@article {pmid42478649,
year = {2026},
author = {Sarkar, R and Banerjee, K and Das, S and Sadhukahn, I and Bose, B and Biswas, R and Pan, S and Adhikary, K and Maiti, R},
title = {Micronutrient-Assisted Biomaterial Strategies as Neuropharmacological Modulators of Neuroinflammation and Oxidative Stress in Neurodegenerative Diseases.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X485083260630050618},
pmid = {42478649},
issn = {1875-6190},
abstract = {Neurodegeneration results from the convergence of several molecular processes, including inflammation in the brain (i.e., neuroinflammation), elevated levels of free radicals that damage cells, mitochondrial dysfunction, and the inability to remove damaged proteins from the brain. Even though many agents provide neuroprotection in research models, their clinical use is limited because they cannot effectively cross the blood-brain barrier to reach the areas of the brain where they are needed. Limitations include the inability to cross the blood-brain barrier, poor bioavailability, rapid metabolism and clearance, non-specific targeting, efflux by transport proteins, toxicity, and low solubility and stability. The classification of micronutrients (e.g., vitamins, polyphenols, minerals), which are naturally present antioxidants and anti-inflammatory substances, plays a role in modulating the most important signaling pathways in the body, including those mediating the inflammatory response (i.e., NF-κB and NLRP3) and the process that causes glial cell death (i.e., JAK/STAT). Micronutrients have a significant drawback for therapeutic use because they are rapidly metabolized and cannot cross the blood-brain barrier. Developments in synthetic biomaterials and nanotechnology offer a potential avenue for addressing the challenges of delivering micronutrients to the brain by targeting them to specific areas and releasing them over a sustained period. This study presents current information on the mechanisms by which micronutrients modulate molecular pathways and their potential application in emerging biomaterials to develop a new class of neuroprotective therapeutic agents that may ultimately be used to treat patients with degenerative diseases (e.g., Alzheimer's, Parkinson's, and Huntington's). Additionally, clinical challenges are addressed to translate these products from the laboratory to the clinic. The idea presented in this review connects molecular neuromodulation via micronutrients and bioactive nutraceuticals with a new strategy for pharmacological delivery using biomaterials. Instead of considering nutrition and those biomaterials as separate therapeutic areas, an integrated mechanistic model is presented that shows how micronutrients can act as endogenous pathway regulators and how biomaterials can enhance pharmacokinetics and targeting.},
}

@article {pmid42478671,
year = {2026},
author = {Sato, K and Niimi, Y and Ihara, R and Iwata, A and Iwatsubo, T},
title = {Projected lecanemab wastage from vial discard: Simulation based on Japanese interim post-marketing surveillance summary statistics.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261469872},
doi = {10.1177/13872877261469872},
pmid = {42478671},
issn = {1875-8908},
abstract = {Lecanemab is dosed by body weight but supplied as fixed-size single-dose vials, which can leave unavoidable leftover drug after preparation. Using published summary statistics from the Japanese lecanemab post-marketing surveillance on body weight, we fitted a body-weight distribution and ran Monte Carlo simulations. Uncertainty was quantified by a parametric bootstrap. With current 200/500-mg vials, mean waste rate was 8.60%. A strategy with 200/250-mg vials reduced waste to 6.30%, and adding a 75-mg vial (≤4 vials/infusion) to 3.67%. At 10,000 person-years, annual waste cost was ∼¥2.36 billion under assumed pricing. Vial-size and dispensing optimization may help reduce avoidable waste.},
}

@article {pmid42478899,
year = {2026},
author = {Zhang, N and Chen, W and Wang, M},
title = {The liver-brain axis: A multidimensional regulatory network implicated in Alzheimer's disease pathogenesis and clinical implications.},
journal = {Animal models and experimental medicine},
volume = {},
number = {},
pages = {},
doi = {10.1002/ame2.70262},
pmid = {42478899},
issn = {2576-2095},
support = {Seed Program (YYZZ202409)//Capital Medical University Affiliated Beijing Friendship Hospital/ ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) deposition. The liver-brain axis underscores the central role of the liver in modulating cognitive function through multidimensional regulatory mechanisms. As a core metabolic and detoxification organ, the liver also helps maintain cerebral homeostasis via pathways including the urea cycle, antioxidant systems, ketone body metabolism, and bile acid regulation. Dysfunction of these processes may lead to ammonia accumulation, exacerbated oxidative stress, and Aβ clearance, thereby accelerating the pathological progression of AD. Liver-derived factors such as apolipoprotein E (APOE), C-reactive protein (CRP), fibroblast growth factor 21 (FGF21), and insulin-like growth factor 1 (IGF-1) significantly increase the risk of AD through dual mechanisms-inhibiting Aβ clearance and activating neuroinflammation, thereby directly affecting cognitive function via modulation of inflammation, metabolism, and blood-brain barrier (BBB) integrity. Neural interfaces formed by the hypothalamic-pituitary-target gland axis and the vagus nerve enable communication from the liver to the brain, with emerging evidence also supporting a reverse influence from the brain to the liver. Emerging technologies such as molecular tracing and nanocarriers provide new tools for deciphering dynamic interactions within the liver-brain axis. Liver-targeted metabolic interventions show potential for reversing cognitive impairment. Unlike previous reviews that mainly focused on single pathways, this review conceptualizes the liver-brain axis as a multidimensional regulatory network in AD. By clearly linking network nodes to potential therapeutic interventions, it provides us with a novel framework that not only describes the various mechanisms but also focuses on identifying actionable targets for disease prevention and treatment.},
}

@article {pmid42479092,
year = {2026},
author = {Goswami, A and Lagad, RR and Rafi, S},
title = {Decoding neuronal gene expression: integrative insights from omics and AI.},
journal = {Brain informatics},
volume = {},
number = {},
pages = {},
doi = {10.1186/s40708-026-00323-z},
pmid = {42479092},
issn = {2198-4018},
abstract = {Neuronal functional diversity and pathological vulnerability are governed by multi-layered regulatory programs. While high-throughput omics and neuroimaging provide high-resolution snapshots of these programs, bridging the gap between molecular dynamics and macro-scale brain architecture remains a significant informatics challenge. This review synthesizes the evolution of computational frameworks in neuro-omics-transitioning from descriptive co-expression modules to causal graph neural networks and cross-scale foundation models. We evaluate these methodologies within the context of Alzheimer's disease, schizophrenia, and epilepsy, identifying critical bottlenecks in data harmonization, spatial alignment, and causal interpretability.},
}

@article {pmid42479178,
year = {2026},
author = {Agrawal, S and Wagner, M and Leurgans, SE and Agarwal, P and van der Weerd, L and Bennett, DA and Bush, AI and Ayton, S and Schneider, JA},
title = {Cerebral amyloid angiopathy, brain iron concentrations, and cognitive decline in older people.},
journal = {Acta neuropathologica},
volume = {152},
number = {1},
pages = {},
pmid = {42479178},
issn = {1432-0533},
mesh = {Humans ; *Cerebral Amyloid Angiopathy/pathology/metabolism/complications/psychology ; Female ; *Iron/metabolism ; Aged, 80 and over ; *Brain/pathology/metabolism ; *Cognitive Dysfunction/pathology/metabolism ; Male ; Aged ; Aging/pathology ; Longitudinal Studies ; },
abstract = {Cerebral amyloid angiopathy (CAA) is a common brain pathology in older people and has been recently recognized as a major risk factor for amyloid-related imaging abnormalities during anti-amyloid antibody therapy. CAA pathophysiology may involve iron released from ruptured vessels, but the association between postmortem CAA and brain iron is unclear. This study investigates the association between CAA and brain iron and whether elevated iron modifies the association between CAA and cognitive decline. We studied 626 Rush Memory and Aging Project decedents (mean age at death = 90 [SD = 6.1] years, 70% women) who completed baseline and longitudinal cognitive assessments and underwent detailed neuropathologic evaluation for CAA, Alzheimer's disease neuropathologic changes (ADNC), and other brain pathologies. Brain iron content was assessed from the inferior temporal cortex using Inductively Coupled Plasma Mass Spectrometry (ICP-MS). Linear regression and mixed-effects models were used for analysis. CAA was common: 266 (42%) had mild, 153 (24%) had moderate, and 75 (12%) had severe CAA. In analyses adjusted for demographics, intermediate/high ADNC, and other pathologies, the presence and severity of CAA were associated with elevated cortical brain iron (Est = 0.033, SE = 0.011, p = 0.002; Est = 0.017, SE = 0.004, p < 0.001, respectively). When examining associations with nonlinear cognitive change before death (mean follow-up = 7.7 [SD = 3.9] years), both CAA and elevated iron were independently associated with faster annual rates of decline in global cognition and semantic memory (all p < 0.04). Elevated iron was also associated with faster declines in episodic and working memory and perceptual speed (all p < 0.02). When exploring whether brain iron modulates the association of CAA with cognitive decline, we found that CAA had steeper decline in perceptual speed when elevated iron was present compared to when low iron was present (p = 0.03). Together, these findings suggest that brain iron may contribute to the clinical impact of CAA in older age.},
}

Humans
*Cerebral Amyloid Angiopathy/pathology/metabolism/complications/psychology
Female
*Iron/metabolism
Aged, 80 and over
*Brain/pathology/metabolism
*Cognitive Dysfunction/pathology/metabolism
Male
Aged
Aging/pathology
Longitudinal Studies

@article {pmid42479245,
year = {2026},
author = {An, X and Wu, D and Wang, Y and Ren, Z and Yu, W},
title = {Seipin modulates Alzheimer's disease pathogenesis by regulating ferroptosis through a glycine-mediated metabolic pathway.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {42479245},
issn = {1573-7365},
support = {82160225//the National Natural Science Foundation of China/ ; },
mesh = {Animals ; *Alzheimer Disease/metabolism/genetics/pathology ; *Ferroptosis/physiology ; *GTP-Binding Protein gamma Subunits/metabolism/genetics ; *Glycine/metabolism ; Mice ; Mice, Transgenic ; Microglia/metabolism ; *Metabolic Networks and Pathways/physiology ; *Heterotrimeric GTP-Binding Proteins/metabolism/genetics ; Humans ; Hippocampus/metabolism ; },
abstract = {Alzheimer's disease (AD) remains an incurable neurodegenerative disorder with an elusive pathogenesis, where emerging evidence implicates metabolic dysregulation and ferroptosis in neuronal loss. Although the BSCL2 gene, which encodes Seipin, is crucial for lipid metabolism, its specific role in the progression of AD remains undefined. This study employed Mendelian randomization (MR) analysis, in vivo APP/PS1 mouse models, and in vitro BV2 microglial assays to elucidate the mechanistic axis linking BSCL2, metabolites, and ferroptosis in AD. MR analysis demonstrated a causal relationship between genetically predicted elevated BSCL2 expression and an increased risk of AD, partially mediated by glycine. Supporting these genetic findings, stereotactic knockdown of Seipin in the hippocampus of APP/PS1 mice significantly ameliorated cognitive deficits without inducing systemic metabolic toxicity. Mechanistically, Seipin deficiency reduced ferroptosis in both AD mouse brains and Aβ-stimulated microglia, as evidenced by the upregulation of anti-ferroptotic markers (GPX4, Nrf2, HO-1) and the suppression of pro-ferroptotic effectors (ACSL4, NCOA4). Moreover, glycine supplementation partially ameliorated the aggravated ferroptotic phenotype caused by Seipin overexpression, indicating a functional feedback mechanism in which glycine facilitates glutathione synthesis to mitigate Seipin-induced lipid peroxidation. These findings collectively identify Seipin as a novel regulator of ferroptosis in the pathogenesis of AD and underscore the potential of the BSCL2-glycine-ferroptosis axis as a therapeutic target. Future research should aim to elucidate the specific molecular interactions between Seipin and the iron-handling machinery and to validate glycine-based interventions in clinical settings as a means to prevent neurodegeneration.},
}

Animals
*Alzheimer Disease/metabolism/genetics/pathology
*Ferroptosis/physiology
*GTP-Binding Protein gamma Subunits/metabolism/genetics
*Glycine/metabolism
Mice
Mice, Transgenic
Microglia/metabolism
*Metabolic Networks and Pathways/physiology
*Heterotrimeric GTP-Binding Proteins/metabolism/genetics
Humans
Hippocampus/metabolism

@article {pmid42479414,
year = {2026},
author = {Cai, Y and Chen, Y and Huang, G and Ren, M and Chai, Y and Gai, C and Huang, X and Yan, T},
title = {Integrated bioinformatics and experimental analysis identify apoptosis- and pyroptosis-related hub genes as candidate diagnostic biomarkers in Alzheimer's disease.},
journal = {Journal of applied genetics},
volume = {},
number = {},
pages = {},
pmid = {42479414},
issn = {2190-3883},
support = {KYCX24_2248//Postgraduate Research & Practice Innovation Program of Jiangsu Province/ ; },
abstract = {Apoptosis and pyroptosis-mediated neuronal death represent major pathogenic mechanisms underlying Alzheimer's disease (AD). Given the potential crosstalk between these two forms of cell death, investigation of a single death pathway may be insufficient to identify robust diagnostic biomarkers for AD. Therefore, this study aimed to explore hub genes involved in both apoptosis and pyroptosis as potential diagnostic biomarkers for AD. First, 23 common cell death-related genes (CDRGs) were identified through bioinformatic analysis. Functional enrichment analyses using GO, KEGG, and GeneMANIA revealed significant associations between AD and biological processes including apoptosis, pyroptosis, and neuronal death. Subsequently, machine learning algorithms combined with ROC curve analysis identified CASP3, IL1B, NLRP3, and PYCARD as candidate biomarkers with potential diagnostic and therapeutic implications for AD. These findings were further validated by the in vitro experiments, which confirmed that the expression levels of these four biomarkers were consistent with the predicted results. Additionally, in patients with AD, CASP3, IL1B, NLRP3, and PYCARD were negatively correlated with macrophages. Collectively, these results suggest that the identified biomarkers may co-regulate apoptosis and pyroptosis through macrophages, thereby contributing to the pathogenesis of AD.},
}

@article {pmid42479540,
year = {2026},
author = {Zhang, J and Yu, P and Xu, M and Liang, F and Chen, Y and Dong, Y and Zhang, Y and Yu, S and Hua, F and Otu, HH and Libermann, TA and Inouye, SK and Marcantonio, ER and Yang, G and Xie, Z},
title = {Anesthesia and surgery induce sex-dependent Tau phosphorylation and behavior changes in aged mice.},
journal = {Anesthesiology},
volume = {},
number = {},
pages = {},
doi = {10.1097/ALN.0000000000006261},
pmid = {42479540},
issn = {1528-1175},
abstract = {BACKGROUND: Preoperative blood Tau phosphorylated at threonine 217 (Tau-PT217), a newly identified blood biomarker of Alzheimer's disease, is associated with postoperative delirium in patients. Anesthesia/surgery is also associated with postoperative increased blood Tau-PT217 amounts in patients. Moreover, in female aged mice, anesthesia/surgery increases Tau-PT217 in lungs, blood and brain tissues, leading to behavioral changes. However, whether these effects are sex-dependent remain largely undetermined.

METHODS: Eighteen-month-old female and male mice (C57BL/6J) underwent abdominal surgery under general anesthesia (1.4% isoflurane and 40% oxygen). Levels of Tau-PT217, inflammatory markers, and GSK3β activity were measured in lungs, blood, and brain tissues of aged mice using nanoneedle technology, Western blot, immunohistochemistry, RT-PCR and others. Postoperative delirium-like behavior was assessed using a battery of behavioral tests (buried food, open filed and Y maze). To explore causality, we performed orchiectomy and administered androgen receptor antagonist enzalutamide in aged male mice. Finally, testosterone was delivered via inhalation to aged female mice.

RESULTS: Anesthesia/surgery increased the amounts of Tau-PT217 in lungs (2.29±0.16 fold versus 1.15±0.71 fold, P<0.01), blood, and brain tissues of aged female, but not male, mice compared to control condition, leading to postoperative delirium-like behavior, as evidenced by increases in the composite Z score (3.74±1.46 versus 0.60±1.17, P<0.01), in the aged female, but not male, mice. Anesthesia/surgery elevated inflammatory markers and GSK3β activity in aged female mice, which exhibited lower baseline testosterone levels and androgen receptor expression in lungs compared to males. Both orchiectomy and enzalutamide treatment in male mice reduced testosterone levels and androgen receptor expression, leading to elevation of Tau-PT217 amounts and behavior changes following anesthesia/surgery. Conversely, testosterone inhalation in aged female mice mitigated the anesthesia/surgery-induced elevation of Tau-PT217 amounts and behavior changes.

CONCLUSIONS: Testosterone and androgen receptor signaling may contribute to the sex-dependent differences in Tau phosphorylation and postoperative behavior changes in aged mice.},
}

@article {pmid42479638,
year = {2026},
author = {Qin, R and Caiqi, L and Qingchun, Q and Xu, W and Lai, X and Chen, L},
title = {The burden of neurological diseases in East Asia: an analysis for the Global Burden of Disease Study 2023.},
journal = {Neuroepidemiology},
volume = {},
number = {},
pages = {1-25},
doi = {10.1159/000553093},
pmid = {42479638},
issn = {1423-0208},
abstract = {Background and Objectives Neurologic disorders represent a growing global health burden. According to the Global Burden of Disease Study 2023, they remain a major cause of morbidity and mortality worldwide. However, a comprehensive assessment specifically focused on East Asia has been lacking. This study investigates data from the GBD 1990-2023 study to provide detailed and updated insights into the burden of neurologic disorders in East Asia. Methods We analyzed the 1990-2023 burden of thirteen neurologic disorders in East Asia (e.g., stroke, dementia, epilepsy, migraine) using incidence, prevalence, deaths, and DALYs, stratified by sex, age, year, and location. Joinpoint regression assessed temporal trends and annual changes in age-standardized rates. Results In 2023, the neurologic disorders with the highest absolute DALYs in East Asia were stroke (44.42 million, 95% UI 39.17-49.56), Alzheimer's disease and other dementias (12.02 million, 95% UI 5.87-23.28), and migraine (6.80 million, 95% UI 4.56-9.33). Stroke was the leading cause of neurologic deaths (2.13 million, 95% UI 1.81-2.42), followed by Alzheimer's disease and other dementias (0.61 million, 95% UI 0.15-1.44) and Parkinson's disease (0.03 million, 95% UI 0.03-0.04 million). From 1990 to 2023, the overall Age-standardized DALY rates (ASDR) for neurologic disorders showed a slight decline (EAPC = -0.05; 95% CI: -0.1 to -0.01). However, both the absolute number of DALYs and the prevalence of neurological disorders demonstrated a steady increase, driven primarily by population growth and aging. This divergence between declining age-specific risk and rising absolute burden poses a mounting challenge for healthcare systems in the region. Substantial regional variation was observed in age-standardized rates across East Asia. Joinpoint regression analysis further revealed declining trends in the ASDR, ASIR, and ASPR for stroke, whereas Alzheimer's disease and other dementias showed significant increases across all three metrics. Migraine exhibited increases in ASDR, ASIR, and ASPR. Discussion This study provides the first comprehensive analysis of the burden of neurological disorders in East Asia from 1990 to 2023, revealing an urgent need for targeted public health strategies to address the growing challenge of neurological disorders.},
}

@article {pmid42479667,
year = {2026},
author = {Liang, C and Pearlson, G and Bustillo, J and Kochunov, P and Chen, J and Zhang, X and Jiang, R and Hutchison, KE and Sui, J and Fu, Z and Yang, X and Du, Y and Zhang, D and Qi, S and Calhoun, VD},
title = {Brain aging patterns among nine neurological disorders: A case-control study.},
journal = {PLoS medicine},
volume = {23},
number = {7},
pages = {e1004860},
pmid = {42479667},
issn = {1549-1676},
mesh = {Humans ; *Brain/diagnostic imaging/pathology ; Female ; *Aging/pathology ; Case-Control Studies ; Magnetic Resonance Imaging ; Male ; *Nervous System Diseases/diagnostic imaging/pathology/genetics ; Adult ; Middle Aged ; Neuroimaging ; Young Adult ; },
abstract = {BACKGROUND: The difference between neuroimaging-predicted brain age and chronological age, the predicted age difference (PAD), has been studied as a potential biomarker reflecting individual brain health. Although previous large-scale studies have shown that brain age deviations occur across multiple disorders, cross-disorder comparisons of PAD within a unified framework, together with identification of the neuroimaging features associated with these differences and their related gene expression profiles, remain limited. Our aims are to systematically compare brain aging across multiple common brain disorders and explore the brain patterns and biological processes underlying these differences.

METHODS AND FINDINGS: In this study, structural MRI data from 45,900 healthy controls (HCs) and 2,698 patients with developmental disorders (attention-deficit/hyperactivity disorder [ADHD] and autism spectrum disorder [ASD]), addiction (alcohol use disorder [AUD], tobacco use disorder [TUD], and AUD&TUD-A&TUD), dementia (Alzheimer's disease [AD], and mild cognitive impairment [MCI]) or other psychiatric disorders (schizophrenia [SZ], bipolar disorder [BP], and major depressive disorder [MDD]), were collected to generate PAD, along with transcriptome data. Then, we calculated the PAD difference between patient and HC as Cohen's d effect sizes, derived from a linear model that accounted for age, age2, sex, and site, and further identified the interpretable brain patterns associated with the PAD difference for each diagnostic group. Finally, enrichment analyses was conducted to identify the biological function of genes relatively over- or underexpressed in association with these patterns. Results showed that while PAD was consistently greater across disorders, different brain disorders showed different degrees of abnormality, the highest effects in dementia (AD: d = 0.97, 95% confidence interval (CI) [0.82,1.13]; p < 0.001 and MCI: d = 0.45, 95% CI [0.34,0.56]; p < 0.001), followed by addiction (A&TUD: d = 0.84, 95% CI [0.44,1.23]; p < 0.001, TUD: d = 0.72, 95% CI [0.49,0.96]; p < 0.001, and AUD d = 0.62, 95% CI [0.39,0.84]; p < 0.001) and psychiatric disorders (SZ: d = 0.53, 95% CI [0.30,0.76]; p < 0.001, BP: d = 0.46, 95% CI [0.22,0.69]; p < 0.001 and MDD: d = 0.28, 95% CI [0.11,0.46]; p < 0.001), but not different from expected in developmental disorders (ASD: d = 0.06, 95% CI [-0.04,0.16]; p = 0.36) and ADHD: d = 0.01, 95% CI [-0.14,0.15]; p = 0.98). Furthermore, higher PAD values in patient groups were linked to specific spatial brain patterns, including the frontotemporal network in psychiatric disorders, default mode network-salience network-putamen-thalamus in addiction and fronto-occipital network in dementia. Prefrontal cortex involvement was common across disorders, and disorder-specific brain patterns associated genes were enriched in different biological processes. A limitation of our study is that psychiatric disorders and addiction have high comorbidity, and these potential confounders were not considered.

CONCLUSIONS: In summary, the different brain aging patterns, each based around specific underlying circuits, may serve as neuroimaging biomarkers for understanding the neural aging mechanisms in commonly occurring brain disorders. Future studies should test whether these disorder-specific brain aging patterns can serve as useful biomarkers to guide critical clinical decision-making.},
}

Humans
*Brain/diagnostic imaging/pathology
Female
*Aging/pathology
Case-Control Studies
Magnetic Resonance Imaging
Male
*Nervous System Diseases/diagnostic imaging/pathology/genetics
Adult
Middle Aged
Neuroimaging
Young Adult

@article {pmid42479708,
year = {2026},
author = {Lee, Y and Kim, S and Kim, S and Kang, Y and , },
title = {Feature integration of [18F]FDG PET brain imaging using deep learning for sensitive cognitive decline detection.},
journal = {PloS one},
volume = {21},
number = {7},
pages = {e0341995},
pmid = {42479708},
issn = {1932-6203},
mesh = {Humans ; *Positron-Emission Tomography/methods ; *Fluorodeoxyglucose F18 ; *Deep Learning ; *Brain/diagnostic imaging ; Convolutional Neural Networks ; *Cognitive Dysfunction/diagnostic imaging ; Female ; Male ; Aged ; Alzheimer Disease/diagnostic imaging ; },
abstract = {BACKGROUND: Distinguishing individuals with cognitive decline (CD), including early Alzheimer's disease, from cognitively normal (CN) individuals is essential for improving diagnostic accuracy and enabling timely intervention. Positron emission tomography (PET) captures metabolic brain alterations associated with CD, but its broader application is often limited by cost and radiation exposure. To enhance the clinical utility of PET while addressing data limitations, we propose a data-efficient framework that integrates complementary multi-scale PET representations at voxel-level and region-level.

METHODS: Voxel-level features were extracted using convolutional neural networks (CNN) or principal component analysis networks (PCANet) from [¹⁸F]FDG PET imaging. Region-level features were derived from standardized uptake value ratio measurements across predefined brain regions and processed using a deep neural network (DNN). These voxel- and region-level information are integrated through direct concatenation. For the final prediction, different machine learning models and ensemble technique were applied. The models were trained and validated using 5-fold cross-validation on PET scans from 252 participants in the Alzheimer's Disease Neuroimaging Initiative, comprising 118 CN and 134 CD subjects. Additional correlation analysis and disease classification comparison with the Mini-Mental State Examination (MMSE) were also performed.

RESULTS: In 5-fold cross-validation, CNN, PCANet, and DNN models achieved classification accuracies of 0.69 ± 0.04, 0.69 ± 0.06, and 0.82 ± 0.06, respectively. The integrated DNN-CNN model using direct concatenation yielded the highest accuracy (0.87 ± 0.05), with a 6.33% improvement in accuracy and reduced standard deviation relative to the DNN-only model. Overall, there were an increase of 14.22% in Recall (0.77 to 0.88) and an increase of 7.92% in F1-Score (0.82 to 0.88). Moreover, the predicted probability of CD showed a significant correlation with MMSE scores, and the model achieved higher accuracy, recall, and F1-score than MMSE-based classification.

CONCLUSION: Combining complementary voxel-level and region-level PET representations with deep learning improved classification performance over single-representation models, particularly by enhancing sensitivity to cognitive decline. These findings support the potential utility of multi-scale FDG-PET representations for machine learning-based cognitive decline detection.},
}

Humans
*Positron-Emission Tomography/methods
*Fluorodeoxyglucose F18
*Deep Learning
*Brain/diagnostic imaging
Convolutional Neural Networks
*Cognitive Dysfunction/diagnostic imaging
Female
Male
Aged
Alzheimer Disease/diagnostic imaging

@article {pmid42479714,
year = {2026},
author = {Buard, G and Verny, M},
title = {[Focus on limbic-predominant age-related TDP-43 encephalopathy (LATE)].},
journal = {Geriatrie et psychologie neuropsychiatrie du vieillissement},
volume = {24},
number = {3},
pages = {0},
doi = {10.1684/pnv.2026.1294},
pmid = {42479714},
issn = {2115-7863},
abstract = {In 2019, an international working group described a new clinicopathological entity: limbic-predominant age-related TDP-43 encephalopathy (LATE). Neuropathologically, LATE is characterized by the abnormal accumulation of TDP-43 protein in limbic structures, particularly the hippocampus and parahippocampal regions. Clinically, LATE presents as a slowly progressive, isolated mesiotemporal amnestic syndrome, typically affecting individuals aged over 75 years. Brain MRI usually reveals marked hippocampal atrophy, while FDG-PET may demonstrate medial temporal hypometabolism. A diagnosis of probable LATE requires the exclusion of underlying amyloid pathology, although concomitant Alzheimer's disease pathology is common in older adults. To date, no symptomatic or disease-modifying pharmacological treatment has demonstrated efficacy in LATE. However, its clinical course appears to differ from that of typical Alzheimer's disease, with potentially slower progression and longer preservation of functional independence. LATE therefore represents a common and likely underrecognized cause of memory impairment in older adults, and its identification has important implications for diagnosis, prognosis, and therapeutic decision-making.},
}

@article {pmid42479744,
year = {2026},
author = {Bonarota, S and Caruso, G and Di Domenico, C and Di Lorenzo, F and Koch, G and Caltagirone, C and Bozzali, M and Serra, L},
title = {Are MMSE and ACE-R useful for detecting the earliest stages of Alzheimer's disease? A comparative study.},
journal = {Journal of neuropsychology},
volume = {},
number = {},
pages = {},
doi = {10.1111/jnp.70064},
pmid = {42479744},
issn = {1748-6653},
support = {//Ricerca Corrente 2026/ ; //Ministero della Salute-Ministry of Health/ ; },
abstract = {Subjective cognitive decline (SCD) is an at-risk condition for future cognitive decline, making its early identification crucial. We examined whether two widely used screening tools, the Addenbrooke's Cognitive Examination-Revised (ACE-R) and the Mini Mental State Examination (MMSE), can distinguish SCD individuals from healthy elderly (HS) and from individuals with objective cognitive impairment. 110 participants were recruited: 22 HS, 25 SCD, 31 amnestic mild cognitive impairment (aMCI), and 32 Alzheimer's disease (AD) patients. All participants underwent an extensive neuropsychological battery and the ACE-R, which incorporates the MMSE. Partial ACE-R (ACER_P) scores were derived. Between-group comparisons were performed and discriminant analyses were run to evaluate sensitivity, specificity, and accuracy of total ACE-R (ACER_TOT), ACER_P, and MMSE. Despite no screening test significantly distinguishing SCD from HS, a progressive downward trend emerged across groups, with AD performing worst, followed by aMCI, then SCD and HS. Discriminant analyses indicated ACER_TOT had the highest sensitivity for AD (84.4%), with overall accuracy of 59.1%. Sensitivity for HS (68.2%) and aMCI (51.6%) was good but weaker. ACER_P and MMSE yielded similar or lower accuracy. Importantly, all measures poorly detected SCD, with sensitivity below 30%, leading to frequent misclassification as HS or aMCI. Although ACE-R and MMSE are moderately effective for identifying AD, HS and aMCI, they fail to distinguish SCD from other groups. Given the higher risk of SCD of being in AD continuum, such misclassification may prevent appropriate clinical follow-up. More sensitive screening instruments are needed to capture subtle cognitive changes and support early intervention strategies.},
}

@article {pmid42479987,
year = {2026},
author = {Ghorbani, E and Hajihashemi, S and Fahanik-Babaei, J and Nazari, M},
title = {Chronic 40-Hz Light-Emitting Diode (LED) Therapy Attenuates Cognitive and Behavioral Deficits and Modulates BDNF and Caspase-3 Expression in a D-galactose/Aluminum Chloride-Induced Sporadic Alzheimer's-Like Rat Model.},
journal = {The International journal of neuroscience},
volume = {},
number = {},
pages = {1-17},
doi = {10.1080/00207454.2026.2706611},
pmid = {42479987},
issn = {1563-5279},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegenerative condition marked by gradual deterioration of cognition, synaptic integrity, and neuronal viability. Experimental exposure to D-galactose (D-gal) combined with aluminum chloride (AlCl3) produces oxidative and inflammatory damage within the brain, closely resembling AD-related neuropathology. Photobiomodulation therapy (PBMT) has recently gained attention as a safe, non-pharmacological approach with neuroprotective potential; however, the impact of sustained 40-Hz light-emitting diode (LED) stimulation in this context remains insufficiently explored.

METHODS: In the present study, rats received D-gal (60 mg/kg, i.p.) and AlCl3 (200 mg/kg, oral) for six weeks to induce AD-like changes. The treatment group was exposed to 40-Hz pulsed LED light (425-550 nm, 15 min/session, three times weekly). Behavioral analyses were performed using the elevated plus maze (EPM), novel object recognition (NOR), and passive avoidance (PA) paradigms. Western blotting quantified brain-derived neurotrophic factor (BDNF) and cleaved-caspase-3 expression in whole brain tissue.

RESULTS: D-gal/AlCl3 administration produced anxiety-like behavior, recognition deficits, and impaired memory retention, accompanied by decreased BDNF and elevated caspase-3. Remarkably, 40-Hz LED exposure reversed these alterations, up-regulating BDNF and suppressing caspase-3, in parallel with improvements in cognitive and emotional outcomes.

CONCLUSION: These data suggest that 40-Hz LED stimulation confers neuroprotection in the D-gal/AlCl3-induced AD model, potentially through enhancement of neurotropic signaling and inhibition of apoptosis, supporting its promise as a non-invasive strategy against neurodegenerative decline.},
}

@article {pmid42479989,
year = {2026},
author = {Magee, RG and Xie, SX and Ohm, DT and Rhodes, E and Massimo, L and Van Deerlin, VM and Wolk, DA and Lee, EB and Mcmillan, CT and Irwin, DJ},
title = {Association Between Postmortem Pathologic Burden and the Rate of Clinical Progression in Patients With Frontotemporal Lobar Degeneration.},
journal = {Neurology},
volume = {107},
number = {3},
pages = {e218278},
doi = {10.1212/WNL.0000000000218278},
pmid = {42479989},
issn = {1526-632X},
mesh = {Humans ; Female ; *Frontotemporal Lobar Degeneration/pathology ; *Disease Progression ; Male ; Middle Aged ; Retrospective Studies ; Aged ; tau Proteins/metabolism ; *Brain/pathology ; DNA-Binding Proteins/metabolism ; Longitudinal Studies ; Autopsy ; },
abstract = {BACKGROUND AND OBJECTIVES: Histopathologic staging of Alzheimer disease has led to validation of imaging techniques that guide diagnosis and treatment. We previously constructed preliminary phases of the sequential progression of TDP-43 and tau to guide similar efforts in behavioral-variant frontotemporal dementia (bvFTD). In this article, we expand this work using digital pathology and longitudinal clinical data to more comprehensively model the relationship between clinical progression and the distribution and severity of postmortem frontotemporal lobar degeneration (FTLD) pathology.

METHODS: In this retrospective cohort study, 101 patients (42% female, median age at symptom onset = 63 years) were selected from the Penn Integrated Neurodegenerative Disease Database and had both longitudinal assessments and primary neuropathologic diagnosis of FTLD-Tau or FTLD-TDP. We used validated methods to quantify the burden of primary pathology from up to 6 cortical regions across hemispheres. FTLD-TDP pathologic phase was constructed from diagnostic pathology data based on published criteria. We tested the association between pathologic metrics and (1) disease duration or (2) the rate of clinic progression measured by 2 independent global measures (Clinical Dementia Rating Scale-Sum of Boxes [CDR-SB] and Mini-Mental State Examination [MMSE]). Linear regression and linear mixed-effects models were adjusted for hemisphere sampled, sex, age at onset, pathogenic variant status, and pathologic subtype.

RESULTS: Disease duration did not associate with pathologic burden in multiple regression (FTLD-TDP β = 0.01 [-0.06, 0.09]; p = 0.7; FTLD-Tau β = 0.1 [-0.4, 0.7]; p = 0.7). By contrast, mean TDP-43 burden, but not FTLD-Tau burden, was associated with both worse relative CDR-SB (β = 0.1 [0.06, 0.2]; p = 0.0001) and MMSE (β = -0.1 [-0.2, -0.03]; p = 0.009) among all FTLD-TDP patients. TDP-43 phase also associated with worse CDR-SB (β = 0.07 [0.02, 0.1]; p = 0.005) and MMSE (β = -0.2 [-0.3, -0.1]; p = 0.000005). TDP-43 burden (CDR-SB (β = 0.1 [0.03, 0.2]; p = 0.005 and MMSE (β = -0.2 [-0.4, -0.05]; p = 0.009)), but not phase (CDR-SB (β = 0.02 [-0.03, 0.08]; p = 0.4 and MMSE (β = -0.04 [-1, 0.07]; p = 0.5)), associated with relative decline in sensitivity analyses limited to bvFTD.

DISCUSSION: Greater TDP-43 burden was most closely associated with antemortem clinical decline rather than cumulative aggregation through the disease course. These human data suggest that the temporal dynamics of protein aggregation may differ among FTLD proteinopathies, with implications for the interpretation of FTLD-Tau and FTLD-TDP‑specific biomarkers as these are developed.},
}

Humans
Female
*Frontotemporal Lobar Degeneration/pathology
*Disease Progression
Male
Middle Aged
Retrospective Studies
Aged
tau Proteins/metabolism
*Brain/pathology
DNA-Binding Proteins/metabolism
Longitudinal Studies
Autopsy

@article {pmid42479994,
year = {2026},
author = {Oliveira-Junior, MS and Rodrigues, MS and Amaral, L and Povala, G and Rocha, A and Scop Medeiros, M and Abbas, S and Ferrari-Souza, JP and Saha, P and Lussier, FZ and Ferreira, PCL and Bauer-Negrini, G and Soares, C and Roh, HW and Zimmer, ER and Karikari, T and Karim, H and Rosa-Neto, P and Hong, CH and Tudorascu, D and Son, SJ and Bellaver, B and Pascoal, T},
title = {Association Between Plasma GFAP and Medial Temporal Atrophy and Cognition in Amyloid-Negative Cerebrovascular Disease.},
journal = {Neurology},
volume = {107},
number = {3},
pages = {e218336},
doi = {10.1212/WNL.0000000000218336},
pmid = {42479994},
issn = {1526-632X},
mesh = {Humans ; Male ; Female ; *Glial Fibrillary Acidic Protein/blood ; Atrophy/pathology ; Cross-Sectional Studies ; Aged ; *Temporal Lobe/pathology/diagnostic imaging ; *Cognitive Dysfunction/blood/pathology/diagnostic imaging ; *Cerebrovascular Disorders/blood/pathology/diagnostic imaging/complications ; Biomarkers/blood ; Magnetic Resonance Imaging ; Amyloid beta-Peptides/metabolism ; Gray Matter/pathology/diagnostic imaging ; Middle Aged ; *Cognition/physiology ; },
abstract = {BACKGROUND AND OBJECTIVES: Plasma glial fibrillary acidic protein (GFAP), a marker of astrocyte reactivity, is elevated across multiple neurodegenerative conditions, including Alzheimer disease. However, its role in neurodegeneration and cognitive decline driven by cerebrovascular pathology, independent of β-amyloid (Aβ) copathology, remains poorly characterized. We investigated whether plasma GFAP is associated with medial temporal atrophy and cognition across a spectrum of cerebrovascular burden in Aβ-negative cognitively impaired individuals.

METHODS: In this cross-sectional multicenter study, Aβ PET-negative cognitively impaired participants were recruited from South Korean memory clinics. Plasma GFAP was measured using ultrasensitive Simoa assays. White matter hyperintensity burden was graded using the Fazekas scale and stratified into low (LVP: Fazekas 1) and high (HVP: Fazekas 2-3) cerebrovascular burden groups. Medial temporal gray matter density was assessed using voxel-based morphometry, and hippocampal and amygdalar volumes were derived from T1-weighted MRI adjusted for intracranial volume. Linear regression, interaction, and bootstrap mediation models were used to assess associations among GFAP, brain structure, and cognition.

RESULTS: A total of 324 participants were included (LVP n = 203; HVP n = 121; median age 73 years [interquartile range 66-78]; 67.9% female). Compared with LVP, HVP participants were older (75 vs 71 years; p < 0.0001), had lower Mini-Mental State Examination (MMSE) scores (22.7 vs 24.5; p = 0.005), and higher plasma GFAP (136.7 vs 112.1 pg/mL; p = 0.001). Higher GFAP was associated with lower medial temporal gray matter density in HVP (β = -0.311; p = 0.001) but not LVP (β = -0.012; p = 0.858), with a significant GFAP-vascular burden interaction (β = -0.309; p = 0.008). In HVP, higher GFAP was associated with smaller hippocampal (β = -0.179; p = 0.044) and amygdalar volumes (β = -0.169; p = 0.049) and lower MMSE (β = -0.194; p = 0.039). Medial temporal atrophy statistically explained the GFAP-MMSE association (indirect β = -0.071, 95% CI -0.140 to -0.010; p = 0.016). Vascular comorbidities (diabetes, dyslipidemia, hypertension) did not modify the GFAP-cognition association.

DISCUSSION: In Aβ-negative cognitively impaired individuals with high cerebrovascular burden, elevated plasma GFAP is associated with medial temporal atrophy and cognitive decline, suggesting GFAP may capture astrocyte-reactivity relevant to vascular cognitive impairment beyond amyloid pathology. These cross-sectional findings require confirmation in longitudinal and ethnically diverse cohorts.},
}

Humans
Male
Female
*Glial Fibrillary Acidic Protein/blood
Atrophy/pathology
Cross-Sectional Studies
Aged
*Temporal Lobe/pathology/diagnostic imaging
*Cognitive Dysfunction/blood/pathology/diagnostic imaging
*Cerebrovascular Disorders/blood/pathology/diagnostic imaging/complications
Biomarkers/blood
Magnetic Resonance Imaging
Amyloid beta-Peptides/metabolism
Gray Matter/pathology/diagnostic imaging
Middle Aged
*Cognition/physiology

@article {pmid42480159,
year = {2026},
author = {Zhou, M and Tong, X and Zhao, J and Cheng, M and Yang, L and Tian, L and Wan, N},
title = {DCL-SE: Dynamic curriculum learning for spatiotemporal encoding of brain imaging.},
journal = {Neural networks : the official journal of the International Neural Network Society},
volume = {205},
number = {Pt A},
pages = {109409},
doi = {10.1016/j.neunet.2026.109409},
pmid = {42480159},
issn = {1879-2782},
abstract = {High-dimensional neuroimaging analyses for clinical diagnosis are often constrained by compromises in spatiotemporal fidelity and the limited adaptability of large-scale, general-purpose models. To address these challenges, we introduce Dynamic Curriculum Learning for Spatiotemporal Encoding (DCL-SE), an end-to-end framework centered on data-driven spatiotemporal encoding (DaSE). We leverage Approximate Rank Pooling (ARP) to efficiently encode three-dimensional volumetric brain data into information-rich, two-dimensional dynamic representations, and then decode this representation through a DGM-implemented architectural curriculum, where the fixed hierarchical decoder progressively refines features from global anatomical structures to fine pathological details without introducing a threshold-controlled stage-switch scheduler. Evaluated across six publicly available datasets, including Alzheimer's disease and brain tumor classification, cerebral artery segmentation, and brain age prediction, DCL-SE consistently outperforms existing methods in accuracy, robustness, and interpretability. These findings underscore the critical importance of compact, task-specific architectures in the era of large-scale pretrained networks.},
}

@article {pmid42480386,
year = {2026},
author = {Koek, L and Jo, HN and Kennedy, MJ and Dell'Acqua, ML},
title = {Anchored kinase and phosphatase signaling networks in amyloid β-induced synaptic dysfunction.},
journal = {Molecular pharmacology},
volume = {108},
number = {8},
pages = {100141},
doi = {10.1016/j.molpha.2026.100141},
pmid = {42480386},
issn = {1521-0111},
abstract = {Impaired excitatory synaptic function and synapse loss are early hallmarks of Alzheimer's disease (AD). There is strong biochemical, genetic, physiological, and anatomical evidence that the accumulation of soluble amyloid beta (Aβ) oligomers in the brain leads to AD-related synapse dysfunction and cognitive impairment. Long-term potentiation (LTP), a key form of synaptic plasticity for learning and memory, is disrupted in several mouse models harboring familial early-onset AD-linked mutations that lead to Aβ accumulation, and even acute applications of Aβ oligomers block LTP within minutes and promote synapse loss within days. How does Aβ cause such profound synaptic dysfunction? It is increasingly appreciated that Aβ hijacks normal synaptic signaling pathways involved in plasticity, biasing them toward long-term depression (LTD) and eventual synapse elimination. LTP and LTD in the hippocampus are ultimately driven by insertion and removal of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptors (AMPARs) from synapses, respectively, in response to Ca[2+] signals generated by N-methyl-d-aspartate-type glutamate receptors or L-type voltage-gated Ca[2+] channels. Central to the signaling pathways regulating AMPAR trafficking during LTP and LTD is a postsynaptic Ser/Thr kinase/phosphatase signaling network that is coordinated by the scaffold protein A-kinase anchoring protein (AKAP) 79/150 (human79/rodent150; AKAP5/Akap5 gene). This AKAP-organized signalosome includes N-methyl-d-aspartate-type glutamate receptors, AMPARs, L-type voltage-gated Ca[2+] channels, G-protein-coupled receptors, adenylyl cyclase, the cyclic adenosine mono-phosphate (cAMP)-dependent protein kinase, and the Ca[2+]-calmodulin-dependent protein phosphatase 2B/calcineurin. This minireview will highlight recent findings that Gαs-coupled β2-adrenergic and Gαq-coupled group 1 metabotropic glutamate (mGlu1/5) receptors signal through AKAP79/150-anchored cAMP-dependent protein kinase and protein phosphatase 2B/calcineurin to mediate multiple aspects of Aβ synaptotoxicity. SIGNIFICANCE STATEMENT: Recent studies reveal that amyloid beta engages A-kinase anchoring protein-scaffolded G-protein-coupled receptor signaling pathways to disrupt synaptic plasticity and promote synapse loss. These pathways contain several potential therapeutic targets involved in both local cAMP-dependent protein kinase and calcineurin/protein phosphatase 2B (CaN) signaling that regulates L-type voltage-gated calcium channels, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, and N-methyl-d-aspartate receptors to impair synaptic plasticity as well as distal CaN signaling to the nucleus that regulates gene expression to drive synapse loss.},
}

@article {pmid42480581,
year = {2026},
author = {Cornish, B and Van Ooteghem, K and Pieruccini-Faria, F and Montero-Odasso, M and McIlroy, W},
title = {Ankle-worn Accelerometers for Gait Analysis in Individuals with Alzheimer's disease and Mild Cognitive Impairment: Reliability of a Finite State Machine Approach.},
journal = {Medical engineering & physics},
volume = {},
number = {},
pages = {},
doi = {10.1088/1873-4030/ae8dd0},
pmid = {42480581},
issn = {1873-4030},
abstract = {Clinical gait analysis is essential for understanding motor and cognitive contributions to mobility impairment. Continued methodological advancement in gait analysis is needed to detect important and subtle changes in walking behaviour that will inform this understanding. This study evaluated the reliability of a Finite State Machine (FSM) algorithm for stride segmentation during preferred walking and dual task walking (DTW) and examined changes to temporal and accelerometry kinematic outcomes between tasks. Participants diagnosed with Alzheimer's disease or mild cognitive impairment completed a gait assessment as part of the Ontario Neurodegenerative Disease Research Initiative foundational study. Ankle worn accelerometers and a GAITRite walkway captured data during preferred walking and three DTW conditions (counting backwards by ones, animal naming, counting backwards by sevens). Acceleration data were processed using the FSM algorithm to extract temporal and accelerometry kinematic outcomes defined by the FSM intra stride segments. Stride time demonstrated excellent reliability (ICC≥0.97). Gait speed was significantly associated with gait variability during animal naming and counting backwards by sevens (p<0.05), but not during counting backwards by ones. The FSM approach showed changes to stride phases and accelerometry derived kinematics not seen with conventional stride-based approaches. There was a reduction in flat-foot phase and an increase in push-off phase across all dual-task conditions compared with PREF (p<0.05), where conventional stance-phase segmentation did not show consistent differences. Kinematic outcomes were also significantly lower during DTW conditions when compared to preferred walking trials (p<0.05) for the mid-swing peak amplitude and the slope of the accelerometer push-off. Findings demonstrate differences in performance between preferred and DTW conditions, the influence of gait speed on gait variability, and unique accelerometry derived kinematics. The FSM segmentation method advances gait assessment by providing precise stride characteristics using low cost, clinically accessible tools.},
}

@article {pmid42480738,
year = {2026},
author = {Yuan, X and McElroy, C and Kengwerere, MK and Zhu, CF and Qiang, W},
title = {Effects of broadband mid-infrared radiation and 1,8-cineole on β-amyloid aggregation: a biophysical characterization of moxibustion-based Alzheimer's therapeutic factors.},
journal = {International journal of biological macromolecules},
volume = {376},
number = {},
pages = {153610},
doi = {10.1016/j.ijbiomac.2026.153610},
pmid = {42480738},
issn = {1879-0003},
abstract = {Moxibustion is a traditional Chinese medicine (TCM) external therapy that shows notable preventive effects on Alzheimer's disease (AD). It has been postulated that the therapeutic effect of moxibustion may be mediated through the combined action of multiple factors, including heat, infrared radiation, and volatile combustion products of Artemisia argyi. However, direct evidence supporting the influence of moxibustion-related factors on AD-related pathological processes is limited, creating a knowledge gap between the clinical outcomes of moxibustion-based AD therapy and the modern biomedical understanding of its underlying mechanisms. We use biophysical approaches to investigate influences of two moxibustion-related factors, namely the broadband mid-infrared (mid-IR) radiation and 1,8-cineole (CIN), on the aggregation kinetics of β-amyloid (Aβ) peptides and the molecular structures of the resulting Aβ aggregates. Our results showed that Aβ fibrillation was decelerated with these influential factors. The macroscopic morphologies and packing, as well as the molecular-level structures of resultant Aβ aggregates are also significantly modulated. Overall, our results provide molecular-level insights into how these therapeutic factors may act on Aβ amyloidosis.},
}

@article {pmid42480871,
year = {2026},
author = {Zhang, X and Yang, X and Zhuang, D and Mu, Z and Ju, C},
title = {Retigabine alleviates cognitive deficits, decreases neuropathology and activates the AKT/GSK-3β pathway in APP/PS1 transgenic mice.},
journal = {Behavioural brain research},
volume = {},
number = {},
pages = {116391},
doi = {10.1016/j.bbr.2026.116391},
pmid = {42480871},
issn = {1872-7549},
abstract = {Neuronal hyperexcitability is crucial to the pathogenesis of Alzheimer's disease (AD). Activating the Kv7 channel is an effective way to reduce neuronal excitability. The Kv7 channel opener retigabine (RTG) has been demonstrated to alleviate spatial memory deficits in APP/PS1 transgenic mice. However, the mechanism by which RTG reduces cognitive deficits in APP/PS1 mice remains unclear. In this study, we revealed that RTG could ameliorate learning and spatial memory deficits in APP/PS1 mice during novel object recognition and Morris water maze tests. Meanwhile, RTG increased NeuN neuronal fluorescence intensity, increased the expression of the synaptic proteins postsynaptic density protein 95 (PSD95) and synaptophysin (SYN), improved synaptic plasticity, increased insulin-degrading enzyme (IDE) expression, decreased beta-secretase 1 (BACE1) expression, reduced Aβ1-40 and Aβ1-42 levels, and increased pAKT (ser473) and pGSK-3β (ser9) expression. These results indicated that RTG alleviates learning and spatial memory deficits in APP/PS1 mice, with potential mechanisms involving a reduction in neuronal loss, attenuation of synaptic damage, a decrease in β-amyloid (Aβ) deposition, and activation of the AKT/GSK-3β pathway.},
}

@article {pmid42481033,
year = {2026},
author = {Traub, J and Frey, A and Homola, G and Morbach, C and Frantz, S and Pham, M and Störk, S and Stoll, G and Otto, M and Oeckl, P},
title = {Longitudinal trajectories of neurodegenerative biomarkers in the blood of patients with chronic heart failure.},
journal = {ESC heart failure},
volume = {},
number = {},
pages = {},
doi = {10.1093/eschf/xvag202},
pmid = {42481033},
issn = {2055-5822},
abstract = {BACKGROUND AND AIMS: Chronic heart failure is associated with mild cognitive impairment, vascular dementia, and Alzheimer's disease, but the underlying mechanisms remain poorly defined. Blood-based neurodegenerative biomarkers may support early risk stratification and outcome prediction in heart failure.

METHODS: In the prospective Cognition.Matters-HF cohort study, serum neurofilament light chain, glial fibrillary acidic protein, and phosphorylated tau protein-181, as well as plasma amyloid-β peptides (Aβ38, Aβ40, Aβ42) and β-synuclein, were quantified longitudinally over 36 months using ultrasensitive immunoassays and immunoprecipitation mass spectrometry. Cerebral magnetic resonance imaging and standardized domain-specific cognitive testing were performed. Multivariable logistic regression was used to assess associations with future mild cognitive impairment, brain structural changes, and 5-year all-cause mortality.

RESULTS: Among 104 patients with chronic heart failure (10% female, age 64 ± 10 years), all biomarkers except neurofilament light chain increased significantly over 3 years (p < 0.05). Median annual percentage changes were 36.6% for phosphorylated tau protein-181, 4.6% for glial fibrillary acidic protein, 2.6% for β-synuclein, 0.6% for Aβ38, 0.5% for Aβ40, and 0.3% for Aβ42. In multivariable models adjusted for clinical confounders, increases in Aβ38 and Aβ42 independently associated with future mild cognitive impairment, pathological white matter hyperintensity progression (>5% per year), and 5-year mortality (all p < 0.05). Glial fibrillary acidic protein levels and phosphorylated tau protein-181 trajectories independently associated with pathological brain atrophy (>0.3% per year).

CONCLUSIONS: In clinically stable patients with chronic heart failure, longitudinal increases in circulating amyloid-β peptides associated with cognitive decline, structural brain changes, and mortality. Serial biomarker assessment provided stronger prognostic information than baseline measurements alone. Replication in larger cohorts is required.},
}

@article {pmid42481072,
year = {2026},
author = {Strating, TR and Haapanen, MJ and Ma, D and Gordon, EH and Rockwood, K and Hubbard, RE and Ward, DD},
title = {Frailty and accelerated dementia onset in genetic, sociodemographic and neuropathologic subgroups.},
journal = {Journal of neurology, neurosurgery, and psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1136/jnnp-2026-338460},
pmid = {42481072},
issn = {1468-330X},
abstract = {BACKGROUND: Quantifying how risk factors shape the timing of dementia onset can inform care and prevention strategies. We aimed to establish the degree to which and in whom frailty accelerates time to a diagnosis of dementia.

METHODS: Longitudinal data came from community-dwelling participants of the Rush Memory and Aging Project in Northeastern Illinois. At baseline, participants had data on age, education, sex, APOE ε4 status and sufficient health/functional variables to calculate a frailty index score. In a subset of participants who underwent autopsy, neuropathologic burden was quantified using a 10-item index of markers of Alzheimer's disease and mixed brain pathology. Accelerated failure time models estimated associations of frailty and age at dementia diagnosis.

RESULTS: In 1614 participants (mean age 79.6 years, 75% female) over 23.9 years of follow-up, frailty (frailty index scores ≥0.25) was associated with 3.6% younger age at dementia diagnosis (time ratio, TR 0.96 (95% CI 0.95, 0.98)), equating to 2-3 years earlier. That association was stronger in males than females, but present across each sex, education and APOE ε4 subgroup. In the autopsy subset (n=906), frailty was associated with 9.8% younger dementia diagnosis among those who died with low neuropathologic burden (TR 0.90 (95% CI 0.85, 0.96)) but had no association in those with intermediate or high burden.

CONCLUSIONS: Frailty appears to independently accelerate dementia onset, particularly for individuals whose neurodegenerative lesions might be insufficient to explain their dementia diagnosis. Its routine measurement in clinical practice could hold benefit for risk stratification and care.},
}

@article {pmid42481198,
year = {2026},
author = {Ihalainen, L and Barbera, M and Törmäkangas, T and Hyvärinen, P and Willberg, T and Linder, P and Solomon, A and Dietz, A},
title = {Proof-of-concept randomised controlled trial of data-driven hearing rehabilitation versus standard care in older adults with hearing loss: the healthy hearing for healthy ageing protocol.},
journal = {BMJ open},
volume = {16},
number = {7},
pages = {e122681},
doi = {10.1136/bmjopen-2026-122681},
pmid = {42481198},
issn = {2044-6055},
mesh = {Humans ; *Hearing Aids ; Aged ; *Hearing Loss/rehabilitation/psychology ; Quality of Life ; Male ; Proof of Concept Study ; Female ; Speech Perception ; *Healthy Aging ; *Correction of Hearing Impairment/methods ; },
abstract = {INTRODUCTION: Hearing aids (HAs) can alleviate hearing loss; however, HA rehabilitation is frequently hampered by delayed diagnosis, suboptimal fitting and lack of systematic follow-up. Although the association between hearing loss and cognitive decline has been identified, evidence from randomised controlled trials remains limited. Addressing these gaps is essential for reducing hearing loss-related experiences and evaluating whether effective HA use could reduce the risk of cognitive decline.

METHODS AND ANALYSIS: The healthy hearing for healthy ageing study is a proof-of-concept, single-site, two-arm parallel-group 12-month randomised controlled trial with a 12-month extended follow-up. Up to two hundred participants with hearing loss and without cognitive decline referred for an initial HA rehabilitation are recruited and randomised 1:1 to either data-driven hearing rehabilitation or standard care. The primary outcome is the change in two speech perception in noise tests validated for the Finnish language: the Finnish matrix sentence test and the digits-in-noise test. The secondary outcomes are patient-reported outcomes (eg, Hearing in Real-Life Environment and Speech, Spatial and Quality questionnaires), quality of life (eg, 15D-questionnaire), cognitive (eg, Consortium to Establish a Registry for Alzheimer's Disease test) and psychosocial measures. Exploratory outcomes include event-related responses, cortical auditory evoked potentials, structural brain imaging and vision-related measures.

ETHICS AND DISSEMINATION: Ethical approval has been obtained from the Regional Medical Research Ethics Committee of the well-being Services County of North Savo (approval no. 697/2023). Findings from this study will be disseminated through peer-reviewed publications, conference presentations and relevant clinical and patient communities.

TRIAL REGISTRATION NUMBER: NCT06495268.},
}

Humans
*Hearing Aids
Aged
*Hearing Loss/rehabilitation/psychology
Quality of Life
Male
Proof of Concept Study
Female
Speech Perception
*Healthy Aging
*Correction of Hearing Impairment/methods

@article {pmid42481306,
year = {2026},
author = {Li, H},
title = {Retraction notice to "Molecular structure and protein function of mitochondrial fusion protein Mfn2 alleviate Alzheimer's disease: exercise assisted regulation" [Int. J. Biol. Macromol. 311 (2025) 143696].},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {153569},
doi = {10.1016/j.ijbiomac.2026.153569},
pmid = {42481306},
issn = {1879-0003},
}

@article {pmid42481337,
year = {2026},
author = {Huang, X and Wang, J and Zhao, X and Sooranna, SR and Liao, B and Jian, C and Shang, J and Li, X},
title = {Retraction notice to "Molecular mechanisms of MAPK9, BAX, and TFEB proteins: Genetic correlations between oxidative stress and autophagy pathways in Alzheimer's disease" [Int. J. Biol. Macromol. 309 (2025) 143196].},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {153568},
doi = {10.1016/j.ijbiomac.2026.153568},
pmid = {42481337},
issn = {1879-0003},
}

@article {pmid42481384,
year = {2026},
author = {Puljak, L and Kurtz, A and Koporc, Z},
title = {Evaluation of data from the hPSCreg®, a global registry for human pluripotent stem cell lines (hPSC-lines).},
journal = {Vox sanguinis},
volume = {},
number = {},
pages = {},
doi = {10.1111/vox.70332},
pmid = {42481384},
issn = {1423-0410},
abstract = {BACKGROUND AND OBJECTIVES: This descriptive retrospective study evaluated the content, completeness and usability of information available in the Human Pluripotent Stem Cell Registry (hPSCreg®), including registered cell lines, research projects, clinical studies, donor characteristics and regulatory information.

MATERIALS AND METHODS: We analysed data registered in hPSCreg® from January 2008 to December 2021. We analysed the data regarding cell lines, research projects, clinical studies, diseases, countries and legal issues.

RESULTS: There were 7538 total cell lines registered in the hPSCreg®. The most common derivation and generation countries were the United Kingdom, the United States, Germany and China. There were 3139 (46.5%) cell lines labelled as readily obtainable for a third party; few (7.2%) were labelled as available for commercial use. The most common diseases of the donor were Parkinson's disease, Alzheimer's disease and diabetes mellitus. Complete characterization data were available for the minority of the cell lines. The most common sponsor of research projects registered in the hPSCreg® was the European Union's Seventh Framework Programme (FP7). There were 97 registered clinical trials in the hPSCreg®. Challenges identified were incomplete user-entered information, entry of non-standardized information about diseases and continuing verification of the evolving legal status of embryonic stem cell (ESC) research per country.

CONCLUSION: The hPSCreg® represents an important international resource for stem cell research; however, this evaluation identified substantial variation in data completeness and standardization across registry fields. Future development should focus on improving the completeness of key metadata, standardization of terminology and systematic monitoring of registry data quality.},
}

@article {pmid42481480,
year = {2026},
author = {Rumpf, SL and Strübing, FL and Nalbach, K and Vargiu, CM and Berg, G and Lichtenthaler, SF and Parchi, P and Gao, P and Chen, W and Brendel, M and Gnörich, JS and Bernhardt, A and Dias Rodrigues, L and Höglinger, GU and Herms, J and Koeglsperger, T},
title = {Spatial multi-omics identifies early synaptic pruning and context-specific dopaminergic vulnerability in synucleinopathies.},
journal = {Nature communications},
volume = {17},
number = {1},
pages = {},
pmid = {42481480},
issn = {2041-1723},
mesh = {Humans ; alpha-Synuclein/metabolism/genetics ; *Dopaminergic Neurons/metabolism/pathology ; *Parkinson Disease/pathology/metabolism/genetics ; Proteomics/methods ; Synapses/metabolism/pathology ; Alzheimer Disease/pathology/metabolism/genetics ; *Synucleinopathies/metabolism/pathology/genetics ; Male ; Spatial Transcriptomics ; Lewy Body Disease/pathology/metabolism/genetics ; Female ; Aged ; Multiomics ; *Neuronal Plasticity ; Complement C1q/metabolism ; Substantia Nigra/pathology/metabolism ; Aged, 80 and over ; Mesencephalon/metabolism/pathology ; },
abstract = {Parkinson's disease (PD) is characterized by degeneration of dopaminergic neurons in the substantia nigra pars compacta, but the molecular events preceding neuronal loss remain unclear. Here, we combine spatial transcriptomics, spatial proteomics, and α-synuclein (αSyn) seed amplification assays to profile post-mortem midbrain tissue from controls, incidental Lewy body disease (iLBD), PD, Alzheimer's disease (AD), and AD with Lewy body pathology (AD + LBP). We find that αSyn seeding activity correlates with dopaminergic neuron loss in PD-spectrum cases but not in AD-associated LBP, indicating disease-context dependent relationships between αSyn pathology and neurodegeneration. In iLBD, before overt substantia nigra Lewy pathology or detectable αSyn aggregation, we detect increased expression of the complement component C1QC together with loss of inhibitory synaptic markers. These findings support early complement-associated remodeling of inhibitory synapses as a potential pathogenic event preceding overt αSyn aggregation and neuronal degeneration in PD.},
}

Humans
alpha-Synuclein/metabolism/genetics
*Dopaminergic Neurons/metabolism/pathology
*Parkinson Disease/pathology/metabolism/genetics
Proteomics/methods
Synapses/metabolism/pathology
Alzheimer Disease/pathology/metabolism/genetics
*Synucleinopathies/metabolism/pathology/genetics
Male
Spatial Transcriptomics
Lewy Body Disease/pathology/metabolism/genetics
Female
Aged
Multiomics
*Neuronal Plasticity
Complement C1q/metabolism
Substantia Nigra/pathology/metabolism
Aged, 80 and over
Mesencephalon/metabolism/pathology

@article {pmid42481525,
year = {2026},
author = {Lian, X and Chen, A and Zhu, X and Huang, Y and Yang, C and Huang, Y and Ran, M and Yin, L and Zhang, B},
title = {Early-life sugar rationing, brain aging, and long-term neurodegenerative and psychiatric health outcomes: a population-based natural experiment study.},
journal = {npj aging},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41514-026-00452-z},
pmid = {42481525},
issn = {2731-6068},
support = {2024A04J3999 and 2024A03J1178//Guangzhou Planned Project of Science and Technology/ ; K-20240111//KRT Plan of Guangdong Medical Development Foundation/ ; 82170234//National Natural Science Foundation of China/ ; 20241A011019//Health Science and Technology General Guidance Program of Guangzhou/ ; },
abstract = {Early-life nutrition is linked to adult brain health, yet evidence from quasi-experimental studies remains scarce. Leveraging the UK's historical sugar rationing as a natural experiment, we examined whether early-life sugar restriction reduces the risk of neurodegenerative and psychiatric disorders in later life. Among 60,394 UK Biobank participants (born 1951-1956), three groups were defined: in-utero-only, in utero plus 2 years, and non-rationed controls. Compared with non-rationed individuals, those exposed to sugar restriction during the first 1000 days after conception, showed significantly lower risks of all-cause dementia (by 27%), Alzheimer's disease (46%), depression (11%), and anxiety (20%). Dose-response analyses revealed stronger protective associations against depression and anxiety when postnatal sugar restriction extended beyond 6 months of age. Sex-stratified analyses showed consistent protective effects in women for Alzheimer's disease, depression, and anxiety. Neuroimaging revealed decelerated brain aging, reflected by a 0.39-year reduction in the brain age gap, alongside structural changes in reduced gray-white matter contrast and larger subcortical volumes, including the hippocampus and thalamus. Minimal associations were observed for in‑utero‑only exposure. These quasi-experimental findings suggest that early-life sugar restriction is associated with attenuated neurobiological aging and lower risks of dementia and psychiatric disorders, highlighting sugar intake as a potential modifiable factor of lifelong brain health.},
}

@article {pmid42481587,
year = {2026},
author = {Vogrinc, D and Holcar, M and Lenassi, M and Gregorič Kramberger, M and Emeršič, A and Čučnik, S and Dolžan, V and Goričar, K},
title = {Association of target miRNAs expression in blood plasma and cerebrospinal fluid with Alzheimer's disease biomarkers level and cognitive decline.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-63369-3},
pmid = {42481587},
issn = {2045-2322},
abstract = {Epigenetic changes can affect Alzheimer's disease (AD) susceptibility. miRNAs are novel potential circulating biomarkers of AD and mild cognitive impairment (MCI) that could support cerebrospinal fluid (CSF) biomarkers in earlier diagnosis of the disease or determination of disease stage. Our aim was to assess differences in expression of target miRNAs in patients with different stages of cognitive impairment and to evaluate the association with CSF biomarkers or cognitive test score (MMSE). We included 117 patients with cognitive impairment, among them 62 AD patients, 24 MCI patients with pathological CSF biomarker levels, and 31 MCI patients with normal CSF biomarker levels. Expression of seven target miRNAs was measured in patients' blood plasma, CSF and extracellular vesicles (EVs) enriched from plasma and CSF. None of the investigated miRNAs were differentially expressed between AD and MCI groups. Four miRNAs were associated with CSF biomarker levels, both in plasma (hsa-miR-375-3p) and CSF (hsa-miR-146a-5p, hsa-miR-29c, hsa-miR-107). The observed findings suggest that investigated miRNAs are not suitable for differentiation between different stages of cognitive impairment. However, miRNAs were associated with typical hallmarks of AD, which supports their important role in neurodegeneration. Therefore, miRNA regulatory networks could contribute to better understanding of the biological processes involved in cognitive impairment.},
}

@article {pmid42481708,
year = {2026},
author = {Qi, T and Fu, J and Wang, Y and Zhao, M and Zhang, Z and Peng, W and Liu, Q and Liu, M and Li, S and Duan, Q and Wang, C and Zhuang, J and Yan, X and Liu, Y and Wang, H and Huang, X},
title = {Computationally guided design of bioactive nanostructures for targeted clearance of amyloid-β aggregates in Alzheimer's disease.},
journal = {Nature nanotechnology},
volume = {},
number = {},
pages = {},
pmid = {42481708},
issn = {1748-3395},
support = {32425032//National Natural Science Foundation of China (National Science Foundation of China)/ ; 32271448//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82472134//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82471465//National Natural Science Foundation of China (National Science Foundation of China)/ ; },
abstract = {Targeted clearance of pre-existing amyloid-β (Aβ) aggregation remains a central challenge in Alzheimer's disease (AD) therapy. Here we report a computationally guided protein-gold hybrid nanostructure, Aβ3FTn[Au], that integrates Aβ-recognition motifs into self-assembled human ferritin nanocages containing structurally defined gold nanoclusters composed of 12 gold atoms with Au-Au distances of 2.4-4.5 Å, enabling the selective recognition and disassembly of aggregated human Aβ. Structural analysis, mutagenesis and molecular simulations identify key interactions between gold-coordinating residues within Aβ3FTn[Au] (H118, T122, C130) and the Met35 residue of Aβ, revealing a mechanism in which multivalent engagement destabilizes fibrillar interfaces and promotes progressive plaque disassembly. In 5 × familial AD transgenic mice, systemic administration of Aβ3FTn[Au] reduced cerebral amyloid burden, preserved synaptic integrity and improved cognitive performance. This work establishes a rationally designed bioactive nanomaterial for targeted remodelling of pathological protein aggregates.},
}

@article {pmid42481784,
year = {2026},
author = {Aghaei, M and Gheisavandi, O and Carpenter, BD and Vahabi, Z and Sharifi, F and Etesam, F},
title = {Validity and reliability of the Persian version of the Alzheimer's Disease Knowledge Scale among Iranian healthcare professionals and students.},
journal = {Discover mental health},
volume = {},
number = {},
pages = {},
doi = {10.1007/s44192-026-00546-w},
pmid = {42481784},
issn = {2731-4383},
abstract = {Alzheimer's disease (AD) is the leading cause of dementia worldwide. With rising prevalence in countries such as Iran, assessing healthcare professionals' knowledge of AD is essential. This study translated and adapted the Alzheimer's Disease Knowledge Scale (ADKS) into Persian and provided preliminary evidence of validity and reliability. A cross-sectional study was conducted with 304 healthcare professionals and students. The mean Persian version of the Alzheimer's Disease Knowledge Scale (ADKS-P) score was 20.27 (standard deviation (SD) = 3.62; possible range 0-30). The ADKS-P was developed using forward-backward translation, expert review, and pilot testing. Content validity, item-level performance, internal consistency estimated with Kuder-Richardson Formula 20 (KR-20), and two-week test-retest reliability were assessed. Known-groups validity was examined through education, occupation, and familiarity with dementia. All items met the critical Content Validity Ratio (CVR) threshold. Internal consistency was modest (KR-20 = 0.64), test-retest reliability was moderate (r = 0.53, p = 0.016), and several items showed weak discrimination (item-total r < 0.20 for 15 items; item 24 r = - 0.05). Higher ADKS-P scores were associated with greater education, professional role, and dementia familiarity. The ADKS-P offers a preliminary, culturally adapted tool for group-level baseline knowledge assessment in Persian-speaking contexts. Further refinement and validation are recommended before broader application.The study was approved by the ethics committee of the Tehran University of Medical Sciences (IR.TUMS.MEDICINE.REC.1401.202).},
}

@article {pmid42481826,
year = {2026},
author = {Wong, HY and Jin, C and Yuen, SL and Yang, X and Gill, SS and Xu, J and Lai, KPE and Fu, WY and Gao, W and Wang, X and Wang, J and Cao, H and Lv, G and Mok, KY and Tian, R and Fu, AKY and Chen, H and Ip, NY},
title = {DeepPlaque: a scalable multimodal platform for Aβ pathology and cell analysis in Alzheimer's disease.},
journal = {EMBO molecular medicine},
volume = {},
number = {},
pages = {},
pmid = {42481826},
issn = {1757-4684},
support = {T13-605/18W//Research Grants Council of Hong Kong (the Theme-Based Research Scheme)/ ; HKUST16104624 and HKUST16102824//Research Grants Council of Hong Kong (the General Research Fund)/ ; AoE/M-604/16//Areas of Excellence Scheme of the University Grants Committee/ ; ITCPD/17-9//the Innovation and Technology Fund for State Key Laboratory/ ; JLFS/M-604/24//SIAT-HKUST Joint Laboratory for Brain Science (Joint laboratory Scheme)/ ; 2023B1212120004//the Guangdong-Hong Kong Joint Laboratory for Psychiatric Disorders/ ; No. 62202403//the National Natural Science Foundation of China/ ; },
abstract = {Histological analysis is essential for understanding disease pathology and the microenvironment, particularly in Alzheimer's disease (AD), characterized by beta-amyloid (Aβ) plaques that exist as diffuse, fibrillar, and core species, with distinct toxicity levels. However, accurate classification of Aβ plaque types in postmortem brain tissues and profiling of surrounding cells present significant challenges. To address these challenges, we developed "DeepPlaque", an integrated system featuring "PlaqueNet", a deep learning model for automated classification of Aβ plaque species from diverse imaging platforms. DeepPlaque includes automated workflows for cellular phenotyping and proteomic profiling through targeted laser microdissection. PlaqueNet achieves expert-level accuracy (AUC > 90%) in classifying the 3 major Aβ plaque species, supporting consistent and large-scale annotation. By integrating spatial cellular phenotyping with laser microdissection, DeepPlaque enables high-throughput proteomic analysis of Aβ plaque niches, revealing that microglia are more abundant around core and fibrillar Aβ plaques, with increased expression of apolipoprotein E and amyloid precursor protein in core Aβ plaques. This customizable platform enhances the molecular and cellular characterization of Aβ plaque-associated environments, providing critical insights into AD pathology.},
}

@article {pmid42481875,
year = {2026},
author = {Sahin, U and Firat-Karalar, EN},
title = {The centrosome-cilium-centriolar satellite axis in neurodegenerative diseases.},
journal = {EMBO reports},
volume = {},
number = {},
pages = {},
pmid = {42481875},
issn = {1469-3178},
support = {101078097//EC | H2020 | PRIORITY 'Excellent science' | H2020 European Research Council (ERC)/ ; 3336//European Molecular Biology Organization (EMBO)/ ; 3622//European Molecular Biology Organization (EMBO)/ ; YIP//European Molecular Biology Organization (EMBO)/ ; (SU PREG)//Sabanci University President's Research/ ; },
abstract = {Neurodegenerative diseases (NDDs), including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and hereditary ataxias, remain major global health challenges with limited therapeutic options. Although clinically and genetically diverse, these diseases share extensively studied cellular and molecular hallmarks, including protein aggregation, impaired proteostasis, cytoskeletal abnormalities, altered energy metabolism, nucleic acid damage, and chronic inflammation. Emerging evidence indicates that dysfunction of the centrosome-cilium-satellite axis intersects with these established pathways in disease- and cell type-specific contexts. This axis, composed of centrosomes, primary cilia, and centriolar satellites, coordinates cytoskeletal organization, ciliary signaling, trafficking, proteostasis, and stress responses and acquires specialized functions in neurons that support polarity, connectivity, and long-term maintenance. In this review, we outline the structure, function, and neuronal specializations of the centrosome-cilium-satellite axis, then examine how its dysfunction has been reported in neurodegenerative disease models. We also discuss centriolar satellites as regulators of centrosome and cilium biology whose disease-specific roles in classical NDDs remain comparatively underexplored, with insights from Huntington's disease and schizophrenia. Finally, we discuss therapeutic strategies aimed at restoring axis structure and dynamics, modulating ciliary signaling, and correcting disease-linked genetic or transcript-level defects, emphasizing mechanism-based approaches that require validation in disease-relevant models. Together, the centrosome-cilium-satellite axis provides an emerging framework for understanding context-dependent organelle dysfunction in neuronal vulnerability and neurodegeneration.},
}

@article {pmid42482153,
year = {2026},
author = {Li, X and Zhao, D and Jia, X and Du, G and Xu, J and Qi, Y and Chen, Y and Wu, Y and Gu, J and Zhu, J and Shang, X},
title = {Deciphering spatial heterogeneity by multimodal spatial transcriptomics modelling with SpatialModal.},
journal = {Bioinformatics (Oxford, England)},
volume = {},
number = {},
pages = {},
doi = {10.1093/bioinformatics/btag540},
pmid = {42482153},
issn = {1367-4811},
abstract = {MOTIVATION: Advances in spatial transcriptomics (ST) technologies have made it possible to jointly acquire gene expression and histological image information while preserving spatial coordinates. This breakthrough presents unprecedented opportunities for the precise dissection of spatial heterogeneity in complex tissues. However, existing computational methods remain limited in their capacity for effective integration and synergistic modelling of multimodal ST data.

RESULTS: We propose SpatialModal, a multimodal graph learning framework that learns robust joint representations by combining a hierarchical representation strategy with a dual-level contrastive learning mechanism. We perform extensive validation of SpatialModal across diverse ST datasets spanning human and mouse tissues. The results demonstrate that SpatialModal effectively reveals intricate brain architectures in humans and mice, dissects tumour microenvironment heterogeneity in breast cancer, delineates Alzheimer's disease patterns, and characterizes spatiotemporal developmental trajectories within the embryonic heart, underscoring its capability to decipher the spatial heterogeneity of biological tissues. Furthermore, SpatialModal exhibits remarkable versatility and robustness, maintaining superior efficacy even on unimodal datasets devoid of histological images, thereby ensuring its broad applicability across diverse ST platforms.

SpatialModal is implemented in Python and is freely available at https://github.com/xingyili/SpatialModal. The source code used in this study has been archived on Zenodo at DOI: https://doi.org/10.5281/zenodo.21264356. All datasets used in this study are publicly available at https://doi.org/10.5281/zenodo.18220735.},
}

@article {pmid42482244,
year = {2026},
author = {Bonnì, S and Esposito, R and Mencarelli, L and Di Lorenzo, F and Ricci, F and Di Iulio, F and Savastano, E and Candeo, F and De Masi, F and Coletta, A and Vinci, AC and Ferraresi, M and Mancini, M and Casula, EP and Borghi, I and Spampinato, DA and Maiella, M and Cinnera, AM and Assogna, M and Bruno, M and Nocilli, M and Ferrara, M and Russo, M and Tagliamonte, NL and Ferrari, C and Bertino, S and Calabrò, RS and Maggio, MG and De Luca, R and Burrascano, R and Gjonaj, E and Mirabile, A and De Pasquale, P and d'Avella, A and Quartarone, A and Koch, G},
title = {Personalized non-invasive combined magnetic and electrical stimulation of the default mode network in mild AD patients (CMES-AD): a multicentric randomized sham-controlled trial protocol.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02145-x},
pmid = {42482244},
issn = {1758-9193},
support = {PNRR- MCNT2-2023-12377518//Ministero della Salute/ ; },
abstract = {BACKGROUND: Patients with Alzheimer's disease (AD) exhibit early alterations in the Default Mode Network (DMN), a key brain network involved in episodic memory where the precuneus plays a central role. Precision-targeted, non-invasive brain stimulation represents a promising strategy to improve cognitive function in individuals with dementia. The DMN can be modulated through personalized non-invasive electromagnetic stimulation, a therapeutic approach that enhances neural plasticity and stabilizes network connectivity. This trial implements an innovative therapeutic protocol based on precision delivery of personalized electromagnetic stimulation targeting the precuneus, the main hub of the DMN.

METHODS: This phase 2 multicenter, randomized, double-blind, sham-controlled, three-arm trial evaluates the safety and efficacy of combined repetitive transcranial magnetic stimulation (rTMS) and transcranial alternating current stimulation (tACS) targeting the precuneus in AD patients. rTMS will be applied using the intermittent theta burst stimulation (iTBS) protocol, while tACS will be delivered at gamma frequency (70 Hz). Personalization of iTBS-tACS treatment is established using neuronavigated TMS with electroencephalography (TMS-EEG). The 24-week intervention starts with a 2-week intensive course of daily combined treatment over the precuneus (5 sessions per week), followed by a 22-week maintenance phase with weekly stimulation. The primary outcome measure is the change in the integrated Alzheimer Disease Rating Scale (iADRS) between baseline and week 24. Secondary outcomes include score changes in the Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) scale, Clinical Dementia Rating Scale-Sum of Boxes (CDR-SoB), the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog13), the Mini-Mental State Examination (MMSE), the Montreal Cognitive Assessment (MoCA), the Frontal Assessment Battery (FAB), the Face-Name Association Task (FNAT), the Neuropsychiatric Inventory (NPI), and the Apathy Motivation Index (AMI). Exploratory outcomes will include changes in cortical activity and connectivity (assessed through TMS-EEG, MRI), in blood based biomarkers of neurodegeneration, synaptic activity and neural inflammation, and sensorimotor functions in virtual environments. Evaluation at week 12 and a follow-up assessment at week 32 will be conducted to assess short-term and follow-up treatment effects, respectively.

SIGNIFICANCE: This trial aims to provide evidence that personalized combined electrical and magnetic stimulation of the DMN may slow functional and cognitive decline in AD patients, contributing to the development of personalized interventions for AD treatment.

TRIAL REGISTRATION: ClinicalTrials.gov, NCT07075770, registered 10 July 2025.},
}

@article {pmid42482583,
year = {2026},
author = {Yang, SM and Guo, WQ and Dong, WG and Huang, JY and Huang, ST and Huang, Y and Zhan, SJ and Lin, L and Wang, F and Liu, LL},
title = {[Effects of electroacupuncture on motor function and PGC-1α/FNDC5/BDNF pathway in muscle and brain of SAMP8 mice].},
journal = {Zhen ci yan jiu = Acupuncture research},
volume = {51},
number = {7},
pages = {887-895},
doi = {10.13702/j.1000-0607.20250437},
pmid = {42482583},
issn = {1000-0607},
mesh = {Animals ; *Electroacupuncture ; *Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism/genetics ; *Brain-Derived Neurotrophic Factor/metabolism/genetics ; Mice ; *Muscle, Skeletal/metabolism ; Male ; *Fibronectins/metabolism/genetics ; Humans ; *Brain/metabolism ; *Alzheimer Disease/genetics/metabolism/therapy/physiopathology ; Signal Transduction ; Motor Activity ; Acupuncture Points ; },
abstract = {OBJECTIVES: To observe the effect of electroacupuncture (EA) on motor function and skeletal muscle morphology in SAMP8 mice, and to explore the mechanisms of EA improving motor dysfunction in Alzheimer's disease from the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α)/fibronectin type Ⅲ domain-containing protein 5 (FNDC5)/brain-derived neurotrophic factor (BDNF) pathway.

METHODS: SAMP8 mice were randomly divided into model and EA groups, with 9 mice in each group. Nine anti-aging SAMR1 mice were used as control group. In the EA group, "Baihui"(GV20), "Dazhui"(GV14) and "Shenshu"(BL23) were needled with EA for 20 min every day, 8 d as a course of treatment, with an interval of 2 d between courses. A total of 3 courses was proceeded. The motor function of mice was detected by grasping test, swimming test, suspension test and hind limb clamping test. The morphological structure of gastrocnemius muscle was observed by HE staining. The positive expressions of PGC-1α, FNDC5 and BDNF in gastrocnemius muscle were observed by immunohistochemical staining. The expression levels of PGC-1α, FNDC5 and BDNF mRNAs in gastrocnemius muscle and cerebral motor cortex were detected by real-time fluorescence quantitative PCR. The expression levels of PGC-1α, FNDC5 and BDNF proteins in gastrocnemius muscle and cerebral motor cortex were detected by Western blot.

RESULTS: Compared with the control group, the peak grip strength, average and maximum swimming speed, and suspension test score of the model group were significantly decreased (P<0.01), and the hind limb clamping test score was significantly increased (P<0.01). The gastrocnemius muscle fibers were loose and irregularly arranged, the spacing was widened and the cytoplasmic staining was uneven. The positive expression area ratios of PGC-1α, FNDC5 and BDNF in gastrocnemius muscle were significantly decreased (P<0.01), and the relative expression levels of PGC-1α, FNDC5 and BDNF mRNAs and proteins in gastrocnemius muscle and cerebral motor cortex were significantly decreased (P<0.01). Compared with the model group, the peak grip strength, average and maximum swimming speed, and suspension test score of the EA group were significantly increased (P<0.01), and the hind limb clamping test score was significantly decreased (P<0.01). The muscle fibers were intact and arranged regularly, the spacing was narrowed, and the cytoplasmic staining was uniform.The positive expression area ratios of PGC-1α, FNDC5 and BDNF were significantly increased (P<0.01), and the relative expression levels of PGC-1α, FNDC5 and BDNF mRNAs and proteins in gastrocnemius muscle and cerebral motor cortex were significantly increased (P<0.01, P<0.05). The correlation analysis results of PGC-1α, FNDC5 and BDNF mRNA expression in gastrocnemius and cerebral motor cortex showed a highly positive correlation (r>0.70, P<0.01).

CONCLUSIONS: EA can improve motor dysfunction and skeletal muscle morphology in SAMP8 mice, and its mechanism may be related to up-regulation of PGC-1α, FNDC5 and BDNF expressions in gastrocnemius and cerebral motor cortex.},
}

Animals
*Electroacupuncture
*Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism/genetics
*Brain-Derived Neurotrophic Factor/metabolism/genetics
Mice
*Muscle, Skeletal/metabolism
Male
*Fibronectins/metabolism/genetics
Humans
*Brain/metabolism
*Alzheimer Disease/genetics/metabolism/therapy/physiopathology
Signal Transduction
Motor Activity
Acupuncture Points

@article {pmid42482587,
year = {2026},
author = {Li, L and Hong, C and Xie, WT and Zhang, RZ and Wei, YT and Ma, C and Yan, XK},
title = {[Research progress on acupuncture-moxibustion regulating brain energy metabolism to intervene in Alzheimer's disease].},
journal = {Zhen ci yan jiu = Acupuncture research},
volume = {51},
number = {7},
pages = {923-932},
doi = {10.13702/j.1000-0607.20250813},
pmid = {42482587},
issn = {1000-0607},
mesh = {Humans ; *Alzheimer Disease/therapy/metabolism/genetics ; *Energy Metabolism ; *Acupuncture Therapy ; *Brain/metabolism ; *Moxibustion ; Animals ; Mitochondria/metabolism ; },
abstract = {Alzheimer's disease (AD) is a common neurodegenerative disorder, and brain energy metabolism disorders are closely related to the onset of AD. Acupuncture-moxibustion is one of the effective treatments for AD, which can significantly improve AD symptoms and slow down the progression of the disease. The mechanism of its action has also been continuously studied. This article summarizes the relevant research on acupuncture-moxibustion regulating brain energy metabolism to improve AD. The results show that acupuncture-moxibustion mainly improves AD brain energy metabolism disorders from the following aspects: 1) regulating glucose metabolism disorders (promoting glucose transport, increasing glucose uptake and utilization, and regulating glycolytic activity in the brain), 2) regulating mitochondrial structure and dysfunction (improving mitochondrial structure and dynamics, enhancing electron transfer chain activity and ATP production, inhibiting abnormal opening of mitochondrial permeability transition pores), 3) improving insulin resistance and damage to the insulin signaling pathway, and 4) restoring amino acid and lipid metabolic imbalance. It plays a role in neuroprotection and delaying the progression of the disease.},
}

Humans
*Alzheimer Disease/therapy/metabolism/genetics
*Energy Metabolism
*Acupuncture Therapy
*Brain/metabolism
*Moxibustion
Animals
Mitochondria/metabolism

@article {pmid42482646,
year = {2026},
author = {Ren, C and Li, Z and Cai, J and Li, J and Hong, X},
title = {The Relationship between Biological Aging and Cognitive Function: A Machine Learning Model.},
journal = {Yonsei medical journal},
volume = {67},
number = {7},
pages = {563-575},
doi = {10.3349/ymj.2025.0195},
pmid = {42482646},
issn = {1976-2437},
support = {JLSWSRCZX2023-24//Jilin Provincial Medical and Health Talent Project/China ; },
mesh = {Humans ; *Machine Learning ; *Aging/physiology ; Female ; *Cognition/physiology ; Male ; Aged ; ROC Curve ; Middle Aged ; *Cognitive Dysfunction/physiopathology ; Nutrition Surveys ; Predictive Learning Models ; },
abstract = {PURPOSE: The relationship between cognitive impairment and biological age (BA) is unclear. This study aimed to investigate the association between BA and cognitive impairment.

MATERIALS AND METHODS: A total of 2202 participants from the 2011-2012 and 2013-2014 National Health and Nutrition Examination Survey were included. Klemera-Doubal method age (KDM-Age), phenotypic age (PhenoAge), and their acceleration values were calculated based on laboratory parameters. Six machine learning models were constructed to compare performance metrics such as area under the receiver operating characteristic curve (AUC-ROC) and accuracy, and Shapley additive explanations (SHAP) was used to interpret feature contributions.

RESULTS: After fully adjusting for confounders, each 1-year increase in PhenoAge was associated with a 6%, 8%, and 5% higher risk of cognitive impairment on the Consortium to Establish a Registry for Alzheimer's Disease (CERAD), Digit Symbol Substitution Test (DSST), and Animal Fluency Test (AFT) tests, respectively (all p<0.001); the highest quartile group exhibited a 5.98-17.48-fold increase in risk compared to the lowest. KDM-Age showed only a marginal association with DSST [odds ratio (OR)=1.02, p=0.049]. Among all models, the random forest (RF) performed best for CERAD prediction (AUC-ROC=0.997, sensitivity=99.5%), significantly outperforming the other algorithms (p<0.001). SHAP results demonstrated that sociodemographic factors had mean contribution values (0.014-0.135) significantly higher than those of BA indicators (<0.011), underscoring the dominant role of social determinants.

CONCLUSION: PhenoAge is a biological aging indicator with suggestive value for identifying the risk of cognitive impairment in older adults. Combining the RF model with key sociodemographic information may help facilitate early risk screening.},
}

Humans
*Machine Learning
*Aging/physiology
Female
*Cognition/physiology
Male
Aged
ROC Curve
Middle Aged
*Cognitive Dysfunction/physiopathology
Nutrition Surveys
Predictive Learning Models

@article {pmid42482698,
year = {2026},
author = {Almostafa, M and Ali, I and Yahya, G and Siddiqi, AR},
title = {Unveiling the structural insights and inhibitory potential of coumarin-1,2,3-triazole hybrids against BACE1: a promising approach for Alzheimer's disease therapy.},
journal = {Frontiers in chemistry},
volume = {14},
number = {},
pages = {1824875},
pmid = {42482698},
issn = {2296-2646},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid beta (Aβ) plaque accumulation, in which β-secretase (BACE1) plays a central role in the amyloidogenic pathway. Inhibition of BACE1 represents a promising therapeutic strategy; however, effective and safe inhibitors remain limited. This study aimed to identify novel coumarin-1,2,3-triazole hybrids as potential BACE1 inhibitors using comprehensive in silico approaches. Molecular shape and distance-based features derived from co-crystal ligands were used to generate and validate a pharmacophore model through ROC-based area under the curve analysis. A designed library of hybrids underwent pharmacophore-based virtual screening, yielding 92 hits with ≤0.6 RMSD. These compounds were further evaluated via structure-based molecular docking, from which six top candidates were selected, demonstrating superior docking scores relative to reported inhibitors. ADMET and density functional theory analyses indicated favorable pharmacokinetic profiles and electronic properties, highlighting potential reactive sites. The selected compound, CUM-0199, was subsequently validated through a 200 ns molecular dynamics simulation and MMGBSA binding free energy analysis, confirming structural stability and favourable binding affinity toward BACE1. Overall, the findings suggest CUM-0199 as a potential lead candidate for AD therapy, warranting further experimental validation and clinical investigation.},
}

@article {pmid42483155,
year = {2026},
author = {Na, C and Gupta, G and Kim, M and Choe, Y and Lee, J and Lee, CY and Lim, MH},
title = {Metal-organic macrocycles as molecular modulators of amyloid-β aggregation and cytotoxicity.},
journal = {Chemical science},
volume = {},
number = {},
pages = {},
pmid = {42483155},
issn = {2041-6520},
abstract = {Metal-organic macrocycles provide a versatile platform for integrating multiple chemical functions within a single, well-defined architecture, yet their potential for regulating pathological protein aggregation remains largely unexplored. Here we report rationally designed metal-organic macrocycles that combine piano-stool ruthenium or iridium complexes with a photoactivatable bis(difluoroboron)-1,2-bis((1H-pyrrol-2-yl)methylene)hydrazine (BOPHY)-based ligand to enable dual-mode modulation of amyloid-β (Aβ) aggregation associated with Alzheimer's disease. These macrocycles directly engage Aβ species through surface interactions and, upon light activation, induce oxidative modifications via singlet oxygen, collectively altering aggregation behavior and aggregate morphologies. As a result, they suppress the formation of toxic Aβ assemblies and attenuate Aβ-induced cytotoxicity. Overall, this work establishes metal-organic macrocycles as effective modulators of amyloidogenesis and provides a potential strategy for controlling complex protein aggregation processes in neurodegenerative diseases.},
}

@article {pmid42483205,
year = {2026},
author = {Beydoun, MA and Song, M and Yun, C and Noren Hooten, N and Weiss, J and Beydoun, HA and Duggan, MR and Walker, KA and Launer, LJ and Evans, MK and Zonderman, AB},
title = {The proteomic and metabolomic signature of inherited chromosomally integrated HHV-6 and its role in all-cause dementia and mortality risk: The UK Biobank study.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {3},
pages = {e70286},
pmid = {42483205},
issn = {2352-8737},
abstract = {OBJECTIVE: To examine associations of inherited chromosomally integrated human herpesvirus 6 (iciHHV-6) with incident dementia and mortality, characterize proteomic and metabolomic correlates of carrier status, and evaluate whether these biomarkers relate to dementia and mortality risk.

METHODS: We analyzed UK Biobank participants ≥50 years of age with plasma metabolomics (N = 138,676) and proteomics (N ≤ 15,416) data and ≈15 years of follow-up. Cox proportional hazards models adjusted for key confounding factors evaluated associations of iciHHV-6 with dementia and mortality. Multivariable linear models assessed iciHHV-6 associations with metabolomic and proteomic profiles. Mediation and interaction were evaluated using structural equation models and Cox models with biomarker interactions. Least absolute shrinkage and selection operator regression identified independent proteomic and metabolomic predictors using imputed biomarker data.

RESULTS: iciHHV-6 was associated with higher dementia risk (hazard ratio [HR] = 1.32), particularly among women (HR = 1.66) and individuals with elevated Alzheimer's disease polygenic risk (HR = 1.49). Branched-chain amino acids (leucine and isoleucine) were elevated among carriers without mediating dementia risk. Proteomic analyses identified 126 nominally associated iciHHV-6-related proteins, many of which (Neurofilament Light Chain (NEFL), Glial Fibrillary Acidic Protein (GFAP), Yes-Associated Protein 1 (YAP1), Sialic Acid-binding Immunoglobulin-like Lectin 5 (SIGLEC5), Interleukin 19 (IL19), A Disintegrin And Metalloproteinase with Thrombospondin Motifs 16 (ADAMTS16), Sphingomyelin Phosphodiesterase 1 (SMPD1)) were also associated with dementia and/or mortality. Exploratory pathway analyses suggested enrichment of proteins related to immune regulation and post-translational modification. Predictive models identified NEFL, GFAP, Vascular Endothelial Growth Factor A (VEGF), Brevican (BCAN), remnant cholesterol, and polyunsaturated fatty acids as dementia predictors (area under the curve [AUC] = 0.83), whereas NEFL, Growth Differentiation Factor 15 (GDF15) Latent Transforming Growth Factor Beta Binding Protein 2 (LTBP2), Ectodysplasin A2 Receptor (EDA2R) and Advanced Glycosylation End-product Specific Receptor (AGER) predicted mortality (AUC = 0.70).

DISCUSSION: iciHHV-6 was associated with increased dementia risk, particularly among women and genetically susceptible individuals, with neuroimmune and metabolic biomarker profiles potentially relevant to brain aging and mortality risk.},
}

@article {pmid42483224,
year = {2026},
author = {Angom, RS and Li, Z and Rachamala, HK and Castanedes-Casey, M and Kulkarni, T and Chakravarty, T and Dutta, S and Wang, E and Dickson, D and Mukhopadhyay, D and Das, P},
title = {Correction: Vascular endothelial growth factor receptor-1 (VEGFR-1) knock-down is protective against hypoxia, Aβ1-42 oligomer and Aβ1-42 fibril-induced neuronal cell death: implications in AD pathogenesis.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1901421},
doi = {10.3389/fnins.2026.1901421},
pmid = {42483224},
issn = {1662-4548},
abstract = {[This corrects the article DOI: 10.3389/fnins.2026.1799391.].},
}

@article {pmid42483443,
year = {2026},
author = {Altuna, M},
title = {From cognitive screening to digital phenotyping: rethinking early detection of cognitive impairment in primary care.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1870463},
pmid = {42483443},
issn = {1664-2295},
abstract = {Early detection of cognitive impairment has become a clinical and public-health priority in the therapeutic era of Alzheimer's disease (AD). Brief instruments such as the Mini-Mental State Examination, Montreal Cognitive Assessment, Mini-Cog, Clock Drawing Test, Fototest, Memory Alteration Test, Eurotest, and AD8 remain widely used because they are inexpensive, clinically interpretable, and feasible in routine care. However, most were developed to identify established cognitive impairment rather than subtle mild cognitive impairment or biologically defined early AD. Ceiling effects, educational and cultural bias, examiner variability, and limited integration with functional, neuropsychiatric, subjective, and biomarker data restrict their value as stand-alone tools in contemporary diagnostic pathways. Digital cognitive assessment may address selected limitations of conventional screening by standardizing administration, reducing scoring variability, enabling repeated measurement, and capturing process-level features such as response latency, intra-individual variability, learning effects, speech and language markers, graphomotor dynamics, gaze, and ecologically sampled behavior. These signals may support earlier risk stratification and longitudinal monitoring, but they do not resolve diagnostic uncertainty or establish AD etiology on their own. This narrative review examines the transition from traditional cognitive screening to digital cognitive phenotyping. It considers established brief and contextual instruments, digitized conventional tests, remote repeated assessments, speech and language-derived digital cognitive biomarkers, digital clock drawing, prospective-memory tools, virtual reality and serious games, oculomotor and graphomotor metrics, passive sensing, multimodal platforms, and their integration with structural MRI, blood-based biomarkers, cerebrospinal fluid markers, and amyloid/tau PET. In the context of evolving AD criteria and disease-modifying therapies, digital screening should be understood as a governed triage and phenotyping layer rather than a stand-alone diagnostic label. A staged pathway is proposed that combines analog cognitive instruments, informant and functional measures, neuropsychiatric assessment, digital signals, and biological markers to support earlier, more equitable, and clinically actionable detection of cognitive impairment.},
}

@article {pmid42483593,
year = {2026},
author = {Zeng, HX and Li, G and Zeng, QG and Zhang, Q and Liu, L and Zeng, XW},
title = {Circular RNA circDNAJC5 Regulates Ultrafine Particle-Disrupted Microglial Lipid Metabolism via the Sphingolipid Signaling Pathway.},
journal = {Environment & health (Washington, D.C.)},
volume = {4},
number = {7},
pages = {1454-1468},
pmid = {42483593},
issn = {2833-8278},
abstract = {Ultrafine particles (PM0.1) can penetrate the brain and disrupt microglial function. Dysregulated lipid metabolism in activated microglia contributes to the development of Alzheimer's disease (AD), yet the epigenetic mechanisms underlying PM0.1-induced lipid metabolic disruption remain poorly understood. Circular RNAs (circRNAs) are emerging regulators of lipid metabolism, prompting us to investigate their role in PM0.1-exposed microglia. In vitro models of PM0.1-treated microglia (HMC3 and BV2) were established. We identified circDNAJC5, a lipid metabolism-associated circRNA, as significantly downregulated during PM0.1-induced lipid metabolic disruption. circDNAJC5 silencing aggravated lipid dysregulation, whereas its overexpression mitigated PM0.1-induced metabolic alterations. circDNAJC5 functioned as a molecular sponge for miR-98-5p, thereby regulating sphingomyelin synthase 1 (SMS1), a key enzyme in the sphingolipid signaling pathway. circDNAJC5 downregulation and lipid metabolic abnormalities were further validated in the brains of PM-exposed mice and AD mouse models, as well as in the blood of elderly individuals with cognitive impairment and hyperlipidemia. These findings highlight an epigenetic mechanism linking environmental exposure to microglial lipid metabolism and suggest circDNAJC5 as a potential biomarker for neurodegenerative and metabolic disorders.},
}

@article {pmid42483652,
year = {2026},
author = {Chen, IW and Chang, LC and Lai, YC and Hung, KC},
title = {Association of low vitamin B12 status with incident dementia and stroke: an EHR database study.},
journal = {Frontiers in nutrition},
volume = {13},
number = {},
pages = {1877529},
pmid = {42483652},
issn = {2296-861X},
abstract = {BACKGROUND: Epidemiological evidence linking low vitamin B12 status to dementia risk remains inconsistent, partly reflecting differences in exposure definitions, study designs, and analytical approaches. This study evaluated the association between low vitamin B12 status and long-term risks of incident dementia, related neurocognitive, and cerebrovascular outcomes.

METHODS: This propensity score-matched retrospective cohort study used de-identified electronic health record data from the TriNetX Global Collaborative Network. Adults aged ≥50 years with two vitamin B12 measurements <300 pg./mL within a 2-year window were matched 1:1 with patients who had two vitamin B12 measurements of 300-900 pg./mL using the same framework. A 1-year landmark period was applied, with outcome follow-up beginning on day 366 after the index date. The primary outcome was incident all-cause dementia over 10 years. Secondary outcomes included Alzheimer's disease, vascular dementia, other dementia subtypes, mild cognitive impairment, stroke, and all-cause mortality. An exposure-gradient analysis was performed among patients with vitamin B12 deficiency, defined as two measurements <200 pg./mL.

RESULTS: After matching, 129,159 patients remained in each group. Low vitamin B12 status was associated with a higher risk of all-cause dementia (Hazard ratio [HR] 1.33, 95% confidence interval [CI] 1.27-1.39, p < 0.001). Associations were also observed for Alzheimer's disease, vascular dementia, and other dementia subtypes (HRs 1.31-1.34), mild cognitive impairment (HR 1.33), stroke (HR 1.31), and all-cause mortality (HR 1.23; all p < 0.001). Among patients with vitamin B12 deficiency, the association with all-cause dementia was stronger (HR 1.64, p < 0.001). Results were consistent across six prespecified sensitivity analyses and sex-stratified subgroup analyses.

CONCLUSION: Low vitamin B12 status was associated with an increased long-term risk of incident all-cause dementia, with a numerically stronger association among patients with vitamin B12 deficiency. Given the observational design and potential residual bias, these findings should be interpreted as hypothesis-generating rather than causal. Further prospective studies with serial biomarker monitoring and interventional studies of vitamin B12 correction are needed to clarify this association.},
}

@article {pmid42483706,
year = {2026},
author = {Clavel-Pérez, PI and Phillips-Farfán, BV and Camacho-Castillo, L and Calderón-Garcidueñas, AL and Carvajal, K},
title = {Up regulated hippocampal insulin pathway and oxidative stress are related to opposite changes in olfaction and episodic memory in a compensatory metabolic syndrome model in rats.},
journal = {Frontiers in cellular neuroscience},
volume = {20},
number = {},
pages = {1845387},
pmid = {42483706},
issn = {1662-5102},
abstract = {Insulin resistance, a major component of metabolic syndrome (MetS), is involved in phosphorylated tau and beta amyloid buildup, linking MetS to neurodegenerative processes, e.g., Alzheimer's disease. One of the initial signs of neurodegeneration, in diseases such as Parkinson's and Alzheimer's, is olfactory dysfunction. Accordingly, in previous reports we found that high carbohydrate diet based on 30% sucrose in drinking water, increased visceral fat and insulin resistance, leading to an augment of oxidative stress and reduced brain energy metabolism, upregulating amyloidogenic genes (APP and BACE1) in hypothalamus and hippocampus. Thus, herein we comparatively evaluated the effect of sucrose induced MetS on episodic memory, olfaction, protein expression in amyloidogenic and insulin pathways, lipoperoxidation, antioxidant and BACE1 enzymatic activity between the hippocampus and olfactory bulb in male Wistar rats. Also, cellular structure of the olfactory bulb was analyzed. After 24 weeks of 30% sucrose consumption, we found preserved performance in a memory test; decreased hippocampal expression of APP and hyperactivation of the insulin pathway, low levels of lipoperoxidation, and high activity of antioxidant and BACE1 enzymes. Olfactory dysfunction was present in MetS rats, accompanied by morphological alterations in the olfactory bulb along with BACE1 increased activity. Thus, chronic high-sucrose consumption may prime the brain for neurodegenerative processes by modulating insulin signaling, oxidative stress homeostasis and amyloidogenic pathways in a region-dependent manner, with the olfactory system emerging as an early and sensitive target of metabolic dysfunction.},
}

@article {pmid42483783,
year = {2026},
author = {Wen, Y and Zhan, S and Duan, Y and Pang, M and Yan, J and Deng, M and Fan, H},
title = {Efficacy and Safety of Mesenchymal Stem Cell Therapy for Alzheimer's Disease: A Systematic Review and Meta-Analysis.},
journal = {Stem cells and development},
volume = {},
number = {},
pages = {15473287261468404},
doi = {10.1177/15473287261468404},
pmid = {42483783},
issn = {1557-8534},
abstract = {Alzheimer's disease (AD) is the leading cause of dementia, and effective disease-modifying therapies remain limited. Mesenchymal stem cells (MSCs) have shown therapeutic potential because of their neuroprotective and immunomodulatory properties, but clinical evidence remains inconclusive. We systematically evaluated the efficacy and safety of MSC therapy in AD. Following the PRISMA 2020 guidelines and a PROSPERO-registered protocol (CRD420261329891), we searched PubMed, the Cochrane Library, Embase, Web of Science, CNKI, and Wanfang from inception to March 1, 2026. Clinical studies of patients with primary AD treated with MSCs were included. Outcomes covered cognition, daily function, neuropsychiatric symptoms, biomarkers, imaging findings, and adverse events. Standardized mean differences (SMDs) with 95% confidence intervals (CIs) were pooled using R. Risk of bias was assessed with the RoB 2 tool, and evidence certainty was assessed with GRADE. Six studies involving 196 patients were included. Overall analyses showed no significant improvement in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) or Mini-Mental State Examination (MMSE) at 12-16 weeks or 24-26 weeks after MSC treatment versus placebo, with substantial heterogeneity. Dose-stratified analyses suggested significant benefits of low-dose MSCs on ADAS-Cog (SMD = -1.33, 95% CI: -2.35 to -0.31) and MMSE (SMD = 2.59, 95% CI: 0.52-4.66). MSC therapy significantly improved Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL; SMD = 3.27, 95% CI: 1.79-4.75), but not Neuropsychiatric Inventory (NPI) or Quality of Life in Alzheimer's Disease (QOL-AD) scale. Biomarker analyses showed no significant overall effects on Aβ42 or total tau, although subgroup analyses suggested possible increases in Aβ42 and reductions in total tau at certain doses. Imaging data from two studies indicated potential protective effects on hippocampal atrophy. MSC therapy was generally well-tolerated, although intracerebroventricular administration was associated with more transient adverse events. Evidence certainty was low to very low for most outcomes. MSC therapy for AD appears feasible and relatively safe, with potential cognitive and disease-modifying effects. However, current clinical evidence remains insufficient to confirm its efficacy.},
}

@article {pmid42483877,
year = {2026},
author = {S, V and K, V and Raja, R and A, R},
title = {Mathematical mapping of circadian genes in Alzheimer's disease.},
journal = {Chronobiology international},
volume = {},
number = {},
pages = {1-15},
doi = {10.1080/07420528.2026.2705386},
pmid = {42483877},
issn = {1525-6073},
abstract = {Sleep-wake disturbances commonly occur in Alzheimer's disease (AD). However, the precise mechanisms underlying the breakdown of the circadian gene network remain elusive. This study examined 23 circadian genes in 253 post-mortem samples (80 AD, 173 controls) from the hippocampus, entorhinal cortex, and superior frontal cortex, using three metrics: a Circadian Disruption Index (CDI), a Network Coherence Score (NCS), and a Circadian Entropy Index (CEI). AD brains showed a modest overall shift in circadian gene expression (CDI = 0.101), concentrated mainly in CRY2, PER3, and PER2. The PER3-CRY2 gene pair showed the most significant co-expression alteration of any gene pair examined, a 60.4% reduction in coherence (∆ρ 0.604). Network-wide coherence (NCS) and CEI, averaged across all 23 genes, did not differ significantly between the AD and control groups (NCS: 6.7% reduction, p = 0.356; CEI: -0.4% change, p = 0.923), suggesting the alteration is concentrated in specific gene relationships rather than global network collapse. Regional CDI did not differ significantly across brain areas (p = 0.724). A 10-gene panel classified AD versus control with cross‑validated area under the curve (AUC) = 0.759 ± 0.069 (nested cross-validation AUC = 0.759 ± 0.069, zero optimism bias), though external validation in an independent cohort (GSE5281) did not exceed chance level (AUC = 0.500). These results identify the PER3-CRY2 co-expression change as a specific, reproducible molecular signature of AD and support a validated circadian gene-based classifier, while showing that global circadian network disruption is not a consistent feature of this cohort. The findings identify a localized alteration in circadian gene co-expression in AD brain tissue, with potential implications for future therapeutic targeting of the PER3-CRY2 interaction.},
}

@article {pmid42476327,
year = {2026},
author = {Pattnaik, PP and Prusty, SK and Pati, S and Jew, KA and Bora, AK and Sahoo, J and Sahu, PK},
title = {Exploring shared genetic pathways and gene interplay in major neurodegenerative diseases: a comprehensive review.},
journal = {Gene},
volume = {},
number = {},
pages = {150318},
doi = {10.1016/j.gene.2026.150318},
pmid = {42476327},
issn = {1879-0038},
abstract = {Neurodegenerative diseases are progressive disorders that involve the loss and dysfunction of neurons. Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, Huntington's disease, Frontotemporal dementia are examples of diseases. While different clinically, these disorders have a common genetic, molecular and cellular basis. This review examines the common genetic pathways, along with the interactions between genes of major neurodegenerative diseases, with a focus on the key genes, such as APOE, SNCA, MAPT, TARDBP, LRRK2 and HTT. The common pathogenic mechanisms considered to play a major role in disease progression include protein misfolding and aggregation, mitochondrial dysfunction, oxidative stress, neuroinflammation, diminished autophagy, and impaired lysosomal function, as well as synaptic degeneration. The review also emphasizes the role of systems biology strategies, such as genome-wide association studies, transcriptomics, proteomics, metabolomics, interactome analysis, and multi-omics integration, to unveiling complex molecular networks in neurodegeneration. Furthermore, the emerging biomarker strategies and therapeutic strategies targeting convergence signaling pathways including NF-κB, PI3K-Akt-mTOR, MAPK and Wnt/β-catenin are summarized. The common genetic basis and the cross-connecting molecular mechanisms of the various neurodegenerative diseases could help in the discovery of new biomarkers and pan-therapeutic targets. Further advances in molecular genetics, computational biology and precision medicine are needed to enhance early detection and the creation of effective disease-modifying treatments.},
}

@article {pmid42476460,
year = {2026},
author = {Fowler, CF and Osipyan, E and Devenyi, GA and Madularu, D and Breitner, J and Near, J},
title = {Early treatment with naproxen alters hippocampal metabolites in the TgF344-AD rat model of Alzheimer's disease.},
journal = {Neurochemistry international},
volume = {},
number = {},
pages = {106226},
doi = {10.1016/j.neuint.2026.106226},
pmid = {42476460},
issn = {1872-9754},
abstract = {Alzheimer's disease (AD) is characterized by the appearance of brain pathology decades prior to clinical symptoms. The pre-symptomatic phase of AD provides opportunity for early detection and intervention. One early intervention that has been proposed is the use of non-steroidal anti-inflammatory drugs (NSAIDs), such as naproxen. However, evidence suggests that effects of naproxen intervention differ with stage of the disease, and the optimal intervention time is not clear. Accordingly, in this study, we investigated the impact of the timing of naproxen treatment in a rat model of AD. We used the TgF344-AD rat model of AD which develops characteristic pathological features of human AD, including abundant amyloid plaque pathology, astrogliosis, and microgliosis by 6 months of age, and neurofibrillary tangles and neuronal loss by 16 months of age. We examined the effects of naproxen treatment beginning at 1, 4, and 10 months of age in transgenic (Tg) animals and their wild-type (WT) littermates. We used longitudinal in vivo magnetic resonance spectroscopy (MRS) to study the impact of naproxen treatment on hippocampus neurochemistry. Previous studies have used MRS to non-invasively characterize the trajectory of altered hippocampal neurochemistry across the lifespan in the TgF344-AD rat model. In the current study, we employed MRS at 4, 10, and 16 months, i.e. prior to or after the appearance of amyloidosis and gliosis (6 months) and tau pathology (16 months), respectively, in Tg animals. Naproxen treatment altered neurochemistry in Tg animals only if administered beginning at 1 or 4 months of age, mitigating an otherwise observed increase in total choline and decrease in taurine. A more subtle effect was observed on the otherwise-expected increase in myo-inositol. These results highlight the possibility that earlier naproxen intervention could have distinct neurochemical effects compared to delayed treatment, though mechanistic implications remain to be clarified. Moreover, these findings support the use of MRS as a useful non-invasive method of monitoring treatment-related changes in neurochemistry in transgenic animal models.},
}

@article {pmid42476554,
year = {2026},
author = {Dyer, AH and Dolphin, H and Roitto, HM and O'Connor, A and Welsh, TJ and Kennelly, SP},
title = {Recent breakthroughs in blood-based biomarkers of Alzheimer disease: opportunities and challenges in older adults.},
journal = {Age and ageing},
volume = {55},
number = {7},
pages = {},
doi = {10.1093/ageing/afag213},
pmid = {42476554},
issn = {1468-2834},
mesh = {Humans ; Biomarkers/blood ; *Alzheimer Disease/blood/diagnosis ; Aged ; *tau Proteins/blood ; Predictive Value of Tests ; Age Factors ; *Aging/blood ; },
abstract = {Recent advances in Blood-Based Biomarkers (BBMs) are transforming the diagnostic landscape of Alzheimer Disease (AD), with plasma p-tau217 emerging as a highly accurate and scalable diagnostic marker of AD pathology. Across multiple analytical platforms, plasma p-tau217 has demonstrated consistently strong diagnostic performance for the detection of amyloid pathology. The interpretation of BBMs in older adults presents unique challenges due to the high prevalence of multimorbidity, chronic kidney disease, polypharmacy and frailty. Although these factors may influence absolute biomarker concentrations, current evidence suggests the diagnostic performance of p-tau217 remains largely preserved across diverse older populations when interpreted appropriately. Frailty may modify the relationship between AD pathology and clinical expression of mild cognitive impairment/dementia and may influence the absolute concentration of BBMs underscoring the importance of contextualising test results within a comprehensive assessment. Importantly, these factors should not preclude a clinical-biological diagnosis of AD. The clinical value of BBMs such as p-tau217 in older adults lies not in their use in isolation, but in their integration with a gerontologically attuned diagnostic pathway. Current evidence and international guidelines support the use of BBMs only in symptomatic older adults presenting to specialist services and not in asymptomatic individuals. This commentary reviews recent advances in BBM performance, emerging clinical guidelines, real-world evidence and potential diagnostic pitfalls relevant to older adults. We propose that incorporating BBMs within a Comprehensive Geriatric Assessment framework offers a pragmatic approach to achieving timely, accurate and equitable clinical-biological diagnosis whilst preserving the holistic, person centred principles of geriatric medicine.},
}

Humans
Biomarkers/blood
*Alzheimer Disease/blood/diagnosis
Aged
*tau Proteins/blood
Predictive Value of Tests
Age Factors
*Aging/blood

@article {pmid42476630,
year = {2026},
author = {Hanyu, H and Sano, M and Koyama, Y and Momose, T and Watanabe, S},
title = {Variations in Amyloid PET Positivity Among Patients With Different Alzheimer's Disease Subtypes.},
journal = {Geriatrics & gerontology international},
volume = {26},
number = {7},
pages = {e70646},
doi = {10.1111/ggi.70646},
pmid = {42476630},
issn = {1447-0594},
}

@article {pmid42476773,
year = {2026},
author = {Fujii, S and Takahashi-Iwata, I and Matsushima, M and Yaguchi, H and Takatsuka, A and Hara, N and Ikeuchi, T and Yabe, I},
title = {A Novel p. (Leu173del) Mutation in the Presenilin 1 (PSEN1) Gene in Two Sisters with Dominantly Inherited Alzheimer's Disease.},
journal = {Internal medicine (Tokyo, Japan)},
volume = {},
number = {},
pages = {},
doi = {10.2169/internalmedicine.7327-26},
pmid = {42476773},
issn = {1349-7235},
abstract = {We report two sisters with dominantly inherited Alzheimer's disease carrying a novel presenilin 1 (PSEN1) mutation. Case 1 presented with depression at 39 years of age, gradually developed dementia and involuntary movements, and died at 51 years of age. Case 2 presented with dementia at 46 years of age, which progressed gradually, with no other neurological symptoms. The mother also had early onset dementia. A novel c.517_519del, p. (Leu173del) mutation in exon 6 of PSEN1 (NM_000021.3), confirmed by Sanger sequencing, was identified in both cases. Patients with PSEN1 mutations present with diverse neurological symptoms. Therefore, a careful follow-up is recommended.},
}

@article {pmid42476833,
year = {2026},
author = {Piao, S and Wang, J and He, K and Wang, N and Liu, X and Yang, L and Xie, F and Li, Y and Bao, Y},
title = {Multimodal Imaging of Tau Pathology and Network Connectivity Dynamics Across the Alzheimer's Continuum: A Pilot Study Using Second-Generation Tracer [[18]F]MK6240.},
journal = {Academic radiology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.acra.2026.06.040},
pmid = {42476833},
issn = {1878-4046},
abstract = {RATIONALE AND OBJECTIVES: Alzheimer's disease (AD) progression involves distinct spatiotemporal changes in functional connectivity (FC) within anterior-temporal (AT) and posterior-medial (PM) networks. This study characterizes FC alterations between medial temporal lobe (MTL) subregions and AT/PM networks across the AD continuum and examines their associations with tau/Aβ pathology and atrophy using second-generation tau-PET.

MATERIALS AND METHODS: Eighty-four participants, including 26 cognitively unimpaired Aβ negative(CU Aβ-), 19 cognitively unimpaired Aβ positive (CU Aβ+), 19 mild cognitive impairment Aβ positive(MCI Aβ+), 20 AD Aβ positive(AD Aβ+) underwent 3 T MRI, resting-state fMRI, [¹⁸F]florbetapir (Aβ), and [¹⁸F]MK6240 (tau) PET. MTL subregions were segmented via ASHS-T1, while AT/PM networks were defined using Harvard-Oxford Atlas. Group differences in FC, Aβ/tau standard uptake value ratio(SUVR), and gray matter volume (GMV) were assessed. Network SUVR values, GMV and intra-FC correlation analyses and correlation coefficient matrix plots were calculated.

RESULTS: Compared to CU Aβ-, CU Aβ+ exhibited increased intra-/inter-network FC (peak in anterior MTL: p < 0.001), while MCI/AD groups showed progressive FC declines. Posterior network FC reduction was pronounced in AD (p < 0.01). Left BA35 connectivity increased in CU Aβ+, whereas AD demonstrated FC reductions in bilateral posterior cingulate/hippocampus. Network-level A/T/N-FC correlations were integrated in CU Aβ+ but modular in AD, with strong tau-GMV anticorrelation.

CONCLUSION: Early AD stages feature compensatory AT/anterior MTL hyperconnectivity, transitioning to PM/posterior MTL disintegration as pathology advances. Multimodal biomarker-FC coupling reflects dynamic network reorganization, highlighting MTL-AT/PM connectivity as a biomarker of disease progression.},
}

@article {pmid42476847,
year = {2026},
author = {Li, Z and Bai, X and Li, J and Geng, W and Xing, X and Liang, J and Li, J and Li, J},
title = {Corrigendum to "Network meta-analysis of different traditional Chinese medicine therapies as adjuvant treatments for Alzheimer's disease" [Compl. Ther. Clin. Pract. 64 (2026) 102075].},
journal = {Complementary therapies in clinical practice},
volume = {},
number = {},
pages = {102078},
doi = {10.1016/j.ctcp.2026.102078},
pmid = {42476847},
issn = {1873-6947},
}

@article {pmid42476928,
year = {2026},
author = {Jia, M and Mei, J and Guan, Y and Wang, Z and Ai, H},
title = {Alzheimer's Disease: A Review of Molecular Mechanisms and Interventions Targeting Aβ-Binding Receptors.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.6c00207},
pmid = {42476928},
issn = {1948-7193},
abstract = {In the pathogenesis of Alzheimer's disease (AD), the aggregation of Aβ peptides into Aβ oligomers (AβOs) plays a critical neurotoxic role. By binding to various cell membrane receptors, AβOs can trigger abnormal intracellular signaling transduction, leading to neuronal damage. This article systematically summarizes the interaction mechanisms of nearly ten AβO-binding receptors and focuses on reviewing recent therapeutic strategies aimed at neuroprotection through interventions in AβO-receptor interactions or by blocking/modulating relevant receptor signaling pathways. The discussed content provides a molecular theoretical foundation and research perspectives for the rational design of anti-AD drugs targeting AβO receptors.},
}

@article {pmid42476932,
year = {2026},
author = {Yu, M and Tang, S and Huang, L and Wang, Y and Xu, J and Zhu, H and Yao, H},
title = {From Structure to Selectivity: Integrating CADD and AIDD in Rational Medicinal Chemistry Strategies for DYRK1A Inhibitor Discovery.},
journal = {Journal of medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jmedchem.6c00774},
pmid = {42476932},
issn = {1520-4804},
abstract = {Dual specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A), a member of the CMGC kinase family, regulates diverse cellular processes and is implicated in Alzheimer's disease, Down syndrome, cancer, and diabetes. However, the clinical translation of DYRK1A inhibitors remains challenging due to limited selectivity arising from the high structural conservation of the ATP-binding pocket within the DYRK and CMGC kinase families, which represents the primary binding region for most DYRK1A inhibitors. Recent advances in computer-aided drug design (CADD), artificial intelligence-driven drug design (AIDD), and rational design strategies have enabled the discovery of small-molecule DYRK1A inhibitors with improved potency, selectivity, and drug-like properties. These approaches have expanded the structural diversity of DYRK1A inhibitors and provided new strategies to address selectivity and pharmacokinetic limitations. Particular emphasis is placed on how CADD and AIDD have expanded the accessible chemical space, informed structure-guided optimization, and enabled new paradigms for DYRK1A-focused drug discovery.},
}

@article {pmid42477094,
year = {2026},
author = {Bellomo, G and Vermunt, L and In 't Veld, S and Doecke, JD and Hok-A-Hin, YS and Veverová, K and Houtkamp, IM and Alcolea, D and Halbgebauer, S and Quesada, C and Mattsson, N and Martinez-Castillo, M and López-Martínez, MJ and Rábano, A and Boonkamp, L and Fowler, C and Fortea, J and Gaetani, L and Toja, A and Pijnenburg, Y and Lemstra, A and van der Flier, WM and Sánchez-Juan, P and Hort, J and Otto, M and Anderl-Staub, S and Sieben, A and de Viel, B and Engelborghs, S and Hansson, O and Masters, C and Lleó, A and Parnetti, L and Teunissen, CE and Del Campo, M},
title = {Plasma proteome profiling identified biomarkers for the differential diagnosis and molecular staging of neurodegenerative dementias.},
journal = {Nature aging},
volume = {},
number = {},
pages = {},
pmid = {42477094},
issn = {2662-8465},
support = {J99C18000210005//EU Joint Programme - Neurodegenerative Disease Research (Programi i Përbashkët i BE-së për Kërkimet mbi Sëmundjet Neuro-degjeneruese)/ ; 99C18000210005//EU Joint Programme - Neurodegenerative Disease Research (Programi i Përbashkët i BE-së për Kërkimet mbi Sëmundjet Neuro-degjeneruese)/ ; J99C18000210005//EU Joint Programme - Neurodegenerative Disease Research (Programi i Përbashkët i BE-së për Kërkimet mbi Sëmundjet Neuro-degjeneruese)/ ; J99C18000210005//EU Joint Programme - Neurodegenerative Disease Research (Programi i Përbashkët i BE-së për Kërkimet mbi Sëmundjet Neuro-degjeneruese)/ ; J99C18000210005//EU Joint Programme - Neurodegenerative Disease Research (Programi i Përbashkët i BE-së për Kërkimet mbi Sëmundjet Neuro-degjeneruese)/ ; J99C18000210005//EU Joint Programme - Neurodegenerative Disease Research (Programi i Përbashkët i BE-së për Kërkimet mbi Sëmundjet Neuro-degjeneruese)/ ; J99C18000210005//EU Joint Programme - Neurodegenerative Disease Research (Programi i Përbashkët i BE-së për Kërkimet mbi Sëmundjet Neuro-degjeneruese)/ ; J99C18000210005//EU Joint Programme - Neurodegenerative Disease Research (Programi i Përbashkët i BE-së për Kërkimet mbi Sëmundjet Neuro-degjeneruese)/ ; PF-PRF-934916//Parkinson's Foundation (Parkinson's Foundation, Inc.)/ ; ZEN24-1069572/ALZ/Alzheimer's Association/United States ; SG-23-1061717/ALZ/Alzheimer's Association/United States ; 2022-0231//Knut och Alice Wallenbergs Stiftelse (Knut and Alice Wallenberg Foundation)/ ; },
abstract = {Blood-based biomarkers are emerging as scalable tools for the diagnosis and monitoring of neurodegenerative diseases, but markers enabling differential diagnosis across major dementias remain limited. Here we show that large-scale plasma proteomics identifies disease-associated signatures across Alzheimer's disease, dementia with Lewy bodies and frontotemporal dementia. We analyzed 1,318 plasma samples from well-characterized international cohorts and identified more than 200 dysregulated proteins across disease groups. Glial fibrillary acidic protein showed the strongest increase along the Alzheimer's disease continuum, whereas integrin alpha-V and integrin alpha-M were consistently reduced in Lewy body disorders, including autopsy-confirmed cases. Elevated neurofilament light chain and lower glial fibrillary acidic protein were associated with frontotemporal dementia. We translated these findings into a 21-protein quantitative multiplex panel and validated it in an independent multicenter cohort (n = 805). These findings support plasma proteomics as an approach for biomarker-based differential diagnosis and disease staging across major neurodegenerative dementias.},
}

@article {pmid42477212,
year = {2026},
author = {Angelovski, A and Hribkova, H and Sedmik, J and Liscakova, B and Svecova, O and Cesnarikova, S and Amruz Cerna, K and Pospisilova, V and Kral, M and Kolajova, M and Klimes, P and Bohaciakova, D and Bebarova, M},
title = {Patient-Derived PSEN1 Cerebral Organoids Revealed Parallel Development of Amyloid-β Accumulation and Network Dysfunction.},
journal = {Cellular and molecular neurobiology},
volume = {},
number = {},
pages = {},
doi = {10.1007/s10571-026-01779-7},
pmid = {42477212},
issn = {1573-6830},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterised by progressive dementia, brain atrophy, and ultimately death. Using cerebral organoids derived from human-induced pluripotent stem cells (hiPSCs) carrying the familial PSEN1 A246E variant, we investigated the temporal relationship between amyloid-β (Aβ) dysregulation and spontaneous neuronal activity. Multielectrode array recordings from the differentiation day 60 (DD60) to at least DD130 revealed that AD organoids exhibited transient hyperexcitability and hypersynchrony compared with wild-type (WT) controls, followed by a gradual decline in activity. During the enhanced excitability stage, both elevated Aβ42/40 and Aβ aggregate size showed positive correlations with the percentage of active electrodes and the global synchrony index (GSI) in AD organoids. These findings indicate that Aβ dysregulation might contribute to transient network hyperexcitability in early AD. The results also suggest that patient-derived cerebral organoids may serve as a translational model to examine early network dysfunction and inform future investigations of potential Aβ-induced changes in excitability during the preclinical stages of AD.},
}

@article {pmid42477313,
year = {2026},
author = {Pini, L and Imbimbo, BP and Pomara, N},
title = {Revisiting the cognitive potential of lithium in alzheimer's disease: the role of cholinergic system and brain connectivity.},
journal = {Translational psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41398-026-04307-9},
pmid = {42477313},
issn = {2158-3188},
abstract = {Recent evidence demonstrating a marked reduction in endogenous brain lithium levels in mild cognitive impairment and Alzheimer's disease (AD) has renewed interest in lithium as a physiological modulator of brain aging and neurodegeneration. Experimental data indicate that lithium deficiency accelerates amyloid-β deposition, tau pathology, synaptic and myelin loss, whereas physiological lithium replacement mitigates neuropathology and cognitive decline. Here, we argue that lithium's cognitive potential in AD has been underestimated due to the historical neglect of two interrelated mechanisms: modulation of the cholinergic system and preservation of brain connectivity. Lithium has long been shown to inhibit cholinesterase activity and to increase choline and glycine availability, suggesting a capacity to enhance central cholinergic tone. Given the established role of cholinergic dysfunction in AD, this mechanism may represent an unrecognized contributor to lithium's neurocognitive effects. In parallel, converging human neuroimaging evidence indicates that lithium modulates functional brain networks and is associated with improved white matter integrity, supporting a role in maintaining structural and functional connectivity. We propose brain connectivity as a systems-level integrator of lithium's effects on synaptic plasticity, neuroinflammation, myelination, and cholinergic signaling. Future trials in early AD should incorporate physiological-dose lithium, candidate cholinergic biomarkers, and multimodal connectivity imaging to clarify lithium's translational potential as a network-stabilizing intervention. To bridge prior clinical disappointments and the renewed lithium hypothesis, we further propose a de-risked trial strategy centered on biomarker-confirmed early disease, physiological-dose exposure, structured safety surveillance, and imaging-based target engagement.},
}

@article {pmid42477315,
year = {2026},
author = {Zhang, N and Ye, X and Wang, K and Hu, Y and Wang, Z and Huang, L and Chen, X and Yan, D and Fu, W and Xue, Q and Sun, S and Xu, Y and Tang, D and Chen, X and Zhou, L and Liu, J},
title = {GV-971 remodels the gut microbiota-bile acid-FXR axis to ameliorate obesity and metabolic dysfunction.},
journal = {Cell discovery},
volume = {12},
number = {1},
pages = {},
pmid = {42477315},
issn = {2056-5968},
abstract = {Obesity and its associated metabolic complications represent a global health crisis, yet effective microbiota-targeted pharmacotherapies remain limited. Here, we report that GV-971 (sodium oligomannate), a marine-derived oligosaccharide originally developed for Alzheimer's disease, exerts potent anti-obesity and metabolic benefits by reprogramming gut microbial and host signaling networks. In high-fat diet-induced obese mice, GV-971 reduced adiposity, improved glucose homeostasis, and alleviated hepatic steatosis without affecting food intake. Multi-omics and causal intervention experiments revealed that GV-971 selectively decreased the abundance of Clostridium scindens, a keystone bacterium responsible for secondary bile acid synthesis. This decrease downregulated the expression of the baiF gene encoding 7α-hydroxysteroid dehydrogenase, leading to reduced intestinal deoxycholic acid (DCA) levels and inhibition of intestinal farnesoid X receptor (FXR) signaling. Restoration of C. scindens abundance, baiF expression, or DCA supplementation abrogated the metabolic benefits of GV-971, confirming the causal role of the C. scindens-DCA-FXR axis. Mechanistically, inhibition of intestinal FXR promoted thermogenic gene expression and white adipose tissue browning, thus enhancing systemic energy expenditure. These findings uncover a bacterium-metabolite-host signaling pathway underlying the effects of GV-971 and establish microbiota-directed FXR modulation as a promising therapeutic approach for obesity and metabolic disease.},
}

@article {pmid42477465,
year = {2026},
author = {Wang, Y and Liu, L and Zhang, Y and Luo, P and Xiang, Q and Tang, L},
title = {Integrating transcriptome, metabolome and 16S rRNA sequencing to reveal the effect of celastrol on Alzheimer's disease in rats.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-61602-7},
pmid = {42477465},
issn = {2045-2322},
support = {2026JJ81247//The Natural Science Foundation of Hunan province/ ; LSKJ202465//Project of Regional Collaborative Innovation Special Program of Lhasa/ ; },
abstract = {Celastrol is a promising therapeutic candidate for neurodegenerative diseases. However, the underlying mechanism of celastrol on Alzheimer's disease (AD) remains poorly understood. This study aims to investigate the potential effect of celastrol on treating AD using multi-omics. The AD rat model was established using D-galactose combined with Aβ25-35 and subsequently treated with celastrol at doses of 0.7 mg/kg and 2.8 mg/kg respectively. Cognitive and memory impairments were assessed using the Morris water maze test. Neuronal damage in the hippocampal region was evaluated through Nissl staining. The expression levels of Iba1, Aβ1-42, and p-tau were determined using immunohistochemical staining, ELISA, and western-blotting. Transcriptomic and metabolomic analyses were performed to profile RNA and metabolite expression. The composition and diversity of gut microbiota were analyzed via 16S rRNA gene sequencing. Spearman correlation analysis was employed to integrate transcriptomic-metabolomic and 16S rRNA-metabolomic data. Compared with the AD group, a intervention of 2.8 mg/kg celastrol could significantly reduce the escape latency (p < 0.05), increase the frequency of crossing the target platform and duration in the target quadrant (p < 0.05). In addition, celastrol could significantly inhibited the expression levels of Iba1, TNF-α, and IL-1β (p < 0.05), reduce the number of damaged neurons (p < 0.05), and decrease the expression levels of p-tau and Aβ1-42 (p < 0.05). Furthermore, a total of 309 differentially expressed genes (DEGs) and 96 differentially expressed metabolites (DEMs) were detected between the celastrol and AD groups. Among the DEMs, phospholipids including 16:0-22:6 PE and 18:0-22:6 PC were significantly regulated by celastrol. 16S rRNA analysis indicated that celastrol could increase the Firmicutes/Bacteroidota ratio, as well as enhance the abundances of g_Romboutsia and g_Clostridium_sensu_stricto_1. Combined transcriptomic-metabolomic analysis indicated that the expressions of 16:0-22:6 PE and 18:0-22:6 PC might be regulated by multiple genes including LOC103689940, Impad1, and Sult1c2a. And combined 16S rRNA-metabolomic analysis indicated that 16:0-22:6 PE and 18:0-22:6 PC metabolism might be significantly correlated with g_Romboutsia, g_Clostridium_sensu_stricto_1, and g_Turicibacter. In conclusion, celastrol could improve cognitive and memory dysfunction in AD rats. The regulation of phospholipids or sphingolipid metabolism and gene expression in metabolic pathway might be linked with alteration in intestinal microbiota.},
}

@article {pmid42477561,
year = {2026},
author = {Farrokhi, MR and Askari, A and SoukhakLari, R and Moosavi, M},
title = {Cholinergic inhibition disrupts retrieval-specific phosphorylation of CaMKII-α and CaMKII-β alongside ERK hyperactivation in the hippocampus during novel object recognition memory.},
journal = {BMC neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12868-026-01027-0},
pmid = {42477561},
issn = {1471-2202},
support = {26573//Shiraz University of Medical Sciences/ ; 24393//Vice-Chancellor for Research, Shiraz University of Medical Sciences/ ; },
abstract = {BACKGROUND: Alzheimer's disease (AD), the most common form of dementia, is characterized by cholinergic dysfunction and early impairments in episodic and recognition memory. Although retrieval failure represents a hallmark of cognitive decline in AD, the task- and phase-specific molecular mechanisms underlying cholinergic-dependent memory retrieval remain poorly defined.

OBJECTIVE: This study investigated whether acute muscarinic cholinergic blockade disrupts the retrieval phase of recognition memory. We also examined the associated regulation of hippocampal calcium/calmodulin-dependent protein kinase II (CaMKII) isoforms α and β, together with extracellular signal-regulated kinase (ERK) signaling.

METHODS: Adult male SWR/J mice were trained in the NOR paradigm and administered scopolamine (1 mg/kg, i.p.) or saline 30 min prior to the retrieval phase. Recognition memory performance was assessed using the discrimination index and exploratory preference. Immediately following behavioral testing, hippocampal tissue was collected for Western blot analysis of phosphorylated and total CaMKII-α, CaMKII-β, and ERK.

RESULTS: Scopolamine significantly impaired recognition memory retrieval, as evidenced by a reduced discrimination index and decreased preference for the novel object, without diminishing overall exploratory activity. At the molecular level, scopolamine-induced cholinergic inhibition selectively decreased hippocampal phosphorylation of both CaMKII-α and CaMKII-β while increasing ERK phosphorylation, with no significant changes in total protein expression of any kinase.

CONCLUSIONS: These findings identify a retrieval-specific, scopolamine-induced molecular signature of cholinergic inhibition in the hippocampus, characterized by concurrent suppression of both CaMKII isoform activities (α and β) alongside dissociable ERK hyperactivation. By extending prior molecular observations from aversively motivated paradigms to an ethologically relevant model of recognition memory, this study provides mechanistic insight into how cholinergic dysfunction contributes to memory retrieval deficits and suggests that cholinergic signaling maintains the functional (CaMKII-α) and structural (CaMKII-β) dimensions of hippocampal memory retrieval machinery through coordinated kinase activation.},
}

@article {pmid42477703,
year = {2026},
author = {Yang, Y and Kwak, YT},
title = {Associations of Ginkgo biloba extract exposure with 12-month cognitive trajectories in amyloid PET-positive mild cognitive impairment and Alzheimer's disease: a pooled retrospective cohort study.},
journal = {BMC complementary medicine and therapies},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12906-026-05469-1},
pmid = {42477703},
issn = {2662-7671},
support = {HI22C0667//Korea Health Industry Development Institute/Republic of Korea ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) and mild cognitive impairment (MCI) show considerable heterogeneity in treatment response, underscoring the need for individualized therapeutic approaches. Ginkgo biloba extract is commonly used in cognitive disorders, but its efficacy in amyloid biomarker-confirmed populations remains unclear. To evaluate the association between Ginkgo biloba extract exposure and 12-month cognitive and functional change patterns in amyloid PET-positive MCI/AD, and to assess whether baseline plasma MDS-OAβ (amyloid oligomerization tendency) is associated with cognitive trajectory subgroup membership.

METHODS: In this 12-month retrospective study, 165 drug-naïve amyloid PET-positive patients (83 with documented Ginkgo biloba extract use in routine care and 82 without documented Ginkgo use) were assessed for changes in Korean Mini-Mental State Examination (K-MMSE-2), Clinical Dementia Rating-Sum of Boxes (CDR-SB), Korean Instrumental Activities of Daily Living (K-IADL), and plasma MDS-OAβ levels. K-means clustering was used to define three cognitive trajectory subgroups, and exploratory one-vs-rest adjusted logistic regression analyses were performed to examine baseline variables associated with trajectory group membership.

RESULTS: Three cognitive trajectories were identified: Improver (n = 36), Stabler (n = 113), and Decliner (n = 16). Compared with patients without documented Ginkgo use, patients with documented Ginkgo exposure showed significantly greater cognitive gains (ΔK-MMSE-2 + 1.42 vs. - 0.30, p = 0.012), less IADL decline (p < 0.001), and greater reductions in MDS-OAβ levels (p < 0.001). Baseline plasma MDS-OAβ did not significantly differ among the trajectory groups and was not interpreted as a robust independent predictor of trajectory membership. Ginkgo use differed significantly across trajectory groups and was least frequent in the Decliner group.

CONCLUSIONS: In this amyloid PET-positive MCI/AD cohort, Ginkgo biloba extract exposure was associated with more favorable 12-month cognitive, functional, and plasma MDS-OAβ changes. However, baseline MDS-OAβ should be regarded as an exploratory biomarker rather than a validated predictor of improvement or Ginkgo-related benefit.},
}

@article {pmid42477717,
year = {2026},
author = {Deshayes, NAC and van Wetering, J and Wesseling, A and Vos, F and Ingrassia, A and Galis, Y and Jonkman, LE and Rozemuller, AJM and van de Berg, WDJ},
title = {Amygdalar nuclei vulnerability to protein aggregates in Lewy body diseases.},
journal = {Acta neuropathologica communications},
volume = {},
number = {},
pages = {},
doi = {10.1186/s40478-026-02381-0},
pmid = {42477717},
issn = {2051-5960},
abstract = {The amygdala is highly vulnerable to protein aggregation and heavily affected in Lewy body diseases (LBDs). However, vulnerability might vary per amygdalar nucleus and it is unclear if the pattern of vulnerability across the nuclei differs between types of protein aggregation and between LBDs. In this study, we aimed to assess the vulnerability of amygdalar nuclei to multiple types of protein aggregation across LBDs. Post-mortem amygdala tissue of donors with incidental LBD (iLBD, n = 6), Parkinson's disease (PD; n = 18), dementia with Lewy bodies (DLB; n = 9) and Alzheimer's disease with Lewy bodies (AD + LB; n = 15) was immunostained with antibodies against alpha-synuclein (aSyn; EP1536Y and 5G4), amyloid beta (Aβ; 4G8), phosphorylated tau (p-tau; AT8) and phosphorylated TDP-43 (p-TDP-43; 11-9), and quantitatively analyzed using QuPath. Neuronal and astrocytic aSyn pathology were most pronounced in the parahippocampal-amygdaloid transition area (PHA) and the basal nucleus, a pattern shared by all disease groups. Vulnerability to Aβ pathology varied per group but was highest in the PHA in AD + LB, whereas diffuse plaques were most common in the accessory basal nucleus. The PHA of DLB and both the basal and accessory basal nucleus of AD + LB cases were most susceptible to p-tau pathology, with fine granular cytoplasmic neuronal tau inclusions being mostly observed in the basal nucleus and neurofibrillary tangles in the accessory basal nucleus. The nuclei in the ventromedial part of the amygdala (PHA, ventral part of the basal nucleus, and cortical nucleus) were found to be hotspots for protein aggregation across LBDs. aSyn pathology in these nuclei predominantly correlated with dementia, hallucinations and anxiety. Our results show that amygdalar nuclei vulnerability differs per protein aggregate and disease entity, although the PHA, basal nucleus and cortical nucleus are generally more vulnerable. Together, our study provides a deeper insight into the selective vulnerability of amygdalar nuclei to protein aggregates and their relation to clinical characteristics in LBDs.},
}

@article {pmid42477755,
year = {2026},
author = {Bayly, H and Tripodis, Y and Lenio, S and Patil, P and , },
title = {Reducing overconfident errors in clinical prediction models.},
journal = {BMC medical informatics and decision making},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12911-026-03681-0},
pmid = {42477755},
issn = {1472-6947},
abstract = {Machine Learning (ML) models are increasingly being used in clinical workflows. Evaluation of these models tends to focus on global performance metrics, which can obscure error patterns and lead to bias in clinical decision making. Here, we propose Proximal Error-Based Confidence Adjustment (PECA), a framework designed explicitly to improve the safety of ML predictions by reducing a model's confidence in regions of the feature space associated with historical prediction errors. Rather than optimizing global metrics alone, PECA targets confident misclassifications by attenuating prediction confidence proportional to similarity with previously observed errors. Across extensive simulations, PECA reduced the rate at which a model made confident misclassifications while preserving the overall predictive ability of the model. We applied this framework to a clinical trial enrollment workflow for Alzheimer's disease and demonstrated consistent results with the simulations while also demonstrating superior statistical power compared to baseline models. The results of this paper suggest that taming a model's tendency to predict overconfidently using historical error patterns may be a critical step towards safer and more reliable ML systems for digital public health.},
}

@article {pmid42477860,
year = {2026},
author = {Touroutoglou, A and Katsumi, Y and Hensel, J and Schindler, SE and Ibanez, L and Brickhouse, M and Eloyan, A and Eckbo, R and Zaitsev, A and La Joie, R and Thangarajah, M and Taurone, A and Vemuri, P and Jack, CR and Hammers, DB and Foroud, T and Aisen, P and Beckett, L and Koeppe, R and Kukull, WA and Toga, A and Atri, A and Clark, D and Day, GS and Duara, R and Graff-Radford, NR and Grant, IM and Honig, LS and Johnson, ECB and Jones, DT and Masdeu, JC and Mendez, MF and Musiek, E and Onyike, CU and Riddle, M and Rogalski, E and Salloway, S and Sha, S and Turner, RS and Wingo, TS and Wolk, DA and Womack, K and Carrillo, MC and Rabinovici, GD and Apostolova, LG and Dage, JL and Dickerson, BC and Eldaief, MC and , },
title = {Relationships of CSF biomarkers to cortical atrophy in early-onset Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71479},
doi = {10.1002/alz.71479},
pmid = {42477860},
issn = {1552-5279},
support = {U24 AG072122/NH/NIH HHS/United States ; P30 AG010133/NH/NIH HHS/United States ; P30 AG062422/NH/NIH HHS/United States ; P30 AG066462/NH/NIH HHS/United States ; P30 AG066507/NH/NIH HHS/United States ; P30 AG062421/NH/NIH HHS/United States ; P30 AG066506/NH/NIH HHS/United States ; P30 AG072977/NH/NIH HHS/United States ; P30 AG066444/NH/NIH HHS/United States ; P30 AG066515/NH/NIH HHS/United States ; P30 AG062677/NH/NIH HHS/United States ; P30 AG072980/NH/NIH HHS/United States ; P30 AG072979/NH/NIH HHS/United States ; P30 AG066511/NH/NIH HHS/United States ; R01 DC014296/NH/NIH HHS/United States ; R21 DC019567/NH/NIH HHS/United States ; R21 AG073744/NH/NIH HHS/United States ; K01 AG084820/NH/NIH HHS/United States ; K23 DC016912/NH/NIH HHS/United States ; R01 AG085377/NH/NIH HHS/United States ; P50 AG005134/NH/NIH HHS/United States ; P30 AG062421/NH/NIH HHS/United States ; P41EB015896/NH/NIH HHS/United States ; S10RR021110/NH/NIH HHS/United States ; S10RR023043/NH/NIH HHS/United States ; S10RR023401/NH/NIH HHS/United States ; LEADS GENETICS-19-639372/ALZ/Alzheimer's Association/United States ; LDRFP-21-824473/ALZ/Alzheimer's Association/United States ; LDRFP-21-828356/ALZ/Alzheimer's Association/United States ; },
mesh = {Humans ; *Alzheimer Disease/cerebrospinal fluid/pathology ; Atrophy/pathology ; Biomarkers/cerebrospinal fluid ; Female ; Male ; Neurofilament Proteins/cerebrospinal fluid ; *Cerebral Cortex/pathology ; tau Proteins/cerebrospinal fluid ; Amyloid beta-Peptides/cerebrospinal fluid ; Middle Aged ; Peptide Fragments/cerebrospinal fluid ; Magnetic Resonance Imaging ; Aged ; },
abstract = {INTRODUCTION: Although cerebrospinal fluid (CSF) biomarkers reflect neurodegeneration in Alzheimer's disease (AD), it remains unclear whether these biomarkers track neurodegeneration in early-onset Alzheimer's disease (EOAD).

METHODS: In 80 EOAD patients, we examined correlations between eight CSF biomarker levels and cortical thickness decreases within the EOAD cortical atrophy signature. Significant correlations were then entered into a multiple regression analysis. We also examined contributions of EOAD atrophy and CSF biomarkers to cognitive impairment.

RESULTS: The levels of four CSF biomarkers correlated to EOAD signature atrophy. Stepwise regression analyses revealed that CSF neurofilament light chain (NfL) levels best predicted EOAD signature atrophy. Multiple regression showed EOAD signature atrophy combined with CSF NfL levels explained more variance in cognitive impairment than either factor alone.

DISCUSSION: Within EOAD patients, CSF NfL levels relate to the magnitude of cortical atrophy, and a combination of EOAD signature atrophy and CSF NfL levels most robustly predict cognitive impairment.},
}

Humans
*Alzheimer Disease/cerebrospinal fluid/pathology
Atrophy/pathology
Biomarkers/cerebrospinal fluid
Female
Male
Neurofilament Proteins/cerebrospinal fluid
*Cerebral Cortex/pathology
tau Proteins/cerebrospinal fluid
Amyloid beta-Peptides/cerebrospinal fluid
Middle Aged
Peptide Fragments/cerebrospinal fluid
Magnetic Resonance Imaging
Aged

@article {pmid42478074,
year = {2026},
author = {Kumar, N and Yarlagadda, V},
title = {Microbes and Microbial Chemical Matter in the Seeding of Alzheimer's Disease: Prospects for Orthogonal Therapies.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.6c00255},
pmid = {42478074},
issn = {1948-7193},
abstract = {Alzheimer's disease (AD) remains the leading cause of dementia, with mortality rates having doubled over the past two to three decades and projected to rise with continued population aging. Despite its profound health and economic impact, effective therapeutic and preventive interventions remain limited, largely owing to an incomplete understanding of its etiopathogenesis. Emerging evidence indicates that microbes, including viruses, bacteria, and fungi, as well as their associated metabolites, toxins, and structural components, are involved in the development of AD. Microbial invasion, through dysbiosis or infection, can trigger neuroinflammation that drives overproduction of amyloid β peptide (AβP). AβP functions as a broad-spectrum antimicrobial agent, and its accumulation, a key pathological hallmark of AD, is promoted by microbial presence as part of the immune response. Maintaining microbial eubiosis, preventing infections that impact the nervous system (e.g., herpes zoster), supporting gut microbiome homeostasis through prebiotics, and the judicious use of antimicrobial interventions may mitigate AD onset and progression. This Review delineates the involvement of microbes and their components in the initiation of AD and presents the prospects of orthogonal therapies to control AD.},
}

@article {pmid42478598,
year = {2026},
author = {Martens, CR and Decker, KP and DeConne, TM and Sanjana, F and Horvat, F and Rizzi, NA and Awad, C and Habash, E and Hobson, JC and Kramer, MK and Armstrong, ML and Reisdorph, N and Pohlig, RT and Lanzi, AM and Johnson, CL and Cohen, ML and Ellison, JM},
title = {A phase-II randomized controlled pilot study of nicotinamide riboside supplementation in older adults with amnestic mild cognitive impairment.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71605},
doi = {10.1002/alz.71605},
pmid = {42478598},
issn = {1552-5279},
support = {K01AG054731/AG/NIA NIH HHS/United States ; P20GM113125/GM/NIGMS NIH HHS/United States ; },
mesh = {Humans ; Pilot Projects ; *Cognitive Dysfunction/drug therapy/diagnostic imaging ; Aged ; Double-Blind Method ; Female ; *Niacinamide/analogs & derivatives/therapeutic use/administration & dosage ; Male ; *Dietary Supplements ; Cerebrovascular Circulation/drug effects ; Pyridinium Compounds ; Neuropsychological Tests ; Cognitive Enhancement ; NAD/blood ; *Amnesia/drug therapy ; Blood Pressure/drug effects ; Treatment Outcome ; Aged, 80 and over ; },
abstract = {INTRODUCTION: Declining nicotinamide adenine dinucleotide (NAD[+]) may elevate risk of Alzheimer's disease.

METHODS: We conducted a 12-week double-blind, randomized, placebo-controlled pilot study to evaluate the safety, tolerability, and preliminary efficacy of the NAD[+] precursor, nicotinamide riboside (NR), for enhancing cognitive function and cerebral blood flow (CBF) in adults with amnestic mild cognitive impairment (aMCI).

RESULTS: 42 participants completed the study (NR = 22, placebo = 20). Adherence was similar between groups with no serious adverse effects. Blood NAD[+] increased twofold in the NR group. There were no improvements in cognitive function (primary outcome), total CBF, or blood pressure (secondary outcomes). Exploratory analyses revealed potential increases in regional CBF, particularly in the hippocampus.

DISCUSSION: NR effectively raises NAD[+] in people with MCI but does not improve cognitive function, total CBF, or blood pressure over 12 weeks. Future studies should investigate regional effects on CBF over longer treatment durations.},
}

Humans
Pilot Projects
*Cognitive Dysfunction/drug therapy/diagnostic imaging
Aged
Double-Blind Method
Female
*Niacinamide/analogs & derivatives/therapeutic use/administration & dosage
Male
*Dietary Supplements
Cerebrovascular Circulation/drug effects
Pyridinium Compounds
Neuropsychological Tests
Cognitive Enhancement
NAD/blood
*Amnesia/drug therapy
Blood Pressure/drug effects
Treatment Outcome
Aged, 80 and over

@article {pmid42471199,
year = {2026},
author = {Yang, S and Astill-Vaccaro, J},
title = {Transdermal Methylphenidate for Apathy in Alzheimer's Dementia.},
journal = {Journal of the Academy of Consultation-Liaison Psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jaclp.2026.07.005},
pmid = {42471199},
issn = {2667-2960},
}

@article {pmid42471426,
year = {2026},
author = {Ahmad, A and Khan, MM},
title = {DNA Sensing and Neuroinflammation: Mechanistic Insights into cGAS-STING Biology and Therapeutic Translation in Age-Related Neurodegenerative Diseases.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42471426},
issn = {1559-1182},
mesh = {Humans ; Animals ; *Neurodegenerative Diseases/metabolism/therapy/genetics/pathology ; cGAS-STING Signaling Pathway ; *Nucleotidyltransferases/metabolism ; STING Protein ; *Membrane Proteins/metabolism ; *Aging/pathology/metabolism/genetics ; Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase ; *Neuroinflammatory Diseases/metabolism/genetics/therapy ; *DNA/metabolism ; Inflammation ; },
abstract = {Emerging evidence suggests that some of the earliest events contributing to neurodegeneration may occur upstream of classical proteinopathies, underscoring the urgency of identifying molecular pathways that link age-associated genomic instability to chronic neuroinflammation. Among these, DNA sensing through the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) axis has emerged as an important mechanism by which nuclear and mitochondrial stress may promote innate immune activation. In aging and Alzheimer's disease (AD), oxidative stress, impaired DNA repair, and mitochondrial dysfunction can lead to the accumulation of cytosolic DNA and activation of cGAS-STING, contributing to sustained inflammatory signaling, cellular senescence, and synaptic dysfunction. In this review, we synthesize emerging mechanistic and translational insights linking cGAS-STING to genomic instability and neuroinflammation. We highlight the expanding roles of this pathway beyond classical immunity, including its influence on autophagy, cellular senescence, microglial activation, and neurovascular integrity as well as its interactions with key pathological features of age-related neurodegenerative disorders, particularly AD. Finally, we highlight recent advances in pharmacological and genetic modulation of cGAS-STING that support its potential as a therapeutic target for age-related neurodegenerative diseases. By reframing neurodegeneration through the lens of DNA sensing, this review provides an updated perspective on the potential role of cGAS-STING in age-related neurodegenerative diseases.},
}

Humans
Animals
*Neurodegenerative Diseases/metabolism/therapy/genetics/pathology
cGAS-STING Signaling Pathway
*Nucleotidyltransferases/metabolism
STING Protein
*Membrane Proteins/metabolism
*Aging/pathology/metabolism/genetics
Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
*Neuroinflammatory Diseases/metabolism/genetics/therapy
*DNA/metabolism
Inflammation

@article {pmid42471447,
year = {2026},
author = {Zhu, Y and Brown, DC and Chen, C and Singh, RK and Bekena, S and Ances, BM and Lenze, EJ and Carr, DB and Trani, JF and Babulal, GM},
title = {Tau pathology and depression interact to accelerate driving decline in cognitively normal older adults.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {42471447},
issn = {1476-5578},
support = {R01AG056466//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG067428//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; },
abstract = {Driving is a complex task that can be compromised by mood disorders and neurodegenerative conditions. Major depressive disorder (MDD) and Alzheimer's disease (AD) increase in prevalence with older age. Preclinical AD, identified through protein biomarkers, is strongly associated with an increased risk of developing AD. This study tracked the daily driving behaviors of older adults over an average period of 54 months and found participants with MDD and Positron Emission Tomography (PET) biomarker tau had a faster increase in risky driving behaviors, such as hard braking, and a slower decline in randomness of driving patterns, compared to healthy controls. Notably, participants with MDD were more likely to exhibit PET tau positivity than PET amyloid positivity, suggesting a potential interaction between MDD and tau pathology. These findings highlight the importance of monitoring older drivers for emerging functional vulnerability associated with mood disorders and neurodegeneration at an early stage.},
}

@article {pmid42471578,
year = {2026},
author = {Li, Z and Zeng, C and Ge, S},
title = {Bayesian brain edge-based connectivity (BBeC): a Bayesian model for brain edge-based connectivity inference.},
journal = {BMC bioinformatics},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12859-026-06549-2},
pmid = {42471578},
issn = {1471-2105},
abstract = {BACKGROUND: Brain connectivity analysis based on magnetic resonance imaging is crucial for understanding neurological mechanisms. However, edge-based connectivity inference faces significant challenges, particularly the curse of dimensionality when estimating high-dimensional covariance matrices. Existing methods often struggle to account for the unknown latent topological structure among brain edges, leading to inaccurate parameter estimation and unstable inference.

METHODS: To address these issues, this study proposes a Bayesian hierarchical model based on a finite-dimensional Dirichlet distribution. Unlike non-parametric approaches, our method utilizes a finite-dimensional Dirichlet distribution to model the latent topological structure of brain networks, ensuring constant parameter dimensionality and improving algorithmic stability. We reformulate the covariance matrix structure to guarantee positive definiteness and employ a Metropolis-Hastings algorithm to simultaneously infer network topology and correlation parameters. Furthermore, to alleviate the computational burden of parameter inference in large-scale networks, we optimized the calculation process of the likelihood function to reduce the algorithm's time complexity. Our implementation is available at https://github.com/mimi6501/BBeC.

RESULTS: Simulations validated the recovery of both network topology and correlation parameters across various settings. Furthermore, we quantitatively compared the proposed framework with the Graphical Lasso and a Dirichlet process-based non-parametric Bayesian model. Experimental results show our model offers flexible parameter tuning while outperforming baselines in estimation accuracy and convergence stability. Sensitivity analysis reveals the diagonal adjustment parameter λ has minimal impact on model accuracy, and parameter sampling order has negligible impact on final inference. When applied to the Alzheimer's Disease Neuroimaging Initiative dataset, the model successfully identified structural subnetworks. The identified clusters were not only validated by composite anatomical metrics but also consistent with established findings in the literature, collectively demonstrating the model's reliability. The estimated covariance matrix also revealed that intragroup connection strength is stronger than intergroup connection strength.

CONCLUSIONS: This study introduces a Bayesian framework for inferring brain network topology and high-dimensional covariance structures. The model configuration effectively reduces parameter dimensionality while ensuring the positive definiteness of covariance matrices. As a result, it offers an efficient and reliable tool for investigating intrinsic brain connectivity in large-scale neuroimaging studies.},
}

@article {pmid42471701,
year = {2026},
author = {Marshall, CR and Moser, FA and Scott, CF and Ventura-Antunes, L and Romero-Fernandez, W and Migas, ŁG and Tideman, LEM and Colley, ME and Dufresne, M and Schrag, MS and Van de Plas, R and Spraggins, JM},
title = {Multimodal molecular mapping of the vasculature in human cortex reveals lipid markers of cerebral amyloid angiopathy.},
journal = {Acta neuropathologica communications},
volume = {},
number = {},
pages = {},
doi = {10.1186/s40478-026-02361-4},
pmid = {42471701},
issn = {2051-5960},
abstract = {Cerebral amyloid angiopathy (CAA) commonly co-occurs with Alzheimer's disease (AD), yet the molecular changes that accompany vascular [Formula: see text]-amyloid deposition in human tissue remain incompletely defined. Herein, we use a novel imaging approach that combines matrix-assisted laser desorption/ionization imaging mass spectrometry (IMS) with immunofluorescence microscopy on the same sections of postmortem human frontal cortex to map the lipid microenvironment of leptomeningeal vasculature in cases with and without CAA. Autofluorescence-guided regions-of-interest were imaged by IMS in both negative and positive ion modes and registered to post-IMS-acquired microscopy images. Immunofluorescence microscopy using markers for collagen IV, [Formula: see text]-smooth muscle actin ([Formula: see text]SMA), and thiazine red enabled automated segmentation of total, amyloid-positive, and amyloid-negative vasculature regions. A CAA index, the ratio of amyloid-positive area to total vasculature area in a region imaged by IMS, was used to define vasculature and classify each case into having CAA, or CAA-present, and not having CAA, or CAA-absent. An interpretable machine learning approach (XGBoost models with Shapley additive explanations for interpretation) was trained on pixel-level spectra and identified lipid signatures of vascular identity shared across groups as well as class-specific marker candidates that distinguished CAA-present from CAA-absent vasculature. CAA-absent vessels were characterized by higher contributions from phosphatidylserines (e.g., long-chain polyunsaturated PS species). Univariate differences were inconsistent between the two groups, but multivariate models in negative mode yielded stable discriminatory features. These results define spatial lipid correlates of vascular amyloid pathology in the human brain and establish a multimodal framework for mechanistically linking lipid metabolism, vascular integrity, and CAA in AD.},
}

@article {pmid42471719,
year = {2026},
author = {Yamada, K and Ishida, K and Sakamoto, A and Shimada, H and Watanabe, M and Shimojo, M and Igarashi, H and Iwatsubo, T},
title = {AQP4-dependent enhancement of glymphatic function attenuates tau pathology and neurodegeneration in PS19 mice.},
journal = {Molecular neurodegeneration},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13024-026-00977-7},
pmid = {42471719},
issn = {1750-1326},
support = {JP23wm0625001//AMED/ ; 23H0279//Japan Society for the Promotion of Science/ ; 25K10766, 20K21568, 18H02762//Japan Society for the Promotion of Science/ ; 2023-23012//Niigata University/ ; },
abstract = {BACKGROUND: The glymphatic system facilitates cerebrospinal fluid-interstitial fluid exchange and contributes to the clearance of pathogenic proteins from the brain. Glymphatic dysfunction has been associated with Alzheimer's disease and related tauopathies; however, whether impaired glymphatic transport causally drives tau accumulation and neurodegeneration, and whether its enhancement confers therapeutic benefit, remains unclear.

METHODS: Glymphatic water dynamics in PS19 tau transgenic mice were assessed using JJVCPE, a novel MRI-based approach for evaluating brain water exchange. The effect of pharmacological activation of aquaporin-4 (AQP4) with TGN-073 on glymphatic cerebrospinal fluid influx was examined in wild-type mice using dynamic contrast-enhanced MRI. Tau pathology, neurodegeneration, and cerebrospinal fluid tau levels were analyzed in PS19 mice following chronic TGN-073 treatment. AQP4-deficient PS19 mice were examined to determine target specificity.

RESULTS: PS19 mice exhibited significant impairment of glymphatic water exchange at early disease stages, which progressively worsened with ageing. Pharmacological activation of AQP4 with TGN-073 robustly enhanced glymphatic-related tracer influx, reduced tau accumulation, neuronal loss, and gliosis, and was accompanied by increased cerebrospinal fluid tau levels. TGN-073 also restored perivascular AQP4 enrichment without significantly altering overall AQP4 abundance. Importantly, these beneficial effects were abolished in AQP4-deficient PS19 mice, demonstrating that both glymphatic enhancement and suppression of tau pathology and neurodegeneration are AQP4-dependent.

CONCLUSIONS: Our findings support a mechanistic contribution of impaired glymphatic function to tau accumulation and neuronal vulnerability in tauopathy. Pharmacological activation of AQP4 enhances glymphatic function, restores perivascular AQP4 organization, and ameliorates tau pathology, neurodegeneration, and gliosis. These findings identify AQP4-mediated glymphatic modulation as a disease-relevant and therapeutically tractable pathway for tau-related neurodegenerative disorders.},
}

@article {pmid42471753,
year = {2026},
author = {Travison, TG and Davis-Plourde, K and Goldfeld, KS and Li, F and Lou, Y and Monin, JK and Taljaard, M and Turner, J and Vranceanu, AM and Allore, HG},
title = {The design of embedded pragmatic clinical trials: methodological developments and statistical lessons learned from the first cycle of the NIA IMPACT collaboratory.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71660},
pmid = {42471753},
issn = {1552-5279},
support = {U54AG063546/NH/NIH HHS/United States ; },
mesh = {Humans ; *Pragmatic Clinical Trials as Topic/methods ; *Research Design ; United States ; National Institute on Aging (U.S.) ; *Alzheimer Disease/therapy ; },
abstract = {INTRODUCTION: The National Institute on Aging-funded IMbedded Pragmatic Alzheimer's disease and AD-Related Dementias Clinical Trials (IMPACT) Collaboratory was established to build capacity for conducting embedded pragmatic clinical trials (ePCTs) within healthcare systems for people living with dementia and their care partners. Here we present methodology and describe lessons learned from the first five years of IMPACT's Design and Statistics Core (DSC).

METHODS: The DSC assembled a multidisciplinary team focused on advancing the design, analysis, and implementation of ePCTs.

RESULTS: The DSC developed and disseminated methods for design and sample size of cluster randomized designs with complex correlation structures; guidance for pilot ePCTs; approaches to patient-care partner ePCTs; approaches to testing health-equity-relevant hypotheses; and guidance for training quantitative and clinical scientists developing ePCTs.

DISCUSSION: Key gaps remain in applying dyadic designs and when studying heterogeneity of treatment effects, which will be major priorities for the next funding cycle.},
}

Humans
*Pragmatic Clinical Trials as Topic/methods
*Research Design
United States
National Institute on Aging (U.S.)
*Alzheimer Disease/therapy

@article {pmid42471754,
year = {2026},
author = {Xia, CA and Salarian, M and Gartshore, CJ and Scaglione, A and Hayes, T and Liu, S and Tsai, HM and Echavarren, J and Cid, JM and Matzeu, A and Szardenings, AK},
title = {Development and characterization of a novel TDP-43 positron emission tomography tracer: [[18]F]JNJ-TDP43-1.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71675},
pmid = {42471754},
issn = {1552-5279},
support = {//Johnson & Johnson/ ; },
mesh = {Animals ; *Positron-Emission Tomography/methods ; *DNA-Binding Proteins/metabolism ; *Brain/diagnostic imaging/metabolism ; Rats ; Mice ; Humans ; Male ; Disease Models, Animal ; TDP-43 Proteinopathies/diagnostic imaging ; *Radiopharmaceuticals/pharmacokinetics ; Fluorine Radioisotopes ; },
abstract = {INTRODUCTION: Neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), limbic-predominant age-related TDP-43 encephalopathy (LATE), and Alzheimer's disease (AD) are associated with TAR DNA-binding protein 43 (TDP-43) pathology. A positron emission tomography (PET) tracer targeting TDP-43 aggregates could improve early diagnosis and guide treatment development for TDP-43-related conditions.

METHODS: Specific binding was evaluated using fluorescent labeling of compound, surface plasmon resonance (SPR), and autoradiography (ARG). Brain PET imaging in rats, nonhuman primate (NHP), and a disease mouse model was performed to characterize tracer pharmacokinetics and in vivo target binding.

RESULTS: JNJ-TDP43-1 exhibited high binding affinity for pathological TDP-43 (Kd = 7.1 nM) and remarkable selectivity over other proteinopathies. PET imaging demonstrated robust brain uptake and rapid washout in rodents and NHP. In vivo target engagement was confirmed in an AAV-hTDP43 disease model.

DISCUSSION: [[18]F]JNJ-TDP43-1 is a promising PET ligand for early diagnosis and evaluating therapies in TDP-43-related diseases.},
}

Animals
*Positron-Emission Tomography/methods
*DNA-Binding Proteins/metabolism
*Brain/diagnostic imaging/metabolism
Rats
Mice
Humans
Male
Disease Models, Animal
TDP-43 Proteinopathies/diagnostic imaging
*Radiopharmaceuticals/pharmacokinetics
Fluorine Radioisotopes

@article {pmid42472451,
year = {2026},
author = {Docteur, NG and Huston, HGP and Krupa, AA and Callahan, BL},
title = {A systematic review of neuroimaging studies of adults aged 35 and older with clinical, symptomatic and genetic risk for attention-deficit/hyperactivity disorder.},
journal = {Dialogues in clinical neuroscience},
volume = {28},
number = {1},
pages = {259-276},
doi = {10.1080/19585969.2026.2700984},
pmid = {42472451},
issn = {1958-5969},
mesh = {Humans ; *Attention Deficit Disorder with Hyperactivity/genetics/diagnostic imaging ; *Neuroimaging/methods ; Adult ; *Brain/diagnostic imaging/pathology ; Middle Aged ; Aged ; *Genetic Predisposition to Disease ; Aging ; },
abstract = {Attention-deficit/hyperactivity disorder (ADHD) affects 2.5% of adults and is associated with cognitive decline and dementia. The neurobiological mechanisms contributing to adverse outcomes in ADHD are poorly understood. ADHD-related brain alterations may persist into later life and interact with ageing-related processes, potentially increasing susceptibility to neuropathology. This preregistered systematic review synthesised neuroimaging findings in adults aged 35 years and older with clinical, symptomatic, or genetic risk for ADHD, and summarised cognitive and clinical correlates. A search of five databases produced 13 included studies. Risk of bias was assessed using the Newcastle-Ottawa Scale. Most studies (11/13) had low risk of bias. Compared to controls, ADHD groups exhibited alterations in fronto-striatal, fronto-parietal, and limbic systems implicated in executive control and attention. Middle-aged adults with clinical ADHD showed more widespread cortical structural differences, whereas older adults demonstrated abnormalities primarily in frontal regions, possibly reflecting attenuation of differences through ageing. Two functional studies in those with clinical ADHD reported frontal hypoactivation alongside parietal hyperactivation, consistent with compensatory recruitment. Among undiagnosed samples, there were interactions between genetic risk for ADHD and Alzheimer's disease-related pathology affecting brain and cognitive outcomes. Overall, ADHD-associated neurobiological alterations appear to persist into older age. Longitudinal investigations are needed to clarify these relationships.},
}

Humans
*Attention Deficit Disorder with Hyperactivity/genetics/diagnostic imaging
*Neuroimaging/methods
Adult
*Brain/diagnostic imaging/pathology
Middle Aged
Aged
*Genetic Predisposition to Disease
Aging

@article {pmid42472492,
year = {2026},
author = {Damirchi, EK and Barani, A and Hamidi, SM and Ebrahimzadeh, MA},
title = {Melatonin hybrids as multifunctional therapeutic agents: A comprehensive review.},
journal = {European journal of medicinal chemistry},
volume = {318},
number = {},
pages = {119156},
doi = {10.1016/j.ejmech.2026.119156},
pmid = {42472492},
issn = {1768-3254},
abstract = {Compound hybridization has received attention due to its potential to address several diseases, including neurological disorders, cancer, infectious diseases, and others. Melatonin is a hormone with antioxidant, anti-inflammatory, and neuroprotective effects. Some drug design research has focused on synthesizing hybrid molecules in which melatonin is hybridized with other pharmacologically active compounds to increase therapeutic efficacy and reduce toxicity. These hybrids demonstrate improved binding affinity, selectivity, and pharmacokinetic characteristics compared to their separate components. This review shows the pharmacological assessment and therapeutic potential of diverse melatonin-based hybrids. These hybrids have exhibited significant efficacy in the treatment of complex diseases such as Alzheimer's disease, cancer, and inflammatory disorders. Hybridization leads to the synthesis of a new generation of structures that represent a promising therapeutic approach for disease treatment.},
}

@article {pmid42472573,
year = {2026},
author = {Yanagisawa, D and Ohgita, T and Kawashima, H and Yoshikawa, H and Saito, H and Tooyama, I and Takata, K},
title = {Neurotheranostics in Alzheimer's Disease: Current concepts and experimental strategies.},
journal = {Pharmacology & therapeutics},
volume = {},
number = {},
pages = {109084},
doi = {10.1016/j.pharmthera.2026.109084},
pmid = {42472573},
issn = {1879-016X},
abstract = {In Alzheimer's disease (AD), pathological changes start decades before symptoms appear; by the time cognitive issues are noticeable, widespread neuronal and glial dysfunction and significant neuronal loss have already occurred. Recent regulatory approvals of monoclonal antibodies targeting aggregated amyloid-β (Aβ) species, including oligomers and fibrils, represent a major advance in disease-modifying therapy. However, therapeutic efficacy is strongly dependent on intervention at the earliest pathological stages, underscoring the importance of early diagnosis and treatment. Early diagnosis requires biomarkers that accurately reflect the initiation and progression of AD pathology as well as the development of methodologies capable of capturing these pathological states in vivo. Effective early treatment necessitates strategies that suppress the formation, activation, or toxicity of molecules that trigger downstream neurodegenerative cascades, thereby interrupting disease progression at its source. In parallel, advances in targeted brain delivery technologies are essential to enable sensitive detection and effective therapeutic modulation of central nervous system targets. Neurotheranostics is an integrated conceptual framework that aims to achieve early diagnosis and targeted therapy either simultaneously or in a coordinated manner using shared molecular targets and biological readouts. By unifying molecular imaging, biomarker analysis, and disease-modifying intervention, neurotheranostics aims to overcome the limitations of conventional diagnostic and therapeutic paradigms in neurodegenerative disorders, including AD. In this review, we summarize recent advances in neurotheranostic approaches for AD and highlight emerging molecular probes, low-molecular-weight compounds, and delivery technologies, including contributions from our studies.},
}

@article {pmid42472607,
year = {2026},
author = {Ren, K and Lu, D and Wang, L and Yang, J and Zhang, H},
title = {Phytochemicals modulating HSF-1-associated pathways: A systematic review of longevity-extending mechanisms in Caenorhabditis elegans.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103265},
doi = {10.1016/j.arr.2026.103265},
pmid = {42472607},
issn = {1872-9649},
abstract = {Aging is characterized by progressive loss of proteostasis, and heat shock transcription factor 1 (HSF1) is the master regulator of the cellular stress response, making it an attractive pharmacological target for interventions aimed at extending lifespan. However, a systematic synthesis of phytochemicals that modulate HSF1 has been lacking. Following PRISMA 2020 guidelines, we systematically searched PubMed, Web of Science, Scopus, Embase, and the Cochrane Library from March 2016 to March 2026, identifying 42 original studies that provided clear evidence of HSF-1 activation (nuclear translocation, phosphorylation, or transcriptional activity), together with downstream stress-response markers such as upregulation of heat shock protein genes by phytochemicals with lifespan-extending or health span-improving outcomes. All 42 studies exclusively used Caenorhabditis elegans as the model organism, and the phytochemicals were classified into six categories: plant extracts/mixtures (11 studies), flavonoids (9 studies), carbohydrates/sugars (8 studies), terpenoids (7 studies), phenolic compounds (4 studies), and alkaloids (3 studies). Across all studies, these phytochemicals extended lifespan, enhanced resistance to thermal and oxidative stress, and delayed neurodegenerative pathology (Alzheimer's, Parkinson's, and Huntington's disease models) through activation of HSF-1 and its cooperating transcription factors DAF-16/FOXO and SKN-1/Nrf2. While sharing a common dependency on HSF-1, different classes engaged additional signaling pathways including autophagy, mitochondrial unfolded protein response, insulin/IGF-1 signaling, and lipid metabolism, reflecting class-specific mechanistic signatures. This systematic review provides the first comprehensive evidence base for developing HSF-1-associated longevity strategies using phytochemicals; however, all available evidence is limited to C. elegans models, and urgent validation in mammals and clinical translation are needed before these findings can be applied to human aging.},
}

@article {pmid42472674,
year = {2026},
author = {Jancev, M and Eliasson, B and Biessels, GJ and DeVries, JH and Serné, EH and Visseren, FLJ and Rawshani, A and Rawshani, A and Cukierman-Yaffe, T and Sattar, N and Gerstein, HC and van Sloten, TT},
title = {Age of Type 1 Diabetes Onset and Dementia Risk: A Swedish Nationwide, Register-Based Cohort Study.},
journal = {Diabetes, obesity & metabolism},
volume = {},
number = {},
pages = {},
doi = {10.1111/dom.71123},
pmid = {42472674},
issn = {1463-1326},
support = {2021.81.004//Diabetes Fonds/ ; 2024.35.001//Diabetes Fonds/ ; //European Foundation for the Study of Diabetes/ ; },
abstract = {AIMS: Individuals with Type 1 diabetes are at a higher risk of dementia compared to individuals without diabetes. Younger age at Type 1 diabetes onset has been linked to an increased risk of cardiovascular disease and higher mortality. This study aimed to determine whether younger age at Type 1 diabetes onset was also associated with all-cause dementia.

MATERIALS AND METHODS: This nationwide prospective cohort study used data from individuals with Type 1 diabetes from the Swedish National Diabetes Register. All-cause dementia, including Alzheimer's disease, vascular dementia and non-Alzheimer's-non-vascular dementia, was prospectively ascertained as ICD-10 codes. Age at onset was stratified into < 10 years, 10-17 years and 18-30 years. The 18-30 years group was used as the reference group for all analyses. Cox regression modelling with age as the time-axis, from age at diabetes onset, was deployed to investigate dementia risk.

RESULTS: Of 43 440 included individuals (mean age 33.0 (SD 14.0) years; 44% female), Type 1 diabetes developed before age 10 in 11 776 individuals (27%), between age 10 and 17 in 15 846 (36%) and between 18 and 30 (reference group) in 15 818 (36%). During a median 29.3 [17.6-43.7] years follow-up, 530 (1.2%) developed all-cause dementia. Compared to the reference group, all-cause dementia risk was increased in individuals aged < 10 years at onset (HR 1.37 [95% CI 1.08-1.73]), but not in individuals aged 10-17 years at onset (HR 1.04 [95% CI 0.85-1.26]) (fully adjusted model).

CONCLUSIONS: Type 1 diabetes onset before age 10 is associated with an increased risk of all-cause dementia compared to onset between ages 18 and 30.},
}

@article {pmid42472714,
year = {2026},
author = {Khan, M and Khan, T and Tariq, A},
title = {From biomarker expansion to equitable implementation in mild cognitive impairment.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {8},
pages = {},
pmid = {42472714},
issn = {1590-3478},
mesh = {Humans ; *Cognitive Dysfunction/diagnosis/cerebrospinal fluid ; *Biomarkers/cerebrospinal fluid ; *Alzheimer Disease/diagnosis/cerebrospinal fluid ; },
abstract = {The expanding role of cerebrospinal fluid (CSF) biomarkers in Alzheimer's disease diagnosis represents a major shift toward biologically driven dementia care. In response to the article by Poli et al., we discuss important considerations regarding the broader implementation of CSF biomarker testing in patients with mild cognitive impairment (MCI), particularly in the era of emerging anti-amyloid therapies. While biomarker-guided approaches may improve identification of atypical or non-amnestic Alzheimer's disease presentations, widespread adoption remains limited by disparities in diagnostic infrastructure, standardized testing availability, expertise in lumbar puncture procedures, and longitudinal monitoring capacity across healthcare systems. In addition, expanded eligibility for anti-amyloid therapies introduces challenges related to patient selection, treatment accessibility, and equitable allocation of healthcare resources. Ethical considerations surrounding biomarker disclosure and prognostic uncertainty also warrant continued discussion. We emphasize the need for future studies evaluating accessibility, cost-effectiveness, and standardized patient selection frameworks to support equitable integration of biomarker-guided dementia care into routine neurological practice.},
}

Humans
*Cognitive Dysfunction/diagnosis/cerebrospinal fluid
*Biomarkers/cerebrospinal fluid
*Alzheimer Disease/diagnosis/cerebrospinal fluid

@article {pmid42472726,
year = {2026},
author = {Chen, Y and Li, Z and Luo, S and Li, Z and Jiang, Y and Chen, K and Wang, J and Zhang, Z and , },
title = {Apolipoprotein E ε4 and type 2 diabetes cooperatively accelerate amyloid beta and tau neurodegeneration.},
journal = {European journal of nuclear medicine and molecular imaging},
volume = {},
number = {},
pages = {},
pmid = {42472726},
issn = {1619-7089},
support = {2023YFC3605400//National Key Research and Development Program of China/ ; 2022ZD0211600//Science and Technology Innovation 2030 Major Projects/ ; Beijing Nova Program//Beijing Nova Program/ ; },
abstract = {PURPOSE: Both type 2 diabetes mellitus (T2DM) and Apolipoprotein E (APOE) ɛ4 allele are recognized risk factors for Alzheimer's disease (AD). However, the impact of the APOE ɛ4 allele on the accumulation of AD-related neuropathology in patients with T2DM remains unclear.

METHODS: We analyzed amyloid beta (Aβ) and tau deposition patterns via positron emission tomography (PET) imaging in 163 T2DM patients (64 ɛ4 carriers) and 1654 normal glucose metabolism subjects (687 ɛ4 carriers).

RESULTS: Findings reveal that Aβ deposition has a broader range of influence in diabetics carrying the ɛ4 allele, especially in the deep cortical areas. In terms of tau accumulation, diabetic carriers exhibit progression to the posterior and frontal cortices. Specifically, a greater Aβ PET burden is associated with higher levels of plasma Aβ42 and lower levels of cerebrospinal fluid (CSF) Aβ42, Aβ42/40, and Aβ42/38. A significant positive correlation was observed between tau PET burden and CSF tau and phosphorylated tau (pTau), and plasma pTau181. Importantly, higher Aβ and tau standardized uptake value ratio were associated with poorer memory performance and lower scores on the Montreal Cognitive Assessment.

CONCLUSIONS: These findings highlight the allele's region-specific synergism with T2DM in driving AD-related pathology, potentially informing the development of a neuroimaging-based grading system to evaluate diabetic neuropathology severity and progression dynamics.},
}

@article {pmid42472733,
year = {2026},
author = {Kwon, HS and Moon, SY and Hwang, M and Kim, HJ and Lee, SM and Jung, NY and Jang, H and Baek, JM and Kim, MJ and Han, MH and Zetterberg, H and Blennow, K and Apostolova, LG and Koh, SH and Kim, EJ and , },
title = {Blood-based multimodal biomarker models for differentiating early-onset Alzheimer's disease from frontotemporal dementia: a longitudinal study of early-onset dementia and family members (LEAF) study.},
journal = {Journal of neurology},
volume = {273},
number = {8},
pages = {},
pmid = {42472733},
issn = {1432-1459},
support = {2021-ER1004-01//Korea National Institute of Health research project/ ; 2024-ER1001-00//Korea National Institute of Health research project/ ; },
mesh = {Humans ; *Alzheimer Disease/blood/diagnosis ; Female ; *tau Proteins/blood ; Male ; *Frontotemporal Dementia/blood/diagnosis ; Biomarkers/blood ; *Glial Fibrillary Acidic Protein/blood ; Longitudinal Studies ; Middle Aged ; Diagnosis, Differential ; *Neurofilament Proteins/blood ; Age of Onset ; Aged ; Adult ; },
abstract = {BACKGROUND: Plasma phosphorylated tau (p-tau) biomarkers have improved the diagnosis of Alzheimer's disease (AD), but evidence in early-onset populations remains limited. We evaluated the diagnostic performance of plasma p-tau217 and p-tau181 levels in patients with early-onset AD (EOAD) and early-onset frontotemporal dementia (EOFTD).

METHODS: We analyzed 185 patients (EOAD = 150, EOFTD = 35) aged ≤ 65 years from the LEAF study (2021-2023). Plasma p-tau217, p-tau181, neurofilament light (NfL), and glial fibrillary acidic protein (GFAP) levels were measured by immunoassays.

RESULTS: Both plasma p-tau217 (AUC = 0.831) and p-tau181 (AUC = 0.862) levels demonstrated high discriminative performance, with no significant difference between the two p-tau isoforms. P-tau levels were higher in patients with EOAD, whereas NfL levels were higher in EOFTD and were elevated in those with EOAD participants with severe hippocampal atrophy. Adding NfL, GFAP, and APOE ε4 status further improved the discriminative accuracy for differentiating EOAD from EOFTD.

CONCLUSIONS: Plasma p-tau217 and p-tau181 are effective biomarkers for distinguishing biologically defined EOAD from EOFTD. Incorporating NfL, GFAP, and APOE ε4 status further enhances diagnostic accuracy.},
}

Humans
*Alzheimer Disease/blood/diagnosis
Female
*tau Proteins/blood
Male
*Frontotemporal Dementia/blood/diagnosis
Biomarkers/blood
*Glial Fibrillary Acidic Protein/blood
Longitudinal Studies
Middle Aged
Diagnosis, Differential
*Neurofilament Proteins/blood
Age of Onset
Aged
Adult

@article {pmid42473039,
year = {2026},
author = {Koppisetti, RK and Barthélemy, NR and Horie, K and Ly, CV and Roberts, KF and Koutarapu, S and Perrin, RJ and Franklin, EE and Pedicone, C and Orrick, J and Melendez, J and Miller, TM and Sato, C and Ghoshal, N and Goate, AM and Karch, CM and Bateman, RJ and Mukherjee, S},
title = {Distribution of Big Tau Isoforms in the Human Central and Peripheral Nervous System.},
journal = {Annals of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/ana.78300},
pmid = {42473039},
issn = {1531-8249},
support = {UL1TR004419/TR/NCATS NIH HHS/United States ; 1U54NS123746-01/NS/NINDS NIH HHS/United States ; R01NS095773/NS/NINDS NIH HHS/United States ; R01NS110890/NS/NINDS NIH HHS/United States ; U54NS123985/NS/NINDS NIH HHS/United States ; P41GM103422/GM/NIGMS NIH HHS/United States ; P01AG026276/AG/NIA NIH HHS/United States ; P01AG03991/AG/NIA NIH HHS/United States ; P30AG066444/AG/NIA NIH HHS/United States ; },
abstract = {OBJECTIVE: Tau is widely studied in neurodegeneration, yet most work has focused on canonical brain tau isoforms. A longer isoform, "big tau," produced by inclusion of exon 4a, is expressed in the peripheral nervous system (PNS) and central nervous system (CNS) regions. We sought to characterize big tau composition, anatomic distribution, and disease relevance.

METHODS: Mass spectrometry (MS) was used to sequence big tau and map its distribution across the human nervous system. Postmortem samples included brain tissue from Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and controls; spinal cord and peripheral nerves. Big and canonical ("small") tau isoforms were also quantified in cerebrospinal fluid (CSF) from controls and participants stratified by amyloid status and cognitive impairment.

RESULTS: Human big tau results from insertion of either 355 or 251 amino acids encoded by exon 4a-long and exon 4a-short, respectively. Alternative splicing of exons 2, 3, and 10 generates multiple big tau isoforms. Total tau levels were approximately 1,000-fold higher in the brain than in the PNS; however, the relative abundance of big tau increased from the CNS to the PNS, comprising 50% of the total tau in the periphery and approximately 1% in the brain, primarily localized to the cerebellum. In CSF, big tau levels were unchanged by amyloid abnormalities or cognitive impairment, whereas canonical tau increased with AD pathology.

INTERPRETATION: Big tau represents a distinct tau population enriched in the PNS and uncoupled from disease-associated changes in brain-derived tau, suggesting that distinguishing big tau from canonical tau may improve interpretation of tau biomarkers and help differentiate CNS neurodegeneration from peripheral nerve pathology. ANN NEUROL 2026.},
}

@article {pmid42473091,
year = {2026},
author = {Jessup, RE and Ehrlich, RS and Teppang, KL and Dasgupta, S and Sigurdson, CJ and Yang, J},
title = {Development of Aryl Cyano Amides for Fluorescence Discrimination of Tau and Amyloid Beta Deposits in Tissue.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.6c00316},
pmid = {42473091},
issn = {1948-7193},
abstract = {The accumulation of amyloid aggregates such as amyloid beta (Aβ) and tau deposits in the brain is a hallmark of many neurodegenerative diseases including Alzheimer's disease. Recent advances in optical imaging have shown that fluorescent probes can detect amyloids in living patients, potentially aiding in diagnosis. Here, we investigate structural modifications of amyloid-targeting Aryl Cyano Amide-based fluorophores aimed at enhancing their ability to discriminate between different amyloid aggregates, such as Aβ and tau. We identify two structural parameters that synergistically enable increased sensitivity to environmental polarity, which makes it possible to discriminate these amyloids through inspection of the color of fluorescence emission. This colorimetric discrimination can provide detailed information on amyloid composition and could expand the use of fluorescence imaging for diagnosis and monitoring of neurodegenerative diseases.},
}

@article {pmid42473207,
year = {2026},
author = {Dutta, S and Singh, MK and Dehury, B},
title = {Unlocking the Dynamics of Human SPPL2a: First Atomistic Characterization of an Alzheimer's-Linked Intramembrane Protease.},
journal = {Journal of chemical information and modeling},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jcim.6c01556},
pmid = {42473207},
issn = {1549-960X},
abstract = {The failure of γ-secretase inhibitors in clinical trials of Alzheimer's disease (AD) has shifted the focus toward more selective targets, specifically SPPL2a (signal peptide-peptidase-like 2a), which is emerging as a critical therapeutic target in AD because of its role in processing TMEM106B. While recent cryo-EM structures have provided essential static snapshots, the dynamic mechanisms governing substrate entry and inhibitor recognition remain unresolved. Here, we present the first microsecond-time scale, all-atom molecular dynamics characterization of human SPPL2a in its apo and inhibitor-bound states, alongside a comparative analysis of the γ-secretase catalytic subunit, PS1. Our simulations reveal that SPPL2a is highly dynamic and undergoes an inhibitor-induced disorder-to-order transition in the TM6a region, where the helicity increases from 10% to 77%. We characterized the lateral gate dynamics of TM2, revealing that inhibitor binding fundamentally remodels the interhelical contact network and quenches conformational sampling. Moreover, we identified a unique inhibitor-stabilized lipid hotspot at Trp189 and demonstrated that SPPL2a utilizes a distributed polar network for binding energy, in contrast to the concentrated aspartate-driven affinity of PS1. These findings provide a quantitative atomistic blueprint of SPPL2a dynamics, offering a structural basis that can be exploited for the design of selectivity-guided therapeutics to bypass the clinical failures associated with nonspecific intramembrane protease inhibition.},
}

@article {pmid42473218,
year = {2026},
author = {Keskin, A and Mogulkoc, R and Baltaci, AK},
title = {Relationship Between miRNA and Neurodegenerative Diseases Such as Alzheimer's disease, Parkinson's, Huntington's disease, Amyotrophic Lateral Sclerosis.},
journal = {Mini reviews in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113895575484348260702044851},
pmid = {42473218},
issn = {1875-5607},
abstract = {The regulatory roles of miRNAs on CNS homeostasis, neuronal differentiation, and synaptic plasticity make these molecules indispensable for healthy brain functions. miRNA dysregulation, by triggering abnormal neurodevelopment, has a critical impact on the etiology and progression of neurodegenerative diseases. MicroRNAs (miRNAs) are short, single-stranded, non-coding ribonucleic acid (RNA) molecules, 18 to 24 nucleotides long. They play a role in posttranscriptional gene regulation by binding to complementary sequences on messenger RNA (mRNA), thereby promoting mRNA degradation or preventing translation into protein. MiRNAs are essential regulators of the genome because they bind targets and alter gene expression. MiRNA biogenesis and functions are tightly regulated, and their dysregulation is associated with various diseases, including cancer, cardiovascular diseases, and neurodegenerative disorders. In particular, disruption of the Blood-Brain Barrier in neurodegenerative diseases allows molecules to leak into the bloodstream, enabling the detection of miRNAs in other body fluids and making these fluids potential biomarker sources. In this context, miRNAs can be measured in blood, cerebrospinal fluid, and other biological samples. It has significant potential for early diagnosis, disease progression monitoring, and evaluation of treatment efficacy. In this review, the relationship between MiRNAs and neuronal degeneration diseases was evaluated. In this review, prepared in light of the current literature scanned through the PubMed database, we examined data from the last 5 years (2021-2026) on neurodegenerative diseases associated with miRNA dysregulation, including Alzheimer's Disease (AD), Parkinson's Disease (PD), Amyotrophic Lateral Sclerosis (ALS), and Huntington's Disease (HD).},
}

@article {pmid42473227,
year = {2026},
author = {Rodrigues, JFR and Rodrigues, LP and Rodrigues, FCP and Cavalcante, LL and Payão, SLM and Tavares, AR and Forlenza, OV and de Godoy, MF and Filho, GMA},
title = {Cardiovascular Comorbidities with Alzheimer's Disease: A Systematic Review and Meta-analysis.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050468989260629094050},
pmid = {42473227},
issn = {1875-5828},
abstract = {INTRODUCTION: Alzheimer's disease stands as the most prevalent form of dementia, characterized by a progressive decline in cognitive function and memory. Numerous risk factors have been linked to its development, creating a complex interplay of influences. In this study, we aim to delve into the relationship between cardiovascular disease and Alzheimer's disease, exploring how conditions affecting heart health may impact the onset and progression of this debilitating neurological disorder. Through this research, we could find potential connections that inform prevention strategies and therapeutic approaches.

MATERIALS AND METHODS: We adopted the PRISMA guidelines and defined the PECOS framework as follows: Population (P) = individuals; exposure (E) = cardiovascular disease; comparison (C) = without cardiovascular disease; outcome (O) = Alzheimer's disease; and study design(S) = all kinds of studies with an association between cardiovascular disease and Alzheimer's disease without time limits. A meta-analysis was conducted using case-control, cohort, and genetic studies to estimate Odds Ratios (ORs) or Hazard Ratios (HRs).

RESULTS: The pooling of data in meta-analysis demonstrated that a person with any Cardiovascular Disease (CVD), Heart Failure (HF), Coronary Artery Disease (CAD), Atrial Fibrillation (AF), Hypertension (HTN), and Myocardial Infarction (MI) had more risk of developing Alzheimer's disease [CVD: HR = 1.30 (CI: 1.27-1.33) / HF: HR = 1.63 (CI: 1.37-1.94) / CAD: HR = 1.43 (CI: 1.40-1.46) / AF: HR = 1.38 (CI: 1.34-1.42) / HTN: HR = 1.22 (CI: 1,10-1.35) / MI: HR = 1.07 (CI: 1,01-1.13)]. Cross-sectional studies demonstrated an association between cardiovascular diseases and Alzheimer's disease [OR = 1.29 (CI: 1.23-1.35)]. Mendelian randomization meta-analysis did not demonstrate a causal relation between cardiovascular disease and Alzheimer's disease [AF: OR = 1.03 (CI: 1.00-1.01) / HF: OR = 1.00 (CI: 0,79-1.36)]. A Mendelian randomization meta-analysis demonstrated that a person with AD had a higher risk of developing myocardial infarction [OR = 1.07 (CI: 1.03-1.10)].

DISCUSSION: This review examines the connection between AD and CVD, noting that HF increases the risk of developing AD with a hazard ratio of 1.63. It suggests that altered brain perfusion and hypoxia appear to be one important neurodegenerative factor. Some genetic changes in individuals with CVD made them more vulnerable to AD. Effective prevention and treatment of CVD can help reduce the risk of AD.

CONCLUSION: HF, AF, and CAD were the CVDs with the highest risk of developing AD. The results suggest that changes in cerebral blood perfusion are a principal neuropathological event that leads to genetic alterations that end in AD.},
}

@article {pmid42473272,
year = {2026},
author = {Kouchache, T and Chan, T and Sun, S and Liu, L and Delva, A and Gan-Or, Z and Rosa-Neto, P and Gagnon, JF and Dagher, A and Postuma, RB and Sharp, M},
title = {Association Between Plasma Phosphorylated Tau-217 and Cognition in Parkinson's Disease.},
journal = {Movement disorders : official journal of the Movement Disorder Society},
volume = {},
number = {},
pages = {},
doi = {10.1002/mds.70400},
pmid = {42473272},
issn = {1531-8257},
support = {N/A//Fonds de Recherche du Québec - Santé/ ; N/A//Healthy Brains for Healthy Lives/ Canada First Research Excellence Fund/ ; N/A//Parkinson Canada/ ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) co-pathology contributes to dementia in PD, but its role in earlier cognitive impairment remains uncertain.

OBJECTIVE: To determine if p-tau217, a biomarker of early AD, is associated with cognitive impairment in PD.

METHODS: Plasma p-tau217 levels in 167 PD patients without dementia and 63 controls were related to performance on standard neuropsychological testing, and to cognitive impairment as defined by a MoCA score <26 and by self-report. Plasma GFAP, NfL and APOE ε4 carrier status were also examined.

RESULTS: No significant differences in p-tau217, GFAP and NfL level were observed between groups (pFDR > 0.08). Higher p-tau217 was associated with worse visuospatial function and greater self-reported cognitive impairment, but these associations did not survive correction (pFDR > 0.08). There was no association with cognitive impairment (pFDR > 0.08).

CONCLUSION: These results suggest that co-morbid AD pathology is not a major contributor to early cognitive changes in this sample of PD patients without dementia. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.},
}

@article {pmid42473545,
year = {2026},
author = {Gabriel, V and Chabran, E and Sourty, M and Cretin, B and Philippi, N and Muller, C and Anthony, P and Demuynck, C and de Sousa, PL and Botzung, A and Sanna, L and Bousiges, O and Blanc, F},
title = {Cerebrospinal fluid α-synuclein and Aβ42 link with default mode and salience networks connectivity in dementia with Lewy bodies.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {3},
pages = {e70266},
pmid = {42473545},
issn = {2352-8737},
abstract = {INTRODUCTION: Dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) are neurocognitive disorders characterized by distinct but often overlapping pathological processes. These include α-synuclein, amyloid-beta 42 (Aβ42), and tau protein aggregation. While cerebrospinal fluid (CSF) biomarkers provide in vivo insight into these pathologies, their relationship with large-scale brain network dysfunction remains poorly understood. This study aimed to investigate the associations between CSF biomarker concentrations and resting-state functional connectivity in patients with DLB, AD, and mixed AD/DLB.

METHODS: Sixty-nine DLB patients, 17 AD patients, and 24 patients with mixed AD/DLB underwent clinical and neuropsychological evaluations, lumbar puncture for CSF biomarker analysis (total α-synuclein, Aβ42, pTau181, and tTau), and resting-state functional MRI. Patients were stratified by disease stage for subgroup analyses. Besides CSF total α-synuclein levels, α-synuclein seeding activity was assessed using real-time quaking-induced conversion (RT-QuIC) assays. ROI-to-ROI analyses were conducted using the CONN toolbox to explore associations between CSF biomarker levels and functional connectivity within and between major brain networks.

RESULTS: In DLB patients, lower CSF α-synuclein levels correlated with increased connectivity within the default mode network (DMN) (p FDR < 0.05). In dementia-stage DLB (d-DLB), lower Aβ42 levels correlated with reduced connectivity within the salience network (SN) (p FDR < 0.05). In AD, higher tTau levels correlated with decreased connectivity between the DMN and the SN (p FDR < 0.05). No significant associations were observed for CSF pTau181 or any RT-QuIC metric in any group, and the mixed AD/DLB group showed no biomarker-connectivity correlations at all.

DISCUSSION: We identified distinct patterns of DMN and SN connectivity changes associated with CSF α-synuclein and Aβ42 levels, respectively. These findings reflect key functional disruptions that may contribute to core clinical symptoms. They underscore the value of combining CSF biomarkers with functional MRI to elucidate DLB pathophysiology.},
}

@article {pmid42473637,
year = {2026},
author = {Kashiwagi-Hakozaki, M and Uchigami, H and Naka, Y and Kokawa, A and Mano, T and Cho, J and Yamada, K and Miyashita, A and Hara, N and Ikeuchi, T and Serrano-Pozo, A and Frosch, MP and Hyman, BT and Toda, T and Fukayama, M and Ushiku, T and Wakabayashi, T and Iwatsubo, T and Hashimoto, T},
title = {Soluble high-molecular-weight amyloid-β species derived from amyloid-β-laden brains induce cerebral β-amyloidosis.},
journal = {Brain communications},
volume = {8},
number = {4},
pages = {fcag188},
pmid = {42473637},
issn = {2632-1297},
abstract = {Spatiotemporal spreading of amyloid-β peptide deposition as senile plaques is a key pathogenic process in the brains of patients with Alzheimer's disease; however, the molecular properties of amyloid-β strains that initiate the spreading of amyloid-β peptide as aggregation seeds in vivo remain poorly understood. In this study, we discovered that the intrahippocampal injection of soluble amyloid-β species with a molecular weight of >150 kDa isolated from the brains of plaque-laden amyloid-β precursor protein transgenic mice or patients with Alzheimer's disease using size-exclusion chromatography, dramatically accelerated β-amyloidosis in the transgenic mice brains. In contrast, intrahippocampal injection of soluble amyloid-β species with 50-70 kDa or 10-20 kDa never induced β-amyloidosis. Moreover, injection of the soluble amyloid-β species with >150 kDa into cerebrospinal fluid of young transgenic mice via the cisterna magna predominantly induced amyloid-β deposition within the wall of leptomeningeal arteries surrounding the brain, reminiscent of cerebral amyloid angiopathy. The seeding activity of the soluble high-molecular-weight amyloid-β was prevented by the immunodepletion of amyloid-β and abolished by formic acid denaturation, suggesting that these amyloid-β oligomers are crucial in inducing β-amyloidosis. Furthermore, we have shown that the soluble high-molecular-weight amyloid-β is present in the brains of patients with Alzheimer's disease and induced β-amyloidosis. These results indicate that the soluble high-molecular-weight amyloid-β oligomers may play an important role in the spatiotemporal spreading of amyloid-β deposition in Alzheimer's disease brains.},
}

@article {pmid42473871,
year = {2026},
author = {Guarnieri, B and Hoxhaj, D and Buracchi Torresi, F and Arnaldi, D and Bonanni, E and Carpi, M and Cremascoli, R and Liguori, C and Lombardi, G and Mainieri, G and Provini, F and Silvestri, R and Puligheddu, M and Tassoni, MM},
title = {A gradual and sustainable approach to diagnosing sleep and circadian disturbances in dementia.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71654},
doi = {10.1002/alz.71654},
pmid = {42473871},
issn = {1552-5279},
mesh = {Humans ; *Sleep Wake Disorders/diagnosis/etiology ; *Dementia/complications ; *Chronobiology Disorders/diagnosis/etiology ; Circadian Rhythm/physiology ; Polysomnography ; Surveys and Questionnaires ; },
abstract = {Evidence linking sleep and circadian disruptions to the course of dementias, particularly Alzheimer's disease, has expanded. Such alterations are detectable from preclinical stages and parallel the disease progression. Assessing and managing sleep and circadian disturbances in patients with dementia remains challenging. New technologies are emerging, but their validation is still pending. We prepared a clinical review outlining a stepped-care, gradual, and sustainable approach aimed at achieving the most accurate possible diagnosis of different sleep disturbances. This review encompasses diagnostic methods ranging from questionnaires to instrumental assessments, progressing from simpler to more complex techniques including biological evaluations of circadian rhythm alterations. This work reflects a scientific consensus within the "Sleep" study group of the Italian Association for Dementia (SINdem), supported by certified sleep specialists. The document aims to support clinicians in adopting a tailored approach to the evaluation of sleep disturbances in dementia offering a dynamic framework balancing complexity and feasibility.},
}

Humans
*Sleep Wake Disorders/diagnosis/etiology
*Dementia/complications
*Chronobiology Disorders/diagnosis/etiology
Circadian Rhythm/physiology
Polysomnography
Surveys and Questionnaires

@article {pmid42473913,
year = {2026},
author = {Ay, U and Alaylioglu, M and Sahin, E and Oner, SSY and Iskan, G and Cakan, GCY and Kizilates-Evin, G and Hari, E and Kurt, E and Dursun, E and Bilgic, B and Hanagasi, H and Gurvit, H and Demiralp, T and Gezen-Ak, D and Samanci, B},
title = {Stage-Dependent β-Synuclein Links MRI and Cognitive Decline in Alzheimer's Disease.},
journal = {Annals of clinical and translational neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/acn3.70494},
pmid = {42473913},
issn = {2328-9503},
abstract = {OBJECTIVE: Synaptic degeneration drives cognitive decline in Alzheimer's disease (AD), but synaptic biomarkers are scarce. Brain-enriched β-synuclein emerged as a synaptic damage marker. We investigated its diagnostic, prognostic, and structural correlates across the AD continuum.

METHODS: In a tertiary-center cohort (n = 306), CSF β-synuclein was measured. Cognitively unimpaired (CU), AD-MCI, AD dementia (ADD), and non-AD (FTD, PD, DLB, others) groups were included. ANCOVA compared groups (age/sex adjusted); ROC assessed diagnostic performance. Multivariable regression examined 2-year MMSE decline associations. Voxel-wise interaction models evaluated β-synuclein-gray matter volume (GMV) relationships.

RESULTS: CSF β-synuclein differed across groups (p < 0.001), with highest levels observed in AD-MCI and lower levels in ADD. AD-MCI levels exceeded CU/ADD. AD-MCI versus CU AUC was 0.874. Baseline β-synuclein predicted greater MMSE decline in AD-MCI (β = 0.72, p < 0.001) and ADD (β = 0.47, p = 0.017). Voxel-wise analyses revealed stage-dependent β-synuclein-GMV reversals in precentral and temporoparietal regions.

CONCLUSION: CSF β-synuclein shows a stage-dependent pattern across the AD continuum, predicts cognitive decline, and dynamic structural coupling. It supports β-synuclein as a relevant synaptic biomarker in AD.},
}

@article {pmid42474014,
year = {2026},
author = {Yu, Y and Zhao, H and He, Y and Zhao, J and Yang, X and Liu, X and Cheng, X},
title = {Therapeutic Effects of the Traditional Chinese Formula Qifuyin on Cognition, Lipid Metabolism, and Gut Microbiota in ApoE4 Mice.},
journal = {Combinatorial chemistry & high throughput screening},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113862073453341260621182306},
pmid = {42474014},
issn = {1875-5402},
abstract = {INTRODUCTION: Apolipoprotein E4 (ApoE4) is the strongest genetic risk factor for sporadic Alzheimer's disease (AD). Qifuyin is a promising herbal formula used clinically for cognitive decline, but its effects on ApoE4-associated cognitive and systemic phenotypes remain unclear. This study aimed to evaluate the effects of Qifuyin on cognitive performance in ApoE4 transgenic mice and to preliminarily explore its associations with lipid metabolism and gut microbiota alterations.

METHODS: Ten-month-old ApoE4 transgenic mice were treated with Qifuyin by gavage for 321 days, once daily for the first 123 days and once every two days thereafter. Cognitive function was assessed using the step-down test, novel object recognition test (NORT), and Morris water maze test (MWM). Aging- and frailty-related phenotypes were evaluated using senescence grading scores. Serum triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and apolipoprotein B (ApoB) levels were measured to assess lipid metabolism. Gut microbiota composition and functional profiles were analyzed by 16S rRNA and metagenomic sequencing.

RESULTS: Qifuyin treatment significantly reduced error counts and prolonged latency in the stepdown test, increased the 24h preference index in the NORT, shortened escape latency, and increased platform crossings in the MWM in ApoE4 transgenic mice. High-dose Qifuyin reduced aging scores in males and in all doses in females and in the pooled dataset. Qifuyin decreased serum TG and ApoB levels, and increased serum HDL-C levels. 16S rRNA sequencing indicated that Qifuyin increased alpha diversity and shifted beta diversity toward the control profile. At the phylum level, Qifuyin altered the relative abundances of Firmicutes, Bacteroidota, Cyanobacteria, and Synergistota. At the family and genus levels, Qifuyin treatment was associated with increased abundances of Helicobacteraceae, Bacteroidaceae, Helicobacter, and Bacteroides, and a reduced abundance of Ruminococcaceae. Metagenomic annotation analysis showed altered abundances of K02003, K06147, COG1961, CBM37, and GH35-related features.

DISCUSSION: These findings suggest that Qifuyin may benefit ApoE4-associated cognitive and systemic dysfunction through its integrated effects on lipid metabolism and gut microbiota alterations. The microbiota-related changes observed in this study may provide a potential link between peripheral metabolic regulation and cognitive improvement, although their mechanistic significance requires further validation.

CONCLUSIONS: Qifuyin improved cognitive performance and lipid metabolism, and was associated with alterations in gut microbiota composition in ApoE4 transgenic mice. These findings suggest that Qifuyin may exert beneficial effects on cognitive and systemic phenotypes in this model, while the biological significance of specific microbial changes warrants further investigation.},
}

@article {pmid42474022,
year = {2026},
author = {Li, OY and Herrera Guerra, D and Anthony, M and Oh, K and Vankee-Lin, F and Turnbull, A},
title = {Combining MRI-Derived Imaging Measures and Peripheral Proteomics to Improve the Mechanistic Understanding of Alzheimer's Disease Beyond Core Pathology: A Scoping Review.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050472412260629113636},
pmid = {42474022},
issn = {1875-5828},
abstract = {INTRODUCTION/BACKGROUND: Alzheimer's Disease (AD) core pathology involves amyloidβ and ptau, leading to neurodegeneration (ATN model), yet individuals with comparable core pathology show considerable biological and clinical heterogeneity, motivating new models that consider non-specific processes and co-pathology. MRI and peripheral proteomics offer complementary, non-invasive approaches for capturing biological variation beyond core pathology, and many researchers have begun integrating them. However, no systematic overview of this literature exists. This scoping review evaluated studies combining MRI and peripheral plasma proteomics in AD within revised diagnostic frameworks, summarizing strengths and gaps.

MATERIALS AND METHODS: Following PRISMA 2020 guidelines, PubMed, Embase, and Scopus were searched through June 14, 2023, yielding 3,185 records; 63 studies met the inclusion criteria. For each study, study design, participant characteristics, proteomic platforms, imaging modalities, statistical approaches, and significant associations between non-core-pathological proteins and MRIderived measures were extracted.

RESULTS: Across studies, methodological variability was high. Grey matter volume was the most commonly examined imaging metric, followed by cerebrovascular dysfunction, cortical thickness, white-matter and whole-brain volume, and connectivity measures. Overall, 127 non-core-pathology proteins, mostly related to inflammation/immune function, were associated with MRI metrics, though only three appeared in five or more studies. Roughly half of the studies incorporated core AD biomarkers.

DISCUSSION: This scoping review of 63 studies demonstrates that integrating peripheral proteomics with MRI is an increasingly common approach in AD research, with GFAP, CRP, and IL-6 as the most frequently reported proteins, and grey matter volume and vascular dysfunction as the most commonly examined imaging phenotypes. However, effect sizes are generally modest, findings are heterogeneous, and many studies lack core AD biomarkers, highlighting the need for greater methodological consensus and more mechanistic, multimodal, and longitudinal research.

CONCLUSION: Integrating MRI and peripheral proteomics is increasingly common in AD research, but consensus on analytic and imaging approaches is limited. Heterogeneity in proteomic platforms and statistical methods constrains comparability; most associations are modest, and observational designs limit causal inference. Future work should emphasize methodological harmonization, reproducibility, multivariate and machine-learning approaches, and randomized trials to test mechanistic pathways.},
}

@article {pmid42474120,
year = {2026},
author = {Zhang, J and Wang, Y and Huang, X and Wu, H and Lin, Q and Gu, H and Jiang, L and Zhu, L and Xu, H},
title = {Radical-Mediated In Situ Fluorescence Dye Deposition: A Simple Interfacial Signal Amplification Reaction for Ultrasensitive Immunoassay on Barcode Beads.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e76670},
doi = {10.1002/advs.76670},
pmid = {42474120},
issn = {2198-3844},
support = {2023YFB3210301//National Key Research and Development Program of China/ ; 2024YFA0917700//National Key Research and Development Program of China/ ; 2024YFA1803501//National Key Research and Development Program of China/ ; 2023YFA1802000//National Key Research and Development Program of China/ ; 82272122//National Natural Science Foundation of China/ ; 82172062//National Natural Science Foundation of China/ ; 22507071//National Natural Science Foundation of China/ ; 20250202//SJTU Trans-Med Awards Research/ ; YG2024ZD12//Fundamental Research Funds for the Central Universities/ ; YG2024QNA09//Fundamental Research Funds for the Central Universities/ ; 24ZR1432500//Natural Science Foundation of Shanghai/ ; },
abstract = {Ultrasensitive detection of low-abundance protein biomarkers is crucial for early disease diagnosis but remains challenging for the conventional barcode beads-based suspension chip platform due to the limited detection sensitivity. Here, we report a conceptually novel reaction termed "radical-mediated in situ fluorescence dye deposition" (RIFD) as a simple interfacial signal amplification strategy to overcome the limitation. This first discovered RIFD follows a universal "three-element principle", where the coexistence of beads, free radicals, and dyes suffices for fluorescence labeling, eliminating the pre-conjugation of dyes to detection probes required in traditional methods. Mechanistic studies reveal that this radical-triggered RIFD possibly follows three distinct pathways, including amide condensation on lysine residues, covalent biphenyl formation on tyrosine residues, or radical-dye co-deposition. It facilitates local and ultrafast (within 5 min) dye-trapping specifically on target-positive barcode beads. Consequently, the established RIFD-based immunoassay achieves a limit of detection of 12 fg/mL for IL-10, a 100-fold improvement over the conventional suspension chip method, and also successfully differentiates Alzheimer's disease patients from healthy controls by quantifying low-abundance plasma p-Tau217. Multiplexed detection is further validated with a three-plex cytokines panel. Our reported RIFD represents a powerful in situ fluorescence labeling tool, advancing protein biomarker detection toward the sub-pg/mL level with broad implications for clinical diagnostics.},
}

@article {pmid42474289,
year = {2026},
author = {Fang, S and Sha, Y and Zhou, Y and Sun, G and Li, E and Yao, M and Zhou, L and Zhu, Y and Peng, B and Ni, J},
title = {Brain iron, cortical atrophy and cognition impairment in cerebral amyloid angiopathy: A quantitative susceptibility mapping study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261469524},
doi = {10.1177/13872877261469524},
pmid = {42474289},
issn = {1875-8908},
abstract = {BackgroundBrain iron deposition is associated with cognitive impairment in cerebral amyloid angiopathy (CAA) and Alzheimer's disease, but the exact mechanisms remain unclear.ObjectiveTo investigate whether cortical atrophy mediates iron-related cognitive impairment in CAA.MethodsWe prospectively enrolled CAA patients to collect clinical characteristics, conduct global cognitive assessment and magnetic resonance imaging. Iron levels of each brain region were quantified by susceptibility values from quantitative susceptibility mapping. Three-dimensional T1-weighted imaging was collected to calculate cortex volume. For statistical analyses, first, we conducted univariable linear regressions to identify regions with potential associations to cognitive impairment, with p < 0.1 as threshold. Second, we used elastic net analysis to identify regions where iron depositions strongly correlated with cognitive deficits. Finally, we conducted mediation analysis, using these selected regions to test whether iron-related cognitive dysfunction occurs through cortical atrophy.ResultsForty-four patients were included. The median age was 71.5 years old (IQR 62.3, 75.0), and twenty-two were male. Two-thirds of patients presented with mild cognitive impairment or dementia. Elastic net analysis revealed that iron accumulations in the right Rolandic area, left inferior occipital gyrus, left posterior cingulate gyrus and cerebellum were associated with worse cognitive performance. Mediation analysis showed significant total effect of iron in left posterior cingulate gyrus on Mini-Mental State Examination (β = -0.156, p = 0.002), but the average causal mediation effect was insignificant (p = 0.77).ConclusionsWhile regional iron deposition was associated with cognitive impairment in CAA, cortical atrophy did not significantly mediate this relationship in this exploratory study.},
}