@article {pmid40844393,
year = {2025},
author = {Grøntvedt, GR},
title = {[Blood-based biomarkers in Alzheimer’s disease].},
journal = {Tidsskrift for den Norske laegeforening : tidsskrift for praktisk medicin, ny raekke},
volume = {145},
number = {},
pages = {},
doi = {10.4045/tidsskr.25.0118},
pmid = {40844393},
issn = {0807-7096},
}

@article {pmid42039580,
year = {2026},
author = {Balaan, C and Patwardhan, GY and Sachs, RK and Kumasaka, H and Sadagopan, S and Aou, S and Lee, AJ and Nelson, LT and Hew, BE and Owens, JB and Polgar, N and Ortega, MA and Nichols, RA and Fogelgren, B},
title = {The exocyst is an insulin-sensitive regulator of amyloid precursor protein trafficking and amyloid-beta generation in neurons.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
pmid = {42039580},
issn = {2692-8205},
abstract = {Intracellular trafficking of amyloid precursor protein (APP) critically influences amyloidogenic processing, yet the mechanisms regulating this pathway remain incompletely defined. The exocyst is a highly conserved, insulin-responsive, eight-protein Rab effector complex that directs intracellular transport vesicle targeting and docking. We identified APP in a proteomics screen of neuronal cell surface proteins altered after chemical inhibition of exocyst activity. In SH-SY5Y cells expressing a mutant APP that enhances amyloidogenic processing, RNAi-mediated silencing of exocyst subunits significantly decreased sAPP and Aβ secretion, leading to significant intracellular APP accumulation. We found high-resolution co-localization of APP with exocyst subunits in soma and neurites of differentiated human SH-SY5Y neurons and mouse primary hippocampal neurons, and live-cell TIRF microscopy identified highly coordinated movement between fluorescently-tagged exocyst and APP proteins. These interactions were confirmed in these cells and in mouse brain histological sections by proximity ligation assays (PLAs) demonstrating close (<40nm) APP-EXOC5 association. To examine if exocyst activity in neurons is regulated by insulin, as it is in adipocytes and muscle, we generated a SH-SY5Y cell line with pHluorin-tagged GLUT4. Inhibition of the exocyst prevented exocytosis of GLUT4 to the plasma membrane in response to insulin. Additionally, using PLAs in mouse primary hippocampal neurons and SH-SY5Y neurons, we found that GLUT4-EXOC5 associations were increased by insulin signaling, but APP-EXOC5 associations were markedly reduced, indicating insulin-dependent retargeting of the exocyst complex away from APP+ vesicles towards GLUT+ vesicles. All together, these data identify the exocyst as a novel insulin-regulated mediator of neuronal APP trafficking and Aβ secretion.},
}

@article {pmid42085916,
year = {2026},
author = {Abbas, A and Tsai, HC and Hsu, YL and Kenneth, MJ and Hussain, B and Lai, LM and Hsu, BM},
title = {Multimodal deep learning neuroimaging approach to enhance CT-based diagnosis of Alzheimer's disease.},
journal = {Psychiatry research. Neuroimaging},
volume = {361},
number = {},
pages = {112234},
doi = {10.1016/j.pscychresns.2026.112234},
pmid = {42085916},
issn = {1872-7506},
abstract = {Neuroimaging plays a critical role in the diagnosis of Alzheimer's disease (AD), with Magnetic Resonance Imaging (MRI) and Positron Emission Tomography (PET) providing detailed structural and functional information for deep learning (DL) based classification. However, their high cost and limited availability restrict widespread clinical use. Computed Tomography (CT), while affordable and widely accessible, is diagnostically insufficient for detecting subtle neurodegenerative changes associated with early AD. To address this limitation, this study proposes a multimodal DL framework that enhances CT-based AD diagnosis by leveraging complementary feature representations learned from MRI. A custom convolutional neural network (CNN) was trained and evaluated using paired CT and MRI data from the Open Access Series of Imaging Studies (OASIS-3). A total of 772 participants with available MRI and CT scans were selected based on Clinical Dementia Rating (CDR) scores and corresponding clinical diagnoses. Participants were categorized as Normal Control (NC) (CDR = 0, n = 300), mild cognitive impairment (MCI) (CDR = 0.5, n = 250), or AD (CDR ≥ 1, n = 222). The overall sex distribution comprised 352 males and 420 females. The CT-only model achieved an accuracy of 84%, with 92% sensitivity and 83% specificity for AD classification. The proposed multimodal model demonstrated superior performance, achieving 92% accuracy, 95% sensitivity, and 91% specificity. Importantly, during CT-only inference, the multimodal framework retained high diagnostic accuracy in identifying disease status, indicating effective transfer of MRI-derived features to CT. These results demonstrate a scalable solution for improving AD detection using CT imaging in resource-limited healthcare.},
}

@article {pmid42085921,
year = {2026},
author = {Wang, C and Piao, S and Chen, Z and Chen, T and Li, Z and Zhang, T and Li, Y and Zhao, XM and Shan, H and , and , },
title = {E[2]AD: Enhanced and explainable Alzheimer's disease detection framework via anatomy- and relation-aware cross-modal knowledge distillation.},
journal = {Medical image analysis},
volume = {112},
number = {},
pages = {104099},
doi = {10.1016/j.media.2026.104099},
pmid = {42085921},
issn = {1361-8423},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder for which MRI and PET provide complementary structural and molecular information. Yet PET remains costly and often unavailable, motivating MRI-only diagnostic systems that still benefit from multimodal supervision. Existing methods either synthesize PET from MRI or limit cross-modal learning to low-dimensional spaces, underutilizing MRI-PET complementarity and leading to limited robustness and generalizability. To address these challenges, we introduce E[2]AD, an Enhanced and Explainable AD detection framework that leverages anatomy- and relation-aware cross-modal knowledge distillation (KD). Using paired MRI-PET data during training but only MRI at inference, E[2]AD augments traditional logit-based KD through two synergistic components: (1) anatomy-aware distillation that transfers within-subject anatomical dependencies through an anatomical Mixture-of-Mappers, yielding spatially meaningful and clinically traceable cues; and (2) relation-aware distillation that promotes stable between-subject structural relations through generalizable pairwise alignment, yielding a representation space with better cross-cohort generalization. To enhance clinical utility, we further introduce a tailored multi-agent workflow that translates E[2]AD's anatomical attention into structured, clinician-oriented MRI reports. Extensive experimental results on the internal ADNI cohort and two external cohorts (AIBL and NACC) demonstrate that E[2]AD outperforms state-of-the-art baselines, offering faster convergence, improved data efficiency, stronger cross-cohort generalization, and enhanced explainability. Source code is available at https://github.com/thibault-wch/E2AD-for-Alzheimer-disease.},
}

@article {pmid42086074,
year = {2026},
author = {Si, P and He, N and Liu, J and Wang, Q and Lin, J and Dai, C},
title = {Investigation of the Therapeutic Effects of Transcorneal Electrical Stimulation on Alzheimer's Disease Using Optical Coherence Tomography.},
journal = {Journal of biophotonics},
volume = {19},
number = {5},
pages = {e70274},
doi = {10.1002/jbio.70274},
pmid = {42086074},
issn = {1864-0648},
support = {62175156//National Natural Science Foundation of China/ ; 22S31903000//Science and Technology Commission of Shanghai Municipality/ ; },
mesh = {*Tomography, Optical Coherence ; *Alzheimer Disease/therapy/diagnostic imaging/pathology ; Animals ; Mice ; *Cornea/diagnostic imaging ; Retina/diagnostic imaging ; *Electric Stimulation Therapy ; Male ; *Electric Stimulation ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder lacking reliable noninvasive indicators for early diagnosis. Transcorneal electrical stimulation (TES) has emerged as a noninvasive neuromodulation approach, yet its effects on AD-related pathology and eye-brain interactions remain unclear. In this study, TES was applied to wild-type (WT) and AD mice, followed by longitudinal optical coherence tomography (OCT) and OCT angiography (OCTA) imaging of the retina and cerebral cortex over a 30-day period. Quantitative imaging metrics, together with histologically assessed amyloid-β (Aβ) plaque deposition, were used to assess TES-associated structural and neurovascular changes. In addition to retinal thickness, retinal vascular density (VD) was evaluated as an objective, noninvasive imaging metric associated with AD-related neurovascular alterations. These findings demonstrate the utility of longitudinal OCT/OCTA imaging for investigating intervention-associated retinal and cerebral neurovascular changes along the eye-brain axis.},
}

*Tomography, Optical Coherence
*Alzheimer Disease/therapy/diagnostic imaging/pathology
Animals
Mice
*Cornea/diagnostic imaging
Retina/diagnostic imaging
*Electric Stimulation Therapy
Male
*Electric Stimulation

@article {pmid42086094,
year = {2026},
author = {Wang, E and Kang, Y and Chen, D and Tian, R and Hu, Y and Wang, H and Jun, L and Zhou, Z and Tian, T and Xu, H and Huang, J},
title = {Alternative splicing fuels the functional diversity of GPCR in neurological and psychiatric disorders: An emerging path toward RNA-targeted neurotherapeutics.},
journal = {Biochemical pharmacology},
volume = {},
number = {},
pages = {118026},
doi = {10.1016/j.bcp.2026.118026},
pmid = {42086094},
issn = {1873-2968},
abstract = {Dysfunction in intricate neural circuits contributes to numerous neurological and psychiatric disorders, affecting a substantial portion of the global population and significantly contributing to the global disease burden. This highlights the urgent need for more precise therapeutic targets. G protein-coupled receptors (GPCRs) are the predominant targets commonly utilized in the development of novel therapeutics for nervous system disorders. Alternative splicing (AS) generates numerous tissue- and cell type-specific GPCR isoforms that are regulated by cis-acting elements, trans-acting factors, and underlying epigenetic modifications. These isoforms exhibit distinct distributions, leading to signaling bias and conformational diversity. However, their role in GPCR signaling heterogeneity is often overlooked due to limited data on expression and function in various neuropathological conditions. This review examines GPCR splicing variants (SVs) in neurodegenerative diseases such as Alzheimer's and Parkinson's, neuropsychiatric disorders including depression, anxiety, autism spectrum disorder, and schizophrenia, as well as pain and addiction. It emphasizes how alternative splicing shapes tissue-specific GPCR expression and diverse biological functions. Emerging technologies and AI-based structural modeling are underscored as powerful tools for resolving GPCR variant structures and enabling isoform-specific drug development. The review aims to provide new insights into GPCR functional heterogeneity and promote an isoform-focused therapeutic strategy based on GPCR-ligand interactions to guide future treatments.},
}

@article {pmid42086102,
year = {2026},
author = {Chen, M and Huang, X and Li, Y and Hu, L and Lu, R and Li, L},
title = {Microplastics as an emerging environmental pollutant potentially leading to neurodegenerative diseases.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2026.04.033},
pmid = {42086102},
issn = {1873-7544},
abstract = {Microplastics (MPs), defined as plastic fragments less than 5 mm in diameter, are ubiquitous in the environment. As an emerging environmental pollutant, MPs can infiltrate the human body through multiple pathways, including inhalation, ingestion, dermal contact and bloodborne transmission.Correspondingly, MPs, which can penetrate the blood-brain barrier and enter the central nervous system (CNS), have been linked to the development of neurodegenerative diseases (NDs).In this review, we provide a comprehensive analysis of the environmental distribution of MPs, the pathways of entry into the human body, and the distribution within the CNS. Furthermore, we explore intrinsic factors influencing the neurotoxicity of MPs and elucidate the mechanisms underlying MPs-induced NDs, including Alzheimer's disease, Parkinson's disease, and Amyotrophic lateral sclerosis. Beyond mechanistic insights, we offer a novel perspective by exploring the potential adaptation of emerging environmental MPs detection and removal technologies for CNS applications. Ultimately, elucidating these mechanisms positions the reduction of MPs accumulation as a critical intervention point, highlighting the adaptation of environmental technologies as a promising strategy for the prevention and management of NDs.},
}

@article {pmid42086126,
year = {2026},
author = {Bai, X and Dai, J and Wang, X and Gao, H},
title = {Exploring the differences in efficacy and mechanisms of Schisandra chinensis and its processed products in treating Alzheimer's disease based on UPLC-Q-TOF-MS/MS, network pharmacology, and experimental validation.},
journal = {Fitoterapia},
volume = {},
number = {},
pages = {107268},
doi = {10.1016/j.fitote.2026.107268},
pmid = {42086126},
issn = {1873-6971},
abstract = {This study aims to elucidate the efficacy differences and underlying mechanisms of Schisandra chinensis (SC) and its processed products against Alzheimer's disease (AD). A total of 39 compounds were identified from SC and its processed products through UPLC-Q-TOF-MS/MS in both positive and negative ion modes. Multivariate statistical analysis revealed significant differences in chemical composition among the various processed products, with schisandrol A, epigomisin O, and angeloylgomisin O identified as key significantly differential components. Based on the identified compounds, potential targets were predicted via Swiss Target Prediction, which were then intersected with AD targets from the GeneCards and OMIM databases to construct a protein-protein interaction (PPI) network of "SC-AD" intersection targets. Enrichment analysis indicated that the core mechanism of its anti-AD effect involves the regulation of the PI3K/AKT signaling pathway. Experimental validation was conducted using the Aβ25-35-induced HT22 cell injury model and a D-galactose combined with scopolamine-induced AD mouse model. The results demonstrated that SC and its processed products significantly improved the behavioral performance of AD mice, alleviated pathological damage in brain tissue, and reduced pro-inflammatory factor levels. Furthermore, they upregulated AKT protein expression and inhibited mTOR protein expression. Notably, the regulatory effects of the processed products on these indicators were significantly superior to those of the raw products. In conclusion, both SC and its processed products can ameliorate AD by activating the PI3K/AKT pathway, with the effect significantly enhanced post-processing. This mechanism may be associated with the regulation of the PI3K/AKT signaling pathway.},
}

@article {pmid42086387,
year = {2026},
author = {Sah, NKP and Saxena, S and Desai, D},
title = {Comment on "Alzheimer's disease diagnosis: An update and review of biomarkers, positron emission tomography, and emerging therapies".},
journal = {Journal of the Formosan Medical Association = Taiwan yi zhi},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jfma.2026.04.135},
pmid = {42086387},
issn = {0929-6646},
}

@article {pmid42086543,
year = {2026},
author = {Liu, WZ and Huang, LY and Chi, S and Ma, YH and Tan, CC and Tan, L and , and Xu, W},
title = {Correction: The blood lipidome fatty acid profile predicts the disease risk and clinical phenotypes of Alzheimer's disease: associations from two prospective cohort studies.},
journal = {Translational psychiatry},
volume = {16},
number = {1},
pages = {},
doi = {10.1038/s41398-026-04062-x},
pmid = {42086543},
issn = {2158-3188},
}

@article {pmid42086977,
year = {2026},
author = {Khan, TTS and Wong, CYJ and Sheikh, Z and Fathi, A and Maleknia, S and Oveissi, F and Abrams, T and Knox, W and van der Hoven, J and Antonito, A and Murray, M and Svolos, M and Suman, J and Tietz, O and Ong, HX and Traini, D},
title = {Repurposing insulin for Alzheimer's disease treatment: intranasal delivery of a thermoresponsive nanocarrier-based insulin formulation to the brain.},
journal = {Drug delivery and translational research},
volume = {},
number = {},
pages = {},
pmid = {42086977},
issn = {2190-3948},
abstract = {The Intranasal route provides an effective pathway for insulin delivery to the brain compared to oral/subcutaneous routes as it provides direct access to the brain, bypassing the restrictive blood-brain barrier (BBB), while minimizing systemic exposure. The present study investigated the potential of a thermoresponsive polymer, PNPHO, as a nanocarrier for brain-targeted insulin delivery through the intranasal route, with the aim of repurposing insulin for Alzheimer's disease treatment. Insulin-loaded nanoparticles (NP) were formulated using an advanced crossflow mixing technology with lower (F1) and higher (F2) PNPHO concentrations and characterised in vitro for size, zeta potential, encapsulation efficiencies, stability, drug deposition, and transport and in vivo for biodistribution. Both F1 and F2 NP demonstrated particle sizes ranging from 35.9 to 49.8 nm with low polydispersity index (< 0.3), negative surface charges, high encapsulation efficiencies (> 99%), and conserved structural integrity post 4 weeks of stability study. NP demonstrated significantly greater in vitro nasal deposition compared to insulin alone. Notably, the PNPHO nanocarrier protected insulin from enzymatic degradation, overcoming a key barrier associated with protein/peptide delivery. In vitro drug transport studies showed an initial delay in NP transport across nasal cells due to PNPHO-mucoadhesive properties, followed by increased transport. Significantly enhanced time-dependent NP transport across the BBB cells compared to insulin alone (p < 0.0001) confirmed NP's ability to cross the BBB. In vivo, NP demonstrated prolonged nasal retention and higher brain: serum ratio in mice, suggesting sustained drug release and improved brain delivery compared to insulin alone. Collectively, the study highlight the potential of PNPHO as a promising nanocarrier for achieving targeted and efficient intranasal delivery of insulin to the brain.},
}

@article {pmid42087072,
year = {2026},
author = {Cho, J and Won, J and Kim, YG and Jeon, CY and Lim, KS and Seo, J and Seong, JB and Yeo, HG and Kim, K and Kim, M and Gwon, LW and Jung, Y and Nguyen, TTH and Min, J and Moon, G and Choi, WS and Park, SH and Lee, HY and Jeong, KJ and Bae, GS and Jeon, E and Cheong, DY and Lee, G and Kim, HC and Baeg, E and Yang, S and Huh, JW and Park, J and Lee, Y},
title = {Repeated Intra-cisterna Magna Injections with Amyloid-beta Oligomers to Induce Alzheimer's Disease in Cynomolgus Monkey (Macaca fascicularis): A Pilot Study.},
journal = {Experimental neurobiology},
volume = {},
number = {},
pages = {},
doi = {10.5607/en25052},
pmid = {42087072},
issn = {1226-2560},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder which results in cognitive decline and memory loss, characterized by the accumulation of amyloid beta (Aβ) plaques and neurofibrillary tangles in the brain. Despite numerous efforts to develop animal models of AD across various species to understand its pathological characteristics and underlying mechanisms, the model that accurately mimics the pathological phenotypes of AD remains elusive. In this study, we aimed to induce sporadic AD pathological progression in non-human primates (NHP) through the repeated administration of Aβ oligomers (AβO) via the CBCT-guided intra-cisterna manga (ICM) injection. Cynomolgus monkeys were administered AβO twice a week for four weeks, and then euthanized one week after the final injection. We found that AβO-injected NHP developed AD pathologies, including Aβ deposition, synaptic impairment, and neuroinflammation in the CA1 area of the hippocampus. Additionally, the levels of hyperphosphorylated tau were significantly increased in the cerebrospinal fluid (CSF) of AβO-injected NHP. Our results demonstrate that repeated AβO injection via the ICM route induces several early-stage AD-like neuropathological alterations, including intracellular Aβ accumulation, tau phosphorylation, and synaptic dysfunction. The present study indicates that repeated ICM administration of AβO could be good approach to reproduce a translational NHP model of AD, enabling the study of AD pathogenesis and pre-clinical testing of potential therapeutic candidates for AD.},
}

@article {pmid42087418,
year = {2026},
author = {Yin, X and Peng, H and Li, Y and Song, Y and Chen, L and Yao, N and Li, P and He, Z and Chen, H and Huang, L and Shen, Z and Chen, Q},
title = {The Association Between Physical Activity and Domain-Specific Cognitive Function in the Elderly: A Cross-Sectional Study and Genetic Analysis.},
journal = {Brain and behavior},
volume = {16},
number = {5},
pages = {e71423},
doi = {10.1002/brb3.71423},
pmid = {42087418},
issn = {2162-3279},
support = {82360943//National Natural Science Foundation of China/ ; },
mesh = {Humans ; Cross-Sectional Studies ; Aged ; Male ; *Exercise/physiology ; Female ; *Cognition/physiology ; Middle Aged ; Nutrition Surveys ; Aged, 80 and over ; *Aging/genetics/physiology ; Mendelian Randomization Analysis ; Neuropsychological Tests ; Cognitive Dysfunction/genetics ; },
abstract = {BACKGROUND: Population aging is intensifying worldwide, increasing the prevalence of dementia. More than 50 million people globally are affected by dementia. There is some evidence that physical activity (PA) benefits cognitive function (CF). However, it is unclear which types and amounts of PA are best for specific cognitive domains.

METHODS: This study used a cross-sectional design and genetic analysis to test its hypotheses. Participants were drawn from the National Health and Nutrition Examination Survey (NHANES) 2011-2014, including 2578 adults aged 60 years or older. Cognitive abilities were measured using standardized tests, and PA levels were assessed with the Global Physical Activity Questionnaire (GPAQ). The analysis included multivariable regression, threshold effect testing, and subgroup analysis to explore links between PA patterns, intensities, and specific CF domains. Furthermore, a Mendelian randomization (MR) approach was employed to assess whether PA intensity exerts an effect on CF.

RESULTS: NHANES data analysis showed that the regular activity (RA) pattern was positively associated with the Consortium to Establish a Registry for Alzheimer's Disease Word Learning test (CERAD-WL) scores (β = 0.07; 95% confidence interval [CI]: 0.02, 0.16; p = 0.018), Animal Fluency Test (AFT) scores (β = 0.31; 95% CI: 0.21, 0.41; p = 0.002), Digit Symbol Substitution Test (DSST) scores (β = 0.19; 95% CI: 0.09, 0.30; p = 0.017), and overall CF (β = 0.23; 95% CI: 0.14, 0.32; p < 0.004). Threshold-effect analysis revealed an inverted U-shaped relationship between PA levels and cognitive performance. The inflection points occurred at 650, 535, and 550 min per week for AFT, DSST, and overall CF, respectively. Above these values, further cognitive gains plateaued. The inverse-variance weighted (IVW) method of the MR analyses showed that moderate-intensity physical activity (MPA) increased correct counting (odds ratio [OR] = 0.710; 95% CI: 0.606, 0.832; p < 0.001), fluid intelligence (OR = 0.470; 95% CI: 0.346, 0.638; p < 0.001), and overall cognitive performance (OR = 0.707; 95% CI: 0.653, 0.764; p < 0.001). For vigorous-intensity physical activity (VPA), we observed causal associations with memory outcomes, reaction time, correct matches, fluid intelligence, and cognitive performance.

CONCLUSION: The findings suggest that PA is associated with multiple domains of CF, and the RA pattern is linked to better cognitive performance. Genetically, VPA appears to have a stronger promotive effect. Thus, different patterns and intensities of PA may help delay cognitive decline and maintain brain health in older adults.},
}

Humans
Cross-Sectional Studies
Aged
Male
*Exercise/physiology
Female
*Cognition/physiology
Middle Aged
Nutrition Surveys
Aged, 80 and over
*Aging/genetics/physiology
Mendelian Randomization Analysis
Neuropsychological Tests
Cognitive Dysfunction/genetics

@article {pmid42087556,
year = {2026},
author = {Loncke, J and Callens, M and Bultynck, G and Vervliet, T},
title = {RYR:ATP6V0A1 complexes couple ER-lysosome contact sites to dynamic autophagy control.},
journal = {Autophagy},
volume = {},
number = {},
pages = {},
doi = {10.1080/15548627.2026.2669981},
pmid = {42087556},
issn = {1554-8635},
abstract = {Ryanodine receptors (RYRs) are ER-resident Ca[2] [+] -release channels enriched in excitable cells, including neurons. RYR hyperactivity is implicated in early pathogenesis of disorders such as Alzheimer's disease (AD), which is associated with impaired autophagy. We recently uncovered a mechanism linking RYR activity to lysosome availability for autophagy. RYRs localize to ER - lysosome contact sites via direct binding to ATP6V0A1, a V-ATPase subunit that also suppresses RYR-mediated Ca[2] [+] release. In human iPSC-derived cortical neurons, spontaneous RYR activity promotes lysosomal secretion, depleting the intracellular lysosomal pool and inhibiting autophagic flux. RYR inhibition promotes ER - lysosome contacts, limits lysosomal secretion, and restores lysosome availability for autophagosome fusion and cargo degradation (including APP). Conversely, disrupting the RYR:ATP6V0A1 interaction using a RYR-derived protein fragment serving as a "decoy" for ATP6V0A1 evokes RYR hyperactivity and stimulates lysosomal secretion. In this Punctum, we discuss how this RYR2:ATP6V0A1 "contact-site hub" may be perturbed in disease and highlight open questions on how lysosomes decode RYR-derived Ca[2] [+] signals.},
}

@article {pmid42087592,
year = {2026},
author = {Liu, X and Xu, H and Zhao, Y and Yang, J and Zhang, L and Wang, Z and Lim, K and Zhang, C and Lu, L},
title = {Roles of POU3F2 in Brain Development and Neuropsychiatric Disorders.},
journal = {Developmental neurobiology},
volume = {86},
number = {3},
pages = {e70034},
doi = {10.1002/dneu.70034},
pmid = {42087592},
issn = {1932-846X},
support = {202200331//Cooperative Research Project/ ; //Shanxi Province Higher Education/ ; 82571379//National Natural Science Foundation of China/ ; },
mesh = {Animals ; Humans ; *Brain/growth & development/metabolism ; *Mental Disorders/metabolism/genetics ; *POU Domain Factors/metabolism/genetics ; *Homeodomain Proteins/metabolism ; *Nerve Tissue Proteins/metabolism ; },
abstract = {POU3F2, a member of the Pit-Oct-Unc (POU) domain transcription factor family, is widely expressed in the central nervous system and essential for the development and maturation of brain. POU3F2 deletion results in impaired hypothalamus and neocortex development, and most mice die between postnatal days 0 and 10. Recently, emerging evidences have demonstrated that POU3F2 is involved in neuropsychiatric disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, bipolar disorder, schizophrenia, and autism spectrum disorder, albeit still with some limitations in current studies. Besides, POU3F2 also plays a vital role in the reprogramming of somatic cells into neuronal lineages, which provides new ideas and directions for the treatment of neuropsychiatric disorders. This review aims to systematically summarize and analyze the diverse roles of POU3F2 in brain development, neuropsychiatric disorders, and neuronal reprogramming. Furthermore, the potential of POU3F2-targeted therapies for neuropsychiatric disorders and proposed key questions for future research are also emphasized. POU3F2 plays a pivotal role in brain development, the pathogenesis of neurological and psychiatric disorders, and the reprogramming of neural cells. A more comprehensive and systematic understanding of its molecular mechanism might provide novel therapeutic approaches for neuropsychiatric disorders.},
}

Animals
Humans
*Brain/growth & development/metabolism
*Mental Disorders/metabolism/genetics
*POU Domain Factors/metabolism/genetics
*Homeodomain Proteins/metabolism
*Nerve Tissue Proteins/metabolism

@article {pmid42087776,
year = {2026},
author = {Rodriguez Colmenares, NA and Alvarez, L and Gilbreath, J and Markaki, A and Schexnayder, J and Puga, F},
title = {Anticipatory grief among caregivers of people living with dementia: A scoping review.},
journal = {Palliative & supportive care},
volume = {24},
number = {},
pages = {e130},
doi = {10.1017/S1478951526102478},
pmid = {42087776},
issn = {1478-9523},
mesh = {Humans ; *Caregivers/psychology ; *Dementia/psychology/complications ; *Grief ; Adaptation, Psychological ; Stress, Psychological/psychology ; },
abstract = {OBJECTIVES: As Alzheimer's disease and related dementias (ADRD) progress, family caregivers may experience grief before the death of the person living with ADRD. This type of grief is commonly referred to as anticipatory grief, which can contribute to increased psychological distress (i.e., depressive and anxiety symptoms) and potentially affect caregivers' long-term mental health. This scoping review aimed to synthesize evidence on risk and resilience factors associated with anticipatory grief, its relationship with caregiver mental health, and psychosocial interventions targeting anticipatory grief among caregivers of people living with ADRD.

METHODS: Guided by the Stress Process Model and the Grief-Stress Model, a literature search was conducted in PubMed, CINAHL, Embase, Scopus, Web of Science, and PsycINFO in May 2025.

RESULTS: Thirty articles met the inclusion criteria. Caregiver characteristics, such as being a spousal caregiver and greater caregiving involvement, were associated with higher levels of anticipatory grief. Caregiving-related stressors and relationship changes across the ADRD trajectory were consistently linked to anticipatory grief across studies, while psychosocial resources, such as adaptive coping and social support, were generally associated with lower levels of anticipatory grief. Anticipatory grief was consistently associated with depressive symptoms. Intervention studies were limited, but those focused on acceptance and preparedness showed potential for reducing anticipatory grief.

SIGNIFICANCE OF RESULTS: Anticipatory grief represents an important dimension of caregiver mental health that reflects ongoing loss. Conceptualizing anticipatory grief within caregiving stress frameworks highlights how vulnerability to distress may emerge from the interplay between caregiving stressors, relationship changes, and psychosocial resources. This conceptual framing may inform future research and palliative care interventions to support the well-being of family caregivers across the dementia trajectory.},
}

Humans
*Caregivers/psychology
*Dementia/psychology/complications
*Grief
Adaptation, Psychological
Stress, Psychological/psychology

@article {pmid42087813,
year = {2026},
author = {Magadi, SS and Jonson, M and Lucena, PB and Caliandro, MF and Almeida, B and Bilalli, L and Budinger, D and Tsoi, A and Ntzouni, M and Maqdissi, JA and Kaczmarczyk, L and Zijlstra, JJ and Faketija, M and Perkins, M and Paul, G and Hallbeck, M and Ingelsson, M and Watts, JC and Reichenbach, N and Petzold, GC and Schieweck, R and Heneka, MT and Jackson, WS},
title = {Neuroinflammation and neurodegeneration trigger a specific splice form of ribosomal protein S24.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag166},
pmid = {42087813},
issn = {1460-2156},
abstract = {Neuroinflammation, particularly that involving reactive microglia, the brain's resident immune cells, is implicated in the pathogenesis of major neurodegenerative diseases (NDs). Multiple studies have reported changes in ribosomal protein (RP) expression during neurodegeneration, but the significance of these changes remains unclear. Ribosomes are evolutionarily conserved protein-synthesizing machines, and although commonly viewed as invariant, accumulating evidence suggests functional ribosome specialization through variation in their protein composition. Among RPs, S24, encoded by RPS24 in humans and Rps24 in mice, is unique as its transcripts undergo alternative splicing to produce protein variants with different C-terminal sequences that are differentially expressed across tissues and cell types. Understanding heterogeneous RP expression patterns across brain regions and cell types could reveal mechanisms underlying selective vulnerability in NDs and provide new biomarkers for neuroinflammatory responses. To identify RP expression patterns across brain regions in neurons, astrocytes, and microglia we analyzed cell type-specific translating mRNAs from mice. To investigate Rps24 isoform-specific expression, we performed cell type-resolved transcript analysis and developed antibodies specific for the S24-PKE protein variant encoded by mRNA isoform Rps24c. We examined Rps24c/S24-PKE expression in brains from mouse models of aging and neurodegeneration, as well as in human postmortem tissue from patients with Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). This work revealed distinct RP expression patterns across brain regions and between neurons, astrocytes, and microglia, including neuron-enriched RPs Rpl13a and Rps10. Analysis of RP paralogs revealed complex expression relationships with their canonical counterparts, suggesting regulated mechanisms for generating heterogeneous ribosomes. Across brain regions and cell types, Rplp0 and Rpl13a, commonly used normalization references, showed heterogeneous expression, raising important methodological considerations for gene expression studies. Rps24 isoforms exhibited striking cell type-specific expression patterns. Rps24c was predominantly expressed in microglia and was increased by neuroinflammation caused by aging, neurodegeneration, or inflammatory chemicals. Using S24-PKE-specific antibodies, we verified increased expression of this protein variant in brains with AD, PD, and HD, and in relevant mouse models. These findings establish heterogeneous RP expression as a feature of brain cell types which may enable cell type-specific translation regulation via specialized ribosomes. This work also identifies Rps24c/S24-PKE as a potential novel marker for neuroinflammation and neurodegeneration and provides new tools for monitoring these responses.},
}

@article {pmid42087846,
year = {2026},
author = {Yang, Y and Wu, T and Fan, X and Yao, Y and Chen, C and Kang, K and Tang, X and Huang, T and Xu, Y and He, Y and Chen, Z and Chen, Z and Yang, H},
title = {Dynamic Covalent Peptide-Drug Conjugates Address the Heterogeneity in Alzheimer's Disease Progression.},
journal = {Advanced materials (Deerfield Beach, Fla.)},
volume = {},
number = {},
pages = {e16343},
doi = {10.1002/adma.202516343},
pmid = {42087846},
issn = {1521-4095},
support = {22421002//National Natural Science Foundation of China/ ; 22334004//National Natural Science Foundation of China/ ; 22577014//National Natural Science Foundation of China/ ; 22404025//National Natural Science Foundation of China/ ; C2301011//Shenzhen Medical Academy of Research and Translation/ ; KJZD20230923114406014//Shenzhen Science and Technology Major Project/ ; //New Cornerstone Science Foundation/ ; },
abstract = {A growing understanding of the pathophysiological evolution of Alzheimer's disease (AD) underscores the heterogeneity in its progression as a critical factor undermining the success of various candidate interventions and complicating the establishment of effective pharmacotherapeutic regimens. Here, we introduce the development of a hierarchical-responsive therapeutic agent self-assembled from phenylboronate ester-linked Tjernberg's KLVFF peptide-curcumin conjugates (CPKNAs), which is designed to dynamically track the spatiotemporal coordinates of biomarkers associated with AD heterogeneity in progression. The dynamic covalent phenylboronate ester bond undergoes varying degrees of dissociation in response to the temporal evolution patterns of amyloid-β, reactive oxygen species, and glucose, three key indicators for staging AD progression, enabling self-adaptive regulation of drug distribution and dosing tailored to specific phenotypes. Employing seven cellular models and three types of transgenic mice simulating different AD stages, we demonstrate that CPKNAs effectively minimize the risks of under- or overtreatment, achieving consistent therapeutic outcomes in mitigating cellular damage and improving brain dysfunction.},
}

@article {pmid42087981,
year = {2026},
author = {Wang, Q and Zhou, K and Zhang, M and Dong, Y and Zhao, M},
title = {Association between dentition defects and Alzheimer's disease risk: a systematic review and meta-analysis.},
journal = {Frontiers in dental medicine},
volume = {7},
number = {},
pages = {1783171},
pmid = {42087981},
issn = {2673-4915},
abstract = {BACKGROUND: Alzheimer's Disease (AD) is the most common neurodegenerative disorder among the elderly, with a steadily rising prevalence that poses a significant global public health challenge. Recently, dentition defects (DD), such as tooth loss, have gained attention as potential risk factors influencing neurocognitive health. However, the relationship between DD and AD remains inconclusive, necessitating a systematic analysis to clarify this association.

METHODS: This systematic review and meta-analysis was conducted in accordance with PRISMA guidelines. We searched PubMed, Embase, Web of Science, and Cochrane Library databases to identify relevant studies published between 1996 and 2022. Eligible studies assessing the relationship between DD and AD were included. A random-effects model was applied to estimate the pooled odds ratios (ORs) with 95% confidence intervals (CIs). Heterogeneity and publication bias were also assessed.

RESULTS: Fourteen studies were included, with sample sizes ranging from 52 to 156,450 participants. The meta-analysis revealed a significant association between DD and an increased risk of AD (OR=1.38, 95% CI: 1.09-1.74, P < 0.05). Heterogeneity among the studies was substantial (I² = 97%), reflecting considerable variability in study designs, populations, and exposure definitions. Sensitivity analysis and publication bias assessments indicated the reliability of the results despite high heterogeneity. Mechanistic analyses suggested that DD may elevate AD risk through pathways such as chronic inflammation, nutritional deficiencies, alterations in the oral microbiome, and reduced cognitive reserve.

CONCLUSIONS: DD are significantly associated with an increased risk of AD. Improving oral health may represent a modifiable factor warranting. However, further high-quality prospective studies are needed to validate these findings and explore the underlying mechanisms.},
}

@article {pmid42088060,
year = {2026},
author = {Hou, DL and Ho, J and Guan, T and Dong, XX and Zeng, L and Sanders, LH and Wu, YC and Tan, EK and Zhou, ZD},
title = {E3 ubiquitin ligases in neurodegenerative diseases.},
journal = {Military Medical Research},
volume = {13},
number = {1},
pages = {100032},
pmid = {42088060},
issn = {2054-9369},
mesh = {Humans ; *Ubiquitin-Protein Ligases/therapeutic use ; *Neurodegenerative Diseases/physiopathology ; },
abstract = {Neurodegenerative diseases (NDs) are characterized by progressive neuronal loss and proteostatic failure, driven by impaired clearance of misfolded proteins via the ubiquitin-proteasome system (UPS) and autophagy. In UPS, E3 ubiquitin ligases are crucial for regulating protein ubiquitination and degradation. Mutations in E3 ligases, along with dysfunctions of specific ligases such as Parkin, the C-terminus of HSC70-interacting protein (CHIP), and tripartite motif-containing proteins, have been identified as key factors in the buildup of amyloid-β, α-synuclein, tau, trans-active response DNA-binding protein 43, and mutant huntingtin. These accumulations are associated with NDs like Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. Therapeutic strategies targeting E3 ligases, particularly proteolysis-targeting chimeras (PROTACs), are being developed for ND treatment and are currently in clinical trials. These approaches aim to enhance E3 ligase activity and promote selective protein degradation. Here, we examine how individual E3 ligases influence cell-fate decisions in NDs, showing that their substrate selection determines whether neurons survive or die. Building on this knowledge, we present an innovative therapeutic pipeline that includes ligase activators, PROTAC degraders, and miRNA switches, which are molecules designed to transition from research to clinical application.},
}

Humans
*Ubiquitin-Protein Ligases/therapeutic use
*Neurodegenerative Diseases/physiopathology

@article {pmid42088084,
year = {2026},
author = {Kim, H and Lee, J and Park, HK and Lee, KB and Kim, JP and Lee, BH},
title = {Baseline Clinical and Neuropsychological Characteristics of Amyloid PET-Confirmed Alzheimer's Disease Treated With Lecanemab: Early Experience at a Tertiary Hospital in Korea.},
journal = {Dementia and neurocognitive disorders},
volume = {25},
number = {2},
pages = {137-139},
pmid = {42088084},
issn = {2384-0757},
}

@article {pmid42088086,
year = {2026},
author = {Shim, Y},
title = {Stage-Specific Efficacy of Lecanemab and Donanemab in Early Alzheimer's Disease: An Indirect, Comparative Interpretation of Phase 3 Trials.},
journal = {Dementia and neurocognitive disorders},
volume = {25},
number = {2},
pages = {130-133},
pmid = {42088086},
issn = {2384-0757},
}

@article {pmid42088293,
year = {2026},
author = {Li, JH and Lian, TH and Guo, P and Li, J and Qi, J and He, MY and Luo, DM and Zhang, YN and Liu, GF and Huang, Y and Zhang, WJ and Zheng, ZJ and Yue, H and Guan, HY and Liu, Z and Zhang, F and Meng, Y and Zhang, W},
title = {Different stages of Alzheimer's disease with periodontitis: clinical features and potential mechanisms involving gingipains, neuropathological biomarkers and neurological damage.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1737524},
pmid = {42088293},
issn = {1663-4365},
abstract = {BACKGROUND: Alzheimer's disease (AD) and periodontitis are common in older adults aged over 65 years. However, the clinical features and mechanisms at the stages of mild cognitive impairment and dementia due to AD (AD-MCI and AD-D) remain unknown.

METHODS: In 110 patients with AD-MCI and AD-D, oral hygiene, periodontitis status, clinical symptoms and the levels of gingipain, neuropathological biomarkers and neurological damage indicators in cerebrospinal fluid were evaluated.

RESULTS: The frequency of periodontitis was 38.18% in the AD-MCI group and 67.27% in the AD-D group. The AD-MCI with periodontitis group had significantly worse cognition and lower β-amyloid (Aβ) level than those without periodontitis (all p < 0.05). The AD-D with periodontitis group had further impaired cognition and more severe neuropsychiatric symptoms. Gingipain K (K-GP) level was significantly correlated with Aβ, phosphorylated tau 199 and synaptosomal-associated protein 25 levels in the cerebrospinal fluid from AD-D with periodontitis group (all p < 0.05).

CONCLUSION: Periodontitis is more prevalent and severe in AD patients. K-GP plays a significant role in AD with periodontitis, and is associated with AD pathology and impairs cognition at the MCI stage. K-GP contributes to the exacerbation of AD pathology and neurodegeneration, and is potentially involved in the aggravation of symptoms at the dementia stage.},
}

@article {pmid42088298,
year = {2026},
author = {Zhang, F and Wang, Y and Lv, D and Cai, L and Zhou, F},
title = {Mindfulness-based stress reduction combined with reminiscence therapy: a non-pharmacological approach for older adults with mild cognitive impairment or mild dementia due to Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1772932},
pmid = {42088298},
issn = {1663-4365},
abstract = {OBJECTIVES: Non-pharmacological approaches are preferable to improve functional capacity and reduce emotional disorders for dementia patients with cognitive decline. This study aimed to assess the effectiveness of mindfulness-based stress reduction (MBSR) combined with reminiscence therapy (RT) on cognitive function and behavioral and psychological symptoms in older adults with mild cognitive impairment (MCI) or mild dementia due to Alzheimer's disease (AD).

METHODS: A total of 114 participants were randomly assigned to receive the reminiscence therapy combined with the MBSR program (n = 58) and to receive the reminiscence therapy only (n = 56) by using a computer-generated random table. The primary outcome measure was the Alzheimer's Disease Assessment Scale-Cognitive section (ADAS-Cog) scale for assessing cognitive impairment. The secondary outcome measures were scores of the Cornell Scale for Depression in Dementia (CSDD) scale, Neuropsychiatric Inventory (NPI) scale, and Spirituality Index of Well-Being (SIWB) scale to evaluate depressive symptoms, behavioral symptoms, and spiritual wellbeing, respectively.

RESULTS: The RT+MBSR group exhibited lower scores in the ADAS-Cog scale, CSDD scale, and NPI scale, with a higher score in the SIWB scale than the RT group post intervention and 3 months post intervention, suggesting MBSR program combined with RT could improve cognitive function, depressive, behavioral symptoms, and spiritual wellbeing of older adults with MCI or mild dementia.

CONCLUSION: The positive effects of MBSR program combined with RT on cognitive function and neuropsychiatric symptoms among patients with MCI or mild dementia suggest the need for more widespread use of this combination for older adults in geriatric care units.},
}

@article {pmid42088504,
year = {2026},
author = {Shibata, T and Bhat, SA and Cao, D and Saito, S and Bernstein, EA and Okwan-Duodu, D and Tourtellotte, WG and Bernstein, KE and Khan, Z},
title = {Angiotensin-converting enzyme overexpression in mouse neutrophils prevents Alzheimer's-like cognitive decline.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1674330},
pmid = {42088504},
issn = {1664-3224},
mesh = {Animals ; *Alzheimer Disease/genetics/prevention & control/metabolism/pathology ; *Neutrophils/enzymology/immunology/metabolism ; Mice ; Mice, Transgenic ; Disease Models, Animal ; *Peptidyl-Dipeptidase A/genetics/metabolism ; *Cognitive Dysfunction/prevention & control/genetics ; Amyloid beta-Peptides/metabolism ; Brain/pathology/metabolism ; Male ; Phagocytosis ; Humans ; },
abstract = {Angiotensin-converting enzyme (ACE), a dipeptidyl carboxypeptidase, is known to cleave amyloid-beta (Aβ), and its reduced activity has been linked to the progression of Alzheimer's disease (AD). Our research indicates that ACE is vital for myeloid cell functions. Using ACE10/10 recombinant mice, we demonstrated that overexpressing ACE in macrophages mitigates AD pathology in these mice. Given that neutrophils are the most abundant white blood cells, this study investigates whether ACE overexpression in neutrophils influences AD progression. We crossed NeuACE mice, which overexpress ACE in neutrophils, with 3xTg-AD mice to create AD-NeuACE mice. Behavioral changes and brain pathology were assessed through various behavioral mazes and histological assays. AD-NeuACE mice demonstrated improved cognitive functions and lower Aβ levels in the cortex and hippocampus compared to AD mice. In-vitro data indicate that ACE-overexpressing neutrophils are significantly more effective at phagocytosing and clearing Aβ fluorescence particles. This study suggests that overexpressing ACE in neutrophils could be a promising approach to managing AD-like phenotypes.},
}

Animals
*Alzheimer Disease/genetics/prevention & control/metabolism/pathology
*Neutrophils/enzymology/immunology/metabolism
Mice
Mice, Transgenic
Disease Models, Animal
*Peptidyl-Dipeptidase A/genetics/metabolism
*Cognitive Dysfunction/prevention & control/genetics
Amyloid beta-Peptides/metabolism
Brain/pathology/metabolism
Male
Phagocytosis
Humans

@article {pmid42088648,
year = {2026},
author = {Chen, K and Nong, Y and Liu, Y and Ye, Z},
title = {Insulin Resistance Across Cerebrovascular and Related Disorders: Mechanisms, Measurement, Genetics, and Clinical Implications.},
journal = {Neuropsychiatric disease and treatment},
volume = {22},
number = {},
pages = {575306},
pmid = {42088648},
issn = {1176-6328},
abstract = {Insulin resistance (IR) Insulin resistance (IR) is a central metabolic disturbance implicated in a broad range of cardiometabolic and neurological disorders. Increasing evidence suggests that IR plays a pivotal role in the initiation and progression of cerebrovascular diseases (CeVD) and contributes to neurodegeneration through shared molecular and vascular mechanisms. In the brain and its vasculature, impaired insulin signaling-particularly involving the IRS-PI3K-Akt-GSK-3β axis-interacts with inflammation, oxidative stress, endothelial dysfunction, and neurovascular unit impairment, thereby linking CeVD with Alzheimer's disease, Parkinson's disease, and cerebral small-vessel disease. Advances in the assessment of IR, ranging from traditional indices such as HOMA-IR to surrogate markers including the triglyceride-glucose (TyG) index and METS-IR, have enabled large-scale population studies and improved risk stratification for cardiometabolic disorders, with emerging relevance to cerebrovascular and cognitive outcomes. In parallel, genetic and Mendelian randomization studies support a causal contribution of IR-related traits to hypertension, atherosclerosis, and stroke risk, highlighting shared susceptibility pathways across metabolic and neurological phenotypes. This review synthesizes current evidence on the mechanisms, measurement, genetic architecture, and clinical implications of IR across cerebrovascular and related disorders. By integrating mechanistic insights with epidemiological and translational data, we propose IR as a tractable, cross-cutting therapeutic target. Future priorities include standardizing IR assessment, validating brain-relevant biomarkers, and linking mechanistic pathways to longitudinal cerebrovascular and neurodegenerative outcomes to advance precision prevention and individualized care.},
}

@article {pmid42088780,
year = {2026},
author = {Marongiu, R and Cordato, D and Reiss, AB},
title = {Editorial: Genetic underpinnings of Alzheimer's and Parkinson's: insights and innovations.},
journal = {Frontiers in genetics},
volume = {17},
number = {},
pages = {1846361},
pmid = {42088780},
issn = {1664-8021},
}

@article {pmid42088846,
year = {2026},
author = {Hammers, DB and Polsinelli, A and Eloyan, A and Taurone, A and Thangarajah, M and Foroud, T and Gao, S and Beckett, L and La Joie, R and Touroutoglou, A and Vemuri, P and Zetterberg, H and Blennow, K and Nemes, S and Kostadinova, R and Aisen, P and Nudelman, KN and Kirby, K and Atri, A and Clark, D and Day, GS and Duara, R and Graff-Radford, NR and Grant, I and Honig, LS and Johnson, ECB and Jones, DT and Masdeu, JC and Mendez, MF and Parand, L and Womack, K and Musiek, E and Onyike, CU and Riddle, M and Rogalski, E and Salloway, S and Sha, SJ and Turner, RS and Wingo, TS and Wolk, DA and Carrillo, MC and Rabinovici, GD and Dickerson, BC and Dage, JL and Apostolova, LG and , },
title = {Criterion and convergent validity of plasma biomarkers in early-onset Alzheimer's disease: Initial findings from LEADS.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {},
pages = {e70342},
pmid = {42088846},
issn = {2352-8729},
abstract = {INTRODUCTION: Despite expanding use of plasma biomarkers for Alzheimer's disease (AD), minimal examination has been undertaken in early-onset AD (EOAD). Prior analyses assessed criterion and convergent validity of common plasma biomarkers in a well-characterized sample with sporadic EOAD. METHODS: Plasma amyloid beta (Aβ) 42/40, tau phosphorylated at threonine 231 (p-tau231), glial fibrillary acidic protein (GFAP), and neurofilament light change (NfL) levels were obtained for 189 EOAD, 52 early-onset non-AD (EOnonAD), and 83 cognitively normal (CN) participants. Diagnostic group differences, convergence with imaging biomarkers, and the capacity to predict specific cognitive domains were investigated. RESULTS: After controlling for cognitive status, EOAD participants exhibited more pathologic levels of Aβ42/40, p-tau231, and GFAP relative to EOnonAD participants. However, NfL displayed the greatest sensitivity to non-amnestic cognitive impairment across the sample. DISCUSSION: These results establish criterion and convergent validity of plasma biomarkers in sporadic EOAD and highlight complementary roles that AD-specific and non-specific plasma markers may play across the course of AD care.},
}

@article {pmid42089062,
year = {2026},
author = {Gao, J and Song, ML and Liu, J and Jiang, Z and Li, W and Chen, Y},
title = {Epimedium attenuates neuroinflammation and ameliorates Alzheimer's disease through a KAT2B-dependent mechanism.},
journal = {Frontiers in medicine},
volume = {13},
number = {},
pages = {1811410},
pmid = {42089062},
issn = {2296-858X},
abstract = {BACKGROUND: Alzheimer's disease (AD) is the leading cause of dementia worldwide, yet effective therapies for this neurodegenerative disorder remain scarce. Epimedium, a herb with a history of thousands of years in traditional Chinese medicine, exhibits diverse biological activities and holds potential therapeutic effects against Alzheimer's disease. However, studies on its modern pharmacological mechanisms remain relatively limited.

METHODS: TCMSP and PubChem were used to retrieve Epimedium constituents, and SwissTargetPrediction was used to predict potential targets. GeneCards, OMIM, and GEO databases were used to identify targets associated with AD. The AD model was established by intragastric administration of AlCl3 combined with intraperitoneal injection of D-galactose, with the normal saline group serving as controls. Cognitive function was assessed by the Morris water maze, and histopathological changes were observed by H&E staining. ELISA detected IL-1β and TNF-α levels, and qRT-PCR detected KAT2B, NF-κB, IL-1β, and TNF-α expression.

RESULTS: We identified 172 key targets, with KAT2B and ACACB determined as core genes through transcriptomic screening. In vivo studies showed that Epimedium significantly ameliorated cognitive deficits and alleviated histopathological damage in hippocampal neurons. Furthermore, Epimedium suppressed neuroinflammation by reducing IL-1β and TNF-α levels and modulated the mRNA expression of key targets (KAT2B, NF-κB) in the hippocampus.

CONCLUSION: Epimedium improves pathological alterations in the hippocampal tissue and alleviates cognitive and behavioral impairments in rats by modulating neuroinflammation through KAT2B, thereby providing a scientific basis for its potential application and development as a therapeutic agent.},
}

@article {pmid42089471,
year = {2026},
author = {Shu, D and Fu, C and Liu, Z and Li, C},
title = {The role of Annexin A2 in Alzheimer's disease: From cellular functions to therapeutic potential.},
journal = {The FEBS journal},
volume = {},
number = {},
pages = {},
doi = {10.1111/febs.70574},
pmid = {42089471},
issn = {1742-4658},
support = {31900692//National Natural Science Foundation of China/ ; 32070961//National Natural Science Foundation of China/ ; 2024AFB558//Natural Science Foundation of Hubei Province/ ; },
abstract = {Alzheimer's disease (AD), a progressive neurodegenerative disorder with a rising global prevalence, is pathologically characterised by the presence of amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs). These lesions lead to synaptic damage, neuronal loss, and cognitive impairment. Despite the recent approval of immunotherapies for AD treatment, their limited efficacy highlights the urgent need for exploring novel disease mechanisms and developing targeted therapeutic strategies. Annexin A2 (ANXA2), a calcium-dependent phospholipid-binding protein, participates in diverse physiological processes (e.g. membrane organisation, cytoskeleton linkage) and contributes to the pathogenesis of diseases such as cancer and Parkinson's disease. Emerging evidence indicates that ANXA2 interacts with AD-related pathological components (Aβ, tau) and regulates AD-associated inflammatory pathways, suggesting its potential role in AD. However, current evidence regarding ANXA2 in AD remains limited, and the molecular mechanisms underlying its contribution to AD pathogenesis remain unclear. This review comprehensively summarises the current knowledge on ANXA2's cellular and physiological functions in the central nervous system (CNS), as well as its involvement in AD pathology, aiming to provide guidance for research into ANXA2's therapeutic potential for AD prevention and treatment.},
}

@article {pmid42089534,
year = {2026},
author = {Liang, S and Lapane, KL and Ott, BR and Tjia, J and Baek, J and Yuan, Y and Alcusky, M},
title = {Antidepressant Use Among US Nursing Home Residents With Dementia.},
journal = {Journal of the American Geriatrics Society},
volume = {},
number = {},
pages = {},
doi = {10.1111/jgs.70492},
pmid = {42089534},
issn = {1532-5415},
support = {5R01AG068450-03/AG/NIA NIH HHS/United States ; },
abstract = {BACKGROUND: In 2024, 6.9 million Americans lived with Alzheimer's disease and related dementias (ADRD), with nursing homes serving as a major site of care. Antidepressants are the most prescribed psychotropic medications among nursing home residents with ADRD, yet detailed information on prescribing patterns, potential indications, and associated resident and facility characteristics remain limited.

METHODS: Using 2018 minimum data set 3.0 assessments linked to Medicare claims, we conducted a cross-sectional study of long-stay nursing home residents aged ≥ 65 years with ADRD who were continuously enrolled in Medicare fee-for-service for 120 days before their annual assessment. We described usage by drug class and type and compared characteristics of users versus non-users overall and by potential indications: depression, anxiety, pain, and insomnia.

RESULTS: Among 232,543 residents with ADRD, 51.6% used antidepressants. Fewer than 5% had moderate or severe depressive symptoms (PHQ-9 ≥ 10). Use was highest among residents with depression or anxiety (69.5%), pain (61.9%), and insomnia (60.0%). Among those without these conditions, 14.1% were prescribed antidepressants. SSRIs were the most prescribed class (60.7%) overall. Citalopram, mirtazapine, sertraline, and trazodone were the most common medications. Residents with any current level of depression severity were more likely to use antidepressants compared to those without symptoms, whereas all levels of cognitive impairment were associated with lower use compared with cognitively intact residents with ADRD. Polypharmacy was strongly associated with increased use, while diabetes, heart failure, and stroke were associated with reduced use.

CONCLUSIONS: Antidepressants were frequently prescribed to residents with ADRD despite limited documentation of active depressive symptoms. Limitations in accurately capturing depressive symptoms in nursing home records, including underreporting by residents due to cognitive impairment and reliance on staff observation rather than self-report, may contribute to apparent discordance between symptoms and prescribing. Further research should evaluate treatment appropriateness, deprescribing opportunities, and risk-benefit balance of chronic treatment in this population.},
}

@article {pmid42089562,
year = {2026},
author = {Nguyen, TH and Ngo, ST and Derreumaux, P and Nguyen, PH},
title = {Dynamics of Aβ42 Tetramer by REST2-CHARMM36m Simulations.},
journal = {The journal of physical chemistry. B},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jpcb.6c00773},
pmid = {42089562},
issn = {1520-5207},
abstract = {It has long been recognized that one-third of individuals with Alzheimer's disease (AD) have no cognitive deficit, underscoring the limitations of therapeutic strategies based solely on the amyloid cascade hypothesis. This observation does not negate the clinical relevance of targeting amyloid deposition or clearance, but rather emphasizes that amyloid pathology constitutes only one component of a multifactorial disease process. Due to the intrinsic disorder of the Aβ40 and Aβ42 peptides, the early transient oligomers, widely believed to represent the first neurotoxic species, remain inaccessible to atomic-level characterization. In this study, we focus on the Aβ42 tetramer, although the literature remains divided regarding the identity of the earliest dominant detectable oligomeric species. Given the size of the system, it is currently computationally infeasible to capture equilibrium oligomer structures starting from randomly coiled monomers with arbitrary orientations. In a recent study, AlphaFold2, which is not designed for intrinsically disordered proteins (IDP), provided three candidate topologies: (i) a four α-helix bundle in which helices span the C-terminal region and (ii) two conformations with high β-sheet contents. In this study, we initiate our simulations from the helix topology, as the α-helical content is most consistent with circular dichroism and FTIR experimental data. We employ replica exchange with solute tempering (REST2) in combination with the CHARMM36m force field. Our simulations consistently show that the Aβ42 tetramer relaxes to a heterogeneous random-coil ensemble, indicating that oligomers larger than tetramers are required to stabilize structured assemblies and initiate fibril growth.},
}

@article {pmid42089694,
year = {2026},
author = {Bagul, AD and Irfan, M and Jaitak, A and Asati, V and Goyal, K and Monga, V},
title = {Current Landscape of Indole Hybrids in the Design and Development of Anti-Alzheimer Agents: Structural Insights, Therapeutic Potential and In Silico Studies.},
journal = {Archiv der Pharmazie},
volume = {359},
number = {5},
pages = {e70248},
doi = {10.1002/ardp.70248},
pmid = {42089694},
issn = {1521-4184},
mesh = {Humans ; *Indoles/chemistry/pharmacology/chemical synthesis ; *Alzheimer Disease/drug therapy ; *Drug Design ; Structure-Activity Relationship ; Molecular Structure ; Animals ; Computer Simulation ; Drug Development ; Cholinesterase Inhibitors/pharmacology/chemistry/chemical synthesis ; },
abstract = {Alzheimer's disease (AD) is an irreversible neurodegenerative disorder characterised by progressive cognitive decline, neuronal loss and accumulation of β-amyloid plaques and neurofibrillary tangles. Even after many years of intensive research, scientists still have not found a cure for AD. The current medications can only help to manage the symptoms of AD or slow down the disease progression. This highlights an urgent and unmet need for the development of novel therapeutic agents capable of simultaneously modulating the multifactorial pathological pathways that drive the onset and progression of AD. The multitarget-directed ligand approach has garnered considerable attention in this context, aiming to simultaneously modulate multiple disease-relevant targets, including AChE, BChE, MAO-A and MAO-B, BACE1, and oxidative stress mediators. Indole, a fortunate heterocyclic scaffold, has become a valuable tool for the design and development of multi-target directed ligands in anti-Alzheimer drug discovery due to its favourable physicochemical properties, BBB permeability and medicinal attributes. This review summarises recent advancements in the medicinal chemistry of indole hybrids as anti-Alzheimer agents, highlighting the impact of structural modifications on biological activity, including the underlying molecular mechanisms, structure-activity relationships, and computational studies. The findings summarised in the article can pave the way for future anti-Alzheimer drug discovery.},
}

Humans
*Indoles/chemistry/pharmacology/chemical synthesis
*Alzheimer Disease/drug therapy
*Drug Design
Structure-Activity Relationship
Molecular Structure
Animals
Computer Simulation
Drug Development
Cholinesterase Inhibitors/pharmacology/chemistry/chemical synthesis

@article {pmid42089739,
year = {2026},
author = {Jemma, H and Mealing, M and Lorencatto, F and Rapaport, P and Keshavan, A and Schott, JM and Rodda, J and Howard, R},
title = {Factors influencing implementation of an Alzheimer's disease blood test among UK old age psychiatrists: mixed-methods study using the theoretical domains framework.},
journal = {Age and ageing},
volume = {55},
number = {5},
pages = {},
doi = {10.1093/ageing/afag117},
pmid = {42089739},
issn = {1468-2834},
mesh = {Humans ; *Alzheimer Disease/blood/diagnosis/psychology ; Male ; Female ; Biomarkers/blood ; United Kingdom ; Middle Aged ; Attitude of Health Personnel ; *Geriatric Psychiatry ; Aged ; Focus Groups ; Health Knowledge, Attitudes, Practice ; *Practice Patterns, Physicians' ; Predictive Value of Tests ; Psychiatrists ; },
abstract = {INTRODUCTION: Only 6% of UK memory services meet Alzheimer's disease (AD) biomarker access guidelines, limiting psychiatrists' experience. Emerging AD blood biomarker (BBM) tests will potentially expand access. Exploring implementation barriers and enablers a priori can inform rollout strategies. This study examined current clinical practises, barriers and enablers to implementation and potential interventions to support implementation.

METHODS: In November 2024, Royal College of Psychiatrists Old Age Psychiatry Faculty members (n = 172) participated in an online survey and four focus groups (n = 16 participants), informed by the Theoretical Domains Framework (TDF) and Behaviour Change Wheel. Demographic data were summarised descriptively. Mean (SD) belief statement scores for TDF domains and percentage agreement were calculated. Multiple linear regression examined associations between TDF domains and intention to use BBMs.

RESULTS: Respondents were mainly consultants in England; <33% had used biomarkers. Key barriers to use were: 'Knowledge,' 'Environmental Context and Resources' and 'Goals.' Enablers included: 'Behavioural Regulation,' 'Social Influences' and 'Intention.' Mixed enablers/barriers included: 'Beliefs about Consequences', 'Optimism' and 'Social/Professional Role & Identity'. In regression analyses, 'Memory, Attention and Decision Processes' (B = 0.44, 95%CI 0.20-0.68), 'Beliefs about Consequences'(B = 0.45, 95%CI 0.11-0.78), and 'Social Influences' (B = 0.24, 95%CI 0.04-0.44) were positively associated with intention, while 'Optimism' (B = -0.31,95% CI-0.58 to-0.04) and 'Emotion' (B = -0.33, 95%CI -0.60 to-0.06) were negatively associated. Key interventions were 'Guidelines' (e.g. appropriate use criteria) and 'Environmental Restructuring' to expand resources and re-organise pathways.

DISCUSSION: A complex interplay of barriers and enablers influences AD BBM implementation. Interventions targeting clinician, service and policy levels are required to support their introduction.},
}

Humans
*Alzheimer Disease/blood/diagnosis/psychology
Male
Female
Biomarkers/blood
United Kingdom
Middle Aged
Attitude of Health Personnel
*Geriatric Psychiatry
Aged
Focus Groups
Health Knowledge, Attitudes, Practice
*Practice Patterns, Physicians'
Predictive Value of Tests
Psychiatrists

@article {pmid42089777,
year = {2026},
author = {Carrión, N and Heredia, L and Peña-Casanova, J and Torrente, M},
title = {Clinical applicability of the BT2-NPS for assessing neuropsychiatric symptoms across the Alzheimer's disease continuum.},
journal = {Archives of clinical neuropsychology : the official journal of the National Academy of Neuropsychologists},
volume = {41},
number = {4},
pages = {},
doi = {10.1093/arclin/acag029},
pmid = {42089777},
issn = {1873-5843},
support = {PID2019-103888RB-I00//DEM-BIOTA/ ; 2025 FI-1 00107//the predoctoral program AGAUR-FI ajuts/ ; //Joan Oró from the Department of Research and Universities of the Generalitat de Catalunya/ ; //Fons Social Europeu Plus/ ; },
mesh = {Humans ; *Alzheimer Disease/diagnosis/psychology/complications ; Aged ; Male ; Female ; Aged, 80 and over ; *Cognitive Dysfunction/diagnosis/psychology ; Middle Aged ; *Neuropsychological Tests ; Disease Progression ; *Psychiatric Status Rating Scales ; Severity of Illness Index ; },
abstract = {OBJECTIVE: This study aimed to examine the clinical applicability of the Barcelona-2 Test Neuropsychiatric Symptomatology Scale (BT2-NPS) in a Spanish population comprising healthy controls (HC), individuals with single-domain amnestic mild cognitive impairment (aMCI), and individuals with Alzheimer's disease (AD). Specifically, the study sought to characterize the distinct trajectories of neuropsychiatric symptoms (Behavioral and Psychological Symptoms of Dementia [BPSD]) across the cognitive continuum and evaluate the scale's diagnostic utility.

METHOD: A total of 37 HC, 31 aMCI, and 76 AD participants, aged 60-85 years, were assessed using the BT2-NPS. Quade's test (controlling for age and education) was used to examine the differences in BT2-NPS scores across diagnostic groups and Global Deterioration Scale (GDS) stages. Symptom progression was analyzed descriptively to identify patterns, and partial convergent validity was explored using the Goldberg Anxiety and Depression Scale (GADS).

RESULTS: The BT2-NPS Total score significantly differentiated between diagnostic groups and GDS stages. Three distinct symptom patterns emerged: a "Severity-Dependent" Pattern (e.g., apathy, insight loss) increasing linearly with severity; an "Inverted-U Pattern" (e.g., anxiety, depression) peaking in prodromal stages before declining; and a "Late-Emergence Pattern" (e.g., hallucinations) appearing only in advanced stages. No gender differences were observed. Correlations with self-reported GADS were weak.

CONCLUSION: Findings support the BT2-NPS as a clinically meaningful tool for staging BPSD in older adults. Crucially, the study demonstrates that affective symptoms may decline in later stages not due to clinical remission, but due to the progression of apathy and loss of insight. The scale captures this complex behavioral landscape, contributing to more personalized and compassionate care approaches.},
}

Humans
*Alzheimer Disease/diagnosis/psychology/complications
Aged
Male
Female
Aged, 80 and over
*Cognitive Dysfunction/diagnosis/psychology
Middle Aged
*Neuropsychological Tests
Disease Progression
*Psychiatric Status Rating Scales
Severity of Illness Index

@article {pmid42089797,
year = {2026},
author = {Ulitsa, N and Werner, P and AboJabel, H and Endgau, S and Marey-Sarwan, I},
title = {What Non-Professional Community Members From Minority Groups in Israel Think About Alzheimer's Disease: A Comparative Perspective.},
journal = {Dementia (London, England)},
volume = {},
number = {},
pages = {14713012261449850},
doi = {10.1177/14713012261449850},
pmid = {42089797},
issn = {1741-2684},
abstract = {Alzheimer's disease (AD) is the most common cause of dementia worldwide, yet awareness, diagnosis-seeking, and caregiving practices are strongly shaped by cultural and social contexts. Minority groups often face compounded barriers due to stigma, limited knowledge, and systemic inequalities. In Israel, a multicultural society, little is known about how non-professional community members from different minority groups perceive AD, seek diagnosis, and conceptualize appropriate care. We conducted a qualitative comparative study using six focus groups with 43 non-professional community members from three minority groups in Israel: Israeli Arabs (n = 14), immigrants from the Former Soviet Union (FSU; n = 15), and Ethiopia (n = 14). Discussions were conducted in Arabic, Russian, and Hebrew, audio-recorded, transcribed, and analyzed thematically. Three overarching themes emerged across groups: (1) Stigma: across all groups, participants demonstrated limited knowledge and misconceptions about AD, accompanied by stigmatizing stereotypes, fear, and behavioral responses such as social distancing, with variations in how stigma was expressed; (2) Diagnosis-seeking patterns: Participants from Arab community and Ethiopian descent reported delayed help-seeking linked to low awareness, stigma, and cultural or spiritual interpretations, whereas FSU participants more often emphasized consulting physicians, despite ongoing confusion between normal aging and AD; (3) Care preferences: Participants from Arab community and Ethiopian descent strongly preferred family-based home care, reflecting cultural and religious obligations, whereas FSU immigrants expressed greater support for institutional care, shaped by medicalized perceptions of dementia, their older age profile, and smaller family caregiving networks. The findings highlight both shared and culturally specific perceptions of AD among minority groups in Israel and demonstrate how stigma, diagnosis-seeking, and care preferences are closely interconnected. These insights underscore the need for culturally responsive public education, stigma-sensitive communication in primary care, and efforts to support earlier recognition and engagement with diagnostic services that account for diverse understandings of aging and dementia. At the system level, the findings point to the importance of targeted community outreach, culturally adapted information and interpretation services, and flexible care arrangements that better align formal dementia services with family-based caregiving norms across minority communities.},
}

@article {pmid42089822,
year = {2026},
author = {Vaccaro, R and Lorenzini, P and Giaquinto, F and Matascioli, F and Salvi, E and Carnevale, G and Locuratolo, N and Vanacore, N and Bacigalupo, I and , and , },
title = {A snapshot of Italian nursing homes for people with dementia: A national survey of 1671 facilities.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261442226},
doi = {10.1177/13872877261442226},
pmid = {42089822},
issn = {1875-8908},
abstract = {BackgroundNursing homes (NHs) that provide for people with dementia (PWD) are responsible for meeting the needs of patients and their families through medical, personal, and rehabilitative care. However, little is known regarding the Italian facilities.ObjectiveTo describe the characteristics of NHs and to detail the care services and treatments provided.MethodsIn 2023, the Italian National Institute of Health conducted a national survey to assess dementia care services and update the Dementia Observatory's online Map of Services through a detailed facility questionnaire.ResultsOverall, 1671 NHs accommodating PWD participated, representing 46.3% of facilities and 53.1% of beds. Significant disparities emerged when estimating the number of PWD per available NH across macro-area (North 214; Centre 332; South/Islands 850).R2D classification was more frequent in southern than central and northern facilities (28%, 10.9%, and 13.1%, respectively; p<0.001). Northern facilities had more rooms (North: 46, Centre: 28, South and Islands: 29; p<0.001) and beds (North: 87, Centre: 55, South and Islands: 58; p<0.001). Southern NHs had shorter admission wait times and longer stays. Conversely, Northern facilities had more staff, better training, and more digital systems and were more often integrated with day care centers and palliative care services.ConclusionsThis is the first national study assessing the accessibility and affordability of Italian NHs housing PWD. The lack of special units, tailored environments and uneven services distribution and staff highlight the fragmentation of Italy's long-term care system. NH geographical distribution is inconsistent with epidemiological estimates of PWD.},
}

@article {pmid42089894,
year = {2026},
author = {Zhu, W and Zhou, D and Zhang, G and Dai, W},
title = {Exploring peripheral immune mechanisms and potential therapeutic drugs for Alzheimer's disease.},
journal = {Naunyn-Schmiedeberg's archives of pharmacology},
volume = {},
number = {},
pages = {},
pmid = {42089894},
issn = {1432-1912},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterised by cognitive decline. Peripheral immune dysregulation often precedes central immune abnormalities and may therefore provide valuable clues for the early diagnosis and stratification of AD. Current research on peripheral immunity in AD remains limited. This study provides new insights into the pathogenesis and therapeutic strategies for AD. Bioinformatics and single-cell RNA sequencing were used to analyse peripheral immune-related gene expression in AD. Key genes and immune cell populations linked to AD were identified. Quercetin (Que) was selected as a potential therapeutic agent using drug prediction methods. Molecular docking, Western blotting (WB), and qRT-PCR were further performed to preliminarily assess the regulation of these hub genes by quercetin in an H2O2-induced HT22 neuronal oxidative stress model. Several immune-related genes, including ACTB, TP53, HIF1A, and BCL-2, were differentially expressed in AD. Gene function analysis revealed their involvement in processes like apoptosis and viral response. Pathway enrichment analysis highlighted the significance of the p53, apoptosis, and HIF-1 signaling pathways in AD. Single-cell sequencing identified key immune cell populations, such as CD4 + memory cells and NK cells. Drug prediction and experimental results indicated that quercetin may modulate these genes in a neuronal stress context, providing preliminary experimental support for its regulatory effects on AD-related hub genes. This study identified peripheral immune-related molecular features of AD and highlighted several hub genes that may represent shared molecular nodes linking peripheral immune alterations and central neuronal stress responses. The in vitro findings provide preliminary support for the regulatory effects of quercetin on these AD-related hub genes, although further validation in peripheral immune cell and in vivo models is still required.},
}

@article {pmid42089987,
year = {2026},
author = {Chen, S and Zhao, K and Shi, Z and Zhang, C and Wu, H and Tian, M and Sun, Y and He, L},
title = {Study on the improvement effect and mechanism of resveratrol on cognitive impairment in tau mutant adenovirus-induced alzheimer's disease model mice.},
journal = {Psychopharmacology},
volume = {},
number = {},
pages = {},
pmid = {42089987},
issn = {1432-2072},
abstract = {RATIONALE: Tau protein hyperphosphorylation and neuroinflammation playimportant roles in the onset and progression of Alzheimer's disease (AD). SIRT1has been implicated in the regulation of synaptic plasticity, cognitive function, andmemory, and is associated with the modulation of autophagy-and inflammation-related signaling pathways, including AMPK/mTOR/ULK1 and NF-κB. Resveratrol(RSV) has been reported to ameliorate cognitive impairment in AD models,primarily in the context of Aβ-related pathology; however, its potential effects andunderlying mechanisms in Tau-driven pathology remain incompletely understood.

OBJECTIVES: To investigate the effect of RSV on cognitive impairment in mice withTau mutation-induced Alzheimer's disease, and to explore its effects on autophagyand neuroinflammation.

METHODS: Tauopathy models were established using AAV-P301L-Tau. Cognitivefunction was assessed via behavioral tests; Hippocampal injury was evaluatedAccepted manuscriptACCEPTED MANUSCRIPTusing HE and Nissl staining, while autophagy was assessed byimmunofluorescence staining. Mechanisms were examined using Western blot,qRT-PCR, and CCK-8 assays.

RESULTS: RSV treatment was associated with attenuation of neuronal damage,reduction of p-Tau accumulation, and improvement of cognitive impairment in ADmice. Consistent trends were observed in vitro, where RSV treatment wasassociated with increased cell viability and modulation of autophagy-relatedmarkers in AAV-P301L-Tau-induced BV2 cells. In addition, RSV administration wasaccompanied by coordinated changes in signaling components related to SIRT1,AMPK/mTOR/ULK1, and NF-κB pathways, along with reduced expression ofinflammatory mediators.

CONCLUSIONS: RSV treatment was associated with coordinated modulation ofsignaling components related to the AMPK/mTOR/ULK1 and NF-κB pathways,together with improvements in cognitive performance in AD mice. These findingssupport the potential therapeutic relevance of RSV in Tau-drivenneurodegenerative pathology, while further studies are required to clarify theunderlying mechanisms.},
}

@article {pmid42089995,
year = {2026},
author = {Lu, J and Shi, L and Jin, G and Yang, Y and Zhu, F and Zhou, G},
title = {The role of DAP12 in immune-related inflammatory diseases.},
journal = {Inflammation research : official journal of the European Histamine Research Society ... [et al.]},
volume = {75},
number = {1},
pages = {},
pmid = {42089995},
issn = {1420-908X},
support = {82200591//National Natural Science Foundation of China/ ; 82270562//National Natural Science Foundation of China/ ; ZR2025MS1260//National Natural Science Foundation of Shandong Province/ ; 202503030856//Development plan of Medicine and Health Science and Technology in Shandong Province/ ; M20254301//TCM science and technology development plan of Shandong Province/ ; },
mesh = {Humans ; Animals ; *Inflammation/immunology/metabolism ; *Adaptor Proteins, Signal Transducing/immunology/metabolism ; *Immune System Diseases/immunology/metabolism ; *Membrane Proteins/immunology/metabolism ; },
abstract = {DNAX-activated protein 12 (DAP12) is a key transmembrane adaptor protein containing an immunoreceptor tyrosine-based activation motif. DAP12 associates with a broad spectrum of cell surface receptors, including triggering receptors expressed on myeloid cells (TREM1 and TREM2), myeloid DAP12-associating lectin-1 (MDL-1), sialic acid-binding immunoglobulin-like lectin 15 (Siglec15), killer cell immunoglobulin-like receptor (KIR), NKG2C/CD94, and NKp44. They form a sophisticated signaling network that precisely regulates cellular activation, differentiation, and the balance between pro-inflammatory and anti-inflammatory responses. DAP12 is predominantly expressed in innate immune cells, including monocytes/macrophages, microglia, osteoclasts, and natural killer (NK) cells, where it governs key processes like cytokine production, cytoskeletal remodeling, and cytotoxic activity. Dysregulation of DAP12 signaling has been implicated in the pathogenesis of multiple immune-related inflammatory diseases, such as multiple sclerosis, Alzheimer's disease, rheumatoid arthritis, inflammatory bowel disease, and systemic lupus erythematosus. In these conditions, DAP12 contributes to either protective or pathological outcomes depending on the receptor complex and microenvironment. This review provides a comprehensive overview of the structural characteristics of DAP12, its interaction with relevant receptors, and its specific functions in various cell types and immune-mediated inflammation.},
}

Humans
Animals
*Inflammation/immunology/metabolism
*Adaptor Proteins, Signal Transducing/immunology/metabolism
*Immune System Diseases/immunology/metabolism
*Membrane Proteins/immunology/metabolism

@article {pmid42090385,
year = {2026},
author = {Rajamohan, HR and Xu, Y and Zhu, W and Kijowski, R and Cho, K and Geras, KJ and Razavian, N and Deniz, CM},
title = {Robust disease prognosis via diagnostic knowledge preservation: A sequential learning approach.},
journal = {PloS one},
volume = {21},
number = {5},
pages = {e0344600},
doi = {10.1371/journal.pone.0344600},
pmid = {42090385},
issn = {1932-6203},
mesh = {Humans ; Prognosis ; Female ; *Alzheimer Disease/diagnosis/diagnostic imaging ; *Breast Neoplasms/diagnosis/diagnostic imaging ; *Deep Learning ; *Osteoarthritis, Knee/diagnosis/diagnostic imaging ; Magnetic Resonance Imaging ; Aged ; ROC Curve ; Disease Progression ; Male ; Middle Aged ; Mammography ; },
abstract = {Accurate disease prognosis is essential for patient care but is often hindered by the scarcity of longitudinal data. This study explores deep learning training strategies that utilize large, accessible diagnostic datasets to pretrain models aimed at predicting future disease progression in knee osteoarthritis (OA), Alzheimer's disease (AD), and breast cancer (BC). While diagnostic pretraining improves prognostic task performance, naive fine-tuning for prognosis can cause 'catastrophic forgetting,' where the model's original diagnostic accuracy degrades, a significant patient safety concern in real-world settings. To address this, we propose a sequential learning strategy with experience replay. We used cohorts with knee radiographs, brain MRIs, and digital mammograms to predict 4-year structural worsening in OA, 2-year cognitive decline in AD, and 5-year cancer diagnosis in BC. Our results showed that diagnostic pretraining on larger datasets improved prognosis model performance compared to standard baselines, boosting both the Area Under the Receiver Operating Characteristic curve (AUROC) (e.g., Knee OA external: 0.770 vs 0.747; Breast Cancer: 0.874 vs 0.848) and the Area Under the Precision-Recall Curve (AUPRC) (e.g., Alzheimer's Disease: 0.752 vs 0.683). Additionally, a sequential learning approach with experience replay achieved prognostic performance comparable to dedicated single-task models (e.g., Breast Cancer AUROC 0.876 vs 0.874) while also preserving diagnostic ability. This method maintained high diagnostic accuracy (e.g., Breast Cancer Balanced Accuracy 50.4% vs 50.9% for a dedicated diagnostic model), unlike simpler multitask methods prone to catastrophic forgetting (e.g., 37.7%). Our findings show that leveraging large diagnostic datasets is a reliable and data-efficient way to enhance prognostic models while maintaining essential diagnostic skills.},
}

Humans
Prognosis
Female
*Alzheimer Disease/diagnosis/diagnostic imaging
*Breast Neoplasms/diagnosis/diagnostic imaging
*Deep Learning
*Osteoarthritis, Knee/diagnosis/diagnostic imaging
Magnetic Resonance Imaging
Aged
ROC Curve
Disease Progression
Male
Middle Aged
Mammography

@article {pmid42090611,
year = {2026},
author = {Jung, ES},
title = {Tooth loss and long-term dementia risk: A nationwide population-based cohort study in the Republic of Korea.},
journal = {Community dental health},
volume = {},
number = {},
pages = {265539X261450847},
doi = {10.1177/0265539X261450847},
pmid = {42090611},
issn = {0265-539X},
abstract = {Objective: Evidence linking tooth loss to dementia is limited by cross-sectional designs and short follow-ups. This study examined the association between tooth loss and long-term dementia incidence in a nationwide cohort in the Republic of Korea, from a dental public health perspective. Basic research design: Observational cohort study. Participants: Data from 112,070 adults aged ≥40 years in the National Health Insurance Service-Health Screening Cohort who completed general and oral health examinations in 2005-2006 and were followed for up to 15 years. Main outcome measures: Tooth loss was categorized as 0, 1-7, 8-14, or ≥15 missing teeth. Incident all-cause dementia, Alzheimer's disease, and vascular dementia were identified using diagnostic codes. Cox models estimated adjusted hazard ratios (aHRs) with sensitivity analyses requiring ≥2 diagnoses and subgroup analyses by sex and age. Results: Over a mean 13.5-year follow-up, 7616 participants (6.8%) developed dementia, with higher cumulative incidence observed across increasing levels of tooth loss. Higher aHRs were observed with increasing levels of tooth loss; participants with ≥15 missing teeth had the highest estimates (1 diagnosis: aHR 3.23, 95% CI 2.85-3.64; ≥2 diagnoses: aHR 2.01, 95% CI 1.77-2.28). Associations were similar for Alzheimer's disease and weaker for vascular dementia. Conclusion: Tooth loss was associated with higher long-term dementia risk, supporting its role as a potential population-level oral health indicator relevant to dental public health surveillance and prevention strategies.},
}

@article {pmid42090736,
year = {2026},
author = {Malotaux, V and Ku, V and Ospina Lopera, P and Su, Y and Chen, Y and Singh, A and Ruiz-Triviño, J and Hidalgo, MJ and Osorio, L and Serna, L and Giraldo, D and Alzate, D and He, B and Tristão-Pereira, C and Ramirez Gomez, L and Do Carmo, S and Cuello, AC and Ashton, NJ and Reiman, EM and Aguillón, D and Quiroz, YT},
title = {Associations of plasma biomarkers with age in the presenilin-1 E280A autosomal dominant Alzheimer's disease kindred.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {6},
pages = {100578},
doi = {10.1016/j.tjpad.2026.100578},
pmid = {42090736},
issn = {2426-0266},
abstract = {BACKGROUND: Autosomal-dominant Alzheimer's disease (ADAD) offers a model to define early biological changes in Alzheimer's disease due to its predictable age at symptom onset. Although ultrasensitive plasma assays are available, their associations with age in ADAD remain incompletely characterized.

OBJECTIVES: To characterize age-related changes in plasma biomarkers and examine associations with cognition in PSEN1 E280A ADAD.

DESIGN AND SETTING: Cross-sectional observational study in members of the Colombian PSEN1 E280A kindred.

PARTICIPANTS: A total of 164 individuals were included, comprising 83 mutation carriers (mean age 34.36±9.82 years; 54% female) and 81 non-carriers (mean age 33.75±9.84 years; 52% female).

MEASUREMENTS: Plasma Aβ42/Aβ40, phospho-tau217 (p-tau217), brain-derived tau (BD-tau), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) were quantified. Sex-adjusted associations with age, divergence ages between groups, classification performance (ROC curves), and associations with cognition (MMSE and CERAD delayed recall) were assessed.

RESULTS: All plasma biomarkers were associated with age (p < .01). Divergence between carriers and non-carriers began with Aβ42/Aβ40 before age 18, followed by p-tau217 (26.0 years), GFAP (26.1 years), BD-tau (27.9 years), and NfL (38.7 years). Aβ42/Aβ40 showed the highest discrimination of mutation status (AUC=0.99), followed by p-tau217 (AUC=0.87) and GFAP (AUC=0.84). Among carriers, p-tau217, GFAP, BD-tau, and NfL were associated with MMSE, while p-tau217, GFAP, and NfL predicted CERAD delayed recall.

CONCLUSION: Plasma biomarkers exhibit a temporal cascade in PSEN1 E280A ADAD. P-tau217 and GFAP show the strongest associations with early cognitive decline, suggesting their potential utility for tracking disease progression and monitoring treatment effects in E280A carriers.},
}

@article {pmid42090782,
year = {2026},
author = {Schiel, K and Salas, J and Urban, A and Hoft, DF and Scherrer, JF},
title = {Tetanus, diphtheria and pertussis vaccination and risk for incident dementia among adults with down syndrome.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {7},
pages = {100583},
doi = {10.1016/j.tjpad.2026.100583},
pmid = {42090782},
issn = {2426-0266},
abstract = {BACKGROUND: Adult vaccination is inversely associated with incident Alzheimer's Disease and Related Dementias.

OBJECTIVES: We determined if Tetanus, Diphtheria and Pertussis (Tdap) vaccination was linked to incident Alzheimer's Disease and dementia among adults with Down Syndrome, 50% of whom develop Alzheimer's Disease by age 60.

DESIGN: This is a retrospective cohort study using TriNetX nationally distributed electronic health records from 2013 to 2024.

SETTING: Historical medical record data.

PARTICIPANTS: 5591 patients with Down Syndrome across the United States. Eligible patients were free of Alzheimer's Disease and dementia prior to index. Index date could occur 1/1/2015 to 1/1/2020 allowing for 5 to 10 years of possible follow-up time.

MEASUREMENTS: Vaccination was measured using product name and procedure codes and Alzheimer's Disease and dementias was defined by ICD-10 codes.

RESULTS: The mean age of the cohort was 50.0 (±8.3), 50.1% were female and 72.1% were White. After controlling for confounding, Tdap vaccination vs. remaining without Tdap vaccination was associated with lower Alzheimer's Disease and dementia risk (HR=0.74; 95%CI:0.57-0.98).

CONCLUSIONS: In a cohort of patients with Down Syndrome, Tdap vaccination was associated with a 26% lower risk for Alzheimer's Disease and dementia. This is a novel and important finding because existing studies of vaccination and reduced risk for Alzheimer's Disease and dementia have been among cognitively intact adults. This study reveals benefits of vaccination even among those at high risk for Alzheimer's Disease and dementia due to Down Syndrome. Future studies are needed to understand the mechanisms underlying this relationship.},
}

@article {pmid42090783,
year = {2026},
author = {Wang, J and Wu, C and Zhu, K and Qi, X and Chen, G},
title = {Virtual reality-based training in patients with alzheimer's disease: A systematic review and meta-analysis.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {7},
pages = {100590},
doi = {10.1016/j.tjpad.2026.100590},
pmid = {42090783},
issn = {2426-0266},
abstract = {BACKGROUND AND OBJECTIVES: Prior meta-analyses have suggested that training utilizing virtual reality (VR) serves as a secure and effective intervention for elderly individuals experiencing mild cognitive impairment (MCI). Nevertheless, the effectiveness of such interventions appears to differ among various populations and cognitive domains. Furthermore, there remains a significant gap in understanding the effectiveness of VR-based training, specifically among individuals diagnosed with Alzheimer's disease (AD).

METHODS: The researchers conducted a comprehensive search of databases, including Web of Science, PubMed, Cochrane Library, and EMBASE up until July 1, 2025, focusing on randomized controlled trials that investigated VR-based training in patients diagnosed with AD. The outcomes measured were categorized and analyzed separately, encompassing overall cognitive performance, distinct cognitive domains, psychosocial function, physical capabilities, and the execution of daily living activities within the context of AD trials.

RESULTS: Of the 265 publications identified, 11 (4.15%) randomized controlled trials (RCTs) eventually met all eligibility criteria. Those who received VR-based training showed significantly better global cognitive function [SMD (95%CI) = 0.44 (0.21-0.68)] and Short-term memory [SMD (95%CI) = 0.62 (0.25-0.99)] than the controls. However, no significant improvements were observed in areas such as executive function, spatial memory, activities of daily living, quality of life, balance and coordination, fear of falling, risk of falls, and depression levels.

CONCLUSION: VR-based interventions demonstrated beneficial effects on global cognitive function and short-term memory in AD populations. Due to the small sample size, the current research on evidence for efficacy in people with AD is weak and limited in many indicators.},
}

@article {pmid42090785,
year = {2026},
author = {Sánchez Valle, R and Lleó Bisa, A and Villarejo Galende, A and Cuartero Rodríguez, E and Escudero-Torrella, J and Bargallo Alabart, N},
title = {Adapting the spanish healthcare system for disease-modifying treatments in early-stage alzheimer's disease.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {7},
pages = {100586},
doi = {10.1016/j.tjpad.2026.100586},
pmid = {42090785},
issn = {2426-0266},
abstract = {BACKGROUND: The emergence of disease-modifying therapies targeting amyloid pathology represents a major paradigm shift in the management of Alzheimer disease (AD). However, their implementation poses substantial organizational, infrastructural, and clinical challenges for health systems.

OBJECTIVES: To identify the key challenges and establish priority recommendations for the effective incorporation of amyloid-targeting therapies into the Spanish National Health System.

This multiphase consensus study was conducted within the Spanish National Health System between September 2024 and July 2025. The study comprised a narrative literature review, qualitative research, regional workshops, and a modified RAND/UCLA Delphi process. A total of 56 experts participated, including a scientific committee of 6 Alzheimer disease specialists and an expert panel of 50 multidisciplinary professionals involved in AD care.

MEASUREMENTS: Identification of key challenges across the AD care pathway; development, evaluation, and prioritization of consensus-based recommendations; and estimation of patient demand, including projected increases in day hospital activity and magnetic resonance imaging utilization.

RESULTS: Ten key challenge areas were identified, encompassing early detection and referral, diagnostic confirmation, assessment of patient eligibility, treatment administration in day hospitals, monitoring of amyloid-related imaging abnormalities, evaluation of treatment effectiveness, infrastructure and capacity, professional training, patient information and support, and health care planning. Of the 43 recommendations assessed, 38 were rated as appropriate and necessary, with 14 prioritized for immediate implementation. Demand estimation models indicated that 11 to 26 patients per 100,000 inhabitants could be treated under current care patterns, increasing to 17 to 115 per 100,000 inhabitants under alternative eligibility scenarios.

CONCLUSIONS: This consensus defines the clinical, organizational, and infrastructural requirements necessary to integrate amyloid-targeting therapies into routine care within the Spanish National Health System. The prioritized recommendations define immediate actions to address the challenges identified and may serve as a reference for other health systems facing similar implementation processes.},
}

@article {pmid42090829,
year = {2026},
author = {Bassiouny, MSK and Shahin, MI and Jaballah, MY and Ahmed, TE and Henary, M and Samir, N},
title = {Donepezil-derived multi-target-directed ligands: design, synthesis, and anti-Alzheimer's evaluation.},
journal = {Bioorganic chemistry},
volume = {178},
number = {},
pages = {109924},
doi = {10.1016/j.bioorg.2026.109924},
pmid = {42090829},
issn = {1090-2120},
abstract = {Alzheimer's disease (AD), a leading cause of dementia with high mortality and disability, has prompted the emergence of multi-target drug development as a key therapeutic strategy due to its complex and not yet fully understood pathogenesis. Herein, we present new multi-target-directed ligands combining pharmacophore fragments capable of simultaneously inhibiting key enzymes implicated in AD pathology. These compounds exhibit inhibitory activities against acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and β-secretase (BACE-1), while also demonstrating anti-aggregation effects on β-amyloid (Aβ) and hyperphosphorylated tau (p-tau), both of which contribute to neurodegeneration. Among the synthesized series, compound 13f illustrated a well-balanced inhibitory profile, with IC50 values of 0.387 μM for AChE, 0.430 μM for BuChE, and 0.531 μM for BACE-1. Furthermore, In vivo studies revealed that compound 13f effectively reduced AChE concentrations in the brain by 30%, alongside a more substantial suppression of BuChE and BACE-1, with reductions of 60% and 62%, respectively. Additionally, 13f reduced Aβ and p-tau brain aggregates concentrations by over 30%, highlighting its potential as a promising lead for further optimization. These findings offer a compelling foundation for the development of effective multi-target directed ligands (MTDLs) for AD intervention.},
}

@article {pmid42090911,
year = {2026},
author = {Rodrigues, HC and Belal, R and Joshi, G and Rathore, T and Joshi, K and Verma, K},
title = {Multi-scale sleep dynamics in memory consolidation: From microstructural oscillations to macro-architecture.},
journal = {Sleep medicine},
volume = {144},
number = {},
pages = {108998},
doi = {10.1016/j.sleep.2026.108998},
pmid = {42090911},
issn = {1878-5506},
abstract = {Sleep serves as a dynamic multiscale process supporting the stabilization and transformation of memory. A multilevel integrated interaction exists in which macrostructures coordinate and contain guiding smaller scale microstructural activities that collectively facilitate information transfer. The nesting of the slow oscillation-spindle-ripple triplet facilitates the reactivation and transfer of memory traces from the hippocampus to neocortical networks. While Non-Rapid Eye Movement sleep supports declarative memory stabilization, Rapid Eye Movement sleep modulates emotional tone and integrates memories into existing schemas. Research gaps persist regarding the integration of these scales, as traditional models often treat sleep stages as uniform. Distortions in either macro- or microstructural layers, observed in neurodegenerative disorders such as Alzheimer's disease, concurrently impair cognitive function and memory. Future advancements highlight the need for the development of a Sleep-Dependent Health Index and multi-scale causal models to predict individual cognitive vulnerability and track memory reactivation across the lifespan. The proposed unified framework emphasizes the bidirectional interaction of cellular plasticity, local oscillations, and global sleep architecture to elucidate sleep-dependent memory consolidation.},
}

@article {pmid41327893,
year = {2026},
author = {Akçimen, F and Daida, K and Lange, LM and Moller, A and Miano-Burkhardt, A and Malik, L and Paquette, K and Alvarez Jerez, P and Mingle, J and Baker, B and Meredith, M and Kouam, C and Jarreau, P and Markham, A and Anderson, J and Jain, M and Chaisson, M and Cookson, M and Casey, B and Iwaki, H and Bandres-Ciga, S and Saffie-Awad, P and Nalls, MA and Fang, ZH and Singleton, AB and Blauwendraat, C and Billingsley, KJ},
title = {Long-read sequencing identifies FGF14 repeat expansions in Parkinson's disease.},
journal = {Brain : a journal of neurology},
volume = {149},
number = {5},
pages = {1514-1521},
doi = {10.1093/brain/awaf456},
pmid = {41327893},
issn = {1460-2156},
support = {/AG/NIA NIH HHS/United States ; /NS/NINDS NIH HHS/United States ; Z01-AG000949//National Institutes of Health, Department of Health and Human Services/ ; 1ZIANS003154//National Institutes of Health, Department of Health and Human Services/ ; //NIH HPC Biowulf cluster/ ; },
mesh = {Humans ; *Parkinson Disease/genetics/diagnostic imaging ; Male ; Female ; Aged ; *Fibroblast Growth Factors/genetics ; Middle Aged ; *Trinucleotide Repeat Expansion/genetics ; Whole Genome Sequencing ; alpha-Synuclein/metabolism ; Cohort Studies ; Aged, 80 and over ; },
abstract = {Pathogenic GAA repeat expansions in FGF14 are an established cause of late-onset cerebellar ataxia, but have not been linked to Parkinson's disease. Given emerging evidence that repeat expansions in ataxia-associated genes like RFC1 can contribute to atypical or familial forms of Parkinson's disease, we investigated whether FGF14 expansions might play a similar role. Using long-read whole-genome sequencing, we analysed 411 individuals with Parkinson's disease and 197 neurologically healthy controls from the Parkinson's Progression Markers Initiative (PPMI) cohort, together with 1429 additional controls from the National Institutes of Health (NIH) Center for Alzheimer's Disease and Related Dementias (CARD) initiative, the 1000 Genomes Project, and the All of Us program, representing globally diverse populations. We identified pathogenic FGF14 GAA repeat expansions in five individuals with Parkinson's disease and one control subject. All five individuals fit the clinical criteria of Parkinson's disease and showed typical patterns of neurodegeneration on DaTSCAN imaging; α-synuclein aggregation was confirmed by a positive seeding assay among four individuals with available data. These findings broaden the phenotypic spectrum of FGF14 repeat-associated disease and suggest a rare, previously unrecognized genetic contributor to Parkinson's disease. To our knowledge, this is the first report implicating FGF14 in Parkinson's disease and underscores the utility of long-read sequencing for detecting hidden forms of pathogenic variation in unresolved cases.},
}

Humans
*Parkinson Disease/genetics/diagnostic imaging
Male
Female
Aged
*Fibroblast Growth Factors/genetics
Middle Aged
*Trinucleotide Repeat Expansion/genetics
Whole Genome Sequencing
alpha-Synuclein/metabolism
Cohort Studies
Aged, 80 and over

@article {pmid42082123,
year = {2026},
author = {Fan, YH and Fan, KS and Lin, TL},
title = {Reduced dementia risk in middle-aged and older atopic dermatitis patients treated with dupilumab: A target trial emulation.},
journal = {Brain, behavior, and immunity},
volume = {},
number = {},
pages = {106796},
doi = {10.1016/j.bbi.2026.106796},
pmid = {42082123},
issn = {1090-2139},
abstract = {BACKGROUND: Middle-aged and older adults with atopic dermatitis (AD) are at increased risk of dementia, possibly driven by chronic inflammation and involving IL-4 and IL-13 pathways. Whether treatment with dupilumab, an IL-4/IL-13 inhibitor, influences subsequent dementia risk in this population remains unclear.

METHODS: This target trial emulation study utilized the TriNetX database. Patients aged ≥ 50 years with AD were identified and divided into two groups: those newly prescribed dupilumab and those newly prescribed conventional systemic agents without dupilumab exposure. Propensity score matching (1:1) was performed based on age, sex, race, and comorbidities. Dementia risk was assessed using Cox regression.

RESULTS: After matching, each group included 10,039 patients (∼52% female; mean age, 63 years; 63% White). The 5-year cumulative incidence of dementia was lower among dupilumab users than controls (2.37% vs 3.33%; P = 0.001). Dupilumab use was associated with a reduced risk of all-cause dementia (HR 0.68; 95% CI, 0.54-0.86), with similar reductions observed across dementia subtypes, including secondary (HR 0.69; 95% CI, 0.48-0.99), unspecified (HR 0.70; 95% CI, 0.53-0.93), and Alzheimer's dementia (HR 0.61; 95% CI, 0.40-0.93). Subgroup and sensitivity analyses showed consistent results, with control outcome analyses supporting the robustness of the findings. In a validation analysis of middle-aged and older asthma patients, dupilumab users likewise had a lower dementia risk than omalizumab users (HR 0.68; 95% CI, 0.47-0.98).

CONCLUSIONS: Dupilumab use was associated with a reduced risk of dementia in middle-aged and older adults with AD compared with conventional systemic agents.},
}

@article {pmid42082387,
year = {2026},
author = {Alpert, JM and Rothberg, MB and Paasche-Orlow, MK and Hashmi, AZ and Perez-Protto, S and Fox, J and Criswell, V and Wittenberg, E},
title = {A communication phenotype for varying information needs among caregivers of persons with dementia.},
journal = {The Gerontologist},
volume = {},
number = {},
pages = {},
doi = {10.1093/geront/gnag091},
pmid = {42082387},
issn = {1758-5341},
abstract = {BACKGROUND AND OBJECTIVES: Informal caregivers of persons with Alzheimer's disease and Alzheimer's disease-related dementias (AD/ADRD) have limited knowledge of the disease, yet they have immense responsibility, such as medication administration, managing symptoms, assisting with activities of daily living, and making end-of-life decisions. Our objective was to explore information seeking among informal caregivers to learn about their information needs.

RESEARCH DESIGN AND METHODS: We interviewed informal caregivers of persons with AD/ADRD who passed away in the last two years. Interviews occurred from July 2024 to June 2025 in a large academic health system. We analyzed information needs of AD/ADRD caregivers using an adapted version of the Four States of Information Needs conceptual framework. We used a deductive-inductive approach, beginning with the existing framework, and then refining it with inductive observations.

RESULTS: Twenty-seven informal caregivers were interviewed (median age 65 years; 77.8% female; 81.5% white; care provided for a median of 5 years; 63.0% were the patient's child). Four phenotypes were revealed: 1) Proactive Caregivers, who were assertive communicators and motivated to seek information in advance, 2) Activated Caregivers, who had less knowledge than Proactive Caregivers, but communicated with staff and took preemptive measures, 3) Responsive Caregivers, who were overwhelmed and rarely communicated their needs to clinical staff, and 4) Reflective Caregivers, who identified information gaps, but did not always attempt to rectify them.

DISCUSSION AND IMPLICATIONS: The needs of informal caregivers vary. Potentially, clinicians can recognize caregivers' phenotypes and adapt the support they provide to improve the caregiver experience.},
}

@article {pmid42082519,
year = {2026},
author = {Wang, J and Mao, Y and Liu, X and Hao, W and , },
title = {Learning patient-specific spatial biomarker dynamics via operator learning for Alzheimer's disease progression.},
journal = {NPJ systems biology and applications},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41540-026-00719-x},
pmid = {42082519},
issn = {2056-7189},
support = {1R35GM146894/GM/NIGMS NIH HHS/United States ; 1R35GM146894/GM/NIGMS NIH HHS/United States ; },
abstract = {Alzheimer's disease (AD) is a complex, multifactorial neurodegenerative disorder with substantial heterogeneity in progression and treatment response. Despite recent therapeutic advances, predictive models capable of accurately forecasting individualized future biomarker states remain limited. Here, we present a machine learning-based operator learning framework for personalized modeling of AD progression, integrating longitudinal multimodal imaging, biomarker, and clinical data. Unlike conventional models with prespecified dynamics, our approach directly learns patient-specific disease operators governing the spatiotemporal evolution of amyloid, tau, and neurodegeneration biomarkers. Using Laplacian eigenfunction bases, we construct geometry-aware neural operators capable of capturing complex brain dynamics. Embedded within a digital twin paradigm, the framework enables individualized predictions, simulation of therapeutic interventions, and in silico clinical trials. Applied to AD clinical data, our method achieves high prediction accuracy exceeding 90% across multiple biomarkers, substantially outperforming existing approaches. This work offers a scalable, interpretable platform for precision modeling and personalized therapeutic optimization in neurodegenerative diseases.},
}

@article {pmid42082780,
year = {2026},
author = {Khalili, E and Sodaei, F and Noroozian, M and Sheldrick-Michel, TM and Vafaee, MS},
title = {Structural MRI in frontotemporal dementia and Alzheimer's disease: stage-dependent atrophy patterns.},
journal = {Journal of neural transmission (Vienna, Austria : 1996)},
volume = {},
number = {},
pages = {},
pmid = {42082780},
issn = {1435-1463},
abstract = {Differentiating Alzheimer's disease (AD) from frontotemporal dementia (FTD) remains a major clinical challenge, particularly in early disease stages when phenotypic overlap is common and in later stages when cortical degeneration becomes widespread. Structural magnetic resonance imaging (MRI) provides a widely available, non-invasive framework for assessing region-specific brain atrophy patterns associated with these disorders. This narrative review synthesizes current evidence on MRI-based approaches for distinguishing FTD from AD across disease stages. FTD, particularly the behavioral variant, is characterized by early and prominent degeneration of frontal and anterior temporal networks, frequently with hemispheric asymmetry and early behavioral change, including apathy as a core feature. In contrast, AD typically demonstrates a posterior-predominant pattern, with medial temporal and temporoparietal atrophy reflecting a posterior-to-anterior trajectory, while frontal involvement emerges later except in atypical variants. Quantitative MRI techniques, including voxel-based morphometry, cortical thickness analysis, and asymmetry indices, together with validated visual rating scales, enhance the detection of these spatial patterns. Fluid-attenuated inversion recovery imaging supports interpretation by identifying vascular burden, and complementary biomarkers, including FDG-PET, cerebrospinal fluid, and blood-based markers, provide molecular and functional context in diagnostically ambiguous cases. The diagnostic specificity of frontal atrophy is greatest in early stages and decreases as AD and FTD converge anatomically in moderate to advanced disease. Accurate differential diagnosis, therefore, requires a stage-aware, integrative framework that combines structural MRI with longitudinal clinical assessment, neuropsychological profiling, and biomarker information. Structural MRI remains the cornerstone of differentiation, with regional atrophy patterns interpreted within a broader clinical and biological context rather than in isolation.},
}

@article {pmid42082800,
year = {2026},
author = {Nazli, D and Poyraz, YK and Can, K and Ipekgil, D and Cakmak, N and Turhanlar-Sahin, E and Hacoglu, S and Erdost, HA and Iyilikci, L and Ozhan, G},
title = {Dexmedetomidine Exerts Multi-level Effects to Ameliorate Alzheimer's Disease Pathology in the Adult Zebrafish Brain.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42082800},
issn = {1559-1182},
mesh = {Animals ; Zebrafish ; *Dexmedetomidine/pharmacology/therapeutic use ; *Alzheimer Disease/drug therapy/pathology/genetics ; *Brain/pathology/drug effects/metabolism ; Amyloid beta-Peptides/metabolism ; Disease Models, Animal ; *Aging/pathology/drug effects ; Behavior, Animal/drug effects ; Peptide Fragments ; },
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative condition involving β-amyloid (Aβ) deposition, tau abnormalities, neuroinflammation, neuronal degeneration, and progressive impairment of cognitive functions. Despite extensive research, effective disease-modifying therapies remain limited, highlighting the need for translationally relevant models and repurposable therapeutic candidates. Dexmedetomidine (DEX), an α2-adrenergic receptor agonist with known neuroprotective properties, was investigated in an adult zebrafish model of AD established through cerebroventricular administration of Aβ42. DEX treatment significantly reduced Aβ accumulation and was associated with reduced amyloidogenic gene expression, indicating transcriptional changes in amyloidogenic pathway-related genes. DEX attenuated neuroinflammation by reducing glial activation, lowering pro-inflammatory cytokine gene expression, and increasing expression of the anti-inflammatory gene il10. Immunofluorescence assessment further demonstrated reduced astrogliosis and preserved neuronal marker integrity, as indicated by increased HuC/D levels. Interestingly, DEX attenuated Aβ-induced proliferative responses, characterized by decreased PCNA expression, while enhancing cleaved caspase-3 levels, suggesting changes in proliferation and apoptotic signaling under Aβ stress conditions. Behavioral assessments further demonstrated that DEX alleviated Aβ42-induced anxiety- and aggression-like behaviors, improving behavioral phenotypes in this model. Overall, these findings underscore the multi-level effects of DEX in modulating AD-related pathological features. As a clinically available agent, DEX represents a promising candidate for repurposing in neurodegenerative disease contexts. Further preclinical studies in mammalian models are warranted to validate its translational relevance and therapeutic potential.},
}

Animals
Zebrafish
*Dexmedetomidine/pharmacology/therapeutic use
*Alzheimer Disease/drug therapy/pathology/genetics
*Brain/pathology/drug effects/metabolism
Amyloid beta-Peptides/metabolism
Disease Models, Animal
*Aging/pathology/drug effects
Behavior, Animal/drug effects
Peptide Fragments

@article {pmid42082802,
year = {2026},
author = {Motieiyan, E and Motahari, R and Aliabadi, A and Khaksar, S and Abdolmaleki, S},
title = {Cobalt complexes in biology and medicine: enzymatic functions, pharmacological applications, and health challenges.},
journal = {Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry},
volume = {},
number = {},
pages = {},
pmid = {42082802},
issn = {1432-1327},
abstract = {Cobalt is an essential trace element in biochemistry that plays a crucial role in the structure and function of several important biomolecules. In this review, vitamin B12 is discussed as one of the best-known examples in this area. Various forms of this vitamin, including methylcobalamin and adenosylcobalamin, play a crucial role in metabolic reactions in mammals and prokaryotes. It also discusses cobalt-containing enzymes that are essential for various biological processes. These enzymes are B12-dependent enzymes, which are well studied, and cobalt-containing enzymes, which are less well known, such as methionine aminopeptidase, nitrile hydratase, glucose isomerase, and prolidase. In addition to the significant role of cobalt complexes in biochemistry, these complexes are considered potent anticancer agents that can exert their antiproliferative effects through the production of ROS, cell cycle arrest, MMP breakdown, and induction of apoptosis in cancer cells. Cobalt complexes are also being explained here for their antimicrobial properties against a variety of pathogens, including bacteria, fungi, and viruses. Furthermore, examples of these complexes are presented as promising agents for the suppression of AD, which could be effective by binding to Aβ-peptides and preventing their aggregation, which is a central feature of the pathogenesis of AD, or by combating the oxidative damage associated with the disease, or even by interfering with the enzyme activities associated with this disease. Finally, the challenges related to the toxicity of cobalt and its compounds in medicine are discussed, and chelation therapy is considered an effective treatment for cobalt poisoning.},
}

@article {pmid42082835,
year = {2026},
author = {Zheng, X and Chen, P and Li, D and Li, W and Liao, J and Zhang, M},
title = {Lamotrigine Improves Spatial Learning and Attenuates AD-Related Pathology in APP/PS1 Mice, with Possible Involvement of the cAMP/PKA/CREB Pathway.},
journal = {Neurochemical research},
volume = {51},
number = {3},
pages = {},
pmid = {42082835},
issn = {1573-6903},
mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism/pathology ; *Lamotrigine/pharmacology/therapeutic use ; Cyclic AMP-Dependent Protein Kinases/metabolism ; Amyloid beta-Protein Precursor/genetics/metabolism ; *Spatial Learning/drug effects ; Mice, Transgenic ; Mice ; Presenilin-1/genetics ; Cyclic AMP Response Element-Binding Protein/metabolism ; Signal Transduction/drug effects ; Cyclic AMP/metabolism ; Male ; Brain/drug effects/metabolism/pathology ; Maze Learning/drug effects ; },
abstract = {Alzheimer's disease (AD) is characterized by impaired spatial learning functions, amyloid-β accumulation, tau hyperphosphorylation, and neuroinflammation. Antiepileptic drugs such as lamotrigine have shown promise in improving brain functions in AD, but the underlying mechanisms remain unclear. This study aimed to evaluate the therapeutic effects of lamotrigine in amyloid precursor protein/presenilin 1 (APP/PS1) transgenic mice and elucidate the underlying molecular mechanisms using integrated transcriptomic and metabolomic analyses. APP/PS1 mice were treated with lamotrigine from 3 months of age, and spatial learning performance was assessed using the Morris water maze test. Histological and molecular changes were evaluated through hematoxylin and eosin staining, Western blotting, ELISA, and immunohistochemistry. High-throughput RNA sequencing and untargeted metabolomics were performed to explore differentially expressed genes, metabolites, and enriched signaling pathways. Western blot validation and pharmacological inhibition were used to verify pathway involvement. Lamotrigine treatment significantly improved spatial learning performance, ameliorated neuronal degeneration, and decreased Aβ1 levels and tau phosphorylation in the brains of APP/PS1 mice. Inflammatory markers and glial activation were also markedly suppressed. Multi-omics analysis revealed alterations in key pathways related to synaptic plasticity, lipid metabolism, and autophagy. Notably, both omics data and protein validation highlighted the cAMP/PKA/CREB pathway as a potentially relevant pathway. Co-administration of the PKA inhibitor H89 abolished lamotrigine-induced upregulation of p-CREB and BDNF, supporting the involvement of this pathway. Lamotrigine improves spatial learning and attenuates AD-related pathology in APP/PS1 mice, possibly through modulation of the cAMP/PKA/CREB signaling pathway, highlighting its potential as a candidate for further investigation.},
}

Animals
*Alzheimer Disease/drug therapy/metabolism/pathology
*Lamotrigine/pharmacology/therapeutic use
Cyclic AMP-Dependent Protein Kinases/metabolism
Amyloid beta-Protein Precursor/genetics/metabolism
*Spatial Learning/drug effects
Mice, Transgenic
Mice
Presenilin-1/genetics
Cyclic AMP Response Element-Binding Protein/metabolism
Signal Transduction/drug effects
Cyclic AMP/metabolism
Male
Brain/drug effects/metabolism/pathology
Maze Learning/drug effects

@article {pmid42082911,
year = {2026},
author = {Müller, T and Hornung, R and Szymczak, S and Buchner, H},
title = {ShadowVIMP: permutation-based multiple testing-controlled variable selection.},
journal = {BMC bioinformatics},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12859-026-06412-4},
pmid = {42082911},
issn = {1471-2105},
support = {DFG-Einzelförderung HO 6422/1-3//German Science Foundation/ ; },
abstract = {BACKGROUND: Identifying relevant biomarkers is critical in clinical research and precision medicine, particularly when analysing high-dimensional data. Random forests (RFs) are promising for such settings due to their flexibility, ease of use, and their ability to handle data sets with more variables than samples. RFs assess the importance of each variable in predicting the outcome using variable importance (VIMP) scores. However, since the distribution of VIMP scores is intricate, standard statistical testing and multiple testing adjustments for variable selection are challenging.

METHODS: We propose shadowVIMP, a novel method for multiple testing-controlled variable selection, based on an approach similar to permutation testing. It generates permuted counterparts for each variable and compares their VIMPs with those of the original variables over multiple iterations to calculate p-values. Unlike conventional permutation testing, shadowVIMP preserves the correlation structure between variables, mitigating biases caused by the over-selection of correlated variables in RFs. We evaluated shadowVIMP against three competing RF variable selection approaches using simulation designs previously employed in studies considering VIMPs and variable selection for RFs. These designs included high- and low-dimensional data, as well as correlated and categorical variables. For illustration, we also applied the method to a real-world example on Alzheimer's disease.

CONCLUSIONS: Our results showed that, compared to competing approaches, shadowVIMP offers advantages in high-dimensional settings, improving sensitivity while enabling multiple testing-adjusted results. Additionally, it demonstrated robustness against VIMP biases induced by correlated and categorical variables when using permutation-based VIMP. The method can be used to annotate standard VIMP plots, visually presenting selected variable sets based on different types of multiple testing adjustments and significance levels. Overall, shadowVIMP is a promising approach for providing multiple testing-adjusted variable selection while explicitly addressing known biases of RF's permutation-based VIMP measure. The shadowVIMP method is implemented in an R package shadowVIMP, which is available on CRAN.},
}

@article {pmid42082924,
year = {2026},
author = {Salian, V and Wang, Z and Curran, G and Podulso, JF and Kandimalla, KK},
title = {Estimation of Various Physiological Parameters Affecting Amyloid Plaque Distribution of a Novel MRI Contrast Agent in the Brain of Alzheimer's Disease Transgenic Mice.},
journal = {Molecular pharmaceutics},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.molpharmaceut.5c01565},
pmid = {42082924},
issn = {1543-8392},
abstract = {Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β (Aβ) peptides as plaques in the brain parenchyma and as deposits in the cerebral vasculature. Early detection of amyloid plaques and deposits is imperative for diagnosing AD before the onset of cognitive decline. Magnetic resonance (MR) imaging using Gd (III)-based agents for contrast enhancement and plaque targeting provides a promising avenue. However, there remains a challenge due to the limited permeability of these contrast agents across the blood-brain barrier (BBB), which restricts its delivery. Furthermore, clearance mechanisms in the brain also reduce retention of contrast agents. To identify mechanisms that limit the success of contrast agents, we investigated the pharmacokinetics and the brain distribution of contrast agent, Gd[N-4ab/Q-4ab]Aβ30, using AD transgenic mouse models and compartmental modeling. Our results demonstrate that the contrast agent is internalized by parenchymal cells, which limits its availability to bind to extracellular plaques. Sensitivity analysis conducted on the compartmental model identified systemic clearance and plasma-to-brain influx as key parameters that limit the delivery of the contrast agent to the brain. The analysis also highlights the BBB as a formidable barrier for delivery and the importance of improving BBB permeability to increase the accumulation of the contrast agent in the brain. Furthermore, model simulations revealed that glymphatic drainage contributes to the poor retention and rapid elimination of the contrast agent from the brain. By elucidating the role of these biological processes and parameters, this study contributes to understanding factors limiting contrast agent efficacy in amyloid plaque imaging in the AD brain. These findings also reveal important targets for optimizing contrast agent design to improve its brain delivery.},
}

@article {pmid42082960,
year = {2026},
author = {Liu, S and Zhu, J and Zhong, H and Zhou, D and Long, Q and Zhang, Z and Yang, X and Wu, Q and Cheng, C and Wu, J and Luu, HN and Wang, J and Zhao, B and Wu, C and Deng, Y and Wu, L},
title = {Investigating causal associations among inflammatory proteins, blood metabolites, and Alzheimer's disease risk.},
journal = {BMC psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12888-026-08136-4},
pmid = {42082960},
issn = {1471-244X},
abstract = {Alzheimer's disease (AD) is a prevalent degenerative neurological disorder with limited treatment options. Prior studies reported specific metabolites and inflammatory proteins to be related to AD risk. However, the intricate relationship between inflammatory proteins, blood metabolites, and AD risk in European population remains unclear. Genetic instruments for 1,091 metabolites and 736 inflammatory proteins were derived from two recent comprehensive genome-wide association studies. Univariable Mendelian Randomization was employed to assess potential causal effects of metabolites on AD risk, potential effects of inflammatory proteins on metabolites, and effects of inflammatory proteins on AD risk. Multivariable MR (MVMR) was further applied to disentangle direct effects of proteins and metabolites on AD. Twelve metabolites were identified to be associated with AD risk, and 226 inflammatory proteins demonstrated likely to be causal effects on these 12 metabolites. Further examining the associations between such inflammatory proteins and AD risk revealed 22 associations for which the effect directions from inflammatory proteins to metabolites, from metabolites to AD risk, and from inflammatory proteins to AD risk were aligned, suggesting inflammatory protein - metabolite - AD risk pathway. MVMR further highlighted four trios in which the effect directions were consistent with the UVMR results, supporting a metabolite‑mediated pattern. This large‑scale genetic analysis highlights specific metabolites as direct contributors to AD risk and suggests that certain inflammatory proteins may influence AD primarily through downstream metabolic pathways. Our findings offer potential novel therapeutic targets for AD intervention.},
}

@article {pmid42083037,
year = {2026},
author = {López-López, V and Iniesta, G and Galán-Ganga, M and Expósito-Coca, A and Durán-Laforet, V and Bhojwani-Cabrera, AM and Navarrón, CM and Guillot-Fernández, M and Venero, JL and Sánchez-Mut, JV and Barco, A and Giralt, A and López-Atalaya, JP},
title = {Sex-dependent interferon signaling contributes to female-biased vulnerability in Alzheimer's disease.},
journal = {Journal of neuroinflammation},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12974-026-03840-0},
pmid = {42083037},
issn = {1742-2094},
abstract = {Alzheimer's disease (AD) disproportionately affects women, yet the biological basis of this sex bias remains unclear. Here, we identify sex-dependent interferon signaling as a contributor to this disparity. Transcriptomic profiling of postmortem AD tissue and APP/PS1 mice revealed preferential enrichment of interferon-responsive gene programs in females. In APP/PS1 mice, heightened interferon responses were associated with increased neurodegenerative features, and single-cell transcriptomic analyses identified microglia as a major cellular compartment engaging interferon responses. To test causality, we manipulated interferon signaling in vivo. Acute systemic interferon activation promoted AD-like neuropathological alterations. Genetic amplification of interferon signaling in microglia exacerbated neuroinflammatory and neurodegenerative features in APP/PS1 mice, whereas pharmacological inhibition through cGAS-STING blockade suppressed interferon responses, reduced neuropathology, and preserved cognitive performance in female APP/PS1 mice. Together, these findings identify microglial interferon signaling as a modifiable contributor to AD-associated neuropathology and suggest a neuroimmune mechanism underlying the increased vulnerability of females to the disease.},
}

@article {pmid42083115,
year = {2026},
author = {Jiang, X and O'Bryant, SE and Rissman, RA and Johnson, LA and Braskie, MN and Yaffe, K and , },
title = {Multimorbidity and Associations with Cognition and Alzheimer's Disease Biomarkers.},
journal = {Annals of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/ana.78238},
pmid = {42083115},
issn = {1531-8249},
abstract = {OBJECTIVE: Multimorbidity, the coexistence of 2 or more chronic conditions, has been linked to cognitive aging and Alzheimer's disease (AD) and AD-related dementias, yet the mechanisms remain unclear. We aimed to examine the associations of multimorbidity with cognition and biomarkers across multiple mechanistic pathways.

METHODS: We cross-sectionally analyzed 3,808 dementia-free participants (mean age 64.9 ± 8.5 years, 62% female) from the Health and Aging Brain Study: Health Disparities. Multimorbidity burden was assessed using a latent construct derived from chronic conditions identified through objective measures, medical history, and self-report. A latent factor score for cognition was estimated using confirmatory factor analysis and neuropsychological tests. Using linear and logistic regression, we examined the associations of multimorbidity burden with biomarkers of AD (positron emission tomography [PET] amyloid, plasma β-amyloid 42/40, and phosphorylated tau [p-tau] measures), neurodegeneration (cortical thickness, hippocampal volume, and plasma neurofilament light and total tau), and cerebral small vessel disease (SVD) (magnetic resonance imaging white matter hyperintensities, cerebral microbleeds, and lacunes).

RESULTS: Greater multimorbidity burden was associated with worse cognition and biomarkers of AD (PET amyloid standardized uptake value ratios and positivity, p-tau181, and p-tau217), neurodegeneration (neurofilament light, total tau, cortical thickness, and hippocampal volume), and SVD (white matter hyperintensity volume and presence of lacune and cerebral microbleeds).

INTERPRETATION: Among dementia-free individuals, higher multimorbidity burden was associated with biomarkers for greater AD pathology, neurodegeneration, and SVD. These findings support a more holistic approach to managing chronic disease burden, which has the potential to reduce overall pathophysiological burden and delay cognitive decline. ANN NEUROL 2026.},
}

@article {pmid42083360,
year = {2026},
author = {Pandey, H and Kaur, A and Khan, J and Sharma, A},
title = {Nanomedicine for Alzheimer's Disease: Diagnostic and Therapeutic Progress.},
journal = {MicroRNA (Shariqah, United Arab Emirates)},
volume = {},
number = {},
pages = {},
doi = {10.2174/0122115366427696260203074113},
pmid = {42083360},
issn = {2211-5374},
abstract = {The complex nature of the pathophysiology and limited treatment options of AD make it a huge challenge in healthcare. The recent developments in nanotechnology have given fresh hope for diagnosing and treating AD, which could serve as a way out of the existing problems. This review dwells on the role of nanotechnology in AD and its applications at its early stages through the development of nanosensors and boost imaging methods. Additionally, nanotechnology-driven therapeutic strategies are being investigated with nanoparticle-based drug delivery systems that aim to target the blood-brain barrier, among others. Current research innovations, clinical trials, and prospects highlight the transformative potential of nanotechnology in reshaping AD management. Ethical issues related to applying nanomedicine in neurodegenerative diseases, as well as fears about nanoparticles, are carefully analyzed herein. Finally, this review concludes with a synthesis of how nanotechnology has affected Alzheimer's Disease (AD) while emphasizing emerging trends and future directions toward advancing research on Alzheimer's Disease (AD). This comprehensive overview underscores the pivotal role of nanotechnology in revolutionizing AD prognosis and therapy, paving the way for personalized and effective treatment strategies.},
}

@article {pmid42083372,
year = {2026},
author = {Yoshida, H and Inoue, T and Suzuki, S and Tomata, Y},
title = {Sodium-to-Potassium Ratio and Alzheimer's Disease: A Mendelian Randomization Study.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050472115260421093303},
pmid = {42083372},
issn = {1875-5828},
abstract = {INTRODUCTION: A higher urinary sodium-to-potassium (Na/K) ratio has been associated with increased risk of hypertension and cardiovascular diseases, which are known risk factors for Alzheimer's Disease (AD). Mendelian Randomization (MR), which uses genetic variants as instrumental variables to infer causality while reducing confounding and reverse causation, was applied to investigate whether the urinary Na/K ratio is causally associated with AD risk.

METHODS: A two-sample MR study was conducted using 31 single-nucleotide polymorphisms associated with urinary Na/K ratio as instrumental variables. The primary analysis employed Genome- Wide Association Study (GWAS) summary statistics for AD (n=85,934 individuals, including ADby- proxy). For sensitivity analysis, GWAS data specific to clinically diagnosed late-onset AD (n=21,982 individuals) were analyzed.

RESULTS: Genetically predicted urinary Na/K ratio was not statistically significantly associated with AD risk in the primary analysis; odds ratio (OR per 1 mol/mol increase) = 1.02, 95% confidence interval (CI): 0.77-1.36. In the sensitivity analysis using clinically diagnosed late-onset AD, the point estimate was higher (OR = 1.49, 95% CI: 0.99-2.24), although the association was not statistically significant.

DISCUSSION: Although no statistically significant causal association was observed, the study's findings may be consistent with previous observational studies linking higher sodium intake or a higher urine Na/K ratio to poorer cognitive performance. However, the sensitivity analysis suggested a possible association that warrants further investigation in larger MR studies using clinically confirmed AD datasets. As all data were derived from individuals of European ancestry, generalizability to other populations may be limited.

CONCLUSION: This MR study did not provide clear evidence supporting a causal association between urinary Na/K ratio and AD risk.},
}

@article {pmid42083373,
year = {2026},
author = {Zhang, Y and Tong, S and Chen, Y and Li, C and Yao, Y and Tang, S and Shang, Y},
title = {An Inverse Association Between the Composite Dietary Antioxidant Index and Alzheimer's Disease: Evidence from an NHANES-Based Cross-Sectional Study.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050462427260407045906},
pmid = {42083373},
issn = {1875-5828},
abstract = {INTRODUCTION: The relationship between the dietary Complex Antioxidant Index (CDAI) and Alzheimer's Disease (AD) is not clear. Our study is to investigate the relationship between CDAI and the risk of AD in general adults.

METHODS: This study included 116876 participants from the National Health and Nutrition Survey (NHANES). CDAI was calculated based on the intake of six dietary antioxidants. We used multivariate logistic regression to examine the relationship between CDAI and AD prevalence, and used restricted cubic splines to examine the nonlinear association.

RESULTS: The study showed that in the multivariate logistic regression model with fully adjusted confounding variables, the odds ratio (OR) of CDAI and AD was 0.9983 (95% confidence interval: 0.9969,0.9998; P=0.024). In addition, restricted cubic spline analysis revealed a linear correlation (P for non-linearity = 0.097).

DISCUSSION: This cross-sectional study reveals a linear negative association between the CDAI and AD prevalence in U.S. adults, with vitamin E, carotenoids, and selenium showing independent protective effects. These findings align with the hypothesis that dietary antioxidants may mitigate oxidative stress-related neurodegeneration. However, due to the cross-sectional design, causal inference is not possible, and reverse causation cannot be excluded. The modest effect size and reliance on self-reported dietary data necessitate cautious interpretation. These hypothesis-generating findings underscore the need for prospective cohort studies to confirm whether antioxidant-rich diets could serve as a primary prevention strategy for AD.

CONCLUSION: This cross-sectional study found a negative linear association between CDAI and AD prevalence in US adults. These hypothesis-generating findings require confirmation in prospective cohort studies.},
}

@article {pmid42083380,
year = {2026},
author = {Mai, X and Chen, J and Yong, K and Chen, Y and Wen, H and Sun, M and Yu, H and Xiong, K and Yu, L},
title = {A Dual-Functional Two-Photon PLIM Probe Based on Ruthenium(II) Complex: Sequence Selectivity and Aβ Aggregation Monitoring.},
journal = {Analytical chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.analchem.5c08075},
pmid = {42083380},
issn = {1520-6882},
abstract = {A key pathological feature of Alzheimer's disease (AD) is β-amyloid (Aβ) plaque formation from abnormal peptide aggregation. In addition to full-length Aβ1-42, various N/C-truncated Aβ fragments exist in the human brain and are found to be associated with AD etiology. However, the precise toxic Aβ species, aggregation states, and neurotoxic mechanisms remain unclear, highlighting the urgent need for probes with sequence selectivity and real-time aggregation monitoring capability─functions lacking in reported Aβ probes. Herein, we present Ru-dmpip, a two-photon phosphorescence lifetime imaging microscopy (PLIM) probe synthesized by conjugating a hydrophilic ruthenium complex and a hydrophobic ThT moiety. Ru-dmpip exhibits high specificity for AβX-42 peptides (Aβ1-42/Aβ11-42), with 7.4/3.7-fold higher affinity than Aβ1-40, and can bind all AβX-42 aggregated states (monomers/oligomers/fibrils), inducing sensitive phosphorescence intensity and lifetime changes (the lifetime increased from 436 to approximately 900 ns). It can visualize Aβ1-42 aggregation at the single-fiber level, enable in vitro cellular imaging, and specifically identify plaques formed by Aβ1-42 in APP-PS1 transgenic mouse brain sections. Its ultralong excited-state lifetime can effectively mitigate interference from background, allowing clear observation of loose small oligomers surrounding plaques─species that are barely detectable via conventional spectral imaging. Binding mechanism studies show Ru-dmpip interacts with Aβ1-42 via hydrogen bonding with the C-terminus and electrostatic attraction with the N-terminus. As the first two-photon PLIM probe integrating sequence selectivity and aggregation monitoring, Ru-dmpip provides a valuable tool for AD pathological research and inspires the design of sequence-specific Aβ sensors.},
}

@article {pmid42083474,
year = {2026},
author = {Aktar, BSK and Karaküçük-İyidoğan, A and Yılmaz, GT and Oruç-Emre, EE and Sıcak, Y and Bakırdöven, A and Turgut-Solak, ZD and Öztürk, M},
title = {Therapeutic potential of sulfonate-based hydrazide hydrazones in neurodegenerative diseases: SAR insights and molecular modeling studies.},
journal = {Future medicinal chemistry},
volume = {},
number = {},
pages = {1-19},
doi = {10.1080/17568919.2026.2665469},
pmid = {42083474},
issn = {1756-8927},
abstract = {AIMS: Cholinesterase inhibitors represent an important therapeutic strategy in combating Alzheimer's disease.

MATERIAL AND METHODS: The novel 4-((2-(substitutedbenzoyl)hydrazinylidene)methyl)phenyl 2/3/4-(trifluoromethoxy)benzene-1-sulfonates (1-40) were synthesized from the reaction of 4-Formylphenyl-2/3/4-trifluoromethoxybenzene-1-sulfonate with various substituted benzoic acid hydrazides. The structures of all hybrid molecules were conclusively elucidated by elemental analysis and some spectroscopic techniques (IR, NMR, MS). These compounds were evaluated for their cholinesterase (AChE and BChE) inhibitory activities.

RESULTS: Compound 33, carrying a nitro group at the 4-position of the phenyl ring among the series, exhibited the highest inhibitory activity, showing IC50 values of 8.11 ± 0.52 µM for AChE and 12.09 ± 0.28 µM for BChE. The molecular docking studies elucidated the interactions of the active compounds with the actives sites of AChE and BChE enzymes were elucidated by molecular docking, supporting their observed anticholinesterase activity.

CONCLUSION: The compatible results of experimental data and in silico analyses demonstrate that these compounds can be considered among effective and potential lead candidates for cholinesterase inhibition targeting AD.},
}

@article {pmid42083542,
year = {2026},
author = {Garg, A and Lavania, K and Parhi, R and Singh, GK and Ahmad, J and Jain, A},
title = {Nanomedicine-Based Approaches for Therapeutic Delivery Across the Blood-Brain Barrier in Neurological Disorders.},
journal = {Current pharmaceutical design},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113816128412258251127103243},
pmid = {42083542},
issn = {1873-4286},
abstract = {Therapeutic delivery to the Central Nervous System (CNS) is challenging for formulation scientists due to the transfer of therapeutics across the Blood-Brain Barrier (BBB). The BBB consists of a selective semi-permeable anatomical structure of the capillary basement membrane, capillary endothelial cells, pericytes, and astrocytes. It restricts the drug transfer from the blood compartment to the brain tissues. Therefore, the desirable effects of various therapeutics in different CNS disorders (like Alzheimer's disease, schizophrenia, Parkinson's disease, etc.) require the transfer of drugs across the BBB. Hence, various approaches have been explored for deeper penetration of CNS-acting drugs across the BBB. Among various formulation approaches, Drug Delivery Systems (DDS) utilizing colloidal carrier systems are one of the most promising strategies to overcome BBB limitations and achieve brain targeting in different CNS disorders. This review provides a comprehensive discussion of drug delivery challenges across the BBB and technology advancements utilized to achieve improved therapeutic efficacy in different CNS disorders.},
}

@article {pmid42083556,
year = {2026},
author = {Soliani, AG and Muratori, BG and Baptista, JS and Cerutti, SM},
title = {Rodents' episodic-like memory: concepts, ageing, neurodegeneration, future.},
journal = {Translational neuroscience},
volume = {17},
number = {1},
pages = {20250392},
pmid = {42083556},
issn = {2081-3856},
abstract = {Episodic memory (EM), traditionally defined as the conscious recollection of what, where, and when events occurred, was long considered uniquely human due to its reliance on autonoetic awareness. However, behavioural criteria allow memory assessment based on observable features, enabling the study of EM-related processes in non-human species and leading to the concept of episodic-like memory (ELM) in animal models. We review conceptual advances and methodological challenges in ELM research, focusing on rodent models that provide mechanistic insights into neural circuits and molecular pathways supporting memory formation and persistence. Converging evidence highlights the role of hippocampal-prefrontal networks in integrating spatial, temporal, and emotional dimensions of experience. We also discuss data from our laboratory, which provides evidence for cellular and synaptic mechanisms, such as tagging-and-capture, ensemble allocation, and reactivation, that contribute to memory linking and consolidation in the fear-based ELM paradigm. These findings indicate that novelty-dependent recruitment of neuronal ensembles in the dorsal CA1 is impaired during ageing, leading to deficits in the persistence of weak experiences. Additionally, studies using cholinergic hypofunction models, a hallmark of late-onset Alzheimer's disease (LOAD), reveal severe impairments in object recognition, spatial location, and integrated ELM, partially reversed by pharmacological interventions. Collectively, these data emphasise the translational relevance of ELM paradigms for modelling age-related memory decline and neurodegeneration. We also address open questions regarding neuromodulatory influences, sex differences, and the boundary between normal ageing and LOAD. By integrating conceptual, behavioural, and neurobiological perspectives, ELM approaches provide powerful tools for probing memory dynamics and informing therapeutic strategies.},
}

@article {pmid42083572,
year = {2026},
author = {Minhas, AM and Khan, AU and Gul Qazi, N and Nadeem, H and Ali, F},
title = {Pharmacological investigation of oxadiazole derivatives in Alzheimer's disease: Modulation of oxidative stress, neuroinflammation, and iNOS signaling.},
journal = {Iranian journal of basic medical sciences},
volume = {29},
number = {3},
pages = {423-437},
pmid = {42083572},
issn = {2008-3866},
abstract = {OBJECTIVES: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by deposition of amyloid-beta (Aβ) aggregates. Aβ peptides alter synaptic function and produce neuroinflammation. The neurotoxic mechanisms are also related to increases in the expression of iNOS (inducible nitric oxide synthase), resulting in further neuronal degeneration and memory impairment.

MATERIALS AND METHODS: In the current study, we assessed the in vivo effect of the 1,3,4-oxadiazole derivative 2-{[5-(2-aminophenyl)-1,3,4-oxadiazol-2-yl] sulfanyl}-
N-(1,3-benzothiazol-2-yl) acetamide (MA) on spatial memory and inflammatory responses induced by AlCl3 administration in animals.

RESULTS: A notable improvement in memory function was observed in the AlCl3-induced group at 29[th] post-injection, following MA treatment (5, 10, and 20 mg/kg), as indicated by the behavioral analysis. This effect is correlated with decreases in inflammatory markers such as NFKƁ, IL-6/ß1, IFN-γ, TNϜ-α, and NO levels, as well as a reduction in expression of neurodegenerative markers: β-amyloid and p-tau (*P<0.05, **P<0.01, ***P<0.001 vs disease control). The results from our study suggested that MA significantly enhances the levels of glutathione, catalase, and glutathione S-transferase while decreasing the lipid peroxidation (LPO) in comparison to the disease control group, and also improves mitochondrial dysfunction. The effects are further enhanced when MA was used in combination with aminoguanidine (AG), an iNOS inhibitor. Molecular dynamics (MD) simulations, along with protein mRNA expression and iNOS western blotting, further supported the results of in vivo experiments.

CONCLUSION: Our study proposed that MA attenuated the cytokine release, decreased oxidative stress, and iNOS expression, leading to a decrease in neurodegeneration.},
}

@article {pmid42083861,
year = {2026},
author = {Stokes, JE and Pugh, EA and Briggs, E and Lee, G and Leggett, AN and López-Anuarbe, M},
title = {The long arm of divorce and death: Loss, loneliness, and cognition in mid and later life.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251394316},
doi = {10.1177/13872877251394316},
pmid = {42083861},
issn = {1875-8908},
abstract = {BackgroundEarly life adversities can have lifelong consequences for health, including for cognitive functioning and Alzheimer's disease and related dementias. Moreover, early-life disadvantages stemming from parental death and divorce have been linked with later life social, mental, and physical well-being outcomes, including social isolation. Therefore, loneliness stands out as an intervenable aspect of well-being that may mediate long-term consequences of early life exposure to parental death and divorce for midlife and older adults' cognitive decline.ObjectiveThe present study aims to determine whether early life exposures to parental death and/or divorce are associated with cognitive functioning in later life, and whether loneliness in midlife mediates such effects.MethodsWe used the 2014-2020 Health and Retirement Study (HRS), 2015 HRS Life History data and longitudinal structural equation modeling to address our research questions.ResultsEarly-life exposure to parental divorce, but not death, was associated with greater loneliness in late midlife and older age, and loneliness predicted more rapid declines to cognitive functioning over time. Mediation was statistically significant (p < 0.05).ConclusionsAlthough racial/ethnic minorities had higher exposure to both parental death and divorce, the effects of parental death and divorce were similar across race/ethnicity. Our results underscore the long-term impacts of parental divorce on well-being and health in adulthood and highlight loneliness as a critical determinant of cognitive declines and disparities in later life.},
}

@article {pmid42083869,
year = {2026},
author = {Alhasan, DM and Hamlin, AM and Meier, HC and Manning, M and Yu, X and Gutierrez, S and Webster, NJ},
title = {Association of childhood residential change with later life memory function and rate of decline in the US Health and Retirement Study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251394333},
doi = {10.1177/13872877251394333},
pmid = {42083869},
issn = {1875-8908},
abstract = {BackgroundChildhood residential change may affect later-life memory function and risk for Alzheimer's disease. However, few studies have examined this relationship, particularly in minoritized racial/ethnic groups.ObjectiveTo assess the association between number of residences and moving due to financial difficulties in childhood with memory trajectories in later life.MethodsData were from the U.S. Health and Retirement Study. Childhood residential change was measured by the self-reported number of residences before age 16 (0-1, 2, 3, 4 or more; n = 4704). Moving due to financial difficulties before age 16 was categorized as yes versus no (n = 4651). Memory function was measured using composite memory z-scores incorporating direct and proxy assessments from 1996-2016. We utilized mixed-effects linear regression models with subject-specific random slopes and intercepts adjusting for sociodemographic characteristics to estimate associations between residential change and memory overall and by race/ethnicity and parental education.ResultsThe mean age at baseline was 57.6 ± 6.1 years, 78.7% self-identified as non-Hispanic (NH) White, 15.7% as NH-Black, and 5.6% as Other/Unknown. Descriptively, NH-Black adults reported fewer residential changes and had lower baseline memory performance compared to NH-White participants. More frequent residential change in childhood was associated with a slower rate of memory decline but not baseline memory function. Moving due to financial difficulties during childhood was not associated with initial memory levels or rates of memory decline. We did not observe effect modification by race/ethnicity or parental education.ConclusionsResults suggest that childhood residential change may contribute to later life memory trajectories.},
}

@article {pmid42083876,
year = {2026},
author = {Nah, S and Chek, CJ and Montoya, A and Duarte, A and Ryan, LH and Chopik, WJ},
title = {Health behavior mechanisms linking childhood socioeconomic status to Alzheimer's disease and related dementia risk: Exploring gender and racial/ethnic differences.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251394317},
doi = {10.1177/13872877251394317},
pmid = {42083876},
issn = {1875-8908},
abstract = {BackgroundLower childhood socioeconomic status (cSES) has been linked to a higher risk of Alzheimer's disease and related dementia (ADRD). Yet, the mechanisms underlying this association remain unclear.ObjectiveThis study examined whether poorer health behaviors in adulthood mediate the association between lower cSES and ADRD risk. We further explored whether the mediating effects of health behaviors vary by gender or race/ethnicity.MethodsData were drawn from 26,631 participants in the Health and Retirement Study (Mage = 61.18 years). Cox proportional hazard models were used to estimate the association between cSES and ADRD risk, as well as the mediating effects of health behaviors, including smoking, heavy drinking, physical activity, and influenza vaccination.ResultsLower cSES was associated with a higher risk of ADRD (hazard ratio = 1.06, [1.02, 1.09]). Lower physical activity mediated this association, accounting for 17.1% of the total effect of cSES on ADRD risk. Subgroup analyses revealed that this mediation was consistent across all gender and racial/ethnic groups, except for foreign-born Hispanics. Smoking mediated the association only for men, explaining 4.2% of the total effect.ConclusionsThese findings suggest that lower cSES may be a risk factor for ADRD partially through lower physical activity across most demographic groups. Interventions promoting physical activity in adulthood could help mitigate the adverse effect of low cSES on ADRD risk. Furthermore, smoking prevention programs may be particularly beneficial for men from lower socioeconomic backgrounds.},
}

@article {pmid42083879,
year = {2026},
author = {Walters, ME and Wong, R and Scambray, KA and Antonucci, TC and Tarraf, W},
title = {The association of adverse childhood experiences and life course relationship quality with late-life cognitive health: Moderation by race/ethnicity and gender.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251394324},
doi = {10.1177/13872877251394324},
pmid = {42083879},
issn = {1875-8908},
abstract = {BackgroundAdverse childhood experiences (ACEs) may increase Alzheimer's disease risk. How particular ACEs differentially relate to cognition and what role life course relationship quality (LCRQ) plays are unclear.ObjectiveAssess how ACEs subgroups relate to cognition and whether associations are impacted by LCRQ.MethodsAdults (ages 50-64 at baseline) from the Health and Retirement Study participated (n = 3225; 2006/2008 = baseline; 2018/2020 = follow-up). Latent class and profile analyses identified ACEs and LCRQ subgroups, respectively. Linear and multinomial logistic regressions related ACEs and LCRQ subgroups to global cognition, cognitive impairment, not dementia (CIND), and dementia at follow-up.ResultsWe identified 4 ACEs (High Adversity, Family Disruptions, Elevated Household Trauma, Low Adversity) and 3 LCRQ ("Strong", "Mixed", "Weak" Ties) classes. Racially/ethnically minoritized adults were more likely to belong to Family Disruptions and Weak Ties classes than White adults. Participants with Family Disruptions (versus Low Adversity) had worse cognition (global: b = -0.78, 95% CI [-1.19;-0.37]; CIND: RRR = 1.50, 95% CI [1.13;1.99]); controlling for LCRQ and sociodemographics attenuated associations. Participants with Weak Ties (versus Strong) had worse cognition (global: b = -2.90, 95% CI [-3.53;-2.26]; CIND: RRR = 3.16, 95% CI [2.12;4.70]; dementia: RRR = 3.64, 95% CI [1.92;6.90]); associations were not explained by covariates.ConclusionsFamily Disruptions negatively impacted cognition, but associations were attenuated by sociodemographics. Assessing life course resources as contributors to resilience may help explain the untenable ACEs-cognition association. However, negative LCRQ was consistently harmful to cognition. Targeting life course social relationships may benefit cognition.},
}

@article {pmid42083945,
year = {2026},
author = {Kumar, D and Walhekar, V and Kasaragod, MS and Kini, S},
title = {Discovery of Novel Quinazoline Thiazole Uredio Analogs as Dual Inhibitors of GSK-3β and CK-1δ as Anti-Alzheimer's Agents: Catching Two Fish with One Net.},
journal = {Current topics in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115680266378266251017045841},
pmid = {42083945},
issn = {1873-4294},
abstract = {INTRODUCTION: AD is a widespread and debilitating neurodegenerative disorder, and existing treatments have demonstrated limited efficacy, emphasizing the need for novel therapeutic strategies. This study focused on the design of drug-like molecules with enhanced efficacy and minimized side effects through the application of structure-based scaffold hopping and molecular hybridization strategies.

METHODS: Molecular docking was carried out on the Glide module, Molecular dynamics simulation of 500 ns was executed employing Desmond, and ADMET prediction was achieved by the QikProp modules of Schrodinger.

RESULTS: Through molecular docking studies targeting the GSK-3β and CK-1δ enzymes, the compounds VDK12 and VDK14 were identified as promising inhibitors, showing favorable interactions within the active sites of these proteins, with docking energies of -9.9 kcal/mol and -10.1 kcal/mol, respectively. Molecular dynamics simulations further revealed that the VDK12 and VDK14 complexes exhibited stable interactions within the active sites of GSK-3β and CK-1δ throughout a 500 ns simulation. Additionally, in silico ADMET analysis demonstrated that VDK1 exhibited an excellent human oral absorption rate of 91.349%, outperforming other compounds in the series.

DISCUSSION: Molecules as dual inhibitors were designed successfully by the application of scaffold hopping and molecular hybridization. Designed molecules demonstrated excellent molecular docking and dynamics simulation results with an appropriate ADMET profile.

CONCLUSION: These findings strongly suggest the potential of VDK12 and VDK14 as dual inhibitors of GSK-3β and CK-1δ, offering a promising foundation for the development of new lead compounds for AD treatment.},
}

@article {pmid42083963,
year = {2026},
author = {Kanojia, N and Deswal, G and Grewal, AS and Kumar, J and Thapa, K and Sharma, A and Sharma, A and Dheer, D and Puri, V and Rani, L and Saini, V},
title = {Advances in Microneedle Technology for Targeted Therapy in Alzheimer's and Parkinson's Disease.},
journal = {Current drug delivery},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672018425956260117232402},
pmid = {42083963},
issn = {1875-5704},
abstract = {INTRODUCTION: The fourth major cause of death worldwide is Neurodegenerative Diseases (NDs), including Alzheimer's and Parkinson's disease. The existing therapies have only a small effect on alleviating symptoms, mainly because the therapeutic agents are difficult to cross the bloodbrain barrier. The purpose of the review is to discuss the potential of microneedle-based transdermal delivery systems to improve the delivery of drugs to the central nervous system and thereby manage neurodegenerative diseases effectively.

METHODS: The article summarizes and synthesizes the available literature that targets the strategies of microneedle-mediated drug delivery. The literature on the design, composition, pharmacokinetics, and mechanistic benefits of different microneedle platforms for surmounting central nervous system barriers was identified and thematically synthesized.

RESULTS: Microneedle systems have emerged as non-invasive delivery systems with the potential for localized and sustained drug delivery, overcoming the stratum corneum and the blood-brain barrier. Micro-needles can be used to deliver small molecules, peptides, and nanoparticles to the brain, thereby avoiding systemic side effects and enhancing drug bioavailability. Some of those designs include dissolving, coated, hollow, hydrogel-forming, and stimuli-responsive microneedles, which have been shown to target the brain and exhibit higher therapeutic efficiency in preclinical models.

DISCUSSION: Although technological advances have improved, the clinical translation of microneedlebased strategies remains limited. The future directions could include using microneedles with stem cell-based therapies, CRISPR/Cas9 gene editing, artificial intelligence-based delivery systems, and responsive release technology to facilitate customized treatment.

CONCLUSION: The Microneedle-based drug delivery systems are promising in overcoming the current limitations in the treatment of neurodegenerative diseases. Nonetheless, a large-scale clinical validation is necessary to guarantee safety, efficacy, and scalability to be applied to real-life scenarios.},
}

@article {pmid42083975,
year = {2026},
author = {Saffold, K and Tall, A and Lowery, AT and Pryor, T and Jones-Muhammad, M and Shao, Q and Warrington, JP},
title = {Mouse Offspring Exposed to Preeclampsia/Eclampsia-like Symptoms Exhibit Cerebral Hypoperfusion & Mild Cognitive Impairment at 2 months of age.},
journal = {American journal of physiology. Heart and circulatory physiology},
volume = {},
number = {},
pages = {},
doi = {10.1152/ajpheart.00711.2025},
pmid = {42083975},
issn = {1522-1539},
support = {5R25HL145817//HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; 1 R56 HL159447//HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; P30GM103328//HHS | NIH | National Institute of General Medical Sciences (NIGMS)/ ; Startup/Bridge Funds from the Department of Neurology//University of Mississippi (UM)/ ; },
abstract = {Preeclampsia is a pregnancy complication characterized by high blood pressure and signs of organ damage, after the 20[th] week of pregnancy. Children born to mothers with preeclampsia or eclampsia (new-onset seizures during pregnancy) are more likely to develop learning and memory deficits and are more susceptible to neurovascular diseases compared to those born from normal pregnancies. The contributing mechanisms are unknown. In this study, we assessed whether exposure to reduced uteroplacental perfusion (RUPP), modeling placental hypoperfusion and preeclampsia, with or without pentylenetetrazol (PTZ) injection (to induce seizures and model eclampsia), results in cognitive impairment, Alzheimer's disease markers, and regional cerebral perfusion changes in adult offspring. On gestational day (GD)13.5, pregnant C57BL/6 mice (n=22) underwent Sham or RUPP surgery followed by injection or no treatment with PTZ (40 mg/kg) on GD18.5. At 2 months of age, spatial learning and cerebral perfusion were measured in randomly selected offspring or averaged to obtain mean data per sex, per litter (n=4-6 data points per group/treatment). RUPP-exposed offspring took a longer distance and made more errors navigating the Barnes maze. Cerebral perfusion was reduced in offspring exposed to RUPP, specifically in the prefrontal cortex, superior sagittal sinus, and whole brain. There was a significant reduction in perfusion in seizure-exposed offspring in the superior sagittal and transverse sinuses, whole brain, and cerebellum. Our results support the hypothesis that exposure to preeclampsia/eclampsia-like symptoms leads to mild learning impairment through reduced cerebral perfusion to cortical regions and decreased drainage of waste from the brain via the cerebral sinuses.},
}

@article {pmid42083983,
year = {2026},
author = {Au, R and Gifford, KA and Paschalidis, IC and Wighton, P and Levin, M and Imam, F and Bose, N and Pratap, A},
title = {The myth of digital biomarkers in Alzheimer's disease: how to make them a reality.},
journal = {Current opinion in psychiatry},
volume = {},
number = {},
pages = {},
pmid = {42083983},
issn = {1473-6578},
abstract = {PURPOSE OF REVIEW: With an estimated 41.1B digital devices, the term "digital biomarkers" has been increasingly bandied about in the research literature. There is, however, a significant disconnect between the presumption of digital biomarkers and the reality of digital biomarkers.

RECENT FINDINGS: The research literature embraces the concept of digital biomarkers without concomitant evidence for validation of digital measures as biomarkers. Unlike imaging or blood-based biomarkers, there is a woeful lack of research dedicated to validating digital measures as biomarkers. This gap also presents an opportunity. Regulatory agencies worldwide have long-standing protocols used by pharmaceutical and biotech companies to stand up quality management systems (QMS) that track research from inception to regulatory approved submissions. The recent United States (US) Food and Drug Administration (FDA) approval of Alzheimer's disease (AD) plasma biomarkers is another example where successful QMS implementation provided the processes and transparency necessary to obtain approval. Regulatory guidelines for digital technology validation are more circumspect on validation pathways of AD digital biomarkers, but FDA provides a framework for building a QMS that could potentially do so.

SUMMARY: Building an open source QMS for AD digital biomarker validation will be a critical breakthrough for harnessing the potential of digital technologies for detection, monitoring and treatment of AD and related disorders.},
}

@article {pmid42084056,
year = {2026},
author = {Komoto, Y and Takahagi, W and Ohshiro, T and Nishihata, S and Fujishima, K and Taniguchi, M},
title = {Single-molecule detection of amino acid phosphorylation using electron tunnelling currents: toward neurodegenerative disease diagnosis.},
journal = {Nanoscale},
volume = {},
number = {},
pages = {},
doi = {10.1039/d6nr00687f},
pmid = {42084056},
issn = {2040-3372},
abstract = {Protein phosphorylation is one of the most prevalent post-translational modifications regulating biological functions, and its dysregulation is closely associated with neurodegenerative diseases such as Alzheimer's and Parkinson's disease. Despite extensive studies, direct detection of phosphorylation at the single-molecule level remains challenging because conventional mass spectrometry and antibody-based assays require complex pretreatments and cannot comprehensively resolve site-specific modifications. To address this challenge, we employed mechanically controllable break junction (MCBJ) measurements to probe the single-molecule conductance of serine (Ser), threonine (Thr), tyrosine (Tyr), and their phosphorylated counterparts. Distinct conductance trends were observed depending on the amino acid species, reflecting the influence of phosphate substitution on the electronic states. Density functional theory (DFT) calculations revealed that phosphorylation-induced shifts in HOMO levels and changes in π-conjugation account for the observed conductance variations. Furthermore, statistical analysis combined with machine-learning-based classification enabled discrimination between phosphorylated and non-phosphorylated amino acids with high accuracy, demonstrating that single-molecule electrical signals contain sufficient molecular information for identifying phosphorylation. This study establishes an electronic readout approach for amino acid phosphorylation and provides a proof of concept for extending single-molecule electrical techniques toward quantitative and sequencing-oriented analyses of protein modifications.},
}

@article {pmid42084083,
year = {2026},
author = {Boutajangout, A and Masurkar, AV and Osorio, R and Debure, L and Ghuman, M and Ahmed, W and Vedvyas, A and Pirraglia, E and Links, J and Bokacheva, L and Vega, B and Bernard, MA and Marsh, K and Bubu, OM and Shao, Y and Chodosh, J and Rusinek, H and Wisniewski, T},
title = {Association of plasma biomarkers with amyloid and tau PET in pre-dementia stages.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71441},
doi = {10.1002/alz.71441},
pmid = {42084083},
issn = {1552-5279},
support = {P30AG066512//National Institutes of Health grants/ ; R01AG077422//National Institutes of Health grants/ ; U24NS141774//National Institutes of Health grants/ ; U24NS141774/NS/NINDS NIH HHS/United States ; R01AG077422/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *tau Proteins/blood/metabolism ; *Biomarkers/blood ; Male ; *Positron-Emission Tomography ; Female ; *Amyloid beta-Peptides/blood ; *Cognitive Dysfunction/blood/diagnostic imaging ; Aged ; Glial Fibrillary Acidic Protein/blood ; Neurofilament Proteins/blood ; Middle Aged ; Peptide Fragments/blood ; Alzheimer Disease/blood/diagnostic imaging ; Aged, 80 and over ; },
abstract = {INTRODUCTION: Measuring plasma biomarkers effectively assesses early-stage Alzheimer's disease.

METHODS: Subjects were categorized as cognitively unimpaired (CU) (n = 66), CU with subjective cognitive decline (SCD) (n = 100), and mild cognitive impairment (MCI) (n = 25). Plasma biomarkers measured were amyloid beta (Aβ) 40, Aβ42, neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), tau phosphorylated at threonine 181 (pTau181), neuroinflammatory biomarkers, and blood-brain barrier biomarkers. Amyloid and tau positron emission tomography (PET) imaging was performed in 186 and 144 subjects, respectively.

RESULTS: Comparing those having MCI, both CU and SCD participants had significantly lower amyloid PET standardized uptake value ratio (SUVR) (p < 0.001; p = 0.005). Higher amyloid PET SUVR was significantly associated with higher pTau181 (p = 0.001) and a higher pTau181/Aβ42 ratio (p < 0.001). Higher tau PET SUVR was associated with lower plasma Aβ42 (p = 0.020), older age (p = 0.005), higher GFAP (p = 0.020), and lower interleukin-8 levels (p < 0.001).

DISCUSSION: Our study supports plasma biomarker monitoring of at-risk patients at various stages of pre-dementia.},
}

Humans
*tau Proteins/blood/metabolism
*Biomarkers/blood
Male
*Positron-Emission Tomography
Female
*Amyloid beta-Peptides/blood
*Cognitive Dysfunction/blood/diagnostic imaging
Aged
Glial Fibrillary Acidic Protein/blood
Neurofilament Proteins/blood
Middle Aged
Peptide Fragments/blood
Alzheimer Disease/blood/diagnostic imaging
Aged, 80 and over

@article {pmid42084109,
year = {2026},
author = {Gabel, M and Goswami, S and Bekena, S and Solomon, ED and Moulder, KL and Morris, JC and Mozersky, J},
title = {The impact of learning about financial compensation on enrollment in Alzheimer's disease longitudinal research.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71356},
doi = {10.1002/alz.71356},
pmid = {42084109},
issn = {1552-5279},
support = {P01AG003991/AG/NIA NIH HHS/United States ; P30AG066444/AG/NIA NIH HHS/United States ; P01AG026276/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/economics/psychology ; Female ; Longitudinal Studies ; Male ; *Patient Selection ; Aged ; Aged, 80 and over ; *Compensation and Redress ; },
abstract = {INTRODUCTION: Recruitment and retention remains a major challenge in Alzheimer's disease research. This study examined the impact of describing potential financial compensation during recruitment on participant enrollment to a longitudinal cohort.

METHODS: Participant recruitment calls (N = 337) were randomized to either a compensation-mentioned group (n = 170) or a control group (n = 167). An intention-to-treat logistic regression assessed the effect of compensation on enrollment.

RESULTS: Of 320 analyzed, 124 (38.75%) enrolled. The intervention group's consent rate was lower than the control group's in intention-to-treat (-9.72 points; p = 0.074), per-protocol (-12.72 points; p = 0.026), and complier average causal effect analyses (-11.36 points; p = 0.72).

DISCUSSION: Disclosing compensation during recruitment may reduce enrollment, potentially due to perceptions that compensation conflicts with altruistic motives. However, this was observed in a highly educated sample; compensation may affect those with lower levels of education and socioeconomic status differently by helping offset participation burden, warranting further investigation.},
}

Humans
*Alzheimer Disease/economics/psychology
Female
Longitudinal Studies
Male
*Patient Selection
Aged
Aged, 80 and over
*Compensation and Redress

@article {pmid42084231,
year = {2026},
author = {Barolo, L and Farina, MV and Cimaglia, G and Gigante, Y and Mirone, A and Mautone, L and Boffi, A and Di Angelantonio, S and Baiocco, P},
title = {From Food Additives to Neurodegeneration: The Emerging Role of Polyphosphates in Tauopathies.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00915},
pmid = {42084231},
issn = {1948-7193},
abstract = {Neurodegenerative diseases are characterized by progressive molecular and biochemical dysfunctions that disrupt neuronal homeostasis, leading to impaired nervous system function. In tauopathies, a specific class of neurodegenerative disorders, tau protein aggregation and mitochondrial dysfunction are pathological processes interconnected in a self-reinforcing cycle. In fact, tau fibrils impair mitochondrial transport, bioenergetics, and quality control, while mitochondrial dysregulation causes tau post-translational modifications, detachment from neurons, and aggregation. In this context, inorganic polyphosphates located in cells are recently emerging as a possible modulator of both tau aggregation and mitochondrial dysfunction, thereby contributing to the onset and progression of tauopathies, including Alzheimer's disease. Additionally, inorganic polyphosphates are widely present in diets worldwide as food additives, suggesting a possible frightening connection between nutrition and tauopathies, especially in vulnerable individuals. Understanding these biochemical and nutritional interactions may support the development of novel therapeutic approaches and provide effective preventive strategies to mitigate the risk of neurodegeneration in aging populations. This review explores the current state of the art for in vivo and in vitro studies, exploring the role of endogenous polyphosphates in tau aggregation and mitochondrial dysfunction, including a novel focus point: how exogenous polyphosphates present in everyday processed food could potentially facilitate the onset of pathological conditions in humans.},
}

@article {pmid42084241,
year = {2026},
author = {Bae, Y and Kim, M and Jeon, SR and Lee, SW and Jung, H},
title = {Risk of Alzheimer Disease and Other Dementias in Patients With Parkinson Disease: A Nationwide Cohort Study.},
journal = {Alzheimer disease and associated disorders},
volume = {},
number = {},
pages = {},
doi = {10.1097/WAD.0000000000000722},
pmid = {42084241},
issn = {1546-4156},
abstract = {INTRODUCTION: Dementia is a major nonmotor complication of Parkinson disease (PD), yet its subtype-specific and time-dependent risk remains incompletely characterized.

METHODS: We conducted a nationwide retrospective cohort study using Korean National Health Insurance claims and health screening data. Newly diagnosed PD patients (ICD-10: G20) and propensity score-matched controls were followed after a 3-year washout period. Dementia outcomes were defined using ICD-10 codes and classified as Alzheimer disease dementia (F00, G30), other dementias (F01-F03), and overall dementia. Incidence rate ratios (IRRs) and adjusted hazard ratios (aHRs) were estimated using Cox models.

RESULTS: PD was associated with higher dementia incidence across all subtypes. IRRs were 3.38 (95% CI: 3.12-3.67) for Alzheimer disease dementia, 4.67 (95% CI: 4.16-5.23) for other dementias, and 3.60 (95% CI: 3.33-3.90) for overall dementia. Elevated risks persisted after multivariable adjustment and were more pronounced in younger patients and men, with variation by dementia subtype and time since diagnosis.

CONCLUSIONS: PD was associated with an increased risk of dementia in this nationwide cohort. The heterogeneity observed by subtype, age, and follow-up period suggests that dementia risk may emerge early in specific subgroups, supporting early cognitive monitoring without implying causality.},
}

@article {pmid42084363,
year = {2026},
author = {Wu, L and Li, S and Huang, L and Li, L and Zhou, P and Lu, Z and Liu, T and Wang, J},
title = {Non-Invasive Temporal Interference Electrical Stimulation Modulates Neurotransmitter Release and Improves Aberrant Neural Oscillations in Alzheimer's Disease.},
journal = {CNS neuroscience & therapeutics},
volume = {32},
number = {5},
pages = {e70848},
doi = {10.1002/cns.70848},
pmid = {42084363},
issn = {1755-5949},
support = {2025SF-YBXM-254//Shaanxi Province Key Research and Development Program Project/ ; 82102179//National Natural Science Foundation of China/ ; ZR2024QF287//Natural Science Foundation of Shandong Province/ ; ZR2024YQ077//Natural Science Foundation of Shandong Province/ ; tsqn202211226//Taishan Scholar Foundation of Shandong Province/ ; tstp20221144//Taishan Scholar Foundation of Shandong Province/ ; K2025LC0102//Clinical Research Capacity Improvement Special Project of University of Health and Rehabilitation Sciences/ ; SRICSPYF-BS2025076//Scientific Research Innovation Capability Support Project for Young Faculty/ ; },
mesh = {Animals ; *Alzheimer Disease/therapy/physiopathology/metabolism/genetics ; Mice, Transgenic ; Mice ; *Neurotransmitter Agents/metabolism ; Disease Models, Animal ; Amyloid beta-Protein Precursor/genetics ; Male ; Humans ; *Electric Stimulation Therapy/methods ; Presenilin-1/genetics ; Mice, Inbred C57BL ; *Brain/physiopathology/metabolism ; },
abstract = {BACKGROUND: Modulating brain oscillations has significant therapeutic promise. Traditional non-invasive neuromodulation techniques can alleviate clinical signs of Alzheimer's disease (AD) by restoring normal neural oscillatory activity in certain brain regions. As a novel non-invasive brain modulation technique, temporal interference (TI) has been demonstrated to precisely control hippocampus neural oscillations while minimizing its impact on cortical neural activity, but its exact mechanism of action is still unclear.

METHOD: We simulated and experimentally measured the intracranial electric field under TI to determine the precision of TI intervention. Subsequently, TI stimulation was applied to the APP/PS1 transgenic AD mouse model, and the impact of TI stimulation on the stimulated brain region was compared from the perspectives of behavior, electrophysiology, and cell biology.

RESULTS: This work showed that in the APP/PS1 Alzheimer's disease mice model, TI stimulation significantly increased GABA levels and decreased NMDA receptor activation at the targeted region. Following neurotransmitter regulation, the rhythm of the gamma oscillations they associate also changed. This, in turn, influenced other memory-related neural oscillation frequencies and brain regions through cross-frequency coupling and brain connectivity, ultimately improving the behavioral performance of AD model mice.

CONCLUSIONS: The results of our work demonstrated how TI stimulation alters brain oscillations to enhance memory in mice with Alzheimer's disease, offering a possible theoretical foundation for TI's clinical application.},
}

Animals
*Alzheimer Disease/therapy/physiopathology/metabolism/genetics
Mice, Transgenic
Mice
*Neurotransmitter Agents/metabolism
Disease Models, Animal
Amyloid beta-Protein Precursor/genetics
Male
Humans
*Electric Stimulation Therapy/methods
Presenilin-1/genetics
Mice, Inbred C57BL
*Brain/physiopathology/metabolism

@article {pmid42084488,
year = {2026},
author = {Hernandez, A and Massihzadegan, S and Coyle, C},
title = {Adult Social Day Services: A Promising, Yet Underutilized Community-Based Support for Individuals With Alzheimer's Disease and Related Dementias.},
journal = {Journal of applied gerontology : the official journal of the Southern Gerontological Society},
volume = {},
number = {},
pages = {7334648261448267},
doi = {10.1177/07334648261448267},
pmid = {42084488},
issn = {1552-4523},
abstract = {As Alzheimer's disease and related dementias (ADRD) become more common, there is a growing need for programs that improve the quality of life for individuals living with these conditions. Understanding existing community-based models of engagement is essential for identifying effective, scalable solutions. Adult Social Day Services (ASDS) offer opportunities for socialization and cognitive engagement for individuals who require minimal assistance with activities of daily living. Although promising, ASDS programs are used unevenly, and their overall effectiveness remains unclear. To address this gap, we conducted a parallel convergent mixed-methods study using data from a fee-based ASDS program located at a senior center in a northeastern U.S. town. Using a population-level survey, stakeholder focus groups, and in-depth interviews with current and former participants and their families, we examined the program from multiple perspectives. Findings suggest the ASDS model has strong potential for scaling, replication, and adaptation as a community-based dementia intervention, with benefits for participant well-being and caregiver support.},
}

@article {pmid42084584,
year = {2026},
author = {Lee, S and Gunaga, S and Liu, SW and Luo, Q and Bayer, TA and Rudolph, JL and Carnahan, RM},
title = {Emergency Department Boarding for Older Adults: The Impact of Geography, Temporal Trends, and Dementia Status.},
journal = {Annals of emergency medicine},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.annemergmed.2026.03.011},
pmid = {42084584},
issn = {1097-6760},
abstract = {STUDY OBJECTIVE: Emergency department (ED) boarding, defined as the time an admitted patient remains in the ED awaiting an inpatient bed, has become a growing challenge in the United States, particularly for older adults with Alzheimer's disease-related dementia. We examined trends in ED boarding from 2015 to 2022, focusing on geographic variation, rurality, and differences by Alzheimer's disease-related dementia status.

METHODS: We conducted a cross-sectional analysis using National Hospital Ambulatory Medical Care Survey (NHAMCS) data from 2015 to 2022. Adults aged ≥65 years who were admitted to the hospital were included. Weighted estimates characterized annual boarding rates (≥2, 4, and 8 hours). Linear probability models assessed associations of study year, region, rurality, and Alzheimer's disease-related dementia status with boarding as binary outcomes; linear regression examined boarding duration in minutes.

RESULTS: Among an estimated 7.05 million eligible encounters, 4.45 million had complete data; 85.2% experienced boarding ≥2 hours. Rates remained in the mid-80% range from 2015 to 2018, dipped in 2017 and 2020, and rose to 92% in 2021 to 2022. Mean boarding time increased from 138 minutes (95% confidence interval [CI] 112 to 164) in 2018 to 343 minutes (95% CI 238 to 448) in 2022, reaching 501 minutes (95% CI -20 to 1,022) among patients with Alzheimer's disease-related dementia. Each additional calendar year was associated with a 3.2% increase in 4-hour boarding (95% CI 2.4% to 4.0%) and 15.3 more minutes of boarding time (95% CI 10.0 to 20.0). In the Alzheimer's disease-related dementia subgroup, boarding increased most among those aged ≥75 years and in metropolitan areas.

CONCLUSION: Emergency department boarding among older adults has worsened over time, especially for those with Alzheimer's disease-related dementia. Regional disparities and disproportionate impacts on vulnerable populations highlight the urgent need for targeted policy and operational interventions.},
}

@article {pmid42084750,
year = {2026},
author = {Hafez, MM and Abbas, HA and Shoman, NA and Soubh, AA and Aly, O and Sallam, MF and Seliem, M and Malaak, FA},
title = {A new era in neuropharmacology: assessing the efficacy and safety of novel anti-amyloid and non-amyloid drug targets for Alzheimer's disease.},
journal = {Journal of neurology},
volume = {273},
number = {5},
pages = {},
pmid = {42084750},
issn = {1432-1459},
mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism ; *Neuropharmacology/trends/methods ; *Amyloid beta-Peptides/metabolism/antagonists & inhibitors ; *Antibodies, Monoclonal/therapeutic use/pharmacology ; Animals ; },
abstract = {BACKGROUND: Alzheimer disease (AD) is the most common cause of dementia in the world with the prevalence expected to increase threefold to 152.8 million people by 2050. The current medications provide a short-term ameliorative effect, and this requires development of disease-modifying treatments, which address the biological pathogenesis.

METHODS: This review assesses the changing neuropharmacological environment offering a critical analysis of anti-amyloid monoclonal antibodies and investigates the so-called expanding frontier of non-amyloid targets. It also examines the approaches of clinical trials and the trend of biomarker-based patient selection and precision medicine.

RESULTS: Although β-site APP-cleaving enzyme 1 (BACE1) and secretase inhibitors did not achieve success in clinical trials because of mechanism-based toxicity and cognitive impairment, new monoclonal antibodies such as lecanemab and donanemab have shown high amyloid plaque clearance and reduced cognitive deterioration. Nevertheless, the treatments are associated with amyloid-related imaging abnormalities (ARIA). In addition to amyloid, studies are focusing on tau hyperphosphorylation, neuroinflammation through triggering receptor on myeloid cells 2 (TREM2) and NLR family pyrin domain containing 3 (NLRP3) and growth factor-mediated synaptic plasticity through brain-derived neurotrophic factor (BDNF).

CONCLUSIONS: AD treatment has entered the new era that demands a paradigm shift from monotherapies to multi-target cocktails. The future lies in precision neuropharmacology, where genetic stratification and individual biomarker analysis are used to provide the correct treatment at the most appropriate biological stage.},
}

Humans
*Alzheimer Disease/drug therapy/metabolism
*Neuropharmacology/trends/methods
*Amyloid beta-Peptides/metabolism/antagonists & inhibitors
*Antibodies, Monoclonal/therapeutic use/pharmacology
Animals

@article {pmid42084972,
year = {2026},
author = {Kumar, D and Singh, SB and Sagar, V and Prasad, MK and Kapoor, N and Mukul, A and Nishant, A},
title = {Breakthrough Vaccines and Transformative Therapies on the Horizon of Progress toward Diabetes Management.},
journal = {Indian journal of public health},
volume = {},
number = {},
pages = {},
doi = {10.4103/ijph.ijph_102_25},
pmid = {42084972},
issn = {0019-557X},
abstract = {Diabetes mellitus (DM) affects millions of people globally. Over the years, diabetes has emerged as a significant global health concern, with steadily increasing prevalence. This review explores the various aspects of DM and delves into the evolving field of new emerging treatments and diabetes vaccines, highlighting the potential they hold in revolutionizing diabetes management in the future. Therefore, it is imperative to know about the potential vaccines and novel emerging treatment options for DM and to understand the challenges faced in making novel therapies. It is also needed to recognise the intricate relationship between diabetes and Alzheimer's disease, an emerging entity known as type 3 diabetes. Literature search was done in PubMed database, and relevant articles were selected for the narrative review. The review reveals that currently, most vaccines that have been developed are in animal studies and early phases of trials. Only few human trials have been conducted, but, with positive outcome. There are also some novel therapeutics emerging as potential management options for diabetes. There are evidences to support that Alzheimer's disease can rightly be called type 3 diabetes. In conclusion, there is a growing interest in the development of vaccines as a revolutionary approach to diabetes management. As our understanding of diabetes deepens and vaccine technology advances, the prospect of a diabetes vaccine becoming a reality offers hope for millions living with this condition and in reducing the burden of diabetes-related complications.},
}

@article {pmid42085565,
year = {2026},
author = {Singh, K and Ahmad, I and Jain, D and Mim, TJ and Noman, AA and Shihab, MPR and Kondaveeti, SB and Gupta, JK and Wal, P},
title = {Novel Cellular Signalling Axes in Neurodegenerative Diseases: From NLRP3 Inflammasome to Wnt/β-Catenin and Hippo-YAP Pathways.},
journal = {Journal of biochemical and molecular toxicology},
volume = {40},
number = {5},
pages = {e70880},
doi = {10.1002/jbt.70880},
pmid = {42085565},
issn = {1099-0461},
mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology ; *Inflammasomes/metabolism ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *Wnt Signaling Pathway ; Animals ; Hippo Signaling Pathway ; *beta Catenin/metabolism ; YAP-Signaling Proteins ; *Adaptor Proteins, Signal Transducing/metabolism ; *Protein Serine-Threonine Kinases/metabolism ; *Transcription Factors/metabolism ; Signal Transduction ; },
abstract = {Neurodegenerative diseases (NDs), including Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), and Parkinson's disease (PD), are characterised by impaired cellular homeostasis and progressive neuronal loss. Emerging evidence highlights the critical role of cellular signalling pathways in the progression and pathogenesis of these disorders. With a focus on the NLRP3 inflammasome, Wnt/β-catenin, and Hippo-YAP cascades, this review focuses on new signalling pathways linked to neurodegenerative disorders. Among them, the NLRP3 inflammasome is a crucial mediator of neuroinflammation, causing neuronal damage and persistent immune activation. In contrast, these pathways regulate neurogenesis, synaptic plasticity, and cell survival, offering potential neuroprotective functions. Dysregulation of these pathways disrupts cellular integrity, exacerbates disease progression, and represents a convergence point for therapeutic intervention. In NDs, knowing how these pathways interact offers fresh perspectives on disease processes and finds new targets for the creation of disease-modifying treatments.},
}

Humans
*Neurodegenerative Diseases/metabolism/pathology
*Inflammasomes/metabolism
*NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
*Wnt Signaling Pathway
Animals
Hippo Signaling Pathway
*beta Catenin/metabolism
YAP-Signaling Proteins
*Adaptor Proteins, Signal Transducing/metabolism
*Protein Serine-Threonine Kinases/metabolism
*Transcription Factors/metabolism
Signal Transduction

@article {pmid42085591,
year = {2026},
author = {Martínez-Bujidos, M and Menéndez, A and Pulido-Gracia, JA and Vilas, D and Samaniego, D and Ispierto, L and Morales-Indiano, C and Pastor, P},
title = {Analytical agreement and platform-specific decision thresholds for plasma p-tau217 measured on Lumipulse G600II and Cobas e801 in a paired CSF-plasma cohort.},
journal = {Clinical chemistry and laboratory medicine},
volume = {},
number = {},
pages = {},
pmid = {42085591},
issn = {1437-4331},
abstract = {OBJECTIVES: Plasma phosphorylated tau at threonine 217 (p-tau217) has emerged as a highly accurate blood-based biomarker of Alzheimer's disease (AD) pathology. As disease-modifying anti-amyloid therapies enter clinical practice, scalable biomarkers with robust and clinically interpretable decision thresholds are required. However, evidence on inter-platform comparability and threshold transferability across automated assays remains limited.

METHODS: We conducted a head-to-head comparison of two automated platforms - Lumipulse[®] G600II and Cobas[®] e801 - for plasma p-tau217 measurement in 157 consecutive patients undergoing lumbar puncture. Amyloid status was defined by the CSF Aβ42/Aβ40 ratio. Agreement was assessed using intraclass correlation coefficients and Bland-Altman analysis. Diagnostic performance was evaluated using receiver operating characteristic curves. Optimal thresholds were derived using the Youden index. Predefined rule-out (≥95 % sensitivity) and rule-in (≥95 % specificity) thresholds were explored, alongside alternative ≥90 % thresholds.

RESULTS: Agreement between platforms was excellent (Spearman ρ=0.922; ICC(3,1)=0.922), although Bland-Altman analysis revealed a small systematic difference in absolute concentrations. Both assays showed comparable diagnostic accuracy for amyloid positivity (AUC=0.923 for both platforms; DeLong p>0.99), but required platform-specific thresholds. Rule-out and rule-in thresholds achieved ≥95 % sensitivity and specificity, with strong likelihood ratios and excellent categorical agreement (weighted κ=0.870). Approximately 30 % of individuals were classified in the grey zone. Using ≥90 % thresholds reduced the grey zone to 9-13 % while maintaining excellent agreement.

CONCLUSIONS: Plasma p-tau217 demonstrates high analytical concordance and comparable diagnostic performance across automated platforms despite systematic concentration differences. Platform-specific dual-threshold strategies may support structured and clinically interpretable implementation, pending prospective multicenter validation.},
}

@article {pmid42085745,
year = {2026},
author = {Xie, R and Lin, X and Chen, S and Li, J and Zhou, J and Xu, K and Zheng, Y and Huang, W and Zhang, L},
title = {Aortic aneurysm and dissection and its multidimensional impact on cognitive function: The pivotal role of PRDX6 in pathophysiological mechanisms.},
journal = {Atherosclerosis},
volume = {417},
number = {},
pages = {120773},
doi = {10.1016/j.atherosclerosis.2026.120773},
pmid = {42085745},
issn = {1879-1484},
abstract = {AIMS: This study aims to explore the relationship between aortic aneurysm and dissection (AAD) and cognitive impairment, with an emphasis on uncovering the potential biological mechanisms.

METHODS: Utilizing the UK Biobank database, a matched cohort study was performed to assess the association between AAD and the risk of Alzheimer's disease. Cognitive function was evaluated in a β-aminopropionitrile (BAPN)-induced AAD mouse model through a series of behavioral assays. Drug-target Mendelian randomization analysis was conducted to identify candidate genes implicated in this association. Expression levels of PRDX6 were examined in brain tissues from Alzheimer's disease patients using datasets from the Gene Expression Omnibus (GEO), as well as in aortic tissues and blood samples obtained from both AAD patients and AAD model mice. Correlative analyses between PRDX6 and pro-inflammatory cytokines (IL-1β and TNF-α) were performed in mouse hippocampal tissues of the mouse model. Additionally, in vitro experiments employing SH-SY5Y cells were carried out to investigate the functional role of PRDX6 in modulating synaptic protein expression and inflammatory responses.

RESULTS: Competing risk regression analysis indicated that AAD is significantly associated with an increased incidence of cognitive impairment. Behavioral testing revealed that AAD model mice exhibited deficits in cognitive performance. Mendelian randomization prioritized PRDX6 was prioritized as a candidate gene of interest. Elevated PRDX6 expression was observed in brain tissues from Alzheimer's disease patients. Both AAD patients and AAD model mice demonstrated markedly increased PRDX6 levels in aortic tissues and circulating blood; notably, PRDX6 expression was also upregulated in the hippocampus of AAD mice. In the hippocampus, PRDX6 expression positively correlated with levels of IL-1β and TNF-α expression in AAD mice. In SH-SY5Y cells, silencing of PRDX6 resulted in increased expression of synaptic proteins, reduced pro-inflammatory cytokine production, and decreased apoptosis, whereas overexpression of PRDX6 elicited inverse effects.

CONCLUSIONS: The present findings establish a significant association between AAD and heightened risk of cognitive impairment. PRDX6 has been identified as a potential mediator in this relationship, and PRDX6-related neuroinflammation is proposed as a plausible mechanistic pathway linking AAD to cognitive dysfunction.},
}

@article {pmid42085824,
year = {2026},
author = {Gaba, A and Li, P and Cai, R and Chhajed, M and Hu, K and Gao, L},
title = {Fractal cardiac activity regulation during exercise and delirium risk in older adults.},
journal = {Archives of gerontology and geriatrics},
volume = {148},
number = {},
pages = {106264},
doi = {10.1016/j.archger.2026.106264},
pmid = {42085824},
issn = {1872-6976},
abstract = {OBJECTIVES: Delirium, acute confusion marked by fluctuations of attention and concentration, is associated with increased risk for poor long-term health outcomes, including Alzheimer's disease (AD), institutionalization, and mortality. Cardio-autonomic control is implicated in modulating response to acute stressors, and alteration is separately shown to predict mortality. Heart rate (HR) fluctuations display fractal correlations (similar temporal autocorrelation across different time scales) that reflect a dynamic interplay between sympathetic and vagal outflows, where disruption is thought to contribute to neuronal damage. We hypothesized that fractal cardiac activity regulation FCAR (α1) correlations in HR predicts incident delirium.

DESIGN: Prospective cohort study using UK Biobank data.

SETTING: Community-based participants undergoing ECG-monitored exercise testing.

PARTICIPANTS: 41,109 adults (mean age 58.0 years) free from delirium or AD at baseline who completed a 7-minute stationary bike test (2009-2010) and had ≥1 hospitalization by March 2021.

MEASUREMENTS: Detrended fluctuation analysis was used to derive short-term fractal scaling exponents (α1) from ECG data. Cox proportional hazard models examined the association between FCAR (α1) and incident delirium, adjusting for demographics, lifestyle, comorbidities cognition, and exercise parameters.

RESULTS: Over a median of 11.4 years (IQR 11.3-11.5), 442 cases (11 per 1000) developed delirium. FCAR (α1) was normally distributed, (mean 1.25 ± 0.35 (SD)). Compared to those in the highest FCAR (α1) quartile (>1.50), participants in the lowest quartile (<1.01) had a 40% increased risk of delirium (HR 1.40; 95% CI: 1.05-1.88; p = 0.02). This risk increase was equivalent to being 3.3 years older in the fully adjusted models.

CONCLUSIONS: Lower FCAR (α₁) during exercise predicted higher long-term risk of delirium, suggesting a potential prognostic indicator associated with brain-heart resilience. Future research should examine its role in shared vulnerability to delirium and neurodegenerative disorders.},
}

@article {pmid42085850,
year = {2026},
author = {Xu, Y and Liang, W and Tang, Z and Lu, F and Xia, L and Xie, H and Zhong, M and Li, S},
title = {Akt at the crossroads of microglial function: a double-edged sword in Alzheimer's disease neuroinflammation.},
journal = {International immunopharmacology},
volume = {181},
number = {},
pages = {116773},
doi = {10.1016/j.intimp.2026.116773},
pmid = {42085850},
issn = {1878-1705},
abstract = {Alzheimer's disease (AD) pathology is increasingly understood to be driven by complex neuroinflammatory processes, with microglia-the resident immune cells of the brain playing a pivotal role. The PI3K/Akt signaling pathway serves as a critical intracellular hub, orchestrating the diverse and often opposing functions of microglia. This review synthesizes current insights into the multifaceted role of Akt signaling in modulating microglial activity in the context of AD. We explore the dualistic nature of Akt, which can promote pro-inflammatory neurotoxicity through pathways such as NF-κB while simultaneously mediating neuroprotective functions, including anti-inflammatory resolution, amyloid-β (Aβ) phagocytosis, and regulation of key clearance receptors like triggering receptor expressed on myeloid cells 2 (TREM2). Additionally, we examine how the Akt/mTOR axis governs microglial immunometabolism, facilitating the transition between glycolytic, pro-inflammatory states and oxidative phosphorylation-driven, phagocytic phenotypes. Emerging therapeutic strategies are discussed, including natural compounds, pharmacological agents, indirect modulation via the gut-brain axis and physical brain stimulation, as well as advanced nanotechnology platforms designed to target this pathway in microglia with precision. Finally, we address key challenges such as isoform specificity, therapeutic timing, and translational relevance, and outline future perspectives aimed at achieving "precision immunomodulation" of the Akt pathway. Such fine-tuning of microglial function represents a promising yet complex avenue for developing effective therapies to combat AD.},
}

@article {pmid42070356,
year = {2026},
author = {Arancibia-Díaz, A and Trujillo-Fernández, S and Astudillo-Castro, C and Vergara-Castro, M and Soto-Maldonado, C and Córdova, A and Zúñiga-Hansen, ME and Vega-Letter, AM and Fuentes, P and Altamirano, C},
title = {Neuroprotective and antioxidant effects of fermented spent coffee ground fractions against Alzheimer's-related oxysterol 27-hydroxycholesterol in SH-SY5Y neuronal cells.},
journal = {Food chemistry},
volume = {517},
number = {},
pages = {149435},
doi = {10.1016/j.foodchem.2026.149435},
pmid = {42070356},
issn = {1873-7072},
abstract = {Spent coffee grounds (SCG) constitute a phenolic-rich agro-industrial residue with underexplored biomedical potential. This study developed a sequential bioprocess comprising solid-state fermentation, hydroalcoholic extraction, and ultrafiltration to selectively enrich low-molecular-weight phenolic fractions and assess their effects in Alzheimer's-related stress conditions. Phenolic compounds Total (TPC) and composition were quantified, and bioactivity was assessed in SH-SY5Y neuronal cells exposed to hydrogen peroxide (H2O2) or the oxysterol 27-hydroxycholesterol (27-OHC), a key driver of redox imbalance and amyloidogenic pathways. Assessed parameters included cell density and viability, reactive oxygen species (ROS), superoxide dismutase (SOD) activity and amyloid-β peptide 40 (Aβ40) accumulation. Bioprocessing enhanced the total phenolic content by up to 4.2-fold and redirected the metabolite profiles toward highly diffusible, low-molecular-weight compounds. The <3 kDa fraction exhibited the strongest functional response, markedly suppressing ROS generation (∼90%), restoring SOD activity and reducing Aβ40 levels under 27-OHC challenge. These results evidence an enrichment strategy that yields SCG-derived fractions with potent antioxidant and neuroprotective properties.},
}

@article {pmid42070480,
year = {2026},
author = {Lu, SY and Zhu, Z and Zhang, B and Zhang, YD and Yao, YD},
title = {A lightweight vision transformer with context-aware convolution and uniformity normalization for Alzheimer's Disease diagnosis.},
journal = {Computer methods and programs in biomedicine},
volume = {282},
number = {},
pages = {109413},
doi = {10.1016/j.cmpb.2026.109413},
pmid = {42070480},
issn = {1872-7565},
abstract = {BACKGROUND: Early and accurate diagnosis of Alzheimer's Disease (AD) is crucial for effective clinical intervention.

METHOD: In this study, we propose a lightweight vision transformer architecture specifically designed for AD classification using 2D brain MRI slices. LICAUN-ViT incorporates three key innovations: Mono-Head Self-Attention (MOHSA) to reduce computational overhead, Uniformity Normalization (Uni-Norm) to mitigate oversmoothing and enhance feature diversity, and Context-Aware Convolution (CAC) to integrate long-range dependencies with local structural features.

RESULTS: Evaluated on two benchmark datasets derived from the Alzheimer's Disease Neuroimaging Initiative (ADNI), our model achieves state-of-the-art performance with an accuracy of 93.03 % on axial slices and 94.15 % on sagittal slices, while maintaining relatively low floating-point operations (FLOPs) for efficient deployment. Extensive ablation studies and singular value analyses confirm the effectiveness and robustness of the proposed components.

CONCLUSION: These results demonstrate that the proposed model offers a computationally efficient and promising solution for automated AD diagnosis, with strong potential for clinical integration.},
}

@article {pmid42070656,
year = {2026},
author = {Molinatti, F and De Gracia, L and Oliva, A},
title = {Descriptive analysis of mortality due to Parkinson's disease and Alzheimer disease in Argentina.},
journal = {Neurologia},
volume = {},
number = {},
pages = {502084},
doi = {10.1016/j.nrleng.2026.502084},
pmid = {42070656},
issn = {2173-5808},
abstract = {INTRODUCTION: Parkinson's disease (PD) and Alzheimer disease (AD), along with other nervous system disorders, are the leading causes of global disease burden. Although global trends have remained stable in recent decades, an increase in years of life lost due to these diseases has been recorded. In Argentina, though no prevalence records are available for PD and AD, reliable mortality data do exist. Similarities and differences in mortality caused by PD and AD are analysed in the present study.

METHODS: The study was performed in the total population between 2000 and 2019. Age-standardised mortality rates (ASMR) were calculated. At the national level, annual trends were analysed and comparisons between provinces were made. Subsequently, spatial autocorrelation in the Centre Region (CR) was examined.

RESULTS: Between 2000 and 2019, there were no statistically significant changes in ASMR for PD or AD, in either sex. In most cases, ASMR in the CR and its provinces were higher than the national average. At the department level, a trend towards the concentration of similar values was observed, with the exception of mortality due to PD among women.

CONCLUSIONS: The CR exhibits a higher ASMR than the national average, with rates of mortality due to AD in men in Santa Fe province being particularly noteworthy. It also shows a distinct spatial concentration pattern, with 2 distinct clusters. Further research is required to investigate the underlying sociodemographic and environmental factors contributing to this pattern.},
}

@article {pmid42070757,
year = {2026},
author = {Liu, JY and Liu, SY and Ran, LX and Qiao, WH and Zhang, F and Zhang, KS and Liang, XX and Liu, MY and Yu, ZH and Wei, MJ and Zhong, X},
title = {Organelle-orchestrated cGAS-STING signaling and its role in neurodegeneration.},
journal = {Pharmacological research},
volume = {},
number = {},
pages = {108216},
doi = {10.1016/j.phrs.2026.108216},
pmid = {42070757},
issn = {1096-1186},
abstract = {The cGAS-STING signaling pathway serves as a central signalling axis of the innate immune system, and its aberrant activation plays a pivotal role in inflammatory responses. Recent studies have demonstrated that its regulation depends not only on individual organelles but also on a coordinated interorganelle network. This review systematically analyze how mitochondria, centrosomes, the endoplasmic reticulum (ER), membrane contact sites (MCSs), the Golgi apparatus, endosomes, and lysosomes collectively orchestrate cGAS-STING signaling. Mitochondria initiate signaling by releasing mitochondrial DNA; centrosomes serve as platforms for double-stranded DNA accumulation to potentiate cGAS activation; the ER anchors STING in a calcium homeostasis-dependent manner; mitochondrial-associated ER membranes (MAMs) integrate calcium and lipid signaling as regulatory checkpoints governing STING trafficking to the Golgi apparatus; the Golgi amplifies downstream signaling through site-specific post-translational modifications of STING; finally, the endosome-lysosome system, together with ER-lysosome MCSs, acts as a coordinated hub for STING sorting, lysosomal degradation and signal termination. Consequently, disruption of organelle homeostasis leads to persistent STING activation. In neurodegenerative conditions including Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis and Huntington's disease, organelle dysfunction resulting from calcium overload, impaired organelle clearance, proteolytic cleavage of tethering proteins or multi-source attacks drives aberrant STING signaling. Sustained STING activity exacerbates pathological cascades such as protein misfolding, chronic neuroinflammation, and progressive neuronal loss. Therefore, therapeutic strategies targeting key regulatory nodes of the STING pathway, from upstream organelle repair to direct pharmacological inhibition, offer significant potential to mitigate disease-associated pathological progression and constitute a promising foundation for precision therapeutics in neurodegenerative disorders.},
}

@article {pmid42071065,
year = {2026},
author = {Fikry, H and Sadek, DR and Saleh, LA and Hasanin, MTM and Alkhalek, HAA},
title = {Dual protective role of curcumin- encapsulated chitosan nanoparticles against gastric and neural injury in a rat model of gut-brain axis dysfunction: a histological and biochemical study.},
journal = {Naunyn-Schmiedeberg's archives of pharmacology},
volume = {},
number = {},
pages = {},
pmid = {42071065},
issn = {1432-1912},
abstract = {Gastric ulcer (GU) and Alzheimer's disease (AD) are prevalent age-associated disorders frequently accompanied by systemic oxidative stress and inflammation. Emerging evidence suggests that gastrointestinal dysfunction and inflammatory signaling may aggravate neurodegenerative processes. Curcumin (Cur) exhibits well-established antioxidant, anti-inflammatory, neuroprotective, and gastroprotective properties; however, its therapeutic utility is limited by poor bioavailability. The present study aimed to formulate and characterize Curcumin- encapsulated chitosan nanoparticles (Cur-CSNPs) and evaluate their dual protective effects in a clinically relevant comorbid rat model combining scopolamine-induced AD-like pathology and ethanol-induced GU. Male Wistar rats were divided into six groups: control, Cur-CS-NPs alone, GU, AD, GU + AD, and GU + AD treated with Cur-CSNPs. Behavioral assessments, biochemical analyses, histopathological evaluation, and immunohistochemical investigations were performed on brain and gastric tissues. GU + AD rats exhibited cognitive deficits, neuronal degeneration, amyloid-β accumulation, astrocyte activation, gastric mucosal injury, increased oxidative stress, NF-κB activation, elevated inflammatory cytokines, and enhanced apoptotic signaling. Cur-CSNP treatment significantly improved cognitive performance, reduced oxidative stress and inflammation, suppressed NF-κB signaling, decreased amyloid-β deposition, inhibited apoptosis, and restored gastric mucosal integrity. In conclusion, Cur-CSNPs exert concurrent neuroprotective and gastroprotective effects in a comorbid AD and GU model through coordinated modulation of oxidative stress, inflammation, amyloidogenic activity, and apoptotic pathways. These findings demonstrate that Cur-CSNPs exert dual neuroprotective and gastroprotective effects by modulating oxidative stress, inflammation, amyloidogenic pathways, and apoptosis, highlighting nano-curcumin as a promising therapeutic strategy for gut-brain axis-related disorders. Further investigations are warranted to elucidate the detailed molecular mechanisms and to explore the clinical applicability of nano-formulated curcumin as a therapeutic strategy for disorders involving concurrent gastrointestinal and neurodegenerative pathology.},
}

@article {pmid42071101,
year = {2026},
author = {Li, K and Shacham, E and Zhu, Y and Trani, JF and Babulal, GM},
title = {Driving the neural exposome: Latent mobility states from naturalistic GPS data in older adults.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71425},
doi = {10.1002/alz.71425},
pmid = {42071101},
issn = {1552-5279},
support = {/NH/NIH HHS/United States ; R01AG068183 (GMB)/AG/NIA NIH HHS/United States ; R01AG067428 (GMB)/AG/NIA NIH HHS/United States ; R01AG074302 (GMB)/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; Male ; Female ; *Automobile Driving ; Aged ; *Geographic Information Systems ; *Alzheimer Disease/diagnosis ; *Cognitive Dysfunction/diagnosis ; Aged, 80 and over ; Markov Chains ; Neuropsychological Tests ; },
abstract = {INTRODUCTION: Naturalistic driving provides real-world behavioral indicators of early cognitive and functional changes. This study integrated naturalistic driving GPS trajectories collected from in-vehicle sensors with points of interest (POIs) to quantify daily environmental engagement among older adults who were cognitively normal at enrollment.

METHODS: Data from 438 participants enrolled in the Driving Real-world in-Vehicle Evaluation System Project were used to generate daily POI share vectors and model latent engagement patterns using a logistic-normal hidden Markov model (HMM). Thirteen latent states described distinct modes of environmental interaction. From each participant's inferred state sequence, we derived mobility features - state occupancy, dwell time, transition entropy, and self-transition probability - and examined their differences across clinical status groups and associations with Preclinical Alzheimer's Cognitive Composite (PACC) performance.

RESULTS: Transition entropy and several state-specific occupancy and dwelling metrics differed across clinical groups, but none of the mobility features were significantly associated with PACC scores.

DISCUSSION: Mobility-derived behavioral features differentiate clinical status groups and may reflect early functional changes preceding cognitive decline.},
}

Humans
Male
Female
*Automobile Driving
Aged
*Geographic Information Systems
*Alzheimer Disease/diagnosis
*Cognitive Dysfunction/diagnosis
Aged, 80 and over
Markov Chains
Neuropsychological Tests

@article {pmid42071133,
year = {2026},
author = {Gebril, NM and Elettreby, AM and Younis, AH and Moawad, MHED and Hafez, AM and Sayed, GE and Abdelrahman, KM and El-Kot, SM},
title = {From Cerebrospinal Fluid to Blood Draw: Plasma p-Tau217 as a Non-Invasive Biomarker for Alzheimer's Disease: A Fagan Nomogram-Based Meta-Analytic Study.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42071133},
issn = {1559-1182},
mesh = {*Alzheimer Disease/blood/cerebrospinal fluid/diagnosis ; Humans ; *tau Proteins/blood/cerebrospinal fluid ; Biomarkers/blood/cerebrospinal fluid ; *Nomograms ; Phosphorylation ; },
abstract = {Alzheimer's disease (AD) is the leading cause of dementia worldwide and is pathologically defined by amyloid-β and tau accumulation. Current diagnostic methods, such as PET imaging and cerebrospinal fluid (CSF) assays, are accurate but invasive, costly, and limited in accessibility. Plasma phosphorylated tau at threonine 217 (p-tau217) has emerged as a promising blood-based biomarker, but evidence from individual studies remains heterogeneous. We conducted a systematic review and meta-analysis to evaluate the diagnostic performance of plasma p-tau217 for AD. Following PRISMA guidelines, PubMed, Scopus, and Web of Science were searched up to July 2025. Eligible studies included clinical or biomarker-defined AD cohorts that reported plasma p-tau217 accuracy against amyloid or tau positivity or clinical diagnosis. Data on sensitivity, specificity, likelihood ratios, and diagnostic odds ratio (DOR) were extracted. Study quality was assessed using QUADAS-2. Pooled estimates were calculated using a Bayesian bivariate model, and heterogeneity was explored with meta-regression and subgroup analyses. Twenty-seven studies including 19,652 participants were analyzed. Plasma p-tau217 demonstrated high diagnostic accuracy for biomarker-defined AD, with pooled sensitivity of 85.4% (95% posterior intervals [PI]: 81.4-88.7), specificity of 88.0% (95% PI: 85.1-90.6), positive likelihood ratio (PLR) 7.13, negative likelihood ratio (NLR) 0.167, and DOR 42.7. Performance was consistent across amyloid PET and CSF reference standards. Subgroup analyses showed robust accuracy for amyloid positivity (sensitivity 87.3%, specificity 85.5%), tau positivity (sensitivity 84.9%, specificity 93.8%), and clinical AD diagnosis (sensitivity 72.9%, specificity 89.5%). Plasma p-tau217 consistently outperformed other blood biomarkers and correlated with cognitive decline, frailty, and behavioral impairment. Risk of bias was generally low, with no major publication bias detected. This meta-analysis indicates that plasma p-tau217 demonstrates promising diagnostic accuracy for detecting AD pathology across biomarker-defined reference standards. However, heterogeneity across assays, populations, and reference definitions, along with the use of optimized cut-offs in some studies and the limited power of publication-bias assessments, warrant cautious interpretation. Plasma p-tau217 appears well suited as a triage biomarker to guide confirmatory testing, but further large, prospectively designed studies with standardized assays and externally validated thresholds are needed before widespread clinical implementation.},
}

*Alzheimer Disease/blood/cerebrospinal fluid/diagnosis
Humans
*tau Proteins/blood/cerebrospinal fluid
Biomarkers/blood/cerebrospinal fluid
*Nomograms
Phosphorylation

@article {pmid42071158,
year = {2026},
author = {Abuhassan, Q and Saeed, TN and Al-Hussainy, AF and Roopashree, R and Mishra, S and Nanda, A and Mukherjee, G and Rizaev, J and Taher, SG and Alwan, M and Jawad, M and Mushtaq, H},
title = {Viral Mimicry of Alzheimer's Disease: Innate Sensing of Self-Nucleic Acids as a Driver of Glial Senescence.},
journal = {Journal of molecular neuroscience : MN},
volume = {76},
number = {2},
pages = {},
pmid = {42071158},
issn = {1559-1166},
mesh = {Humans ; *Alzheimer Disease/immunology/virology/metabolism/genetics ; *Immunity, Innate ; Animals ; *Neuroglia/immunology/metabolism ; *Molecular Mimicry ; *Cellular Senescence ; },
abstract = {Alzheimer's disease (AD) is a devastating neurodegenerative disorder defined by progressive memory loss and synaptic failure. For decades, therapeutic development has focused on clearing amyloid-beta plaques, yet the repeated clinical failures of this approach necessitate a fundamental paradigm shift toward the brain's immunometabolic landscape. The "Viral Mimicry" hypothesis posits that AD represents a state of sterile autoimmunity where the innate immune system mistakenly identifies self-nucleic acids as viral pathogens. This "ghost war" is ignited by the convergence of metabolic dysfunction and genomic instability: specifically, the leakage of mitochondrial DNA into the cytosol and the epigenetic derepression of ancient retrotransposons (LINE-1, HERVs). These endogenous ligands activate the cGAS-STING cytosolic sensing axis, a pathway that drives a chronic interferon response. Consequently, microglia and astrocytes are transformed into senescent, pro-inflammatory phenotypes that release a toxic Senescence-Associated Secretory Phenotype (SASP), directly fueling synaptic elimination. Crucially, major genetic risk factors, including APOE4 and TREM2 variants, exacerbate this cascade by compromising mitochondrial integrity and lipid metabolism, thereby sensitizing the brain to innate surveillance failure. By reconceptualizing AD as an acquired interferopathy driven by the "enemy within," this framework highlights novel therapeutic targets. Specifically, repurposing Nucleoside Reverse Transcriptase Inhibitors (NRTIs) to block retrotransposition and deploying senolytics to clear dysfunctional glia offer promising strategies to arrest the progression from healthy aging to cognitive decline. This review synthesizes current research on the molecular mechanisms of viral mimicry, detailing the impact of genetic risk factors and evaluating emerging therapeutic interventions targeting this innate immune axis.},
}

Humans
*Alzheimer Disease/immunology/virology/metabolism/genetics
*Immunity, Innate
Animals
*Neuroglia/immunology/metabolism
*Molecular Mimicry
*Cellular Senescence