@article {pmid42261768,
year = {2026},
author = {Deng, R and Shargorodsky, A and Teopiz, K and Dri, CE and Wong, S and Le, GH and Zheng, YJ and McIntyre, RS},
title = {Lithium and long-term cognitive outcomes in bipolar disorder and early dementia: a systematic review.},
journal = {CNS spectrums},
volume = {31},
number = {1},
pages = {e18},
doi = {10.1017/S1092852926100996},
pmid = {42261768},
issn = {2165-6509},
mesh = {Humans ; *Bipolar Disorder/drug therapy/psychology ; *Lithium Compounds/therapeutic use ; *Cognitive Dysfunction/drug therapy ; *Antimanic Agents/therapeutic use ; *Dementia/drug therapy/psychology ; Randomized Controlled Trials as Topic ; *Alzheimer Disease/drug therapy/psychology ; Cognitive Enhancement ; },
abstract = {Cognitive impairment is a major determinant of disability in bipolar disorder (BD) and a defining feature of both mild cognitive impairment (MCI) and Alzheimer's disease (AD). Lithium, a first-line maintenance treatment for BD, is implicated in neuroprotective mechanisms including glycogen synthase kinase-3β inhibition, amyloid and tau modulation, and neurogenesis promotion. The overarching aim of this systematic review is to evaluate the long-term effects of lithium on cognition across BD, MCI, and early-to-moderate AD using randomized controlled trial (RCT) evidence. Online databases were searched from inception through May 2025 for RCTs reporting lithium's effect on cognitive outcomes in BD, MCI, or early-to-moderate AD with ≥8 weeks of follow-up. Risk of bias was assessed using the Cochrane RoB 2 tool. Eight RCTs met the inclusion criteria, ranging from 10 weeks to 3 years in duration. Across four BD trials, lithium did not exhibit consistent improvement or worsening on composite cognitive scores. Three of four MCI/AD trials reported attenuated global cognitive deterioration with low-dose lithium, especially when exposure was ≥12 months. Methodological limitations included small sample sizes, exploratory endpoints, and variable measures for cognitive function as well as lithium strategies. Lithium demonstrates preliminary signals of slower cognitive decline in MCI/AD. Available evidence suggests lithium has neutral effects on cognitive impairment in BD. Future adequately powered RCTs with cognition as a primary endpoint, functional measures, and biomarker outcomes are warranted to clarify lithium's role as a maintenance treatment in psychiatric disorders and its potential neuroprotective effects in neurodegenerative diseases.},
}

Humans
*Bipolar Disorder/drug therapy/psychology
*Lithium Compounds/therapeutic use
*Cognitive Dysfunction/drug therapy
*Antimanic Agents/therapeutic use
*Dementia/drug therapy/psychology
Randomized Controlled Trials as Topic
*Alzheimer Disease/drug therapy/psychology
Cognitive Enhancement

@article {pmid42364284,
year = {2026},
author = {Ramabharathi, TG and Subramaniam, K},
title = {Ternary pattern-driven feature extraction and self-attending GRU for clinical score prediction in Alzheimer's disease.},
journal = {Psychiatry research. Neuroimaging},
volume = {362},
number = {},
pages = {112269},
doi = {10.1016/j.pscychresns.2026.112269},
pmid = {42364284},
issn = {1872-7506},
abstract = {This article presents a unique deep learning technique to identify AD using data from magnetic resonance imaging (MRI). However, deep learning models' lack of interpretability prevents them from being used in clinical settings, where explainability is crucial for winning over medical personnel. In order to diagnose AD, this work proposes a self-attending bidirectional gated recurrent unit (SA-Bi-GRU) method based on explainable AI (XAI) that makes use of a deep learning model. Before the diagnosis process, an integrated Ternary pattern and Fourier-Bessel series expansion based empirical wavelet transform (TP-FBSE-EWT) method is used to extract features. Then, a hybrid binary teaching learning and Horse herd optimization (H-BTL-HHO) algorithm is presented to minimize the dimensions and screen properties of brain regions associated with AD. Additionally, by using the Gradient-weighted Class Activation Mapping (Grad-CAM) technique, the proposed structure seeks to improve the interpretability of deep learning models, giving clinicians important insights into disease diagnosis and an understanding of the decision-making process. The process is implemented using the MATLAB tool. The simulation findings reveal that the proposed CAD system for clinical score prediction outperforms prevailing systems by boosting accuracy, sensitivity, and specificity to 99.97%, 99.34%, and 98.89% for multi-class problems, respectively.},
}

@article {pmid42364425,
year = {2026},
author = {Rodrigues, EA and Dionizio, A and Rosa, CM and Campos, DHS and Damatto, FC and Reyes, DRA and Souza, LM and Santos, PP and Gatto, M and Borim, PA and Pagan, LU and Araújo, TT and Buzalaf, MAR and Cunha, TM and Okoshi, K and Okoshi, MP},
title = {Effects of SGLT2 inhibitor dapagliflozin on the heart of rats with long-standing Type 1 diabetes mellitus: Protein profile.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {201},
number = {},
pages = {119719},
doi = {10.1016/j.biopha.2026.119719},
pmid = {42364425},
issn = {1950-6007},
abstract = {UNLABELLED: Sodium-glucose cotransporter 2 (SGLT2) inhibitors have beneficial outcomes on the renal and cardiovascular system in diabetes mellitus (DM) patients. As most clinical trials were performed in Type 2 DM, the effects of SGLT2 inhibition in Type 1 DM are not completely clarified.

OBJECTIVE: To evaluate the effects of long-standing SGLT2 inhibitor dapagliflozin on the protein profile in rats with a Type 1 DM model.

METHODS: Male Wistar rats were divided into Control (C), DM, and DM treated with dapagliflozin (DM+DAPA) for 30 weeks. DM was induced by a single injection of streptozotocin (40 mg/kg); dapagliflozin was added to chow (5 mg/kg/day). Label-free mass spectrometry was used to assess left ventricular proteome. The bioinformatic tools used were STRING, Cytoscape, Cluster Marker, and ClueGO.

STATISTICAL ANALYSIS: ANOVA and Tukey or Kruskal-Wallis and Dunn.

RESULTS: Dapagliflozin attenuated body weight loss (C 574 ± 43; DM 339 ± 31*; DM+DAPA 413 ± 30*# g; p < 0.05 * vs C; # vs DM) and reduced glycemia [C 108 (101-111); DM 554 (529-562)*; DM + DAPA 343 (237-416)*# mg/dL; p < 0.05 * vs C; # vs DM]. Most proteins identified in the networks downregulated in DM vs C were upregulated in DM + DAPA vs DM. Proteins related to energy metabolism (CKm, Ak1, Atp5pf, Mdh1, Idh2), excitation-contraction coupling (Actc1, Casq2, Serca1, Serca2a), and oxidative stress (Sod1, Sod2) were upregulated in DM + DAPA. KEGG pathways enriched in DM vs Control included gap junction, necroptosis, and fatty acid degradation (upregulated), and Alzheimer's disease, cardiac contraction, and glycolysis/gluconeogenesis (downregulated). In DM + DAPA vs DM, upregulated pathways included Parkinson's disease, cardiac contraction, citrate cycle, necroptosis, and cyclic guanosine monophosphate-dependent protein kinase (PKG) signaling pathway; downregulated proteins were linked to ketone body metabolism.

CONCLUSION: Dapagliflozin modulates cardiac protein abundance by attenuating DM-induced changes in Type 1 DM rats.},
}

@article {pmid42364498,
year = {2026},
author = {Hu, H and Zhao, S and Xu, L and Ma, Z and Ma, R and Huang, F and Shi, L},
title = {Sequential targeting nanochaperone disrupts positive feedback loop of mitochondrial dysfunction for Alzheimer's disease therapy.},
journal = {Biomaterials},
volume = {335},
number = {},
pages = {124408},
doi = {10.1016/j.biomaterials.2026.124408},
pmid = {42364498},
issn = {1878-5905},
abstract = {Mitochondrial dysfunction is recognized as a key pathogenic mechanism of Alzheimer's disease (AD), involving a self-perpetuating feedback loop with three aspects: upstream β-amyloid protein (Aβ), downstream calcium ion (Ca[2+]) and reactive oxygen species (ROS). However, current therapeutic strategies only focus on one aspect and fail to address multiple factors within this cycle. Moreover, the lack of targeted approaches to the mitochondria within damaged neurons further limits their application. Herein, we developed a sequential targeting nanochaperone to selectively target damaged neuronal mitochondria and disrupt this vicious cycle for AD treatment. In this strategy, with the sequence mediation of damaged neuron-targeting and mitochondria-targeting peptides decorated on surface, the nanochaperone can first localize to the damaged neurons in AD brain and then translocate to mitochondria within them. Subsequently, this nanochaperone can effectively bind upstream Aβ proteins and inhibit their aggregation toxicity to mitochondria through the synergic effect of chaperone-mimicking microdomains and Aβ-targeting peptide on surface, thereby halting downstream mitochondrial Ca[2+] dyshomeostasis and ROS overload in the damaged neuron. Furthermore, the modified mitochondria-targeting peptide with antioxidant property can further scavenge overproduced ROS and regulate Ca[2+] homeostasis, which in turn contributes to reducing the Aβ-induced mitochondrial damage. Consequently, the nanochaperone efficiently restores the mitochondrial dysfunction by disrupting the self-amplifying feedback loop of "Aβ-Ca[2+]-ROS" in the AD mitochondrial microenvironment, resulting in the significant alleviation of neuronal damage and cognitive deficits in 5xFAD transgenic mice. Taken together, our work presents a novel therapeutic strategy against mitochondrial dysfunction for AD treatment.},
}

@article {pmid42364649,
year = {2026},
author = {Lamichhane, B and Niraula, A and Merindol, N and Gélinas, SE and Lagüe, P and Ricard, S and Germain, H and Desgagné-Penix, I},
title = {A Golgi-localized N-methyltransferase and reversible aldo-keto reductases coordinate dual terminal routes in galanthamine biosynthesis.},
journal = {The Plant journal : for cell and molecular biology},
volume = {126},
number = {6},
pages = {e70910},
pmid = {42364649},
issn = {1365-313X},
support = {CRC-2023-00353//Canada Research Chairs/ ; },
mesh = {*Galantamine/biosynthesis/metabolism ; *Methyltransferases/metabolism/genetics ; *Golgi Apparatus/metabolism/enzymology ; *Plant Proteins/metabolism/genetics ; *Alcohol Oxidoreductases/metabolism/genetics ; *Liliaceae/enzymology/metabolism/genetics ; *Amaryllidaceae/enzymology/metabolism/genetics ; },
abstract = {Galanthamine, a therapeutic Amaryllidaceae alkaloid produced exclusively by species within the Amaryllidoideae subfamily, is a key treatment for early-stage symptoms of Alzheimer's disease. Elucidating its biosynthetic pathway is essential for strategies aimed at enhancing production through metabolic engineering. Galanthamine derives from the metabolic precursor 4'-O-methylnorbelladine, which undergoes cytochrome P450-mediated para-ortho' C-C phenol coupling to yield nornarwedine. Two competing terminal routes have been proposed: (i) reduction of nornarwedine to norgalanthamine, followed by N-methylation, or (ii) N-methylation of nornarwedine to narwedine prior to reduction. Here, we identify three aldo-keto reductase (AKR) candidates (LaAKR1, LaAKR2, and LaAKR3) and three N-methyltransferase (NMT) candidates from Leucojum aestivum: LaNMT, homologous to coclaurine N-methyltransferase-like (NMT-like), and two γ-tocopherol methyltransferases (TMT) homologs, LaTMT1 and LaTMT2. Subcellular localization studies revealed distinct compartmentalization, with LaNMT targeted to the ER-cytosol, LaTMT1 to plastids, and LaTMT2 to the Golgi apparatus. In vitro, LaTMT2 methylated both nornarwedine and norgalanthamine, with a kinetic preference for nornarwedine. LaTMT1 methylated γ-tocopherol to α-tocopherol (vitamin E). All three AKRs catalyzed reversible interconversions between nornarwedine and norgalanthamine, and between narwedine and galanthamine, with LaAKR3 favoring the reduction reaction whereas LaAKR1 the oxidation reaction. These findings identify LaTMT2 and LaAKRs as key branch-enabling enzymes, reconcile long-standing models of galanthamine biosynthesis, and provide a strategic target for metabolic engineering strategies to enhance galanthamine production.},
}

*Galantamine/biosynthesis/metabolism
*Methyltransferases/metabolism/genetics
*Golgi Apparatus/metabolism/enzymology
*Plant Proteins/metabolism/genetics
*Alcohol Oxidoreductases/metabolism/genetics
*Liliaceae/enzymology/metabolism/genetics
*Amaryllidaceae/enzymology/metabolism/genetics

@article {pmid42364669,
year = {2026},
author = {Qiu, X and Liu, Z and Wang, L and Yuan, Y and Tan, J and Han, Y and Li, Z and Meng, Y and Wang, W and Tan, Y},
title = {Time-dependent circulating metabolic changes and key regulatory pathways in Alzheimer's disease: A combined animal model and public database study.},
journal = {Experimental gerontology},
volume = {222},
number = {},
pages = {113216},
doi = {10.1016/j.exger.2026.113216},
pmid = {42364669},
issn = {1873-6815},
abstract = {Early diagnosis remains a major challenge in Alzheimer's disease (AD), as clinical symptoms often appear after irreversible pathological progression. This study aimed to identify early diagnostic biomarkers and clarify metabolic regulatory mechanisms in AD by integrating metabolomic profiling from a mouse model with validation using public human datasets. AD models were established in 42 C57BL/6J mice by intraperitoneal injection of D-galactose (120 mg/kg) combined with intragastric administration of aluminum chloride (20 mg/kg) for 8 weeks. Plasma samples were collected at weeks 0, 3, 6, and 8 for untargeted metabolomic profiling. Public plasma/cerebrospinal fluid metabolomic datasets and brain transcriptomic datasets from AD patients were further analyzed for validation. Time-dependent metabolic alterations were observed in AD mice, characterized by predominant metabolite depletion at weeks 3-6 and compensatory accumulation at week 8. The metabolic profile of AD mice was clearly separated from that of controls at week 8. Nicotinamide metabolism and sphingosine-related pathways showed dynamic dysregulation during AD progression. Notably, nicotinamide and sphingosine were persistently increased in AD mice and were also elevated in plasma samples from AD patients, whereas metabolites such as N,N-diethyl-m-toluamide were decreased. Transcriptomic analysis revealed abnormal expression of key genes involved in nicotinamide metabolism (NMNAT1 and SIRT1) and sphingosine metabolism (SPTSSA and SPHK1) in brain tissues from AD patients. In conclusion, AD is characterized by stage-dependent metabolic dysregulation, featuring early depletion followed by late compensation. Dysregulated nicotinamide and sphingosine metabolism may contribute to AD pathogenesis, and related metabolites and regulatory genes may serve as potential diagnostic biomarkers and therapeutic targets.},
}

@article {pmid42365084,
year = {2026},
author = {Kumar, D and Martin, AJ},
title = {Integrated machine learning, molecular docking, and molecular dynamics simulations for in silico identification of GSK3β inhibitors for Alzheimer's disease.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-59744-9},
pmid = {42365084},
issn = {2045-2322},
abstract = {Glycogen Synthase Kinase-3 Beta is a multifunctional serine/threonine kinase, involved in regulating multiple cellular processes. Its dysregulation plays a key role in progression of Alzheimer's disease and no FDA-approved GSK3β inhibitors for AD therapy are available, due to challenges in isoform selectivity, safety and pharmacokinetic limitations. Here, an OECD guideline-compliant, two-stage machine learning-based virtual screening framework is developed for GSK3β inhibitors. A chemically diverse dataset from different databases were pre-processed and used for model development and validation. A comparative study confirmed the superiority of this two-stage approach over standard multiclass models, by yielding significantly higher balanced accuracy on the internal test set (0.86 against 0.74) and specificity. The best predictive models were deployed as an open-access web tool and were used for screening ASINEX Synergy Library. In the structure-based approach, molecular docking with a validated docking protocol was performed and the best molecules were subjected to molecular dynamics simulation, binding free energy and per-residue decomposition analysis. Principal component analysis of trajectories confirmed global stability and consistent binding modes. Cross-screening against the homologous GSK3α isoform and the structurally distinct Cyclin-dependent kinase 2 (CDK2) by molecular docking revealed distinct mechanistic interaction profiles. Rather than exhibiting strict single-target exclusivity, the top hits showed binding affinity profiles consistent with potential CMGC family Multi-Target Directed Ligands (MTDLs), warranting experimental kinome validation. This presumed polypharmacological profile is advantageous for Alzheimer's therapeutics, positioning these compounds as robust candidates for simultaneously mitigating multiple kinase pathways that drive Tau hyperphosphorylation. Overall, this integrated ML model development, validation, screening, protein selection, molecular docking and molecular dynamics workflow provides a reproducible, interpretable, and high-confidence method for identification of GSK3β inhibitors for Alzheimer's disease.},
}

@article {pmid42365183,
year = {2026},
author = {Park, DK and Constant, AB and Honig, LS and Marder, KS and Provenzano, FA and , },
title = {Machine learning classification and regional differentiation of neuropathologically-confirmed Alzheimer's disease and comorbid Lewy body disease.},
journal = {Communications medicine},
volume = {},
number = {},
pages = {},
doi = {10.1038/s43856-026-01652-0},
pmid = {42365183},
issn = {2730-664X},
abstract = {BACKGROUND: Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) co-occur frequently, and growing evidence, including neuropathology, supports synergistic interplay between the diseases. We tested whether a single T1-weighted MRI scan may differentiate neuropathologically confirmed comorbid AD/DLB and AD controls using heterogeneously acquired neuroimaging.

METHODS: We obtained structural neuroimaging, on two groups, AD with and without DLB pathology. Convolutional neural networks are trained across dimensions. We introduce a triple-ensemble strategy consisting of majority voting schemes within a variety of plane permutations. In addition, we conduct voxel-wise statistical analyses.

RESULTS: Here we show convolutional neural networks record a classification accuracy of 0.820 and an f1 score of 0.79 in identifying comorbid DLB/AD from AD patients. Prediction accuracy is higher proximal to date of death, while the trained model largely outperforms clinical baseline diagnosis. The slice-level performance varies depending on the sampled brain location, with sensitivity highest in the temporal lobe and specificity highest in the occipital lobe. In DLB/AD, gray matter is relatively preserved though atrophy is observed in the occipital lobe, suggesting that the comorbidity differentially affects brain loss and may accelerate it in the occipital lobe.

CONCLUSIONS: This study demonstrates how machine learning approaches can address diverse neuroimaging data from clinical sources to differentiate neurodegenerative diseases using a true gold standard of neuropathological confirmation. The frameworks utilized here can be extended to other diseases that are frequently co-occurring and feasibly extend to single scan diagnostic clinical utility of scans already being acquired.},
}

@article {pmid42365239,
year = {2026},
author = {Novak, P and Katina, S and Brandoburova, P and Jezberova, M and Reznakova, V and Hanes, J and Jurcaga, F and Koson, P and Novak, M and Jönsson, L and Zilka, N},
title = {Which assessment tools best distinguish between mild cognitive impairment and dementia? Lessons from a Slovak memory clinic cohort.},
journal = {BMC geriatrics},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12877-026-07801-3},
pmid = {42365239},
issn = {1471-2318},
support = {20-0447//Agentúra na Podporu Výskumu a Vývoja/ ; 20-0447//Agentúra na Podporu Výskumu a Vývoja/ ; 20-0447//Agentúra na Podporu Výskumu a Vývoja/ ; 20-0447//Agentúra na Podporu Výskumu a Vývoja/ ; 20-0447//Agentúra na Podporu Výskumu a Vývoja/ ; ADDITION: Alzheimer's disease data-driven insights on individual outcomes of importance//EU Joint Programme - Neurodegenerative Disease Research/ ; ADDITION: Alzheimer's disease data-driven insights on individual outcomes of importance//EU Joint Programme - Neurodegenerative Disease Research/ ; ADDITION: Alzheimer's disease data-driven insights on individual outcomes of importance//EU Joint Programme - Neurodegenerative Disease Research/ ; ADDITION: Alzheimer's disease data-driven insights on individual outcomes of importance//EU Joint Programme - Neurodegenerative Disease Research/ ; },
abstract = {BACKGROUND: The utility of various cognitive assessment tools for distinguishing between mild impairment and dementia, as well as for determining cutoff values for specific populations, continues to be the subject of extensive research. Here, we assessed the utility and feasibility of these tools in the first Slovak memory clinic cohort.

METHODS: We enrolled a Slovak memory clinic cohort of patients with MCI and dementia (MCI, n = 84; dementia, n = 55). The participants were characterized using a range of cognitive assessment tools-Auditory Verbal Learning (AVLT), Category and Letter Fluency (CFT, LFT), Digit Span (DSF, DSB), Digit-Symbol Coding (DS-C), Frontal Assessment Battery (FAB), MMSE, MoCA, Rey Osterrieth Complex Figure (ROCF), and Trail Making Test (TMTA, TMTB); clinical assessments-Amsterdam Instrumental Activities of Daily Living (A-IADL) and 5-level EuroQol questionnaire with 5 dimensions (EQ-5D-5 L); and scales for anxiety, dependency, depression, dignity, and MRI volumetry. The ability of the various assessments to distinguish between MCI and dementia was evaluated.

RESULTS: Over the course of three years, at a single memory clinic, it was feasible to enrol and evaluate a total of 150 participants, 139 of whom fulfilled the definition of either MCI or nonvascular dementia. Of the employed cognitive and clinical assessment tools, the best differentiation between MCI and dementia was observed for the AVLT and A-IADL. The DSF and DSB tests did not reveal differences between the populations. No differences were observed in education, vital signs, or anthropometric measurements. Participants with dementia had greater degrees of brain atrophy in the hippocampi and frontal, parietal, and temporal cortex; lower total brain volumes; and greater ventricular dilation.

CONCLUSIONS: This study confirms the utility of a range of cognitive assessment tools and scales for differentiating between MCI and dementia but reveals that some commonly employed tools, such as the DSF and DSB, may not be sensitive to these differences. This study highlights the importance of accurate assessment of the ability to perform activities of daily living and supports the development of objective, ecologically valid assessments of IADL.},
}

@article {pmid42365511,
year = {2026},
author = {Song, A and Zhao, Y and Wu, S and Xu, X},
title = {Frequency-specific effects of pulsed magnetic field on BV2 microglial cell function.},
journal = {Electromagnetic biology and medicine},
volume = {},
number = {},
pages = {1-9},
doi = {10.1080/15368378.2026.2694326},
pmid = {42365511},
issn = {1536-8386},
abstract = {The objective of this study was to investigate the effects of pulsed magnetic field (PMF) at different frequencies on phagocytosis, migration, and the expression of inflammatory factors in microglia. BV2 microglia were subjected to PMF at different frequencies for 3 d, twice daily. The changes of cell viability, phagocytosis and migration after magnetic stimulation were detected. The mRNA and protein levels of TNF-α and IL-1β were determined using RT-PCR and ELISA. The nuclear translocation of NF-κB P65 and intracellular Ca2+ level was detected through immunofluorescence. PMF at different frequencies did not affect microglial viability. Stimulation at all frequencies enhanced the ability of microglia to phagocytosis and migration. The mRNA expression level of IL-1β and TNF-α was significantly decreased by magnetic stimulation at 20 Hz and 40 Hz. However, only the protein level of IL-1β was significantly reduced by magnetic stimulation at 20 Hz, while TNF-α remained unaffected. Magnetic stimulation at 20 Hz and 40 Hz inhibited the nuclear translocation of NF-κB P65 and increased the intracellular Ca2+ level. Repetitive magnetic stimulation can modulate the secretion of inflammatory cytokines and enhance the phagocytosis and migration capacity of microglia in a frequency-dependent manner. This variation may be linked to differences in the activation of NF-κB and calcium in microglia.},
}

@article {pmid42366122,
year = {2026},
author = {Amado-Riveros, P and Riveros-Perez, E},
title = {Hormone Therapy is Associated with Better Cognitive Performance in Postmenopausal Women: Insights from the National Health and Nutrition Examination Survey (NHANES).},
journal = {Annals of geriatric medicine and research},
volume = {30},
number = {2},
pages = {236-245},
doi = {10.4235/agmr.25.0180},
pmid = {42366122},
issn = {2508-4909},
mesh = {Humans ; Female ; *Postmenopause/psychology/drug effects ; Cross-Sectional Studies ; *Cognition/drug effects ; Nutrition Surveys ; Aged ; Middle Aged ; *Estrogen Replacement Therapy ; United States/epidemiology ; Neuropsychological Tests ; },
abstract = {BACKGROUND: Alzheimer's disease is more prevalent among females. Estrogens influence brain metabolism and function, and low blood levels before, during, and after menopause may be associated with cognitive decline in later years. Here, we investigate the association between hormone therapy and reproductive lifespan with cognitive performance using a nationally representative sample from the National Health and Nutrition Examination Survey (NHANES) database.

METHODS: This cross-sectional study included 1,374 eligible women aged 60 years or older from the NHANES database. Cognitive performance was assessed using the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) word learning subtest, the Animal Fluency Test (AFT), and the Digit Symbol Substitution Test (DSST). Univariate analysis and multivariate logistic regression were employed to evaluate the association between hormone therapy, reproductive span, and cognitive performance. Restricted cubic spline curves were used to assess the relationship between age as a continuous variable and cognitive performance.

RESULTS: After adjusting for age, race, and educational level, hormone therapy was significantly associated with word recall, digit symbol, and animal fluency cognitive performance (p < 0.05). The reproductive span was associated with word recall performance (p = 0.027) but not with digit symbol or animal fluency. The age-related cognitive decline is attenuated by hormone therapy with maximum effect between 65 and 70 years for all dimensions.

CONCLUSION: There is a positive association between hormone therapy and cognitive performance in postmenopausal women, particularly in age groups with the steeper decline. In addition, there is no significant association between reproductive span and cognitive function.},
}

Humans
Female
*Postmenopause/psychology/drug effects
Cross-Sectional Studies
*Cognition/drug effects
Nutrition Surveys
Aged
Middle Aged
*Estrogen Replacement Therapy
United States/epidemiology
Neuropsychological Tests

@article {pmid42366179,
year = {2026},
author = {Sim, SY and Kim, S and Kim, YS and Han, JS},
title = {Age-dependent Upregulation of Selenbp1 in 5XFAD Mice.},
journal = {Experimental neurobiology},
volume = {},
number = {},
pages = {},
doi = {10.5607/en26013},
pmid = {42366179},
issn = {1226-2560},
abstract = {Selenium-binding protein 1 (SELENBP1), previously implicated in several neurological and psychiatric disorders, was recently reported to be altered in the brains of individuals with Alzheimer's disease (AD). However, the cellular specificity of SELENBP1 in AD pathogenesis, including its role in amyloid-beta, remains unclear. Given the prominent role of microglia in amyloid-driven neuroinflammation and the hippocampal regional vulnerability in early AD, clarifying how SELENBP1 is regulated at both regional and cell-type-specific levels is essential. In this study, we examined age- and genotype-dependent changes in Selenbp1 expression in the hippocampus and prefrontal cortex of non-transgenic and 5XFAD mice at 1.5, 3, and 6 months of age by using western blot and immunofluorescence analyses. Western blot analyses revealed robust age-dependent increases in Selenbp1 expression in both regions, with no statistically significant genotype-dependent differences. However, immunofluorescence analyses showed that Selenbp1 levels were selectively increased in amyloid-vulnerable hippocampal subregions, including the dentate gyrus, dorsal subiculum, and retrosplenial cortex. Selenbp1 expression was expressed in microglia and was largely absent from neurons or astrocytes. These findings indicate that Selenbp1 elevation under AD-like conditions is region- and cell-type-specific, reflecting microglial responses detectable only through spatially resolved analysis. Therefore, Selenbp1 may represent a microglial molecular signature associated with early amyloid pathology.},
}

@article {pmid42366201,
year = {2026},
author = {Chen, Y and Gui, H and Ma, K and Zhang, Z and Zhao, T and Wang, M},
title = {Lifestyle-associated blood metabolic pathways and functional performance in cognitive aging.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-58782-7},
pmid = {42366201},
issn = {2045-2322},
abstract = {Functional decline is a major clinical feature of Alzheimer's disease (AD), yet the blood metabolic pathways associated with lifestyle factors and multidimensional functional performance across cognitive stages remain incompletely characterized. We applied a pathway-level blood metabolomics framework to harmonized, de-identified data from aging and dementia-related cohort resources spanning cognitively normal aging (CN), mild cognitive impairment (MCI), and AD. Metabolites were mapped to curated pathways and summarized into pathway activity scores across five domains: energy metabolism, amino acid metabolism, lipid metabolism, inflammation/oxidative stress, and microbiome-linked metabolism. We evaluated associations among physical activity, diet quality, pathway activity scores, and functional outcomes, including activities of daily living, gait speed, grip strength, global cognition, composite function, and frailty. To summarize pathway patterns jointly associated with physical activity and diet quality, we derived a lifestyle-modulated metabolic pathway score (LMPS) using elastic net regression with cross-validation, out-of-fold score estimation, and bootstrap stability assessment. Lifestyle-associated pathway activity showed coordinated patterns across metabolic domains and was associated with functional performance across cognitive groups. Higher LMPS values were associated with better physical and cognitive function and lower frailty, with graded differences observed across CN, MCI, and AD. Internal robustness analyses indicated greater stability at the pathway-domain level than at the individual-pathway coefficient level. Sensitivity analyses adjusting for cognitive group attenuated but did not eliminate the directionally consistent associations between LMPS and major functional outcomes. Convergent pathway patterns involved mitochondrial energy metabolism, lipid remodeling, inflammatory regulation, and microbiome-related metabolism. Pathway-level blood metabolomics identified lifestyle-associated metabolic patterns related to multidimensional functional outcomes across the cognitive aging spectrum. LMPS provides a data-driven summary of lifestyle-associated pathway variation in this cohort and may help generate hypotheses about metabolic correlates of functional performance. Independent and longitudinal validation will be required to determine its reproducibility, temporal relevance, and translational utility.},
}

@article {pmid42366234,
year = {2026},
author = {Rong, W and Xu, J and Li, B and Li, Y and Xu, Y},
title = {Correction: 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 = {26},
number = {1},
pages = {},
doi = {10.1007/s10238-026-02238-9},
pmid = {42366234},
issn = {1591-9528},
}

@article {pmid42366246,
year = {2026},
author = {Liao, K and Li, J and Jiao, F and Zhang, Z and Xu, L and Wang, Z and Li, W and Pang, H},
title = {Impact of reduced [18]F-MK6240 PET/MR acquisition duration on image quality and tau pathology assessment in patients with cognitive impairment.},
journal = {EJNMMI physics},
volume = {},
number = {},
pages = {},
doi = {10.1186/s40658-026-00914-z},
pmid = {42366246},
issn = {2197-7364},
support = {82472019//National Natural Science Foundation of China/ ; 82502406//National Natural Science Foundation of China/ ; },
abstract = {BACKGROUND: [18]F-MK6240 tau positron emission tomography (PET) is critical in Alzheimer's disease diagnosis and therapeutic monitoring. However, the standard 20-minute static acquisition poses challenges for cognitively impaired patients with limited tolerance for prolonged scans. This study evaluates the feasibility of reducing scan time while maintaining diagnostic accuracy through image quality and quantitative comparisons.

METHODS: 69 memory clinic patients (27 males and 42 females) who underwent [18]F-MK6240 PET examinations were retrospectively analyzed. All 20-minutes scans were acquired 90 min post-injection of ~ 3.7 MBq/kg ¹⁸F-MK6240 and reconstructed mainly into 5-, 10-, 15-, and 20-minute datasets. Images were rated on a 5-point scale for overall quality, noise, and diagnostic confidence. Tau status (positive/negative) was the visually defined, and standardized uptake value ratios (SUVr) of Braak regions were calculated using cerebellar gray matter as reference. Agreement across durations was assessed via Bland-Altman analysis.

RESULTS: Among the 69 patients, 50 were classified as tau-positive and 19 as tau-negative. Diagnostic efficacy remained consistent across acquisition times compared to the 20-minute reference. The slight reduction in image quality for the 5-minute images relative to the other groups, but none of the images across any of the four durations were rated as poor (score < 3). For 16 predefined regions used for visual assessment of regional tau involvement, both readers showed near-perfect agreement in scoring the extent of involvement (0%, 1-25%, 26-75%, or > 75%) across the four scan durations, as evidenced by Kendall's W coefficients ranging from 0.984 to 1.000 (all p < 0.001). Negative scans showed lower SUVr spread over Braak stages of four different time duration. Bland-Altman analysis demonstrated high agreement in Braak-stage SUVr values between the 20-minute images and the shortened acquisitions with mean differences close to zero across all comparisons.

CONCLUSION: Shortening ¹⁸F-MK6240 PET acquisition to 5 min on a modern high-sensitivity PET/MR system results in a small, clinically acceptable decline in image quality. It does not compromise the reliability of visual reads or the stability of semi-quantitative measures compared to the standard 20-minute scan. These findings support the feasibility of 5-minute protocols, which offer practical benefits like reduced motion artifacts and improved patient throughput, as an operationally efficient alternative in clinical tau imaging.},
}

@article {pmid42366338,
year = {2026},
author = {Dey, AK and Al-Amin, MY and Ferdous, R and Alam, AHMK and Rahman, AA and Hossen, MB and Mollah, MNH and Sadik, MG},
title = {Isolation and identification of hasubanan alkaloids having anti-cholinesterase and antioxidant activity from the stem Stephania japonica.},
journal = {BMC complementary medicine and therapies},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12906-026-05447-7},
pmid = {42366338},
issn = {2662-7671},
support = {37-01-0000-073-04-012/2019//University Grants Commission of Bangladesh/ ; },
abstract = {BACKGROUND: A recent report showed that Stephania japonica chloroform fraction has potential anticholinesterase and antioxidant activities and is able to improve learning and memory in mice. Therefore, the aim of the present study was to isolate and identify compounds from the chloroform fraction with cholinesterase inhibitory and antioxidant activity that may be useful as new candidates for the treatment of AD.

METHODS: Chromatographic methods were used for isolation of compounds and the isolated compounds were analyzed by spectroscopic methods for structure elucidation. Acetyl- and butyryl-cholinesterase inhibitory activity were evaluated for by Ellman's method and the antioxidant activity by several in vitro models such as DPPH and hydroxyl radicals scavenging, reducing power, total antioxidant activity, and inhibition of brain lipid peroxidation. The interaction of cholinesterase enzymes and isolated compounds were examined by molecular docking studies.

RESULTS: Bioactivity guided approach led to the isolation of four compounds from the chloroform fraction and identified as aknadinine, aknadilactam, aknadicine and stephisoferuline on the basis of their [1]H-NMR and [13]C-NMR spectral data. All the compounds were of hasubanan type. They showed significant inhibition against acetylcholinesterase and butyrylcholinesterase, with at least two fold increased affinity for butyrylcholinesterase than acetylcholinesterase. The IC50 values of the alkaloids were in the range of 9.36-14.89 µg/mL against acetylcholinesterase and 3.97-6.66 µg/mL against butyrylcholinesterase. Kinetic analysis revealed that all the four compounds exhibited mixed type of inhibition against both acetylcholinesterase and butyrylcholinesterase. The interaction of compounds with several amino acids of enzymes was supported by molecular docking studies. All the hasubanan alkaloids showed antioxidant activity in all in vitro assays and inhibited peroxidation of brain lipid. The IC50 values of the compounds for scavenging of DPPH and hydroxyl radicals, and lipid peroxidation inhibition were found to be in the range of 5.1-40.91, 10.44-19.41, and 20.60-31.72 µg/mL, respectively.

CONCLUSION: The hasubabanan alkaloids isolated from S. japonica may represent a new class of anti-cholinesterase compounds. The multitargeted activity of hasubanan alkaloids may lead to new candidates for the treatment of AD.},
}

@article {pmid42366401,
year = {2026},
author = {Sun, W and Xing, R and Zhou, J and Li, Y and Xu, G},
title = {Facial phenotypes in Alzheimer's disease: from neurobiology to artificial intelligence.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02129-x},
pmid = {42366401},
issn = {1758-9193},
support = {KYCX25_0823 to RX//Major Project of Philosophy and Social Science Research for Universities of Jiangsu Province/ ; 82171330//National Natural Science Foundation of China/ ; 4004013//Shenzhen Talent Introduction Fund/ ; 2023ZD0504800, 2023ZD0504801, 2023ZD0504802, 2023ZD0504803, 2023ZD0504804//Noncommunicable Chronic Diseases-National Science and Technology Major Project/ ; },
abstract = {Facial analysis is increasingly being explored as a source of scalable behavioral signals relevant to Alzheimer's disease (AD) and AD-related cognitive impairment. In this narrative review, informed by a structured literature search, we summarize current evidence on the biological and behavioral basis of facial alterations in AD, with particular emphasis on affective expressivity, neuropsychiatric manifestations, and dynamic facial behavior. We also review representative artificial intelligence-based facial analysis methods, including commonly used datasets, feature representations, and modeling strategies, ranging from facial landmarks and texture descriptors to spatiotemporal video models, multimodal fusion, and language-enhanced frameworks. Current evidence remains limited by small and largely single-center cohorts, heterogeneity in acquisition settings and outcome definitions, inadequate control of confounding factors, limited external validation, poor calibration reporting, and persistent concerns regarding interpretability and clinical specificity. Within the evolving biomarker-based diagnostic framework of AD, facial analysis is better viewed as a candidate, non-specific, and context-dependent tool for auxiliary risk stratification, triage support, and longitudinal monitoring rather than as stand-alone diagnostic tests. Future progress will depend on standardized data acquisition, integration with clinical and biomarker data, improved explainability, and prospective real-world validation.},
}

@article {pmid42366433,
year = {2026},
author = {Chen, Y and Yao, C and Yan, F and Xiao, P and Lu, X},
title = {[Finite-element simulation and experimental investigation of nanosecond transcranial pulsed electric field propagation and distribution in a three-dimensional brain model].},
journal = {Sheng wu yi xue gong cheng xue za zhi = Journal of biomedical engineering = Shengwu yixue gongchengxue zazhi},
volume = {43},
number = {3},
pages = {504-512},
pmid = {42366433},
issn = {1001-5515},
mesh = {Humans ; *Finite Element Analysis ; *Brain/physiology ; Computer Simulation ; Alzheimer Disease/therapy ; *Transcranial Direct Current Stimulation/methods ; Electromagnetic Fields ; Amyloid beta-Peptides/metabolism ; },
abstract = {Nanosecond pulsed electric field (nsPEF) exposure can disrupt and disaggregate amyloid-β, indicating its potential to improve symptoms of Alzheimer's disease. However, the propagation and distribution patterns of nsPEF within brain tissue remain insufficiently understood, making related simulation analysis necessary. In this study, a high-resolution three-dimensional human head model incorporating the scalp, skull, cerebrospinal fluid, gray matter, white matter, and hippocampus was constructed. Based on the spectral characteristics of nsPEF, the dielectric properties of human tissues at different frequency ranges were assigned, and a transient finite-element model of nsPEF exposure in the human brain was established. The simulation analysis identified two optimal electrode-pair positions and characterized the spatial distributions of intracranial electric field strength as well as current density. It further elucidated the dependence of the hippocampal electric field response and current density on pulse parameters. In addition, a physical human brain model was constructed to experimentally validate the finite-element simulation results. The results showed that transcranial nsPEF can reach deep brain regions with extremely narrow pulse widths, and pulsed electric fields with kilovolt-level amplitudes and nanosecond-scale pulse widths can generate electric field strengths of approximately 10 [3] V/m in the hippocampus. In summary, this work provides a theoretical basis and experimental support for optimizing the electrode configuration and stimulation parameters of transcranial nsPEF, thereby laying a foundation for future research on its application in non-invasive physical interventions for Alzheimer's disease.},
}

Humans
*Finite Element Analysis
*Brain/physiology
Computer Simulation
Alzheimer Disease/therapy
*Transcranial Direct Current Stimulation/methods
Electromagnetic Fields
Amyloid beta-Peptides/metabolism

@article {pmid42366543,
year = {2026},
author = {Sui, Z and Feng, A and Gong, Y and Zha, S and Lv, Y and Zheng, Q and Li, L and Wang, Y},
title = {Predicting cognitive function in Alzheimer's clinical trials via amyloid β-protein biomarkers.},
journal = {British journal of clinical pharmacology},
volume = {},
number = {},
pages = {},
doi = {10.1002/bcp.70665},
pmid = {42366543},
issn = {1365-2125},
support = {2025ZHYL037//Shanghai Municipal Health Commission Smart Healthcare Special Project/ ; 2024YFC3506600//National Key R&D Program of China/ ; LSLSKL20240203//Open Research Program of the State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine/ ; },
abstract = {OBJECTIVES: This study investigates the association between amyloid-β (Aβ) biomarkers and clinical cognitive outcomes and quantitatively elucidates their relationship, providing robust evidence supporting the amyloid hypothesis and advancing the development of novel anti-amyloid therapeutics, such as aducanumab, lecanemab and donanemab.

METHODS: Placebo-controlled randomized clinical trials reporting Aβ-related biomarkers and cognitive function clinical outcomes were retrieved from PubMed, EMBASE and Cochrane Library. Pearson correlation analysis was first used to screen indices, and then a model-based meta-analysis (MBMA) using non-linear mixed-effect modelling was established to predict cognitive function based on biomarkers while examining relevant factors affecting the relationship.

RESULTS: Primary outcomes included changes in the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) and the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-COG-11). The analysis included 57 articles representing 93 417 subjects, with a modelling subset of 18 246 patients providing paired biomarker-endpoint data for Alzheimer's disease or mild cognitive impairment. Results showed significant correlations between the standard uptake value ratio (SUVR) of β-amyloid plaques and CDR-SB, centiloid and CDR-SB, and SUVR and ADAS-COG-11. Three prediction models of cognitive function scales based on imaging index of β-amyloid plaques were established and found to be significantly impacted by factors such as baseline CDR-SB, treatment duration and the proportion of patients receiving basic treatment.

CONCLUSIONS: This study clarified the correlation and established predictive models for CDR-SB and ADAS-COG-11 based on amyloid imaging. This research identifies potential biomarkers and model-derived benchmarks for future dose selection and decision-making in Alzheimer's drug development, potentially accelerating the development of new treatments.},
}

@article {pmid42366747,
year = {2026},
author = {Abed, H},
title = {Postoperative Experiences After Dental Treatment Under General Anesthesia in People Living With Alzheimer's Disease: A Descriptive Study With Caregiver and Staff Reports.},
journal = {Special care in dentistry : official publication of the American Association of Hospital Dentists, the Academy of Dentistry for the Handicapped, and the American Society for Geriatric Dentistry},
volume = {46},
number = {4},
pages = {e70201},
doi = {10.1111/scd.70201},
pmid = {42366747},
issn = {1754-4505},
mesh = {Humans ; *Anesthesia, General ; *Alzheimer Disease/complications ; Female ; Aged ; *Caregivers/psychology ; Male ; Aged, 80 and over ; *Anesthesia, Dental ; Postoperative Complications/epidemiology ; Middle Aged ; *Dental Care for Chronically Ill ; Anesthesia Recovery Period ; },
abstract = {AIMS: To describe the demographic and clinical characteristics of people living with Alzheimer's disease (AD) undergoing dental treatment under general anesthesia, to summarize peri-recovery challenges reported by healthcare staff, and to describe caregiver-reported postoperative experiences at three time points. The occurrence of postoperative delirium or hallucinations was also descriptively examined.

METHODS: In this single-center descriptive study, postoperative information was obtained through structured telephone contacts with caregivers and relevant clinical staff at three time points (immediate recovery, 2 days, and 2 weeks). Responses were analyzed using inductive content analysis and summarized descriptively.

RESULTS: Participants (n = 14) were elderly and predominantly in the moderate to late stages of AD, with substantial dependence on caregivers. Staff-reported observations indicated that agitation and behavioral disturbance during emergence and early recovery were the most prominent challenges. Resistance to care with monitoring devices was also noted. Caregivers reported increased pain, agitation, and care demands within the first 48 h following general anesthesia. By one week, most caregivers reported physical recovery and behavioral improvement. No documented cases of postoperative delirium or hallucinations were identified.

CONCLUSIONS: In this exploratory descriptive study, dental treatment under general anesthesia in people living with AD was followed by short-term postoperative behavioral and physical challenges that generally improved within one week. Given the small sample size and descriptive design, findings should be interpreted cautiously.},
}

Humans
*Anesthesia, General
*Alzheimer Disease/complications
Female
Aged
*Caregivers/psychology
Male
Aged, 80 and over
*Anesthesia, Dental
Postoperative Complications/epidemiology
Middle Aged
*Dental Care for Chronically Ill
Anesthesia Recovery Period

@article {pmid42366768,
year = {2026},
author = {},
title = {Corrigendum to "Electromagnetic field induced activation of amyloid-β degrading enzyme, neprilysin, for accelerated Alzheimer's disease therapy".},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261463830},
doi = {10.1177/13872877261463830},
pmid = {42366768},
issn = {1875-8908},
}

@article {pmid42366949,
year = {2026},
author = {González, EG and Dicu, M and Villar, JR and Chira, C},
title = {Transformer-Based Anomaly Detection for Neurodegenerative Screening in MRI Images.},
journal = {International journal of neural systems},
volume = {},
number = {},
pages = {2650052},
doi = {10.1142/S0129065726500528},
pmid = {42366949},
issn = {1793-6462},
abstract = {The automatic detection of anomalies in medical images is a significant challenge in the assisted diagnosis of neurodegenerative diseases such as Alzheimer's. This paper presents an anomaly detection model based on Transformers for the analysis of brain magnetic resonance images. The proposed architecture combines a Vision Transformer as an encoder with a memory bank module that allows modeling the distribution of healthy brains and detecting deviations through reconstruction error. The model is trained using a one-class learning approach, using only images considered normal, with the aim of learning the representation of normality and automatically flagging atypical structural patterns. To adapt volumetric studies to the architecture, a preprocessing procedure is designed that transforms three-dimensional information into a two-dimensional representation compatible with the model. The results obtained demonstrate a solid ability to characterize normality and generate reliable predictions, confirming the viability of Transformer-based architectures for unsupervised anomaly detection in neuroimaging. This approach lays the foundation for future extensions in clinical settings and other medical imaging applications.},
}

@article {pmid42367034,
year = {2026},
author = {West, NR and Lindberg, MF and Dairou, J and MacGregor, S and Puthireddy, S and Meijer, L and Bhattacharyya, A},
title = {Leucettinib-21 decreases dosage effects of DYRK1A in human trisomy 21 induced pluripotent stem cell-derived neural cells.},
journal = {Disease models & mechanisms},
volume = {19},
number = {6},
pages = {},
doi = {10.1242/dmm.052740},
pmid = {42367034},
issn = {1754-8411},
support = {//School of Medicine and Public Health, University of Wisconsin-Madison/ ; //Wisconsin Alumni Research Foundation/ ; P50HD105353//National Institute of Child Health and Human Development/ ; //Fondation Jérôme Lejeune/ ; //Agence Nationale de la Recherche/ ; //France 2030/ ; //Bpifrance/ ; 848077//HORIZON EUROPE Innovative Europe/ ; 190138295//HORIZON EUROPE European Innovation Council/ ; //University of Wisconsin-Madison/ ; },
mesh = {Humans ; Dyrk Kinases ; *Protein Serine-Threonine Kinases/metabolism/genetics/antagonists & inhibitors ; *Protein-Tyrosine Kinases/metabolism/genetics ; *Down Syndrome/pathology/enzymology/genetics ; *Induced Pluripotent Stem Cells/drug effects/pathology/metabolism/enzymology ; *Neural Stem Cells/drug effects/pathology/metabolism/enzymology ; *Neurons/drug effects/pathology/metabolism/enzymology ; *Gene Dosage/drug effects ; Protein Kinase Inhibitors/pharmacology ; Cell Differentiation/drug effects ; Dioxoles ; Imidazoles ; },
abstract = {Dosage imbalance of dual specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A) is a feature of several neurodevelopmental and neurodegenerative diseases, including Down syndrome, DYRK1A syndrome, autism spectrum disorders, Alzheimer's disease and Parkinson's disease. Thus, manipulating DYRK1A activity in the brain has emerged as a potential therapeutic target for neurological disorders. Several DYRK1A inhibitors have shown promise for improving cognition in rodent models of Down syndrome and Alzheimer's disease, for example, but the ability of these inhibitors to affect DYRK1A levels or activity in relevant human cells has not been established. We filled this gap by testing the effects of a new DYRK1A inhibitor on trisomy 21 induced pluripotent stem cell (iPSC)-derived neural progenitor cells and neurons, in which DYRK1A expression and activity are increased. Our results demonstrated that Leucettinib-21, a potent and selective low-molecular-mass pharmacological inhibitor of DYRK1A, decreases DYRK1A activity in human trisomy 21 iPSC-derived neural progenitor cells and cortical neurons. Leucettinib-21 reduces DYRK1A activity in a relevant human disease model, supporting future human trials.},
}

Humans
Dyrk Kinases
*Protein Serine-Threonine Kinases/metabolism/genetics/antagonists & inhibitors
*Protein-Tyrosine Kinases/metabolism/genetics
*Down Syndrome/pathology/enzymology/genetics
*Induced Pluripotent Stem Cells/drug effects/pathology/metabolism/enzymology
*Neural Stem Cells/drug effects/pathology/metabolism/enzymology
*Neurons/drug effects/pathology/metabolism/enzymology
*Gene Dosage/drug effects
Protein Kinase Inhibitors/pharmacology
Cell Differentiation/drug effects
Dioxoles
Imidazoles

@article {pmid42367320,
year = {2026},
author = {Csikos, V and Thyfault, JP and Wilkins, HM},
title = {The impact of exercise on brain mitochondrial health and its relevance to Alzheimer's disease.},
journal = {Brain and environment},
volume = {5},
number = {},
pages = {},
pmid = {42367320},
issn = {3050-5917},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by memory loss, cognitive decline, and accumulation of amyloid-β (Aβ) plaques and tau neurofibrillary tangles in the brain. Mounting evidence implicates mitochondrial dysfunction as an upstream driver of AD pathogenesis, contributing to bioenergetic deficits, oxidative stress, impaired calcium homeostasis, and chronic neuroinflammation. Given the high energy demand of the brain, the preservation of mitochondrial function is critical for neuronal health. Physical exercise is recognized for its neuroprotective effects, with growing support that it may attenuate AD progression through enhancing mitochondrial quality control. This review explores how exercise influences key mitochondrial quality control processes in the brain-including mitochondrial-biogenesis, -dynamics, and mitophagy-and how these adaptations counteract AD-related pathologies. We further examine the dual role of reactive oxygen species, the impact of exercise-induced signaling molecules such as brain-derived neurotropic factor, irisin, and insulin-like growth factor 1, and the importance of cardiorespiratory fitness in fostering mitochondrial resilience. Finally, we highlight critical gaps in our understanding of how different exercise modalities uniquely affect brain mitochondria and AD pathology. Collectively, this underscores the potential of exercise as a non-pharmacological strategy to enhance brain mitochondrial health and promote cognitive resilience in aging and AD.},
}

@article {pmid42367372,
year = {2026},
author = {Cabán, M and Brown-Bradley, C and Wetmore, JB and Ottman, R and Siegel, K},
title = {Latinos' beliefs regarding the role played by nonmedical factors in the quality of Alzheimer's disease care: Findings from a NYC community-based sample.},
journal = {SSM. Qualitative research in health},
volume = {9},
number = {},
pages = {},
pmid = {42367372},
issn = {2667-3215},
abstract = {Latinos represent the fastest-growing subpopulation in the United States and are expected to experience the steepest increase in the coming decades in adults 65 and older living with Alzheimer's disease (AD). However, they also have a higher likelihood of delayed diagnosis, greater difficulty in accessing specialist referrals, treatments and support services and have fewer long-term and nursing care options than non-Latino Whites. A New York City community-based sample of Latinos completed qualitative interviews in English (63%) or Spanish (37%). We investigated participants' beliefs regarding Latinos' access to quality AD-related care. Data were coded by three team members using ATLAS.ti and thematic analysis was conducted by the senior qualitative team members. The results are organized along the care continuum from diagnosis through medical, supportive, and long-term care. The data revealed that participants (n = 155) believed a combination of nonmedical factors contributed to Latinos being diagnosed at a more advanced stage of AD and receiving poorer quality of care once diagnosed than non-Latino Whites. These included: limited financial assets, restricted health insurance coverage, cultural values and tendencies, limited availability of providers who understood their background and experiences or spoke Spanish, and to a lesser extent prejudice or discrimination. These findings are important because expectations of poor care may deter care seeking or once diagnosed may influence patients' level of engagement in care and treatment adherence. They have implications for enhancing patient-centered care for Latinos with AD as it emphasizes the incorporation of their perspectives when assessing the quality of care being delivered.},
}

@article {pmid42367689,
year = {2026},
author = {Liu, Y and Zhao, J and Shi, Z},
title = {Anti-Metabotropic Glutamate Receptor 5 Autoimmune Encephalitis with a Typical Alzheimer's Disease Biomarker Profile: A Case of Rapidly Progressive Dementia Unresponsive to Cholinesterase Inhibitors.},
journal = {Case reports in neurology},
volume = {18},
number = {1},
pages = {280-284},
pmid = {42367689},
issn = {1662-680X},
abstract = {INTRODUCTION: The distinction between neurodegenerative and autoimmune causes of rapidly progressive dementia can be challenging, particularly when atypical Alzheimer's disease (AD) biomarkers are present. We present a case of anti-metabotropic glutamate receptor 5 (mGluR5) autoimmune encephalitis (AE) initially misdiagnosed as AD due to concordant clinical, imaging, and biomarker findings.

CASE PRESENTATION: A 51-year-old woman developed progressive memory decline, apathy, and stereotyped paper-folding behavior over 2 years. She was diagnosed with rapidly progressive AD and treated with donepezil and memantine without improvement. Initial workup showed hippocampal neurodegeneration on magnetic resonance imaging/MRS and elevated plasma phosphorylated tau181, tau217, and GFAP - consistent with an AD biomarker profile. Neurological examination later revealed bilateral pyramidal signs. Re-evaluation identified serum anti-mGluR5 antibodies. Treatment with intravenous methylprednisolone and immunoglobulin led to marked improvement in cognition and behavior within 2 weeks.

CONCLUSION: This case demonstrates that anti-mGluR5 AE can manifest with a biomarker profile highly suggestive of AD, leading to prolonged misdiagnosis. It underscores the importance of considering AE in treatment-refractory or atypical dementia, even in the presence of supportive AD biomarkers, and highlights the potential for significant recovery with timely immunotherapy.},
}

@article {pmid42367849,
year = {2026},
author = {Gabal, E and Nguyen, TKO and Kovalenko, T and Gao, H and Rappaport, N and Funk, C and Baloni, P and Trushina, E},
title = {Mitochondrial Complex I Modulator Restores Network Resilience in Advanced Alzheimer's Disease Through Metabolic Reprogramming.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.14.732179},
pmid = {42367849},
issn = {2692-8205},
abstract = {Mitochondrial dysfunction and lipid dysregulation are among the earliest abnormalities in Alzheimer's disease (AD), yet their mechanistic interplay and therapeutic potential remain poorly understood. Here, we investigated whether restoration of mitochondrial function can reverse metabolic dysfunction and promote resilience in advanced-stage AD. Female APP/PS1 mice were treated with the brain-penetrant mitochondrial complex I (mtCI) modulator CP2 beginning at 19 months of age, when pathology and cognitive deficits were well established. To define the metabolic mechanisms underlying therapeutic response, we developed iMiceBrain , the first brain-specific genome-scale metabolic model of the mouse brain, and integrated transcriptomics, targeted metabolomics, lipidomics, and metabolic network analyses. CP2 treatment broadly reprogrammed AD-associated molecular signatures and restored pathways involved in mitochondrial function, glucose utilization, lipid metabolism, synaptic activity, and cellular stress responses. Metabolic modeling identified enhanced mitochondrial substrate flexibility, activation of fatty acid utilization, restoration of pyruvate dehydrogenase flux, and normalization of cholesterol metabolism as key features of the therapeutic response. Lipidomic analyses further demonstrated correction of disease-associated alterations in cholesteryl esters, phospholipids, and sphingolipids. Together, these findings demonstrate that mild mtCI modulation restores metabolic resilience by coordinating mitochondrial and lipid metabolism, establishing it as a disease-modifying therapeutic strategy for AD.},
}

@article {pmid42367894,
year = {2026},
author = {Morgan, GC and Gregory, A and Hanscom-Trofy, Y and Dong, R and Fan, F},
title = {Anatomical Identification and Pressure Myography of the Rat Middle Cerebral Artery: A Comprehensive Protocol for Diverse Genetic Models.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.12.718520},
pmid = {42367894},
issn = {2692-8205},
abstract = {The middle cerebral artery (MCA) is critical for cerebral blood flow autoregulation and a primary site of cerebrovascular pathology in stroke, Alzheimer's disease, and vascular dementia. Pressure myography enables precise ex vivo quantification of MCA structure and function, but requires accurate anatomical identification and careful vessel handling to ensure reproducibility across diverse rat genetic models. This chapter provides a comprehensive, step-by-step protocol for isolating and cannulating the rat MCA M2 segment for pressure myography. We detail precise anatomical landmarks to ensure consistent vessel selection across strains. The protocol includes optimized solutions, cannulation techniques, and pressure protocols validated across multiple rat models, including transgenic (TgF344-AD), diabetic (T2DN), consomic (SS.5 [BN] , FHH.1 [BN]), and genome-edited strains. Extensive troubleshooting notes address common technical challenges, including vessel viability assessment, pressure integrity, and strain-specific autoregulatory ranges. This methodology bridges molecular genetic findings with fundamental cerebrovascular physiology, enabling researchers to characterize myogenic reactivity, passive mechanical properties, and structural remodeling in rat models of cerebrovascular disease.},
}

@article {pmid42367902,
year = {2026},
author = {Huang, Y and Xie, X and Fernaine, M and Li, Z and Wang, X and Wang, J},
title = {Subregion-Specific Input Organization of Prefrontal-Projecting Basal Forebrain Cholinergic Neurons and Weakened Striatal-NBM Inhibitory Transmission in 5xFAD mice.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.11.731708},
pmid = {42367902},
issn = {2692-8205},
abstract = {UNLABELLED: Basal forebrain cholinergic neurons regulate cortical activity and cognition and are vulnerable in Alzheimer's disease (AD). However, the upstream circuits controlling projection-defined basal forebrain cholinergic populations remain incompletely understood. Here, we used projection-specific rabies-mediated monosynaptic tracing to map whole-brain inputs to medial prefrontal cortex (mPFC)-projecting cholinergic neurons in the nucleus basalis of Meynert (NBM) and horizontal limb of the diagonal band of Broca (HDB). mPFC-projecting NBM and HDB cholinergic neurons received broad but distinct input patterns. NBM cholinergic neurons received prominent striatal input, including input from D1-expressing medium spiny neurons, whereas HDB cholinergic neurons showed proportionally weaker striatal input and broader non-striatal contributions. Optogenetic electrophysiology confirmed that striatal inputs formed monosynaptic GABAergic inhibitory synapses onto NBM cholinergic neurons. This inhibitory transmission was weakened in 5xFAD mice, indicating impairment of a striatal-NBM inhibitory circuit in an AD mouse model. Together, these findings reveal subregion-specific input organization of mPFC-projecting basal forebrain cholinergic neurons and identify a vulnerable striatal-NBM circuit in AD.

HIGHLIGHTS: Whole-brain rabies tracing reveals input organization of mPFC-projecting BF cholinergic neurons.NBM and HDB cholinergic neurons projecting to mPFC show distinct monosynaptic input profiles.Striatal D1-MSNs are a major input source to mPFC-projecting NBM cholinergic neurons.Striatal-NBM inhibitory transmission is functionally impaired in 5xFAD mice.},
}

@article {pmid42367939,
year = {2026},
author = {Montenegro, P and Kim, R and Zedek, M and Chicas, M and Yeh, P and Yeh, H},
title = {Prenatal Alcohol Exposure Disrupts γ-Secretase Activity and Impairs Learning and Memory in Wild-Type and 3xTg-AD Mice.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.11.731622},
pmid = {42367939},
issn = {2692-8205},
abstract = {Although prenatal alcohol exposure (PAE) has been proposed as an early-life risk factor for Alzheimer's disease and related dementias (AD/ADRD), the mechanistic underpinnings are underexplored. Mutations in the Presenilin genes contribute to AD/ADRD, with Presenilin 1 acting as the catalytic subunit of the γ-secretase complex responsible for cleaving Notch and amyloid precursor protein (APP). We hypothesized that PAE disrupts γ-secretase activity during brain development, which persists and is associated with behavioral deficits later in life. Pregnant wild-type B6129 and 3xTg-AD mice were fed an ethanol-containing liquid diet during gestational days 13-15. From birth to adulthood, PAE increased APP C-terminal fragments and Notch intracellular domain (NICD) levels in cortical lysates. These changes were associated with impaired hippocampal-dependent learning and memory in wild-type mice at 3 and 6 months of age and exacerbated behavioral deficits in 4-month-old 3xTg-AD mice. Our findings provide the first mechanistic insight linking PAE to AD/ADRD vulnerability.},
}

@article {pmid42367943,
year = {2026},
author = {Ee, R and Amouzgar, M and Afaghani, J and Vijayaragavan, K and Cannon, BJ and Mrdjen, D and Tebaykin, D and Spence, A and Sant, C and Aley, D and Guo, Z and Sedov, K and Zafar, F and Montine, KS and Perna, A and Serrano, GE and Beach, TG and Angelo, M and Schüle, B and Corces, MR and Montine, TJ and Bendall, SC},
title = {APOE4 Drives Uniquely Dysfunctional Human Microglial States in Alzheimer's Disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.18.733295},
pmid = {42367943},
issn = {2692-8205},
abstract = {UNLABELLED: Variation in APOE, notably the ε4 allele, profoundly shapes risk and severity of late-onset Alzheimer's disease (AD), yet how it remodels human microglial states remains unresolved. We combine spatially resolved proteomic profiling with single-nuclear multiomic analyses to define microglial organization across APOE3/3 and APOE4/4 genotypes in AD. Quantifying condition-associated variation across the cellular manifold reveals a continuous landscape of microglial states. APOE4/4 shifts cells toward terminal states marked by loss of homeostatic identity, metabolic disruption, and incomplete acquisition of disease-associated programs. We identify an APOE4/4-enriched population in AD that exhibits inflammatory signaling without effective metabolic or phagocytic engagement, localizing to niches of gliosis and senescence, and coupled to chronic stress adaptation programs. Together with evidence that APOE4/4 potentiates the activation threshold of nascent microglia, these findings establish a unified framework for human microglial state change, linking genetic risk to spatial and molecular organization of immune responses in the AD brain.

GRAPHICAL ABSTRACT: APOE4/4 in Alzheimer's disease reshapes microglial fate along continuous trajectories characterized by proteomic, transcriptional, and epigenetic programs consistent with chronic stress adaptation, alongside distinct composite spatial niches comprised of astrocytic gliosis and cellular senescence.},
}

@article {pmid42367992,
year = {2026},
author = {Haynes, KA and Pandey, RS and Doud, EH and Cope, ZA and Little, GJ and Williams, SP and Nepali, U and Quinney, SK and Nagar, A and Charbe, NB and da Silva, L and Dage, JL and Duong, DM and Seyfried, NT and Sasner, M and Lamb, BT and Oblak, AL and Territo, PR and Carter, GW and Sukoff Rizzo, SJ},
title = {Molecular mechanisms underlying amyloid lowering by aducanumab: differential and comparative effects of sex and IgG reveal the post-treatment disease brain.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.16.731973},
pmid = {42367992},
issn = {2692-8205},
abstract = {INTRODUCTION: Improving the predictive validity of preclinical studies for Alzheimer's disease (AD) requires rigorous evaluation of therapeutic efficacy, safety, and sex-specific responses in translationally relevant models. As amyloid-targeting monoclonal antibodies continue to advance clinically, there is an urgent need to define the molecular milieu that persists after amyloid is reduced and disease progression continues. Leveraging the NIA-funded MODEL-AD Preclinical Testing Core, we investigated the biochemical, functional, and multi-omic signatures associated with chronic administration of murine chimeric aducanumab (chAdu) in 5XFAD mice, including the contribution of IgG-mediated effects.

METHODS: Male and female 5XFAD mice were treated weekly with chAdu beginning at 8 months of age and compared to age-and sex-matched murine IgG2aκ isotype (IgG) and saline controls. Plasma and brain pharmacokinetics, amyloid-beta (Aβ), behavioral assessments, and treatment-emergent anti-drug antibodies (ADAs) were quantified. Post-treatment transcriptomic and proteomic analyses were performed to assess molecular pathways associated with chAdu and IgG exposure following 17-week treatment.

RESULTS: chAdu produced sex-dependent changes in Aβ, including increased plasma Aβ42:40 and reductions in brain Aβ which were associated with mild behavioral impairments in the absence of improvements in cognitive function. IgG control treatment produced similar reductions, indicating biologically active IgG-mediated processes independent of Aβ-targeted specificity. Treatment-emergent ADAs occurred in 10% of chAdu-treated mice and were associated with reduced drug exposure and efficacy. Multi-omics analyses confirmed sex-dependent and IgG-mediated effects at both the transcriptomic and proteome level revealing disease-associated genes and proteins not altered despite reductions in amyloid with treatment.

DISCUSSION: These findings demonstrate sex-dependent PK and pharmacodynamic responses to chAdu, identify biologically meaningful IgG-driven effects, and reveal molecular signatures that persist after amyloid reduction. This work provides biological insights into pathways that may remain insufficiently addressed following amyloid lowering; revealing novel targets for future drug discovery to prevent and treat disease.},
}

@article {pmid42368021,
year = {2026},
author = {Wang, R and Maloney, B and Nho, K and Beck, JS and Counts, SE and Lahiri, DK},
title = {MicroRNA-181 influences Alzheimer's risk by regulating neprilysin and microtubule-associated tau pathways, offering a novel target.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.11.731747},
pmid = {42368021},
issn = {2692-8205},
abstract = {UNLABELLED: Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) peptide plaques and neurofibrillary tangles from hyperphosphorylated tau, though factors linking amyloid and tau pathology remain unclear. We investigated whether microRNA-181d-5p (miR-181d) associates with AD-related brain changes and regulates neprilysin and tau. Modeling miR-181d across individuals with no cognitive impairment, mild cognitive impairment, and AD revealed region- and sex-specific associations. Higher miR-181d levels associated with greater AD probability in the temporal lobe and cerebellum, and lower probability in the posterior cingulate cortex of males; miR-181c attenuated these probabilities. SNPs near MIR181 associated with altered entorhinal cortical thickness. In cellular models, miR-181 reduced neprilysin 3'-UTR activity, mRNA, protein, and enzymatic activity, while increasing tau mRNA and protein. Neprilysin diminution impairs Aβ clearance and elevates tau, contributing to AD. RNA sequencing identified miR-181d-responsive neurodegenerative pathways. These findings identify miR-181 as a regulator of AD-relevant amyloid and tau pathways, providing novel targets.

TEASER: MiRNA-181 is a key regulator of Alzheimer's risk through its effects on neprilysin and tau proteins, a novel potential target.},
}

@article {pmid42368109,
year = {2026},
author = {Dorogan, M and Namballa, HK and Patra, S and Harding, WW},
title = {Recent Advances in Dopamine Receptor Ligands as Chemical Biology Tools.},
journal = {ACS omega},
volume = {11},
number = {24},
pages = {34870-34884},
pmid = {42368109},
issn = {2470-1343},
abstract = {Dopamine receptors (DRs) have been implicated in numerous disorders and diseases (e.g., Alzheimer's disease, Parkinson's disease, schizophrenia, and substance use disorders) and have served as attractive drug targets for these ailments. Despite their potential clinical utility, the development of selective DR ligands has been challenging due to difficulties in selectivity among the DR subtypes as well as other biogenic amine receptors and poor pharmacokinetic properties. The realization of their full potential necessitates continued advancements in DR ligands as investigative tools. This review aims to highlight the recent developments made in the chemical biology of DR ligands (e.g., bivalent ligands, photoactivatable ligands, photoswitchable probes, and fluorescent probes).},
}

@article {pmid42368154,
year = {2026},
author = {Sha, J and Geng, Z and Qi, S and Du, L and Hu, Q and Cai, M and Chen, D and Chen, Y and Liu, S and Song, H and Ling, T and Chang, C and Bai, B},
title = {Characterization of the Anti-Alzheimer Drug Lecanemab by Mass Spectrometry.},
journal = {ACS omega},
volume = {11},
number = {24},
pages = {35903-35912},
pmid = {42368154},
issn = {2470-1343},
abstract = {Lecanemab is a humanized mouse monoclonal antibody that is clinically approved for treating Alzheimer's disease by binding to amyloid oligomers, protofibrils, and insoluble fibrils to clear Aβ aggregates in the brain. Although therapeutically effective, lecanemab is also associated with side effects, and its quality might vary among different batches due to impurities and modifications. Herein, we provide proteomics, intact protein, and N-glycoproteomics analyses of lecanemab by liquid chromatography coupled with mass spectrometry. We found that the lecanemab drug is highly pure but displays two major peaks in the chromatography and contains many species with close molecular weights around 150 kDa under mass spectrometric scanning. There were 40 N-glycans found at the N304 site of lecanemab of the heavy chain. Further analysis by MSFragger identified other modifications and additional glycosites. These results provide data as resource for the identification of critical quality attributes of lecanemab in studying its therapeutic effectiveness, side effects, and possible batch-to-batch qualities.},
}

@article {pmid42368190,
year = {2026},
author = {Meng, J and Deng, ZJ and Zhang, J and Yu, W and Wu, X and Lei, P},
title = {Atypical involvement of Alzheimer's tau proteins in diseases beyond tauopathies.},
journal = {Life medicine},
volume = {5},
number = {3},
pages = {lnag016},
pmid = {42368190},
issn = {2755-1733},
abstract = {Tau is a microtubule-associated protein traditionally involved in a collective group of disorders termed "tauopathy", including Alzheimer's disease. Tau protein self-aggregates and forms neurofibrillary tangles in neurons, which are considered a pathological hallmark of tauopathies. While the roles of neuronal tau in tauopathies have been extensively investigated, recent studies have shed light on its roles in other diseases without tau pathology and in other cells. In this review, we aim to discuss the "atypical" pathological involvement of tau in diseases other than tauopathies, including brain diseases (e.g., amyotrophic lateral sclerosis, multiple sclerosis, and spinal cord injury), vascular diseases (stroke and hypertension), diabetes, and cancers. We have discussed the expression and functions of tau in cell types other than neurons, and have summarized the evidence supporting a role of tau in these diseases. These cross-disease studies collectively suggest that tau protein is more broadly implicated in mechanisms such as axonal instability, dysregulated cell signaling, inflammatory activation, and cell death, independent of its aggregation, contributing to our knowledge of the functions of tau and the myriad ways in which it may be involved in pathological processes.},
}

@article {pmid42368192,
year = {2026},
author = {Lei, S and Huang, Z and Wang, W and Meng, Y},
title = {Depletion of microglial compensation in glial network: Disease-associated response dynamics in the revised amyloid hypothesis.},
journal = {Neuroprotection (Chichester, England)},
volume = {4},
number = {2},
pages = {131-142},
pmid = {42368192},
issn = {2770-730X},
abstract = {Microglia mount coordinated, stage-dependent compensatory programs in response to early amyloid β (Aβ) accumulation that preserve proteostasis and neuronal integrity during preclinical Alzheimer's disease. We propose the "microglial compensation-depletion" framework that describes a distributed compensatory network whose failure constitutes a mechanistic tipping point. Once compensatory capacity falls below a critical threshold, positive-feedback loops amplify irreversible pathology, eventually leading to cognitive decline. Integrating single-cell transcriptomics, chromatin accessibility, and genetic evidence from human cohorts and animal models, we synthesize evidence for stage-dependent microglial transitions and for glial interactions that shape resilience or vulnerability. The microglial compensation-depletion framework in the revised amyloid hypothesis is a multiscale, dynamical perspective and highlights potential strategies for modeling and clinical intervention. Intercellular ligand-receptor networks may provide quantitative substrates for defining glial-state patterns and even identifying key communication axes that delineate transitions. For example, microglial triggering receptor expressed on myeloid cells 2 (TREM2)-apolipoprotein E (APOE) signaling exemplifies an intercellular axis that modulates microglial phenotype and Aβ handling. Clinically, in vivo imaging and biofluid biomarkers may offer potential means to track glial functional reserve and to detect approaching tipping points.},
}

@article {pmid42368193,
year = {2026},
author = {Li, S and Ji, X and Walczak, P and Boltze, J},
title = {Novel approaches for neuroprotection: Focus on neurodegenerative and ischemic central nervous system diseases.},
journal = {Neuroprotection (Chichester, England)},
volume = {4},
number = {2},
pages = {95-98},
pmid = {42368193},
issn = {2770-730X},
}

@article {pmid42368196,
year = {2026},
author = {Liu, Y and Luo, S and Zhang, H and Lin, J and Xiao, H and Ma, Y and Ye, D and Cong, L and Li, Y},
title = {Research status and trends of Piezo1 and brain: A bibliometric analysis.},
journal = {Neuroprotection (Chichester, England)},
volume = {4},
number = {2},
pages = {178-187},
pmid = {42368196},
issn = {2770-730X},
abstract = {AIM: As a key mechanosensitive ion channel, Piezo1 plays a critical role in various brain functions, including the regulation of cerebral blood flow and neuronal excitability, by converting mechanical stimuli into biochemical signals. This study conducted a quantitative and visual analysis of the global research landscape, evolving trends, and knowledge structure of Piezo1 in brain research from 2014 to 2025.

METHODS: A comprehensive bibliometric analysis was conducted. We conducted a comprehensive literature search in the Web of Science and Scopus databases for publications focusing on Piezo1 in the brain from January 1, 2014, to October 1, 2025. After rigorous screening and deduplication, 173 studies were finally included in the analysis. Scientometric indicators and visualization tools were employed to examine publication trends, core journals, productive authors and countries, and keyword co-occurrence networks.

RESULTS: Annual publication output in this field increased rapidly, with an average growth rate of 34.48%. Research publications are concentrated in a limited number of high-impact journals, reflecting a strong academic focus. Keyword analysis identified core research hotspots, including "mechanotransduction," "ion channels," and "neuroinflammation," highlighting the pivotal role of Piezo1 in cerebral hemodynamics and neuropathology. Intellectual structure analysis revealed that foundational mechanistic studies dominate the current literature.

DISCUSSION: Although basic research on Piezo1 in the brain has advanced significantly, studies directly targeting its clinical translation are limited. These findings highlight a clear knowledge gap between mechanistic understanding and therapeutic applications. Future research should prioritize bridging this gap by fostering interdisciplinary collaborations that translate fundamental insights into clinical validation, thereby accelerating the development of Piezo1 as a novel therapeutic target for neurological disorders.},
}

@article {pmid42368200,
year = {2026},
author = {Chong, AEY and Sasmita, AO and Koh, RY and Ling, APK},
title = {Neuroprotective effects of ursodeoxycholic acid in Parkinson's disease and Alzheimer's disease.},
journal = {Neuroprotection (Chichester, England)},
volume = {4},
number = {2},
pages = {111-130},
pmid = {42368200},
issn = {2770-730X},
abstract = {Neurodegenerative diseases (NDDs) including Parkinson's disease (PD) and Alzheimer's disease (AD), are progressive disorders characterised by shared pathological features, including mitochondrial dysfunction, oxidative stress, apoptosis, neuroinflammation, neurotoxic protein buildup, and impaired protein clearance. Current treatments can only relieve disease symptoms but cannot delay the disease progression. Ursodeoxycholic acid (UDCA), a hydrophilic bile acid traditionally used in hepatology, has recently gained attention for its neuroprotective properties. This review critically evaluates UDCA's mechanisms of action, including the restoration of mitochondrial function, inhibition of apoptosis, reduction of oxidative stress and neuroinflammation, and enhancement of autophagy in both PD and AD models. In vitro and in vivo studies demonstrate UDCA's ability to preserve neuronal integrity, improve motor and cognitive outcomes, and reduce toxic protein aggregates. Although early-phase clinical trials, such as the UDCA for Parkinson's (UP) study in PD, show promising mitochondrial benefits and safety, clinical evidence in AD remains limited. Future directions emphasise the need for large-scale trials, personalised medicine, improved central nervous system (CNS) delivery strategies, or dietary interventions to modulate UDCA production from the gut microbiome. While not a first-line treatment, UDCA represents a compelling mitochondrial stabiliser with disease-modifying potential in NDDs.},
}

@article {pmid42368255,
year = {2026},
author = {Zhang, J and Nie, X and Yue, J and Shi, Y},
title = {Feynman Kac Reweighted Schrödinger Bridge Matching for Surface-Based Tau PET Harmonization.},
journal = {ArXiv},
volume = {},
number = {},
pages = {},
pmid = {42368255},
issn = {2331-8422},
abstract = {Tau PET imaging is central to tracking Alzheimer's disease progression, but systematic differences between scanners, protocols, and radiotracers across sites introduce nonbiological variability that inflates biomarker variance, reduces sensitivity to disease effects, and can bias downstream clinical assessments. Harmonization methods aim to remove these site-induced shifts while preserving biologically meaningful signal, yet existing approaches struggle when source and target cohorts differ in subgroup composition, risking conflation of site effects with biological variation such as tau-positivity status. We propose the Feynman Kac Reweighted Schröodinger Bridge Matching (FKRSBM) model to address this problem. Rather than routing data through a Gaussian noise prior as in diffusion-based methods, FKRSBM learns a direct stochastic transport process between source and target distributions via entropy-regularized optimal transport. To enforce biologically consistent transport, FKRSBM incorporates a subgroup-aware endpoint proposal derived from a Feynman Kac reweighting of the reference bridge measure, implemented entirely through stratified importance sampling at the data level and requiring no changes to the underlying bridge-matching solver or network architecture. For surface-based neuroimaging, FKRSBM employs a spherical convolutional backbone operating on cortical meshes to perform vertex-level harmonization. We evaluate the method on tau PET SUVR maps, harmonizing PI-2620 data from the HABS-HD cohort into the AV-1451 domain of ADNI. Compared against ComBat, CycleGAN, a diffusion-based method (DF), and unregularized Diffusion Schröodinger Bridge Matching (DSBM), FKRSBM achieves superior distributional alignment, reduced tau-positivity sign mismatch, stronger APOE subgroup alignment, and improved downstream disease classification performance.},
}

@article {pmid42368463,
year = {2026},
author = {Shi, M},
title = {Next-generation TREM2-targeted therapies for Alzheimer's disease: insights and directions from the INVOKE-2 trial.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1837720},
pmid = {42368463},
issn = {1663-4365},
}

@article {pmid42368467,
year = {2026},
author = {Ji, T and Wang, L and Weng, X and Lu, C and Gao, Y and Yu, K and He, J and Shen, X and Gao, X},
title = {Protective effect of baicalein from Pinellia ternate on Alzheimer's disease cell injury: a network pharmacology, molecular docking, and molecular dynamics study.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1848282},
pmid = {42368467},
issn = {1663-4365},
abstract = {INTRODUCTION: Alzheimer's disease (AD) constitutes the primary leading cause of dementia. Pinellia ternata (Thunb.) Breit. is a traditional Chinese herb with unclarified potential therapeutic effects against AD. This study aimed to explore the therapeutic potential and underlying mechanism of Pinellia ternata (Thunb.) Breit. in the treatment of AD.

METHODS: The bioactive components and corresponding targets of Pinellia ternata (Thunb.) Breit. were screened from TCMSP, Herb, and SymMap databases. AD-related targets were retrieved from OMIM, GeneCards, and TTD databases, and key targets were obtained via target intersection analysis. Functional enrichment analyses were performed to identify the main signaling pathways involved in the targets. Core targets and major bioactive components were further screened, and molecular docking as well as dynamics simulations were conducted to verify the binding affinity between key components and core targets. In vitro cell experiments using BV2 cells were implemented to validate the therapeutic effect of the core bioactive component.

RESULTS: A total of 13 bioactive components and 99 corresponding targets of Pinellia ternata (Thunb.) Breit. were identified, and 29 key AD-related targets were screened out through target intersection. Enrichment analysis results showed that these key targets were mainly enriched in neuroactive ligand-receptor interaction and calcium signaling pathways. PTGS2, CASP2, and AKT1 were determined as core therapeutic targets, with β-sitosterol and baicalein identified as the principal bioactive components of Pinellia ternata (Thunb.) Breit. against AD. Molecular docking and dynamics simulations verified the strong binding affinity between baicalein and PTGS2. In vitro experimental results further demonstrated that baicalein pretreatment could relieve the inhibitory effect of Aβ1-42 on BV2 cell proliferation.

DISCUSSION: Pinellia ternata (Thunb.) Breit. exerts therapeutic effects on AD via a synergistic mechanism characterized by multi-component, multi-target, and multi-pathway regulation. The active ingredient baicalein targeting PTGS2 is a crucial material basis for its anti-AD effect. The findings of this study elucidate the potential mechanism of Pinellia ternata (Thunb.) Breit. in AD treatment and provide a reliable theoretical foundation for subsequent in-depth research and clinical exploration of the herb as a therapeutic agent for AD.},
}

@article {pmid42368586,
year = {2026},
author = {Han, M and Wang, N and Song, M and Liu, C and Wu, Y and Yin, J and Jin, L and Jin, W and Gao, Z},
title = {The mechanisms and strategies for Alzheimer's disease prevention: An update.},
journal = {Acta pharmaceutica Sinica. B},
volume = {16},
number = {6},
pages = {3582-3602},
pmid = {42368586},
issn = {2211-3835},
abstract = {Alzheimer's disease (AD), a progressive neurodegenerative disorder, poses growing global health and socioeconomic challenges due to aging populations and limited therapeutic efficacy. Current treatments, including cholinesterase inhibitors and anti-amyloid monoclonal antibodies, can only delay disease progression without reversing pathology. Emphasizing on prevention, this review provides key updates on advancements in the pathogenesis, diagnosis, and intervention of AD highlighting preventive strategies that can target modifiable risk factors. Key findings underscore the role of managing hypertension and diabetes, optimizing trace elements, vitamins, and regular physical exercise in mitigating the risk of AD. Biomarker-based early diagnosis and emerging therapies provide further support for proactive intervention. Future challenges include the long-term validation of preventive measures and policy-driven funding for large-scale cohort studies. Prioritizing prevention through lifestyle modifications, nutritional balance, and precision medicine is pivotal to reduce the burden of AD in aging societies.},
}

@article {pmid42368893,
year = {2026},
author = {Xie, J and Li, Y and Lu, J and Wang, W and Hou, Y and Huang, Y and Wu, H and Zhou, Y and Li, J},
title = {Mechanisms of electroacupuncture for the treatment of Alzheimer's disease by activating Wnt/β-catenin pathway to improve blood-brain barrier function.},
journal = {IBRO neuroscience reports},
volume = {21},
number = {},
pages = {106-113},
pmid = {42368893},
issn = {2667-2421},
abstract = {AIMS: In this study, we used APP/PS1 mice as a research vehicle to illustrate that electroacupuncture can improve the blood-brain barrier function by activating the Wnt/β-catenin pathway for the treatment of Alzheimer's disease (AD).

METHODS: 18 7-month-old SPF APP/PS1 male double-transgenic mice were selected as AD model mice and randomly divided into model group, electroacupuncture group and donepezil hydrochloride group, with 6 mice in each group, and 6 C57BL/6 J male mice as normal group. After the end of the intervention, the mice in each group were subjected to Morris water maze behavioural test. After the behavioural test, the pathological morphology of hippocampal tissue was observed by HE staining method, Aβ was detected in the hippocampal region of mice by IHC method, the mRNA expression of Axin2 and Dkk1 was detected in hippocampal tissue by Real-time PCR method, and the tight junction protein, Claudin-5, was detected in hippocampal region of mice by Western Blot method. Claudin-5, Occludin protein with active β-catenin, p-GSK3β protein expression in mouse hippocampus by Western Blot.

RESULTS: EA can improve the learning ability of APP/PS1 mice, restore the morphology and structure of the hippocampus, reduce the positive expression of Aβ in the hippocampus, down-regulate the expression of Axin2 and Dkk1 mRNA, and elevate the expression of the tight junction-related proteins, Claudin-5, Occludin with active β-catenin, and p-GSK3β.

CONCLUSION: EA can improve the expression of blood-brain barrier-related molecules in AD mice by regulating the expression of molecules related to the Wnt/β-catenin pathway, which is beneficial to the early treatment of AD.},
}

@article {pmid42368914,
year = {2026},
author = {Zhang, Z and Hu, M and Teng, Z and Mu, Y and Yin, P},
title = {Joint association of a healthy low-carbohydrate diet and frailty with the risk of incident Alzheimer's disease and vascular dementia: a prospective cohort study.},
journal = {Frontiers in public health},
volume = {14},
number = {},
pages = {1853648},
pmid = {42368914},
issn = {2296-2565},
mesh = {Humans ; *Dementia, Vascular/epidemiology ; Female ; *Diet, Carbohydrate-Restricted/statistics & numerical data ; *Frailty/epidemiology ; Male ; Aged ; *Alzheimer Disease/epidemiology ; Prospective Studies ; Risk Factors ; United Kingdom/epidemiology ; Middle Aged ; Incidence ; },
abstract = {BACKGROUND: We aimed to investigate the associations between a healthy low-carbohydrate diet (HLCD) score, frailty and their combined effects with the risk of Alzheimer's disease (AD) and vascular dementia (VD).

METHODS: This cohort study analyzed 157,465 participants from the UK Biobank. The HLCD score was calculated based on the intake of total carbohydrates, vegetable proteins, and unsaturated fats, while frailty was assessed using a frailty index incorporating a wide range of biological systems and physical capacities, including sensory functions, mental health, and systemic comorbidities, which was developed and validated by the UK Biobank. Cox proportional hazards models and restricted cubic splines were employed for analysis.

RESULTS: Higher HLCD scores were significantly associated with a lower risk of AD (Q4 vs. Q1: HR = 0.66; 95% CI: 0.52-0.84) and VD (Q4 vs. Q1: HR = 0.54; 95% CI: 0.39-0.75). Frailty was identified as a risk factor for both dementia subtypes. Compared with the nonfrail group, the adjusted HRs for AD were 1.33 (1.08-1.65) for prefrail and 1.62 (1.33-1.98) for frail groups, while the adjusted HRs for VD were 1.61 (1.20-2.17) for prefrail and 2.46 (1.89-3.20) for frail groups. In the joint association analysis, adherence to a high-quality HLCD effectively mitigates the increased risk of AD attributed to frailty. Frail individuals with high HLCD scores exhibited a significantly lower risk of AD compared to those with low HLCD scores (HR = 0.63, 95% CI: 0.47-0.85). For VD, the protective benefit was more pronounced in the prefrailty stage (HR = 0.52, 0.35-0.79) than in the frail stage (HR = 0.83, 0.59-1.17).

CONCLUSIONS: High adherence to the HLCD was associated with a lower risk of AD and VD, whereas frailty independently was associated with an increased the risk of AD and VD. Adherence to a high-quality HLCD effectively mitigates the increased risk associated with frailty. Promoting healthy low-carbohydrate diets may serve as a robust strategy to enhance cognitive resilience in older populations.},
}

Humans
*Dementia, Vascular/epidemiology
Female
*Diet, Carbohydrate-Restricted/statistics & numerical data
*Frailty/epidemiology
Male
Aged
*Alzheimer Disease/epidemiology
Prospective Studies
Risk Factors
United Kingdom/epidemiology
Middle Aged
Incidence

@article {pmid42368974,
year = {2026},
author = {Murden, RJ and Tian, G and Qiu, D and Risk, BB},
title = {Probabilistic Joint and Individual Variation Explained (ProJIVE) for Data Integration.},
journal = {Journal of computational and graphical statistics : a joint publication of American Statistical Association, Institute of Mathematical Statistics, Interface Foundation of North America},
volume = {},
number = {},
pages = {},
pmid = {42368974},
issn = {1061-8600},
abstract = {Collecting multiple types of data on the same set of subjects is common in modern scientific applications including genomics, metabolomics, and neuroimaging. Joint and Individual Variation Explained (JIVE) seeks a low-rank approximation of the joint variation between two or more sets of features captured on common subjects and isolates this variation from that unique to each set of features. We develop an expectation-maximization (EM) algorithm to estimate a probabilistic model for the JIVE framework. The model extends probabilistic PCA to multiple datasets. Our maximum likelihood approach simultaneously estimates joint and individual components, which can lead to greater accuracy compared to other methods. We apply ProJIVE to measures of brain morphometry and cognition in Alzheimer's disease. ProJIVE learns biologically meaningful sources of variation, and the joint morphometry and cognition subject scores are strongly related to more expensive existing biomarkers. Data used in preparation of this article were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Code to reproduce the analysis is available at https://github.com/thebrisklab/ProJIVE.},
}

@article {pmid42369131,
year = {2026},
author = {Merlini, S and Gatta, R and Orini, S and Basharat, A and Farooq, M and Brinton, RD and Vitali, F},
title = {Comorbidity sequence, sex, and APOE-genotype forecast Alzheimer's disease diagnosis.},
journal = {Frontiers in medicine},
volume = {13},
number = {},
pages = {1826377},
pmid = {42369131},
issn = {2296-858X},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a highly heterogeneous neurodegenerative disorder and the leading cause of dementia characterized by the progressive accumulation of non-modifiable (age, female sex, APOE-ε4 genotype) and modifiable factors [hypertension (HTN), diabetes, obesity (OB), hyperlipidemia (HLP), depression (DEP)]. However, the temporal sequencing and interaction patterns between comorbidity burden and biological subgroups defined by sex and APOE genotype remain not fully understood.

METHODS: We applied the Cumulative Event Method (CEM), a novel process mining framework, to longitudinal UK Biobank (UKB) data. Event logs tracked five modifiable risk factors across sex- and APOE-ε4-stratified analyses to identify distinct longitudinal comorbidity patterns associated with AD. Sex-specific findings were validated in an independent CureMD cohort.

RESULTS: Among 1,916 UK Biobank participants, CEM identified 203 distinct comorbidity sequences across 7,316 clinical events. Females more frequently exhibited a hypertension-preceding-AD sequences than males (7.0% vs. 3.8%; p = 0.005), while males exhibited earlier metabolic-vascular patterns involving hyperlipidemia and hypertension (7.7% vs. 4.5%; p = 0.0085). APOE-ε4 carriers exhibited accelerated multi-comorbidity patterns, whereas non-carriers more frequently transitioned from hypertension to non-AD (p = 1 × 10[-4]). External validation in CureMD confirmed sex-specific patterns across 191 sequences and 5,176 events.

CONCLUSION: Longitudinal comorbidities patterns preceding AD differ by sex and APOE genotype, supporting Alzheimer's as a multisystem failure disease with subgroup-specific comorbidity sequences and clinically relevant windows for precision prevention.},
}

@article {pmid42369182,
year = {2026},
author = {Carlozzi, NE and Lombard, WL and Fansher, M and Freeman, JL and Capellari, E and Graves, CM and Miner, JA and Hampstead, BM and Lai, JS and Leggett, AN},
title = {Understanding how informal dementia caregiver networks are assessed in the literature: results from a scoping review.},
journal = {Frontiers in dementia},
volume = {5},
number = {},
pages = {1824829},
pmid = {42369182},
issn = {2813-3919},
abstract = {OBJECTIVES: Alzheimer's disease and related dementias currently affect millions of Americans, with increasing prevalence expected as the population ages. Care for individuals with dementia is typically provided by informal caregiver networks encompassing family, friends, and nontraditional care partners. Despite societal changes in caregiving roles and family structure, there is limited consensus on how caregiver networks are conceptualized and measured in research literature. The purpose of this analysis was to systematically map existing measurement approaches used to capture and characterize informal dementia caregiver networks, and to identify common data elements and validated instruments within the literature.

METHODS: We conducted a rigorous literature review guided by the JBI Manual for Evidence Synthesis for conducting scoping reviews, the Preferred Reporting Items for Systematic reviews and Metal-Analyses extension for Scoping Reviews (PRISMA-ScR). The protocol was registered on OSF (DOI: 10.17605/OSF. IO/2XGSR). Inclusion criteria comprised peer-reviewed, quantitative, English-language articles that defined or measured caregiver networks, with no geographic or date restrictions. Independent raters performed title, abstract, and full-text screening, supplemented by artificial intelligence (AI)-supported data extraction and latent content analysis to identify measurement approaches and data elements.

RESULTS: Out of 14,625 initial references, 197 studies were included that assessed caregiver networks for individuals with dementia. Only 19 studies utilized validated instruments, while the remaining 177 (89%) relied on study-specific measures. Thirteen validated tools were identified, although most were used only once or twice. Latent content analysis revealed seven recurring data elements in network characterization: (1) availability of another caregiver (45.2%), (2) amount of help provided (39.1%), (3) number of caregivers (23.4%), (4) type of activities assisted with (16.2%), (5) relationships of helpers (13.7%), (6) satisfaction with support (12.7%), and (7) demographic details of caregivers (2.5%). Most studies assessed just one or two network attributes, with marked variability and limited adoption of standardized measures.

CONCLUSION: There is substantial heterogeneity and inconsistency in how informal caregiver networks are assessed in dementia research, and there is no consensus approach in the literature. As caregiving networks diversify in response to changing demographics and family structures, robust, inclusive assessment instruments are critically needed. Future research should prioritize developing and validating standardized measures to better capture the complexities of modern informal dementia caregiver networks, thereby enhancing policy, support, and interventions for these populations.

OSF Registration found at https://osf.io/2xgsr/overview.},
}

@article {pmid42369233,
year = {2026},
author = {Ding, S and Johns, E and Orlichenko, A and Fredericks, C and Zhao, Y},
title = {A NOVEL BAYESIAN FRAMEWORK UNCOVERING BRAIN CONNECTIVITY-TO-SHAPE RELATIONSHIP IN PRECLINICAL ALZHEIMER'S DISEASE.},
journal = {The annals of applied statistics},
volume = {20},
number = {2},
pages = {1429-1451},
pmid = {42369233},
issn = {1932-6157},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-beta plaques and tau tangles, with significant pathological changes occurring in subcortical brain regions. While previous research has focused primarily on volumetric reductions in areas such as the hippocampus, thalamus, and caudate, emerging evidence suggests that their fine-grained shape deformations may offer greater sensitivity to early disease pathology. Moreover, understanding how these shape alterations influence brain functional connectivity (FC) networks could provide critical insights into the neurobiological mechanisms underlying the progression of AD. In this context, we propose a novel statistical approach, the Connectivity-on-Shape Regression (COSR) model, designed to investigate the spatially varying impact of brain subcortical shape on FC, accounting for the intrinsic modularity of functional networks. Under a Bayesian framework, COSR employs a relaxed-thresholded Gaussian process prior model to promote feature selection and integrates a stochastic block model to capture the unknown modular organization of FC. To facilitate the practical application of COSR with vertex-level shape measurements, we develop a computationally efficient variational inference approach to achieve posterior inference. Extensive simulations demonstrate the superiority of COSR over existing alternatives in accurately uncovering connectivity-to-shape associations and identifying neurobiological signals. Applying COSR to data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's study, we discover meaningful neural structural-functional relationships in amyloid-positive individuals, highlighting the potentially complex interplay between structural and functional brain alterations during this crucial preclinical stage of AD.},
}

@article {pmid42369248,
year = {2026},
author = {García-Zamora, M and Pardo, J and Esteve, M and Martinez-Gracia, A and Cháfer-Pericás, C and Falcó, A},
title = {Polypharmacy is associated with lower progression from MCI to Alzheimer's disease, with sex-specific patterns across drug classes.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {2},
pages = {e70379},
pmid = {42369248},
issn = {2352-8729},
abstract = {INTRODUCTION: Polypharmacy is often considered harmful in older adults, yet several cardiovascular and psychiatric drugs target modifiable dementia risk factors. We examined the association between polypharmacy and progression from mild cognitive impairment (MCI) to Alzheimer's disease (AD), overall and by sex.

METHODS: In a retrospective cohort of 4557 adults ≥ 50 years with MCI, followed for a mean of 68.7 months, polypharmacy was defined as ≥ 5 medications. Cox models adjusted for age and sex estimated hazard ratios (HRs), including sex-stratified analyses.

RESULTS: Polypharmacy may be associated with lower likelihood of progression to AD. Sex-stratified analyses suggested differences: antidiabetics, antithrombotics, sedatives, and antidepressants were mainly associated with lower progression in women; antihypertensives in men; anxiolytics, antipsychotics, and antidementia drugs in both sexes.

DISCUSSION: These observational findings indicate possible associations between medication use and MCI to AD progression, with potential sex-specific patterns, but causality cannot be inferred. Unmeasured factors and limited covariate adjustment may contribute.},
}

@article {pmid42369375,
year = {2026},
author = {Yadav, B and Gangwar, P and Kumari, K and Yadav, A and Rao, R and Kumar, K and Verma, H and Dhiman, M and Mantha, AK},
title = {Mechanistic insights into the synaptic damage-repair and regeneration processes in neurodegenerative Alzheimer's disease: phytochemicals as neuroprotective agents.},
journal = {Frontiers in synaptic neuroscience},
volume = {18},
number = {},
pages = {1835778},
pmid = {42369375},
issn = {1663-3563},
abstract = {Synaptic failure is one of the earliest and most significant contributors to the cognitive decline in Alzheimer's disease (AD), preceding extensive neuronal loss. Although amyloid beta (Aβ) plaques and neurofibrillary tangles (NFTs) of tau protein characterize the disease, memory impairment primarily results from the gradual deterioration of synaptic communications. This decline is caused by a complex interaction among mitochondrial energy deficits, cytoskeletal instability, disrupted exosomal signaling, and immune-mediated synaptic pruning. Mitochondrial dysfunction, particularly affecting complexes I and IV, leads to reduced ATP production, faulty mitophagy and disrupted calcium (Ca[2+]) homeostasis, placing the synapse under constant metabolic stress. Elevated reactive oxygen species (ROS) further activate stress pathways, including p38 MAPK and JNK, contributing to synaptic protein damage and impaired long-term potentiation (LTP). Furthermore, tau hyperphosphorylation destabilizes the neuronal cytoskeleton, weakening dendritic spine integrity and synaptic connectivity. At the same time, Aβ alters the cargo carried by exosomes, facilitating the spread of pathogenic Aβ and tau species between the neurons and modulating microglial activation and complement-mediated synaptic pruning. Additionally, emerging studies highlight the role of NETosis in exacerbating neuroinflammation and compromising the blood-brain barrier (BBB) integrity, thereby increasing synaptic damage. In contrast, phytochemicals such as resveratrol, ginkgolide B, curcumin, ferulic acid, epigallocatechin gallate (EGCG), and quercetin exert neuroprotection by restoring redox balance, altering exosomal communications, stabilizing cytoskeletal signaling, and reducing neuroinflammation. Moreover, delivery techniques such as nanoparticles and engineered exosomes enhance BBB permeability and enable targeted synaptic intervention. Overall, this review summarizes current mechanistic findings and highlights the potential of phytochemicals as multitarget therapeutic agents for synaptic repair and functional recovery in AD.},
}

@article {pmid42369416,
year = {2025},
author = {Zhao, M and Niu, Y and Huang, Q and Li, W},
title = {Exploring the Mechanisms of EDCs-Induced Metabolic Disorders in Humans Using Network Toxicology and Molecular Docking.},
journal = {NAM journal},
volume = {1},
number = {},
pages = {100041},
pmid = {42369416},
issn = {3050-6204},
abstract = {OBJECTIVE: This study aims to investigate the potential mechanisms by which EDCs, recognized as emerging pollutants, induce metabolic disorders leading to metabolic diseases in humans.

METHODS: Network toxicology and molecular docking techniques were employed to elucidate the molecular mechanisms underlying EDCs-induced pathogenesis of the six diseases. Potential targets associated with EDCs and these diseases were identified using databases such as PubChem, ChEMBL, Super-PRED, GeneCards, OMIM, and TTD. STRING analysis and Cytoscape software were further utilized to determine core targets most significantly linked to these metabolic disorders. GO and KEGG pathway enrichment analyses were performed on the core targets using the DAVID database. Finally, molecular docking was conducted to validate the binding affinities between EDCs and core target proteins.

RESULTS: EDCs may potentially induce metabolic disorders by modulating cellular expression, influencing apoptosis and proliferation, and regulating related signaling pathways. Notably, a close interrelationship was observed among lipid metabolism disorders and atherosclerosis, Alzheimer's disease, type 2 diabetes mellitus, osteoporosis, hyperuricemia, and non-alcoholic fatty liver disease.

CONCLUSION: This study provides novel insights into the mechanisms through which EDCs induce metabolic diseases in humans and highlights correlations among distinct disorders, thereby establishing a theoretical foundation for disease prevention and therapeutic strategies.},
}

@article {pmid42369427,
year = {2025},
author = {Liu, H and Tang, M and Che, L and Lu, J and Zhang, L},
title = {Investigating the potential mechanism of bisphenols on neurodegeneration through network toxicology and molecular docking.},
journal = {NAM journal},
volume = {1},
number = {},
pages = {100044},
pmid = {42369427},
issn = {3050-6204},
abstract = {This study aims to elucidate the mechanisms underlying bisphenols (BPs)-induced neurodegeneration and their contribution to neurodegenerative diseases. Focusing on four major disorders-Alzheimer's Disease, Parkinson's Disease, Amyotrophic Lateral Sclerosis, and Huntington's Disease-we systematically examined key molecular pathways potentially perturbed by BPs during disease progression. Preliminary toxicological profiling of four representative BPs was conducted using ProTox-3.0, ADMETlab 3.0, and the Xundrug database. Subsequent target identification involved integrated analyses of multiple bioinformatics resources, including CHEMBL and STITCH. Protein-protein interaction networks constructed with STRING and Cytoscape identified core targets such as HSP90AA1, ESR1, BCL2, and PTGS2. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses further revealed critical biological processes, including enzyme binding and heme binding, as well as key pathways associated with BPs neurotoxicity, such as chemical carcinogenesis-receptor activation, chemical carcinogenesis-DNA adducts, and arachidonic acid metabolism. Molecular docking studies demonstrated strong binding affinities between BPs and core targets, supported by low free energy values. Molecular dynamics simulations further validated stable binding conformations and dynamic interactions. Additionally, we analyzed regulatory networks of mRNA-miRNA-lncRNA interactions for core targets. In summary, our findings establish a novel multi-target and multi-pathway framework for BPs-induced neurodegeneration, revealing synergistic effects of pathways including carcinogenic signaling activation and metabolic dysregulation. This study advances understanding of environmental neurotoxicity and provides a foundation for developing preventive strategies against neurodegenerative diseases.},
}

@article {pmid42369461,
year = {2026},
author = {Mukumbi, K and Liu, Y and Shi, Z and Liu, E and Toyli, A and Hung, GU and Chen, QH and Sha, Q and Chiu, PY and Zhou, W},
title = {Low-Density Lipoprotein Cholesterol and Dementia Risk: Integrating Mendelian Randomization and Target Trial Emulation Within the Heart-Brain Axis.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.10.26355413},
pmid = {42369461},
abstract = {BACKGROUND: The heart-brain axis links cardiovascular and neurodegenerative disease through shared vascular and inflammatory mechanisms. Although low-density lipoprotein cholesterol (LDL-C) is an established causal factor in atherosclerotic cardiovascular disease (ASCVD), its relationship with dementia remains uncertain, with midlife elevations associated with increased risk but late-life associations often appearing null or inverse. To address this cholesterol paradox, we integrated mendelian randomization (MR) with an active-comparator new-user target trial emulation.

METHODS: We applied a triangulated causal inference framework integrating two-sample MR with observational target trial emulation. Genetic variants associated with LDL-C were used as instrumental variables to evaluate Alzheimer's disease (AD), Dementia with Lewy bodies (DLB), Frontotemporal dementia (FTD), and any dementia (AnyDem), with causal estimates derived using inverse-variance weighted models and sensitivity analyses for heterogeneity and pleiotropy. In parallel, an active-comparator new-user design compared statin versus ezetimibe initiation among adults aged ≥60 years using propensity score (PS) overlap weighting and Cox proportional hazards models to evaluate cardiovascular and dementia outcomes.

RESULTS: Genetically predicted LDL-C was associated with increased risk of DLB (OR 1.65, 95% CI 1.30-2.10; p<0.001), but not AD or AnyDem; FTD estimates were inconsistent. Sensitivity analyses suggested heterogeneity and possible pleiotropy for DLB. In the observational analysis (n=6,977), statin initiation was associated with higher risks of ASCVD (HR 1.26, 95% CI 1.11-1.45) and AnyDem (HR 1.66, 95% CI 1.16-2.38), although estimates attenuated after lipid adjustment and lagged analyses, suggesting residual confounding, treatment selection, and reverse causation in late-life observational associations.

CONCLUSIONS: These findings suggest that LDL-C reflects accumulated vascular and metabolic risk rather than a direct causal driver of AD or overall dementia, although a subtype-specific association was observed for DLB. Late-life associations appeared influenced by timing, reverse causation, and treatment selection, warranting cautious interpretation.},
}

@article {pmid42369475,
year = {2026},
author = {White, P and Budak, M and Moallemian, S and Fausto, BA and Gluck, MA},
title = {Preserved Medial Temporal Lobe Flexibility Predicts Memory Generalization Only in the Context of Good Sleep Quality among Older African Americans.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.15.26355704},
pmid = {42369475},
abstract = {OBJECTIVES: Poor sleep quality is a risk factor for Alzheimer's disease (AD). Older African Americans experience disproportionately high rates of sleep disturbance and AD. Medial temporal lobe (MTL) flexibility reflects dynamic neural reorganization and may be a marker of generalization performance. This study examined whether sleep quality moderates the association between MTL flexibility and memory generalization.

METHODS: Fifty older African Americans (MeanAge=69.7±6.21 years; 80% women) underwent rs-fMRI to quantify MTL flexibility, Rutgers Acquired Equivalence Task for memory generalization, and Pittsburgh Sleep Quality Index for sleep quality.

RESULTS: Greater MTL flexibility was associated with better generalization (r=0.367, p=.017). Good sleepers showed higher MTL flexibility (F (1,44) =8.11, ηp [2] =.156, p=.007) and superior generalization (F (1,46) = 12.33, ηp [2] =.211, p=.001). Sleep quality significantly moderated the MTL flexibility-generalization relationship (β=-1.519, p=.012).

CONCLUSIONS: Preserved MTL flexibility may confer generalization only in good sleepers, suggesting that sleep disturbance may disrupt the MTL neural resilience among older African Americans.

WHAT WAS KNOWN: Prior research has established that poor sleep quality is associated with increased Alzheimer's disease (AD) risk, hippocampal dysfunction, and impaired memory. Studies also show that medial temporal lobe (MTL) network dynamics, including flexibility, support key features of cognition including memory generalization. However, limited work has examined how sleep quality interacts with neural flexibility to influence cognition, particularly in older African Americans, a population at elevated risk for both sleep disturbance and AD.

WHAT THIS STUDY ADDS: This study demonstrates that sleep quality significantly moderates the relationship between MTL flexibility and memory generalization. While greater MTL flexibility is associated with better generalization, this benefit is evident only among individuals with good sleep quality. These findings suggest that sleep disruption may impair the functional expression of neural resilience mechanisms, even when underlying network flexibility is preserved.},
}

@article {pmid42369486,
year = {2026},
author = {Cifello, J and Feng, R and Grenn, FP and Carter, L and Liu, A and Sun, H and Li, R and Empawi, JA and Greenfest-Allen, E and Katanic, Z and Valladares, O and Kuzma, AB and White, H and Farrer, LA and Goate, AM and Raj, T and Wang, M and Cruchaga, C and Wang, LS and Klein, H and Chen, H and , and De Jager, PL and Marcora, E and Tcw, J and Zhang, X and Kuksa, PP and Wang, G and Leung, YY},
title = {A TAD-informed aging-brain xQTL atlas of multi-modal and cell-type-resolved regulatory variation.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.21.26353713},
pmid = {42369486},
abstract = {Understanding the regulatory consequences of genetic variation in the aging human brain requires molecular maps that span brain regions, cell types and regulatory modalities. We present the Alzheimer's Disease Sequencing Project Functional Genomics (FunGen-AD) xQTL Atlas, a harmonized resource of molecular quantitative trait loci from four postmortem brain studies, ROSMAP, MSBB, Knight-ADRC and MiGA. The atlas integrates histone acetylation, DNA methylation, gene expression, splicing and protein abundance QTLs across 14 brain regions, 7 major cell types and 17,566 samples, with standardized association, significance-filtered and fine-mapping outputs. To expand discovery beyond conventional 1-Mb cis windows, we include variants within Topologically Associating Domains (TAD) and their boundaries where appropriate, identifying on average 21% more variant-molecular-trait associations per dataset. Statistical fine-mapping reduced broad association sets by 95% into credible sets of candidate regulatory variants. Distributed through the NIAGADS xQTL portal and bulk-download services, the atlas provides a comprehensive functional-genomic foundation for interpreting genetic risk variants in Alzheimer's disease and aging-brain research.},
}

@article {pmid42369493,
year = {2026},
author = {Abeywardana, D and Tsokos, CP},
title = {Data Driven Stochastic Model for Detecting Patients with Alzheimer's Disease.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.06.26355081},
pmid = {42369493},
abstract = {Alzheimer's disease (AD) is a critical neurological disorder that causes the brain to shrink and leads to the eventual death of brain cells, adversely affecting a person's ability to function. AD is a fast-growing disease in the United States and was the fifth leading cause of death among Americans 65 years of age or older in 2023. In the United States, 6.9 million people aged 65 or older were diagnosed with AD, along with a high rate of undiagnosed patients. Thus, the objective of our study is to develop a real data-driven predictive model to identify a patient with AD based on eight risk factors: Age, Gender, ADAS-Cog13, Entorhinal, Fusiform, Intracranial Volume (ICV), Amyloid-Beta, and Tau Protein, with a high degree of accuracy. The quality of the model was evaluated using well-established and sophisticated statistical measures: the area under the receiver operating characteristic curve, calibration plot, Hosmer-Lemeshow goodness-of-fit test, and K-fold cross-validation. If a patient is given information on the above risk factors, our proposed binary logistic regression model can classify the patient as having AD or not with at least 98% accuracy.},
}

@article {pmid42369495,
year = {2026},
author = {Li, MY and Tolosa-Tort, P and Heston, MB and Insel, PS and Andrews, SJ and , },
title = {Multi-domain AD risk burden and plasma biomarkers in cognitively unimpaired adults.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.11.26355499},
pmid = {42369495},
abstract = {INTRODUCTION: Alzheimer's disease (AD) pathology accumulates decades before symptom onset, yet how the cumulative effect of genetic, familial, and modifiable lifestyle risk burden jointly affects plasma biomarker levels and trajectories in cognitively unimpaired older adults remains unknown.

METHODS: We analyzed data from 261 participants in the PREVENT-AD cohort. A composite risk score integrating APOE ε4 status, polygenic score, family history, and modifiable/lifestyle risk was examined against six plasma biomarkers using linear regression and linear mixed-effects models.

RESULTS: APOE ε4 was the strongest predictor of plasma biomarker levels. Higher composite risk burden was associated with elevated ptau 181 , ptau 217 , ptau 217 /Aβ 42 , and GFAP levels, and lower Aβ 42/40 levels. A higher risk burden was predictive of accelerated ptau 181 accumulation.

DISCUSSION: Cumulative AD risk burden is broadly associated with plasma biomarker levels and specifically predicts accelerated ptau 181 accumulation in cognitively unimpaired older adults, supporting structured composite risk profiling as a framework for AD risk stratification.},
}

@article {pmid42369507,
year = {2026},
author = {Boutin, S and Houzé, B and Bedetti, C and Pichet Binette, A and Brambati, SM and , },
title = {Grey- and white-matter resilience to tau, cognition and sex in Alzheimer's disease.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.16.26355812},
pmid = {42369507},
abstract = {INTRODUCTION: Brain resilience to tau has been mainly studied in relation to grey matter, while its role in white matter remains unclear in Alzheimer's disease (AD). Sex may moderate associations between brain resilience and cognition.

METHODS: We analyzed medial temporal lobe tau PET SUVR, entorhinal cortical thickness, cingulum-hippocampal mean diffusivity, and cognition in 205 amyloid-positive individuals from ADNI. Associations between grey- and white-matter resilience to tau and cognitive performance or decline were examined using linear and mixed-effects models, including sex interactions and stratified analyses.

RESULTS: Higher grey-matter resilience to tau related to better cross-sectional memory and language performance (p<0.005), whereas higher white-matter resilience related to slower decline in these domains (p<0.03). These associations were seen in men but not women. DISCUSSION: White-matter resilience may better capture early cognitive changes in AD. Sex differences suggest greater sensitivity of cognition to brain resilience in men.},
}

@article {pmid42369518,
year = {2026},
author = {Pradhan, MM and Upadhayaya, R and Wenyon, SC and Viszolay, A and Rethlefsen, M and Metzger, V and Villarreal, G and Alvarez Lesmes, S and Andrade, D and Timm, J and Malec, SA},
title = {A Pilot Project Leveraging Large Language Models for Automated Screening and Variable Extraction in Observational Studies.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.13.26355589},
pmid = {42369518},
abstract = {BACKGROUND: Systematic reviews of observational studies are central to causal inference in chronic disease epidemiology but are increasingly limited by the scale of the literature and heterogeneity in confounder control. There is a need for transparent, open methods that reduce screening burden and make reported exposures, outcomes, and covariates comparable across studies.

OBJECTIVE: To develop and evaluate modular LLM-based pipelines, LitScreen and VarEx, that automate study screening and variable extraction for observational systematic reviews across multiple use cases, including hypertension as a primary exposure with Alzheimer's disease and related dementias (ADRD) as outcomes, and posttraumatic stress disorder (PTSD) as the exposure with self-harm, self-injury, and suicidality as outcomes.

METHODS AND MATERIALS: We built an end-to-end workflow in which reproducible MEDLINE via Ovid queries yield RIS corpora that are processed by LitScreen, a three-phase screening pipeline combining abstract-level evidence extraction, criterion-wise inclusion adjudication with high-recall gates, and full-text retrieval-augmented verification. Screened-in articles enter VarEx, a retrieval-augmented extraction pipeline that identifies role-specific passages and performs evidence-grounded extraction and semantic classification of exposures, outcomes, and covariates into predefined categories aligned with Metaconfoundr. Performance was evaluated on six labeled SYNERGY datasets and expert-annotated hypertension-to-ADRD and education-to-dementia corpora using precision, recall, F 1 , a strict score requiring correct variable identity and category, and time-per-reference estimates.

RESULTS: In the primary hypertension-to-ADRD reference set, VarEx achieved covariate-level precision of 0.80, recall of 0.79, and F 1 of 0.76, with classification accuracy of 0.97 and similar performance for education-to-dementia and SYNERGY validation datasets. LitScreen preserved high recall while excluding most ineligible records and reduced total screening and extraction time by roughly 80-90 percent relative to manual review baselines by routing only uncertain or borderline citations to full-text verification.

CONCLUSION: A retrieval-augmented LLM framework can automate major components of screening and variable extraction for observational systematic reviews, generating reusable structured covariate inventories that integrate with causal confounder assessment tools and substantially improve the efficiency and reproducibility of evidence synthesis, while remaining an assistant to, rather than a replacement for, human reviewers.},
}

@article {pmid42369569,
year = {2026},
author = {Liu, T and Zhang, Y and Hou, W and Hao, H and Geng, A and Zhao, G and Zhang, Y},
title = {From cellular heterogeneity to precision medicine: single-cell multi-omics in CNS disease research.},
journal = {Frontiers in cellular neuroscience},
volume = {20},
number = {},
pages = {1848558},
pmid = {42369569},
issn = {1662-5102},
abstract = {Single-cell sequencing and multi-omics technologies are revolutionizing research on central nervous system (CNS) diseases by enabling high-resolution analysis of cellular heterogeneity and molecular dynamics. Traditional technologies (e.g., bulk sequencing, routine histology) often lack cellular resolution, fail to capture heterogeneity among individual cells, and struggle to reveal subtle molecular changes in early pathogenesis, limiting their ability to clarify complex CNS disease mechanisms and develop precise diagnostic tools. This review comprehensively summarizes the latest advances in single-cell multi-omics methodologies, including genomics, transcriptomics, proteomics, metabolomics, and spatial omics, and their applications in elucidating the pathogenesis, diagnosis, and treatment of common CNS disorders. Representative diseases such as ischemic stroke, Alzheimer's disease, Parkinson's disease, viral meningitis, bacterial meningitis, multiple sclerosis, autism spectrum disorder, and depression are used as examples to discuss the current status and future prospects of single-cell multi-omics technologies in CNS disease research. Currently, these technologies have enabled the identification of rare pathogenic cell subsets, the mapping of cell-specific molecular pathways, and the discovery of potential diagnostic biomarkers in several common CNS disorders, though their clinical translation is still hindered by technical costs and standardization issues. In the future, the integration of single-cell multi-omics with spatial transcriptomics, artificial intelligence, and clinical data is expected to further decode the complex pathogenesis of CNS disorders, accelerate the development of targeted therapies, and promote the shift toward personalized medicine in CNS disease management-aligning with translational goals of neuropsychopharmacology.},
}

@article {pmid42369587,
year = {2026},
author = {Hubbard, EE and Reagle, K and Lui, MK and Derbez-Morin, M and Merrihew, GE and MacCoss, MJ and Julian, RR},
title = {Spontaneous Isomerization of Tau is Most Prevalent in Alzheimer's Disease.},
journal = {NeuroMarkers},
volume = {3},
number = {2},
pages = {},
pmid = {42369587},
issn = {2950-5887},
abstract = {Alzheimer's disease is the most common cause of dementia in humans and has been the subject of intense study for decades. Despite these efforts, the precise underlying cause or causes of Alzheimer's disease have remained elusive. Here we implement novel analysis of mass-spectrometry derived proteomics data to examine an understudied phenomenon related to Alzheimer's disease, isomerization of the protein tau. Isomerization is a spontaneous chemical modification that occurs in long-lived proteins and evolves most rapidly at aspartic acid. Recent results have demonstrated that isomerization of tau is more prevalent in Alzheimer's disease relative to healthy controls. To further map out the importance of tau isomerization in neurodegeneration, we examined its prevalence in several additional diseases by mining publicly available datasets and our own results, allowing for examination of Parkinson's disease, Lewy body dementia, vascular brain injury, and chronic traumatic encephalopathy. To evaluate the extent of tau isomerization in various locations within the brain in Alzheimer's disease, we examined samples from the frontal cortex, anterior cingulate gyrus, inferior parietal lobule, and caudate. Interestingly, our results demonstrate that significant isomerization of tau occurs only in individuals with Alzheimer's disease. In terms of localization, tau was easily detected in all regions of the brain, and tau isomerization was detected for Alzheimer's disease in all regions except the caudate. Importantly, tau isomerization can be easily and rigorously quantified from proteomics data. Comparison of the extent of tau isomerization with pre-mortem performance on the Mini-Mental State Examination revealed strong correlation. In addition to minimal abundance in other forms of neurodegeneration, tau isomerization was also low for a small number of the individuals designated to have Alzheimer's disease in our study, however consideration of other factors such as genetic predisposition, age, and mental acuity also differentiates these individuals. Importantly, the amount of tau isomerization observed in our studies does not correlate in any meaningful way with tau aggregation. Collectively, these observations suggest that tau isomerization derives from a different pathogenesis than other neurodegenerative markers, one that is only prevalent in Alzheimer's disease and may offer means for delineating the underlying causes of the disease.},
}

@article {pmid42369762,
year = {2026},
author = {Cuperlovic-Culf, M and Surendra, A and Alecu, I and Mahdi, A and Archinuk, F and Jabbari, H},
title = {Unbiased distance correlation with sample-size-aware confidence bounds for comparative omics network analysis.},
journal = {Frontiers in bioinformatics},
volume = {6},
number = {},
pages = {1788010},
pmid = {42369762},
issn = {2673-7647},
abstract = {INTRODUCTION: Data-driven determination is a powerful approach for unbiased investigation of the functional relationships in biomolecular networks. Such networks can be inferred from omics data, where correlation analysis is a commonly used method. However, the correlation values depend strongly on sample variability and size of the sample set in the general case, leading to unstable results and possibly highly erroneous conclusions.

METHODS: In this work, we show that similar to the Pearson and Spearman correlation approaches, distance correlation as a general non-linear polytonic correlation method also depends on the sample size. We show that both the p- and correlation values decrease with increasing sample sizes independent of the type of functional relationship between the features but relative to the correlation level. However, the dependence on sample size is greatly reduced in the unbiased distance correlation formulation. We validate an equation to compute the p-value and propose a threshold based on the false discovery rate (FDR) to identify significant correlations in unbiased distance correlation. Furthermore, we derive an extension of Hoeffding's inequality for estimating the error range of correlation as a function of the sample size as an additional sample-size-dependent confidence measure.

RESULTS: We integrated bias-corrected distance correlation with sample-size-matched bootstrapping, chi-squared p-value calculation, FDR adjustment, and empirical Bernstein/Hoeffding-type confidence bounds to support comparative correlation-network analysis in groups with unequal sample sizes. We also provide an online software solution for this application with extensive graphical presentations of the results. The use of this approach is demonstrated in the analysis of major network changes in Alzheimer's disease (AD) using previously published metabolomics data. Our analysis shows major changes in the metabolic networks, with higher connectivity in the AD group than the control group and examples of network changes for specific metabolites.

CONCLUSION: We present a method for unbiased distance correlation network derivation with permutations and comparisons between the sample groups. All approaches presented here are available through an online application (https://www.insilicobiology.ca/shiny/sidco+/), and all related code is available at https://github.com/computationalmetabolomicsca/sidco_plus.},
}

@article {pmid42370069,
year = {2026},
author = {Timashkov, A and Andreev, S and Safonova, A and Zangieva, S and Kadieva, D and Zinchenko, O},
title = {The inconsistent effects of tDCS in rehabilitation and cognitive enhancement: sources of variability and paths to personalization.},
journal = {Frontiers in human neuroscience},
volume = {20},
number = {},
pages = {1817726},
pmid = {42370069},
issn = {1662-5161},
abstract = {BACKGROUND/AIMS: Transcranial direct current stimulation (tDCS) has emerged as a promising intervention in both rehabilitation and cognitive enhancement, yet its effects remain inconsistent across studies. This variability has raised questions about the underlying mechanisms influencing tDCS efficacy.

METHODS: In this review, we address the issue of the inconsistent effect of tDCS on motor and cognitive domains across studies in healthy individuals and those with neurodegenerative disorders. A review of literature in the field was conducted using PubMed and Google Scholar.

RESULTS: Research indicates that individual anatomical differences among subjects may contribute to the inconsistent outcomes observed, as variations in current density at targeted brain regions and genetic variations responsible for the stimulation effect. Understanding the factors that contribute to the inconsistent effects of tDCS will be essential for enhancing its application in clinical settings and maximizing its potential benefits in cognitive rehabilitation and enhancement.

CONCLUSION: Future research should focus on optimizing tDCS parameters and exploring individualized approaches to treatment, taking into account the diverse responses observed in different populations.},
}

@article {pmid42370176,
year = {2026},
author = {Shi, Y and Zhang, R and Li, M and Xia, Y and Zhou, M and Cao, R and Zhou, Q and Zhang, Y},
title = {Molecular design of MRI probes for targeting amyloid-β species: from in vitro binding to in vivo imaging.},
journal = {Theranostics},
volume = {16},
number = {13},
pages = {7259-7287},
pmid = {42370176},
issn = {1838-7640},
mesh = {*Amyloid beta-Peptides/analysis/metabolism ; *Magnetic Resonance Imaging/methods ; Humans ; *Alzheimer Disease/diagnosis ; Animals ; *Molecular Probes ; *Contrast Media ; },
abstract = {The aberrant aggregation of amyloid-β (Aβ) is a central pathological marker of Alzheimer's disease (AD) and shows different neurotoxic properties in various forms, such as monomers, oligomers, fibers and plaques. In recent years, great progress has been achieved in the molecular design and the development of magnetic resonance imaging (MRI) probes targeting Aβ species. They provide powerful tools for the early diagnosis and pathological investigation of AD. Here, we systematically review the molecular design strategies and recent advances in Aβ-targeted MRI probes. First, we introduce the molecular pathological basis of Aβ aggregation and the importance of Aβ as an imaging target. Second, we detail the core components of probe design, including the selection of targeting ligands (e.g., peptide mimetics, small molecules, and antibody fragments), optimization of signal units (e.g., Gd(III), Mn(II), superparamagnetic iron oxide nanoparticles (SPIONs), and [19]F), and the delivery strategies to enhance blood-brain barrier (BBB) penetration. We focus on how the probes achieve the transition from high-affinity binding in vitro to high-contrast imaging in vivo by means of changes in proton relaxation times (T1/T2) or the chemical exchange saturation transfer (CEST) effect upon binding to Aβ. Furthermore, the imaging performance of various probes (small molecule probes, nanoprobes, and smart responsive probes) in transgenic AD models is compared and evaluated, and the challenges related to sensitivity, specificity, and biosafety are discussed. Finally, we discuss future directions for Aβ-targeted MRI probes, including oligomer-specific probes, multimodal imaging probes, and theranostic platforms that include both diagnostic and therapeutic functions. Through interdisciplinary innovation in molecular design, the next generation of MRI probes is expected to play a key role in preclinical research, early diagnosis, and therapeutic evaluation of AD.},
}

*Amyloid beta-Peptides/analysis/metabolism
*Magnetic Resonance Imaging/methods
Humans
*Alzheimer Disease/diagnosis
Animals
*Molecular Probes
*Contrast Media

@article {pmid42370203,
year = {2026},
author = {Huang, H and Xu, Y and Li, X and Li, C and Peng, W},
title = {The dual role of ATF4 in neurons: from stress adaptation to therapeutic intervention.},
journal = {Frontiers in molecular neuroscience},
volume = {19},
number = {},
pages = {1816333},
pmid = {42370203},
issn = {1662-5099},
abstract = {Activating transcription factor 4 (ATF4) functions as the central transcriptional arbiter of the integrated stress response (ISR) in neurons. Its translation is gated by diverse upstream kinases via the eIF2α pathway, while its functional output is critically shaped by context-dependent interactions with specific protein partners (e.g., C/EBPβ or CHOP). We conceptualize ATF4 as a spatiotemporal rheostat whose regulatory mandate is stage-specific: it acts as a physiological switch during neocortical development and maintains synaptic and mitochondrial integrity in the adult brain. However, this precise regulation fails in neurological disorders, including Alzheimer's disease, Parkinson's disease, cerebral ischemia, and epilepsy. Chronic, maladaptive ATF4 signaling-often driven by pathological heterodimerization-catalyzes neuroinflammation, ferroptosis, and circuit failure. Crucially, contemporary challenges in clinical translation highlight a "therapeutic paradox," where broad or untimely pathway inhibition may inadvertently dismantle essential neuroprotective shields. We therefore advocate for a paradigm shift toward "kinetic recalibration"-the development of precision interventions designed to restore the proteostatic and information-processing homeostasis of the stressed nervous system.},
}

@article {pmid42370254,
year = {2026},
author = {Lukacsovich, D and Young, JI and Gomez, L and Zhang, W and Kunkle, BW and Chen, XS and Martin, ER and Wang, L and Initiative, FTADN},
title = {Longitudinal Blood DNA Methylation Changes During Weight-Loss Intervention and Dementia Progression Risk.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-10029889/v1},
pmid = {42370254},
issn = {2693-5015},
abstract = {Background Weight loss improves metabolic health, but the DNA methylation (DNAm) changes induced by the lifestyle intervention and their relevance to dementia outcomes remain unclear. We studied longitudinal blood DNAm changes during an 18-month weight-loss intervention in the CENTRAL clinical trial and evaluated their relevance to dementia progression in an external cohort. Methods We analyzed paired baseline and 18-month blood DNAm data from 103 male CENTRAL participants, including 47 in diet-only and 56 in diet plus physical activity groups. CpG-level methylation M -value changes between baseline and follow up were tested using linear mixed-effects models adjusted for dietary group, age, smoking score, leukocyte proportions, and random participant effects. Differentially methylated regions were identified using comb-p, and pathway enrichment was assessed using methylGSA software. Weight-loss-associated CpGs and regions were compared with cardiometabolic and dementia epigenome-wide association studies (EWAS) findings. In 117 Alzheimer's Disease Neuroimaging Initiative participants with repeated DNAm and diagnostic follow-up, we tested whether DNAm changes at baseline resembling the reverse of the CENTRAL weight-loss profile predicted dementia progression. Results At a 5% false discovery rate, 51 CpGs and three differentially methylated regions (DMRs) were identified in the diet-only analysis, and 49 CpGs and one DMR were identified in the diet plus physical activity analysis, that were significantly associated with the weight loss interventions. Enriched pathways included DNA double-strand break response and ATM-mediated phosphorylation in the diet-only analysis, as well as energy metabolism and insulin secretion in the diet plus physical activity analysis. Weight-loss-associated DNAm signals overlapped with cardiometabolic, inflammatory, and dementia-related EWAS findings in expected directions. In ADNI, 28 participants progressed clinically. Between-visit DNAm changes at baseline in converters showed higher correlation scores with the reversed diet-only DNAm profile than non-converters (mean correlation score, 0.131 vs. 0.037; P -value = 0.026), and higher correlation scores were associated with increased progression risk in a Cox model adjusted for age, sex, APOE ε4, baseline diagnosis, education, and smoking history (hazard ratio = 1.49 per standard deviation, P -value = 0.041). The diet plus physical activity profile showed a similar but weaker association. Conclusions Weight-loss intervention was associated with blood DNAm changes enriched in genomic maintenance and metabolic pathways. External EWAS comparisons and ADNI validation suggest that weight-loss-responsive DNAm profiles may capture biological processes connecting lifestyle-related metabolic change with dementia progression risk.},
}

@article {pmid42370267,
year = {2026},
author = {Hassanzadeh, R and Abrol, A and Hassanzadeh, HR and Calhoun, VD},
title = {From Structure to Function and Back Again: A GAN-Guided Diffusion Framework for Generating Clinically Meaningful Multimodal Neuroimaging Data.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-9684909/v1},
pmid = {42370267},
issn = {2693-5015},
abstract = {Multimodal brain imaging provides complementary insights into brain structure and function, but its capability is often limited by missing modalities. Traditional imputation and subsampling strategies are computationally simple, but have the risk of introducing bias or discarding valuable samples. Recently, generative models have emerged as powerful alternatives for synthesizing missing modalities. In this study, we introduce a GAN-guided diffusion framework for cross-modality translation, designed to generate both T1-weighted magnetic resonance imaging (MRI) and functional network connectivity (FNC) data. The framework integrates conditional diffusion modeling, adversarial learning, and cycle-consistency, enabling training with both paired and unpaired samples. On Alzheimer's disease data, our approach outperformed baseline methods, achieving higher peak signal-to-noise ratio (PSNR) (24.95) and structural similarity index measure (SSIM) (0.86) for T1 synthesis, as well as improved correlation with real FNCs (0.65). Furthermore, our results demonstrate that the model captures variability across clinical groups without supervision from diagnostic labels, producing realistic and clinically meaningful synthetic modalities for downstream analysis and biomarker discovery.},
}

@article {pmid42370281,
year = {2026},
author = {Chopra, A and Basu, B and Liu, H and Pandey, S and Obeid, H and Flannery, B and Chen, Y and Yun, Y and Qian, A and Parfyonov, D and Zhao, Q and Liu, H and Meng, J and Naveh, G and Hanumanthu, S and Hoffman, J and Silva, E and Leverenz, J and Bekris, L and Keene, C and Bournat, J and He, Y and Mishra, I and Pieper, A and Xu, Y},
title = {Asprosin-PTPRD endocrine resistance links brain dysfunction and systemic wasting in Alzheimer's disease.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-9972826/v1},
pmid = {42370281},
issn = {2693-5015},
abstract = {Alzheimer's disease (AD) is characterized by cognitive decline and systemic frailty, but mechanisms linking brain dysfunction to organismal wasting remain unclear. We identify PTPRD, a human-genetically supported regulator of tau pathology, as a high-affinity receptor for amyloid-β (Aβ). Aβ competitively binds the PTPRD extracellular domain, opposing the endogenous ligand asprosin and producing a state of functional signaling insufficiency despite preserved receptor and ligand levels. Circuit-specific Ptprd deletion reveals anatomically distinct memory domains, while increasing asprosin in two AD mouse models restores Ptprd signaling and improves memory in a stage- and circuit-dependent manner. In advanced disease, asprosin supplementation substantially improves weight loss, muscle atrophy, strength, endurance and frailty. These findings support a model in which Aβ disrupts a CNS metabolic signaling axis linking cognition and systemic physiology and suggest that restoring ligand-receptor balance at PTPRD may ameliorate key features of AD.},
}

@article {pmid42370305,
year = {2026},
author = {Maiese, K},
title = {Dementia, mood disorders, and aging: Bridging new avenues of care through shared biological pathways.},
journal = {Aging advances},
volume = {3},
number = {3},
pages = {142-151},
pmid = {42370305},
issn = {3050-6743},
abstract = {With advancing age and lifespan throughout the globe in both developed and developing nations, the risk for developing cognitive loss and mood disorders increases significantly to the extent that after reaching the age of 65, this risk almost doubles every 5 years thereafter. As a result, a corresponding rise in non-communicable diseases will impact individuals with dementia and mood disorders involving Alzheimer's disease, multiple sclerosis, depression, and anxiety. On a clinical basis, multiple risk factors and presentations that involve the loss of intellectual capacity with the onset of mental health conditions, mood disorders preceding dementia, sleep fragmentation initiation, perivascular pathway disruptions, and circadian clock dysfunction can occur in both cognitive loss and mood disorders, but a much broader scope of shared underlying cellular pathways form the underpinning for the connection of these disorders that rests upon metabolic disorders, such as diabetes mellitus. Cognitive impairment and mood disorders can precede one another as well as coexist with related co-morbidities that involve metabolic disorders with diabetes mellitus, but present treatment strategies for these disorders are primarily symptomatic in nature and rely upon disease-altering therapies that may slow disease progression but also may be accompanied by disabling complications. Given these challenges, the institution of innovative avenues is critical at this juncture to address the mutual cellular mechanisms for the treatment of disorders involving Alzheimer's disease, multiple sclerosis, depression, and anxiety. The pathways of cell senescence and telomere biology with aging, cellular metabolic dysfunction, apolipoprotein E, oxidative stress, programmed cell death with autophagy, ferroptosis, and pyroptosis, mechanistic target of rapamycin, glucagon-like peptide-1 receptor agonism, mammalian forkhead transcription factors of the "O" class, and mitochondrial dynamics offer a compelling potential to bridge these underlying pathways into unifying strategies for transition into efficacious clinical care for dementia and mood disorders. Tempered with this enthusiasm for these mutual disease mechanisms is the complexity of these pathways that will require meticulous oversight of the interdependence among pathway components and their ultimate biological impact on clinical outcomes.},
}

@article {pmid42370350,
year = {2026},
author = {Yasir, M and Maurya, RK and Tripathi, AS},
title = {Curcumin as theranostics: imaging-guided therapeutics in oncology and neurodegenerative diseases.},
journal = {Frontiers in nutrition},
volume = {13},
number = {},
pages = {1790555},
pmid = {42370350},
issn = {2296-861X},
abstract = {Curcumin, a naturally occurring polyphenolic compound isolated from Curcuma longa, has been extensively studied for its nutritional, antioxidant, anti-inflammatory, anticancer, and neuroprotective properties. While traditionally recognized as a dietary bioactive with therapeutic relevance, recent advances in nanotechnology, molecular imaging, and targeted drug delivery have positioned curcumin as a promising theranostics agent. Theranostics integrates diagnostic imaging and therapy within a single platform, enabling real-time visualization of disease processes alongside targeted intervention. This review critically examines the emerging role of curcumin in imaging-guided therapeutics, with particular emphasis on oncology and neurodegenerative disorders. Curcumin's intrinsic fluorescence, affinity for pathological proteins, and modulatory effects on key molecular pathways underpin its potential as both an imaging probe and a therapeutic molecule. Key challenges related to poor aqueous solubility, rapid metabolism, and limited bioavailability are discussed, along with innovative delivery strategies such as nanoparticles, liposomes, radiolabelled conjugates, and stimulus-responsive systems designed to enhance clinical applicability. By bridging its established nutritional significance with advanced theranostics applications, curcumin exemplifies the translational potential of plant-derived bioactive in precision medicine. This review highlights current progress, limitations, and future perspectives, positioning curcumin as a model phytoconstituent for the development of integrated diagnostic and therapeutic platforms in complex chronic diseases.},
}

@article {pmid42370427,
year = {2026},
author = {Leboucher, H and Weaver, DF},
title = {Computational Insights into the Antiviral Properties of the Antimicrobial Peptide β-Amyloid.},
journal = {The journal of physical chemistry. B},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jpcb.6c01436},
pmid = {42370427},
issn = {1520-5207},
abstract = {Beta-amyloid (Aβ) is a peptide that forms extracellular plaques in the brain of patients affected by Alzheimer's disease. Numerous studies have been conducted on Aβ's characteristics, revealing its antibacterial and antiviral properties. Indeed, Aβ can bind to molecules attached to the surface of cell membranes, such as GM1 ganglioside, which are also known as points of entry for viruses. This binding could then explain its antiviral properties, as it may prevent the binding of proteins found on the surface of viruses. All-atom molecular dynamics simulations on protein-membrane systems were conducted to investigate this process. The selected proteins were Aβ42, Aβ40, VP1 from simian virus 40, VP8* from rotavirus, and HSV-1gD (herpes simplex virus 1). These last three viral proteins are already known to interact with either GM1 or Aβ. The membrane was a bilayer containing five different lipids (phospholipids, cholesterol, and GM1). Protein-membrane interactions were studied through the formation of hydrogen bonds and salt bridges over time, and the quantification of the interaction energies. Favorable interactions were observed between all studied proteins and GM1 lipids, especially for VP8*, where a strong network of interactions with the arginine residues was identified. Moreover, we demonstrate that a larger protein does not necessarily result in higher interaction energies, suggesting that smaller peptides may compete with these larger proteins.},
}

@article {pmid42370433,
year = {2026},
author = {Abdelmessih, GT and Bransby, L and Cummins, H and Jackson, ML and Lim, YY},
title = {Associations of self-reported obstructive sleep apnea with cognition and dementia risk in cognitively unimpaired middle-aged adults.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71553},
doi = {10.1002/alz.71553},
pmid = {42370433},
issn = {1552-5279},
support = {GNT1158384//National Health and Medical Research Council/ ; GNT1147465//National Health and Medical Research Council/ ; GNT1111603//National Health and Medical Research Council/ ; GNT1105576//National Health and Medical Research Council/ ; GNT1104273//National Health and Medical Research Council/ ; GNT1171816//National Health and Medical Research Council/ ; /ALZ/Alzheimer's Association/United States ; //Dementia Australia Research Foundation/ ; //Bethlehem Griffiths Research Foundation/ ; //Yulgilbar Alzheimer's Research Program/ ; 102052/WT_/Wellcome Trust/United Kingdom ; //Australian Government Research Training Program (RTP) Scholarship/ ; },
mesh = {Humans ; *Sleep Apnea, Obstructive/complications/epidemiology/genetics ; Middle Aged ; Male ; *Dementia/epidemiology/genetics ; Female ; Self Report ; Apolipoprotein E4/genetics ; Risk Factors ; Neuropsychological Tests ; *Cognition/physiology ; },
abstract = {INTRODUCTION: Obstructive sleep apnea (OSA) is a potential risk factor for cognitive impairment and dementia; however, its contribution in midlife and interactions with APOE ε4 remain unclear.

METHODS: Participants were 2795 cognitively unimpaired, middle-aged adults enrolled in the Healthy Brain Project. OSA status was determined by self-report. Cognition was assessed using the Cogstate Brief Battery, and dementia risk using the Cardiovascular Risk Factors, Ageing, and Incidence of Dementia (CAIDE) score.

RESULTS: Participants with OSA demonstrated poorer memory than those without OSA, although this association was attenuated after adjusting for vascular risk. Individuals with OSA (with or without APOE ε4) had significantly higher CAIDE scores than those with neither risk factor. APOE ε4 did not moderate OSA-cognition associations.

DISCUSSION: OSA may be associated with poorer memory and greater dementia risk, irrespective of APOE ε4 carriage. These findings highlight the need for early OSA screening to identify individuals at elevated dementia risk.},
}

Humans
*Sleep Apnea, Obstructive/complications/epidemiology/genetics
Middle Aged
Male
*Dementia/epidemiology/genetics
Female
Self Report
Apolipoprotein E4/genetics
Risk Factors
Neuropsychological Tests
*Cognition/physiology

@article {pmid42370748,
year = {2026},
author = {Gao, Y and Liang, W and Wang, G and Xu, Z and Liu, Y and Wang, Y and Wang, Y and Zhang, Y and Deng, Y and Zhou, J and Wang, Y and Li, H and Gao, L and Tu, M and Yu, M and Li, S and Zheng, J and Wang, JZ and Xu, H},
title = {Glymphatic system metrics derived from DTI-ALPS are associated with cognitive impairment, brain atrophy, and plasma tauopathy biomarkers of type 2 diabetes patients: Analysis in dual-cohort.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261462893},
doi = {10.1177/13872877261462893},
pmid = {42370748},
issn = {1875-8908},
abstract = {BackgroundGlymphatic dysfunction is implicated in neurodegenerative disorders and may contribute to the elevated risk of mild cognitive impairment (MCI) in type 2 diabetes mellitus (T2DM) patients. The diffusion tensor imaging along the perivascular space (DTI-ALPS) index has been proposed as a non-invasive imaging surrogate that may reflect aspects of glymphatic system activity.ObjectiveWe investigated the relationship between ALPS index, cognition, brain structure, and plasma Alzheimer's disease biomarkers in T2DM patients.MethodsTwo independent cohorts were analyzed: Cohort 1 included 60 age, sex, and education matched participants (20 T2DM with MCI, 20 T2DM with normal cognition, and 20 healthy controls); Cohort 2 comprised 35 elderly T2DM patients assessed for plasma AD biomarkers. All participants underwent MRI for ALPS index calculation and structural imaging. Cognition was evaluated using the Mini-Mental State Examination and Montreal Cognitive Assessment.ResultsThe ALPS index was significantly lower in T2DM patients with MCI compared to cognitively normal T2DM patients and healthy controls, and showed discriminative ability for MCI. Lower ALPS index correlated with poorer cognitive scores and was associated with brain atrophy. Mediation analysis indicated that the volume of the right opercular inferior frontal gyrus mediated the relationship between ALPS index and cognition scores. Furthermore, the ALPS index negatively correlated with plasma pTau217 adjusted by age and sex in T2DM patients.ConclusionsA lower ALPS index is associated with cognitive impairment, brain atrophy, and plasma tauopathy, which may serve as a promising non-invasive imaging biomarker for early identification of neurodegeneration risk in T2DM patients.},
}

@article {pmid42370776,
year = {2026},
author = {Salazar, BH and Hoffman, KA and Ong, M and Welk, B and Stoffel, JT and Wood, D and Stampas, A and Khavari, R},
title = {Engineering Advances in Neurogenic Lower Urinary Tract Dysfunction (NLUTD): Current State and Future Directions - A Report From the Neurogenic Bladder Research Group (NBRG).},
journal = {Neurourology and urodynamics},
volume = {},
number = {},
pages = {},
doi = {10.1002/nau.70356},
pmid = {42370776},
issn = {1520-6777},
support = {1R13DK138734/DK/NIDDK NIH HHS/United States ; },
abstract = {BACKGROUND AND OBJECTIVE: Neurogenic lower urinary tract dysfunction (NLUTD), stemming from neurodegenerative diseases or injuries such as cerebrovascular accidents, spinal cord injuries, and Alzheimer's disease, significantly impacts quality of life. Symptoms, including urinary frequency, urgency, incontinence, and retention, are managed with devices ranging from catheters to sacral neuromodulation. This Neurogenic Bladder Research Group (NBRG) report explores the intersection between clinical, basic science, and engineering research in personalized NLUTD treatment, identifies critical gaps for future investigation, and examines how interdisciplinary collaboration can drive engineering solutions to improve care.

METHODS: In December 2024, NBRG convened its annual meeting, gathering experts from engineering, clinical practice, research, and patient advocacy to discuss challenges in NLUTD research and explore collaborative solutions.

RESULTS: Enhanced collaboration between clinicians and engineers offers promise for improving NLUTD care. Clinicians provide critical insight into patient needs but often lack time for sustained research, while engineers contribute technical innovation yet may lack clinical exposure. Integrating patient perspectives emerged as a key theme, ensuring that technologies are practical, acceptable, and aligned with end-user needs. Discussions emphasized expanding programs that support cross-disciplinary, multi-institutional research and identifying funding pathways tailored to interdisciplinary efforts. Strategies to enhance patient involvement and foster inclusive research that reflects patient diversity and socio-demographic factors influencing care were also discussed.

CONCLUSION: Institutional support, interdisciplinary collaboration, and the active engagement of patients are key to advancing clinical care and NLUTD treatments.},
}

@article {pmid42370793,
year = {2026},
author = {Adler, R and Kozlov, M and Auerbach, E and Lev, R and Boroda, J and Lazar, J and Wein, AJ and Blaivas, JG and Weiss, JP},
title = {Neurourologic Outcomes in Men With Obstructive Sleep Apnea.},
journal = {Neurourology and urodynamics},
volume = {},
number = {},
pages = {},
doi = {10.1002/nau.70349},
pmid = {42370793},
issn = {1520-6777},
abstract = {BACKGROUND: Obstructive sleep apnea (OSA) is a highly prevalent multisystem disorder characterized by intermittent hypoxia, autonomic dysregulation, and sleep fragmentation. Storage-predominant lower urinary tract symptoms (LUTS)-including urgency, urgency incontinence, and overactive bladder-also involve central and autonomic neural pathways. Although OSA has been independently linked to nocturia and cognitive impairment, no large-scale studies have examined OSA, storage LUTS, and neurocognitive outcomes concurrently in a population with male LUTS.

METHODS: Using the TriNetX Research Network, we conducted a retrospective cohort study of men ≥ 50 years with the diagnosis code "BPH without baseline LUTS". Two cohorts were constructed, consisting of men who received a diagnosis of obstructive sleep apnea within 1 year after the initial BPH diagnosis and those with no documented diagnosis of OSA at any time. Propensity score matching (1:1) produced two balanced cohorts of 89,074 patients each. Ten outcomes representing LUTS and cognitive conditions were evaluated using risk ratios, hazard ratios, and Kaplan-Meier analyses.

RESULTS: OSA was associated with increased risk and earlier onset of urgency and urgency incontinence, overactive bladder, frequency of micturition, and neuromuscular bladder dysfunction. OSA was strongly associated with mild cognitive impairment and physiologic neuropsychiatric disorders, with no difference in Alzheimer's disease incidence.

CONCLUSIONS: These findings raise the possibility that lower urinary tract symptoms deserve greater attention in the evaluation of men with OSA, specifically in relation to nervous system as opposed to purely cardio-renal mechanisms.},
}

@article {pmid42370981,
year = {2026},
author = {Li, M and Yu, L and Yang, W and Song, L and Li, M and Bai, X and Yang, Z and Wang, Z and Lv, H and Wang, H},
title = {Impact of modifiable lifestyle factors on dementia subtypes and brain structural changes across KDIGO risk categories in the UK biobank.},
journal = {Brain imaging and behavior},
volume = {20},
number = {4},
pages = {},
pmid = {42370981},
issn = {1931-7565},
support = {82572190, 52227814//National Natural Science Foundation of China/ ; BJPSTP-2025-46//Beijing Physician Scientist Training Project/ ; yyqcjh2023-7, yyqcjh2023-9//Beijing Friendship Hospital, Capital Medical University/ ; },
mesh = {Humans ; *Dementia/epidemiology/pathology/diagnostic imaging/physiopathology ; Female ; Male ; *Life Style ; *Brain/pathology/diagnostic imaging ; United Kingdom/epidemiology ; Aged ; Risk Factors ; Magnetic Resonance Imaging ; UK Biobank ; Middle Aged ; Gray Matter/pathology ; Biological Specimen Banks ; },
abstract = {This study investigated the associations of modifiable lifestyle factors with incident dementia, dementia subtypes, and structural brain changes, examined whether these associations differed across KDIGO-defined kidney function risk categories. We analyzed 304,369 participants from the UK Biobank. Kidney function was classified using the KDIGO risk framework, with participants grouped into low- and increased-risk categories. A composite lifestyle score, derived from the American Heart Association Life's Essential 8 framework, was constructed based on eight modifiable components: diet quality, physical activity, smoking status, sleep duration, body mass index, blood lipid, blood glucose, and blood pressure. Outcomes included incident dementia and total and regional brain volumes. Among participants at increased KDIGO-defined risk, those in the intermediate and highest tertiles of the lifestyle score had a lower risk of dementia compared with those in the lowest tertile (hazard ratios, 0.826 [95% CI, 0.689-0.990] and 0.749 [95% CI, 0.585-0.958], respectively). Associations differed by dementia subtype: higher lifestyle scores were consistently associated with a lower risk of vascular dementia, whereas no overall association was observed with Alzheimer's disease. Higher lifestyle scores were also associated with larger total grey matter volume and greater volumes of subcortical structures, including caudate, pallidum, putamen, and thalamus, as well as lower volumes of total, deep, and periventricular white matter hyperintensities. Similar associations were observed in the low-risk group. A healthier lifestyle was associated with a lower risk of dementia, particularly vascular dementia, and with more favorable structural brain characteristics, with similar associations across KDIGO risk groups.},
}

Humans
*Dementia/epidemiology/pathology/diagnostic imaging/physiopathology
Female
Male
*Life Style
*Brain/pathology/diagnostic imaging
United Kingdom/epidemiology
Aged
Risk Factors
Magnetic Resonance Imaging
UK Biobank
Middle Aged
Gray Matter/pathology
Biological Specimen Banks

@article {pmid42371053,
year = {2026},
author = {Stipa, G and Colosimo, C and Vanacore, N},
title = {Neurodegenerative diseases and environmental risk factors: an overview of the available scientific evidence.},
journal = {Journal of neural transmission (Vienna, Austria : 1996)},
volume = {},
number = {},
pages = {},
pmid = {42371053},
issn = {1435-1463},
abstract = {Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) are among the most well-known and prevalent neurodegenerative disorders. These diseases result from an interaction between the environment and genetically predisposed individuals. This review examines the evidence available in the literature underlying this multifaceted interaction, focusing on various chemical substances such as metals, fertilizers, and herbicides, as well as toxic agents of microbiological origin, including cyanobacteria and their neurotoxins. In addition, the pathways through which toxic substances can enter the human body are discussed, such as air and water, which may lead to absorption through the lungs, the gastrointestinal tract, the skin, and mucosae. The routes by which neurotoxic substances gain access to the human body may help explain the increased risk of developing neurodegenerative diseases observed in sports played on soil and grass surfaces, such as soccer, American football, and golf.},
}

@article {pmid42371165,
year = {2026},
author = {Yosefi, S and Babaeizad, A and Tabibian, SS and Bahar, A and Eslami, M},
title = {The microbiota-mitochondria axis: linking metabolic dysfunction to neurodegeneration.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {42371165},
issn = {1573-7365},
mesh = {Humans ; *Neurodegenerative Diseases/metabolism/microbiology ; *Mitochondria/metabolism ; Animals ; *Gastrointestinal Microbiome/physiology ; Energy Metabolism/physiology ; Oxidative Stress/physiology ; *Metabolic Diseases/metabolism ; *Microbiota/physiology ; Dysbiosis/metabolism ; },
abstract = {The interplay between gut microbiota and mitochondria represents a dynamic relationship that profoundly impacts host physiology, ranging from maintaining intestinal homeostasis to regulating systemic metabolic and neurological functions. Microbial metabolites such as short-chain-fatty-acids, bile acids, and amino acid derivatives serve as pivotal modulators of mitochondrial bioenergetics, oxidative stress management, and fission-fusion processes. These interactions are vital for preserving epithelial integrity, supporting energy metabolism, shaping immune responses, and managing inflammatory signaling pathways. Disruptions within this microbiota-mitochondria axis are associated with various pathologies, including non-alcoholic fatty liver disease, obesity, type 2 diabetes, and chronic inflammatory conditions like inflammatory bowel disease. Additionally, growing evidence connects gut dysbiosis and mitochondrial dysfunction to neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease, highlighting the importance of this bidirectional relationship in maintaining neuronal health. On a mechanistic level, pathways involving AMPK, sirtuins, and PGC-1α govern mitochondrial biogenesis and adaptive responses to microbial signals. Dysregulation of these pathways can heighten oxidative stress, hinder mitophagy, and contribute to systemic inflammation. Emerging therapeutic strategies aim to target this axis through dietary modifications, probiotics and engineered microbes, FMT, and mitochondria-specific pharmacological treatments. These interventions focus on restoring metabolic stability, enhance resilience against oxidative damage, and slowing disease progression. By integrating insights from fields such as metabolism, immunology, and neuroscience, this review positions the microbiota-mitochondria axis as a critical area of focus in biomedical research. A deeper understanding of this communication network offers promising opportunities for precision therapies aimed at addressing metabolic, inflammatory, and neurodegenerative diseases.},
}

Humans
*Neurodegenerative Diseases/metabolism/microbiology
*Mitochondria/metabolism
Animals
*Gastrointestinal Microbiome/physiology
Energy Metabolism/physiology
Oxidative Stress/physiology
*Metabolic Diseases/metabolism
*Microbiota/physiology
Dysbiosis/metabolism

@article {pmid42371177,
year = {2026},
author = {Li, R and Zhang, T and Ren, D and Zhu, H and Xu, J and Xiao, L},
title = {Bushen Huoxue Acupuncture alleviates alzheimer's disease progression via the E3 ubiquitin ligase SMURF2‑mediated ubiquitination of LAPTM5.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {42371177},
issn = {1573-7365},
support = {2024JJ5544//Hunan Provincial Natural Science Foundation of China/ ; },
mesh = {Animals ; *Ubiquitin-Protein Ligases/metabolism ; *Alzheimer Disease/metabolism/therapy ; *Ubiquitination/physiology ; Mice ; Microglia/metabolism ; *Acupuncture Therapy/methods ; Disease Progression ; *Membrane Proteins/metabolism ; Male ; Humans ; },
abstract = {This study investigated the therapeutic potential and mechanism of Bushen Huoxue Acupuncture (BSHXA) against Alzheimer's disease (AD) using integrated in vivo and in vitro approaches. In eight-month-old SAMP8 mice, BSHXA treatment significantly improved cognitive performance, alleviated hippocampal neuronal damage and neuroinflammation, and downregulated LAPTM5 expression. Complementary in vitro experiments in lipopolysaccharide (LPS)-stimulated BV2 microglia demonstrated that LAPTM5 knockdown reduced apoptosis, pathological protein accumulation, and pro-inflammatory M1 polarization. Through bioinformatic prediction and Co-IP assays, SMURF2 was identified as an E3 ubiquitin ligase directly interacting with LAPTM5 and promoting its ubiquitin-dependent degradation. SMURF2 overexpression in vitro reproduced protective effects similar to LAPTM5 knockdown. Importantly, in vivo knockdown of SMURF2 abolished the therapeutic benefits of BSHXA. Collectively, these findings demonstrate that BSHXA ameliorates AD progression by upregulating SMURF2, which promotes the ubiquitination and subsequent degradation of LAPTM5, thereby suppressing microglial M1 polarization, inhibiting neuroinflammatory responses, and attenuating AD pathologies. The SMURF2-LAPTM5 axis is established as a key mechanistic pathway underlying the neuroprotective effects of BSHXA.},
}

Animals
*Ubiquitin-Protein Ligases/metabolism
*Alzheimer Disease/metabolism/therapy
*Ubiquitination/physiology
Mice
Microglia/metabolism
*Acupuncture Therapy/methods
Disease Progression
*Membrane Proteins/metabolism
Male
Humans

@article {pmid42371218,
year = {2026},
author = {Kurmi, S and Parab, SB and Godad, A and Waghmare, P and Doshi, G},
title = {Neuroprotective Effects of Tenoxicam and Phenethyl Isothiocyanate in an Aβ1-42-Induced Rat Model of Alzheimer's Disease: Modulation of NF-κB/NLRP3 Signaling and Redox Homeostasis.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42371218},
issn = {1559-1182},
mesh = {Animals ; Amyloid beta-Peptides/toxicity ; Male ; *Alzheimer Disease/drug therapy/metabolism/pathology ; *NF-kappa B/metabolism ; Rats, Wistar ; *Isothiocyanates/pharmacology/therapeutic use ; *Piroxicam/analogs & derivatives/pharmacology/therapeutic use ; *Signal Transduction/drug effects ; *Neuroprotective Agents/pharmacology/therapeutic use ; Disease Models, Animal ; Peptide Fragments/toxicity ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Oxidation-Reduction/drug effects ; *Homeostasis/drug effects ; Oxidative Stress/drug effects ; Rats ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, neuroinflammation, oxidative stress, and amyloid pathology, yet effective disease-modifying therapies remain limited. This study asked whether combined targeting of inflammatory and oxidative stress pathways could offer enhanced neuroprotection in an Aβ1-42-induced rat model of AD. Tenoxicam, an oxicam-class non-steroidal anti-inflammatory drug with COX-linked anti-inflammatory activity, and phenethyl isothiocyanate (PEITC), a natural compound known for antioxidant and Nrf2-activating properties, were selected on the basis of their complementary mechanisms; however, their combined potential in this model has not been sufficiently explored, providing the rationale for this hypothesis-driven investigation. Male Wistar rats were assigned to control, disease, standard, tenoxicam, PEITC, and combination treatment groups. Cognitive performance was evaluated using the Morris Water Maze, Y-maze, and Novel Object Recognition tests, while neuroinflammatory and oxidative stress markers, including NF-κB, NLRP3, IL-1β, Nrf2, catalase, and malondialdehyde, were assessed alongside histopathological examination of hippocampal integrity and molecular docking against COX-2, NF-κB, and NLRP3. Aβ1-42 administration induced significant cognitive impairment, neuroinflammation, oxidative stress, and neuronal damage. Tenoxicam and PEITC improved behavioral performance, reduced inflammatory signaling, restored antioxidant defenses, and preserved hippocampal architecture, with the combination showing the most pronounced effects. These findings provide preclinical evidence that dual modulation of inflammatory and redox pathways may represent a promising multi-target approach for AD and support further evaluation of this combinatorial strategy.},
}

Animals
Amyloid beta-Peptides/toxicity
Male
*Alzheimer Disease/drug therapy/metabolism/pathology
*NF-kappa B/metabolism
Rats, Wistar
*Isothiocyanates/pharmacology/therapeutic use
*Piroxicam/analogs & derivatives/pharmacology/therapeutic use
*Signal Transduction/drug effects
*Neuroprotective Agents/pharmacology/therapeutic use
Disease Models, Animal
Peptide Fragments/toxicity
*NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
Oxidation-Reduction/drug effects
*Homeostasis/drug effects
Oxidative Stress/drug effects
Rats

@article {pmid42371236,
year = {2026},
author = {Jin, J and Yang, Z and Kang, A and Zhao, Y and Cai, Z and Qiu, M and Song, W and Wu, Y},
title = {Calcium Overloading-Induced UBE2O Upregulation Alleviates Neuronal Apoptosis.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42371236},
issn = {1559-1182},
support = {82293642//National Natural Science Foundation of China/ ; 82271482//National Natural Science Foundation of China/ ; 2023ZY1018//Science and Technology Department of Zhejiang Province/ ; 2026C02A1148//Science and Technology Department of Zhejiang Province/ ; OJQDSP2022013//Oujiang Laboratory/ ; },
mesh = {*Apoptosis/drug effects ; *Neurons/metabolism/pathology/drug effects ; Animals ; *Up-Regulation/drug effects ; *Ubiquitin-Conjugating Enzymes/metabolism/genetics ; *Calcium/metabolism/toxicity ; Calcineurin/metabolism ; MEF2 Transcription Factors/metabolism ; Promoter Regions, Genetic/genetics ; Mice ; Calcineurin Inhibitors/pharmacology ; },
abstract = {Calcium overloading is implicated in the pathogenesis of Alzheimer's Disease (AD) via the activation of calcineurin signaling. Dysregulation of ubiquitin-conjugating enzyme E2 O (UBE2O), an E2-E3 hybrid enzyme, is involved in AD pathogenesis. However, the effect of calcium overloading-mediated calcineurin activation on UBE2O regulation and the role of UBE2O in calcium overloading-induced apoptosis remain elusive. In this study, we aimed to explore the effect of calcium overloading on UBE2O expression and underlying mechanisms, as well as its role in apoptosis. We found that calcium overloading increases the expression of UBE2O in both neuronal and non-neuronal cells, while calcineurin inhibitor alleviates this effect. Moreover, three functional binding sites of MEF2A, a downstream target of calcineurin, are identified within the promoter region of the UBE2O gene. MEF2A facilitates UBE2O promoter activity, as well as its expression at both mRNA and protein levels. Furthermore, increased UBE2O expression attenuates calcium overloading-induced neuronal apoptosis, while reduced UBE2O expression exacerbates calcium overloading-induced neuronal apoptosis. Moreover, neuron-specific overexpression of UBE2O reduced neuronal apoptosis in 5 × FAD mice. This study demonstrated that calcium overloading-induced UBE2O upregulation is mediated by calcineurin-MEF2A signaling pathway, which acts as a protective response to alleviate neuronal apoptosis. It indicates that UBE2O is a potential therapeutic target for neuronal protection in AD.},
}

*Apoptosis/drug effects
*Neurons/metabolism/pathology/drug effects
Animals
*Up-Regulation/drug effects
*Ubiquitin-Conjugating Enzymes/metabolism/genetics
*Calcium/metabolism/toxicity
Calcineurin/metabolism
MEF2 Transcription Factors/metabolism
Promoter Regions, Genetic/genetics
Mice
Calcineurin Inhibitors/pharmacology

@article {pmid42371345,
year = {2026},
author = {Zhang, R and Dong, X and Pei, G and Huang, S},
title = {Correction to: Engineered Alzheimer Organoids Validate the Link Between Intracellular and Soluble p-Tau Biomarkers and Highlight the Contribution of Astrocytic Tau.},
journal = {Neuroscience bulletin},
volume = {},
number = {},
pages = {},
doi = {10.1007/s12264-026-01663-w},
pmid = {42371345},
issn = {1995-8218},
}

@article {pmid42371384,
year = {2026},
author = {Khalifa, MM and Ibrahim, HAM and Gad, ME and Hassan, IAI and Elshanawany, SA and Mogy, SAE and Fatah, AILAE},
title = {Multifunctional in Vitro Biological Activities of Mixed Light Rare Earth Oxides: Antioxidant, Enzyme Inhibitory and Cytotoxic Potential.},
journal = {Biological trace element research},
volume = {},
number = {},
pages = {},
pmid = {42371384},
issn = {1559-0720},
abstract = {Light rare earth oxides (LREEs), such as cerium, lanthanum, neodymium, and praseodymium oxides, have unique redox and catalytic properties that may contribute to various therapeutic effects. Researchers in this study looked at LREEs' in vitro antioxidant, anti-diabetic, anti-Alzheimer's, anti-arthritic, and cytotoxic effects. The antioxidant potential was evaluated using Diphenyl-2-picryl-hydrazyl (DPPH), 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), nitric oxide (NO), hydroxyl (OH), and hydrogen peroxide (H2O2) radical scavenging assays, showing a moderate inhibitory effect compared to ascorbic acid. Enzyme inhibition assays indicated weak AChE inhibition, suggesting limited anti-Alzheimer's disease potential. Moderate anti-arthritic effects were observed through inhibition of protein denaturation and proteinase activity. In anti-diabetic assays, LREEs dose-dependently inhibited α-amylase and α-glucosidase, although less potent than acarbose. Cytotoxicity testing on HepG2 cancer cells showed an IC50 of 281.80 µg/mL, significantly higher than doxorubicin (34.07 µg/mL), indicating weak anticancer potential. Elevated Caspase-3 levels and diminished Bcl-2 levels indicate the initiation of apoptosis. These results indicate that LREEs oxide exhibits adequate biological activity, warranting further exploration of its mechanisms and potential biomedical applications. The investigated material was evaluated as a mixed light rare earth oxide system to obtain an integrated biological response profile rather than to determine the contribution of individual oxide components. Therefore, the present findings represent system-level biological behaviour and serve as a foundation for more detailed component-specific investigations. The investigated material was evaluated as a mixed light rare earth oxide system to obtain an integrated biological response profile rather than to determine the contribution of individual oxide components. Therefore, the present findings represent system-level biological behaviour and serve as a foundation for more detailed component-specific investigations.},
}

@article {pmid42371653,
year = {2026},
author = {Rosen-Lang, Y and Vrillon, A and Pasternak, S and Blazhenets, G and Soleimani-Meigooni, DN and Rabinovici, GD and Weiner, MW and Hantke, N and Silbert, LC and Schwartz, DL and Livny-Ezer, A and Lesman-Segev, O and Ganmore, I and Ravona-Springer, R and Yaffe, K and Landau, SM and Korecka, M and Shaw, LM and La Joie, R and Gardner, RC and , },
title = {Prior Traumatic Brain Injury and Alzheimer Disease Blood Biomarkers.},
journal = {JAMA neurology},
volume = {},
number = {},
pages = {1-11},
doi = {10.1001/jamaneurol.2026.2042},
pmid = {42371653},
issn = {2168-6157},
abstract = {IMPORTANCE: Traumatic brain injury (TBI) is a risk factor for dementia and is known to impact levels of several Alzheimer disease (AD) blood biomarkers. The plasma phosphorylated tau 217 (p-tau217)/amyloid-β 42 (Aβ42) ratio has been reported to be 90% accurate for the detection of brain amyloid in civilian cohorts.

OBJECTIVE: To evaluate the accuracy of emerging AD blood biomarkers in veterans with and without a TBI history.

This cross-sectional cohort study of a diagnostic test assessed the performance of the US Food and Drug Administration-approved plasma p-tau217/Aβ42 ratio and plasma levels of p-tau217 and Aβ42/40 ratio for detecting brain Aβ positivity (eg, amyloid-positron emission tomography [PET] consensus visual read). The accuracy of biomarkers was compared in veterans without TBI, those with TBI with loss of consciousness (LOC) for 0 to 5 minutes, and those with TBI with LOC for greater than 5 minutes. Existing data and banked plasma from the Alzheimer Disease Neuroimaging Initiative Department of Defense (ADNI-DOD) study were used. Years of enrollment were 2013 to 2020. Included in this study were Vietnam War veterans without dementia (cognitively unimpaired and those with mild cognitive impairment) who had amyloid-PET and concurrently collected banked plasma available for analysis. Plasma biomarker analysis took place from 2024 to 2025, and data analysis was performed from July 2025 to February 2026.

EXPOSURES: AD blood biomarkers and TBI history.

MAIN OUTCOMES AND MEASURES: p-Tau217/Aβ42 accuracy in the detection of amyloid-PET consensus visual read positivity across groups with/without TBI exposure.

RESULTS: In 272 participants, mean (SD) age was 70 (4.5) years, 270 were male (99.3%), and 83 (30.5%) were amyloid-PET positive. The plasma p-tau217/Aβ42 ratio was highly accurate in veterans with no TBI (90%; 95% CI, 84%-96%) but not in veterans with TBI with LOC for 0 to 5 minutes (78% accuracy; 95% CI, 69%-87%; P = .03 vs no TBI), nor in veterans with TBI with LOC greater than 5 minutes (63% accuracy; 95% CI, 53%-73%; P < .001 vs no TBI). Results were similar for plasma p-tau217 alone and plasma Aβ42/40 ratio. Results were also similar after excluding veterans with TBI within the past 10 years or when amyloid-PET positivity was defined using a quantitative threshold rather than consensus visual read.

CONCLUSIONS AND RELEVANCE: Results of this cross-sectional cohort study of a diagnostic test suggest that among individuals who are cognitively unimpaired or have mild cognitive impairment and a TBI history, the p-tau217/Aβ42 ratio test may miss over half of amyloid-PET-positive cases. Caution is advised in interpreting AD blood test results in this context.},
}

@article {pmid42371955,
year = {2026},
author = {Andrade-Guerrero, J and Meda-Hernández, A and Sasia-Saldivar, V and Díaz-Miranda, SY and Soto-Rojas, LO},
title = {A Low-Cost Markerless DeepLabCut-Based Workflow for Spontaneous Gait and Locomotion Analysis in Freely Moving Mice.},
journal = {Journal of visualized experiments : JoVE},
volume = {},
number = {232},
pages = {},
doi = {10.3791/70845},
pmid = {42371955},
issn = {1940-087X},
mesh = {Animals ; Mice ; *Locomotion/physiology ; *Gait Analysis/methods ; Mice, Transgenic ; *Gait/physiology ; *Software ; Alzheimer Disease/physiopathology ; Workflow ; Disease Models, Animal ; Motion Capture ; Video Recording/methods ; },
abstract = {Gait is a widely used functional biomarker for detecting motor alterations across various diseases and conditions, as it reflects changes in coordination, strength, balance, and sensorimotor integration. However, traditional methods to analyze gait in animal models often require expensive equipment, complex setups, or invasive procedures that can alter natural behavior. Here, we present a low-cost, markerless workflow based on DeepLabCut, an open-source pose estimation software, for the quantitative analysis of gait and spontaneous locomotion in freely moving mice. The method relies on single-camera video acquisition, markerless tracking of anatomical landmarks, and extraction of spatiotemporal locomotor parameters, without the need for physical markers or specialized hardware. To demonstrate the protocol's applicability, it was implemented in the triple transgenic mouse model of Alzheimer's disease (3xTg-AD) as a representative example of application. This approach preserves free movement and minimizes handling-related stress, enabling non-invasive assessment of motor behavior. The protocol is compatible with standard behavioral testing environments. Overall, this method provides an accessible and non-invasive framework for quantitative analysis of gait and locomotion in preclinical research.},
}

Animals
Mice
*Locomotion/physiology
*Gait Analysis/methods
Mice, Transgenic
*Gait/physiology
*Software
Alzheimer Disease/physiopathology
Workflow
Disease Models, Animal
Motion Capture
Video Recording/methods

@article {pmid42371968,
year = {2026},
author = {Cholerton, B and Godrich, D and Pasteris, J and Rivero, J and Martin, ER and Kunkle, BW and Naj, AC and Hamilton-Nelson, KL and Wang, H and Lee, WP and Dumitrescu, L and Hohman, TJ and Mayeux, R and Larson, EB and Crane, PK and Keene, CD and Latimer, CS and Mukherjee, S and Kofler, JK and Kamboh, MI and Bennett, DA and Molina-Porcel, L and Cuccaro, M and Pericak-Vance, MA and Rundek, T and Scott, WK and Kukull, W and Schellenberg, G and , and Beecham, GW and Montine, TJ},
title = {Genome wide association study meta-analysis of neuropathologic lesions of Alzheimer's disease and related dementias in a multi-site autopsy cohort.},
journal = {PLoS genetics},
volume = {22},
number = {6},
pages = {e1012170},
doi = {10.1371/journal.pgen.1012170},
pmid = {42371968},
issn = {1553-7404},
abstract = {Understanding the genetic foundations of dementia is critical to unraveling its complex molecular basis. Given that a clinical diagnosis of Alzheimer's disease (AD) dementia often results from interplay between multiple underlying neuropathologic co-morbidities, previous genome-wide association studies (GWAS) of clinically diagnosed AD are restricted in their ability to translate genetic associations to potential targeted therapeutics. The current study seeks to address these limitations by presenting the largest GWAS to date (n = 12,509) of neuropathologic hallmarks of AD and AD related dementias (ADRDs). We further performed a candidate-variant analysis using loci previously identified in GWAS of clinically diagnosed AD dementia and Parkinson's disease (PD). Finally, we conducted heritability and genetic correlation analyses using linkage disequilibrium (LD) score regression. We found broad genome-wide significant associations with APOE across AD and ADRDs but not cerebrovascular disease and vascular brain injury. We further identified 12 significant loci across 10 neuropathologic phenotypes, including 5 loci previously implicated in GWAS of clinical AD and ADRDs (variants on BIN1, PICALM/ EED, TMEM106B, GRN, and SNCA/ SNCA-AS1) and 7 novel genome-wide associations (variants on EPHA5, PSMG1, LINC00276, VAPA, LINC00290, DOCK4 and SLAIN2/ SLC10A4). Our analysis of AD and PD clinical candidate variants demonstrated several that were associated with AD neuropathologic change and Lewy body disease, as well as substantial overlap with neuropathologic lesions other than the primary neuropathologic hallmarks of these diseases. Heritability analyses demonstrated heritability that was high for amyloid plaques (78%) relative to prior clinical AD heritability analyses, intermediate for TDP-43 inclusions (41%), and low for remaining AD and ADRD pathologic features. This study underscores the importance of investigating the underlying neuropathologic hallmarks of AD and ADRDs as a step toward refining the translation of genetic associations to biomarker interpretation and development of targeted therapeutics.},
}

@article {pmid42372231,
year = {2026},
author = {Zhang, ZY and Wang, XM and Ma, X and Wang, Y and Wang, SD and Peng, YL and Cheng, K and Shen, YR and Tang, GZ and Wang, CW and Zhou, JN},
title = {Staging of Neuropil Morphological Alterations in Alzheimer's Disease.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2026.0213},
pmid = {42372231},
issn = {2152-5250},
abstract = {Alzheimer's disease (AD) involves the progressive fragmentation of neural connectivity. This study aims to investigate the morphological degeneration of neuropil fibers in AD and evaluate their utility as a marker for pathological severity. Post-mortem brain tissues from 92 cases across eight distinct regions were analyzed. We used Bielschowsky silver staining with automated quantitative morphometry to measure neuritic fiber length and curvature in the neuropil, and immunofluorescence to detect neurite cytoskeletal markers. Finally, a novel histological staging system for neuropil disruption was established to assess disease progression. Morphometric analysis revealed progressive reductions in neuritic fiber length and increased curvature tracking with disease severity, a significant negative correlation confirmed these are coupled degenerative manifestations. Immunofluorescence demonstrated extensive cytoskeletal fragmentation that corresponded to the pattern observed with silver staining. Based on morphometric analysis, a novel four-tier staging system was established, defined neuropil by homogeneous compactness (-), initial (+), extensive (++) disruption, and complete fragmentation (+++), which correlated preferentially with Phospho-Tau load. Crucially, subtle neuropil alterations were detectable in the entorhinal cortex, amygdala, and anterior hippocampus even in Braak 0 stage, suggesting a potential association between these early changes and the initial stages of tau pathogenesis. This study establishes a staging system for assessing neuropil degeneration, demonstrating that neuropil fragmentation and geometric distortion are candidate AD pathological markers. By systematically analyzing neuritic fiber morphology and proposing a neuropil disruption stage, this work provides critical insights into early AD pathogenesis, offering a foundation for future diagnostic strategies pending validation in independent cohorts with clinical correlations.},
}

@article {pmid42363806,
year = {2026},
author = {Kawabe, N and Hosoki, S and Watanabe, C and Maekawa, K and Fukushima, H and Matsuishi, K and Iwata, K and Kohara, N and Kawamoto, M},
title = {Logical memory is associated with amyloid-β positivity in patients with early Alzheimer's disease eligible for lecanemab.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261462928},
doi = {10.1177/13872877261462928},
pmid = {42363806},
issn = {1875-8908},
abstract = {BackgroundLecanemab is an anti-amyloid monoclonal antibody, approved for early Alzheimer's disease (AD), with evidence indicating greater benefit at earlier stages. Sensitive cognitive measures are needed to identify underlying amyloid pathology.ObjectiveTo investigate whether the Logical Memory (LM) subtest of the Wechsler Memory Scale-Revised (WMS-R) can help characterize amyloid positivity in lecanemab-eligible individuals.MethodsWe retrospectively analyzed 91 individuals who attended our center between December 2023 and March 2025; 45 met eligibility criteria (Mini-Mental State Examination ≥ 22, Clinical Dementia Rating 0.5 or 1.0, magnetic resonance imaging compatibility). Amyloid status was determined by positron emission tomography, classified as amyloid-positive (Aβ+, n = 35) or amyloid-negative (Aβ-, n = 10). All participants underwent neuropsychological assessment, including LM. Groups were compared, and LM Aβ status discrimination was evaluated using receiver operating characteristic analyses and multivariable logistic regression.ResultsGroups did not differ in age, sex, or education. LM immediate (LMIR) and delayed recall (LMDR) scores were lower in the Aβ+ group (LMIR median: 5.0 versus 9.0, p = 0.011; LMDR: 0.5 versus 3.0, p = 0.017). Receiver operating characteristic analyses identified cutoffs of 7.5 for LMIR (area under the curve [AUC]: 0.79, sensitivity: 79%, specificity: 77%) and 1.5 for LMDR (AUC: 0.76, sensitivity: 75%, specificity: 77%). Lower LM scores were associated with increasing amyloid positivity. Logistic regression showed significant associations for both LMIR and LMDR (odds ratio: 0.80 and 0.64, 95% confidence interval: 0.64-0.95 and 0.38-0.91, respectively).ConclusionsWMS-R LM scores were significantly associated with amyloid-β accumulation in individuals with early AD meeting lecanemab eligibility criteria.},
}

@article {pmid42363808,
year = {2026},
author = {Shaw, JS and Bray, MJC and Sair, HI and Luna, LP and Hunzinger, KJ and Oh, ES and Rosenberg, PB and Peters, ME},
title = {Relationship between new-onset falls and neuroimaging markers of Alzheimer's disease in the UK Biobank.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261462930},
doi = {10.1177/13872877261462930},
pmid = {42363808},
issn = {1875-8908},
abstract = {BackgroundWhile Alzheimer's disease (AD) is a known risk factor for falls, the association between falls and incident AD is a growing area of study.ObjectiveThe primary aim of this analysis was to examine associations between new-onset falls in older adults and neuroimaging and plasma biomarkers of AD. A secondary aim was to evaluate associations between new-onset falls and neuroimaging markers of motor dysfunction.MethodsData from the UK Biobank study was utilized. Participants were 70 years of age or older at the date of neuroimaging and had no reported history of falls at study enrollment. To determine falls status, participants self-reported data on falls history within the last year prior to neuroimaging.Results15,447 individuals were included in our analysis (No falls, N = 12,522; One fall, N = 2,199, Multiple falls, N = 726). Compared to individuals in the No falls group, individuals in the One fall and Multiple falls group had significantly higher volumes of white matter hyperintensities, while individuals in the Multiple falls group had significantly lower left and right hippocampal volumes. One or more fall was associated with higher plasma levels of pTau181, which did not remain significant after adjusting for multiple comparisons. Plasma amyloid-β 42/amyloid-β 40 ratio did not differ significantly between groups.ConclusionsIn a sample of older adults without history of falls at study enrollment, new-onset falls were associated with decreased hippocampal volumes, which is associated with prodromal AD, as well as an increased volume of white matter hyperintensities, which may also emerge secondary to AD pathology.},
}

@article {pmid42363810,
year = {2026},
author = {Sato, K and Niimi, Y and Ihara, R and Suzuki, K and Iwata, A and Iwatsubo, T},
title = {Potential and biases of large language model simulation for public surveys on Alzheimer's disease therapies.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261464182},
doi = {10.1177/13872877261464182},
pmid = {42363810},
issn = {1875-8908},
abstract = {BackgroundWhile large language models (LLMs) have a potential to simulate public-opinion, their reliability for sensitive medical topics like novel Alzheimer's disease (AD) treatments remains unclear.ObjectiveThis study compared LLM-generated and human answers on AD-therapy dilemmas; assessed model and prompting parameter influences; and identified demographic bias.MethodsUsing survey data on late 2023 from 1671 Japanese Trial Ready Cohort Webstudy participants who are presumably cognitively unimpaired, LLM persona profiles guided four LLMs (Gemini-1.5-flash, Gemini-2.0-flash, GPT-4.1-mini, GPT-4o-mini). The models answered a binary question about acceptance towards patient-prioritization or a 5-point Likert question on concern about amyloid-related imaging abnormalities (ARIA) under varied prompt settings. Aggregate similarity was measured with Jensen-Shannon Divergence (JSD) for binary and Earth Mover's Distance (EMD) for Likert scale; while individual agreement used Cohen's κ and Spearman's ρ.ResultsWhile some LLM models achieved fair group-level agreement in both tasks (JSD ≤ 0.05, EMD < 1.0), individual agreement was negligible across any LLM settings (κ, ρ ≈ 0). Adding detailed attributes like living condition, clinical status, or related personal opinions offered limited improvement. Performance was largely stable for most demographic levels, but deteriorated for minority subgroups, such as those with low education or requiring long-term care.ConclusionsOur study demonstrates that current LLMs can approximate aggregate attitudes toward novel AD therapies but cannot predict individual opinions. They can amplify biases in some small subgroups. LLMs may be useful for pre-testing public survey in the field of AD/dementia treatment but should not replace authentic human data.},
}

@article {pmid42363811,
year = {2026},
author = {Hao, L and Xing, Y and Han, Y},
title = {An application study: 21-item Subjective Cognitive Decline Questionnaire in detecting mild cognitive impairment.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261463667},
doi = {10.1177/13872877261463667},
pmid = {42363811},
issn = {1875-8908},
abstract = {BackgroundSubjective cognitive decline (SCD) is a common early complaint in mild cognitive impairment (MCI). Evidence for the 21-item SCD-Questionnaire (SCD-Q21) to discriminate MCI from normal controls (NCs) is limited.ObjectiveTo investigate the discrimination performance of Chinese SCD-Q21 and compare it with SCD-Q9 for community-based MCI early detection, assess the added value of simple covariates, and determine an optimal SCD-Q21 cut-off.Methods294 NCs and 83 people with MCI were assessed and collected demographic and clinical data. Participants completed SCD-Q21, SCD-Q9, Hamilton Anxiety Scale (HAMA) and Hamilton Depression Scale (HAMD) scale; clinical adjudication used Montreal Cognitive Assessment-Basic, Clinical Dementia Rating, and Activities of Daily Living. Group comparison, logistic regression and ROC analyses were applied. Optimal cut-offs were derived using the Youden index and AUCs were compared using DeLong tests. Within-MCI analyses contrasted screen-positive versus screen-negative subgroups.ResultsTotal SCD-Q21 scores were higher in MCI, although five items [question 1 (Q1), Q2, Q3, Q11, and Q17] did not differ between groups. In multivariable binary logistic regression models, lower education (OR = 0.786), higher body mass index (BMI) (OR = 17.874), and higher SCD-Q21 total scores (OR = 1.114) were independently associated with MCI, whereas SCD-Q9 was not. Standalone AUCs were 0.662 (SCD-Q21) and 0.640 (SCD-Q9). Combing age, sex, education, BMI, and HAMA/HAMD with SCD instrument yielded AUC ∼0.91. SCD-Q21 ≥ 7 gave 69.88% sensitivity and 62.93% specificity. Screen-negative MCI cases showed lower vascular/metabolic comorbidity and lower HAMA/HAMD scores.ConclusionsSCD-Q21 provides independent information but modest stand-alone discrimination. As part of a brief multivariable triage including education, BMI, vascular risk review, and anxiety rating, it supports efficient case-finding in community settings.},
}

@article {pmid42363912,
year = {2026},
author = {Zhou, S and Lee, T and Ji, X and Mackenzie, KR and Li, F},
title = {Characterizing the Reactive Metabolites of Colony-Stimulating Factor 1 Receptor Inhibitor PLX5622 in Liver Microsomes and Mice.},
journal = {Chemical research in toxicology},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.chemrestox.6c00282},
pmid = {42363912},
issn = {1520-5010},
abstract = {Colony-stimulating factor 1 receptor (CSF1R) is a receptor tyrosine kinase involved in cell growth and differentiation, particularly in macrophages and microglia. CSF1R inhibitors are under investigation for various diseases, including cancer, autoimmune/inflammatory diseases, and neurodegenerative disorders. PLX5622 is a highly specific, brain-penetrant, and orally bioavailable CSF1R inhibitor that is being evaluated in a clinical trial for rheumatoid arthritis and considered as an attractive candidate for the treatment of Alzheimer's disease (AD). Drug metabolism significantly influences both the efficacy and safety of therapeutic agents. In particular, bioactivation leading to the formation of reactive metabolites is often implicated in adverse drug effects. In this study, we investigated the metabolism and potential bioactivation of PLX5622 in mouse and human liver microsomes (MLM/HLM) and mice using LC-MS-based metabolomic approaches. Reduced glutathione (GSH) and methoxyamine (NH2OMe) were used to capture reactive intermediates. In total, 12 PLX5622-GSH adducts and five NH2OMe adducts were identified in both HLM and MLM, along with 22 nontrapped metabolites generated from demethylation, hydroxylation, and carbon-carbon cleavage reactions. PLX5622-GSH-related adducts in mice were also assessed and 8 GSH adducts were detected in mouse liver, confirming the occurrence of bioactivation in vivo. Using recombinant human cytochrome P450 (CYP) enzymes and selective chemical inhibitors in liver microsomes, CYP3A was determined to be the primary enzyme responsible for the metabolic activation of PLX5622. These insights into the metabolic pathways of PLX5622 are valuable for further study of its safety and potential drug interactions of CYP3A. Future studies using human primary hepatocytes or physiologically human-relevant models such as liver-on-a-chip systems are warranted to confirm clinical relevance and better predict in vivo outcomes.},
}

@article {pmid42363914,
year = {2026},
author = {Irklı, EB and Selvi-Balo, S},
title = {Preliminary insights into language impairments across the stages of Alzheimer's disease in Turkish-speaking adults.},
journal = {Applied neuropsychology. Adult},
volume = {},
number = {},
pages = {1-11},
doi = {10.1080/23279095.2026.2691093},
pmid = {42363914},
issn = {2327-9109},
abstract = {The present study aims to examine the language impairments observed across various stages of Alzheimer's Disease (AD) in Turkish-speaking individuals. The study involved 24 participants diagnosed with AD (12 women, 12 men; mean age = 82.00 ± 6.75) and a control group of 24 healthy adults (12 women, 12 men; mean age = 80.71 ± 8.61). All participants completed the Test Your Memory-Turkish (TYM-TR) and the Aphasia Language Assessment Test (ADD). Data analysis was conducted using SPSS 24 software with descriptive statistics, Spearman's correlation coefficient, and the Mann-Whitney U test. Participants with AD scored lower on the TYM-TR and ADD than healthy participants. A strong positive correlation was observed between scores on the TYM-TR and ADD tests in both participant groups. The test scores decreased as AD stages progressed. This study provides a framework for SLTs to identify AD stages and tailor language interventions accordingly.},
}

@article {pmid42363974,
year = {2026},
author = {Luo, J and Wu, X and Jiang, D and He, G and Du, Y},
title = {HDAC3 in Alzheimer's Disease: established evidence, unresolved questions, and translational priorities.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42363974},
issn = {1573-4978},
support = {82371203//National Natural Science Foundation of China/ ; 82371194//National Natural Science Foundation of China/ ; CSTB2024NSCQ-QCXMX0004 and 2022NSCQ-LZX0010//Natural Science Foundation of Chongqing/ ; },
mesh = {Humans ; *Alzheimer Disease/metabolism/genetics/pathology/drug therapy ; *Histone Deacetylases/metabolism/genetics ; Histone Deacetylase 3 ; Animals ; Amyloid beta-Peptides/metabolism ; Brain/metabolism/pathology ; Histone Deacetylase Inhibitors/pharmacology/therapeutic use ; tau Proteins/metabolism ; },
abstract = {Histone deacetylase 3 (HDAC3) is increasingly implicated in Alzheimer's disease (AD), yet its precise pathogenic role and therapeutic value remain unresolved. This mini-review critically examines the current evidence for HDAC3 in AD, with a focus on what is established, what remains uncertain, and what is needed for translation. We review the data linking HDAC3 to amyloid-β (Aβ) accumulation, Tau pathology, neuroinflammation, and synaptic dysfunction, while highlighting key limitations in the field, including weak causal evidence, inconsistent cell type-specific findings, insufficient human brain validation, and the lack of proof that HDAC3 serves as a central mechanistic node across AD-related pathways. We also discuss major translational challenges, including poor inhibitor selectivity, uncertain brain penetrance, potential safety concerns, and the absence of standardized preclinical benchmarks. We propose that future progress will require human evidence, cell type-specific causal studies, integrated mechanistic models, and more rigorous pharmacological validation. Together, these considerations define a clearer roadmap for evaluating HDAC3 as a biologically credible and clinically actionable target in AD.},
}

Humans
*Alzheimer Disease/metabolism/genetics/pathology/drug therapy
*Histone Deacetylases/metabolism/genetics
Histone Deacetylase 3
Animals
Amyloid beta-Peptides/metabolism
Brain/metabolism/pathology
Histone Deacetylase Inhibitors/pharmacology/therapeutic use
tau Proteins/metabolism

@article {pmid42364023,
year = {2026},
author = {Ebrahimbabaei, A and Hekmat, AS and Javanmardi, K},
title = {Neurotherapeutic roles of the protective arm of the renin-angiotensin system: from inflammation to cognitive rescue.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42364023},
issn = {1573-4978},
mesh = {Humans ; *Renin-Angiotensin System/drug effects/physiology ; Animals ; *Inflammation/metabolism ; Proto-Oncogene Mas ; Angiotensin-Converting Enzyme 2/metabolism ; Receptor, Angiotensin, Type 2/metabolism ; Receptors, G-Protein-Coupled/metabolism ; *Cognition/drug effects/physiology ; Signal Transduction ; Angiotensin I/metabolism ; Peptide Fragments/metabolism ; Peptidyl-Dipeptidase A/metabolism ; Neuroinflammatory Diseases/metabolism ; Proto-Oncogene Proteins/metabolism ; Blood-Brain Barrier/metabolism ; Brain/metabolism ; Oxidative Stress ; Oligopeptides ; },
abstract = {The renin-angiotensin system (RAS), traditionally recognized for its role in regulating blood pressure and fluid homeostasis, is increasingly understood to exert important effects across multiple organ systems, including the central nervous system (CNS). A local brain RAS contributes to neurovascular regulation, inflammation, oxidative stress, synaptic plasticity, and cognitive function. This review critically summarizes the neurotherapeutic relevance of the protective RAS arm, particularly the angiotensin-converting enzyme 2 (ACE2)-angiotensin-(1-7)-Mas receptor axis, the angiotensin II type 2 receptor (AT2R), and the alamandine/Mas-related G protein-coupled receptor D (MrgD) pathway. Experimental evidence suggests that these pathways may counterbalance angiotensin II type 1 receptor signaling by reducing neuroinflammation, oxidative injury, vascular dysfunction, and neuronal loss in models of ischemic stroke, Alzheimer's disease, Parkinson's disease, and multiple sclerosis. The strongest evidence remains preclinical, with most data derived from cell culture and animal models, whereas human evidence is still indirect and largely based on observational or early translational studies of RAS-modifying drugs. Important uncertainties remain regarding blood-brain barrier penetration, receptor-specific signaling, disease-stage dependency, systemic vascular effects, and reproducibility across models. Therefore, protective RAS signaling should be considered a promising but still exploratory therapeutic framework rather than an established treatment strategy for neurological disease. Future work should prioritize selective brain-penetrant agonists, validated biomarkers of central RAS activity, and rigorously designed clinical trials to determine whether modulation of ACE2-angiotensin-(1-7)-Mas, AT2R, or alamandine/MrgD signaling can produce clinically meaningful neuroprotection.},
}

Humans
*Renin-Angiotensin System/drug effects/physiology
Animals
*Inflammation/metabolism
Proto-Oncogene Mas
Angiotensin-Converting Enzyme 2/metabolism
Receptor, Angiotensin, Type 2/metabolism
Receptors, G-Protein-Coupled/metabolism
*Cognition/drug effects/physiology
Signal Transduction
Angiotensin I/metabolism
Peptide Fragments/metabolism
Peptidyl-Dipeptidase A/metabolism
Neuroinflammatory Diseases/metabolism
Proto-Oncogene Proteins/metabolism
Blood-Brain Barrier/metabolism
Brain/metabolism
Oxidative Stress
Oligopeptides

@article {pmid42364272,
year = {2026},
author = {Cawthray, J},
title = {From PET to targeted radionuclide therapy in the Brain: The emerging role of radiometal-based platforms.},
journal = {Journal of inorganic biochemistry},
volume = {283},
number = {},
pages = {113397},
doi = {10.1016/j.jinorgbio.2026.113397},
pmid = {42364272},
issn = {1873-3344},
abstract = {Radiometal-based radiopharmaceuticals have become central to the advancement of molecular imaging and targeted radionuclide therapy, offering powerful tools for the diagnosis and treatment of diseases affecting the brain. The unique chemical versatility of radiometals - encompassing a broad range of coordination chemistries, physical half-lives, and emission properties - combined with an expanding repertoire of targeting biomolecules enables highly tunable and increasingly modular imaging and therapeutic platforms. In particular, positron emission tomography (PET) using radiometal-labelled tracers provides sensitive, quantitative, and non-invasive assessment of molecular processes in vivo, while radiometal-based therapeutic agents enable the selective delivery of cytotoxic radiation to diseased tissue. This review examines recent progress in the application of radiometal-based radiopharmaceuticals for brain disorders, with a focus on neuro-oncology - including primary brain tumours and brain metastases - as well as neurodegenerative diseases such as Alzheimer's disease and Parkinsons disease. Key challenges unique to brain applications are discussed, including the restrictive nature of the blood-brain barrier, heterogeneous target expression, and off-target biodistribution. Recent advances in chelator development, emerging antigen targets, alternative routes of administration, and strategies to improve brain delivery are highlighted. While imaging agents continue to lead therapeutic development in this space, reflecting the need for accurate disease characterisation, recent progress underscores the potential of radiometal-based therapies for brain disease. In particular, immunoPET has emerged as a powerful tool for evaluating target expression, biodistribution, and treatment response. Collectively, these developments position radiometal-based radiopharmaceuticals as a promising and evolving platform enabling personalised treatment strategies for neurological disorders.},
}

@article {pmid42361864,
year = {2026},
author = {Galushkin, A and Giladi, E and Gozes, I},
title = {Aging ADNP syndrome mice exhibit mutation/sex-dependent disruption of motor behavior and circadian rhythmicity.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107509},
doi = {10.1016/j.nbd.2026.107509},
pmid = {42361864},
issn = {1095-953X},
abstract = {Circadian disruption is an early and clinically relevant feature of Alzheimer's disease and related neurodegenerative conditions, yet the molecular determinants underlying its emergence remain incompletely understood. Activity-dependent neuroprotective protein (ADNP) is a key regulator of neurodevelopment and neuroprotection, with de novo mutations driving the neurodevelopmental ADNP syndrome tauopathy and with somatic mutations implicated in tauopathy and neurodegeneration in Alzheimer's disease, but its role in circadian system function has not been systematically explored. Here, with Alzheimer's disease being twice as prevalent in women, we performed a comprehensive characterization of circadian locomotor activity, explicitly considering sex as a biological variable in aged mouse models of ADNP disruption, representing two key phenotypes of the syndrome. Using recordings of voluntary wheel-running activity combined with cosinor-based rhythmometry, we quantified parameters of circadian organization, including activity levels, timing, and rhythm integrity. We demonstrate that ADNP haploinsufficiency with late tau deposition was associated with impaired circadian organization in a strongly sex-dependent manner. In Adnp[+/-] mice, circadian alterations diverged between sexes: males exhibited a pronounced reduction in overall activity levels and rhythmic output, whereas females showed alterations in circadian timing (phase shift), and increased waveform complexity, indicative of fragmented activity patterns. Notably, reduced rhythm robustness was observed in both sexes, pointing to impaired stability of circadian output. In contrast to Adnp[+/-] mice, mice carrying a heterozygous Adnp p.Tyr718* mutation (with early tauopathy) exhibited marked vulnerability only under a circadian challenge paradigm. This was characterized by a high incidence of arrhythmicity based on cosinor-based zero-amplitude testing, with a particularly severe phenotype in a small exploratory cohort of males, in which all examined Tyr718* mice failed to exhibit detectable circadian rhythmicity. Importantly, the study was conducted in aged mice, a context relevant to age-associated neurodegenerative vulnerability. These findings position ADNP as a contributor to circadian system stability and highlight its associated signaling pathways as candidate targets for future mechanistic and therapeutic investigation.},
}

@article {pmid42361954,
year = {2026},
author = {Roy, KK and Mehta, DK and Das, R},
title = {Pregnancy and Alzheimer's disease: Understanding maternal and neonatal neurological risks.},
journal = {Progress in neuro-psychopharmacology & biological psychiatry},
volume = {},
number = {},
pages = {111808},
doi = {10.1016/j.pnpbp.2026.111808},
pmid = {42361954},
issn = {1878-4216},
abstract = {Alzheimer's disease (AD) is the foremost cause of dementia globally, marked by progressive neurological decline and cognitive impairment. Risk arises from complex interactions between genetic and environmental factors. This review examines how prenatal health influences long-term brain outcomes in both mothers and offspring. Pregnancy triggers significant hormonal, immunological, and physiological changes that support fetal development but also increase the risk of complications such as gestational diabetes and preeclampsia. These conditions promote chronic inflammation, vascular dysfunction, and brain alterations associated with AD and vascular dementia. Maternal cardiovascular and metabolic health critically affect neurodevelopment and cognitive aging across generations. Postpartum hormones, notably progesterone and estrogen, provide neuroprotective and anti-inflammatory effects that may mitigate neurodegeneration. Additionally, reproductive factors including parity and reproductive lifespan modulate women's risk of AD. The immune adaptations and inflammatory processes during pregnancy further contribute to neurodegenerative pathways. This review highlights the importance of optimizing maternal health, implementing early detection of cognitive risks, and fostering interdisciplinary collaboration to improve outcomes. Integrating obstetric, neurological, and psychiatric care can enhance prevention and management strategies. Ultimately, these insights underscore the need for public health initiatives targeting maternal and offspring brain health to reduce the burden of neurological diseases over the lifespan.},
}