@article {pmid42174122,
year = {2026},
author = {Jadiya, P and Berezhnaya, E and Kolmetzky, DW and Tomar, D and Cohen, HM and Shukla, S and Thomas, M and Khaledi, S and Garbincius, JF and Kennedy, L and Salik, O and Raghav, D and Hildebrand, AN and Elrod, JW},
title = {Genetic ablation of neuronal mitochondrial calcium uptake impedes Alzheimer's disease progression.},
journal = {The EMBO journal},
volume = {},
number = {},
pages = {},
pmid = {42174122},
issn = {1460-2075},
support = {R01NS121379//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; P01HL147841//HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; P01HL134608//HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; R01HL136954//HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; R01HL142271//HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; 3R01HL123966-05S1//HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; F32HL151146//HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; 20EIA35320226//American Heart Association (AHA)/ ; 24IPA1273195//American Heart Association (AHA)/ ; 420792//Pennsylvania Department of Health (DOH)/ ; K99AG065445//HHS | NIH | National Institute on Aging (NIA)/ ; F30AG082407//HHS | NIH | National Institute on Aging (NIA)/ ; 24AARG-D-1191292//Alzheimer's Association (AA)/ ; K99DK120876//HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)/ ; P30AG072947//WFU | WFSM | Alzheimer's Disease Research Center, Wake Forest School of Medicine (ADRC)/ ; },
abstract = {Loss of mCa[2+] efflux capacity contributes to the pathogenesis and progression of Alzheimer's disease (AD) by promoting mitochondrial Ca[2+] (mCa[2+]) overload. Here, we utilized loss-of-function genetic mouse models to causally evaluate the role of mCa[2+] uptake by conditionally deleting the mitochondrial calcium uniporter channel (mtCU) in a robust mouse model of AD. Loss of neuronal mCa[2+] uptake reduced Aβ and tau-pathology, synaptic dysfunction, and cognitive decline in 3xTg-AD mice. Knockdown of Mcu in an in vitro model of AD significantly reduced matrix Ca[2+] content, redox imbalance, and mitochondrial dysfunction. The preservation of mitochondrial function rescued the AD-dependent decline in autophagic capacity and protected neurons against amyloidosis and cell death. This was corroborated by in vivo data showing improved mitochondrial structure and apposition in AD mice with loss of neuronal Mcu. These results suggest that inhibition of neuronal mCa[2+] uptake represents a powerful therapeutic target to impede AD progression.},
}

@article {pmid42174284,
year = {2026},
author = {Abugabah, A},
title = {An Automated Framework and Medical Intelligent System for MRI-Based Alzheimer's Diagnosis Classification.},
journal = {Journal of imaging informatics in medicine},
volume = {},
number = {},
pages = {},
doi = {10.1007/s10278-026-02005-y},
pmid = {42174284},
issn = {2948-2933},
abstract = {In the era of artificial intelligence (AI), Alzheimer's disease (AD) can be diagnosed through magnetic resonance imaging (MRI) at accurate times and with precision to make effective clinical interventions. Nevertheless, classification is still problematic because of low-contrast anatomical structures, inter-class variations, imbalances of the classes, and the possibility of data leakage in slice-based methods. To overcome these limitations, this paper will introduce a contrast-sensitive hybrid Swin Transformer V2 that employs a 3D Convolutional Neural Network that is trained with Harris Hawks Optimization (CA-Swin3DNet-HHO) to classify AD using MRI. The framework presented includes gamma-logarithmic contrast enhancement, skull stripping, and intensity normalization to enhance the visibility of disease-relevant features. A 3D-CNN module is used to encode volumetric structural features, and Swin Transformer V2 is trained to learn global contextual dependencies based on efficient window-based self-attention. Automatic hyperparameter tuning is done using Harris Hawks Optimization (HHO), which enhances convergence and generalization. A feature fusion approach combines both local and global features to improve the classification performance in cognitively normal (CN), mild cognitive impairment (MCI), and AD classes. Strict subject-level partitioning is used to evaluate the model on the ADNI-2 and OASIS-2 datasets to avoid data leakage. The experimental results show better performance with 99.3% accuracy, 99.1% F1-score, and 0.996 AUC on ADNI-2 and 98.7% accuracy, 98.3% F1-score, and 0.991 AUC on OASIS-2. Also, Grad-CAM-based visualization can emphasize clinically relevant parts of the brain, enhancing the interpretability and reliability of the model. In general, the suggested framework offers a precise, solid, and readable solution to automated diagnosis of Alzheimer's disease and has a high potential for clinical use in the real world.},
}

@article {pmid42174391,
year = {2026},
author = {Bozigar, M and Weuve, J and Clark, SN and Grady, ST and Cantuaria, ML and Cai, YS and Roscoe, C and Röösli, M and Peters, JL and Seto, E and Vienneau, D and Sørensen, M and Neitzel, RL and Hastings, AL and Luben, TJ and Andersen, ZJ and Clark, C and Hansell, AL and Hystad, P and Brauer, M and Adar, SD},
title = {Integrating noise as a risk factor in studies of Alzheimer's disease and dementia: Guidance for epidemiologic research.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71513},
doi = {10.1002/alz.71513},
pmid = {42174391},
issn = {1552-5279},
support = {U24AG088894/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/epidemiology/etiology ; Risk Factors ; *Noise/adverse effects ; *Dementia/epidemiology/etiology ; *Environmental Exposure/adverse effects ; },
abstract = {Noise exposure is increasingly recognized as a modifiable environmental risk factor for Alzheimer's disease and related dementias (ADRD), yet its integration into epidemiologic research remains limited. We reviewed international noise mapping resources, exposure metrics, and analytic approaches relevant to ADRD studies. Mechanistic pathways and methodological challenges were synthesized from recent studies via expert knowledge. We present a stepwise framework for integrating noise into ADRD research, detailing metric selection, spatiotemporal assignment, and analytic guardrails. Our review recommends the application of 24-hour average, nighttime, and event-based metrics, and stresses that health effects may occur at low noise levels. We further underscore the importance of accounting for indoor, occupational, and life course exposures. Rigorous noise exposure assessment and transparent reporting will improve comparability and causal inference in ADRD studies. Future research should harmonize exposure metrics, integrate co-exposures (e.g., air pollution), and clarify etiologically relevant windows to strengthen prevention strategies.},
}

Humans
*Alzheimer Disease/epidemiology/etiology
Risk Factors
*Noise/adverse effects
*Dementia/epidemiology/etiology
*Environmental Exposure/adverse effects

@article {pmid42174395,
year = {2026},
author = {},
title = {Correction to "Sex differences in Alzheimer's disease plasma biomarker levels and clinical utility".},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71523},
doi = {10.1002/alz.71523},
pmid = {42174395},
issn = {1552-5279},
}

@article {pmid42174650,
year = {2026},
author = {Dakhel, A and Vestin, J and Giedraitis, V and Nyholm, D and Ingelsson, M and Erlandsson, A},
title = {Characterization of a distinct form of vimentin in the neurodegenerative brain.},
journal = {Acta neuropathologica communications},
volume = {14},
number = {1},
pages = {},
pmid = {42174650},
issn = {2051-5960},
mesh = {*Vimentin/metabolism ; Humans ; *Brain/metabolism/pathology ; *Alzheimer Disease/metabolism/pathology ; *Parkinson Disease/metabolism/pathology ; Female ; Male ; Aged ; Astrocytes/metabolism ; Aged, 80 and over ; Middle Aged ; },
abstract = {Alzheimer's disease (AD) and Parkinson's disease (PD) are characterized by brain accumulation of aggregated proteins, leading to neuronal and glial dysfunction. Compelling data indicate that changes in vimentin expression, structure, and localization reflect alterations in cellular homeostasis and may correlate with disease progression. Yet, the involvement of abnormal vimentin in AD and PD remains unclear. Here, we have thoroughly characterized the distribution of modified, disease-associated vimentin in the AD and PD brain parenchyma, as well as in cerebrospinal fluid (CSF), hiPSC-derived astrocytes and organoids. For this purpose, we used the form-specific vimentin antibody [84-1], originally generated to recognize abnormal vimentin on the surface of sarcoma cells. The 84-1 vimentin reactivity pattern was characterized through immunohistochemistry and proximity ligation assay. Moreover, proteomic analysis, Western blot, and ELISA were performed to quantify 84-1 vimentin levels and gain insights into its molecular features. Our data demonstrate that 84-1 can identify a distinct population of vimentin in the human brain that shows low affinity to commonly used vimentin antibodies. The 84-1 vimentin is enriched in disease conditions and forms distinct deposits in the affected regions of the AD and PD brain, often colocalizing with pathological protein aggregates. Interestingly, the 84-1 vimentin pool consists mainly of cleaved proteoforms and reduction-resistant aggregates. Moreover, 84-1 vimentin levels are elevated in the CSF of AD and PD patients as well as in the culture medium of human astrocytes exposed to αSyn or Aβ fibrils. Taken together, our data highlights the importance of modified vimentin in neurodegeneration and presents 84-1 vimentin as a potential biomarker and future treatment target for AD and PD.},
}

*Vimentin/metabolism
Humans
*Brain/metabolism/pathology
*Alzheimer Disease/metabolism/pathology
*Parkinson Disease/metabolism/pathology
Female
Male
Aged
Astrocytes/metabolism
Aged, 80 and over
Middle Aged

@article {pmid42174655,
year = {2026},
author = {Sharma, A and Segawa, E and Chen, X and Park, S and Wang, S and Irmen, RE and Constantino, NJ and Wang, C and Kanan, MF and Colonna, M and Macauley, SL and Cheng, JY and Hatanaka, K and Moline, M and Musiek, ES},
title = {Dual orexin receptor antagonism with lemborexant enhances microglial clearance of β-amyloid in mice.},
journal = {Molecular neurodegeneration},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13024-026-00948-y},
pmid = {42174655},
issn = {1750-1326},
abstract = {BACKGROUND: Sleep disturbances elevate brain amyloid-beta (Aβ) levels and represent a modifiable risk factor for Alzheimer's disease (AD). The orexin/hypocretin system regulates sleep-wake behavior and has emerged as a therapeutic target in AD; however, the effects of FDA-approved dual orexin receptor antagonists (DORAs) on amyloid pathology remain unclear. We compared lemborexant, an FDA-approved DORA, to doxepin, an antihistaminergic sleep medication, on amyloid pathology and microglial responses in PSAPP mice.

METHODS: PSAPP mice received lemborexant (10 or 30 mg/kg/day), doxepin (35 mg/kg/day), or vehicle for 6 weeks beginning prior to plaque onset or 4 weeks after established pathology. Sleep was assessed by piezoelectric monitoring and EEG/EMG polysomnography. Amyloid pathology and microglial responses were quantified by immunohistochemistry, confocal microscopy, and single-cell RNA sequencing. Microglial depletion was induced with the CSF1R inhibitor PLX3397.

RESULTS: Lemborexant enhanced sleep quality with less active-phase sedation than doxepin. Both drugs reduced initial diffuse plaque deposition, but only lemborexant prevented fibrillar plaque accumulation in young mice and slowed plaque growth in older mice. Lemborexant increased peri-plaque microglial CD68 expression and enhanced Aβ phagocytosis in vivo. Single-cell transcriptomics revealed a shift toward activated, DAM-like microglial states with upregulation of phagocytic genes without broad inflammatory induction. Microglial depletion abolished lemborexant's anti-amyloid effects.

CONCLUSIONS: Lemborexant mitigates amyloid pathology by augmenting microglial phagocytic function, positioning DORAs as promising therapeutics that couple sleep promotion with beneficial microglial modulation.},
}

@article {pmid42174727,
year = {2026},
author = {Yang, S and Xiao, X and Yang, Y and Cai, Y and Zou, Y and Tang, Y and Ma, H and Lai, Z},
title = {Alzheimer's disease polygenic risk, APOE ε4 dose, and accelerometer-derived circadian rest-activity rhythms in relation to incident dementia and Alzheimer's disease in UK Biobank: a prospective cohort study.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02088-3},
pmid = {42174727},
issn = {1758-9193},
abstract = {BACKGROUND: Circadian rest-activity rhythm disruption and sleep-wake fragmentation are common in Alzheimer's disease (AD) and may precede clinical diagnosis. Wrist-worn accelerometry enables objective, scalable circadian phenotyping in population cohorts. We examined whether AD polygenic risk and APOE ε4 dose are reflected in accelerometry-derived circadian phenotypes and whether these phenotypes predict subsequent incident dementia/AD.

METHODS: We analyzed 94,241 UK Biobank participants with 7-day wrist accelerometry and genetic data. Circadian phenotypes included relative amplitude (RA), L5 and M10 start hour, interdaily stability (IS), and intradaily variability (IV). Genetic exposures were a standardized AD polygenic risk score (AD-PRS) corresponding to the dataset-provided UK Biobank AD PRS variable standardized within the analytic sample, and APOE ε4 dose. Cross-sectional associations were tested with linear regression. Incident dementia/AD were modeled with Cox proportional hazards models with time zero defined as the accelerometry end date. Prespecified sensitivity analyses included lagged exclusions, competing risk of death, selection into accelerometry (inverse probability weighting), additional adjustment for overall activity, strict versus broad AD definitions, and RA × genetic-risk interaction terms in incident models.

RESULTS: AD-PRS showed no robust association with RA or phase timing (fully adjusted standardized beta = 0.0028; p = 0.358). APOE ε4 dose was associated with earlier M10 timing (standardized beta = -0.0074; p = 0.032). AD-PRS showed a nominal association with IS (standardized beta = 0.0073; p = 0.018) that did not survive multiple-testing correction. In incident analyses (n = 80,378; 949 dementia and 371 AD events), AD-PRS and APOE ε4 dose strongly predicted incident dementia and incident AD. Each 1-SD higher RA was associated with lower risk of incident dementia (HR = 0.80 per SD; p = 4.99 × 10[-19]) and incident AD (HR = 0.90; p = 0.031), meaning that lower RA corresponded to higher risk. The RA-dementia association remained stable across sensitivity analyses, whereas the RA-AD association attenuated after additional adjustment for overall activity. We found no evidence that RA associations differed by AD-PRS or APOE ε4 dose in incident interaction analyses (all interaction p values ≥ 0.362).

CONCLUSIONS: In this population cohort, AD polygenic risk showed minimal cross-sectional association with circadian amplitude or phase, whereas APOE ε4 dose was linked to slightly earlier peak daytime activity timing. Lower circadian amplitude (RA) consistently predicted higher subsequent dementia risk across multiple bias-oriented sensitivity analyses. For incident AD, the RA association was weaker after additional control for overall activity, supporting cautious interpretation of RA as a robust behavioral risk marker for dementia rather than an AD-specific genetic interaction signal.},
}

@article {pmid42174734,
year = {2026},
author = {Xue, H and Bi, S and Wang, M and Zhu, X and Wang, F and Wang, Y and He, Y and Wang, Y and Liu, X and Cui, B and Li, N and Zhao, Z and Zhang, C and Wu, L and Qi, Z and Yan, S and Lu, J},
title = {Optimizing cutoffs for clinical interpretation of brain amyloid status using PET/MRI: a multisite study.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02071-y},
pmid = {42174734},
issn = {1758-9193},
abstract = {BACKGROUND: Amyloid-β PET (Aβ-PET) imaging is playing an increasingly important role in the diagnosis and treatment of Alzheimer's Disease (AD). The Centiloid (CL) scale has been developed to standardize the measurements of Aβ PET imaging. Previous CL threshold settings were based on PET/CT, while our team's preliminary study found that CL values from PET/MRI are higher than those from PET/CT. Therefore, there is an urgent need to establish clinical interpretation cutoffs for Aβ status via PET/MRI to facilitate application in clinical practice.

METHODS: The clinical performance of Aβ PET/MRI and cerebrospinal fluid biomarkers were evaluated in a multisite cohort of 720 participants. Aβ-PET scans were visually read and quantified using CL method. A two-cutoff approach identified thresholds maintaining > 90% sensitivity/specificity and ≤ 20% intermediate cases, selected by maximal Youden index. Group comparisons of cerebrospinal fluid biomarkers and cognition used generalized linear models adjusted for age and sex.

RESULTS: The two-cutoff approach categorized Aβ-PET status as negative (CL ≤ 18.7), gray-zone (18.7-44.2), and positive (CL > 44.2). In Xuanwu cohort, it achieved an accuracy of 94.1%, a positive predictive value of 97.4%, a negative predictive value of 86.1%. In External cohort, the accuracy was 97.4%, positive predictive value 98.5%, negative predictive value 90.8%. Patients in the gray-zone group had lower cerebrospinal fluid(CSF) Aβ-42, Aβ-42/40 levels and a higher P-tau/Aβ-42 ratio.

CONCLUSIONS: This study established optimal CL-cutoff, providing a clinically applicable framework for interpreting Aβ PET/MRI findings. Incorporating a two-cutoff system facilitates the tracking of the AD continuum and supports individualized therapeutic decision-making.},
}

@article {pmid42174744,
year = {2026},
author = {Zülke, AE and Luppa, M and Sander, C and Baber, R and Biemann, R and Wirkner, K and Zeynalova, S and Zachariae, S and Matijevic, M and Engel, C and Reyes, N and Hinz, A and Glaesmer, H and Schroeter, ML and Witte, AV and Villringer, A and Löffler, M and Brayne, C and Riedel-Heller, SG},
title = {Prevalence and associated factors of subjective cognitive decline (SCD Plus): a cross-sectional analysis of three population-based European cohorts.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02087-4},
pmid = {42174744},
issn = {1758-9193},
abstract = {BACKGROUND: Subjective cognitive decline (SCD) is considered an early preclinical marker for Alzheimer's disease (AD). However, prevalence estimates vary widely due to inconsistent definitions. SCD Plus criteria were proposed by experts to improve specificity for preclinical AD. Population-based evidence on the prevalence and correlates of SCD Plus remains limited.

METHODS: Data from three population-based European cohorts (LIFE-Adult-Study, English Longitudinal Study of Ageing, and Cognitive Function and Ageing Study) comprising adults aged ≥ 60 years without dementia or marked cognitive impairment were harmonized to derive a common definition of SCD Plus based on available core criteria. Generalized linear models examined correlates of SCD Plus in pooled and study-specific analyses.

RESULTS: Among 18,795 participants (mean age (SD): 72.1 (6.8) years; 55.5% women), prevalence of SCD Plus, based on the harmonized operationalization, was 37.9% (33.3-53.7% across cohorts). In pooled analyses, SCD Plus was associated with higher education, depression, anxiety, hypertension, diabetes, heart disease, Parkinson's disease, and history of stroke, and inversely associated with smoking and better cognitive performance. Study-specific analyses additionally indicated associations with sleep and hearing-related problems, lower physical activity, thyroid disease, and personality traits (higher neuroticism and lower openness, agreeableness, conscientiousness).

DISCUSSION: SCD Plus was highly prevalent in three large European cohorts, assessed using a harmonized operationalization approach. Associations with several established, modifiable dementia risk factors underscore the relevance of SCD Plus for clinical risk assessment. Longitudinal studies are needed to determine whether the identified correlates influence subsequent cognitive decline in individuals with SCD Plus.},
}

@article {pmid42175484,
year = {2026},
author = {Wang, Z and Hu, X and Wang, Y and Sun, J},
title = {Systemic inflammation mediates the link between cardiometabolic multimorbidity and cognitive function among older U.S. adults: evidence from NHANES.},
journal = {Medicine},
volume = {105},
number = {21},
pages = {e48920},
doi = {10.1097/MD.0000000000048920},
pmid = {42175484},
issn = {1536-5964},
mesh = {Humans ; Male ; Aged ; Female ; *Inflammation/epidemiology/blood/complications ; Middle Aged ; Nutrition Surveys ; *Multimorbidity ; United States/epidemiology ; *Cognition/physiology ; Biomarkers/blood ; *Cognitive Dysfunction/epidemiology ; *Cardiovascular Diseases/epidemiology ; Aged, 80 and over ; Cross-Sectional Studies ; },
abstract = {Existing studies suggest that cardiometabolic multimorbidity (CMM) affects cognitive function, but the role of systemic inflammation in this association remains unclear. Therefore, investigating the mechanistic role of systemic inflammation in the link between CMM and cognitive decline is crucial. This study included 2492 adults aged ≥60 years from the 2011 to 2014 National Health and Nutrition Survey. Cognitive function was assessed using 3 validated tests. Inflammatory biomarkers - systemic immune-inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio, lymphocyte-to-monocyte ratio (LMR), neutrophil-to-platelet ratio (NPR), and white blood cell count - were integrated into a Comprehensive Inflammation Score (CIS) using principal component analysis. Weighted multivariate linear regression model were used to examine the associations among CMM, cognitive function, and inflammatory biomarkers. Restrictive cubic splines were used to explore the nonlinear relationship between systemic inflammation and cognitive function, and the bootstrap method was applied to examine the mediating role of systemic inflammation in the CMM-cognition relationship. Results showed that CMM was significantly associated with poorer Digit Symbol Substitution Test (DSST) performance (β = -6.57, 95% confidence interval [CI]: -8.44 to -4.70, P < .001), and higher systemic inflammation (NLR: β = 0.075, 95% CI: 0.040 to -0.111, P < .001). Systemic inflammation was also associated with poorer cognitive performance (NPR-Consortium to Establish a Registry for Alzheimer Disease: β = -2.21, 95% CI: -3.58 to -0.84, P = .007; LMR-Animal Fluency Test: β = 1.56, 95% CI: 0.25 to 2.87, P = .034; NPR-DSST: β = -5.93, 95% CI: -10.67 to -1.18, P = .017), and nonlinear associations were observed between inflammation and cognitive outcomes. Mediation analyses revealed that the SII, NLR, and LMR significantly mediated the association between CMM and DSST (SII: β = 0.053, 95% CI: 0.002 to 0.128; NLR: β = 0.133, 95% CI: 0.043 to 0.248; LMR: β = 0.118, 95% CI: 0.036 to 0.226), while NPR and CIS mediated the CMM-Consortium to Establish a Registry for Alzheimer Disease relationship (NPR: β = -0.051, 95% CI: -0.104 to -0.004; CIS: β = -0.034, 95% CI: -0.074 to -0.001). These results indicate that systemic inflammation may be a central pathway through which CMM contributes to cognitive dysfunction.},
}

Humans
Male
Aged
Female
*Inflammation/epidemiology/blood/complications
Middle Aged
Nutrition Surveys
*Multimorbidity
United States/epidemiology
*Cognition/physiology
Biomarkers/blood
*Cognitive Dysfunction/epidemiology
*Cardiovascular Diseases/epidemiology
Aged, 80 and over
Cross-Sectional Studies

@article {pmid42175539,
year = {2026},
author = {Liu, J and Zhang, Y and Wu, X and Hou, Z and Li, X and Wang, B and Cao, H and Wei, Y and Chen, L and Lin, F and Chen, M},
title = {Blood Inflammation Indexes Mediate the Association Between Weight-Adjusted-Waist Index and Cognitive Function Among Older Adults in the United States.},
journal = {Geriatrics & gerontology international},
volume = {26},
number = {5},
pages = {e70507},
doi = {10.1111/ggi.70507},
pmid = {42175539},
issn = {1447-0594},
support = {2023CXA004//Medical Innovation Project of Fujian Province/ ; },
mesh = {Humans ; Male ; Female ; Aged ; United States/epidemiology ; *Inflammation/blood ; *Cognition/physiology ; Nutrition Surveys ; Cross-Sectional Studies ; Aged, 80 and over ; *Cognitive Dysfunction/epidemiology ; Neuropsychological Tests ; *Body Weight ; },
abstract = {OBJECTIVES: This study explored the relationship between the weight-adjusted-waist index (WWI) and cognitive function among older individuals in the United States (US) and assessed whether blood inflammation indexes potentially mediate the association between WWI and cognitive function.

METHODS: The National Health and Nutrition Examination Survey data from 2011 to 2014 were collected. The WWI (waist circumference divided by the square root of bodyweight) was calculated, and cognitive performance was assessed using the Consortium to Establish a Registry for Alzheimer's Disease Word Learning (CERAD-WL) test, Delayed Recall (CERAD-DR) test, Animal Fluency Test (AFT), and Digit Symbol Substitution Test (DSST). Test-specific and global cognition z-scores were created. The evaluated blood inflammation indexes included systemic inflammatory response index (SIRI), systemic immune-inflammation index (SII), and neutrophil to lymphocyte ratio (NLR). Generalized linear regression models and mediation analysis were used to quantify the association.

RESULTS: After adjusting for covariates, the results of generalized linear regression analysis showed a significant negative connection between WWI and CERAD-WL (β = -0.47, 95% CI: -0.87, -0.07) and DSST (β = -1.59, 95% CI: -2.45, -0.72) among the 2026 participants. WWI correlated positively with SII, SIRI, and NLR (p < 0.05), whereas SIRI and NLR demonstrated a negative association with CERAD-WL and DSST (p < 0.05). The relationship between WWI and CERAD-WL performance was partially mediated by SIRI/NLR.

CONCLUSIONS: A negative association was observed between cognitive performance and WWI. The blood inflammation indexes were found to partially mediate the relationship between WWI and cognition. These findings warrant further evaluation in different populations.},
}

Humans
Male
Female
Aged
United States/epidemiology
*Inflammation/blood
*Cognition/physiology
Nutrition Surveys
Cross-Sectional Studies
Aged, 80 and over
*Cognitive Dysfunction/epidemiology
Neuropsychological Tests
*Body Weight

@article {pmid42175737,
year = {2026},
author = {Liang, S and Zhang, Q and Wang, X and Peng, L and Ji, X and Wang, J and Zhang, Y and Huang, J and Yang, J and Zhan, S and Xiao, Y and Liu, W and Chen, L},
title = {Electroacupuncture Improves the Learning and Memory by Modulating Hippocampal Glucose Metabolism through IGF1/IGF1R Signaling in Alzheimer's Disease.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e14241},
doi = {10.1002/advs.202514241},
pmid = {42175737},
issn = {2198-3844},
support = {82004440//National Natural Science Foundation of China/ ; 2024J09044//Fujian Provincial Natural Science Foundation of China/ ; 2025Y9600//Joint Funds for the innovation of science and Technology, Fujian Province/ ; 2024Y9533//Joint Funds for the innovation of science and Technology, Fujian Province/ ; 2023ZQNZD015//Health Service Research of Fujian Province/ ; },
abstract = {Alzheimer's disease (AD) is characterized by progressive cognitive decline and cerebral glucose hypometabolism. Emerging evidence suggests that modulating brain glucose metabolism represents a promising therapeutic strategy for AD. Here, we demonstrate that electroacupuncture (EA) improves cognitive function in 5×FAD mice by enhancing glucose metabolism in the hippocampus. EA treatment significantly attenuated learning and memory deficits and reduced β-amyloid (Aβ) deposition in 5×FAD mice. Further analysis revealed that these improvements were associated with enhanced hippocampal glucose metabolism and optimized information processing in the brain metabolic network. In addition, EA specifically activated the IGF1/IGF1R signaling pathway in the hippocampus, which promoted membrane translocation of GLUT3 and consequently enhanced neuronal glucose uptake. The glucose metabolic enhancement boosted tricarboxylic acid cycle activity and improved synaptic plasticity. Our findings establish a novel mechanism by which EA improves the learning and memory through the IGF1/IGF1R pathway, providing both theoretic and experimental support for the clinical application of EA in AD treatment.},
}

@article {pmid42175774,
year = {2026},
author = {Lin, Z and Jiang, Z and Chen, D and Liu, Y and He, Z and Ning, W and Wang, S and Guan, L},
title = {Novel Donepezil-Chalcone Hybrids as Potential Multifunctional Anti-Alzheimer's Disease Agents: Design, Synthesis, Computational Simulation, and In Vitro/In Vivo Biological Evaluation.},
journal = {Chemical biology & drug design},
volume = {107},
number = {5},
pages = {e70316},
doi = {10.1111/cbdd.70316},
pmid = {42175774},
issn = {1747-0285},
support = {22567024//The National Natural Science Foundation of China/ ; },
mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism/pathology ; Amyloid beta-Peptides/metabolism/chemistry ; *Donepezil/chemistry/pharmacology/therapeutic use ; Molecular Docking Simulation ; Mice ; Humans ; *Cholinesterase Inhibitors/chemistry/pharmacology/therapeutic use ; Drug Design ; Peptide Fragments/metabolism ; Acetylcholinesterase/metabolism/chemistry ; *Neuroprotective Agents/chemistry/pharmacology/therapeutic use/chemical synthesis ; Molecular Dynamics Simulation ; Glycogen Synthase Kinase 3 beta/metabolism/antagonists & inhibitors ; Butyrylcholinesterase/metabolism/chemistry ; Amyloid Precursor Protein Secretases/metabolism/antagonists & inhibitors ; *Chalcone/chemistry/pharmacology ; Male ; Protein Aggregates/drug effects ; },
abstract = {A novel series of donepezil-chalcone including pyridine, piperazine, phenylamide skeleton hybrids were designed, synthesized, and evaluated for their inhibitory activities against AChE and BChE. Subsequently, a subset of these derivatives was investigation to inhibit Aβ1-42 aggregation and promote Aβ1-42 disaggregation effects. Among them, compounds 8b, 8c, 8j, and 8ab possessing good activity were further assayed for their inhibitory effects on BACE-1 and GSK3β, as well as their PI displacement activity. 8b (AChE, IC50: 0.11 μM; BChE, IC50: 0.18 μM; Aβ1-42 aggregation, IC50: 3.40 μM; their ability to promote Aβ1-42 disaggregation, IC50: 4.53 μM; BACE-1, IC50: 1.82 μM; GSK3β, IC50: 0.98 μM) exhibited prominent bioactivities across the above assays. Meanwhile, the molecular docking and the molecular dynamics simulations were performed to analyze the interactions between 8b and the key amino acid residues of the target proteins, which verified the stability of the corresponding protein ligand complexes. Furthermore, 8b significantly attenuated the cytotoxicity induced by Fe[3+] and Cu[2+] in BV-2 microglial cells, L-Glu in HT-22 hippocampal neuronal cells, and Aβ1-42 in both BV-2 and SH-SY5Y neuroblastoma cells. Additionally, 8b reduced the levels of intracellular ROS and NO in LPS-stimulated BV-2 cells, demonstrating potent anti-inflammatory and neuroprotective properties. Acute toxicity tests in mice confirmed the safety profile of 8b. In in vivo studies, compound 8b effectively protected against neuroinflammation 8b ameliorated cognitive deficits in mice induced by AlCl3 combined with L-galactose, which was associated with the upregulation of p-GSK3β and the downregulation of p-Tau expression. In conclusion, 8b holds great potential as a promising multitarget-directed new lead compound for the treatment of AD.},
}

Animals
*Alzheimer Disease/drug therapy/metabolism/pathology
Amyloid beta-Peptides/metabolism/chemistry
*Donepezil/chemistry/pharmacology/therapeutic use
Molecular Docking Simulation
Mice
Humans
*Cholinesterase Inhibitors/chemistry/pharmacology/therapeutic use
Drug Design
Peptide Fragments/metabolism
Acetylcholinesterase/metabolism/chemistry
*Neuroprotective Agents/chemistry/pharmacology/therapeutic use/chemical synthesis
Molecular Dynamics Simulation
Glycogen Synthase Kinase 3 beta/metabolism/antagonists & inhibitors
Butyrylcholinesterase/metabolism/chemistry
Amyloid Precursor Protein Secretases/metabolism/antagonists & inhibitors
*Chalcone/chemistry/pharmacology
Male
Protein Aggregates/drug effects

@article {pmid42176081,
year = {2026},
author = {Ibrahim, RW and AlSheikh, MH},
title = {Model Validation Pipeline Against Longitudinal Alzheimer's Biomarker Data.},
journal = {Neuroinformatics},
volume = {24},
number = {2},
pages = {},
pmid = {42176081},
issn = {1559-0089},
mesh = {*Alzheimer Disease/metabolism/diagnostic imaging ; Humans ; Biomarkers/metabolism ; tau Proteins/metabolism ; Amyloid beta-Peptides/metabolism ; *Brain/metabolism ; *Models, Neurological ; Longitudinal Studies ; Connectome/methods ; Computer Simulation ; },
abstract = {This study develops a fractional-order model of Alzheimer's disease using a [Formula: see text]-generalized Atangana-Baleanu-Caputo (ABC) operator to capture the spatiotemporal dynamics of amyloid-beta and tau protein spread, coupled with a neuron regeneration mechanism. The fractional parameters α, [Formula: see text], and τ control memory depth, deformation of the kernel, and temporal scaling, respectively. Numerical simulations demonstrate that: (i) intermediate fractional orders [Formula: see text] produce biologically realistic propagation delays, (ii) lower [Formula: see text] values enhance nonlocal interactions and accelerate tau diffusion across the connectome, and (iii) increasing the scaling parameter τ slows accumulation, mimicking effective clearance or treatment response. Incorporating a treatment term with drug diffusion and decay reveals that sustained low decay rates ([Formula: see text]) markedly reduce tau concentrations and protect neuron populations. These findings show that the [Formula: see text]-ABC framework not only captures the hereditary and memory effects of Alzheimer's progression but also provides a flexible platform for simulating therapeutic interventions and predicting disease trajectories using real brain connectome data.},
}

*Alzheimer Disease/metabolism/diagnostic imaging
Humans
Biomarkers/metabolism
tau Proteins/metabolism
Amyloid beta-Peptides/metabolism
*Brain/metabolism
*Models, Neurological
Longitudinal Studies
Connectome/methods
Computer Simulation

@article {pmid42176146,
year = {2026},
author = {Bashir, B and Andotra, N and Sharma, P and Sharma, T and Chauhan, S and Awasthi, A and Singh, S and Singh, TG and Singh, SK and Vishwas, S},
title = {Neuroprotective role of cyanidin in Alzheimer's and Parkinson's disease: current insights and the road ahead.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {42176146},
issn = {1568-5608},
abstract = {Neurodegenerative diseases (NDs), including Alzheimer's disease (AD) and Parkinson's disease (PD), are characterized by progressive neuronal loss within the central nervous system, affecting more than 64 million individuals worldwide. Degeneration of cholinergic and dopaminergic neurons leads to cognitive impairment, motor dysfunction, and neuropsychiatric disturbances. Currently available pharmacotherapies provide only symptomatic relief, largely targeting single mechanistic pathways without halting disease progression. Increasing evidence supports the therapeutic potential of plant-derived bioactive compounds owing to their multitargeted pharmacological properties. Among these, cyanidin (CN), a naturally occurring flavonoid, exhibits potent antioxidant, anti-inflammatory, anti-apoptotic, and senolytic activities. CN has been shown to mitigate mitochondrial dysfunction and protect cholinergic and dopaminergic neurons, thereby addressing key pathological features of AD and PD. However, its clinical translation is limited by poor aqueous solubility (log P 2.41), reduced systemic bioavailability, and inadequate brain penetration. Nanotechnology-based novel drug delivery systems (NDDS), including lipid-based, polymeric, and inorganic nanoparticles, offer promising strategies to enhance CN solubility, stability, bioavailability, and blood-brain barrier permeability. This review discusses the pathophysiological mechanisms of AD and PD, the neuroprotective potential of CN, limitations associated with its conventional delivery, and the emerging role of nanoformulations in optimizing brain-targeted therapy.},
}

@article {pmid42176392,
year = {2026},
author = {Baron, KG and Alcántara, C and López, I and Euler, M and Baucom, BRW and Bermudez, B and Arones, Y and Carbajal-Salisbury, S and Fabian, G and Grandner, M and Gorovoy, S and Lopez, S and Parthasarathy, S and Troxel, W},
title = {Protocol for Nuestro Sueño: A randomized trial of a couples-based intervention to improve PAP adherence and sleep health among Hispanic patients beginning positive airway pressure (PAP) and their partners.},
journal = {Sleep medicine},
volume = {145},
number = {},
pages = {109019},
doi = {10.1016/j.sleep.2026.109019},
pmid = {42176392},
issn = {1878-5506},
abstract = {BACKGROUND: Obstructive sleep apnea (OSA) is more common among Hispanic individuals and contributes to risk for cardiometabolic diseases, dementia and poor quality of life. Positive airway pressure (PAP) improves sleep and quality of life, and culturally adapted interventions are promising for increasing treatment engagement. The goal of this study is to test Nuestro Sueño, a culturally adapted couples-based intervention to promote positive airway pressure adherence and sleep health for Hispanic couples in which one partner is recently diagnosed with OSA.

METHODS: We are conducting a two-arm, parallel group, single blind, randomized controlled pilot/feasibility trial to compare our novel culturally adapted treatment to an information control (IC). Nuestro Sueño is a culturally adapted dyadic behavioral intervention based on a transdiagnostic model. The digital health program involves 3- weekly sessions delivered via telehealth with a community health worker. Content is focused on education about OSA and PAP, improving both partner's sleep quality, increasing partner support and communication, and couple-level goal-setting around sleep and PAP use. The IC includes standardized patient educational materials. Both groups receive the usual follow-up care. Assessments will be completed pre-treatment, 1 and 3 months after starting PAP. Our main outcomes are feasibility and treatment satisfaction. Secondary outcomes include comparing Nuestro Sueño to IC for PAP adherence, sleep quality (self-report and objective) and cognitive measures of memory, processing speed and verbal fluency.

DISCUSSION: Nuestro Sueño is a novel culturally adapted intervention focused on improving PAP adherence and sleep health among couples in which one partner is recently diagnosed with OSA. Results of this study will be used to inform the design of a subsequent fully adequately-powered clinical trial. If successful, this intervention could significantly advance current clinical practice in the treatment of OSA and sleep health more comprehensively as well as promote sleep health equity among Hispanic patients, who are more likely to face challenges to obtaining diagnosis and treatment for OSA.

TRIAL REGISTRATION: Clinicaltrials.gov, NCT06649929.},
}

@article {pmid42176653,
year = {2026},
author = {Bourg, S and Place, M and Copin, C and Chaikuad, A and Robert, T and Holzmann, H and Müller, S and Bach, S and Ruchaud, S and Knapp, S and Buron, F and Routier, S and Bonnet, P},
title = {Identification of novel CLK1 inhibitors by computational fragment-based ligand design, co-crystallization, chemical synthesis and structure activity relationships.},
journal = {European journal of medicinal chemistry},
volume = {315},
number = {},
pages = {118977},
doi = {10.1016/j.ejmech.2026.118977},
pmid = {42176653},
issn = {1768-3254},
abstract = {CLK1 is one of the four human isoforms of the cdc2-like (CLK) kinases that has been suggested as a therapeutic target in diverse diseases based on its important role regulating mRNA splicing. For example, CLKs and closely related kinases such as DYRK1A have been targeted in Alzheimer's disease and other diseases in which splice site selection contributes to the disease development. Here we have developed an efficient in silico fragment-based ligand design approach to identify novel CLK1 inhibitors with excellent ligand efficiency based on an imidazo[2,1-b][1,3,4]thiadiazole fragment. More than one million docking poses were generated from 26,225 unique virtual compounds, and after applying several filtering steps, 11 compounds were selected, synthesized and their CLK1 inhibition and cellular potency were evaluated. Gratifyingly, inhibitor potencies were in excellent agreement with predicted values and crystallographic data of an inhibitor bound to CLK1 confirmed the unusual binding mode of the compounds.},
}

@article {pmid42176712,
year = {2026},
author = {Han, J and Li, Y and Lee, S and Lynch, KM and Bennett, EE and Ying, Q and Park, ES and Smith, RL and Stewart, JD and Whitsel, EA and Power, MC and Xu, X},
title = {A Critical Review of Potential Modifiers of Air Pollutant Associations with Dementia and Related Outcomes.},
journal = {Neurotoxicology},
volume = {},
number = {},
pages = {103470},
doi = {10.1016/j.neuro.2026.103470},
pmid = {42176712},
issn = {1872-9711},
abstract = {BACKGROUND: Air pollution has been linked with poor cognitive and brain health, including Alzheimer's Disease and Related Dementia (ADRD). However, whether specific individuals are more susceptible than others remains unclear.

PURPOSE: We aimed to review potential modifiers of the air pollution-cognitive/brain health association and identify subgroups potentially susceptible to adverse effects of air pollution exposure.

METHODS: We identified published, peer-reviewed articles in the Embase and Medline databases through the Ovid and PubMed search platforms and used Covidence, an online software tool, to extract relevant data from eligible articles. We then systematically reviewed and summarized the evidence on how health behaviors, genetic/molecular factors, environmental factors, and individual factors modify the association between ambient air pollution and cognitive/brain health.

RESULTS: Seventy-four publications, out of 6,372 relevant publications, met the eligibility criteria and were included in this review. Available studies suggested that race/ethnicity, geographic location, apolipoprotein E (APOE) e4 allele, socioeconomic status (SES), body mass index (BMI), and diet may modify the air pollution-ADRD association, and that age and education do not, although the available evidence precludes firm conclusions. Limited reporting precludes conclusions about other modifiers.

CONCLUSION: Efforts to reduce the harmful effects of air pollution exposure should consider sensitive groups. The current literature suggests differential susceptibility to the adverse effects of air pollution on cognitive and brain health. Future studies should include standardized reporting of effect modification for the likely modifiers identified here, allowing for more robust conclusions.},
}

@article {pmid42176904,
year = {2026},
author = {Li, X and Liao, J and Wang, J and Zhao, J and Liu, Z},
title = {Zinc Exacerbates Tau-Induced Neuronal Damage and Autophagy Dysfunction by Inhibiting the Akt/mTOR Pathway.},
journal = {Brain research bulletin},
volume = {},
number = {},
pages = {111955},
doi = {10.1016/j.brainresbull.2026.111955},
pmid = {42176904},
issn = {1873-2747},
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder in which tau pathology correlates more strongly with clinical progression than amyloid-β (Aβ). Zinc (Zn[2+]) is known to promote tau-mediated neurotoxicity; however, the underlying mechanisms remain incompletely understood. Our previous work demonstrated that Zinc ions (Zn[2+]) binds to the third microtubule-binding repeat (R3) of tau, inducing oligomerization and enhancing neurotoxicity. Here, we demonstrated that Zn[2+]+R3 elevated phosphorylated tau (p-tau) levels, impaired dendritic spine morphology, reduced synaptophysin expression, and disrupted autophagic flux. Mechanistically, Zn[2+]+R3 was associated with suppression of the Akt/mTOR signaling pathway, concurrent with autophagy initiation and impaired autophagosome-lysosome fusion. However, the present findings are associative in nature, as pharmacological or genetic rescue experiments were not performed; such experiments will be required to formally establish causality. Collectively, these findings suggest that targeting the Zn[2+] and R3 interaction may represent a potential therapeutic strategy for AD.},
}

@article {pmid42176916,
year = {2026},
author = {Rapalytė, S and Karalkevičiūtė, V and Baronaitė, I and Veiveris, D and Smirnovas, V and Žiaunys, M and Šulskis, D},
title = {Liquid-liquid phase separation and amyloid aggregation in the 14-3-3 protein family.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {152660},
doi = {10.1016/j.ijbiomac.2026.152660},
pmid = {42176916},
issn = {1879-0003},
abstract = {The 14-3-3 protein family, with over 1300 binding partners, is one of the largest regulators of protein-protein interactions (PPIs) in eukaryotic cells. They recognise and bind to phosphorylation-related motifs in their partner proteins, creating scaffolds to stabilise proteins and allowing or inhibiting kinases' access to their targets. 14-3-3 consists of seven isoforms (β, γ, ε, ζ, η, θ and σ), which are expressed across all tissues. Given their important role in PPIs, their dysregulation can contribute to a variety of diseases, such as cancer or neurodegenerative disorders like Creutzfeldt-Jakob's, Parkinson's or Alzheimer's diseases. Pathological effects can arise due to loss of function, aberrant interactions or protein aggregation. Notably, 14-3-3 aggregates have been detected in Lewy bodies or cerebrospinal fluid, mirroring the presence of amyloid proteins, such as α-synuclein (α-syn) or β-amyloid. Toxic amyloid aggregation signals the onset of neurodegeneration, which can occur through misfolding of proteins or liquid-liquid phase separation (LLPS) - a process during which proteins condense into membraneless organelles. Unlike other amyloidogenic proteins, there is little information on the conditions under which the 14-3-3 protein family members undergo LLPS or their relationship with amyloid aggregation. To address this gap, we examined all isoforms of 14-3-3 in vitro and observed the formation of amyloid aggregates, phase-separated droplets and spheroid-like structures. Our results revealed that the ε and θ isoforms form amyloid-like fibrils that can accelerate α-syn aggregation. Furthermore, molecular crowding conditions promoted phase separation and aggregation in most 14-3-3 proteins. Finally, 14-3-3s incorporated together with α-syn generate heterotypical droplets.},
}

@article {pmid42177194,
year = {2026},
author = {Zhao, Y and Fu, J and Zhao, P and Jiang, Y and Wang, Y and Zhang, Y and Li, Z and Zhao, Y and Li, N and Lang, B and Luo, Y},
title = {Ferroptosis and macrophage polarization: mechanisms, interplay, and implications for medical applications.},
journal = {Cell death discovery},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41420-026-03147-2},
pmid = {42177194},
issn = {2058-7716},
abstract = {Ferroptosis, a unique form of regulated cell death driven by iron-dependent lipid peroxidation, and macrophage polarization, which reflects the high plasticity of the immune system, represent two prominent frontiers in contemporary life sciences. Emerging evidence suggests a profound bidirectional interplay between these processes, mediated by iron metabolism reprogramming, lipid signaling molecules, and complex molecular axes such as RAGE-STAT3. This review systematically summarizes the biological mechanisms of ferroptosis and macrophage polarization, delving into their interaction within the tumor microenvironment, inflammatory responses, and cardiovascular and neurodegenerative diseases (e.g., Alzheimer's and Parkinson's). We highlight how M1 macrophages induce ferroptosis through pro-inflammatory cytokines and reactive oxygen species, while M2 macrophages inhibit it by modulating iron homeostasis and antioxidant capacity. Finally, we discuss therapeutic strategies targeting the ferroptosis-macrophage polarization axis, providing a theoretical foundation and novel perspectives for developing precise medical interventions.},
}

@article {pmid42177211,
year = {2026},
author = {Sheikh, S and Shadin, M and Eity, TA and Oni, MIJ and Khatun, MM and Chowdhury, R and Bhuia, MS and Alfaifi, M and Altemani, FH and Altemani, AH and Saleh, N and Islam, MT},
title = {Lenalidomide ameliorates cognitive impairment via putative AChE inhibition: an in silico and in vivo study in a scopolamine-induced cognitive impairment model.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-49461-8},
pmid = {42177211},
issn = {2045-2322},
abstract = {Alzheimer's disease (AD) causes progressive cognitive decline, and current therapies provide limited benefit. This study evaluated the neuroprotective effects of lenalidomide (LLM), a thalidomide derivative, in a scopolamine-induced mouse model of cognitive impairment, with emphasis on its acetylcholinesterase (AChE) inhibitory potential. Mice received LLM (5, 10, and 20 mg/kg), donepezil (DNP) (3 mg/kg), or a combination and were assessed using Y-maze, passive avoidance, novel object recognition, and Morris water maze tests. In silico analysis, including molecular docking, 100 ns molecular dynamics simulation and ADMET profiling were performed to investigate the interaction of LLM with AChE. Memory performance showed a significant and dose-dependent improvement after the treatment of LLM. The 20 mg/kg dose exhibited effects comparable to DNP. LLM and DNP work together to increase effectiveness. Docking and simulation analyses revealed strong, stable binding to AChE while ADMET values indicated good drug-likeness. LLM exhibits neuroprotective and cognition enhancing effects in the scopolamine-induced model. In silico study also shows its potential as an AChE inhibitor. The study's anti-inflammatory mechanisms might also be helpful but need more exploration.},
}

@article {pmid42177528,
year = {2026},
author = {Chen, L and Lin, X and Fu, M and Chen, S and Yan, Z and Diao, Y and Chen, G and Huang, Z and Sun, Y and Lin, Y and Ye, Z and Zhou, Y and Ye, Q},
title = {Engineered neuronal exosomes mediate α-synuclein clearance to ameliorate Parkinson's disease.},
journal = {Journal of nanobiotechnology},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12951-026-04552-6},
pmid = {42177528},
issn = {1477-3155},
support = {2023XH023//the Postdoctoral Research Project Startup Fund of Fujian Medical University Union Hospital/ ; 2024QH2020//the Startup Fund for Scientific Research of Fujian Medical University/ ; 2023Y9008//the Joint Funds for the Innovation of Science and Technology, Fujian Province/ ; 2024ZD01002//the Major Special Project of Fujian Provincial Health Technology Project/ ; U23A20423//the National Natural Science Foundation of China/ ; 2022Y2005//the Clinical Research Center for Precision Diagnosis and Treatment of Neurological Diseases of Fujian Province/ ; },
abstract = {Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease. A hallmark pathological feature of PD is the abnormal aggregation of α-synuclein (αSyn) into insoluble Lewy bodies. Consequently, developing strategies to inhibit αSyn aggregation in the brain has been a major research focus for PD treatment. This study developed a therapeutic approach using engineered neuronal exosomes. These exosomes were modified to extend their blood circulation half-life to 3.8 h and enhance targeting, with a 2.15 ± 0.09% brain signal proportion (vs. 0.78 ± 0.07% for free dye). They were then loaded with a self-developed αSyn aggregation-blocking peptide (sPep) as well as the antioxidant pyrroloquinoline quinone (PQQ). We investigated the therapeutic efficacy of this system in both in vitro and in vivo models of PD. Our experiments confirmed that the screened sPep effectively targeted and blocked αSyn aggregation both in vitro and in vivo. Neuronal exosomes, isolated by ultracentrifugation and hybridization, demonstrated strong abilities to cross the blood-brain barrier. In vivo studies revealed that the treatment significantly improved motor and cognitive functions in PD model mice. The underlying neuroprotective mechanisms included reducing αSyn aggregation, enhancing antioxidant capacity, ameliorating mitochondrial dysfunction, and suppressing cell apoptosis, collectively promoting the survival of dopaminergic neurons. These findings demonstrate that the engineered exosome-mediated delivery system exerts a protective effect against PD pathology.},
}

@article {pmid42171824,
year = {2026},
author = {Tang, H and Peng, F and Shi, Q and Dai, X and Hou, F and Dong, H and Zhang, L and Shuai, Z},
title = {β-Asarone, Tenuifolin, and YuanZhi Decoction Restore Cognitive Function and Modulate GRIN2B-Associated Autophagy in Alzheimer's Disease.},
journal = {Neurochemical research},
volume = {51},
number = {3},
pages = {},
pmid = {42171824},
issn = {1573-6903},
support = {2024ZL222//Zhejiang Provincial Traditional Chinese Medicine Science and Technology Project/ ; 2022KY479//Zhejiang Provincial Health Science and Technology Program Project/ ; },
mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism ; *Receptors, N-Methyl-D-Aspartate/metabolism/antagonists & inhibitors ; *Autophagy/drug effects/physiology ; Allylbenzene Derivatives ; *Anisoles/pharmacology/therapeutic use ; Molecular Docking Simulation ; Male ; Mice ; *Cognition/drug effects ; *Drugs, Chinese Herbal/pharmacology/therapeutic use ; *Neuroprotective Agents/pharmacology/therapeutic use ; Mice, Inbred C57BL ; Hippocampus/drug effects/metabolism ; },
abstract = {Alzheimer's disease (AD) is characterized by neurodegeneration, autophagy dysregulation, and mitochondrial stress. β-asarone and tenuifolin have shown neuroprotective effects, but their mechanisms remain unclear. YuanZhi decoction, a traditional formula containing Polygala tenuifolia, is used for cognitive impairment, yet its active constituents are not fully understood. A D-galactose-induced AD mouse model (150 mg/kg/day, s.c., 42 days) was established to evaluate β-asarone, tenuifolin, their combination, and YuanZhi decoction. Behavioral tests (MWM and NOR), Nissl staining, IHC, network pharmacology, molecular docking (including the GRIN2B inhibitor ifenprodil as positive control), Western blotting, biochemical assays, and RT-qPCR were performed. All treatments improved cognitive function, attenuated hippocampal neuronal loss and tau pathology, and restored metabolic parameters (ATP, ROS, DT, SOD2). Network pharmacology identified GRIN2B as a key hub target. Molecular docking revealed that β-asarone and senegenin (the active metabolite of tenuifolin) bind to the same allosteric pocket as ifenprodil on GRIN2B, sharing highly consistent interaction residues. GRIN2B upregulation in AD mice was accompanied by autophagic dysfunction (increased LC3B/LC3A ratio and PINK1, reduced p62) and mitochondrial stress. These abnormalities were significantly reversed by all treatments, with the combination and YuanZhi decoction showing greater efficacy. β-asarone, tenuifolin, their combination, and YuanZhi decoction alleviate GRIN2B-linked autophagic imbalance and mitochondrial stress in AD-like mice, supporting their therapeutic potential.},
}

Animals
*Alzheimer Disease/drug therapy/metabolism
*Receptors, N-Methyl-D-Aspartate/metabolism/antagonists & inhibitors
*Autophagy/drug effects/physiology
Allylbenzene Derivatives
*Anisoles/pharmacology/therapeutic use
Molecular Docking Simulation
Male
Mice
*Cognition/drug effects
*Drugs, Chinese Herbal/pharmacology/therapeutic use
*Neuroprotective Agents/pharmacology/therapeutic use
Mice, Inbred C57BL
Hippocampus/drug effects/metabolism

@article {pmid42171826,
year = {2026},
author = {Ghoflchi, S and Vatanparast, RG and Jalili-Nik, M and Kesharwani, P and Hosseini, H and Sahebkar, A},
title = {Emerging roles of combined curcumin and berberine in disease modulation: a comprehensive review of mechanisms and therapeutic relevance.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42171826},
issn = {1573-4978},
mesh = {*Berberine/pharmacology/therapeutic use ; *Curcumin/pharmacology/therapeutic use ; Humans ; Signal Transduction/drug effects ; Animals ; Neoplasms/drug therapy ; Anti-Inflammatory Agents/pharmacology ; },
abstract = {Curcumin, a polyphenolic compound derived from Curcuma longa, and berberine, an isoquinoline alkaloid extracted from plants such as Coptis chinensis, exhibit multifaceted pharmacological properties, including potent antioxidant, anti-inflammatory, antimicrobial, and anticancer effects. This narrative review evaluates their therapeutic potential across a diverse range of conditions, including nonalcoholic fatty liver disease (NAFLD), various malignancies, wound and plant infections, Alzheimer's disease, cardiovascular disorders, irritable bowel syndrome, cyclophosphamide-induced toxicity, interstitial cystitis, and systemic lupus erythematosus. Mechanistically, curcumin and berberine modulate gut microbiota, suppress lipogenic and inflammatory pathways (e.g., SREBP-1c and NF-κB), and activate PI3K/Akt and PPARγ signaling, thereby reducing hepatic steatosis and inflammation. Furthermore, they induce apoptosis, inhibit the PI3K/Akt/mTOR pathway, and modulate the tumor microenvironment, with their enhanced combined effects being significantly amplified by nanodelivery systems, such as liposomes. Their antimicrobial efficacy targets methicillin-resistant Staphylococcus aureus (MRSA) and plant pathogens by disrupting biofilms and generating reactive oxygen species via nanofibers and self-assembled submicron particles. Moreover, they reduce amyloid-beta aggregation, promote autophagy, and mitigate neuroinflammation. Additionally, their immunomodulatory properties effectively suppress autoimmune responses. Ultimately, this review synthesizes the current evidence regarding the therapeutic versatility of curcumin and berberine across multiple pathologies.},
}

*Berberine/pharmacology/therapeutic use
*Curcumin/pharmacology/therapeutic use
Humans
Signal Transduction/drug effects
Animals
Neoplasms/drug therapy
Anti-Inflammatory Agents/pharmacology

@article {pmid42171843,
year = {2026},
author = {Li, Q and Yang, Y and Guo, B and Liu, X and Luo, G and Wu, Y and Nie, J},
title = {Alkaloids from Dendrobium Nobile Lindl Improves Mitochondrial Function by Enhancing the Activity of v-ATPase in APP/PS1 Mice.},
journal = {Neurochemical research},
volume = {51},
number = {3},
pages = {},
pmid = {42171843},
issn = {1573-6903},
support = {Grant No. 82260842//National Natural Science Foundation of China/ ; Grant No. [2020]1Z075//Science and Technology Program of Guizhou Province/ ; },
mesh = {Animals ; *Mitochondria/drug effects/metabolism ; *Dendrobium/chemistry ; Mice, Transgenic ; Amyloid beta-Protein Precursor/genetics/metabolism ; *Alkaloids/pharmacology/therapeutic use/isolation & purification ; Mice ; Presenilin-1/genetics/metabolism ; PC12 Cells ; *Alzheimer Disease/drug therapy/metabolism ; *Vacuolar Proton-Translocating ATPases/metabolism ; Rats ; Male ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by neuronal loss and cognitive deficiency. Mitochondrial dysfunction and lysosomal abnormalities are critical during AD pathogenesis. The vesicular ATPase (v-ATPase) is a core regulator of lysosomal function, and its dysfunction impairs iron-sulfur protein synthesis and mitochondrial function. In this study, 4-month-old amyloid precursor protein/presenilin 1 (APP/PS1) double transgenic mice were treated with alkaloids from Dendrobium nobile Lindl (DNLA) at 20 and 40 mg/kg/day via oral gavage for 5 months (n = 10 per group). The Y-maze test showed that DNLA alleviated cognitive dysfunction in APP/PS1 mice. HE, Nissl, and β-galactosidase staining indicated that DNLA mitigated brain damage. DNLA also increased the protein levels of v-ATPase subunits ATP6V1A and ATP6V0a1 in the cortex, promoted mitochondrial iron uptake and utilization, enhanced mitochondrial function, and reduced neuronal damage. Dendrobine (DDB) accounted for 84.6% in DNLA used for animal experiments, and purified DDB (99.7%) was applied for in vitro assays. In PC12 cells, DDB restored ATP6V1A expression, enhanced v-ATPase activity, delayed cellular senescence, improved iron utilization, and elevated mitochondrial membrane potential and ATP levels in ATP6V1A-knockdown cells. These findings suggest that DNLA may attenuate learning and memory impairment in APP/PS1 mice. The mechanism may be related to enhanced v-ATPase activity, promoted mitochondrial iron uptake and utilization, and improved mitochondrial function.},
}

Animals
*Mitochondria/drug effects/metabolism
*Dendrobium/chemistry
Mice, Transgenic
Amyloid beta-Protein Precursor/genetics/metabolism
*Alkaloids/pharmacology/therapeutic use/isolation & purification
Mice
Presenilin-1/genetics/metabolism
PC12 Cells
*Alzheimer Disease/drug therapy/metabolism
*Vacuolar Proton-Translocating ATPases/metabolism
Rats
Male

@article {pmid42171909,
year = {2026},
author = {Hammad, MO and Shady, T and Moanes, B and El-Sharkawy, AR and Galal, AM and Tawfeek, AE and El-Sisi, AEM and Sameh, A and Mahrous, S and Atya, N and Essam, A and El-Desouky, S and Abd El-Aziz, MH},
title = {Quinoa seed (Chenopodium quinoa W.) extract attenuates Alzheimer's disease-like neurodegeneration: Targeting the SLC7A11/GPX4 pathway.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42171909},
issn = {1573-4978},
mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism/chemically induced ; *Chenopodium quinoa/chemistry/metabolism ; Rats ; Male ; *Plant Extracts/pharmacology ; Disease Models, Animal ; Oxidative Stress/drug effects ; *Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism ; Seeds/chemistry ; Hippocampus/metabolism/drug effects/pathology ; Antioxidants/pharmacology/metabolism ; Aluminum Chloride ; Signal Transduction/drug effects ; Cognitive Dysfunction ; Maze Learning/drug effects ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and hippocampal neuronal loss. Targeting ferroptosis-related pathways represents a promising therapeutic strategy.

OBJECTIVE: This study aimed to investigate the potential effect of quinoa (Chenopodium Quinoa W.) seed extract in an aluminum chloride (AlCl₃)-induced rat model of AD, with a particular focus on the SLC7A11/GPX4 antioxidant axis and NCOA4-mediated ferritinophagy.

METHODS: Adult male rats were randomly divided into four groups (n = 6): GI (Control), GII (AD), GIII (Quinoa + AD), and GIV (Alzemenda + AD). AD was induced by oral AlCl₃ administration. Quinoa extract and Alzemenda were administered concurrently with AlCl₃ throughout the experimental period. Behavioral performance was evaluated using the Morris Water Maze and Open Field Test. Oxidative stress markers, iron parameters, gene expression, and histopathological changes in the hippocampus were assessed.

RESULTS: GII exhibited significant cognitive impairment, increased lipid peroxidation, depletion of antioxidant defenses, downregulation of SLC7A11, and marked hippocampal iron deposition compared with GI. Treatment with quinoa (GIII) significantly improved learning and memory, restored GPX4 activity and GSH levels, upregulated SLC7A11 expression, and attenuated hippocampal iron deposition. GIV showed comparable behavioral and histological improvement. Systemic iron indices, as well as hippocampal FPN1 and NCOA4 expression, did not differ significantly among groups.

CONCLUSION: Quinoa seed extract exerts ameliorating effects in AlCl₃-induced AD by suppressing oxidative stress-associated neurodegeneration through preservation of the SLC7A11/GSH/GPX4 axis rather than modulation of iron export or ferritinophagy pathways.},
}

Animals
*Alzheimer Disease/drug therapy/metabolism/chemically induced
*Chenopodium quinoa/chemistry/metabolism
Rats
Male
*Plant Extracts/pharmacology
Disease Models, Animal
Oxidative Stress/drug effects
*Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism
Seeds/chemistry
Hippocampus/metabolism/drug effects/pathology
Antioxidants/pharmacology/metabolism
Aluminum Chloride
Signal Transduction/drug effects
Cognitive Dysfunction
Maze Learning/drug effects

@article {pmid42171931,
year = {2026},
author = {Shukla, S and Singh, RK},
title = {Crosstalk between death-associated protein kinase 1-regulated mechanisms and dysfunctions in alzheimer's disease.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42171931},
issn = {1573-4978},
mesh = {*Alzheimer Disease/metabolism/pathology/genetics ; Humans ; *Death-Associated Protein Kinases/metabolism/genetics ; Amyloid beta-Peptides/metabolism ; Neurons/metabolism/pathology ; Animals ; Signal Transduction ; Cell Death ; Reactive Oxygen Species/metabolism ; tau Proteins/metabolism ; Brain/metabolism ; Autophagy ; },
abstract = {Alzheimer's disease (AD) is a chronic progressive neurocognitive disorder manifested by increased production and deposition of amyloid beta (Aβ), abnormal tau phosphorylation, and formation of neurofibrillary tangles (NFTs). In addition, the disease progression is found to be associated with neuronal cell death, elevated levels of reactive oxygen species, mitochondrial dysfunction, and loss of synaptic plasticity in specific regions of the brain. AD is seventh leading cause of death and over more than 70%-80% of 57 million people having dementia develop AD worldwide. The disease population is also severely increasing at an alarming rate globally. The currently available treatment strategies remain insufficient to cure the disease because AD involves very complex pathways during its progression. Death-associated protein kinase 1 (DAPK1) is identified as a promising next-generation therapeutic drug target for the management of AD. It belongs to a family of serine/threonine kinases that influences different hypotheses involved in AD pathogenesis, such as tauopathies, Aβ hypothesis, redox, and autophagy pathways. In this review, we highlight the involvement of DAPK1 in various molecular pathways associated with AD pathogenesis and the crosstalk between DAPK1 and synaptic dysfunction and neuronal cell death implicated in AD. Moreover, the various small molecules, microRNAs, and phytoconstituents have been discussed, which have the potential to be developed as a treatment strategy targeting DAPK1-related pathological pathways in AD.},
}

*Alzheimer Disease/metabolism/pathology/genetics
Humans
*Death-Associated Protein Kinases/metabolism/genetics
Amyloid beta-Peptides/metabolism
Neurons/metabolism/pathology
Animals
Signal Transduction
Cell Death
Reactive Oxygen Species/metabolism
tau Proteins/metabolism
Brain/metabolism
Autophagy

@article {pmid42172039,
year = {2026},
author = {Han, X and Xue, J and Zhang, Q and Li, R and Guo, X and Duan, Q and Sang, S},
title = {Nitric oxide-enhanced blood-brain barrier penetration and mitochondria-targeted antioxidant carbon dots for Alzheimer's disease.},
journal = {Journal of materials chemistry. B},
volume = {},
number = {},
pages = {},
doi = {10.1039/d6tb00133e},
pmid = {42172039},
issn = {2050-7518},
abstract = {Alzheimer's disease (AD) involves a complex pathogenesis in which the β-amyloid (Aβ) cascade and oxidative stress hypotheses interact through mitochondrial dysfunction, forming a vicious cycle that underscores the need for multi-targeted therapeutic strategies. In this study, multifunctional carbon dots (EMA-CDs) were rationally designed and synthesised via a simple one-pot hydrothermal approach to integrate antioxidant activity, nitric oxide (NO) release capability, and mitochondrial targeting. EMA-CDs exhibited potent reactive oxygen species (ROS) scavenging abilities, efficiently eliminating hydroxyl radicals, superoxide anions, and DPPH radicals with rates exceeding 80%. Their mitochondrial specificity further alleviated intracellular oxidative stress and neuroinflammation. Notably, EMA-CDs at low concentrations (80 µg mL[-1]) markedly inhibited Aβ42 aggregation and promoted fibril disassembly, achieving inhibition and depolymerisation efficiencies of approximately 97.1% and 99.4%, respectively. In addition, EMA-CDs promoted NO production, which in turn modulated the expression of MMP-9 and ZO-1 proteins. This led to a reversible and transient opening of the blood-brain barrier (BBB), resulting in an enhanced penetration efficiency with a cumulative rate of 65.4% over 12 h. Furthermore, in the C. elegans CL2006 model, EMA-CDs significantly alleviated Aβ42 plaque deposition and reduced intracellular ROS levels by approximately 55%. Moreover, EMA-CDs extended the mean lifespan of the worms by about 6 days and enhanced reproductive capacity to 1.25-fold of the control, demonstrating potent in vivo neuroprotective and antioxidative stress effects. Collectively, this study demonstrates that EMA-CDs function as a versatile therapeutic platform for AD treatment and provide a promising avenue for the development of multi-target nanotherapeutics and novel AD intervention strategies.},
}

@article {pmid42172309,
year = {2026},
author = {Unruh, D and Todtleben, J and Johnson, K and Schlichtmann, B and Szabo, M and Holland, M and Carlson, C and Hinson, J and Levin, S},
title = {Analytical and Clinical Validity of a High-Throughput, Fully Automated Immunoassay for Plasma Neurofilament Light Chain.},
journal = {The journal of applied laboratory medicine},
volume = {},
number = {},
pages = {},
doi = {10.1093/jalm/jfag052},
pmid = {42172309},
issn = {2576-9456},
abstract = {BACKGROUND: Neurofilament light chain (NfL) has emerged as a promising blood-based biomarker for neuroaxonal damage across neurological disorders. Clinical utility has been correlated with disease activity, treatment response, and prognosis. However, routine clinical laboratory implementation requires comprehensive analytical validation to ensure reliability and accuracy.

METHODS: A fully automated Access NfL research use only (RUO) immunoassay was evaluated on the DxI 9000 Immunoassay Analyzer from Beckman Coulter. Analytical validation in plasma assessed precision, analytical sensitivity, linearity, analytical specificity (interference), calibrator and sample stability, and method comparison to the Quanterix Simoa NfL assay. Clinical validity included comparisons of Alzheimer disease (Ad, N = 20) in plasma and multiple sclerosis (MS, N = 16) in serum, vs healthy controls (N = 20 and N = 23, respectively). Plasma-serum equivalence was validated.

RESULTS: The NfL assay met analytical criteria, with precision demonstrating coefficients of variation <3% across runs, a lower limit of quantification of 3.10 pg/mL, linearity with <12% deviation, and <10% interference. Plasma NfL samples remained stable for 18 h at room temperature (<7% difference) and refrigerated (<5%), and through 5 freeze-thaw cycles (<8%). Method comparison yielded high correlation (R2 = 0.981) with positive systematic proportional bias (Passing-Bablok slope = 3.02). Ad patients showed significantly elevated NfL levels (median 49.3 pg/mL, IQR: 28.9-67.8) vs controls (median 29.1 pg/mL, IQR: 22.6-33.8; P = 0.02). MS patients similarly demonstrated higher NfL (median 27.7 pg/mL, IQR: 22.5-50.6) vs controls (median 19.2 pg/mL, IQR: 15.1-25.6; P = 0.003).

CONCLUSIONS: The high-throughput Access NfL assay demonstrated analytical and clinical validity, supporting implementation in research and clinical laboratories.},
}

@article {pmid42172320,
year = {2026},
author = {Kawase, H and Liu, S and Kurz, S and Bengelsdorff, V and Bonnavion, R and Jin, YJ and Roquid, KA and Cho, H and Liang, G and Banićević, M and Shiva, N and Yunes-Leites, PS and Günther, S and Tombor, L and Dimmeler, S and Looso, M and Mattonet, K and Wettschureck, N and Müller, UC and Offermanns, S},
title = {Endothelial soluble APP/APLP2 promote heart repair through KIT-mediated angiogenesis.},
journal = {Science advances},
volume = {12},
number = {21},
pages = {eaeh0301},
pmid = {42172320},
issn = {2375-2548},
mesh = {*Amyloid beta-Protein Precursor/metabolism/genetics ; Animals ; *Neovascularization, Physiologic ; Humans ; Mice ; *Myocardial Infarction/metabolism/pathology/genetics ; *Proto-Oncogene Proteins c-kit/metabolism/genetics ; *Endothelial Cells/metabolism ; Disease Models, Animal ; Angiogenesis ; },
abstract = {Amyloid precursor protein (APP) gives rise to amyloid-β, a pathological factor in Alzheimer's disease. However, the physiological role of APP and its homolog amyloid precursor-like protein 2 (APLP2), which are also widely expressed outside the nervous system, is largely unknown. Here, we show that endothelial APP and APLP2 are required for postischemia angiogenesis after myocardial infarction (MI). We found that hypoxia induced the endothelial expression of α-secretases, resulting in nonamyloidogenic processing of APP and APLP2 into the soluble forms APPsα and APLP2sα. Loss of endothelial APP and APLP2 led to decreased neovascularization as well as increased heart failure and mortality after MI, a phenotype that could be rescued by endothelial expression of APPsα. APPsα and APLP2sα exerted their proangiogenic effect by positive allosteric modulation of the endothelial receptor tyrosine kinase KIT, which promotes postischemia neovascularization. Our data identify a function of APP and APLP2 in endothelial cells, which is required for postischemia tissue repair, and suggest approaches to improve regeneration after MI and other ischemic diseases.},
}

*Amyloid beta-Protein Precursor/metabolism/genetics
Animals
*Neovascularization, Physiologic
Humans
Mice
*Myocardial Infarction/metabolism/pathology/genetics
*Proto-Oncogene Proteins c-kit/metabolism/genetics
*Endothelial Cells/metabolism
Disease Models, Animal
Angiogenesis

@article {pmid42172587,
year = {2026},
author = {Ross, RD and Dulion, B and Wong, J and Gritsenko, MA and Day, LZ and Mcdermott, JE and Jacobs, JM and Leurgans, SE and Yu, L and Bennett, DA},
title = {Establishing bone tissue level changes associated with cognitive impairment.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {},
number = {},
pages = {},
doi = {10.1093/gerona/glag134},
pmid = {42172587},
issn = {1758-535X},
abstract = {Alzheimer's disease (AD) and osteoporosis are common chronic conditions of ageing. Although several studies have reported an association between the two conditions, there is limited information on tissue-level mechanisms. In the current study, we performed unbiased proteomics on thoracic vertebral samples collected from female participants enrolled in the ROS and MAP cohorts to assess bone tissue-level changes associated with AD and other dementia-associated neuropathologies. Cognitive functioning and other participant characteristics were collected as part of ROSMAP study visits. Post-mortem evaluations assessed the burden of β-amyloid and paired helical filament tau (PHFtau) tangles, and other common age-related neuropathologies. A total of 45 bone samples were utilized from 19 female participants with a clinical diagnosis of AD dementia and 26 without AD dementia. The association between bone tissue protein abundance and cognition measured proximate to death, as well as neuropathologic indices, were evaluated using linear regression or logistic regression models, as appropriate. Bone tissue abundance of minichromosomal maintenance protein 3 (MCM3) and ubiquitin carboxyl-terminal hydrolase 24 (USP24) were positively associated with cognition and negatively associated with PHFtau tangle density. MCMC3 was also associated with cerebral arteriosclerosis, while USP24 was associated with cerebral amyloid angiopathy. Our findings suggest that processes regulating bone cell division may be involved in the link between brain and bone aging in a relationship that may not be specific to AD.},
}

@article {pmid42172591,
year = {2026},
author = {Sun, W and Shan, A and Wang, P and Han, X and Xu, C and Luan, H and Li, S and Wei, C},
title = {Plasma myeloperoxidase predicts cognitive decline in mild cognitive impairment: a multicenter longitudinal cohort study.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {},
number = {},
pages = {},
doi = {10.1093/gerona/glag135},
pmid = {42172591},
issn = {1758-535X},
abstract = {Mild cognitive impairment (MCI) is a key stage for early intervention in dementia, and its inflammatory mechanisms remain unclear. Myeloperoxidase (MPO), a key enzyme involved in inflammation and immune regulation, has not been fully studied in MCI. This multicenter longitudinal cohort study prospectively followed 133 patients with MCI for 12 months. Plasma MPO, Alzheimer's disease (AD)-related biomarkers (p-Tau181, p-Tau217, GFAP, NFL, and Aβ42/40), inflammatory cytokines (IL-1β, IL-6, and TNF-α), neuropsychological performance, and APOE genotype were assessed at baseline and follow-up. During follow-up, 58 patients showed cognitive deterioration and 75 remained non-deteriorated. At both baseline and the 12-month follow-up, the cognitive deterioration group showed higher MPO, IL-1β, and IL-6 levels than the non-deterioration group. Within-group longitudinal changes from baseline to follow-up were modest and were not statistically significant. Cross-sectional analyses showed that MPO was associated with IL-1β, IL-6, Aβ42/40, MMSE, and ADAS-Cog at different assessment time points. Longitudinal delta analyses showed that changes in MPO were significantly correlated with changes in MMSE, IL-1β, and IL-6, but not with changes in ADAS-Cog or Aβ42/40. After adjustment for potential confounders, MPO remained an independent predictor of cognitive deterioration in MCI (OR = 1.018, 95% CI: 1.00-1.03, p = 0.015). Nomogram analysis showed that MPO was the most prominent predictor in the model. These findings suggest that elevated plasma MPO may serve as a clinically accessible prognostic biomarker for risk stratification in patients with MCI.},
}

@article {pmid42172661,
year = {2026},
author = {Motisi Bertulli, A and Bezzio, C and Marsano, S and Corradini, I and Stranges, S and Matteoli, M and Armuzzi, A},
title = {Does inflammatory bowel disease play a role in cognitive decline? A systematic review.},
journal = {Journal of Crohn's & colitis},
volume = {20},
number = {5},
pages = {},
doi = {10.1093/ecco-jcc/jjag057},
pmid = {42172661},
issn = {1876-4479},
mesh = {Humans ; *Inflammatory Bowel Diseases/complications/psychology ; *Cognitive Dysfunction/etiology/epidemiology ; },
abstract = {BACKGROUND & AIMS: Inflammatory bowel disease (IBD) has been increasingly linked to cognitive impairment (CI) and dementia, yet the underlying mechanisms driving this association remain poorly understood and population, clinical and experimental studies show controversial results. Among others, factors such as chronic inflammation, gut-brain axis dysfunction, and psychological comorbidities have been proposed as contributors to cognitive deficits in IBD patients. The objective of this systematic review was to evaluate the existing literature on the relationship between IBD and cognitive function, considering observational and preclinical studies, with the aim to identify key factors influencing CI and potential clinical implications. The main focus of this review is on the use of IBD treatments, which may have a potential impact on CI.

METHODS: We conducted a systematic review according to PRISMA guidelines. PubMed and Scopus were searched from database inception up to August 30, 2024, for studies assessing cognitive performance in individuals with IBD. Clinical and epidemiological studies, genetic investigations (Mendelian Randomization and Genome-wide Association studies), and preclinical models examining memory, attention, and executive functions were included. Two reviewers independently extracted data and assessed methodological quality and risk of bias.

RESULTS: The research yielded 66 included studies, including 31 populations studies, 13 genetics studies, and 22 preclinical research studies. Our findings suggest that patients with IBD may exhibit impaired cognitive function, particularly in memory, attention, and executive processing. Disease activity, chronic inflammation and psychological stress appear to contribute to these deficits, while some treatment strategies seem to mitigate the risk of CI.

CONCLUSION: IBD is associated with CI and increased dementia risk, with biologics potentially mitigating neuroinflammation-related decline. More longitudinal studies and randomized clinical trials, also on intermediate endpoints, are needed to clarify the neuroprotective role of some therapies and optimize treatment strategies.},
}

Humans
*Inflammatory Bowel Diseases/complications/psychology
*Cognitive Dysfunction/etiology/epidemiology

@article {pmid42172709,
year = {2026},
author = {Jing, W and Zheng, M and Yang, X and He, B and Zhang, X and Cui, W},
title = {Micro- and nanoplastics in the central nervous system: Transport pathways, neurotoxicity, and implications for brain disorders.},
journal = {Ecotoxicology and environmental safety},
volume = {319},
number = {},
pages = {120278},
doi = {10.1016/j.ecoenv.2026.120278},
pmid = {42172709},
issn = {1090-2414},
abstract = {Micro- and nano-plastics (MNPs) are widely distributed across global ecosystems and have been extensively detected in human tissues, including the brain. The levels of MNPs are highly correlated with the occurrence of various brain disorders, suggesting the potential central nervous system (CNS) toxicity of MNPs. In this review, we summarize the major circuits by which MNPs may transport into and out of the CNS, including blood-brain barrier crossing, nasal-to-brain routes, and glymphatic system transport. Small-sized MNPs are difficult to eliminate from the brain, which may explain why MNPs may accumulate in the brain. We further discuss the potential neurotoxic effects of MNPs, such as inducing synaptic and neuronal injury, promoting neuroinflammation, dysregulating the neuroendocrine system, and modulating the gut-brain axis. MNP-induced CNS toxicity follows a pattern in which increased susceptibility occurs before direct toxicity. We also review evidence that MNPs, together with environmental and genetic factors, may synergistically contribute to cognitive impairment in Alzheimer's disease, motor dysfunction in Parkinson's disease, and depression- and anxiety-like behaviors. Prenatal exposure to MNPs might induce autism spectrum disorder-related phenotypes in offspring. MNPs could also obstruct cerebral vessels and trigger acute cerebrovascular diseases, as well as promote the entry of viruses such as SARS-CoV-2 into the CNS, thereby increasing the occurrence of neurological symptoms. Finally, this review discusses physical, pharmacological, and plastics substitution interventions designed to regulate MNPs transport in the brain and enhance neuroprotection, thereby reducing CNS toxicity of MNPs.},
}

@article {pmid42172854,
year = {2026},
author = {Copeland, EN and Mohammad, A and Baranowski, BJ and Marcella, BM and Beaudette, SM and MacPherson, REK and Fajardo, VA},
title = {Voluntary wheel running combined with low-dose lithium supplementation improves novel object recognition in male DBA/2 J mdx mice.},
journal = {Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS)},
volume = {95},
number = {},
pages = {127893},
doi = {10.1016/j.jtemb.2026.127893},
pmid = {42172854},
issn = {1878-3252},
abstract = {BACKGROUND: Duchenne muscular dystrophy (DMD) is a severe neuromuscular disorder caused by a mutation to the dystrophin gene. Cognitive dysfunction is a lesser-known symptom of DMD; however, approximately one-third of patients experience it. Though the mechanisms underlying these dysfunctions are unknown, research points towards an Alzheimer's disease (AD)-like pathology in clinical and preclinical work. In a recent study, we previously demonstrated that inhibiting glycogen synthase kinase 3 (GSK3) through a combination of low-dose lithium supplementation and voluntary wheel running (VWR) improved muscle quality and function in the mdx mouse model of DMD. Interestingly, both VWR and GSK3 inhibition with lithium can exert neuroprotective effects against Alzheimer's pathology; however, whether this treatment can also benefit cognitive function in mdx mice remains unknown.

METHODS: Here, we conducted a brief follow-up study to determine whether inhibiting GSK3 with a combination of low-dose lithium supplementation and VWR would enhance novel object recognition in mdx mice, while also investigating potential mechanisms, including beta-secretase activity, Tau phosphorylation, and sarco(endo)plasmic reticulum calcium ATPase (SERCA) activity.

RESULTS: Our findings show that lithium and VWR treatment, on average, improved novel object recognition in mdx mice-a result that may be linked to enhanced SERCA activity within the hippocampus but not to any changes in beta-secretase activity or tau phosphorylation.

CONCLUSION: Taken together, these data point to the potential benefits of Li and VWR on cognitive function in mdx mice, highlighting the need for future research aimed at teasing out the potential mechanisms.},
}

@article {pmid42172885,
year = {2026},
author = {Da Ros, LU and Ferrari-Souza, JP and de Bastiani, MA and Hauschild, LA and Bellaver, B and Ferreira, PCL and Leffa, DT and Povala, G and Lussier, FZ and Chamoun, M and Bezgin, G and Benedet, AL and Rahmouni, N and Macedo, AC and Blennow, K and Ashton, N and Zetterberg, H and Borelli, WV and Souza, DO and Pascoal, TA and Rosa-Neto, P and Zimmer, ER and , },
title = {Hypertension acts together with Aβ pathology in late-life to promote memory loss.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {7},
pages = {100579},
doi = {10.1016/j.tjpad.2026.100579},
pmid = {42172885},
issn = {2426-0266},
abstract = {Midlife hypertension (HTN) contributes to cognitive decline in Alzheimer's disease (AD). However, the exact effect of late-life HTN on the AD pathology and on cognitive decline is still controversial. Here, we aimed to assess the impact of HTN and AD pathology in cognitively unimpaired (CU) individuals over 65 years of age on longitudinal cognitive decline. We evaluated 637 CU individuals from two independent cohorts (475 CU individuals from the ADNI cohort; and 162 CU individuals from the TRIAD cohort), with a follow-up of up to 6 years. Linear mixed-effects models showed that HTN and Aβ acted together to promote longitudinal cognitive decline, especially memory loss, in a synergistic way, with a dose-dependent association of blood pressure and Aβ pathology. Hence, HTN in late-life confers additional risk for cognitive decline, particularly for memory loss, in CU individuals at risk of developing dementia due to AD and is a potential modifiable risk factor even at older age.},
}

@article {pmid42172936,
year = {2026},
author = {Li, Y and Li, H and Xu, Z and Zhou, SK and , },
title = {CLIS: Causality-inspired Longitudinal Image Synthesis and its application to Alzheimer's disease characterization.},
journal = {Medical image analysis},
volume = {112},
number = {},
pages = {104126},
doi = {10.1016/j.media.2026.104126},
pmid = {42172936},
issn = {1361-8423},
abstract = {Clinical decision-making relies heavily on causal reasoning and longitudinal analysis of clinical variables, which include demographic variables, biomarkers, measurements, etc., often stored in a tabular format, and visual medical images. For example, for a patient with Alzheimer's disease (AD), how might brain gray matter atrophy evolve over a year under a hypothetical change in the Aβ42 biomarker level in cerebrospinal fluid? Answering such hypothetical questions is important for diagnosis and follow-up treatment, yet these medical images are neither readily acquired nor effectively predicted by correlation-based image synthesis models. Hence, a Causality-inspired Longitudinal Image Synthesis (CLIS) model is valuable. Building such a CLIS model faces three primary challenges: mismatched dimensionality between high-dimensional images and low-dimensional tabular variables, inconsistent intervals in follow-up data, and the complexity of medical causal mechanisms. In this paper, we propose a CLIS model that addresses these challenges via a novel integration of generative imaging, continuous-time modeling, and structural causal models combined with a neural network. Specifically, we first depict dependencies among tabular variables - including demographics, clinical biomarkers, and brain volumes - using a tabular causal graph (TCG), and then extend this to a tabular-visual causal graph (TVCG) to synthesize brain MRIs in a causality-inspired manner. An independent variable is also introduced to explicitly model time intervals. We train our CLIS on the ADNI dataset and evaluate it on two additional AD datasets, demonstrating that the synthesized images are both high-quality and interpretable. Furthermore, the generated MRIs provide insights for AD characterization, illustrating the model's potential utility in clinical applications.},
}

@article {pmid42173146,
year = {2026},
author = {Liu, X and Marin, T and Vafay Eslahi, S and Tiss, A and Chemli, Y and Najmaoui, Y and Jang, SI and El Fakhri, G and Ouyang, J},
title = {Scan-wise generalized PET denoising with contrastive adversarial learning.},
journal = {Physics in medicine and biology},
volume = {},
number = {},
pages = {},
doi = {10.1088/1361-6560/ae7231},
pmid = {42173146},
issn = {1361-6560},
abstract = {ObjectiveDeep learning (DL) has significantly advanced low-count PET denoising. However, models trained on specific distributions often yield biased outputs when applied to scans with different activity distributions caused by anatomical and physiological variations (distribution shifts). Existing methods fail to generalize well across these scan-wise variations. Our goal is to formulate PET denoising as a scan-wise Domain Generalization (DG) problem to mitigate these variations and achieve robust, unbiased denoising for unseen scans.ApproachWe propose a contrastive adversarial domain generalization framework to learn scaninvariant features efficiently. We leverage the property that multiple low-count noise realizations can be generated from a single raw list-mode PET scan to form a scan-wise domain distribution. Unlike conventional adversarial training with cross-entropy loss, we propose a contrastive adversarial framework that minimizes the mutual information between feature and scan-wise domains. Considering that each subject can have multiple scans in longitudinal studies, we further propose an ordered and memoryqueued contrastive adversarial framework. This method efficiently includes realizations from the same scan as positive pairs, different scans of the same subject as pseudopositive pairs, and different subjects as negative pairs in a memory batch. We explicitly exploit their ordered relationship as prior knowledge using a novel noisy-robust multipositive ordinal contrastive loss.Main resultsWe systematically validated the effectiveness of our methods using 1,920 noise realizations derived from 80 subjects with 192 longitudinal scans of MK-6240 tau PET data.The proposed contrastive adversarial domain generalization approach demonstrated superior denoising performance compared to cross-entropybased adversarial methods and standard baselines. The ordered contrastive loss successfully improved the peak signal-to-noise ratio and structural similarity index consistently while reducing bias and standard deviation in Alzheimer-related regions and the whole brain. Significance To our knowledge, this is the first attempt to alleviate the performance degradation in cross-scan denoising from the perspective of domain generalization. Our study is also a pioneering work in utilizing longitudinal scans as pseudo-positives within an ordered contrastive learning scheme to exploit fine-grained relationships for robust clinical PET imaging applications.},
}

@article {pmid42173233,
year = {2026},
author = {Zhang, B and Ran, Z and Li, XY and Wei, ZH and Wang, DM and Lu, MH},
title = {A GPCR atlas across human microglial states in Alzheimer's disease: Insights from snRNA-seq and hiPSC models.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115845},
doi = {10.1016/j.expneurol.2026.115845},
pmid = {42173233},
issn = {1090-2430},
abstract = {Microglia are the resident immune cells of the central nervous system, and their state heterogeneity is closely associated with the pathological progression of Alzheimer's disease (AD). Single-nucleus RNA sequencing (snRNA-seq) studies have identified multiple transcriptional states of microglia in human AD brain. However, the characteristics and potential functions of G protein-coupled receptors (GPCRs) across different states remain poorly systematized. This review systematically searched and reviewed snRNA-seq studies based on human brain tissue published between 2020 and 2025. By re-analyzing GPCR expression across these datasets, we focuses on characterizing the differential expression characteristics and potential functions of GPCRs in five key AD-related microglial states: disease-associated microglia, tau-associated microglia, inflammation-associated microglia, proliferation-associated microglia, and interferon-associated microglia. Furthermore, we cross-reference these findings with single-cell sequencing data from human induced pluripotent stem cell (hiPSC)-derived microglia to prioritize a conserved set of GPCRs of high interest. In summary, by integrating transcriptomic evidence from both post-mortem human brain and hiPSC models, this review not only refines the understanding of microglial heterogeneity in AD but also also provides a set of candidate GPCR targets for subsequent validation and drug discovery efforts against AD.},
}

@article {pmid42173630,
year = {2026},
author = {Karamveer, and Tiwary, BK},
title = {Artificial intelligence in multi-omics analysis of neurological diseases.},
journal = {Progress in molecular biology and translational science},
volume = {222},
number = {},
pages = {207-228},
doi = {10.1016/bs.pmbts.2026.01.016},
pmid = {42173630},
issn = {1878-0814},
mesh = {Humans ; *Artificial Intelligence ; *Nervous System Diseases/genetics/metabolism ; *Genomics ; Multiomics ; },
abstract = {The integration of multi-omics data using Artificial Intelligence (AI) is rapidly transforming the landscape of neurological disease research. As our understanding of complex brain disorders such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, and schizophrenia deepens, there is an ever-increasing demand for sophisticated tools for handling and interpreting high-dimensional biological data. In this chapter, we explore the integration of AI and multi-omics in neurobiology, describing the evolution of AI techniques from classical rule-based systems to cutting-edge deep learning frameworks and foundation models. We provide a comprehensive guide to matching specific omics combinations with appropriate AI methods to answer targeted neuroscientific questions, discuss major neurological disease-specific databases and resources, and present detailed case studies that highlight the real-world potential and clinical translation of these approaches. Additionally, we address the existing technical, ethical, and interpretability challenges that must be overcome for successful clinical implementation. By the end of this chapter, readers will be equipped with both theoretical knowledge and practical guidance to choose and apply appropriate AI tools in multi-omics neurological disease research.},
}

Humans
*Artificial Intelligence
*Nervous System Diseases/genetics/metabolism
*Genomics
Multiomics

@article {pmid42173995,
year = {2026},
author = {Sharhan, O and Al-Madhagi, WM and Al-Ghubari, MM and Al-Gailani, YA and Alzomor, AKY and Al-Madhagy, SA},
title = {Synthesis and in vitro/in silico evaluation studies of arensulfonylhydrazinoxamoyl amine and amino acid derivatives as preliminary acetylcholinesterase inhibitors.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-52865-1},
pmid = {42173995},
issn = {2045-2322},
abstract = {Two arensulfonylhydrazinoxamoyl derivatives were synthesised via a modified two-step procedure involving oxalyl activation followed by sulfonation and were fully characterized using IR, UV-Vis, [1]H NMR, and MS analyses, confirming their structures and high purity. The biological profiles of the compounds were evaluated using combined in vitro and in silico approaches. Both derivatives exhibited measurable acetylcholinesterase (AChE) inhibitory activity, with compound 2 showing greater potency (IC50 = 6.51 ± 0.33 µM) than compound 1 (IC50 = 24.05 ± 1.29 µM), although both less active than the reference inhibitor donepezil. Cytotoxicity evaluation revealed weak activity against MCF-7 breast cancer cells and moderate activity against HepG2 liver cancer cells, with compound 2 again demonstrating superior activity (IC50 = 811.5 ± 32.2 µM). Molecular docking studies supported favourable binding of both compounds within the active gorge of human AChE (PDB: 4EY7), while interactions with BACE1 were weak and non-specific. In silico ADME/T analysis suggested acceptable drug-likeness with no violations of Lipinski's rule, although the high polarity of compound 1 indicated low oral absorption. PASS predictions did not indicate Alzheimer-specific activity but suggested general potential protease- and kinase-related inhibition. Overall, these compounds represent preliminary scaffolds with modest AChE inhibition and limited cytotoxicity, requiring structural optimisation for further therapeutic development.},
}

@article {pmid42167944,
year = {2026},
author = {Demina, A and Casey, D and Amaral, S and Fabus, MS and Béjot, Y and Trojak, B},
title = {Protocol for a living systematic review of randomised controlled trials on the clinical efficacy of transcranial pulse stimulation in neurological and psychiatric conditions.},
journal = {BMJ open},
volume = {16},
number = {5},
pages = {e117329},
doi = {10.1136/bmjopen-2026-117329},
pmid = {42167944},
issn = {2044-6055},
mesh = {Humans ; Systematic Reviews as Topic ; Randomized Controlled Trials as Topic ; *Mental Disorders/therapy ; *Transcranial Direct Current Stimulation ; Research Design ; *Nervous System Diseases/therapy ; Treatment Outcome ; *Alzheimer Disease/therapy ; },
abstract = {INTRODUCTION: Transcranial pulse stimulation (TPS) is a novel technology with therapeutic promise for Alzheimer's disease. Given its novelty and the rapidly evolving research in neurology and mental health using this technology, large randomised controlled trials are expected. Therefore, an independent and up-to-date synthesis of the available evidence is needed. In our effort to create a living systematic review of the clinical efficacy of TPS across various conditions, we aim to describe its methodology to ensure its transparency and scientific rigour. This protocol details the predefined methods related to search frequencies, updates to the review and quantitative synthesis.

METHODS AND ANALYSIS: We will only include randomised controlled trials involving clinically diagnosed populations and comparing active TPS to sham TPS. We will search MEDLINE, CENTRAL and Web of Science, as well as trial registries and grey literature. The principal searches in databases and trial registries will be rerun monthly, and new evidence will be integrated. Study selection, data extraction and risk-of-bias assessments will be performed independently and in duplicate. All relevant clinical outcomes measured with validated psychometric scales and tests will be collected. The relevance of a quantitative synthesis, the studies to be included in pairwise meta-analysis, appropriate scales, questionnaires and time points will be discussed by the research team annually. If a meta-analysis is conducted, we will use the standardised mean difference as the measure of effect size. We will assess our confidence in the cumulative evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach.

ETHICS AND DISSEMINATION: For this systematic review and meta-analysis, we will collect existing data without generating new datasets. Therefore, ethics approval or consent to participate is not required.We will publish our initial systematic review when a total of four randomised controlled trials across different health conditions using active TPS compared with sham TPS are available. At this stage of our project, we anticipate updating the living systematic review annually following the publication of the baseline review. We will conclude the living phase of the review when high certainty of evidence is achieved or if the topic loses its relevance.

CRD42024595947.},
}

Humans
Systematic Reviews as Topic
Randomized Controlled Trials as Topic
*Mental Disorders/therapy
*Transcranial Direct Current Stimulation
Research Design
*Nervous System Diseases/therapy
Treatment Outcome
*Alzheimer Disease/therapy

@article {pmid42168524,
year = {2026},
author = {Akagi, S and Sato, Y and Sakamoto, T and Minamisawa, M},
title = {Sequential co-extraction of gut microbial DNA and fecal polyamines enables integrated microbiome-metabolite profiling in an Alzheimer's disease mouse model.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-54312-7},
pmid = {42168524},
issn = {2045-2322},
support = {FTR-156//Translational Research Grant from Fujita Health University/ ; FTR-156//Translational Research Grant from Fujita Health University/ ; },
abstract = {Early, non-invasive biomarkers for Alzheimer's disease (AD) are urgently needed. Impaired polyamine metabolism, regulated by intracellular pathways and the gut microbiota, has been reported in postmortem brains of AD patients. Here, we developed a sequential co-extraction workflow (Method 10) that enables recovery of gut bacterial DNA and fecal free polyamines-putrescine, spermidine, and spermine-from the same small mouse fecal sample, allowing paired microbiome and metabolite profiling. Applying this workflow to an AD knock-in mouse model and age-matched controls at 8, 32, and 56 weeks revealed an early decrease in Lactobacillus abundance at 8 weeks accompanied by elevated spermidine levels (p < 0.05), while total fecal polyamine concentrations increased further in AD mice at 56 weeks. These findings suggest that integrated fecal microbiome-polyamine profiling may provide exploratory microbiota-polyamine signatures associated with AD progression.},
}

@article {pmid42168643,
year = {2026},
author = {Macedo, AC and Provost, K and Soucy, JP and Haeger, A and Therriault, J and Trudel, L and Rahmouni, N and Fernandez-Arias, J and Aumont, É and Lebrun, A and Chan, T and Hosseini, SA and Bezgin, G and Tissot, C and Servaes, S and Hall, B and Stevenson, J and Hopewell, R and Hsiao, CH and Triana-Baltzer, G and Kolb, HC and Benedet, AL and Massarweh, G and Klostranec, J and Vitali, P and Pascoal, TA and Rosa-Neto, P},
title = {Visual versus quantitative tau-PET Braak staging in Alzheimer's disease using [[18]F]MK6240.},
journal = {European journal of nuclear medicine and molecular imaging},
volume = {},
number = {},
pages = {},
pmid = {42168643},
issn = {1619-7089},
support = {MOP-11-51-31; RFN 152985/NR/NINR NIH HHS/United States ; 159815/NR/NINR NIH HHS/United States ; 162303/NR/NINR NIH HHS/United States ; MOP-11-51-31-team 1//Consortium canadien en neurodégénérescence associée au vieillissement/ ; CFI Project 34874//Fondation Brain Canada/ ; 33397//Fondation Brain Canada/ ; FRQS//Fonds de Recherche du Québec - Santé/ ; 2020-VICO-279314//Fonds de Recherche du Québec - Santé/ ; 2024 VICO-356138//Fonds de Recherche du Québec - Santé/ ; https://doi.org/10.69777/324345//Fonds de Recherche du Québec - Santé/ ; https://doi.org/10.69777/356138//Fonds de Recherche du Québec - Santé/ ; https://doi.org/10.69777/312994//Fonds de Recherche du Québec - Santé/ ; 0000000158//Alzheimer Society Research Program/ ; },
abstract = {PURPOSE: The 2024 Alzheimer's Association Workgroup research framework designates tau proteinopathy (T2) as a key element for Alzheimer's disease (AD) staging, but optimal staging approaches have yet to be determined. Here, we compared visual and quantitative tau-PET-based Braak staging as candidate strategies to implement T2 biological staging in vivo.

METHODS: We included 140 participants from the TRIAD cohort who underwent [[1]⁸F]MK6240 tau-PET. Quantitative Braak staging (qBraak) was derived from regional SUVR thresholds, whereas visual Braak staging (vBraak) was independently performed by three nuclear medicine physicians using an adapted interpretation algorithm. Inter-rater and inter-method agreement were assessed using Cohen's and Fleiss' κ statistics. Associations with clinical severity, cortical thickness, plasma pTau217, and cortical tau extent were examined. Diagnostic performance for identifying amyloid-positive cognitively impaired individuals was evaluated.

RESULTS: vBraak demonstrated substantial to nearly perfect inter-rater agreement (κ = 0.65-0.93). Agreement between vBraak and qBraak was moderate when stages were treated categorically (κ = 0.51), but substantial when their ordinal nature was considered (weighted κ up to 0.73). Both strategies showed comparable associations with clinical severity and neurodegeneration. vBraak was more sensitive to amyloid-β-positive cognitive impairment and identified intermediate-stage involvement at lower global tau extent. Visual-quantitative discordant cases were primarily attributable to off-target binding or spatially heterogeneous tau patterns.

CONCLUSION: Both vBraak and qBraak staging provide complementary and largely concordant approaches for operationalizing T2 staging. Quantitative methods enable scalable, group-level analyses, whereas visual assessment remains essential for identifying atypical tau patterns and informing clinically relevant decision-making.},
}

@article {pmid42168722,
year = {2026},
author = {De Felice, M and Pascazio, A and Piccarducci, R and Germelli, L and Cirinciani, M and Fusi, J and Cintoli, S and Ulivi, M and Trincavelli, ML and Franzoni, F and Baldacci, F and Milazzo, P and Martini, C and Da Pozzo, E and Maestri, M and Bonanni, E},
title = {Mild Cognitive Impairment Associated with Obstructive Sleep Apnoea: A Pilot Study on Oxygen-Related Plasma Biomarkers and Network Analysis.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42168722},
issn = {1559-1182},
mesh = {Humans ; *Sleep Apnea, Obstructive/blood/complications ; Pilot Projects ; *Cognitive Dysfunction/blood/complications ; Male ; *Biomarkers/blood ; *Oxygen/blood ; Female ; Aged ; Middle Aged ; Hypoxia-Inducible Factor 1, alpha Subunit/blood ; },
abstract = {Obstructive sleep apnoea syndrome (OSAS) is a breathing disorder frequently associated with mild cognitive impairment (MCI), a potential prodromal stage of Alzheimer's disease (AD). However, the mechanisms underlying MCI in OSAS remain unclear, making the identification of early biomarkers crucial. This pilot study investigates biochemical parameters related to oxygen disturbance and AD in OSAS patients with and without MCI (OSAS + MCI and OSAS-MCI, respectively) and explores their interplay through a network-based analysis. A total of 45 subjects (30 OSAS patients; 15 healthy controls) were enrolled, undergoing clinical assessment, polygraphy, and blood sampling. Compared to controls, OSAS patients exhibited increased apnoea-hypopnea index, oxygen desaturation index, and the percentage of cumulative time with oxygen saturation below 90% during total sleep time (T90). Notably, in the entire OSAS cohort, T90 positively correlated with HIF-1α levels, which were higher than controls, although not significantly. Interestingly, both T90 and HIF-1α were elevated in OSAS + MCI patients compared to OSAS-MCI, confirming a positive correlation between their levels. Regarding AD-related biomarkers, t-Tau and p-Tau181 levels were elevated in OSAS + MCI. AUROC analysis demonstrated that HIF-1α and t-Tau had fair discriminative ability, whereas p-Tau181 showed good differentiation between OSAS + MCI and OSAS-MCI. Finally, a network-based analysis suggested HIF-1α as possible candidate player in disease pathways, potentially interacting with Tau phosphorylation via GSK-3β. These findings recommend HIF-1α, t-Tau, and p-Tau181 as possible peripheral candidates for early MCI detection in OSAS, pointing out their possible involvement in the pathogenesis of cognitive impairment in OSAS pathology.},
}

Humans
*Sleep Apnea, Obstructive/blood/complications
Pilot Projects
*Cognitive Dysfunction/blood/complications
Male
*Biomarkers/blood
*Oxygen/blood
Female
Aged
Middle Aged
Hypoxia-Inducible Factor 1, alpha Subunit/blood

@article {pmid42168726,
year = {2026},
author = {Liu, Y and Qi, X and Liu, R and Xu, Z and Luo, H and Wu, B},
title = {Oral health, genetic susceptibility, and risk of dementia: a prospective cohort study of UK Biobank.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {42168726},
issn = {2509-2723},
support = {R01AG089856/NH/NIH HHS/United States ; P30AG083257/NH/NIH HHS/United States ; P50MD017356/NH/NIH HHS/United States ; },
abstract = {Poor oral health and genetic susceptibility have each been linked to dementia risk, but their joint effects and subtype-specific associations remain unclear. To examine the independent and combined associations of oral health indicators and genetic susceptibility with incident dementia, we conducted a prospective cohort study using UK Biobank data. A total of 364,557 predominantly White European adults aged 38-73 years who were free of dementia at baseline (2006-2010) and had complete oral health and genetic data were followed for incident dementia through 2022. Cox proportional hazards models estimated hazard ratios (HRs) and 95% confidence intervals (CIs), and interactions were evaluated. Over a median follow-up of 13.64 years, 7,553 participants developed all-cause dementia (ACD), including 3,277 Alzheimer's disease (AD) and 1,578 vascular dementia (VaD). Painful gums (HR 1.26, 95% CI 1.12-1.42) and denture use (HR 1.20, 95% CI 1.13-1.26) were associated with higher ACD risk, with comparable associations observed for AD and VaD. Toothache was associated with ACD (HR 1.24, 95% CI 1.11-1.39) and AD (HR 1.21, 95% CI 1.01-1.45) but not VaD. Dementia risk increased with the number of oral conditions. Higher genetic risk was independently associated with dementia, and moderate additive interactions were observed between oral health and genetic risk. These findings suggest that poor oral health was independently associated with higher risks of ACD, AD, and VaD and may amplify dementia risk among genetically susceptible individuals. Oral health may represent a potentially modifiable factor associated with dementia risk, but its causal role in dementia prevention should be tested in mechanistic and interventional studies.},
}

@article {pmid42168727,
year = {2026},
author = {Carpi, M and Afragola, AP and De Bartolo, M and Lopez, S and Bölükbaş, B and Del Percio, C and Henao Isaza, V and Lizio, R and Noce, G and Barjami, L and Carducci, F and Soricelli, A and Salvatore, M and Giubilei, F and Güntekin, B and Yener, G and Massa, F and Arnaldi, D and Famà, F and Pardini, M and Ferri, R and Lanuzza, B and Stocchi, F and Vacca, L and Coletti, C and Marizzoni, M and Taylor, JP and Hanoğlu, L and Yırıkoğulları, H and Frisoni, GB and Cuoco, S and Barone, P and Amboni, M and Cappiello, A and Bonanni, L and D'Anselmo, A and Biundo, R and Cauzzo, S and Fiorenzato, E and Antonini, A and D'Antonio, F and Bruno, G and Infarinato, F and Romano, P and Marziali, S and De Pandis, MF and Babiloni, C},
title = {Abnormal periodic and aperiodic resting-state electroencephalographic markers in Lewy body and Alzheimer's diseases with cognitive decline.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {42168727},
issn = {2509-2723},
support = {B83C22002820006//Ministero dell'Università e della Ricerca/ ; B53C23002080006//Ministero dell'Università e della Ricerca/ ; 2022FJAXY8//Ministero dell'Università e della Ricerca/ ; PE00000006//Ministero dell'Università e della Ricerca/ ; 2010SH7H3F//Ministero dell'Università e della Ricerca/ ; GAP-101058516//HORIZON EUROPE Framework Programme/ ; PNRR-MAD-2022-12376415//Ministero della Salute/ ; PNRR-MCNT2-2023-12377423//Ministero della Salute/ ; PNRR-MCNT2-2023-12377357//Ministero della Salute/ ; },
abstract = {Lewy body disease (LBD) and Alzheimer's disease (AD) are the most common causes of cognitive decline and dementia and are associated with characteristic alterations in resting-state electroencephalographic (rsEEG) activity. This multicenter exploratory study investigated periodic and aperiodic rsEEG features in patients with cognitive decline due to Lewy body disease (LBCD) and Alzheimer's disease (ADCD), compared with cognitively unimpaired older adults (Nold), and examined the clinical relevance of these markers in LBCD. A total of 140 LBCD, 135 ADCD, and 118 Nold datasets from the PDWAVES archive underwent spectral parameterization to decompose rsEEG power spectra (1-30 Hz) into periodic peaks and aperiodic background activity. Both clinical groups showed a significant slowing of the individual alpha frequency (IAF), more pronounced in LBCD, along with reduced periodic alpha and beta power reflected in a lower vigilance index. The aperiodic exponent was elevated in both groups, and the aperiodic offset was also higher in LBCD, suggesting steeper spectral profiles consistent with increased inhibitory cortical tone. Within the LBCD group, poorer cognition was associated with higher low-frequency alpha power, whereas better cognition was predicted by higher high-frequency alpha power. A reduced vigilance index was associated with the presence of visual hallucinations, while no associations emerged for other symptoms. These findings suggest that combined periodic and aperiodic rsEEG features may provide relevant markers of altered vigilance regulation in LBCD. Future studies should evaluate whether these EEG markers can inform targeted interventions, such as neuromodulatory or audiovisual stimulation, to stabilize quiet-vigilance states and improve clinical outcomes.},
}

@article {pmid42168750,
year = {2026},
author = {Modi, JN and Taylor, AM},
title = {Investigating the Consequences of Aneuploidy in Cancer and Normal Tissue.},
journal = {Advances in experimental medicine and biology},
volume = {1509},
number = {},
pages = {403-422},
pmid = {42168750},
issn = {0065-2598},
mesh = {*Aneuploidy ; Humans ; *Neoplasms/genetics/pathology ; Animals ; Genomic Instability ; },
abstract = {Aneuploidy is an unbalanced number of chromosomes arising from errors during cell division. Under normal conditions, cells use highly precise mechanisms to accurately segregate chromosomes during mitosis and meiosis. Errors in this process lead to chromosome missegregation and result in aneuploid daughter cells. Aneuploidy causes dosage imbalances of hundreds of different genes, disrupting homeostasis and causing adverse effects like genomic instability, metabolic and proteotoxic stress, cell cycle defects, and apoptosis (Hosea et al. 2024). Aneuploidy is the leading cause of miscarriage and congenital birth defects (Nagaoka et al. 2012). Somatic aneuploidy is found at low levels in neuronal cells and has also been observed post-mortem in brains with neurological pathologies such as Alzheimer's. Tetraploidy, octaploidy, and some aneuploidies are widely observed in hepatocytes, though their significance is not clearly understood (Simonetti et al. 2019). Additionally, aneuploidy is a hallmark of cancer, as 90% of solid tumors are aneuploid with whole chromosome or chromosome arm alterations (Taylor et al. 2018). This chapter will explore the causes and consequences of aneuploidy and its potential therapeutic implications.},
}

*Aneuploidy
Humans
*Neoplasms/genetics/pathology
Animals
Genomic Instability

@article {pmid42168765,
year = {2026},
author = {Gogola, A and Minhas, D and Lopresti, B and Snitz, B and Reese, AC and Matan, C and Wu, M and Zeng, X and Saeed, A and Reis, S and Aizenstein, H and Ikonomovic, MD and Lopez, O and Karikari, T and Cohen, A and Villemagne, VL},
title = {Complex interplay of astrogliosis and pathology in preclinical Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71520},
doi = {10.1002/alz.71520},
pmid = {42168765},
issn = {1552-5279},
support = {P50 AG005133/AG/NIA NIH HHS/United States ; R01 AG052446/AG/NIA NIH HHS/United States ; P01 AG025204/AG/NIA NIH HHS/United States ; DAF2255207//Aging Mind Foundation/ ; },
mesh = {Humans ; *Alzheimer Disease/pathology/diagnostic imaging ; *Gliosis/pathology ; Male ; Female ; Cross-Sectional Studies ; Aged ; Amyloid beta-Peptides/blood ; Glial Fibrillary Acidic Protein/blood ; tau Proteins/blood ; White Matter/pathology/diagnostic imaging ; Positron-Emission Tomography ; Hippocampus/pathology ; Magnetic Resonance Imaging ; Prodromal Symptoms ; },
abstract = {INTRODUCTION: We evaluated the effects of astrogliosis on Alzheimer's disease (AD) pathology, co-pathology, and symptoms.

METHODS: Cross-sectional data from 187 non-demented participants were processed to obtain measures of SMBT-1 standard uptake value ration (SUVR), plasma glial fibrillary acidic protein (GFAP), β-amyloid (Aβ), Centiloids (CL), tau (CenTauR), white matter hyperintensities (WMH), hippocampal volume (HV), and cognition. Linear regressions evaluated pairwise associations, linear regression interaction terms indicated moderating association, and causal mediation analysis evaluated mediating associations.

RESULTS: Astrogliosis was associated with CL (p < 0.01), neurodegeneration (0.05 < p < 0.1), and global cognition (p < 0.01). Moderation analyses revealed SMBT-1 SUVR had an attenuating interaction with CL in respect to CenTauR (β = -0.13, p = 0.0006) and memory impairment (β = 0.064, p = 0.05). Plasma GFAP had an attenuating interaction with CL in respect to CenTauR (β = -0.19, p = 0.00001).

DISCUSSION: Reactive astrogliosis is an early and important player in the AD development pathway by having an early attenuating effect against Aβ. More work is needed to further understand these complex associations.},
}

Humans
*Alzheimer Disease/pathology/diagnostic imaging
*Gliosis/pathology
Male
Female
Cross-Sectional Studies
Aged
Amyloid beta-Peptides/blood
Glial Fibrillary Acidic Protein/blood
tau Proteins/blood
White Matter/pathology/diagnostic imaging
Positron-Emission Tomography
Hippocampus/pathology
Magnetic Resonance Imaging
Prodromal Symptoms

@article {pmid42168776,
year = {2026},
author = {van Dyck, CH},
title = {Letter to the editor response for: "Schneider LS, Kennedy RE, Cutter G. Caution in interpreting disease-modification claims with lecanemab: selective reporting and causal inference. Alzheimer's & Dementia. 2026".},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71485},
doi = {10.1002/alz.71485},
pmid = {42168776},
issn = {1552-5279},
}

@article {pmid42168777,
year = {2026},
author = {Aung, KZ and Nelson, PT and Ning, X and Wu, X and Tsuchiya, I and Karanth, S and Abner, EL and Fardo, DW and Katsumata, Y},
title = {GRN rs5848 variant associates with TDP-43 pathology and cancer in opposite directions.},
journal = {Journal of neuropathology and experimental neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/jnen/nlag051},
pmid = {42168777},
issn = {1554-6578},
support = {P30 AG072946/GF/NIH HHS/United States ; R01 NS118584/GF/NIH HHS/United States ; RF1 AG082339/GF/NIH HHS/United States ; P01 AG078116/GF/NIH HHS/United States ; R01 AG076932/GF/NIH HHS/United States ; //University of Kentucky McCullers Scholar 2024/ ; },
abstract = {Epidemiologic studies have reported that cancer survivors have a relatively low risk of developing dementia, but the mechanisms underlying that inverse relationship are mostly unknown. The Granulin (GRN) gene single nucleotide variant rs5848 T allele is associated with increased risk of limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) and hippocampal sclerosis of aging (HS-Aging). The T allele is also associated with lower expression of the cognate protein progranulin (PGRN), which is a mitogen implicated in neoplasia. We examined whether the rs5848 variant associated with LATE-NC/HS-Aging pathology and cancer in the same cohort. This study leveraged genotype data from the Alzheimer's Disease Genomics Consortium (n = 8121) and the Alzheimer's Disease Sequencing Project (n = 3231), with cancer history and neuropathology data drawn from the National Alzheimer's Coordinating Center. The rs5848 T allele was associated with higher odds of LATE-NC (p < 0.001) and was also associated with lower odds of cancer (p = 0.012). Established TMEM106B, APOE, and BIN1 risk alleles for Alzheimer's disease showed no associations with cancer, implying that the GRN-related associations could not be completely explained by selection bias in the study sample. The finding of a specific allele with opposite correlative impact on cancer risk and dementia-related pathology has potential therapeutic implications.},
}

@article {pmid42168780,
year = {2026},
author = {Lyu, X and Brown, CA and Duong, MT and Fischer, EP and McGrew, E and Irwin, DJ and Dickerson, BC and Nasrallah, IM and Shinohara, RT and Young, AL and Yushkevich, PA and Das, SR and Wolk, DA and , },
title = {Uncovering distinct spatiotemporal trajectories of T-N mismatch subtypes with likely co-pathology in Alzheimer's disease using event-based modeling.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71474},
doi = {10.1002/alz.71474},
pmid = {42168780},
issn = {1552-5279},
support = {//NIH/ ; },
mesh = {Humans ; *Alzheimer Disease/pathology/diagnostic imaging/metabolism ; Male ; Female ; Disease Progression ; Aged ; *tau Proteins/metabolism ; Positron-Emission Tomography ; Neuroimaging ; Aged, 80 and over ; Brain/pathology/diagnostic imaging ; },
abstract = {INTRODUCTION: In Alzheimer's disease (AD), tau-neurodegeneration (T-N) mismatch has been proposed to reflect non-AD processes such as transactive response DNA binding protein 43 kDa and vascular disease. We aimed to characterize the spatiotemporal trajectories of T-N mismatch that may reflect non-AD progression.

METHODS: We performed T-N regression on 710 Alzheimer's Disease Neuroimaging Initiative participants using cortical thickness and 18F-flortaucipir uptake across 20 cortical regions. SuStaIn, a data-driven phenotype discovery and staging algorithm, was applied to standardized T-N residuals in canonical (N∼T) and vulnerable (N > T) cases.

RESULTS: SuStaIn identified three vulnerable subtypes with distinct N > T progression patterns. The posterior and anterior subtypes displayed different, but progressively diffuse mismatch patterns, while the limbic subtype exhibited temporal-limbic progression. Subtypes and SuStaIn stages were associated with distinct clinical features. Their longitudinal trajectories aligned with SuStaIn inferred progression.

DISCUSSION: Findings support that T-N mismatch progression captures specific co-pathological processes.},
}

Humans
*Alzheimer Disease/pathology/diagnostic imaging/metabolism
Male
Female
Disease Progression
Aged
*tau Proteins/metabolism
Positron-Emission Tomography
Neuroimaging
Aged, 80 and over
Brain/pathology/diagnostic imaging

@article {pmid42168793,
year = {2026},
author = {Baniowska, MR and Mumford, P and Prestia, F and Stephan, P and Beament, M and Birling, MC and Lanzillotta, C and Ciafardini, L and Barone, E and Lau, G and Chevalier, C and Nahy, C and Messaddeq, N and Lestra, T and Wu, Y and Nalesso, V and Di Domenico, F and Wiseman, F and Herault, Y},
title = {Age-related behavioral and molecular landmarks in new mouse models for studying Alzheimer's disease in Down syndrome.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71498},
doi = {10.1002/alz.71498},
pmid = {42168793},
issn = {1552-5279},
support = {UKDRI-1014//UK Dementia Research Institute/ ; ARUK-SRF2018A-001//Alzheimer's Research UK/ ; 45U-4.IT//Istituto Pasteur-Fondazione Cenci Bolognetti/ ; RG1181642744DF59//Sapienza Università di Roma/ ; ANR-17-EURE-0023//Agence Nationale de la Recherche/ ; ANR-10-IDEX-0002//Agence Nationale de la Recherche/ ; ANR-20-SFRI-0012//Agence Nationale de la Recherche/ ; ANR-10-IDEX-0002-02//Agence Nationale de la Recherche/ ; 848077//European Commission/ ; 2083//Fondation Jérôme Lejeune/ ; },
mesh = {*Down Syndrome/complications/genetics/pathology ; Animals ; *Alzheimer Disease/genetics/pathology/metabolism/complications ; *Disease Models, Animal ; Mice ; Humans ; Amyloid beta-Protein Precursor/genetics/metabolism ; Amyloid beta-Peptides/metabolism/genetics ; Mice, Transgenic ; tau Proteins/metabolism ; *Behavior, Animal ; Male ; Mice, Inbred C57BL ; Amyloid Precursor Protein Secretases/metabolism ; },
abstract = {INTRODUCTION: Down syndrome (DS) is the leading genetic cause of intellectual disability and Alzheimer's disease (AD), with over 90% of individuals developing AD-related dementia (DSAD). The triplication of the APP gene on chromosome 21 drives early amyloid-β (Aβ) accumulation, but other Hsa21 genes also contribute to pathology. Current DSAD models are limited by species-specific Aβ differences.

METHODS: We developed and characterized two novel DSAD mouse models with partial humanization of Aβ.

RESULTS: These models exhibit early AD features: cognitive deficits, hyperactivity, altered novelty and risk responses, tau hyperphosphorylation, and endolysosomal dysfunction. Amyloid precursor protein (APP) processing shifts toward β-secretase, increasing CTF-β and altering Aβ dynamics. Aβ humanization modulates behavior, improving specific cognitive tasks but enhancing anxiety traits. Myelinosome formation and impaired autophagic flux further align these models with human AD pathology.

DISCUSSION: They offer valuable tools to investigate early DSAD mechanisms and therapeutic strategies, pending development of a fully humanized trisomic model.},
}

*Down Syndrome/complications/genetics/pathology
Animals
*Alzheimer Disease/genetics/pathology/metabolism/complications
*Disease Models, Animal
Mice
Humans
Amyloid beta-Protein Precursor/genetics/metabolism
Amyloid beta-Peptides/metabolism/genetics
Mice, Transgenic
tau Proteins/metabolism
*Behavior, Animal
Male
Mice, Inbred C57BL
Amyloid Precursor Protein Secretases/metabolism

@article {pmid42168823,
year = {2026},
author = {Pandey, R and Ruggiero, T and Andrews, B and Urbanc, B},
title = {Spontaneous Insertion of Aβ42 Dimers but Not Monomers into a Cholesterol-Rich Lipid Bilayer.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00942},
pmid = {42168823},
issn = {1948-7193},
abstract = {The leading Alzheimer's disease (AD) hypothesis posits that oligomers formed by amyloid β-protein (Aβ), in particular 42-residue-long Aβ42, interact with a cellular membrane, causing a cascade of events leading to neurodegeneration. The modes of Aβ42-lipid interactions are not well understood. Here, we use explicit-solvent all-atom molecular dynamics (MD) to demonstrate that Aβ42 monomers interact with lipids differently than Aβ42 dimers. In our simulations, lipids in the absence and presence of Aβ42 form a lipid bilayer with a cholesterol-rich domain, resembling a lipid raft. Whereas lipids stabilize the Aβ42 monomer structure, they partially destabilize Aβ42 dimers. Unlike monomers, which interact exclusively with solvent-exposed lipid tails on one side of a bilayer, dimers exhibit additional modes of interactions with lipids, including spontaneous insertion into the cholesterol-rich domain of a bilayer and carpeting, thereby disrupting the lipid bilayer structure. Our findings provide a mechanistic explanation for why Aβ42 monomers are nontoxic and reveal that Aβ42 oligomer-induced toxicity emerges already at the stage of Aβ42 dimer formation.},
}

@article {pmid42168828,
year = {2026},
author = {Xu, J and Meng, R and Zheng, W and Wu, Y},
title = {Aspiration Pneumonia as a Marker of a High Healthcare Utilisation Trajectory in Older Adults With Dementia: A Retrospective Cohort Study.},
journal = {Australasian journal on ageing},
volume = {45},
number = {2},
pages = {e70187},
doi = {10.1111/ajag.70187},
pmid = {42168828},
issn = {1741-6612},
mesh = {Humans ; *Pneumonia, Aspiration/mortality/diagnosis/therapy ; Retrospective Studies ; Aged ; Male ; Female ; Aged, 80 and over ; *Dementia/diagnosis/mortality/therapy/psychology ; Length of Stay ; Risk Factors ; Time Factors ; Age Factors ; *Patient Acceptance of Health Care ; Hospitalization ; },
abstract = {OBJECTIVES: To determine whether recorded aspiration pneumonia in older adults with dementia was associated with subsequent high inpatient use and to estimate its associations with all-cause mortality, any hospital admission and cumulative length of stay.

METHODS: This single-centre retrospective cohort study examined electronic medical records from a single tertiary hospital to identify 500 adults aged 65 years and older with Alzheimer's disease, vascular dementia or mixed dementia. Participants were followed for up to 36 months (median 20 months). Recorded aspiration pneumonia was analysed as an exposure available in the analytic dataset. Multivariable Cox, logistic and negative binomial models were adjusted for age, sex, dementia subtype, baseline dementia severity and baseline Mini-Mental State Examination (MMSE) score. Exact aspiration-event dates and clinically important domains including frailty, functional status, residence before admission, swallowing assessment, oral-health measures, medication burden and comorbidity burden were not available in the dataset.

RESULTS: Recorded aspiration pneumonia occurred in 24% of participants. After adjustment, the cohort-level mortality signal remained imprecise (HR 1.65, 95% CI 0.85-3.21). In contrast, aspiration pneumonia was independently associated with higher odds of hospitalisation (OR 2.02, 95% CI 1.29-3.16) and greater cumulative length of stay among those admitted (IRR 1.54, 95% CI 1.17-2.01).

CONCLUSIONS: In this dementia-specific cohort, recorded aspiration pneumonia was common and consistently associated with greater subsequent inpatient use. The findings support interpreting recorded aspiration pneumonia as a pragmatic clinical marker of heightened service dependence within a broader frailty and illness context and underscore the value of multidisciplinary review and anticipatory care planning after such events.},
}

Humans
*Pneumonia, Aspiration/mortality/diagnosis/therapy
Retrospective Studies
Aged
Male
Female
Aged, 80 and over
*Dementia/diagnosis/mortality/therapy/psychology
Length of Stay
Risk Factors
Time Factors
Age Factors
*Patient Acceptance of Health Care
Hospitalization

@article {pmid42168843,
year = {2026},
author = {Long, T and Satyal, S and Gao, J},
title = {Transcriptome graph transformer: a graph transformer-based unsupervised model for transcriptome data analysis.},
journal = {BMC bioinformatics},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12859-026-06458-4},
pmid = {42168843},
issn = {1471-2105},
support = {2400785//National Science Foundation/ ; },
abstract = {BACKGROUND: Rapidly growing transcriptomic datasets pose challenges for traditional analytical methods, which struggle with high dimensionality, heterogeneity, and nonlinear gene relationships. Existing deep learning models often require fixed-length inputs and fail to integrate biological network information.

METHODS: We introduce Transcriptome Graph Transformer (TGT), an unsupervised graph Transformer framework that constructs a heterogeneous gene-pathway graph using expression data, STRING interactions, and GO/KEGG/Reactome pathway annotations. TGT is pretrained with a masked-node prediction task and fine-tuned for disease classification, biomarker discovery, and zero-shot clustering of single-cell and spatial transcriptomics.

RESULTS: TGT achieves superior performance across Alzheimer's disease, cancer, acute kidney injury, and COVID-19 datasets, outperforming state-of-the-art baselines. The model generalizes well across platforms and yields biologically meaningful gene and pathway importance scores consistent with known disease mechanisms.

CONCLUSIONS: TGT provides an effective and generalizable approach for transcriptomic representation learning by integrating biological network knowledge with graph Transformer architectures. Its strong performance highlights its utility for broad transcriptomic applications and precision medicine.},
}

@article {pmid42169064,
year = {2026},
author = {Güzel, A and İncebacak, F and Issı, ES},
title = {Dementia subtype specification and cognitive evidence visibility in Turkish Court of Cassation decisions: a document analysis of 1,031 decisions (2005-2025).},
journal = {BMC medical ethics},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12910-026-01480-w},
pmid = {42169064},
issn = {1472-6939},
abstract = {BACKGROUND: Dementia is frequently invoked in medico-legal contexts where questions of legal capacity, guardianship, testamentary validity, transactional validity, and criminal responsibility arise. Although subtype differentiation and cognitive assessment are central to clinical dementia evaluation, it remains unclear to what extent such clinically meaningful detail is visible in appellate judicial reasoning. This study examined the visibility of dementia subtype specification and cognitive evidence in decisions of the Turkish Court of Cassation (2005-2025), and examined the ethical implications of these textual patterns for transparency, accountability, and procedural fairness in judicial decision-making.

METHODS: We conducted a retrospective, cross-sectional, document-based analysis of publicly accessible Court of Cassation decisions. Using keyword-based searches ("demans," "bunama," and "Alzheimer"), 1,180 decisions were identified; after screening for legal relevance, 1,031 decisions were included. Each decision was coded across 15 variables, including dementia subtype specification, cognitive evidence visibility, legal context, and medical report source. Descriptive statistics were calculated for all variables. Temporal trends in dementia subtype visibility were analysed using logistic regression, supplemented by year-by-year distributional assessment and multivariable sensitivity modelling. A parallel logistic regression was also conducted for the broader binary outcome of any visible cognitive evidence (specific or non-specific; n = 104 events).

RESULTS: Dementia subtype information was explicitly specified in 46.4% of decisions (478/1,031; 95% CI, 43.3-49.5%), whereas 53.6% used only general or unspecified terminology. Alzheimer's disease was the most frequently reported subtype, appearing in 451 decisions (43.7% of the full sample; 94.4% of subtype-specified decisions). Subtype visibility increased significantly over time (OR = 1.062 per year; 95% CI, 1.034-1.091; p < 0.001). In contrast, visible cognitive evidence remained limited: 89.9% of decisions contained no reference to cognitive assessment, 9.8% included only non-specific references, and only 0.3% explicitly named the Mini-Mental State Examination (MMSE; 95% CI, 0.1-0.8%). No decision referred to the Montreal Cognitive Assessment (MoCA). Any visible cognitive evidence was present in 10.1% of decisions (104/1,031; 95% CI, 8.3-12.1%) and was highest in guardianship/restriction cases (19.7%). Temporal modelling of any visible cognitive evidence was associated with a statistically significant decrease over the study period (OR = 0.918 per year; 95% CI, 0.880-0.958; p < 0.001).

CONCLUSIONS: Dementia subtype specification became moderately more visible in appellate judicial reasoning over time, whereas the textual visibility of cognitive evidence remained limited. These findings concern the traceability of clinically relevant information within decision summaries rather than the adequacy of the underlying evidentiary process itself. Strengthening the structured reporting of diagnostic basis, relevant cognitive findings, and functionally relevant capacity-related findings in medico-legal documentation may support improved transparency and accountability in the translation of clinical evidence into legal reasoning.},
}

@article {pmid42169086,
year = {2026},
author = {Coraglia, F and Cecchetti, G and Rugarli, G and Spinelli, EG and Ghirelli, A and Pisano, S and Canu, E and Filippi, M and Agosta, F},
title = {Plasma ApoE proteotyping for ApoE ε4 stratification in the anti-amyloid therapies era.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02089-2},
pmid = {42169086},
issn = {1758-9193},
abstract = {BACKGROUND: Apolipoprotein E (ApoE) ε4 status informs risk stratification and safety management for anti-amyloid therapies, but genotyping typically requires dedicated procedures, longer turnaround times, and higher costs compared with automated laboratory assays. We evaluated an automated plasma approach for ε4 stratification based on proteotyping, the quantification of isoform-specific ApoE proteins to infer ApoE genotype.

METHODS: We retrospectively included 110 patients (mean age 67.82 ± 10.11 years, 49.1% female) of European ancestry with cognitive impairment across a broad diagnostic spectrum, including 68 AD-spectrum cases, 29 with subjective symptoms, and 16 with other etiologies. ApoE genotyping identified 57 ε4 non-carriers (51.8%), 44 heterozygous carriers (40.0%), and 9 homozygous carriers (8.2%). ApoE4 and total ApoE (PanApoE) were measured on Lumipulse and the ApoE4/PanApoE ratio (ApoE ratio) was derived.

RESULTS: The ratio showed excellent separation across genotypes in our cohort. For ε4 carrier identification, both the ratio and ApoE4 achieved an AUC of 1.00 (95% CI 1.00-1.00), whereas PanApoE showed poor discrimination (AUC 0.30, 95% CI 0.20-0.40), reflecting lower PanApoE levels in ε4 carriers. The ratio also accurately distinguished heterozygotes from homozygotes (AUC 1.00, 95% CI 1.00-1.00).

CONCLUSIONS: Automated plasma ApoE proteotyping mirrored genetic ε4 status. The ApoE ratio provided complete genotype separation, supporting its use for individual-level stratification. These findings should be interpreted cautiously considering the retrospective single-center design and the limited number of ApoE ε4 homozygotes, and require validation in larger, independent cohorts.},
}

@article {pmid42169160,
year = {2026},
author = {Ahn, J and Yun, J and Weiner, MW and Shin, D and Kang, H and Yim, S and Kim, S and Park, H and Jang, H and Chun, MY and Lee, EH and Kim, HJ and Na, DL and Kim, JP and Seo, SW and , },
title = {Longitudinal plasma p-tau217 as a marker for tracking progression and predicting cognitive decline in Alzheimer's disease.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02077-6},
pmid = {42169160},
issn = {1758-9193},
support = {RS-2020-KH106434//Korea Dementia Research Center/ ; RS-2025-02223212//Korea Health Industry Development Institute/Republic of Korea ; RS-2019-NR040057//National Research Foundation of Korea/ ; RS-2021-II212068//Institute of Information & Communications Technology Planning & Evaluation/ ; SMX1250081//Samsung Medical Center, Sungkyunkwan University/ ; 2024-ER1003-01//Korea National Institute of Health/ ; },
abstract = {BACKGROUND: Plasma phosphorylated tau217 (p-tau217) is a promising biomarker for Alzheimer's disease (AD) with strong cross-sectional concordance with beta-amyloid (Aβ) and tau pathology. However, its longitudinal behavior across disease stages and assay platforms, and its prognostic value for cognitive decline according to Aβ status, remain insufficiently characterized. This study aimed to evaluate stage- and assay-specific longitudinal changes in plasma p-tau217 and to determine their utility for predicting cognitive decline.

METHODS: We analyzed longitudinal data from 393 participants in the NA-ADNI, including cognitively unimpaired (CU) and cognitively impaired (CI) individuals. Plasma p-tau217 was measured using five assay platforms. Linear mixed-effects models were used to assess longitudinal biomarker trajectories, with time as the primary predictor and random intercepts and slopes. Aβ status and time-by-Aβ interactions were included to examine differential trajectories. Annualized biomarker changes were derived and related to longitudinal cognitive outcomes using models of Clinical Dementia Rating-Sum of boxes (CDR-SB) scores. Marginal R[2] values quantified the variance explained.

RESULTS: Plasma p-tau217 levels increased significantly over time across all assay platforms in both CU and CI groups (all q < 0.05). The largest standardized time effects were observed for the ALZpath-Simoa assay (βstd = 0.112 in CU; βstd = 0.100 in CI). Aβ + individuals showed steeper longitudinal increases than Aβ- individuals, with interaction effects ranging from βint = 0.102 to 0.164 in CU and from βint = 0.070 to 0.113 in CI. Annualized changes in p-tau217 were associated with cognitive decline in a stage- and assay-dependent manner. In CU, change in %p-tau217 measured by C2N-MS showed the strongest association with CDR-SB progression (β = 0.075, q < 0.001). In CI, absolute p-tau217 change measured by C2N-MS showed the strongest association (β = 0.238, q < 0.001), particularly among Aβ + individuals. Adding annualized change of other plasma biomarkers provided modest and stage-dependent improvements, with GFAP yielding the greatest incremental value in CI.

CONCLUSIONS: Longitudinal plasma p-tau217 is a robust marker of AD progression, but its optimal prognostic application depends on cognitive stage, Aβ status, and assay platform. These findings support stage-specific strategies for using serial plasma biomarkers in clinical monitoring and therapeutic trials.},
}

@article {pmid42169444,
year = {2026},
author = {Siciliano, G and Cillis, A and Clabassi, E and Ferrara, F and Chiriacò, MS and Turco, A and Loiola, C and Zecca, C and Dell'Abate, MT and Logroscino, G and Gigli, G and Malerba, F and Primiceri, E},
title = {Simultaneous Electrochemical Detection of NGF and proNGF Under Native Conditions Using Molecularly Imprinted Polymers: Toward Point-of-Care Diagnosis of Alzheimer's Disease.},
journal = {Advanced healthcare materials},
volume = {},
number = {},
pages = {e71262},
doi = {10.1002/adhm.71262},
pmid = {42169444},
issn = {2192-2659},
support = {PNRR-MR1-2023-12377571.//BIO-TEST - Circulating biomarkers and innovative device/ ; CUPB53C22004000006.//ALT-CAN - BaC HEAL ITALIA PNRR Mission 4 - Component 2Mission 4 - Component 2. Progetto/ ; PONARS01_00906//TITAN: Nano- tecnologie per l'ImmunoTerapia dei Tu0mori - FESR Programme PON "Ricerca e Innovazione"/ ; DGR n.2117 del 21/11/2018//"Tecnopolo per la medicina di precisione" (TecnoMed Puglia)/ ; CUP: B84I180 0 0540 0 02//"Tecnopolo per la medicina di precisione" (TecnoMed Puglia)/ ; Cod.T4-AN-01-CUP//Biotecnologia, Bioinformatica e sviluppo Farmaceutico. Piano operativo Salute: FSC 2014-2020.Traiettoria 4, Azione 4.1 - Cofinanziato dalla Regione Puglia; Fondo Ordinario Enti (FOE D.M 865/2019)/ ; F83C22001560003.//Biotecnologia, Bioinformatica e sviluppo Farmaceutico. Piano operativo Salute: FSC 2014-2020.Traiettoria 4, Azione 4.1 - Cofinanziato dalla Regione Puglia; Fondo Ordinario Enti (FOE D.M 865/2019)/ ; },
abstract = {In the brain, proNGF, the NGF precursor, is in a homeostatic equilibrium with its processing product, mature NGF. Dysregulation of the NGF/proNGF ratio has been associated with neurodegeneration in Alzheimer's disease (AD), positioning these neurotrophins as promising diagnostic biomarkers. Yet, their clinical validation as biomarkers has been hindered by the lack of analytical methods capable of discriminating and quantifying both isoforms under native conditions. Here, we introduce a dual electrochemical sensor based on Molecularly Imprinted Polymers (MIPs) that enables the simultaneous, selective, and label-free quantification of NGF and proNGF. The sensors were fabricated via electropolymerization of o-phenylenediamine on platinum microelectrodes, yielding highly specific recognition sites for each isoform. The MIP-based platform demonstrates remarkable selectivity, reproducibility, and isoform discrimination, achieving picomolar detection limits even for NGF, which is typically present at low concentration in cerebrospinal fluid (CSF). Validated on clinical CSF samples from AD and control patients, this system successfully quantifies both NGF and proNGF without antibodies or sample denaturation. To the best of our knowledge, this represents the first quantitative and simultaneous detection of NGF and proNGF under native conditions. This technology paves the way toward cost-effective, high-throughput, and point-of-care diagnostics for Alzheimer's and other neurodegenerative diseases.},
}

@article {pmid42169497,
year = {2026},
author = {Daoud, S and Taha, M},
title = {Developments in the design and therapeutic applications of GSK3β inhibitors.},
journal = {Future medicinal chemistry},
volume = {},
number = {},
pages = {1-21},
doi = {10.1080/17568919.2026.2675873},
pmid = {42169497},
issn = {1756-8927},
abstract = {Glycogen synthase kinase-3β (GSK3β) has emerged as one of the most thoroughly validated therapeutic targets in modern drug discovery, with dysregulation implicated in neurodegenerative diseases, metabolic disorders, cancer, psychiatric conditions, and inflammatory pathologies. This review provides a comprehensive and critical overview of recent advances in GSK3β inhibitor design, encompassing ATP-competitive compounds, non-ATP-competitive modulators, covalent inhibitors, and targeted protein degradation strategies. We integrate computational approaches-including pharmacophore modeling, molecular dynamics simulations, and emerging artificial intelligence methods-with experimental validation, distinguishing this work from prior reviews. Therapeutic applications across Alzheimer's disease, type 2 diabetes, cancer, bipolar disorder, and inflammatory conditions are critically examined, with particular emphasis on clinical trial outcomes and translational challenges. We analyze why clinical translation has lagged, identifying insufficient CNS penetration, inadequate target engagement validation, and suboptimal patient selection as key factors, and provide recommendations for future development. Emerging directions including isoform-selective inhibition, context-dependent modulation, combination therapies, and biomarker-driven strategies are discussed. This review offers an integrated perspective on the GSK3β inhibitor landscape and outlines actionable opportunities for developing next-generation therapeutics.},
}

@article {pmid42169623,
year = {2026},
author = {Carbone, E and Scibetta, S and Cappella, M and Crestini, A and Perrone, F and Hallulli, M and Rosa, P and Rivabene, R and Maiolo, F and Simonelli, V and Ricceri, L and Di Bari, MA and De Luca, G and Vanacore, N and Lacorte, E and Piscopo, P},
title = {A systematic review on the effects of hypercaloric diet in animal models of Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261448495},
doi = {10.1177/13872877261448495},
pmid = {42169623},
issn = {1875-8908},
abstract = {BackgroundAccording to several published studies, a hypercaloric diet (HD) could be considered a risk factor for neurodegenerative diseases, including Alzheimer's disease (AD). To fully understand the molecular pathways involved, HD has been investigated in several animal models.ObjectiveThe aim of this systematic review (SR) is to provide an overview of recent published data on the effects of HD on animal models of AD to gain insight into the molecular mechanisms potentially involved and to highlight current knowledge gaps for future studies.MethodsStructured bibliographic searches were carried out on PubMed, the Cochrane Library, and ISI Web of Knowledge. The SR was conducted following the Cochrane Handbook and the PRISMA statement. Studies enrolling only wild-type models or not using standard diet (SD) as control were excluded, as were non-original publications. Included studies were assessed for risk of bias using SYRCLE's tool.ResultsA total of 77 studies met inclusion criteria. Most reported significant behavioral differences in HD-exposed mice (Morris Water Maze, Open Field, Y-maze), though with considerable variability due to protocol heterogeneity. A significant increase in tau and amyloid deposition was observed after HD exposure, and most studies reported negatively affected learning and memory. However, nearly half found no significant differences between HD and SD groups, likely reflecting heterogeneity in diet duration and type, animal age, and strain susceptibility. Methodological quality varied widely, with many studies omitting randomization, blinding, or sex-stratified analyses.ConclusionsDespite variability, evidence suggests HD worsens behavioral performance and increases tau and amyloid expression in mouse brain, representing a risk factor for dementia. More rigorous, standardized, and sex-balanced preclinical studies are needed, and findings support dietary interventions as early non-pharmacological strategies in AD prevention.},
}

@article {pmid42170105,
year = {2026},
author = {Bello, E and Long, K and Iwama, S and Steer, J and Cooper, SE and Alasoo, K and Kumasaka, N and Schwartzentruber, J and Panousis, NI and Bassett, AR},
title = {An Alzheimer's disease-associated common regulatory variant in a PTK2B intron alters microglial function.},
journal = {iScience},
volume = {29},
number = {5},
pages = {115688},
pmid = {42170105},
issn = {2589-0042},
abstract = {Identifying and functionally validating the causal variants at genome-wide association study (GWAS) loci is very challenging and has only been achieved for very few variants. Here, we validate a single-nucleotide polymorphism (SNP) associated with increased Alzheimer's disease (AD) risk in an intronic enhancer of PTK2B, by engineering it into human induced pluripotent stem cells (hiPSCs). Upon differentiation to macrophages and microglia, the variant increases chromatin accessibility at the enhancer and binding of transcription factor CEBPB but causes only subtle effects on PTK2B or CLU expression. Nonetheless, this variant affects both the transcriptome and phenotype of the cells: interferon gamma-responsive genes are downregulated, secreted chemokine levels are reduced, and microglial chemotaxis is affected. We propose the variant acts by altering microglial reactivity, consistent with the established role of these cells in AD progression. This work demonstrates the power of isogenic hiPSC models for functionally validating GWAS-identified common regulatory variants.},
}

@article {pmid42170124,
year = {2026},
author = {Patel, D and Patel, T and Patel, PN},
title = {Integrative Analysis of Pharmacological and Non-pharmacological Interventions in Alzheimer's Dementia.},
journal = {Cureus},
volume = {18},
number = {4},
pages = {e107386},
pmid = {42170124},
issn = {2168-8184},
abstract = {Alzheimer's dementia is a progressive neurodegenerative disorder in which cognitive decline, neuropsychiatric symptoms, and functional dependence emerge from a long preclinical and prodromal phase. Effective care increasingly requires an integrative approach: (1) disease-modifying pharmacology for selected patients early in the symptomatic course, (2) symptomatic pharmacotherapy for cognition and behavioral symptoms when benefits outweigh harms, and (3) non-pharmacological interventions that meaningfully affect quality of life, caregiver burden, safety, and functional outcomes across all stages. Recent advances, particularly anti-amyloid monoclonal antibodies, have reshaped early Alzheimer's treatment while raising new implementation challenges around biomarker confirmation, monitoring for amyloid-related imaging abnormalities (ARIA), and health-system capacity. Evidence also supports structured non-pharmacological strategies (e.g., cognitive stimulation, physical activity, caregiver programs, and environmental and behavioral approaches for agitation) as core therapies rather than "adjuncts." This narrative review synthesizes the evidence base and offers a practical, stage-based framework for combining pharmacological and non-pharmacological therapies, emphasizing person-centered goals, safety, feasibility, and equity.},
}

@article {pmid42170416,
year = {2026},
author = {Wang, J and Xia, K and Yang, D and Wu, J and Liu, L and Huang, Y and Shan, Q and Zhang, H and Wang, Y},
title = {Correction: Trends in mortality from Alzheimer's disease and related dementias with hyperlipidemia in the United States from 1999 to 2020-A CDC WONDER database study.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1856837},
doi = {10.3389/fneur.2026.1856837},
pmid = {42170416},
issn = {1664-2295},
abstract = {[This corrects the article DOI: 10.3389/fneur.2025.1705607.].},
}

@article {pmid42170457,
year = {2026},
author = {Qiu, G and Huang, Y and Wang, Q and Si, K and Xu, S and Yu, Y and Hu, P},
title = {The divergent effects of population aging: comparative analysis of the burden of Alzheimer's disease and other dementias in China and G20 countries, 1990-2050.},
journal = {American journal of translational research},
volume = {18},
number = {4},
pages = {3541-3558},
pmid = {42170457},
issn = {1943-8141},
abstract = {OBJECTIVES: Alzheimer's disease and other dementias (ADOD) pose a serious and escalating public health challenge globally, particularly in China. This study aimed to compare the ADOD burden between China and Group of 20 (G20) countries to inform targeted policy development.

METHODS: We assessed the burden of ADOD among adults aged 40 years and older in China and G20 countries during 1990-2021, using data from Global Burden of Disease 2021. Significant temporal trends were observed by joinpoint regression. Decomposition analyses estimated the effects of aging, population increase, and epidemiologic changes. Projections through the mid-century (2050) were derived using the autoregressive integrated moving average (ARIMA) models.

RESULTS: In 2021, China exhibited the highest age-standardized prevalence (900.82 per 100,000), incidence (151.47 per 100,000), and Disability-Adjusted Life Years (DALYs) (562.39 per 100,000) of ADOD among all G20 countries. During 1990-2021, China also experienced the most pronounced increases in these metrics (322.18%, 314.42%, and 272.71%). Aging was the primary driver of the ADOD burden growth in China. In contrast, aging played a dual role in G20 countries, with an adverse effect on the prevalence and incidence while remaining a contributory factor to deaths and DALYs.

CONCLUSION: Despite recent improvements, China faces a growing ADOD burden, largely propelled by population aging. This contrasts with the more complex role of aging in G20 countries, where aging shows a substantially mitigating effect on prevalence and incidence yet a persistent driving effect on deaths and DALYs. This underscores an urgent need for China to develop tailored strategies informed by experience from the G20.},
}

@article {pmid42170625,
year = {2026},
author = {Topal, M and Topal, F and Yilmaz, F and Bulut Atalay, E and Koçyiğit, ÜM and Güzel, E},
title = {Investigation of the enzyme-inhibitory, antibacterial, and anticancer properties of metal phthalocyanines.},
journal = {Turkish journal of chemistry},
volume = {50},
number = {2},
pages = {173-185},
pmid = {42170625},
issn = {1300-0527},
abstract = {In this study, the enzyme inhibitory, antibacterial, and anticancer activities of a phthalonitrile derivative and its metal phthalocyanines (Pcs; indium, zinc, copper, cobalt, and manganese; 1-6) were investigated. The cobalt and manganese Pcs were synthesized for the first time in this study. The inhibitory activities of the symmetric Pcs, which were expected to interact with acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) via their 4-(isopropylbenzyl)oxy substituents through host-guest interactions, were investigated. More selective inhibition of AChE than BChE was observed for these compounds. For AChE, CoPc was identified as the most potent inhibitor (IC50 = 14.81 nM), whereas for BChE, InPc was identified as the most potent inhibitor (IC50 = 56.35 nM). The Ki values indicated that most compounds exhibited competitive inhibition; copper phthalocyanine (CuPc) showed particularly strong inhibition against AChE (Ki = 3.08 nM ± 1.12), whereas the lowest Ki value against BChE was observed for MnPc (Ki = 25.98 ± 1.97 nM). Most compounds exhibited competitive inhibition; however, CuPc showed competitive inhibition toward AChE but a noncompetitive inhibition pattern toward BChE. Dual inhibition of AChE and BChE by these compounds may be promising for addressing cholinergic deficits associated with Alzheimer's disease. In addition, the acceptability of compounds 1-6 with respect to pharmacological drug-likeness criteria was assessed based on predicted absorption, distribution, metabolism, excretion (ADME) outcomes. In antibacterial tests, varying levels of inhibition were observed against selected bacterial strains. In anticancer assays, all compounds exhibited high cytotoxicity against the MCF-7 breast cancer cell line. Higher antiproliferative activity was observed for CuPc than for the other compounds. Morphological changes were induced in cancer cells by CuPc and MnPc. Overall, these compounds may have potential as enzyme inhibitors and as antibacterial and anticancer agents.},
}

@article {pmid42170779,
year = {2026},
author = {Beliraya, MN and Mallya, S and Prabhu, S},
title = {Predictive Analysis of Brain-Derived Neurotrophic Factor and Apolipoprotein E SNPs in Alzheimer's Pathogenesis.},
journal = {BioMed research international},
volume = {2026},
number = {1},
pages = {e3806517},
pmid = {42170779},
issn = {2314-6141},
support = {//MAHE Seed Money Grant/ ; //Manipal Research Board Grant/ ; BT/INF/22/SP43065/2021//DBT-BUILDER/ ; 54/8/GER/2019-NCD-II//Indian Council of Medical Research/ ; },
mesh = {*Brain-Derived Neurotrophic Factor/genetics/chemistry ; *Alzheimer Disease/genetics/pathology ; Humans ; *Polymorphism, Single Nucleotide/genetics ; *Apolipoproteins E/genetics/chemistry ; *Genetic Predisposition to Disease ; Gene Frequency/genetics ; },
abstract = {BACKGROUND: Brain-derived neurotrophic factor (BDNF) and apolipoprotein E (APOE) are key regulators of neuronal function and cognitive health. Genetic variations in these genes, particularly nonsynonymous single-nucleotide polymorphisms (nsSNPs), have been linked to Alzheimer's disease (AD). This study employs a computational approach to predict the potential functional impacts of nsSNPs in BDNF and APOE to explore their contributions to AD pathogenesis.

METHODS: A total of 3590 BDNF and 27,830 APOE SNPs were retrieved from the dbSNP database. Following quality filtering of coding region localization and minor allele frequency (≥ 0.001), 33 BDNF nsSNPs and 95 APOE nsSNPs underwent systematic analysis. Pathogenicity was assessed using SIFT and PolyPhen-2 algorithms, with functional impact evaluated via CADD scoring. Protein stability effects were predicted using MUpro and I-Mutant tools, and posttranslational modifications were analyzed via a GPS prediction system. Secondary structure alterations were assessed using GOR4, and three-dimensional structural models were generated through SWISS-MODEL with Ramachandran plot validation.

RESULTS: Three variants demonstrated concordant pathogenic predictions: rs1048218 (BDNF Q75H), rs7412 (APOE R176C), and rs769455 (APOE R163C). Protein stability analysis of these variants revealed consistent destabilization for rs1048218 (ΔΔG: -1.001 to -2.08 kcal/mol) and rs7412 (ΔΔG: -0.859 to -0.07 kcal/mol), whereas rs769455 showed conflicting predictions between algorithms. Posttranslational modification sites remained conserved across all the variants. Secondary structure analysis demonstrated minimal α-helix reduction (0.31%-0.81%) with compensatory random coil increases. Three-dimensional modeling revealed preserved overall protein folds despite localized structural perturbations, with acceptable model quality metrics (MolProbity scores ≤ 1.39, Ramachandran favored regions >91%).

CONCLUSION: In silico analysis suggested that certain nsSNPs in BDNF and APOE may negatively affect protein function and stability, despite preserved structural and posttranslational features. These computational predictions need further experimental validation to better understand their roles in AD pathogenesis.},
}

*Brain-Derived Neurotrophic Factor/genetics/chemistry
*Alzheimer Disease/genetics/pathology
Humans
*Polymorphism, Single Nucleotide/genetics
*Apolipoproteins E/genetics/chemistry
*Genetic Predisposition to Disease
Gene Frequency/genetics

@article {pmid42170819,
year = {2026},
author = {Abdi, H and Sanchez-Molina, D and Garcia-Vilana, S and Azizi, S and Rahimi-Movaghar, V},
title = {Progression of Cerebral Atrophy in Alzheimer's Disease and Its Consequences on Traumatic Brain Injury: Insights From Longitudinal MRI Studies.},
journal = {International journal for numerical methods in biomedical engineering},
volume = {42},
number = {5},
pages = {e70180},
doi = {10.1002/cnm.70180},
pmid = {42170819},
issn = {2040-7947},
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/pathology/physiopathology ; *Brain Injuries, Traumatic/diagnostic imaging/physiopathology/pathology ; *Magnetic Resonance Imaging ; Atrophy ; Longitudinal Studies ; Finite Element Analysis ; Brain/pathology/diagnostic imaging ; Male ; Biomechanical Phenomena ; Disease Progression ; Aged ; },
abstract = {Alzheimer's disease (AD) is characterized by progressive cerebral atrophy that alters the brain's biomechanical response to external loading and may increase susceptibility to traumatic brain injury (TBI). This study aimed to quantify how varying degrees of AD-related atrophy affect intracranial dynamics under impact conditions and to compare these effects with those observed in normal aging. Three-dimensional finite-element head models were constructed in COMSOL Multiphysics, incorporating skull, cerebrospinal fluid (CSF), and brain tissue. Longitudinal MRI data informed annual volume-reduction rates of 0.5% (healthy aging), 1% (moderate AD), and 4% (severe AD) over a four-year period. Fluid-structure interaction (FSI) was employed to simulate dynamic interactions between the CSF and deformable brain tissue under a standardized blunt impact scenario. Key biomechanical metrics-relative brain-skull displacement and peak intracranial pressure-were recorded in frontal and occipital regions. At approximately 15.07% total volume reduction (severe AD), relative brain-skull displacement increased by 12.6% in the frontal region and 28.0% in the occipital region compared with healthy aging. Peak intracranial pressure decreased by 5.51% in the frontal region and 4.95% in the occipital region under severe atrophy, indicating enhanced energy absorption by the expanded CSF layer but greater overall brain motion. The amplified displacement patterns suggest elevated strain on bridging veins and a higher risk of subdural hematoma formation. Progressive brain atrophy in AD significantly modifies intracranial biomechanics under impact, underscoring the importance of accounting for neurodegenerative changes in TBI risk assessments. Incorporation of patient-specific viscoelastic properties-obtainable via Magnetic Resonance Elastography-into future models may further enhance predictive accuracy for vulnerable populations.},
}

Humans
*Alzheimer Disease/diagnostic imaging/pathology/physiopathology
*Brain Injuries, Traumatic/diagnostic imaging/physiopathology/pathology
*Magnetic Resonance Imaging
Atrophy
Longitudinal Studies
Finite Element Analysis
Brain/pathology/diagnostic imaging
Male
Biomechanical Phenomena
Disease Progression
Aged

@article {pmid42170857,
year = {2026},
author = {Javidnia, S and Roe, JM and Karhunen, V and Gill, D and Bell, S and Deak, JD and Levey, D and Kember, RL and Kranzler, HR and Cronjé, HT and Burgess, S and Gelernter, J and Ebmeier, KP and Topiwala, A},
title = {Opioid use disorder and dementia risk: evidence from observational and genetic analyses in diverse ancestry cohorts.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71418},
doi = {10.1002/alz.71418},
pmid = {42170857},
issn = {1552-5279},
support = {//NIH-NIDA/ ; //NIAAA/ ; 2101BX006482//U.S. Department of Veterans Affairs/ ; K01DA058807//Intramural Research Program, National Institute on Drug Abuse/ ; //UK Research and Innovation MRC/ ; 732592//Horizon 2020/ ; 2021079//University Grants Commission - South Eastern Regional Office/ ; //HDH Wills/ ; 225790/Z/22/Z/WT_/Wellcome Trust/United Kingdom ; 216462/Z/19/Z/WT_/Wellcome Trust/United Kingdom ; },
mesh = {Humans ; Genome-Wide Association Study ; *Opioid-Related Disorders/genetics/complications/epidemiology ; Male ; Female ; *Dementia/genetics/epidemiology ; Mendelian Randomization Analysis ; Magnetic Resonance Imaging ; White People/genetics ; Aged ; Genetic Predisposition to Disease ; Receptors, Opioid, mu/genetics ; Risk Factors ; Cohort Studies ; Middle Aged ; Polymorphism, Single Nucleotide ; White ; },
abstract = {INTRODUCTION: Opioid use disorder (OUD) may adversely affect brain health, but its role in dementia risk remains poorly understood.

METHODS: We investigated associations between OUD and dementia using observational data from 222,518 participants (European and African ancestry) in the Million Veteran Program and Mendelian randomization (MR) using genome-wide association study summary statistics from 6,066,918 individuals. Polygenic risk score (PRS) analyses were conducted in 229 opioid-naïve Lifebrain consortium participants with longitudinal magnetic resonance imaging data.

RESULTS: OUD was associated with increased risk of all-cause dementia (hazard ratio = 1.56, 95% confidence interval [CI]: 1.39 to 1.76), Alzheimer's disease, and vascular dementia. MR supported a potential causal link between genetic liability to OUD and dementia (inverse variance weighted odds ratio = 1.77, 95% CI: 1.43 to 2.19). Genetic variation in the μ-opioid receptor gene was also associated with dementia risk. No PRS associations were found with brain structure.

DISCUSSION: These findings suggest a potential causal role for OUD in dementia, implicating μ-opioid receptor pathways in neurodegeneration.},
}

Humans
Genome-Wide Association Study
*Opioid-Related Disorders/genetics/complications/epidemiology
Male
Female
*Dementia/genetics/epidemiology
Mendelian Randomization Analysis
Magnetic Resonance Imaging
White People/genetics
Aged
Genetic Predisposition to Disease
Receptors, Opioid, mu/genetics
Risk Factors
Cohort Studies
Middle Aged
Polymorphism, Single Nucleotide
White

@article {pmid42170924,
year = {2026},
author = {DeMeglio, M and De Biasi, ES and Breunig, P and Candlish, M and Sauerland, C and Günther, S and Kawase, H and Peguera, B and Bohnstaedt, C and Herms, J and Neubauer, A and Neher, JJ and Nilsson, PR and Hu, J and Hille, S and Müller, O and Acker-Palmer, A and Hammock, BD and Underhill, TM and Junek, S and Offermanns, S and Fleming, I and Hefendehl, JK},
title = {Soluble epoxide hydrolase drives neurovascular dysfunction in a model of amyloidosis.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag184},
pmid = {42170924},
issn = {1460-2156},
abstract = {Recent advances in anti-amyloid therapies for Alzheimer's disease have been promising, but they have also highlighted critical challenges, including increased vascular complications, such as amyloid-related imaging abnormalities. Emerging evidence suggests that the soluble epoxide hydrolase may be a promising therapeutic target due to the involvement of sEH-derived diols in inflammation, oxidative stress, and vascular destabilization. APPPS1 mice, a model of amyloidosis, were crossed with an inducible soluble epoxide hydrolase knock-out mouse line. The knock-out was induced before onset of amyloid deposition, and then the mice were analyzed using histological, molecular, and RNA sequencing techniques. Here, we identify astrocytic soluble epoxide hydrolase as a key mediator of vascular instability in amyloid pathology. Targeted astrocyte-specific deletion of soluble epoxide hydrolase in APPPS1 mice dramatically mitigated vascular changes, reducing the vascular amyloid burden by 67.95% and preserving VE-cadherin architecture. Importantly, vasomotion was markedly impaired in the Alzheimer's disease model and was preserved in soluble epoxide hydrolase-deficient animals. Transcriptomic profiling of vasculature in APPPS1xsEHΔAC mice revealed upregulated expression of genes critical for neurovascular protection. These findings identify soluble epoxide hydrolase as a central regulator of neurovascular dysfunction and underscore its therapeutic potential in increasing vascular stability in amyloidosis-associated diseases, such as Alzheimer's disease.},
}

@article {pmid42171457,
year = {2026},
author = {Li, R and Yang, J and Chai, W and Liu, H and Wang, X and Zhang, S and Cai, H and Wang, J and Guo, T and Han, Y},
title = {Diagnostic and Prognostic Utility of Plasma p-tau217 for Alzheimer's Disease in Chinese Elderly: Insights From the SILCODE Study With a Derived Threshold.},
journal = {European journal of neurology},
volume = {33},
number = {5},
pages = {e70618},
doi = {10.1111/ene.70618},
pmid = {42171457},
issn = {1468-1331},
support = {2022ZD0211800//STI2030-Major Projects/ ; 82327809//National Natural Science Foundation of China/ ; 2025HZGF02//the Construction Fund of Key Medical Disciplines of Hangzhou/ ; KYQD-ZR-21057//Initiative Funding of Hainan University/ ; //Education Funding from Mr Zhenhai Song and Mr Jinbo Yan/ ; },
mesh = {Humans ; *Alzheimer Disease/blood/diagnosis ; *tau Proteins/blood ; Female ; Male ; Aged ; Prognosis ; Biomarkers/blood ; Longitudinal Studies ; Aged, 80 and over ; Cross-Sectional Studies ; *Cognitive Dysfunction/blood/diagnosis ; Amyloid beta-Peptides ; Disease Progression ; China ; Asian People ; Phosphorylation ; East Asian People ; },
abstract = {BACKGROUND: Plasma phosphorylated tau 217 (p-tau217) has emerged as a promising Alzheimer's disease (AD) biomarker, yet its longitudinal associations with neurodegeneration and cognitive decline remain inadequately characterized in Chinese populations, and ethnicity-specific diagnostic thresholds are lacking for optimal clinical application.

METHODS: A total of 541 participants (402 cognitively unimpaired [CU]; 139 cognitively impaired [CI]) from the Sino Longitudinal Study on Cognitive Decline (SILCODE) cohort were enrolled. Cross-sectional and longitudinal associations of plasma p-tau217 with amyloid-β (Aβ) pathology, neurodegeneration, and cognition were evaluated. Diagnostic thresholds were derived using receiver operating characteristic analysis, and Cox regression assessed prognostic value for clinical progression.

RESULTS: Cross-sectionally, baseline p-tau217 was associated with greater Aβ burden, neurodegeneration, and poorer cognition in the whole cohort and CI group; in the CU group, associations were confined to amyloid measures. Longitudinally, accelerated p-tau217 accumulation was associated with faster neurodegeneration and cognitive decline in the whole cohort, with stage-dependent patterns: nominal associations with neurodegenerative markers in CU and prominent cognitive associations in CI. Plasma p-tau217 demonstrated high diagnostic accuracy for amyloid positivity (AUC = 0.891; cutoff: 0.529 pg/mL). Threshold-based stratification effectively differentiated individuals by Aβ burden, neurodegeneration, and cognitive trajectories. Elevated baseline p-tau217 predicted higher progression risk (Whole cohort: HR = 2.66 [1.28-5.53], p = 0.009; CU: HR = 2.44 [1.07-5.59], p = 0.034).

CONCLUSION: Plasma p-tau217 serves as a valuable diagnostic and prognostic biomarker for AD, even among CU individuals, and the ethnicity-specific threshold of 0.529 pg/mL enhances its clinical applicability for early detection and risk stratification in Chinese populations.},
}

Humans
*Alzheimer Disease/blood/diagnosis
*tau Proteins/blood
Female
Male
Aged
Prognosis
Biomarkers/blood
Longitudinal Studies
Aged, 80 and over
Cross-Sectional Studies
*Cognitive Dysfunction/blood/diagnosis
Amyloid beta-Peptides
Disease Progression
China
Asian People
Phosphorylation
East Asian People

@article {pmid42171655,
year = {2026},
author = {Mortazavi, N and Zubkov, M and Chylinski, D and Collette, F and Bastin, C and Maquet, P and Vandewalle, G and Talwar, P},
title = {Sleep arousals are associated with the polygenic risk for developing Alzheimer's disease and with cognitive change in healthy late middle-aged individuals.},
journal = {Sleep},
volume = {},
number = {},
pages = {},
doi = {10.1093/sleep/zsag143},
pmid = {42171655},
issn = {1550-9109},
abstract = {STUDY OBJECTIVES: Sleep disturbances are increasingly recognized as early features of Alzheimer's disease (AD) neuropathology. Specifically, spontaneous arousals during sleep have been associated with the burden of Amyloid beta in the brain of healthy late middle-aged individuals. However, it remains unclear whether heterogeneity of arousals relates to genetic risk for AD in younger adults or to cognitive change later in life. Here, we evaluated the association between arousals, polygenic risk scores (PRS) for AD, and cognitive performance and change in healthy young and late-middle-aged individuals.

METHODS: We classified spontaneous arousals using in-lab EEG sleep recordings in 453 younger individuals (22±2.7y; 49 women) and 87 late middle-aged individuals (59.3±5.3y; 59 women) based on their association with sleep stage transitions and changes in muscle tone. We examined the associations between arousal types, AD-PRS, baseline cognitive performance and, in late middle-aged individuals, cognitive change over 2 and 7 years.

RESULTS: The prevalence of arousals associated with sleep stage transition was higher in late middle-aged vs. younger individuals. In late middle-aged but not younger individuals, transition arousals with muscle tone increases correlated with lower AD-PRS, better attentional performance and lower memory change over follow-ups, whereas transition arousals without muscle tone increases were linked to higher AD-PRS, poorer baseline attention, and greater memory change across follow-up periods.

CONCLUSIONS: The heterogeneity in spontaneous arousals during sleep may reflect their physiological intensity or underlying neural activation, and may indicate vulnerability to AD in late middle-aged individuals. The findings may help identify early markers of neurodegenerative risk.},
}

@article {pmid42171726,
year = {2026},
author = {Agrawal, L and Agrawal, PK and Agrawal, SS and Sonune, MS and Kadu, RK and Kulkarni, MB and Bhaiyya, M},
title = {AI-driven multimodal retinal imaging for early detection and risk stratification of vascular and neurodegenerative diseases.},
journal = {Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie},
volume = {},
number = {},
pages = {},
pmid = {42171726},
issn = {1435-702X},
abstract = {Systemic vascular and neurodegenerative disorders are important causes of disability and death worldwide, mainly because of the late stage of diagnosis and the high cost of current screening tools. Artificial intelligence (AI) and multimodal retinal imaging offer a non-invasive and viable approach for early risk stratification and longitudinal monitoring. This review highlights how changes in the retinal vasculature and nerve layers are markers of underlying pathophysiologies related to cardiovascular, metabolic, and neurological disorders. It gives an account of the critical retinal imaging modalities, such as fundus photography, optical coherence tomography (OCT), OCT angiography (OCTA), and more recently developed metabolic-sensitive imaging modalities, and how current AI approaches, such as deep learning, self-supervised learning, and multimodal fusion, can be leveraged for better risk stratification and decision support. Evidence from hypertension, stroke, coronary artery disease, diabetic complications, Alzheimer's disease, Parkinson's disease, multiple sclerosis, and cognitive impairment shows the potential for the retina to serve as a scalable biomarker for systemic health. However, there are still hurdles to be cleared, such as multicenter validation, prospective clinical trials, data fusion, and regulatory frameworks. In conclusion, AI-assisted retinal analysis may make way for early screening, better prevention, and more accessible precision healthcare.},
}

@article {pmid42159446,
year = {2026},
author = {Lee, WJ and Cho, K and Kim, GW},
title = {Integrated amyloid, neurodegeneration, and vascular biomarkers estimate the risk of dementia progression in mild cognitive impairment.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261445623},
doi = {10.1177/13872877261445623},
pmid = {42159446},
issn = {1875-8908},
abstract = {BackgroundProgression from mild cognitive impairment (MCI) to dementia arises from heterogeneous mechanisms involving Alzheimer's disease (AD) pathology and vascular factors.ObjectiveThis study aimed to develop a multimodal biomarker model to estimate the risk of dementia progression and to examine whether carotid atherosclerosis provides independent prognostic value, particularly in amyloid-β (Aβ)-negative MCI.MethodsWe retrospectively analyzed 300 individuals with MCI who underwent baseline [[18]F]florbetapir PET, structural MRI, carotid Doppler ultrasound, cognitive assessments, and APOE genotyping (2018-2021). Participants were followed for a total of 37 months to dementia based on longitudinal cognitive and functional decline, independent of follow-up amyloid PET findings. Aβ positivity was defined using Brain Amyloid Plaque Load criteria. Multivariable logistic regression and receiver operating characteristic analyses were performed.ResultsAmong 189 Aβ-positive individuals, 30.7% (n = 58) progressed to Aβ-positive AD dementia, while 9.0% (n = 10) of 111 Aβ-negative individuals developed non-AD dementia. Independent factors estimating Aβ-positive AD dementia included higher Aβ burden (OR 2.34, p < 0.001), smaller hippocampal volume (OR 0.71, p < 0.001), greater carotid plaque count (OR 1.45, p = 0.001), lower Mini-Mental State Examination (OR 1.11, p = 0.002), and APOE ε4 carriage (OR 1.82, p = 0.021). The integrated model showed excellent performance (AUC 0.903; 95% CI: 0.814-0.968). In Aβ-negative MCI, carotid plaque burden was the primary estimator of non-AD dementia progression.ConclusionsThe prominent prognostic role of carotid plaques in Aβ-negative MCI underscores the vascular contributions to non-amyloid cognitive decline and highlights the importance of evaluating both AD-related and vascular mechanisms in prodromal dementia.},
}

@article {pmid42159448,
year = {2026},
author = {Arnhardt, S and Singh, S and Steinebach, K and Fuchs, R and Diener, T and Gasser, D and Kornhuber, J and Freiherr, J},
title = {Color-modulated olfactory testing using RAPPIT: An innovative tool for early detection of cognitive decline.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261449410},
doi = {10.1177/13872877261449410},
pmid = {42159448},
issn = {1875-8908},
abstract = {BackgroundOlfactory and visual processing are sensitive biomarkers for cognitive impairment; however, unimodal assessments may fail to capture early deficits in higher order cognitive integration. When sensory cues are mismatched, multisensory processing induces crossmodal conflict that requires inhibitory control, which is particularly vulnerable in early neurodegeneration.ObjectiveWe developed RAPPIT (Rapid, massively APPlicable Identification Test), a color-modulated olfactory test to assess multisensory interference as an early marker of cognitive decline.MethodsRAPPIT includes 16 physically presented odors, with a digital application for task control and response recording. Answer options are displayed on color backgrounds derived from the MONEX-40 color profile, either congruent or incongruent with the presented odors. A total of 163 participants from the German population completed the assessment. Odor identification accuracy, effects of color congruence (ΔE00), associations with cognitive performance (Montreal Cognitive Assessment, MoCA), hedonic ratings, and depressive symptoms were analyzed.ResultsOdor identification declined with age. Participants aged ≥ 60 years, a group at increased risk for neurodegenerative disorders including Alzheimer's disease, showed reduced performance under incongruent conditions. Performance exhibited a non-linear relationship with color difference (ΔE00), declining at mid-range values. Accuracy was significantly associated with MoCA scores. Hedonic ratings varied with color cues, while no associations were found with depressive symptoms.ConclusionsThese findings demonstrate that differences between congruent and incongruent odor-color conditions capture cognitively relevant interference effects beyond unimodal olfactory or visual performance, supporting the utility of this approach for early detection of cognitive impairment in older adults, in clinical and home settings.},
}

@article {pmid42159654,
year = {2026},
author = {Fernández-Lebrero, A and Jiménez-Balado, J and García-Escobar, G and Contador, J and Estraguès-Gázquez, I and Peraferrer-Montesinos, L and Suárez-Pérez, A and Manero-Borràs, RM and Beltrán, B and Gramegna, L and Campello, AR and Palacio-Gili, A and Grau, O and Suárez-Calvet, M and Ois, A and Puig-Pijoan, A and Navalpotro-Gómez, I},
title = {CSF Biomarker Profile of Cerebral Amyloid Angiopathy: Diagnostic Performance and Imaging Correlates in a Hospital-Based Neurology Cohort.},
journal = {European journal of neurology},
volume = {33},
number = {5},
pages = {e70613},
doi = {10.1111/ene.70613},
pmid = {42159654},
issn = {1468-1331},
support = {//Instituto de Salud Carlos III/ ; ERA-CVD_JTC2020-015//European Research Area Network on Cardiovascular Diseases/ ; },
mesh = {Humans ; Male ; Female ; *Cerebral Amyloid Angiopathy/cerebrospinal fluid/diagnostic imaging/diagnosis/complications ; *Amyloid beta-Peptides/cerebrospinal fluid ; Aged ; Biomarkers/cerebrospinal fluid ; *Alzheimer Disease/cerebrospinal fluid/diagnostic imaging/complications/diagnosis ; tau Proteins/cerebrospinal fluid ; *Peptide Fragments/cerebrospinal fluid ; Cohort Studies ; Middle Aged ; Aged, 80 and over ; Magnetic Resonance Imaging ; },
abstract = {BACKGROUND: Cerebral amyloid angiopathy (CAA) frequently co-occurs with Alzheimer's disease (AD), complicating diagnosis in patients with cognitive impairment. The CSF biomarker profile of CAA remains poorly understood, particularly with AD co-pathology. We aimed to characterize CSF biomarkers in CAA, assess diagnostic accuracy, and examine associations with neuroimaging markers.

METHODS: We included 261 participants from a hospital-based cohort, recruited from memory clinic outpatients and neurology inpatients. Groups comprised healthy controls (HC, n = 35), CAA without AD co-pathology (CAA-nonAD, n = 27), CAA with AD co-pathology (CAA-AD, n = 30), and AD (n = 169). CSF Aβ40, Aβ42, p-tau181, and t-tau were quantified using automated immunoassays. Group differences were tested using ANCOVA adjusted for age and sex. ROC analyses with 10-fold cross-validation and bootstrapping assessed diagnostic performance. Associations between CSF biomarkers and CAA-related MRI markers were examined using ANCOVA.

RESULTS: Aβ40 concentrations were lower in CAA-nonAD and CAA-AD compared to AD and HC (p-valuebf < 0.05). Aβ42 was reduced in CAA-AD and AD versus HC, with no difference between CAA-nonAD and AD. p-tau181 and t-tau were elevated in AD and CAA-AD compared with CAA-nonAD and HC (p-valuebf < 0.05). Aβ40 showed the highest diagnostic accuracy for CAA (AUC = 0.73; 95% CI: 0.66-0.80), followed by Aβ42 (AUC = 0.71; 95% CI: 0.64-0.78). In AD patients, Aβ42 best discriminated coexisting CAA (AUC = 0.77). Higher CAA-SVD burden scores were associated with lower Aβ40 (p-valuebf < 0.05).

CONCLUSIONS: CSF Aβ40 and Aβ42 provide complementary diagnostic value for identifying CAA, both in isolation and with AD co-pathology. Reduced Aβ40 is associated with greater CAA-related vascular burden, supporting its role as a marker of vascular amyloid pathology.},
}

Humans
Male
Female
*Cerebral Amyloid Angiopathy/cerebrospinal fluid/diagnostic imaging/diagnosis/complications
*Amyloid beta-Peptides/cerebrospinal fluid
Aged
Biomarkers/cerebrospinal fluid
*Alzheimer Disease/cerebrospinal fluid/diagnostic imaging/complications/diagnosis
tau Proteins/cerebrospinal fluid
*Peptide Fragments/cerebrospinal fluid
Cohort Studies
Middle Aged
Aged, 80 and over
Magnetic Resonance Imaging

@article {pmid42159858,
year = {2026},
author = {Rong, W and Xu, J and Li, B and Li, Y and Xu, Y},
title = {Single-cell atlas reveals the key role of pro-inflammatory IREB2[+] microglia subsets in the microenvironment of Alzheimer's disease.},
journal = {Clinical and experimental medicine},
volume = {},
number = {},
pages = {},
doi = {10.1007/s10238-026-02188-2},
pmid = {42159858},
issn = {1591-9528},
support = {U1904207//National Natural Science Foundation of China/ ; 2017YFA0105003//National Key Research and Development Program of China/ ; },
abstract = {Chronic neuroinflammation driven by activated microglia is a critical hallmark of Alzheimer's disease (AD) progression. Metabolic dysregulation, particularly iron metabolism, has been implicated in neurodegeneration, yet the role of iron-responsive element-binding protein 2 (IREB2) in AD-associated neuroinflammation remains poorly understood. We performed integrative analysis of single-cell RNA sequencing (scRNA-seq) data from AD brain tissues, using non-negative matrix factorization (NMF) and intercellular communication algorithms to map cellular landscapes. We identified microglial subpopulations and their inflammatory signaling. To experimentally validate the functional role of IREB2 in inflammatory responses, we conducted siRNA-mediated knockdown in the human neuroblastoma cell line SH-SY5Y, which serves as a neuronal model for assessing IREB2's effect on cytokine expression. Single-cell analysis revealed a distinct microglial subpopulation (IREB2[+] MC C1) that is significantly expanded in AD. This subpopulation exhibits a hyper-inflammatory state, with enrichment of Toll-like receptor and IL-17 signaling pathways, and functions as a primary source of outgoing inflammatory signals (CCL3, CCL4). Furthermore, IREB2 knockdown in SH-SY5Y cells significantly suppressed the expression of key pro-inflammatory cytokines (IL6, IL-1β, and TNF-α), confirming that IREB2 positively regulates inflammation in neurons as well. IREB2 drives both microglial activation and neuronal inflammatory responses in AD, potentially via the NF-κB pathway. The IREB2[+] microglial subpopulation represents a specific pathogenic entity that orchestrates the inflammatory microenvironment. Targeting IREB2 may therefore offer a dual-pronged therapeutic strategy to mitigate neuroinflammation and slow AD progression.},
}

@article {pmid42159968,
year = {2026},
author = {Ollen-Bittle, N and Boesgaard, I and Roseborough, A and Frank, M and Zhang, Q and Pasternak, SH and Hammond, R and Whitehead, SN},
title = {Wasteosomes accumulate in periventricular white matter hyperintensities and exhibit complex relationships with mixed pathology, sclerotic index, and perivascular space.},
journal = {Brain pathology (Zurich, Switzerland)},
volume = {},
number = {},
pages = {e70110},
doi = {10.1111/bpa.70110},
pmid = {42159968},
issn = {1750-3639},
support = {202104PJT-461038/CAPMC/CIHR/Canada ; RGPIN-2019-04742//Natural Sciences and Engineering Research Council of Canada/ ; //Kappa Kappa Gamma (KKG) Foundation of Canada/ ; },
abstract = {Corpora amylacea or "wasteosomes" are discontinuous lipid labyrinth structures that are polyglucosan rich, retain cellular waste and are thought to be of astrocytic origin. Wasteosomes localize around periventricular (PV) regions, perivascular spaces (PVS), and sub-pial regions; and their accumulation has been found to correlate with aging, vascular disorders, neurodegenerative diseases, and conditions that impair sleep. White matter hyperintensities (WMHs) are diffuse hyperintense areas seen on T2-weighted or fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) scans that represent damage to white matter. PV WMHs are known predictors of mild cognitive impairment, stroke, dementia and death. The relationship between wasteosome accumulation, PV WMHs, vascular pathology and PVS is currently unknown. For the first time, in a mixed diagnostic cohort of pathologically diagnosed: Alzheimer's disease (AD), cerebrovascular disease (CVD), mixed AD/CVD, and control tissue with no pathological diagnosis, we connected the histopathological wasteosome profile in periventricular brain sections in relation to 7T FLAIR-MRI confirmed PV WMHs, vascular sclerosis and PVS. Our results reveal wasteosomes accumulate in PV WMHs, are increased in proximity to large PV venules, and exhibit complex relationships with WMH severity, mixed pathology, sclerotic index and PVS. These findings provide novel insights into the pathophysiology underlying white matter injury.},
}

@article {pmid42160069,
year = {2026},
author = {Angus, DC and O'Connor, MB},
title = {A New Era in Dementia-Advances in Diagnostic Blood Tests, Novel Drugs, and the Power of Lifestyle Changes: A Healthy Dialogue With Gil Rabinovici.},
journal = {JAMA},
volume = {},
number = {},
pages = {e267539},
doi = {10.1001/jama.2026.7539},
pmid = {42160069},
issn = {1538-3598},
}

@article {pmid42160117,
year = {2026},
author = {Chen, H and Wang, T and Xia, K and Li, X and Yao, X and Huang, W},
title = {Emerging Nanoreactors for Precision Disease Treatment: From Principles to Biomedical Applications.},
journal = {Small (Weinheim an der Bergstrasse, Germany)},
volume = {},
number = {},
pages = {e73859},
doi = {10.1002/smll.73859},
pmid = {42160117},
issn = {1613-6829},
support = {BK20251864//Basic Research Program of Jiangsu/ ; 62288102//Natural Science Foundation of China/ ; //Disciplinary Fund of the School of Pharmaceutical Sciences/ ; 20250285//Nanjing Tech University Teaching Reform Project/ ; },
abstract = {Inspired by natural cellular compartments, nanoreactors are spatially confined nanostructures that precisely regulate chemical and biological reactions and act as high-performance catalytic nanocontainers. Multifunctional integration of these systems surmounts the inherent limitations of conventional therapeutic modalities. This review focuses on recent breakthroughs in organic and organic-inorganic hybrid nanoreactors, highlighting three core effects: (1) the spatial confinement effect, which elevates the reactant concentration, accelerates mass transfer, lowers activation energy, modulates electronic states, and boosts reaction rates by orders of magnitude; (2) the synergistic effect of active sites, which enables efficient cascade reactions via spatially segregated or hierarchical catalytic architectures; (3) the stimuli-responsive effect, which dynamically controls catalysis and cargo release under endogenous (pH, enzymes, ROS) or exogenous (light, temperature) cues. Typical nanoreactors (liposomes, polymeric micelles/vesicles, mesoporous silica, protein cages, and organic-inorganic hybrids) are systematically discussed regarding structural merits and biomedical applications in treating diabetes, rheumatoid arthritis (RA), chronic wound healing, cancer, and Alzheimer's disease (AD). Current challenges and future perspectives are also addressed. Intelligent nanoreactors are expected to offer immense potential for disease diagnosis and therapy.},
}

@article {pmid42160281,
year = {2026},
author = {, },
title = {Editorial Note: Zileuton Improves Memory Deficits, Amyloid and Tau Pathology in a Mouse Model of Alzheimer's Disease with Plaques and Tangles.},
journal = {PloS one},
volume = {21},
number = {5},
pages = {e0349725},
doi = {10.1371/journal.pone.0349725},
pmid = {42160281},
issn = {1932-6203},
}

@article {pmid42160315,
year = {2026},
author = {Siegel, K and Cabán, M and Tran, E and Meng, A and Wetmore, JB and Ottman, R},
title = {Memory and thinking problems that aging Latinos in New York City would bring to a doctor's attention.},
journal = {PloS one},
volume = {21},
number = {5},
pages = {e0349635},
doi = {10.1371/journal.pone.0349635},
pmid = {42160315},
issn = {1932-6203},
mesh = {Humans ; *Hispanic or Latino/psychology ; New York City ; Middle Aged ; Female ; Male ; Adult ; *Memory Disorders/psychology/diagnosis ; *Aging/psychology ; *Thinking ; *Alzheimer Disease/diagnosis/psychology ; *Memory ; *Patient Acceptance of Health Care ; White ; },
abstract = {The number of individuals with Alzheimer's disease will grow dramatically in the coming decades. Early diagnosis benefits patients, caregivers and society, but depends heavily on afflicted individuals or their family members recognizing early symptoms as possible indications of a medical problem and seeking medical care. To examine the kinds of memory or thinking problems, Latinos ages 40-64 would seek medical care for, we analyzed data from 161 participants in a community-based study in northern Manhattan of the impact of receiving information about one's risk of developing late-onset Alzheimer's disease. Participants were asked whether experiencing each of 5 different memory or thinking problems multiple times over 2-3 months would make them seek medical care. Participants often offer a benign or normalizing attributions for symptoms. Disorientation was the most frequently endorsed problem. Considerations found to be associated with an inclination or disinclination to want to see a doctor about a symptom were identified. A better understanding of what Latinos would consider in deciding whether or not to bring different memory problems to a doctor's attention can help guide the development of educational interventions to encourage help-seeking and facilitate earlier diagnosis.},
}

Humans
*Hispanic or Latino/psychology
New York City
Middle Aged
Female
Male
Adult
*Memory Disorders/psychology/diagnosis
*Aging/psychology
*Thinking
*Alzheimer Disease/diagnosis/psychology
*Memory
*Patient Acceptance of Health Care
White

@article {pmid42160451,
year = {2026},
author = {Schwartz, M and Croese, T},
title = {Treating the immune system to repair the brain.},
journal = {Science translational medicine},
volume = {18},
number = {850},
pages = {eaeb1677},
doi = {10.1126/scitranslmed.aeb1677},
pmid = {42160451},
issn = {1946-6242},
mesh = {Humans ; *Brain/immunology/pathology ; *Immune System ; Alzheimer Disease/immunology/therapy ; Animals ; Neurodegenerative Diseases/therapy/immunology ; },
abstract = {Non-neuronal brain cells and systemic immunity play a central role in Alzheimer's disease (AD) and other brain disorders. The immune system, initially protective, becomes dysfunctional as the disease progresses. Here, we discuss next-generation therapeutic approaches aimed at treating the immune system rather than the brain to combat AD and other neurodegenerative diseases.},
}

Humans
*Brain/immunology/pathology
*Immune System
Alzheimer Disease/immunology/therapy
Animals
Neurodegenerative Diseases/therapy/immunology

@article {pmid42160739,
year = {2026},
author = {Das, S and Rao Padubidri, S and K V, S and Shetty, KS and Jena, R and K R, H and Dehury, B and Pandurangan, AP},
title = {From mechanistic modeling to AI-driven design: computational strategies for targeting the γ-secretase complex.},
journal = {Briefings in bioinformatics},
volume = {27},
number = {3},
pages = {},
doi = {10.1093/bib/bbag231},
pmid = {42160739},
issn = {1477-4054},
mesh = {*Amyloid Precursor Protein Secretases/chemistry/metabolism/antagonists & inhibitors ; Humans ; Molecular Dynamics Simulation ; *Alzheimer Disease/drug therapy/metabolism/genetics ; *Artificial Intelligence ; Drug Discovery ; *Computational Biology/methods ; *Drug Design ; },
abstract = {Advancements in computational biology are transforming the study of complex membrane proteins and their therapeutic targeting. The γ-secretase complex, a quintessential intramembrane protease implicated in Alzheimer's disease (AD) and more than 150 other substrates, provides a powerful exemplar to illustrate this transformative shift. Traditional γ-secretase inhibitors have been constrained by off-target toxicity, particularly through disruption of Notch signaling, underscoring the need for deeper mechanistic insights, now increasingly enabled by modern computational methodologies. We evaluate the computational strategies driving next-generation drug discovery of γ-secretase. Integrative modeling frameworks, informed by cryo-electron microscopy (cryo-EM) and biophysical data, have facilitated atomic-resolution reconstructions of γ-secretase dynamics and substrate recognition. All-atom molecular dynamics (MD) simulations, supported by enhanced sampling techniques such as umbrella sampling, steered MD, replica exchange, and Gaussian accelerated MD, have mapped conformational landscapes and elucidated molecular determinants of substrate selectivity. Structure-function mapping of familial AD mutations further demonstrates how computational modeling translates genetic variation into mechanistic understanding. Beyond structural modeling, the integration of artificial intelligence (AI) including deep generative models, machine learning-based activity prediction, and high-throughput virtual screening has created accelerated pipelines for discovering modulators predicted to reduce pathogenic amyloid beta (Aβ) production while preserving essential signaling pathways. These approaches demonstrate how computational methods increasingly serve as predictive and design-oriented engines in drug development. Using γ-secretase, this review highlights how state-of-the-art computational techniques, from integrative structural biology to AI-driven drug design, are reshaping the discovery of safer, more selective modulators with broader relevance across diseases requiring precise modulation of protein function.},
}

*Amyloid Precursor Protein Secretases/chemistry/metabolism/antagonists & inhibitors
Humans
Molecular Dynamics Simulation
*Alzheimer Disease/drug therapy/metabolism/genetics
*Artificial Intelligence
Drug Discovery
*Computational Biology/methods
*Drug Design

@article {pmid42160848,
year = {2026},
author = {Zheng, M and Yang, M and Su, W and Tian, L and Gao, W},
title = {Targeting microglia: A new strategy for the treatment of Alzheimer's disease.},
journal = {Journal of neuroimmunology},
volume = {418},
number = {},
pages = {578966},
doi = {10.1016/j.jneuroim.2026.578966},
pmid = {42160848},
issn = {1872-8421},
abstract = {Alzheimer's disease (AD), a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) plaques, neurofibrillary tangles, and chronic neuroinflammation, remains without curative therapies. Emerging evidence underscores microglia, the brain's resident immune cells, as pivotal players in AD pathogenesis, exerting dual roles in neuroprotection and neurotoxicity. This review synthesizes current knowledge on microglial dynamics, including their heterogeneous activation states (e.g., disease-associated microglia), metabolic reprogramming, aging-related dysfunction, and subset heterogeneity, which collectively influence Aβ clearance, tau propagation, and synaptic integrity. We highlight the interplay between microglial receptors-such as TREM2, APOE, and neurotransmitter receptors (e.g., cholinergic, glutamatergic, and cannabinoid receptors)-and AD pathology, emphasizing their roles in modulating neuroinflammation, phagocytosis, and neuronal excitotoxicity. Furthermore, we evaluate therapeutic strategies targeting microglia, including pharmacologic modulation of neuroinflammatory pathways, metabolic interventions, and cell transplantation, which aim to restore homeostatic microglial functions. Challenges in clinical translation, such as temporal specificity of interventions and microglial plasticity, are critically discussed. By integrating recent advances in single-cell genomics and neuroimmunology, this review provides a roadmap for developing microglia-centric therapies to disrupt the vicious cycle of neuroinflammation and neurodegeneration in AD, offering novel insights for future research and therapeutic innovation.},
}

@article {pmid42160907,
year = {2026},
author = {Naomi, R and Al-Amin, M and Smykla, J and Rizman-Idid, M and Chong, TT and Murthy, JK and Zubairi, SI and David, P and Satriawan, H and Bakar, NA and Alias, SA},
title = {Network pharmacology and molecular docking of arctic Pseudogymnoascus australis compounds targeting ionotropic glutamate receptors for neuroprotection.},
journal = {Computational biology and chemistry},
volume = {124},
number = {Pt 1},
pages = {109126},
doi = {10.1016/j.compbiolchem.2026.109126},
pmid = {42160907},
issn = {1476-928X},
abstract = {Neurodegenerative diseases constitute a major public health burden, with neurotoxicity representing a critical pathogenic mechanism underlying Alzheimer's disease and Parkinson's disease. Current therapeutic approaches are primarily symptomatic and fail to prevent disease progression, highlighting the urgent need for neuroprotective agents that can modulate pathological pathways at their source. Natural fungal metabolites have emerged as promising sources of bioactive compounds with potential neuroprotective properties. This study investigates the neuroprotective potential of bioactive compounds derived from the Arctic fungus Pseudogymnoascus australis (P. australis) using an integrated in silico method. From 120 identified compounds, nine were selected based on favorable blood-brain barrier (BBB) permeability and pharmacokinetic profiles using ADMET 3.0 predictions. These included 2-aminohexadecanoic acid (AHA), 11-aminoundecanoic acid (AUA), and seven others, all exhibiting optimal drug-likeness (>0.83) and suitable CNS-targeting properties. Network pharmacology analysis identified 226 overlapping targets between the fungal compounds and neurotoxicity-associated genes. Nine hub genes (Gria1, Gria2, Gria4, Grik1, Grik2, Grin1, Grin2a, Grin2b, and Grin2c) were identified as critical nodes. Enrichment analyses revealed significant involvement in the neuroactive ligand-receptor interaction pathway, suggesting these compounds modulate ionotropic glutamate receptors. Molecular docking analysis showed strong binding affinities, with 78% of ligand-receptor complexes displaying RMSD values below 2.0 Å. AHA and Grik1 emerged as the most promising pair, with a docking score of -7.90 kcal/mol and excellent pharmacokinetic properties (drug-likeness: 0.462, BBB penetration: 0.985). Molecular dynamics simulations over 100 nanoseconds confirmed complex stability, with a mean RMSD of 2.45 Å and binding energies averaging -169.02 kcal/mol, demonstrating sustained ligand-protein interactions. These computational findings provide evidence that P. australis contains bioactive compounds capable of attenuating neurotoxicity through sustained modulation of glutamate receptors, with molecular dynamics validation supporting the thermodynamic stability and potential therapeutic relevance of these interactions.},
}

@article {pmid42160956,
year = {2026},
author = {Yan, Y and Hu, D and Kong, L and Li, K and Su, J and Wu, Y and Zhan, H and Zhang, H and Sun, Y and Dou, X and Huang, P and Zhou, J},
title = {Reductions in neuropsychiatric symptoms after lecanemab treatment and their associations with imaging markers of β-amyloid clearance.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {7},
pages = {100600},
doi = {10.1016/j.tjpad.2026.100600},
pmid = {42160956},
issn = {2426-0266},
abstract = {BACKGROUND: Anti-amyloid-β (Aβ) therapies can slow cognitive decline and reduce cerebral amyloid burden in Alzheimer's disease (AD). Neuropsychiatric symptoms (NPS) are highly prevalent across the disease course and substantially contribute to disability and caregiver burden. However, whether Aβ clearance translates into improvements in NPS remains unclear.

METHOD: We enrolled 144 individuals with AD-related mild cognitive impairment or AD dementia who received intravenous lecanemab infusions. Standardized clinical rating scales, including the Neuropsychiatric Inventory, and amyloid PET were assessed at baseline (V0), 6 months (V1), and 12 months (V2). Longitudinal changes in clinical function and amyloid burden were analyzed.

RESULTS: Lecanemab treatment was associated with robust reductions in amyloid PET biomarkers and significant short-term reductions in NPS scores in patients who completed follow-up. Longitudinal analyses showed that reductions in total NPI scores were significantly associated with amyloid-β clearance in the insular cortex. Reductions in the hyperactivity subsyndrome were associated with amyloid reduction across a broader network, including the frontal and temporal lobes, striatum, and insular cortex.

CONCLUSIONS: In this real-world cohort, lecanemab was associated with short-term reductions in NPS. Changes in NPS severity were linked to regional amyloid-β clearance.},
}

@article {pmid42160959,
year = {2026},
author = {Wang, H and Long, Y and Tang, Y and Duan, L and Wang, Z and Zhang, S and Yin, Y and Zhou, J and Wu, W and Zhong, C},
title = {Identification of a CD44-dependent control of astrocytic autophagic activity in Alzheimer's disease.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {8},
pages = {100601},
doi = {10.1016/j.tjpad.2026.100601},
pmid = {42160959},
issn = {2426-0266},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and memory impairment. Despite extensive research, the precise molecular mechanisms driving AD pathogenesis remain incompletely understood. This study sought to identify robust molecular targets and cellular basis underlying AD progression.

METHODS: We performed a systematic analysis of cross-regional transcriptomic datasets from AD patients, integrating differential expression analysis across 14 Gene Expression Omnibus (GEO) datasets with cross-regional intersection mapping. Single-nucleus RNA sequencing (snRNA-seq) was employed to resolve cell-type-specific expression patterns. Furthermore, cellular communication analysis and functional enrichment of astrocyte-specific genes were conducted. The biological role of the identified candidate was validated in vitro using Aβ42 oligomer-treated primary astrocytes via siRNA-mediated knockdown and plasmid-driven overexpression, with autophagic activity assessed through LC3-II and p62 expression.

RESULTS: The transmembrane glycoprotein receptor CD44 was identified as consistently upregulated across AD-vulnerable brain regions, including the temporal cortex, frontal cortex, entorhinal cortex, and hippocampus. snRNA-seq analysis identified this upregulation primarily to astrocytes. Intercellular signaling analysis indicated that the CD44-SPP1 axis enhanced astrocyte-glial crosstalk. Functional enrichment analysis linked astrocytic CD44 to the modulation of autophagy pathways. In vitro experiments demonstrated that CD44 knockdown promoted autophagic activation (increased LC3-II and decreased p62), whereas CD44 overexpression suppressed autophagic activity.

CONCLUSION: Our findings establish CD44 as a pivotal regulator of astrocytic autophagy in AD, highlighting its potential as a novel therapeutic target.},
}

@article {pmid42161162,
year = {2026},
author = {, and Caligiore, D},
title = {Response to the Letter Regarding "Explainable machine learning on clinical features to predict and differentiate Alzheimer's progression by sex: Toward a clinician-tailored web interface".},
journal = {Journal of the neurological sciences},
volume = {487},
number = {},
pages = {126005},
doi = {10.1016/j.jns.2026.126005},
pmid = {42161162},
issn = {1878-5883},
}

@article {pmid42161225,
year = {2026},
author = {McNamara, O and Delany, T and Kwakowsky, A},
title = {Bumetanide as a potential treatment for neurodegenerative and neurodevelopmental disorders: A systematic review.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {200},
number = {},
pages = {119533},
doi = {10.1016/j.biopha.2026.119533},
pmid = {42161225},
issn = {1950-6007},
abstract = {Neurological disorders represent a major global health burden, affecting an estimated 3.4 billion individuals worldwide. Bumetanide, a clinically approved loop-diuretic and antagonist of the Na[+] -K[+]-Cl[-] cotransporter NKCC1, has recently emerged as a candidate for repurposing in the treatment of neurological disorders. Disrupted excitation-inhibition balance, driven in part by depolarizing GABAA receptor signaling resulting from altered chloride homeostasis, has been implicated across multiple neurodegenerative and neurodevelopmental conditions. This systematic literature review evaluated preclinical and clinical evidence for the efficacy of bumetanide across a range of neurological disorders, including Alzheimer's, Parkinson's, and Huntington's disease, autism spectrum disorder, schizophrenia, tuberous sclerosis, fragile X syndrome, Down syndrome, and Angelman syndrome. Across in vivo and ex vivo models, bumetanide frequently restored hyperpolarizing GABAergic activity and attenuated behavioral and cognitive abnormalities, although translational relevance is constrained by limited central nervous system penetration following systemic administration. Clinical evidence mainly comes from autism spectrum disorder, where some studies have reported modest improvements in behavioral outcomes and measurable neurophysiological changes, although findings remain inconsistent. Collectively, these findings suggest that NKCC1 inhibition represents a mechanistically relevant but clinically unproven therapeutic strategy. Further research is required to clarify the cellular mechanisms underlying bumetanide responsiveness, optimize delivery to the central nervous system, and identify biomarkers to stratify patients most likely to respond to treatment.},
}

@article {pmid42161327,
year = {2026},
author = {Vallikivi, JK and Kooyman, M and , and Kirby, J and Nigel Leigh, P and Iacoangeli, A and Al-Chalabi, A and Al Khleifat, A},
title = {CYP2D6 variants in amyotrophic lateral sclerosis: an association study of risk and survival.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag178},
pmid = {42161327},
issn = {1460-2156},
abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with limited therapeutic options. Riluzole remains the only widely available disease-modifying treatment for ALS, yet its survival benefit is modest and likely to vary substantially between patients. Cytochrome P450 2D6 (CYP2D6), is a highly polymorphic enzyme that contributes to interindividual variability in the metabolism of many drugs. CYP2D6 is also expressed in the brain, and experimental and translational studies indicate that brain CYP2D activity can influence local metabolism of neuroactive compounds. Accordingly, CYP2D6 poor function variants have been examined as susceptibility modifiers in the development of other neurodegenerative diseases, including Parkinson's disease and Alzheimer's disease, with heterogenous evidence; however, the role of CYP2D6 in ALS has not been established.},
}

@article {pmid42161537,
year = {2026},
author = {Fernández-Romero, L and Díez-Cirarda, M and Delgado-Alonso, C and Cabrera-Martin, MN and González-Rosa, JJ and Sanz-Nieto, C and Pérez-Macías, N and Balugo, P and Gómez-Ruiz, N and Matias-Guiu, J and Portolés-Pérez, A and Matias-Guiu, JA},
title = {Long-term effect of transcranial magnetic stimulation and transcranial electrical stimulation in primary progressive aphasia: study protocol for a randomised, double-blind clinical trial (RECONNECT-PLUS).},
journal = {BMJ open},
volume = {16},
number = {5},
pages = {e112999},
doi = {10.1136/bmjopen-2025-112999},
pmid = {42161537},
issn = {2044-6055},
mesh = {Humans ; Double-Blind Method ; *Transcranial Direct Current Stimulation/methods ; *Transcranial Magnetic Stimulation/methods ; *Aphasia, Primary Progressive/therapy ; Female ; Aged ; *Language Therapy/methods ; Male ; Randomized Controlled Trials as Topic ; Treatment Outcome ; Middle Aged ; },
abstract = {INTRODUCTION: Primary progressive aphasia (PPA) is a neurodegenerative syndrome associated with Alzheimer's disease and frontotemporal degeneration. Non-invasive brain stimulation (NIBS) is a promising treatment, especially associated with language therapy, but comparative efficacy and long-term effects between the different techniques (transcranial direct current stimulation (tDCS) and transcranial magnetic stimulation (TMS)) remain unknown. The present study aims to investigate the effects of non-invasive brain stimulation, alone or associated (tDCS/TMS/tDCS plus TMS) combined with language therapy delivered during a period of 6 months, in the progression of language impairment in PPA, compared with sham stimulation combined with language therapy.

METHODS AND ANALYSIS: The study is a randomised, double-blinded, parallel, sham-controlled clinical trial. Patients with PPA in early stages (global Clinical Dementia Rating equal to or less than 1) are eligible. They are to be randomised to one of the four treatment arms of the study (active tDCS-active TMS, active tDCS-sham TMS, sham tDCS-active TMS, sham tDCS-sham TMS). All patients will receive language therapy immediately after each session of NIBS, for 6 months. The primary outcome is the Mini-Linguistic State Examination. The secondary outcomes are naming of trained items, Addenbrooke's Cognitive Examination, Interview for Deterioration in Daily Living Activities, Clinical Dementia Rating including behaviour and language domains, Neuropsychiatric Inventory and regional brain metabolism. Exploratory substudies will be conducted including blood biomarkers, quantitative electroencephalography and spontaneous speech assessment.

ETHICS AND DISSEMINATION: The study is registered (ClinicalTrials.gov: NCT07158216) and approved by the Ethics Committee of the Hospital Clinico San Carlos (code 25/309-IC_P_CE). Patients will be enrolled after signing an informed consent form. Study outcomes will be disseminated through presentations at scientific conferences, publications in peer-reviewed journals and other academic forums.

TRIAL REGISTRATION NUMBER: NCT07158216.},
}

Humans
Double-Blind Method
*Transcranial Direct Current Stimulation/methods
*Transcranial Magnetic Stimulation/methods
*Aphasia, Primary Progressive/therapy
Female
Aged
*Language Therapy/methods
Male
Randomized Controlled Trials as Topic
Treatment Outcome
Middle Aged

@article {pmid42161560,
year = {2026},
author = {Wang, Y and Shi, J and Zhao, L and Kan, B},
title = {LncRNA OIP5-AS1 Is Involved in Alzheimer's Disease by Targeting miR-7-5p to Regulate Microglial Inflammation, Polarization, and Oxidative Stress.},
journal = {The Tohoku journal of experimental medicine},
volume = {},
number = {},
pages = {},
doi = {10.1620/tjem.2025.J173},
pmid = {42161560},
issn = {1349-3329},
}

@article {pmid42161712,
year = {2026},
author = {Burke, E and Gunstad, J and Bond, D and Carroll, I and Crosby, R and Mitchell, JE and Heinberg, LJ and Steffen, K},
title = {Early changes in cognitive function following bariatric surgery: evidence for rapid improvement or practice effects?.},
journal = {Surgery for obesity and related diseases : official journal of the American Society for Bariatric Surgery},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.soard.2026.04.013},
pmid = {42161712},
issn = {1878-7533},
abstract = {BACKGROUND: Metabolic bariatric surgery (MBS) is associated with postoperative improvement in neuropsychological test performance and recent work raises the possibility that these gains may emerge within weeks of surgery. However, repeat testing across brief postoperative intervals introduces the possibility of measurement error that artificially increases test scores and distorts understanding of postoperative changes.

OBJECTIVE: Examine cognitive function prior to and 1-month following bariatric surgery.

SETTING: University Hospital.

METHODS: A total of 111 MBS participants completed the NIH Toolbox for the Assessment of Neurological and Behavioral Function test battery before and 1-month after MBS as part of a larger project.

RESULTS: Repeated measures analysis of covariance revealed improved cognitive test scores following both Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG), though reliability change metrics could not rule out contribution from practice effects. Receiver operating characteristic analyses revealed that lower preoperative body mass index (BMI) was associated with greater likelihood of true cognitive improvement post-MBS on the Pattern Comparison subtest of the NIH Toolbox (area under the curve = .65, 95% confidence interval .53-.76).

CONCLUSIONS: Though both RYGB and SG patients exhibited improved cognitive function 1-month postoperatively, the current results suggest these early gains should be interpreted cautiously as they may reflect more than just neurobiological factors. Preoperative BMI may predict cognitive trajectory post-MBS, though future research is needed to refine cognitive testing procedures with the goals of clarifying the timeline of neurological changes postoperatively and whether MBS may reduce risk of Alzheimer disease and other risk factors for cognitive decline.},
}

@article {pmid42161904,
year = {2026},
author = {Yang, Y and Jia, L and Xu, J and Wu, J and Huang, H and Yang, H and Qi, Z and Wang, Y and Yu, H and Wang, S},
title = {FBXW7α regulates amyloid pathology by mediating ubiquitination and degradation of BACE1 in Alzheimer's disease.},
journal = {Cell death discovery},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41420-026-03159-y},
pmid = {42161904},
issn = {2058-7716},
support = {82201347//National Natural Science Foundation of China (National Science Foundation of China)/ ; },
abstract = {The dysregulation of proteostasis is a hallmark of Alzheimer's disease (AD), characterized by the accumulation of misfolded and aggregated proteins. Dysfunction of the ubiquitin-proteasome pathway is a major contributing factor to proteostasis imbalance. The E3 ubiquitin ligase, F-box and WD repeat domain-containing 7 (FBXW7), a key hub factor in AD, is significantly downregulated in AD patients. FBXW7 mediates the proteasomal degradation of tau and regulates the development of tau pathology. However, the effect of FBXW7 on β-amyloid pathology and the underlying mechanisms remain unclear. This study demonstrated that FBXW7α, the dominant FBXW7 isoform, was localized in both the cytoplasm and nucleus of neurons. Aging led to a decline in FBXW7α protein levels in the brain tissues of both wild-type and 5×FAD mice. Notably, the level of FBXW7 in the brain tissue of 5×FAD mice is significantly lower than that in wild-type mice after 6 months of age. FBXW7α interacted with BACE1 via the conserved phosphodegron motif and targeted BACE1 for degradation. FBXW7 knockdown diminished the ubiquitination of BACE1, impaired its proteasome-mediated degradation, and increased the accumulation of BACE1 in Golgi fractions. Additionally, restoration of FBXW7α in the hippocampus improved cognitive function and ameliorated amyloid pathology in 5×FAD mice. Our findings suggest that FBXW7α acts as a key regulator of amyloid pathology, and highlight FBXW7α as a promising potential therapeutic target for AD intervention.},
}

@article {pmid42161924,
year = {2026},
author = {Yang, Y and Kwak, YT},
title = {Stage-dependent reorganization of amyloid PET region-symptom bipartite networks in drug-naïve, amyloid-positive Alzheimer's disease.},
journal = {Translational psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41398-026-04064-9},
pmid = {42161924},
issn = {2158-3188},
abstract = {Management of neuropsychiatric symptoms (NPS) is pivotal to care in Alzheimer's disease (AD), yet their alignment with amyloid topology may vary by stage. We examined whether the community (modular) structure of a brain-region-symptom co-occurrence network differs by clinical stage, testing the hypothesis that modular organization is more pronounced in earlier AD and becomes less segregated with increasing severity. In a cross-sectional retrospective cohort from a tertiary dementia clinic, we included 301 consecutive, drug-naïve patients with probable AD and amyloid-positive PET ([18]F-FC119S). Patients were stratified by Clinical Dementia Rating (CDR 0.5, n = 38; CDR 1.0, n = 107; CDR 2.0, n = 156). We built bipartite networks linking six cortical regions (bilateral frontal, temporal, parietal; PET positivity from automated SUVRs) to 12 Korean Neuropsychiatric Inventory (K-NPI) domains (presence = frequency × severity ≥ 1). Network density, community structure (Louvain modularity with 2000 within-symptom permutations), node strength/centralities, and stage-matched backbones were assessed. The pooled network was dense and non-modular. Stage-stratified analyses revealed significant modularity at CDR 0.5 only, with increasing density from CDR 0.5 to 2.0 and loss of community structure thereafter. Left temporal and left frontal cortices emerged as consistent regional hubs, while parietal contributions were minimal. On the symptom side, aggression and delusion carried the largest co-occurrence burdens, followed by disinhibition and anxiety; findings were robust across backbone and sensitivity analyses. These results support a stage-dependent reorganization from modest, symptom-specific modularity in early stage AD to diffuse, hub-centric coupling in later stages. Recognizing this transition may reconcile prior inconsistencies and inform clinical strategy: targeted, domain-focused interventions when modularity persists versus global stabilization as networks densify, with implications for enrichment and endpoint selection in NPS-focused trials.},
}

@article {pmid42161925,
year = {2026},
author = {Kim, DY and Kim, SM and Lee, C and Han, IO},
title = {O-GlcNAcylation reprograms microglial inflammatory states and attenuates Alzheimer's disease pathology.},
journal = {Cell death & disease},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41419-026-08862-3},
pmid = {42161925},
issn = {2041-4889},
support = {RS-2024-00346770//National Research Foundation of Korea (NRF)/ ; },
abstract = {Chronic neuroinflammation, primarily driven by microglia, is a hallmark and key contributor to Alzheimer's disease (AD) progression. O-GlcNAcylation, a nutrient-sensitive post-translational modification, has emerged as a key regulator of cellular stress and inflammation, yet its role in microglial activation in AD remains unclear. We observed that hippocampal tissue from AD patients exhibits a marked reduction in O-GlcNAcylation, accompanied by enhanced pro-inflammatory M1 microglial polarization, elevated NF-κB signaling, and NLRP3 inflammasome activation. In an LPS-induced neuroinflammation model exhibiting AD-relevant inflammatory and cognitive features, as well as in in vitro microglial cultures, LPS exposure led to a pronounced decrease in O-GlcNAcylation, particularly within Iba1-positive microglia. Systemic or in vitro treatment with glucosamine (GlcN) effectively restored O-GlcNAc levels, suppressed M1-associated inflammatory pathways, and promoted an anti-inflammatory M2 phenotype. Mechanistically, GlcN enhanced O-GlcNAcylation of NF-κB subunits p65 and c-Rel, limiting their nuclear translocation and downstream pro-inflammatory gene expression. Notably, GlcN treatment ameliorated LPS-induced memory deficits and neuronal loss in mice. Collectively, these findings suggest that O-GlcNAcylation acts as a modulatory regulator of microglial activation and neuroinflammation in AD, and that enhancing O-GlcNAcylation may represent a potential therapeutic strategy to preserve immune homeostasis and neuronal integrity.},
}

@article {pmid42161970,
year = {2026},
author = {Seo, H and Terstege, DJ and Ren, Y and Liu, S and Goring, KR and Ahn, BY and Epp, JR},
title = {Dual platform spatial transcriptomics reveals parvalbumin interneuron subtype vulnerability in mouse models of Alzheimer's disease.},
journal = {Nature communications},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41467-026-73474-6},
pmid = {42161970},
issn = {2041-1723},
support = {190215//Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada)/ ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and synaptic dysfunction. Among the earliest regions affected is the retrosplenial cortex (RSC), where parvalbumin-expressing (PV +) interneurons are particularly susceptible to AD-related pathology. To understand the molecular alterations within these vulnerable neurons we employed a dual-platform spatial transcriptomics approach, integrating GeoMx Digital Spatial Profiler (DSP) and Xenium In Situ. We analyzed the transcriptomic profiles of PV+ and NeuN+ neurons in the RSC of female 5xFAD mice. We leveraged the individual strengths of each platform to generate a robust and comprehensive dataset. Using non-negative matrix factorization and k-means clustering, we identified disease-associated metagenes and examined their spatial distribution. Our analysis revealed distinct transcriptional subpopulations within PV+ interneurons, with specific metagenes differentially expressed in RSC. Dner, Gad1, and Pvalb exhibited significant down-regulation in TG mice, suggesting impairments in PV+ interneuron function and GABAergic signalling. Cross-validation between GeoMx DSP and Xenium In Situ as well as RNAscope and immunohistochemistry confirmed the reproducibility and robustness of these findings. This study provides insights into the heterogeneity and molecular vulnerabilities of PV+ interneurons in AD and demonstrates the power of integrating spatial transcriptomic platforms to uncover disease-associated neuronal subtypes and molecular markers.},
}