that anchoring the tau antibody PHF1 to the synapse effectively captures pathogenic synaptic tau species. Expressing PHF1 synCAR at synapses in mouse primary and human neuronal tau seeding models results in increased tau aggregation, likely due to concentrating pathological tau seeds at the synapse. These findings provide the first published method for the isolation and modulation of synaptic protein function within relevant biological contexts, highlighting synCAR as a relevant instrumental platform for synaptic protein research and neurodegenerative disease drug development.},
}

@article {pmid42325592,
year = {2026},
author = {Bellaver, B and Povala, G and De Bastiani, MA and Pola, I and Ferreira, PCL and Bauer-Negrini, G and Ferrari-Souza, JP and Leffa, DT and Lussier, FZ and Therriault, J and Rahmouni, N and Stevenson, J and Servaes, S and Patira, R and Gauthier, S and Tudorascu, DL and Karikari, TK and Ashton, N and Blennow, K and Zetterberg, H and Zimmer, ER and Benedet, AL and Rosa-Neto, P and Pascoal, TA},
title = {Aβ- and tau-associated neuroinflammatory signatures in Alzheimer's disease.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {2},
pages = {e70275},
pmid = {42325592},
issn = {2352-8737},
abstract = {INTRODUCTION: Neuroinflammation is increasingly recognized as a key contributor to Alzheimer's disease (AD) progression, with distinct responses linked to amyloid beta (Aβ) and tau pathology. Two detrimental waves of neuroinflammation have been proposed, the first during early Aβ accumulation, and the second during widespread tau deposition. However, the neuroinflammatory signatures associated with each phase remain unclear.

METHODS: We studied 63 individuals who underwent Aβ and tau positron emission tomography imaging along with cerebrospinal fluid profiling of 368 inflammation-related proteins. Protein contrasts between cognitively unimpaired Aβ-negative and Aβ-positive individuals defined the signature of the Aβ phase, while comparisons between cognitively impaired Aβ-positive individuals with early versus late tau pathology characterized the tau phase. Gene Ontology enrichment identified biological processes associated with differentially expressed proteins.

RESULTS: During the Aβ phase, 34 proteins were downregulated and mapped to 157 biological processes, including Toll-like receptor signaling, nuclear factor kappa beta activation, and cytokine production. The tau phase showed upregulation of 23 proteins associated with 82 biological processes enriched in adaptive immune responses. A set of 48 biological processes and three proteins including interleukin 4 receptor, cystosolic phospholipidase A2, and secretoglobin family 3A member 2 showed opposite regulation patterns, being downregulated in the Aβ phase and upregulated in the tau phase.

DISCUSSION: Our results revealed distinct neuroinflammatory signatures and biological processes associated with Aβ- and tau-dominant stages of AD. The reversal in protein expression patterns across these stages underscores the need for stage-specific neuroimmune therapeutic strategies.},
}

@article {pmid42325779,
year = {2026},
author = {Zhang, L and Ikeda, N and Takeda, S and Oikawa, N and Murayama, S and Koshimizu, U and Yabe, I and Kondo, T},
title = {Plasma ECRG4 as a novel diagnostic marker for Alzheimer's disease associated with oligodendrocyte dysfunction.},
journal = {American journal of translational research},
volume = {18},
number = {5},
pages = {3765-3782},
pmid = {42325779},
issn = {1943-8141},
abstract = {Current treatments for Alzheimer's disease (AD) primarily focus on slowing disease progression, emphasizing the urgent need for a reliable diagnostic method for early-stage Alzheimer's (EAD). Our investigation, which is based on the finding that the secretory protein Esophageal Cancer Related Gene 4 (ECRG4) is elevated in the hippocampus of AD patients, led to the creation of a novel ELISA system for ECRG4 detection. We observed that ECRG4 peptides, particularly the fragment spanning amino acids 108-132, were elevated in the plasma of approximately 25% of patients with mild cognitive impairment (MCI) and 50% of those with AD, compared to individuals without dementia. RNA sequencing of plasma samples revealed decreased levels of carbohydrate sulfotransferase 3 (CHST3) mRNA, which is mainly expressed in oligodendrocyte (OLG)-lineage cells, in ECRG4-positive patients. Functional analyses demonstrated that the ECRG4 (71-107) peptide induced cytotoxicity in oligodendrocytes in vitro and reduced the expression of the OLG marker galactocerebroside in the corpus callosum following intracerebral injection. Additionally, peptide injection resulted in extravascular IgG leakage and the accumulation of OLG precursor cells (OPCs), which are crucial for myelin regeneration, around the blood vessels. These phenomena were similarly observed in the hippocampi of patients with EAD. Collectively, these findings establish ECRG4 as a novel serum marker for AD and suggest its association with ECRG4-dependent OLG dysfunction.},
}

@article {pmid42325796,
year = {2026},
author = {Wang, C and Song, B and Wang, G and Yan, X and Wu, X and Zhou, S and Hu, P and Wang, K and Ji, G and Wang, Z and Xu, S},
title = {Non-invasive neuromodulation techniques for cognitive impairment intervention.},
journal = {American journal of translational research},
volume = {18},
number = {5},
pages = {3700-3714},
pmid = {42325796},
issn = {1943-8141},
abstract = {Cognitive impairment involves sustained deficits across several key domains: memory, executive function, attention, and behavioral regulation. The condition encompasses cognitive dysfunction linked to Alzheimer's disease, mild cognitive impairment, vascular cognitive impairment, and other forms of neurodegeneration. Existing pharmacotherapies frequently yield inconsistent clinical benefits, are often accompanied by side effects, and generally lack disease-modifying properties. These limitations have spurred increasing attention toward safe, repeatable non-pharmacological strategies. Non-invasive brain stimulation, a central non-pharmacological tool, can regulate excitability in targeted brain regions, shape network-level connectivity, and facilitate activity-dependent neuroplasticity. Evidence from multiple clinical settings supports its potential to improve cognitive outcomes. This review centers on major NIBS techniques: repetitive transcranial magnetic stimulation, transcranial electrical stimulation, gamma-frequency sensory stimulation, photobiomodulation, and transcranial ultrasound stimulation. We synthesize their underlying mechanisms, clinical applications, and supporting evidence, aiming to provide an evidence-based framework to guide standardized clinical implementation and future research design in this area.},
}

@article {pmid42325951,
year = {2026},
author = {Zhao, W and Liu, X and Yao, Y and Yu, Y and Hu, Z},
title = {Exploring ceramide as a novel biomarker and therapeutic target for Alzheimer's disease.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1771302},
pmid = {42325951},
issn = {1662-4548},
abstract = {Metabolic dysregulation is increasingly being recognized as a hallmark across various neurodegenerative diseases. While Alzheimer's disease (AD) is well-established as a dual proteinopathy characterized by amyloid-beta (Aβ) deposition and tau protein tangles, the specific mechanisms mediating lipid homeostasis imbalance have garnered increasing attention. However, translating these findings into safe clinical therapeutic targets remains a formidable challenge, primarily hindered by the pleiotropic roles of ceramides in maintaining neural and immune homeostasis, as well as the blood-brain barrier (BBB) penetration issues and systemic safety limitations of current sphingolipid-targeting strategies. We conducted a comprehensive search of electronic databases, including PubMed, Web of Science, and Google Scholar, to identify relevant studies published from database inception through March 2026. The search term combinations included: "Alzheimer's disease," "AD," "ceramide," "sphingolipid metabolism," "biomarker," "therapeutic target," "neuroinflammation," and "mitochondrial dysfunction." To ensure the depth and rigor of this review, priority was given to peer-reviewed original research, systematic reviews, and meta-analyses. The search was restricted to English-language literature. Additionally, the reference lists of retrieved articles were manually screened to identify further relevant studies. This narrative review aims to comprehensively elucidate the potential roles of ceramides in AD pathogenesis, exploring their associations with triggering inflammatory responses, mediating apoptosis, interfering with signal transduction, and inducing mitochondrial dysfunction.},
}

@article {pmid42325956,
year = {2026},
author = {Zhang, Z and Bai, Y and Zhang, X and Zhang, J and Yang, G},
title = {ALDOC modulates astrocytic glycolysis and AMPK/mTOR/HIF-1α signaling in Alzheimer's disease.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1847340},
pmid = {42325956},
issn = {1662-4548},
abstract = {AIMS: Astrocytes provide crucial metabolic support for neurons and undergo significant metabolic changes in Alzheimer's disease (AD). Aldolase C (ALDOC), an astrocyte-enriched glycolytic enzyme, may play a role in this process. This study aimed to investigate whether ALDOC modulates astrocytic metabolism to support neuronal energy supply in patients with AD and to assess its therapeutic potential.

METHODS: Hippocampal and cortical tissues from 6-month-old APP/PS1 and wild-type mice were subjected to western blotting, qPCR, and immunofluorescence staining for ALDOC and glycolytic proteins. An in vitro AD model was created using oligomeric β-amyloid (oAβ)-treated SVGp12 astrocytes. ALDOC was overexpressed or knocked down via plasmid or siRNA. Downstream effects on AMPK/mTOR/HIF-1α signaling and the expression of glycolytic markers (LDHA and PKM2) were evaluated by western blot and qPCR, as well as by lactate/ATP assays and extracellular acidification rate (ECAR) measurements. Neuron-astrocyte interactions were assessed in an SVGp12/SH-SY5Y coculture. Furthermore, the ability of magnesium ions to restore ALDOC expression was tested.

RESULTS: ALDOC was specifically expressed in astrocytes but was downregulated in APP/PS1 mice, accompanied by reduced HIF-1α and LDHA levels, suggesting glycolytic impairment. Similar downregulation occurred in oAβ-treated SVGp12 cells. ALDOC overexpression was associated with altered AMPK/mTOR/HIF-1α signaling, enhanced glycolysis, and increased lactate and ATP production, whereas its knockdown had the opposite effects. These outcomes appeared to depend on HIF-1α, as suggested by the rescue experiments. In coculture, ALDOC overexpression in astrocytes supported neuronal metabolic function. Moreover, magnesium ions restored ALDOC activity and glycolysis in oAβ-treated astrocytes.

CONCLUSION: These results suggest that ALDOC is downregulated in APP/PS1 mice and is associated with glycolytic impairment. In oAβ-treated astrocytes, ALDOC appears to regulate glycolysis through the AMPK/mTOR/HIF-1α axis and may support neuronal energy via the lactate shuttle. Magnesium ions appear to offer a potential strategy for addressing the metabolic deficits in AD.},
}