@article {pmid42508312,
year = {2026},
author = {Peng, M and Shao, L and Zhai, J and Yao, Y and Mei, X and Zhu, S},
title = {Simultaneous and ultrasensitive detection of Alzheimer's disease blood biomarkers using magnetic SERS-encoded tags-based LFIA assay.},
journal = {Talanta},
volume = {312},
number = {Pt A},
pages = {130348},
doi = {10.1016/j.talanta.2026.130348},
pmid = {42508312},
issn = {1873-3573},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder requiring early diagnosis for effective intervention. The combination of blood Aβ42/Aβ40 ratio and p-tau-181 is recognized as a promising core biomarker panel for AD diagnosis. However, conventional detection methods suffer from limitations including time-consuming procedures, lack of multiplexing capability, and insufficient sensitivity. Herein, we developed a magnetic surface-enhanced Raman scattering (SERS)-encoded tags-based lateral flow immunoassay (LFIA) for simultaneous detection of Aβ42, Aβ40, and p-tau-181 on a single test line. Magnetic Fe3O4@Au nanoparticles were synthesized and modified with three distinct Raman reporters (DTNB for Aβ42, 4-MBA for Aβ40, and 2-MPY for p-tau-181) and corresponding detection antibodies. Under optimal conditions, the assay achieved rapid detection (∼28 min) and high sensitivity, with limits of detection of 93.33 fg/mL for Aβ42, 218.78 fg/mL for Aβ40, and 56.23 fg/mL for p-tau-181. The method exhibited excellent specificity against interfering substances (BSA, human IgG) and closely related species (Aβ38, p-tau-217), as well as good reproducibility (RSD <5%) and stability (≥4 weeks). In clinical plasma samples (n = 40), the combined score (p-tau-181/(Aβ42/Aβ40)) progressively increased with disease severity and correlated well with MMSE scores and MRI MTA grades, capturing both cognitive decline and hippocampal atrophy. This magnetic SERS-encoded LFIA platform offers a rapid, sensitive, user-friendly, and multiplex-capable approach for early AD diagnosis and progression monitoring, showing promise for future point-of-care applications.},
}

@article {pmid42508316,
year = {2026},
author = {Wang, D and Huang, W and Wang, X and Zhang, L and Tao, X and Qin, F and Guo, S and Han, G and Zhang, Z},
title = {Fluorescence lifetime imaging of G-quadruplex RNA dynamics in Alzheimer's disease using a novel nucleic acid-sensitive probe.},
journal = {Talanta},
volume = {312},
number = {Pt A},
pages = {130351},
doi = {10.1016/j.talanta.2026.130351},
pmid = {42508316},
issn = {1873-3573},
abstract = {Real-time monitoring of G-quadruplex (G4) RNA dynamics is vital for understanding their biological roles in the progression and treatment of Alzheimer's disease. However, this remains challenging due to two key difficulties. First, current fluorescent probes lack sufficient selectivity for G4 RNA over G4 DNA and other non-G4 secondary structures in live-cell competitive environments. Second, fluorescence intensity-based imaging cannot detect subtle changes in G4 RNA because of variations in fluorophore uptake and photobleaching. Herein, we report a novel thiazole orange derivative (TOGR) for fluorescence lifetime imaging of G4 RNA in living cells. Structural modifications of thiazole orange enhance RNA-binding affinity and G4 selectivity. TOGR exhibits a unique fluorescence lifetime when bound to G4 structures, enabling sensitive detection of G4 formation independent of local probe concentration via FLIM. FLIM imaging reveals that TOGR primarily colocalizes with RNA in the cytoplasm and nucleoli. Due to its preferential RNA-binding affinity in competitive cellular environments, TOGR enables selective monitoring of G4 RNA dynamics, facilitating the exploration of novel roles of G4 RNA in cells without interference from G4 DNA. Importantly, the dynamic behavior of G4 RNA during Alzheimer's disease pathology and the effects of glucocorticoids on G4 RNA dynamics were successfully revealed using this lifetime-sensitive and RNA-selective imaging probe. This research not only paves the way for advanced probe design for detailed G4 RNA imaging but also lays the foundation for exploring G4 RNA-related pathological mechanisms in Alzheimer's disease.},
}

@article {pmid42508318,
year = {2026},
author = {Christifano, DN and Kelly, E and Sands, SA and Honea, RA and Morris, JK and Burns, JM and Taylor, MK},
title = {Omega-3 fatty acids and Alzheimer's disease-related brain biomarkers in older adults enriched for preclinical Alzheimer's disease.},
journal = {Prostaglandins, leukotrienes, and essential fatty acids},
volume = {210},
number = {},
pages = {102762},
doi = {10.1016/j.plefa.2026.102762},
pmid = {42508318},
issn = {1532-2823},
abstract = {BACKGROUND: Preclinical and limited human data suggest long-chain omega-3 fatty acids, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), may be protective of brain volume and amyloid-beta (Aβ) accumulation, hallmarks of Alzheimer's disease (AD), which may be modulated by Apolipoprotein E ε4 (APOE4) carriage.

METHODS: This cross-sectional study was conducted using baseline data from a clinical trial at the University of Kansas Medical Center that included cognitively normal older adults, enriched for preclinical AD. We investigated serum DHA+EPA's (% total triacylglycerol fatty acids) relationship with MRI-derived gray matter volume and PET-derived Aβ burden (Florbetapir F18) overall and by APOE4 carriage status.

RESULTS: Among all participants (n = 104, 67.3% female, 69.2% preclinical AD, 44.2% APOE4), higher DHA+EPA was related to larger gray matter volume in a left precuneus/postcentral gyrus cluster, with similar relationships between APOE4 carriers and non-carriers. Higher DHA+EPA was also related to lower brain Aβ in the frontoparietal cortex, bilaterally. In APOE sensitivity analyses, higher DHA+EPA was related to lower global and AD-related regional brain Aβ among APOE4 carriers .

CONCLUSIONS: Higher DHA+EPA was associated with larger gray matter volume and lower Aβ in AD-susceptible regions, especially among APOE4 carriers. These findings are consistent with the hypothesis that omega-3 fatty acids influence brain volume and Aβ. Well-designed DHA+EPA supplementation RCTs are needed as DHA supplementation RCTs have inconsistently impacted brain volume and no RCTs investigating the impact of omega-3 on brain Aβ have been reported.

TRIAL REGISTRATION: NCT02000583 (https://clinicaltrials.gov/study/NCT02000583?term=NCT02000583&viewType=Card&rank=1) registered on November 26, 2013.},
}

@article {pmid42508388,
year = {2026},
author = {Gilson, KM and Higueras, AF and Walters, WM and Sanchez-Molano, J and Almeida, VW and Zeier, Z and Dietrich, WD and Bramlett, HM and Kerr, NA},
title = {Intestinal Organoids from Alzheimer's Disease Transgenic Mice Reveal Structural and Molecular Gut Pathology.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2026.0233},
pmid = {42508388},
issn = {2152-5250},
abstract = {Alzheimer's disease (AD) is the most common form of dementia, and early alterations in the gut may contribute to disease progression. The current study focused on generating intestinal organoids from 3xTg-AD transgenic and Wild Type (WT) mice to investigate the role of the gut-brain axis in AD. Intestinal organoid cultures were produced through isolation of leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5+) crypt cells from 4-5-month-old or 1-year-old intestinal tissue. Transmission electron microscopy (TEM) analysis of aged 3xTg organoids demonstrated evidence of impaired gut epithelial viability compared to WT controls. In aged 3xTg organoids, enlarged intercellular spaces, disrupted cell adhesions, diminished tight junction complexes, cellular debris, and amyloid-like fibrils were prominent findings. Immunostaining also demonstrated decreased E-Cadherin and ZO1 expression, along with increased cellular and luminal Aβ in aged 3xTg organoids compared to young 3xTg and WT organoids and p-tau protein accumulation in aged 3xTg organoids compared to all other experimental groups. In the aged 3xTg cohort, increased immunoreactivity of inflammasome components, including IL-1β, ASC, and GSDMD, implicated pyroptosis as a potential mechanism of cell death. These results support the hypothesis that familial AD pathology includes pronounced effects on gut organoid viability, junctional integrity, and abnormal protein accumulation within the intestinal epithelium. This study provides early evidence of gut organoid abnormalities occurring independently of alterations in the AD brain. These findings suggest that the gut epithelium may warrant further investigation as a potential target for future therapeutic strategies in AD.},
}

@article {pmid42508391,
year = {2026},
author = {Gao, W and Lee, HY and Min, KJ},
title = {Aging-Related Metaflammation and Mitochondrial Dysfunction in Neurodegenerative Diseases.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2026.0366},
pmid = {42508391},
issn = {2152-5250},
abstract = {Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) are increasingly recognized as manifestations of aging-associated systemic dysfunction, rather than isolated brain disorders. Central to this dysfunction is the interplay among metaflammation, mitochondrial breakdown, and chronic neuroinflammation. Metaflammation, driven by peripheral metabolic stress, may prime the brain's immune environment through cytokine signaling and blood-brain barrier compromise. This metabolic-inflammatory crosstalk is thought to impair mitochondrial integrity in neurons and glial cells, promoting oxidative stress and the release of pro-inflammatory mitochondrial components. These mitochondrial signals, in turn, may activate microglial and astrocytic innate immune responses, creating a potentially self-reinforcing cycle of neuroinflammation and energy failure that may contribute to neuronal loss. This review outlines a proposed framework linking metaflammation to neurodegeneration, emphasizing shared mechanisms across AD, PD, and ALS. We further examine preclinical and clinical advances in therapeutic strategies that target this axis including anti-inflammatory agents, caloric restriction, mitophagy enhancers, mitochondrial antioxidants, and senescence-targeted therapies. Together, these interventions reflect a shift from symptom management to systemic metabolic and immune modulation, offering a unified framework for understanding and potentially influencing age-related neurodegeneration.},
}

@article {pmid42508392,
year = {2026},
author = {Kumar, V and Jang, S and Choi, Y and Kim, S and Nam, Y and You, M and Moon, M},
title = {Targeting the Microbiota-Butyrate-BHB Axis As a Potential Metabolic Therapeutic Strategy for Alzheimer's Disease.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2026.0606},
pmid = {42508392},
issn = {2152-5250},
abstract = {Alzheimer's disease (AD) is increasingly linked to metabolic and microbial dysregulations, with butyrate and β-hydroxybutyrate (BHB) identified as key modulators. BHB is a ketone body primarily produced by the liver during periods of low glucose availability, and BHB levels are reduced in the AD brain and peripheral blood. Butyrate, a microbiota-derived short-chain fatty acid, is also reduced in the peripheral blood in association with gut microbiota dysbiosis. The reduction of butyrate and BHB, together with gut microbiota dysbiosis, is commonly observed in AD patients and correlates with cognitive decline and AD-related pathologies. Reduced levels of butyrate and BHB may impair energy metabolism, exacerbating amyloid-beta (Aβ) and tau pathologies. In contrast, preliminary evidence from interventional and ketogenic studies suggests that increasing butyrate and BHB levels may attenuate AD-related pathologies, such as Aβ and tau abnormalities, while improving cognitive function. Emerging evidence suggests that both butyrate and BHB can cross the blood-brain barrier (BBB), suppressing oxidative stress and pro-inflammatory cytokines and potentially mitigating Aβ aggregation and tau hyperphosphorylation. Accordingly, therapeutic strategies targeting the microbiota-butyrate-BHB axis represent a promising and biologically plausible approach that warrants further rigorous clinical investigation for the prevention and treatment of AD. This review comprehensively examines the roles of butyrate and BHB in ameliorating key AD-related pathologies, including Aβ aggregation, tau hyperphosphorylation, neuroinflammation, and neurodegeneration. Additionally, the review explores the bidirectional association between butyrate/BHB and gut dysbiosis in AD, including how dysbiosis reduces butyrate/BHB levels while elevating them may reverse dysbiosis and improve gut-brain axis function. Collectively, these findings suggest that butyrate and BHB emerge as promising candidates for potential novel adjunctive therapies for AD, although supporting human evidence remains preliminary and heterogeneous.},
}

@article {pmid42508514,
year = {2026},
author = {Shang, Y and Zhai, Z and Cong, L and Dong, X},
title = {Corrigendum to 'Targeting the APOE4-driven peripheral-central immune axis: A new frontier for Alzheimer's disease therapy' [Pharmacological Research (2026), YPHRS_108339].},
journal = {Pharmacological research},
volume = {},
number = {},
pages = {108355},
doi = {10.1016/j.phrs.2026.108355},
pmid = {42508514},
issn = {1096-1186},
}

@article {pmid42508529,
year = {2026},
author = {Chatterjee, A and Singh, TG and Singh, S and Kaur, A and Vishwas, S},
title = {Interplay between RNA m[6]A modification and transglutaminase 2 inhibitor effects on mitophagy dysfunction in Alzheimer's disease.},
journal = {Drug discovery today},
volume = {},
number = {},
pages = {104748},
doi = {10.1016/j.drudis.2026.104748},
pmid = {42508529},
issn = {1878-5832},
abstract = {Alzheimer's disease (AD) involves amyloid-β aggregation, tau hyperphosphorylation and mitochondrial dysfunction with defective mitophagy. Emerging evidence implicates RNA N6-methyladenosine (m[6]A) modification and transglutaminase 2 (TG2) as critical regulators of mitochondrial quality control in AD. Downregulation of METTL3/METTL14 and upregulation of fat mass and obesity-associated protein reduce m[6]A methylation, impair PTEN-induced putative kinase 1/Parkinson protein 2-mediated mitophagy and promote reactive oxygen species accumulation and synaptic loss. Conversely, TG2 overexpression exacerbates mitochondrial stress by crosslinking Aβ and tau, disturbing dynamin-related protein 1- and mitochondrial fission 1 protein-mediated dynamics and suppressing mitophagy. Crosstalk between TG2-induced oxidative stress and m[6]A dysregulation amplifies neuronal damage. Pharmacological modulation, using TG2 inhibitors (e.g. Z-DON) and m[6]A enhancers (e.g. METTL3 overexpression), restores mitophagic flux and mitigates pathology in preclinical models, suggesting dual m[6]A-TG2 targeting as a promising disease-modifying approach in AD.},
}

@article {pmid42508631,
year = {2026},
author = {Alanazi, SM and Al-Kuraishy, HM and Alexiou, A and Papadakis, M and Faheem, SA and Batiha, GE},
title = {Isoform-selective HSP90 inhibition as a precision therapeutic strategy for neurodegenerative and metabolic diseases.},
journal = {Progress in neuro-psychopharmacology & biological psychiatry},
volume = {149},
number = {},
pages = {111834},
doi = {10.1016/j.pnpbp.2026.111834},
pmid = {42508631},
issn = {1878-4216},
abstract = {Heat shock protein 90 (HSP90) is a central regulator of cellular proteostasis, coordinating the folding, stabilization, and turnover of a wide range of client proteins in the cytosol, endoplasmic reticulum, and mitochondria. Accumulating evidence indicates that the four HSP90 paralogs HSP90α, HSP90β, GRP94, and TRAP1 have distinct pathological roles in neurodegenerative and metabolic diseases. In neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, aberrant HSP90 activity contributes to the persistence of toxic protein conformers, defective autophagy, mitochondrial dysfunction, and chronic neuroinflammation. In metabolic disorders such as obesity, type 2 diabetes, and metabolic dysfunction-associated steatotic liver disease, GRP94- and TRAP1-dependent signaling promotes endoplasmic reticulum stress, impaired mitochondrial metabolism, insulin resistance, and inflammatory remodeling. These mechanistic insights have accelerated the development of a new generation of HSP90 inhibitors with improved selectivity, tissue targeting, and brain penetration. Unlike earlier pan-HSP90 inhibitors, these compounds are designed to exploit paralog-specific vulnerabilities and may enable safer long-term modulation of disease-relevant chaperone networks. This review summarizes current advances in the biology and pharmacology of HSP90 paralogs and proposes isoform-selective HSP90 targeting as a promising therapeutic strategy at the intersection of neurodegeneration and metabolic dysfunction.},
}

@article {pmid42508695,
year = {2026},
author = {Azimzadeh, M and Azimzadeh, M},
title = {From Gut Microbiota to Synaptic Plasticity: Mechanisms Shaping Cognitive Function and Brain Disorders.},
journal = {Behavioural brain research},
volume = {},
number = {},
pages = {116404},
doi = {10.1016/j.bbr.2026.116404},
pmid = {42508695},
issn = {1872-7549},
abstract = {The gut microbiota has emerged as a key regulator of central nervous system development and function. Accumulating experimental and clinical evidence demonstrates that microbial signals influence brain activity through integrated neural, immune, neuroendocrine, and metabolic pathways. These pathways converge on core mechanisms of synaptic plasticity, including neurotrophic signaling, glutamatergic transmission, dendritic remodeling, and adult neurogenesis, thereby shaping learning, memory, executive function, and emotional regulation. Disruption of microbiota-brain communication is implicated in a range of neurodevelopmental and neurodegenerative disorders, including autism spectrum disorder (ASD), major depressive disorder (MDD), Alzheimer's disease (AD), and Parkinson's disease (PD), suggesting shared systems-level vulnerabilities across conditions and highlighting the translational potential of microbiota-targeted interventions such as probiotics, dietary modulation, postbiotics, and precision microbiome-based strategies. Overall, the gut microbiota functions as a dynamic regulator of brain plasticity and cognitive resilience across the lifespan. Future progress will require identification of causal mechanisms at the level of specific microbial metabolites, neural circuits, and developmental windows using integrated multi-omics and spatially resolved approaches, alongside translation into targeted therapeutic strategies.},
}

@article {pmid42508744,
year = {2026},
author = {Datta, D and Arnsten, A and Sukoff Rizzo, SJ and Silva, AC and Joyce, MK and Tripathy, SJ and Roberts, A and Lewis, DA},
title = {Dorsolateral prefrontal cortex circuitry at the intersection of cognition and disease.},
journal = {Biological psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.biopsych.2026.07.012},
pmid = {42508744},
issn = {1873-2402},
abstract = {Schizophrenia, major depressive disorder (MDD), and Alzheimer's disease (AD) involve dysfunction of distributed cortical-subcortical networks that support complex cognitive processes and emotion regulation. Convergent evidence identifies the dorsolateral prefrontal cortex (dlPFC) as a critical site of molecular, cellular, and circuitry alterations in these disorders. The primate dlPFC contains recurrent, excitatory microcircuits in layer III that sustain working memory and top-down control through specialized forms of neurotransmission and intracellular signaling. Specifically, NMDA receptor and cholinergic modulation, as well as tightly regulated calcium-cAMP signaling within dendritic spines, support task-specific firing of layer III pyramidal neurons, but may also increase vulnerability to genetic risk, stress, inflammation and aging. This review integrates findings from human postmortem studies, neuroimaging, and genetics to examine how dlPFC circuitry is altered in these disease states. In schizophrenia, layer III pyramidal neurons exhibit altered synaptic and cytoskeletal signaling, lower dendritic spine density, and compensatory shifts in inhibitory inputs that likely weaken recurrent excitation and network synchrony. In MDD, dysfunction of dlPFC pathways regulating subgenual cingulate cortex contributes to impaired top-down control of emotion and motivation. In AD and frontotemporal lobar degeneration, tau pathology and neurodegeneration target association cortices, including layer III dlPFC circuits, contributing to progressive cognitive decline and impaired executive function. The review also highlights how studies in rhesus macaques and genetically engineered marmosets have provided important insight into the organization, physiology, and disease vulnerability of primate dlPFC circuits. Together, these findings inform the development of emerging therapeutic strategies aimed at strengthening prefrontal network function.},
}

@article {pmid42508750,
year = {2026},
author = {Zhang, X and Zhuang, D and Lai, C and Zheng, C and Soh, ZD and Wagner, S and Cai, VY and Yang, Z and Wang, S and Geng, X and Wang, Z and Feng, S and Qu, Y and Wang, L and Tang, S and Mok, VCT and Cheung, C and Chen, C and Zhu, Z and Cheng, CY and Yu, H},
title = {Retinal Manifestations of Alzheimer's Disease: Insights from Animal Models, Clinical Detection, and Future Translation.},
journal = {Progress in retinal and eye research},
volume = {},
number = {},
pages = {101504},
doi = {10.1016/j.preteyeres.2026.101504},
pmid = {42508750},
issn = {1873-1635},
abstract = {The retina, as an extension of the central nervous system, shares a common embryological origin with the brain. In Alzheimer's disease (AD), studies of human tissue and animal models have revealed that hallmark AD pathologies, including amyloid-β (Aβ) deposits and pathological tau protein tangles, also appear in the retina. These findings, coupled with advances in high-resolution retinal imaging techniques, suggest the potential to detect and characterize AD-related molecular and structural changes in the retina. However, retinal findings across different AD mouse models have significant discrepancies and show limited concordance with human phenotypes, complicating the identification of AD-specific alterations and the selection of optimal models for translational research. Moreover, the temporal sequence and functional significance of retinal abnormalities across the AD continuum, from preclinical stages to mild cognitive impairment and overt dementia, remain poorly defined. Addressing these knowledge gaps is essential to establish the retina as a reliable, non-invasive screening and monitoring approach. This review synthesizes current evidence on the spectrum of retinal alterations in AD, including vascular dysfunction, neuroinflammation, impaired Aβ clearance, and neurodegeneration, as observed in diverse mouse models. We compare these manifestations across species and between different models, highlighting findings along the disease continuum to delineate convergent and divergent pathways. We further discuss how emerging technologies enable the identification of AD-specific retinal alterations, and advocate for a paradigm shift from non-specific morphological assessment ("seeing shapes") toward molecular-level interrogation ("seeing components"). Interdisciplinary efforts and technological integration are crucial to establish retina as a dynamic mirror of pathology in AD.},
}

@article {pmid42508872,
year = {2026},
author = {Zhou, K and Cohn, M and Novik, R and Batur, P and Just, C},
title = {Menopause and Brain Health: Neurobiological Changes, Cognitive Implications, and the Role of Estrogen.},
journal = {Obstetrics and gynecology clinics of North America},
volume = {53},
number = {3},
pages = {449-461},
doi = {10.1016/j.ogc.2026.04.001},
pmid = {42508872},
issn = {1558-0474},
abstract = {The menopausal transition is characterized by significant hormonal fluctuations, culminating in a decline in estrogen levels. This decline impacts synaptic plasticity, neurotransmitter regulation, the blood brain barrier, cerebral blood flow, and metabolism, leading to cognitive symptoms often described as brain fog. Menopause-related cognitive changes, often transient, differ from the progressive decline seen in Alzheimer's Disease (AD). Research continues to explore estrogen's role in AD risk, but current evidence does not support using exogenous estrogen solely for dementia prevention. Hormone therapy can help manage menopausal symptoms and should be personalized based on factors like age, timing, and overall brain health.},
}

@article {pmid42508906,
year = {2026},
author = {de Souza, ID and Queiroz, MEC and Pichon, V and Combès, A},
title = {Online aptamer-based solid-phase extraction coupled with high-performance liquid chromatography-mass spectrometry for the determination of Alzheimer's disease biomarkers.},
journal = {Analytica chimica acta},
volume = {1417},
number = {},
pages = {345809},
doi = {10.1016/j.aca.2026.345809},
pmid = {42508906},
issn = {1873-4324},
abstract = {BACKGROUND: Reliable quantification of amyloid-β (Aβ) peptides in biological fluids is of major clinical and research interest in Alzheimer disease context. Conventional offline extraction approaches often involve labor-intensive manual steps and high solvent consumption, limiting throughput routine applications, reproducibility, and sustainability. To address these limitations, this study reports the development of an online coupling between a monolithic oligosorbent (mOS) in capillary and high-performance liquid chromatography-mass spectrometry (HPLC-MS) method for selective Aβ peptide analysis.

RESULTS: A mOS was incorporated online in a set up including a C18 trap column coupled with an HPLC-MS analytical system. Systematic optimization of mOS loading/elution conditions, trapping column desalting/preconcentration, and chromatographic mobile phase composition enabled efficient retention, transfer, and separation of Aβ40 and Aβ42 in a fully automated method. This method achieved lower limits of quantification down to 0.03 ng mL[-1] with good precision and accuracy (CV ranging from 1.1 to 6.2% for Aβ40 and from 4.3 to 10.9% for Aβ42). Comparative evaluation of offline and online extraction using the same mOS capillary demonstrated improved reproducibility and enhanced sensitivity for the online configuration. The method's applicability to a controlled CSF-like matrix was demonstrated using artificial cerebrospinal fluid (aCSF) diluted 1:2 (v/v) in binding buffer (BB), yielding recoveries of 60% for Aβ40 and 34% for Aβ42.

SIGNIFICANCE: The online coupling of the mOS capillary with HPLC-MS also represents a strategic advance toward environmentally responsible bioanalysis. Indeed, the superior AGREEprep score (0.7) for the online configuration compared to offline mode (0.59), underscores its alignment with green analytical chemistry principles, reflecting reductions in solvent use, manual intervention, and overall environmental burden.},
}

@article {pmid42509195,
year = {2026},
author = {Reichert, L and Delparente, A and Hipfinger, IR and Reininger, L and Castro, AP and Hubin, DJ and Schibli, R and Fraley, AE and Mu, L},
title = {Identification of Pyrazolidine-3-One Derivatives as a Novel Structural Scaffold for ATP Synthase Inhibitors.},
journal = {ChemMedChem},
volume = {21},
number = {14},
pages = {e70399},
pmid = {42509195},
issn = {1860-7187},
support = {205321_192409/1//Swiss National Fundation/ ; #22A047//Novartis Stiftung für Medizinisch-Biologische Forschung/ ; },
abstract = {In a recent study, the oxadiazin-5-one-based compound CJ1-34 was identified as a partial ATP synthase inhibitor, which was found to bind the F1 region of the ATP synthase. These findings were used as a starting point for the design and synthesis of smaller heterocycles, such as pyrazolidine-3-ones and pyrazol-3-ones, as novel structural scaffolds for potential ATP synthase inhibitors. Among the newly synthesized compounds, pyrazolidin-3-one derivatives 9a and 10a outperformed the lead compound CJ1-34 in vitro by inhibiting ATP hydrolytic activity and decreasing ATP levels in HT-22 cells. Subsequent dose-dependent studies identified compound 9a as the most promising ATP synthase inhibitor. Molecular docking revealed similar binding modes for all compounds in the F1-binding site and the calculated docking scores aligned with the measured IC50 values of the tested compounds. This study identified pyrazolidine-3-ones as promising structural scaffolds for ATP synthase inhibition, opening avenues for further biomedical applications in central nervous system diseases such as Alzheimer's and Parkinson's.},
}

@article {pmid42509403,
year = {2026},
author = {Anand, A and Sania, A and Singh, SK and Bajad, N},
title = {Targeting Histone Deacetylase 2 in Alzheimer's Disease: From Molecular Insights to Epigenetic Therapeutic Opportunities.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42509403},
issn = {1559-1182},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder that leads to cognitive impairment, memory loss, and nerve cell dysfunction. Despite substantial research efforts, effective AD therapies remain limited. Histone deacetylase 2 (HDAC2) is a principal epigenetic regulator that is essential for controlling gene expression and neuronal connectivity. Recently, HDAC2 has attracted significant attention as a potential therapeutic target in AD owing to its involvement in key disease hallmarks, including neuroinflammation, Aβ accumulation, and abnormal tau phosphorylation. We have outlined and discussed the molecular insights into HDAC2 in AD and its recently emerged inhibitors. Inhibiting HDAC2 has demonstrated potential in lowering neuroinflammatory signalling and reestablishing synaptic and neuroprotective gene expression patterns in preclinical AD models. Current preclinical evidence indicates that HDAC2 may play a significant role in AD development and may represent a target for therapeutic intervention. Recent progress in HDAC2 inhibitor development offers a rationale for this approach, although further mechanistic and clinical investigations are required. Resolving the precise roles of HDAC2 dysregulation in AD and determining the utility of combination strategies remain important priorities. Whether HDAC2-targeted inhibitors can yield disease-modifying benefits in AD remains to be demonstrated in clinical studies.},
}

@article {pmid42509523,
year = {2026},
author = {Neller, SA and Fernandez Cajavilca, M and Wong, B and Johnson, J and Ellington, L and Eaton, J},
title = {Identifying and Mapping Levels of Active Engagement Within an Arts-Based Intervention: A Qualitative Analysis and Conceptual Development.},
journal = {International journal of behavioral medicine},
volume = {},
number = {},
pages = {},
pmid = {42509523},
issn = {1532-7558},
abstract = {BACKGROUND: Active engagement is crucial in psychoeducational interventions for care partners of persons living with dementia, yet measurement is limited. This manuscript explores participant engagement in an arts-based intervention designed to increase engagement in addressing dementia-related behavioral symptoms. The intervention uses multisensory activities, including caregiver-informed vignettes, to foster engagement and process caregiving experiences.

METHODS: Care partners of persons living with dementia (n = 9) participated in six focus groups. Focus group data were analyzed using process coding to define and map patterns of active engagement across 27 intervention activities. The findings informed development of a conceptual model of active engagement.

RESULTS: Four levels of engagement were identified-Participating, Clarifying, Contributing, and Applying-and explored across participants, time points, and activities. The conceptual model illustrates that (1) antecedents contribute to (2) levels of engagement, leading to (3) the intervention's hypothesized mechanisms of action, proximal outcomes (capacity to adapt, appraisal of caregiving demands), and distal outcomes (perceived stress, caregiver well-being).

CONCLUSION: This manuscript provides a clear framework for operationalizing and measuring active engagement and demonstrates how engagement patterns can be conceptually linked to the intervention's proposed mechanisms of action and outcomes. These findings provide transparency in reporting engagement patterns within an intervention, offering valuable insight into the components of active engagement and how these may be measured. The ability to track active engagement during intervention development and testing has the potential to improve our understanding of intervention dose and fidelity and how active engagement interacts with these to improve outcomes for participants.},
}

@article {pmid42509652,
year = {2026},
author = {Mielke, MM and Gaussoin, SA and Casanova, R and Latham, LA and Manson, JE and Mouton, CP and Ng, TKS and Rapp, SR and Resnick, SM and Sachs, BC and Saquib, N and Shadyab, AH and McEvoy, LK and LaCroix, AZ and Wallace, RB and Espeland, MA and Chen, JC and Hayden, KM},
title = {Alzheimer's blood-based biomarkers, incident dementia, and interactions with age, APOE status, and hormone therapy.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71704},
doi = {10.1002/alz.71704},
pmid = {42509652},
issn = {1552-5279},
support = {/AG/NIA NIH HHS/United States ; /HL/NHLBI NIH HHS/United States ; /NH/NIH HHS/United States ; 75N92021D00001/HL/NHLBI NIH HHS/United States ; 75N92021D00002/HL/NHLBI NIH HHS/United States ; 75N92021D00003/WH/WHI NIH HHS/United States ; 75N92021D00004/WH/WHI NIH HHS/United States ; 75N92021D00005/WH/WHI NIH HHS/United States ; },
abstract = {INTRODUCTION: Cognitive impairment among older adults is often due to multiple pathologies and heterogenous risk factors. We assessed whether Alzheimer's blood-based biomarkers (BBMs) were associated with incident mild cognitive impairment (MCI)/probable dementia, and whether associations were modified by age, apolipoprotein E (APOE), and hormone therapy (HT).

METHODS: Analyses included 2467 Women's Health Initiative Memory Study women (≥65 years of age) randomized between 1995 and 1998 to 3-5-years of HT or placebo. Cox regression (mean 18-year follow-up) assessed associations between the z-scored BBMs and MCI/dementia.

RESULTS: Lower baseline amyloid beta (Aβ)42/40 ratio and higher phosphorylated tau 181 (p-tau181), glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) were associated with an increased risk of MCI and dementia; GFAP was most strongly associated. The p-tau181 and NfL associations were stronger among APOE ε4 carriers; BBMs varied non-linearly by age. The associations of BBMs with the cognitive outcomes also varied inconsistently between HT groups.

DISCUSSION: BBMs for AD and related dementias (ADRD) are associated with incident MCI/dementia in older women. Interactions between the BBMs and HT were inconsistent and require further investigation.},
}

@article {pmid42509698,
year = {2026},
author = {Wang, X and Li, J and Wei, Z and Rong, C and Zhao, D and Wang, Y},
title = {Integrating Multi-Omics and Mendelian Randomization Reveals the Role of Epstein-Barr Virus Infection in Alzheimer's Disease and the Therapeutic Potential of Resveratrol.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050463115260708111634},
pmid = {42509698},
issn = {1875-5828},
abstract = {INTRODUCTION: The pathogenesis of Alzheimer's disease (AD) is complex, with immune system dysregulation playing a critical role. However, the specific molecular mechanisms linking peripheral immune responses to central pathologies in AD remain unclear. This study aims to systematically screen for reliable plasma biomarkers of AD by integrating transcriptomics, Mendelian randomization (MR) of plasma proteomics, and bioinformatics analyses, and to explore their potential pathogenic mechanisms and therapeutic drugs.

MATERIALS AND METHODS: Transcriptomic sequencing of plasma samples from three AD patients and three healthy controls was first performed to identify differentially expressed genes (DEGs) and perform functional enrichment analyses. The aim of this study is to provide a preliminary indication of gene expression changes based on real patient samples for subsequent MR and bioinformatics analyses, rather than serving as confirmatory evidence. Following this, two-sample MR was performed to explore the potential causal relationship between plasma proteins and AD in genetic prediction, and MR-positive results were intersected with transcriptome DEGs to identify highconfidence targets. After that, protein-protein interaction (PPI) analysis, functional enrichment (GO/KEGG), and transcription factor (TF) target network analysis were conducted. Based on the KEGG pathway analysis, the causal association between antibodies related to Epstein-Barr virus and AD in genetic prediction was further evaluated. In the end, the diagnostic power of core biomarkers was validated in the GEO dataset. Potential therapeutic drugs were screened in the CTD database, followed by verification through molecular docking and molecular dynamics simulation.

RESULT: Our transcriptomic enrichment analysis of DEGs indicates that AD is significantly correlated with viral infection and immune and inflammatory pathways. According to the results of MR analyses, 36 plasma proteins have a causal effect on AD in genetic prediction. Among these 36 targets, two pathways are identified as enriched: "EBV Infection" and "Efferocytosis". Seven core targets are CR2, ICAM1, TAPBP, TNFAIP3, THBS1, SCARF1, and SIRPG. Also, the concentration of antibodies against EBV EBNA-1 and VCA p18 was confirmed by MR analyses to be risk factors for AD. According to drug predictions, molecular docking, and molecular dynamics simulations, resveratrol can stabilize CR2.

DISCUSSION: This study systematically identifies major plasma immune biomarkers associated with AD and proposes a mechanism by which EBV infection regulates plasma proteins CR2, TNFAIP3, and THBS1, which may affect AD risk. Resveratrol is thought to have preventive and protective effects, as predicted computationally.

CONCLUSION: This study systematically identified key plasma markers associated with AD. Resveratrol is likely to become a potentially effective preventive and protective drug in the prevention and treatment of AD, providing new ideas and targets for immune intervention of AD.},
}

@article {pmid42509699,
year = {2026},
author = {Barczak, A and Krempa-Kowalewska, A and Golan, M},
title = {Cognitive Profiles in Early- and Late-Onset Alzheimer's Disease: The Role of Dementia Severity in Typical Amnestic Presentations Using the Addenbrooke's Cognitive Examination III.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050489392260702044957},
pmid = {42509699},
issn = {1875-5828},
abstract = {INTRODUCTION: Early-Onset (EOAD) and Late-Onset Alzheimer's Disease (LOAD) are often described as presenting distinct cognitive phenotypes. However, reported differences are inconsistent and may reflect demographic and severity-related confounding rather than stable etiological distinctions.

MATERIALS AND METHODS: A retrospective analysis was conducted in 776 patients with clinically diagnosed Alzheimer's disease (EOAD, n = 175; LOAD, n = 601). Cognitive performance was assessed using the Addenbrooke's Cognitive Examination III (ACE-III) and the Mini-Mental State Examination (MMSE). Dementia severity was staged using the Functional Assessment Staging Tool (FAST). Cognitive outcomes were analysed using age- and severity-adjusted ANCOVA models including a diagnosis × age interaction. Severity-stratified and domain-level analyses were also performed.

RESULTS: Unadjusted analyses revealed limited EOAD-LOAD differences in the Attention and Visuospatial domains, with small effect sizes. After adjustment for demographic variables and dementia severity, no cognitive measure reliably differentiated EOAD from LOAD. Cognitive performance showed similar cross-sectional patterns across groups and was primarily determined by dementia severity.

DISCUSSION: Small, stage-dependent differences observed at mild and moderate stages did not persist in more advanced dementia and did not indicate stable cognitive dissociation between EOAD and LOAD.

CONCLUSIONS: After adjustment for demographic factors and dementia severity, EOAD and LOAD do not exhibit distinct cognitive profiles on ACE-III. Cognitive performance reflects disease stage rather than age at onset, supporting the use of ACE-III for staging cognitive impairment rather than for differentiating EOAD from LOAD in typical amnestic presentations.},
}

@article {pmid42509706,
year = {2026},
author = {Shen, Z and Cheng, J and Wang, L and Hou, Q},
title = {Molecular Mechanisms and Therapeutic Strategies in Parkinson's Disease: From Pathogenic Signaling to Drug Development.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X457429260706102249},
pmid = {42509706},
issn = {1875-6190},
abstract = {Parkinson's Disease (PD) is the second most common neurodegenerative disease after Alzheimer's Disease (AD), yet no effective disease-modifying therapy is currently available. Its pathogenesis is highly complex, involving multiple interacting pathological processes, which poses substantial challenges for therapeutic intervention. Moreover, PD often has a prolonged prodromal phase and lacks sufficiently sensitive and specific diagnostic methods for early-stage detection, further limiting timely identification and treatment. Current pharmacological therapies mainly provide symptomatic relief, but their long-term use is frequently associated with reduced efficacy and motor complications. Therefore, the development of novel therapeutic strategies and potential disease-modifying agents remains an urgent priority. This review systematically summarizes the molecular mechanisms and biomarkers associated with PD, outlines current symptomatic treatments, and discusses emerging therapeutic candidates in clinical development, with particular emphasis on disease-modifying strategies. By integrating pathogenic mechanisms, diagnostic advances, and therapeutic progress, this review aims to provide a comprehensive perspective to support the development of more effective interventions for PD.},
}

@article {pmid42509708,
year = {2026},
author = {Liu, Y and Zhang, Y and Zheng, W and Shi, X and Yao, W and Zhang, J and Bai, F},
title = {Cortico-white Matter Functional Coupling as a Biomarker of Alzheimer's Disease Progression and rTMS Therapeutic Efficacy.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X470892260706231913},
pmid = {42509708},
issn = {1875-6190},
abstract = {INTRODUCTION: Alzheimer's disease (AD) spectrum disorders are characterized by progressive cognitive decline, with white matter degeneration and disrupted cortico-cortical connectivity as early features. Cortico-white matter functional coupling integrates neuronal activity with axonal conduction, yet its natural trajectory across the AD spectrum and ability to be modulated by repetitive transcranial magnetic stimulation (rTMS) remain unclear.

METHODS: Longitudinal resting-state fMRI from the ADNI cohort (n = 160: 59 cognitively normal, CN; 65 mild cognitive impairment, MCI; 36 AD) was used to assess baseline and 1-year changes in mean Fisher's z-transformed coupling between 82 cortical seeds (AAL-90 atlas, excluding subcortical nuclei) and a probabilistic group white matter mask. Specifically, 54 patients with amnestic MCI (aMCI) from the rTMS cohort were allocated to active (n = 40) or sham (n = 14) groups and received four weeks of neuronavigated rTMS targeting the left angular gyrus. Cortico-white matter functional coupling was calculated identically in both cohorts. Changes in coupling strength and their associations with changes in neuropsychological performance were examined across all cortical seeds.

RESULTS: At baseline, mean cortico-white matter functional coupling followed a nonlinear pattern (MCI > AD and CN). One-year follow-up revealed that the CN group exhibited a slight decrease in coupling, and the MCI and AD groups showed a pathological increase. Compared with the sham group, active rTMS significantly attenuated this increase in coupling. After adjusting for covariates, coupling changes were strongly correlated with cognitive decline. The AD group demonstrated the most significant associations (n = 104), whereas the active rTMS group showed 71 associations, predominantly linked to objective memory improvement.

DISCUSSION: This abnormal overcoupling, leading to compensation and decompensation, is associated with the progression of Alzheimer's disease. rTMS effectively moderates this pathological surge by enhancing neural efficiency and stabilizing large-scale network integration. Our findings position cortico-white matter functional coupling as an effective indicator of disease intensity and a measurable link in the chain of rTMS effectiveness for early-stage AD.

CONCLUSION: Overall, cortico-white matter functional coupling may serve as a novel scan-based biomarker for tracking AD progression and evaluating rTMS treatment efficacy in patients with MCI.},
}

@article {pmid42509738,
year = {2026},
author = {Wali, Z and Neha, and Shahwan, M and Dinislam, K and Shamsi, A and Anwar, S},
title = {Network Biology of Alzheimer's Disease and Related Neurodegenerative Disorders: Molecular Mechanisms and Therapeutic Strategies.},
journal = {Biomolecules},
volume = {16},
number = {7},
pages = {},
doi = {10.3390/biom16070944},
pmid = {42509738},
issn = {2218-273X},
support = {NA//Ajman University/ ; },
abstract = {The most persistent biomedical challenges of the 21st century are neurodegenerative disorders (NDs), where molecular alterations lead to devastating clinical consequences and progressive neuronal loss. The prevalence of neurodegeneration is continuously rising and becoming the main contributor to chronic disability and mortality. Despite their clinical differences, many conditions share pathogenic processes, including oxidative stress, protein misfolding and aggregation, mitochondrial dysfunction, and neuroinflammation. Instead of functioning independently, these processes cooperate to form a self-reinforcing network that gradually weakens synapses and ultimately leads to neuronal death. This study redefines neurodegeneration as a disorder of system-level failure by emphasizing poor cellular stress integration. In addition to demonstrating how gut microbiome gene networks impact inflammation and amyloid production, new research highlights the relationships between mitochondrial-lysosomal interactions, endoplasmic reticulum stress responses, and transcriptionally driven synaptic vulnerability. A key molecular topic is the interaction and pathogenic convergence of the JAK/STAT, HIF-1α, and Notch signaling pathways. Under ongoing metabolic stress, prolonged stimulation of this triad increases inflammation, hinders the regenerative processes, and maintains pseudo-hypoxic conditions, explaining why single-target treatments have mostly been unsuccessful. This review also explores progress in fluid, digital, and imaging biomarkers that facilitate early diagnosis and patient stratification, and assesses new disease-modifying approaches such as antisense oligonucleotides, immunomodulators, gene therapies, and small-molecular agents. Artificial intelligence is emphasized as an essential tool for integrating multimodal data, drug discovery and predictive modeling.},
}

@article {pmid42509739,
year = {2026},
author = {Narita, A and Nakano-Doi, A and Nishiyama, R and Sawano, T and Fukushima, K and Matsuyama, T and Nakagomi, T},
title = {Mirtazapine Induces Lipocalin-Type Prostaglandin D Synthase Expression in Brain Pericytes.},
journal = {Biomolecules},
volume = {16},
number = {7},
pages = {},
doi = {10.3390/biom16070945},
pmid = {42509739},
issn = {2218-273X},
abstract = {The brain maintains homeostasis partially by scavenging waste products. Failure of this function is closely associated with the onset and pathogenesis of various brain diseases, such as Alzheimer's disease, sleep disorder, and the delay of the reparative process after brain injuries. We recently demonstrated that brain pericytes (BPCs) are sources of lipocalin-type prostaglandin D synthase (L-PGDS), a waste scavenger, in the brain. Based on the above, chemical compounds which promote L-PGDS production could have potential against brain diseases, such as dementia, sleep disorders, and brain injuries. However, the specific chemical compounds that may enhance L-PGDS production in BPCs have not yet been identified. In this study, we explored 158 chemical compounds from FDA-approved drug libraries with these activities. qPCR analysis showed that mirtazapine (MTZ), a noradrenergic and specific serotonergic antidepressant, can increase L-PGDS expression in BPCs as well as in mouse- (m-BPCs) and human-derived BPCs (h-BPCs) in a dose-dependent manner. Since L-PGDS is a secretory protein, m-BPCs and h-BPCs were treated with various MTZ doses and L-PGDS levels in the culture supernatant were investigated. Western blot analysis showed that L-PGDS levels were significantly increased in a dose-dependent manner in both cell types, indicating that MTZ promoted L-PGDS secretion from m-BPCs and h-BPCs. Thus, MTZ may have the potential to be applied as drug repositioning for various brain diseases other than depression by activating L-PGDS production in BPCs, highlighting the importance of BPCs as the source to maintain brain homeostasis.},
}

@article {pmid42509786,
year = {2026},
author = {Guo, L and Grimaldi, N and Wang, M and Ho, L and Shackleton, B and Neff, R and Wang, E and Tu, Z and Gandy, S and Haroutunian, V and Ehrlich, ME and Mobbs, C and Zhang, B},
title = {Molecular Networks and Key Regulators Underlying Resilience of the Human Brain to Aging and Dementia.},
journal = {Biomolecules},
volume = {16},
number = {7},
pages = {},
doi = {10.3390/biom16070992},
pmid = {42509786},
issn = {2218-273X},
support = {5R01AG057907-05/NH/NIH HHS/United States ; },
abstract = {Alzheimer's disease (AD) is an aging-related neurodegenerative disease characterized by an initial memory impairment that progresses to a widespread cerebrocortical failure, culminating in death. Understanding the molecular mechanisms that protect brain function during aging may help reveal novel targets for the development of effective treatments for the memory and cognitive deficits associated with AD. In this study, we analyzed a gene expression dataset generated from the prefrontal cortices of individuals showing no neurological or cognitive abnormalities. The gene expression profiles were used to identify candidate protective genes. We then compared the expression patterns of these genes in aging with their expression patterns in AD, thereby enabling us to pinpoint the genes that potentially contribute to brain resilience that delays or prevents aging-related dementia. We selected seven genes that are potentially protective for aging and AD, and have known homologues in Caenorhabditis elegans (C. elegans). Among these genes, SRPK2, AAK1, EFR3A and MAPK10 were previously implicated in attenuating AD-related cognitive decline. Our experiments demonstrated that all seven genes prioritized by our resilience model significantly extended the lifespan of C. elegans. Given the important relationship between neuronal functional integrity and lifespan (i.e., lifespan vs. brain health span), this work suggests the predicted AD resilience genes could serve as important candidate targets for therapeutic intervention.},
}

@article {pmid42509845,
year = {2026},
author = {De Oliveira, LF and Karunarathne, K and Zona, D and Muschol, M and Ullah, G},
title = {Shrinking of Extracellular Space During Metabolic Stress Accelerates Amyloid-β Aggregation.},
journal = {Biomolecules},
volume = {16},
number = {7},
pages = {},
doi = {10.3390/biom16071053},
pmid = {42509845},
issn = {2218-273X},
support = {R21AG087910/NH/NIH HHS/United States ; },
mesh = {*Amyloid beta-Peptides/metabolism/chemistry ; *Extracellular Space/metabolism ; *Stress, Physiological ; Humans ; Alzheimer Disease/metabolism/pathology ; Protein Aggregates ; Kinetics ; Neurons/metabolism ; Animals ; *Peptide Fragments/metabolism/chemistry ; *Protein Aggregation, Pathological/metabolism ; },
abstract = {Pathological states associated with metabolic stress, such as traumatic brain injury (TBI), hypoxia, ischemic stroke, and migraine, are considered elevated risk factors for developing Alzheimer's disease (AD). However, the mechanism underlying the effect of these conditions on the progression of AD remains largely unknown. Here, we determine how metabolic stress associated with spreading depolarization (SD)-a hallmark of stroke, hypoxia, TBI, and migraine-modulates amyloid β (Aβ42) aggregation kinetics through dynamic changes in extracellular space (ECS). To achieve this, we used ThT fluorescence to determine how the formation of different Aβ42 aggregate species depends on Aβ42 concentrations. Based on this input, we build a multiscale computational framework that integrates volume regulation, including its dependence on neuronal ion homeostasis, and Aβ42 aggregation kinetics. Our model predicts that neuronal swelling during SD accelerates aggregation, where the impact of metabolic stress is highly dependent on the timing relative to aggregation progression and the initial monomer concentration. At low monomer concentrations, early SD events promote off-pathway oligomer formation, while at higher concentrations they rapidly drive fibril formation to saturation. In the absence of mature fibrils, recurrent metabolic stress events further amplify oligomer accumulation, whereas pre-existing fibril nuclei suppress oligomer formation at the expense of fibril nucleation and growth. Increasing the intensity of metabolic stress prolongs ECS shrinkage and enhances oligomer formation. These findings reveal a mechanistic link between SD-induced microenvironmental changes and Aβ aggregation dynamics, providing a quantitative framework for understanding how acute brain injury and metabolic stress may contribute to early AD pathogenesis.},
}

*Amyloid beta-Peptides/metabolism/chemistry
*Extracellular Space/metabolism
*Stress, Physiological
Humans
Alzheimer Disease/metabolism/pathology
Protein Aggregates
Kinetics
Neurons/metabolism
Animals
*Peptide Fragments/metabolism/chemistry
*Protein Aggregation, Pathological/metabolism

@article {pmid42509854,
year = {2026},
author = {Alessio, M and Giulia, N and Annagrazia, A and Francesco, A and Raffaele, M and Massimo, C and Giacinto, B and Carlo, N and Romano, E and Rossella, R},
title = {Lithium as a Potential Neuroprotective Strategy in Glaucoma: Mechanisms and Therapeutic Perspectives.},
journal = {Biomolecules},
volume = {16},
number = {7},
pages = {},
doi = {10.3390/biom16071062},
pmid = {42509854},
issn = {2218-273X},
abstract = {Glaucoma is a major global health concern, identified as the foremost cause of irreversible blindness, affecting nearly 95 million individuals. It is characterized by the progressive degeneration of retinal ganglion cells (RGCs), leading to significant vision-related disabilities and an extensive socio-economic impact. The concept that glaucoma should be viewed not solely as an ocular condition but also as a neurodegenerative disorder, sharing pathophysiological features with diseases like Alzheimer's and Parkinson's, is now widely accepted. This review examines the convergence of molecular mechanisms, including the roles of amyloid precursor proteins and neuroinflammation, that contribute to RGC loss. Notably, lithium, traditionally used as a mood stabilizer, has emerged as a potential neuroprotective agent for the treatment of Alzheimer's disease. In light of the common neurodegenerative mechanisms linking glaucoma with central neurodegenerative diseases, here, we review the current evidence supporting lithium's therapeutic potential in glaucoma, emphasizing the need for further clinical studies to determine its effectiveness in preserving optic nerve health and improving patient outcomes.},
}

@article {pmid42510415,
year = {2026},
author = {Li, R and Wu, M},
title = {Multidimensional Prosodic and Semantic Coherence Modeling for Mandarin Mild Cognitive Impairment Detection.},
journal = {Bioengineering (Basel, Switzerland)},
volume = {13},
number = {7},
pages = {},
doi = {10.3390/bioengineering13070748},
pmid = {42510415},
issn = {2306-5354},
support = {2025J01001//Fujian Provincial Department of Science and Technology/ ; 32071057, 61673322, 31200769//National Natural Science Foundation of China/ ; Not applicable (Xiamen University Undergraduate Innovation and Entrepreneurship Training Program)//Undergraduate Innovation and Entrepreneurship Training Program of Xiamen University/ ; },
abstract = {Early detection of Alzheimer's disease (AD) and mild cognitive impairment (MCI) remains critically important, yet conventional neuroimaging and biomarker-based approaches are costly, invasive, and poorly scalable for population screening. Speech offers a non-invasive, cost-effective alternative cognitive biomarker, but existing systems rarely integrate its multiple linguistic dimensions. We present Multi-Spec MCI-Net, a multimodal framework for HC/MCI classification that jointly models three complementary speech representations: token-level semantics via dVAE and BERT operating on Mel spectrograms; temporal prosodic dynamics via a 1D-CNN with attention; and discourse-level semantic coherence via a graph convolutional network. A gated fusion mechanism adaptively weights these modalities, yielding clinically interpretable predictions tailored to individual phenotypic profiles. Evaluated on the Chinese NCMMSC2021_AD challenge dataset and the DementiaBank Mandarin subset, the model achieves 89.29% accuracy and 0.9584 ROC AUC on NCMMSC2021_AD, with 92.31% MCI recall-critical for minimizing false negatives in screening contexts. Evaluation on the combined NCMMSC2021_AD and DementiaBank Mandarin dataset attains 77.46% accuracy and 0.8280 AUC, demonstrating robustness across spontaneous dialog and picture description tasks. Ablation studies confirm that multimodal fusion outperforms the semantic-only baseline by 5.16 percentage points, with each branch contributing non-redundant diagnostic information. These results establish an effective, interpretable approach for scalable, speech-based early MCI screening.},
}

@article {pmid42510516,
year = {2026},
author = {Song, C and Deng, C and Zhang, T and Yao, W and Li, D and Wang, X},
title = {Rhodopseudomonas pseudopalustris Mitigates Alzheimer's Disease-Related Pathology in C. elegans Models by Enhancing Antioxidant Defense Capacity and Immune Activity.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {15},
number = {7},
pages = {},
doi = {10.3390/antiox15070785},
pmid = {42510516},
issn = {2076-3921},
support = {32571125//National Natural Science Foundation of China/ ; },
abstract = {Alzheimer's disease (AD) lacks effective disease-modifying therapeutics. Probiotics, promising neuroprotective candidates, exert benefits mainly by modulating gut-brain-axis (GBA) signaling. This study explored the anti-AD effects and mechanisms of Rhodopseudomonas pseudopalustris (R. pse). Using Caenorhabditis elegans (C. elegans) AD models, we evaluated AD-related phenotypes (learning deficits, paralysis) after R. pse administration, and performed genetic analysis and metabolomic profiling to clarify its regulatory pathways and metabolites. Mechanistically, R. pse significantly alleviated AD-related phenotype in C. elegans. It upregulated γ-glutamylcysteine synthetase (GCS-1) to enhance the glutathione (GSH)-dependent antioxidant defense. Knockout of the oxidation repair enzyme methionine sulfoxide reductase A-1 (MSRA-1) abolished the neuroprotective effects of R. pse, which was rescued by methionine. R. pse also activated activating transcription factor 7 (ATF-7)-mediated innate immunity and transforming growth factor β (TGF-β) signaling, with pantothenic acid as its functional metabolite. Collectively, R. pse is a potential anti-AD bacterium that mitigates AD model pathogenesis by enhancing the cellular antioxidant capacity, providing experimental evidence for bacteria-based AD interventions.},
}

@article {pmid42510529,
year = {2026},
author = {Vietri, M and Napolitano, E and Miranda, MR and Marino, C and Musella, S and Di Sarno, V and Ostacolo, C and Manfra, M and Campiglia, P and Tecce, MF and D'Ursi, AM and Moltedo, O and Bertamino, A and Ciaglia, T and Vestuto, V},
title = {Metabolic Reprogramming Associated with Ferroptosis Protection by an Indole-Based Antioxidant in Aβ(25-35)-Treated SH-SY5Y Cells.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {15},
number = {7},
pages = {},
doi = {10.3390/antiox15070798},
pmid = {42510529},
issn = {2076-3921},
support = {J97G22000400006//Ministero dell'università e della ricerca/ ; },
abstract = {Ferroptosis has emerged as a critical mechanism linking iron dysregulation, oxidative stress, and neurodegeneration in amyloid-associated pathologies. Building on our previous work, which identified compound 20 as a promising antioxidant and neuroprotective agent, the present study investigates the molecular mechanisms underlying its protective activity against amyloid-induced ferroptosis in human neuroblastoma SH-SY5Y cells exposed to Aβ(25-35). Compound 20 (3-(((4-hydroxybenzyl)(methyl)amino)methyl)-1-methyl-N-(2-(piperazin-1-yl)ethyl)-1H-indole-5-carboxamide) markedly counteracted Aβ(25-35)-induced ferroptotic damage by restoring intracellular glutathione levels, depleting the labile iron pool, and suppressing lipid peroxidation. In parallel, the compound significantly rescued mitochondrial membrane potential and attenuated endoplasmic reticulum (ER) expansion associated with ER stress, thereby preserving cellular homeostasis under oxidative challenge. These protective effects were further corroborated by real-time PCR analysis, which revealed the modulation of key genes involved in the oxidative stress response, endoplasmic reticulum stress, and inflammatory pathways. To gain a systems-level insight into these mechanisms, untargeted [1]H-NMR metabolomic profiling was performed. This analysis confirmed the activation of antioxidant pathways and disclosed a significant modulation of energy metabolism and GABA-related pathways, both of which are closely linked to redox balance and neuronal resilience. Overall, these findings demonstrate that compound 20 drives metabolic reprogramming that orchestrates its multifactorial protective effect against Aβ(25-35)-induced ferroptosis by coordinating antioxidant defense, iron homeostasis, and ER stress mitigation.},
}

@article {pmid42510588,
year = {2026},
author = {Ciccone, L and Petrarolo, G and D'Agostino, I and Scianò, F and Bernardoni, BL and Leri, M and Ann, J and Nencetti, S and Lee, J and Bucciantini, M and La Motta, C},
title = {Polyphenolic Imidazopyridines as Multifunctional Modulators of Oxidative Stress, Metal Dyshomeostasis, and β1-42 Amyloid Aggregation in an In Vitro Model of Alzheimer's Disease.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {15},
number = {7},
pages = {},
doi = {10.3390/antiox15070857},
pmid = {42510588},
issn = {2076-3921},
abstract = {Alzheimer's disease (AD) involves oxidative stress, metal dyshomeostasis, and toxic oligomers of the amyloid-β peptide (Aβ1-42), calling for multifunctional agents. We investigated a panel of imidazo[1,2-a]pyridines bearing catechol or resorcinol motifs previously designed as SIRT1-activating agents. Their antioxidant profile was evaluated using in vitro DPPH and ABTS assays, which revealed promising radical scavenging activities, and TBARS assays on rat brain homogenates showing inhibition of lipid peroxidation, strictly dependent on the phenolic pattern. UV-Vis studies revealed metal-binding properties, particularly Cu[2+] and Fe[2+] interactions. In Aβ1-42 aggregation assays, the most active derivatives appeared to promote fibril maturation and the growth of large, ThT-low aggregates with distinct morphological features observed by TEM. Notably, Aβ1-42 aggregates generated in the presence of these compounds exhibited reduced cytotoxicity, preserved cell viability, and induced lower ROS levels in RA-differentiated SH-SY5Y cells compared to aggregates formed in their absence. Imaging and FRET analyses further indicated reduced formation of membrane-binding toxic species. Overall, our data suggest that polyphenolic imidazo[1,2-a]pyridines can remodel Aβ1-42 aggregation, redirecting it toward structurally distinct and less toxic assemblies, while also counteracting oxidative and metal-associated damage. These findings highlight their potential as multifunctional agents capable of addressing several pathological hallmarks of AD.},
}

@article {pmid42510665,
year = {2026},
author = {Mitroshina, EV and Strelkova, PL and Korokozova, MV and Vedunova, MV},
title = {HIF1 Stabilization by Roxadustat Improves Cognition and Prevents Neuron Loss in Alzheimer's Diseases In Vivo.},
journal = {Biology},
volume = {15},
number = {14},
pages = {},
doi = {10.3390/biology15141118},
pmid = {42510665},
issn = {2079-7737},
support = {22-15-00178-p//Russian Science Foundation/ ; },
abstract = {Alzheimer's disease (AD) is one of the most prevalent neurodegenerative disorders worldwide and is characterized by progressive memory impairment, cognitive decline, and behavioral dysfunction. The brain's high energy demand makes it vulnerable to hypoxia, which can trigger AD pathology. Hypoxia-inducible factor (HIF) is a transcription factor that mediates cellular and tissue adaptation to low oxygen levels. HIF-1 plays a dual role in AD: on the one hand, it is considered a potential neuroprotective target; on the other hand, its activation may exacerbate disease pathogenesis by promoting amyloid plaque formation. Given this ambiguity, further studies are needed. This study investigated the HIF prolyl hydroxylase inhibitor Roxadustat in 6-month-old male 5xFAD mice. Stabilization of the HIF-1 complex exerted a positive effect on learning ability and the retention of long-term spatial memory in 6-month-old male 5xFAD mice. Four-week treatment with Roxadustat significantly reduced pathological morphological alterations in cells of the prefrontal cortex. In addition, animals treated with Roxadustat exhibited significantly increased expression of the brain-derived neurotrophic factor (BDNF) in the cerebral cortex. Our findings suggest that stabilization of the HIF-1 complex through inhibition of HIF prolyl hydroxylase may represent a promising strategy for neuroprotection in AD.},
}

@article {pmid42510722,
year = {2026},
author = {Avitabile, A and Rusciano, D and Amato, R and Cannizzaro, L and Gagliano, C},
title = {Sex-Dependent Brain Plasticity in Neurological Disease: From Biological Variability to Adaptive, Compensatory, and Maladaptive Trajectories.},
journal = {Biology},
volume = {15},
number = {14},
pages = {},
doi = {10.3390/biology15141176},
pmid = {42510722},
issn = {2079-7737},
abstract = {Brain plasticity is often described as the capacity of the nervous system to change in response to development, experience, injury, disease, or treatment. That definition is useful, but it can obscure two clinically important points: plasticity is biologically constrained, and change is not always beneficial. This narrative review examines sex-dependent brain plasticity as a context-sensitive process rather than as a simple male-female contrast. We distinguish four operational outcomes of plasticity: (i) reparative plasticity, which restores structure or function; (ii) compensatory plasticity, which preserves performance through alternative or more costly strategies; (iii) insufficient plasticity, in which reorganization is too weak or unstable to sustain function; and (iv) maladaptive plasticity, in which plastic change reinforces dysfunction, pain, excitability, rigidity, or decline. We also define adaptive reserve as the integrated capacity of neural, glial, vascular, immune, metabolic, endocrine, and gene-regulatory systems to support useful reorganization under stress. The review evaluates endocrine, synaptic, neuroimmune, mitochondrial, vascular, stress-related, and epigenetic mechanisms, indicating where evidence for sex-dependent effects is relatively strong and where it remains indirect, inconsistent, or context-dependent. Disease examples include autism spectrum disorder, attention-deficit/hyperactivity disorder, epilepsy, intellectual disability, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, traumatic and ischemic injury, multiple sclerosis, chronic pain, aging, and systemic metabolic or inflammatory disorders. Throughout, biological sex is separated from gender-related social, diagnostic, and health-care determinants. We conclude that therapeutic strategies should not aim simply to enhance plasticity, but to guide it by matching intervention, timing, dose, biological readiness, and monitoring to the patient's adaptive state.},
}

@article {pmid42510815,
year = {2026},
author = {Deng, K and Deng, X and Li, S and Fang, S and Wei, F},
title = {The Genetic and Transcriptomic Nexus of Age-Related Hearing Loss and Alzheimer's Disease.},
journal = {Genes},
volume = {17},
number = {7},
pages = {},
pmid = {42510815},
issn = {2073-4425},
support = {2023A1515012713//Guangdong Basic and Applied Basic Research Foundation/ ; },
abstract = {Introduction: Despite the recognized association between age-related hearing loss (ARHL) and Alzheimer's disease (AD), the genetic relationship and shared transcriptional mechanisms between them remain largely unexplored. Methods: We systematically investigated the ARHL-AD axis using a multi-layered genomic strategy, incorporating causal inference, cis-eQTL mediation, Bayesian colocalization, and independent replication cohort validation. Results: Genetically predicted ARHL was associated with a reduced risk of overall AD and its early/late-onset subtypes, with no evidence of reverse causality in reverse MR analyses. Among 36 identified mediating genes, CSK showed the most consistent mediation signals across discovery and replication cohorts, although the replication was statistically partial (Sobel p = 0.078). Pathway analyses revealed that these genetic links predominantly involve Wnt signaling and endoplasmic reticulum protein processing. Discussion: Our integrative multi-omics findings suggest a potential genetic association between ARHL liability and AD risk. More importantly, we identified a prioritized CSK-driven transcriptional network, providing novel mechanistic insights and highlighting a candidate gene for future functional investigation in neurodegeneration.},
}

@article {pmid42510931,
year = {2026},
author = {Schuck, PF and da Costa Ferreira, G and Freitas, HR},
title = {Astrocyte Subtype-Specific Expression of the Sodium-Coupled Citrate Transporter SLC13A5 and Citrate Metabolism Genes Across Alzheimer's Disease Pseudoprogression: A Single-Nucleus RNA Sequencing Analysis of the Human Middle Temporal Gyrus.},
journal = {Current issues in molecular biology},
volume = {48},
number = {7},
pages = {},
doi = {10.3390/cimb48070691},
pmid = {42510931},
issn = {1467-3045},
support = {307377/2023-7//National Council for Scientific and Technological Development/ ; 445305/2024-0//National Council for Scientific and Technological Development/ ; 312744/2025-0//National Council for Scientific and Technological Development/ ; E-26/200.256/2026//Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro/ ; E-26/210.624/2025//Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro/ ; U24NS133077//Allen Institute/ ; 2024/2025 Scholarship for Young Professors and Researchers from Latin American Universities//Coimbra Group/ ; Early-Career Investigator Research Grant (2022/2023)//Tess Research Foundation/ ; },
abstract = {The sodium-coupled citrate transporter NaCT (SLC13A5) imports extracellular citrate into cells. In the CNS, SLC13A5 is described to be expressed predominantly in neurons. Cytosolic citrate levels rely on citrate generated in mitochondria and imported from other CNS cells, regulating intermediary metabolism and supplying acetyl-CoA for lipid synthesis and histone acetylation. Despite evidence for NaCT's role in neurometabolic homeostasis, its transcriptional behavior across Alzheimer's disease (AD) progression and across astrocyte subtypes remains uncharacterized at single-cell resolution. We analyzed single-nucleus RNA sequencing data from 1,378,211 nuclei across 84 donors in the Seattle Alzheimer's Disease Brain Cell Atlas (SEA-AD) Middle Temporal Gyrus dataset to profile SLC13A5 and seven citrate metabolism genes across a continuous AD pseudoprogression score. SLC13A5 expression was restricted to astrocytes (~20% prevalence) and concentrated in the Astro 2 supertype (24.0%), a homeostatic subtype characterized by low C3 (1.6%) and CD44 (5.5%), which expanded with pseudoprogression (Spearman rho = +0.345, FDR < 0.001). The A1-reactive Astro 3 supertype, where SLC13A5 prevalence was 0.87%, declined concordantly (rho = -0.393). Opposing compositional and transcriptional forces produced apparent stability in overall SLC13A5 prevalence. SLC13A3 and ACO1 showed progressive donor-level declines correlating with Braak stage and Thal phase (rho range: -0.307 to -0.349, FDR < 0.01). APOE4 carriers exhibited lower SLC13A5 prevalence specifically within Astro 2 nuclei (median 17.6% vs. 25.9%; Wilcoxon p = 0.025), though this association did not survive multivariate regression. No difference in Astro 2 SLC13A5 expression was detected between cognitively resilient and expected-AD donors with equivalent high Braak burden (p = 0.888). Contrary to the prevailing description of NaCT as a neuronal transporter, SLC13A5 transcript in the SEA-AD MTG dataset was detected almost exclusively in astrocyte nuclei, concentrated in the homeostatic Astro 2 subtype, and maintained as this subtype expanded with advancing AD pathology. Because these are nuclear transcript measurements, they delimit where SLC13A5 mRNA is detectable rather than establishing the cellular site of NaCT protein or activity, which requires in situ validation.},
}

@article {pmid42510934,
year = {2026},
author = {Wang, TS and Tzeng, IS and Chen, YC and Chen, ML},
title = {Herbal Bioactives Targeting Rho GTPases: A Multi-Targeted Strategy for Mitigating Neuroinflammation in Alzheimer's and Parkinson's Diseases.},
journal = {Current issues in molecular biology},
volume = {48},
number = {7},
pages = {},
doi = {10.3390/cimb48070694},
pmid = {42510934},
issn = {1467-3045},
support = {TCRD-TPE-111-28 (1/3) -(3/3)//Taipei Tzu Chi Hospital/ ; },
abstract = {Neuroinflammation plays an essential role in the pathogenesis of several associated brain diseases, including neurodegenerative disorders (Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS)), and traumatic brain injury (TBI). In these diseases, persistent microglial and astrocyte aggregates, elevated proinflammatory cytokines, and oxidative stress drive neuronal injury and cognitive disability. Rho GTPases, in particular the Rho family members Ras homolog family member A (RhoA), Ras-related C3 botulinum toxin substrate 1 (Rac1), and cell division control protein 42 homolog (CDC42), regulate neuroinflammation, cytoskeletal dynamics, immune responses, and the maintenance of BBB integrity. These proteins are involved in many neuropathological diseases due to dysregulation, making them interesting therapeutic targets. Bioactives used in herbal care have attracted interest for their ability to influence neuroinflammation and even their anti-neurodegenerative activity. Studies show that flavonoids, alkaloids, polyphenols, and other botanical compounds alter Rho GTPase activity, which, in turn, leads to decreased inflammation. This review critically summarizes current evidence regarding phytochemical regulation of Rho GTPase signaling in neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD), with particular emphasis on the underlying molecular mechanisms, context-dependent signaling responses, and current translational challenges. Furthermore, existing knowledge gaps and future research priorities are discussed to facilitate the development of mechanism-based therapeutic strategies targeting Rho GTPases.},
}

@article {pmid42511444,
year = {2026},
author = {Suwansukho, B and Poempul, K and Samee, W and Tadtong, S},
title = {The Synergistic Neuroprotective Effect of Honokiol and Magnolol Against Amyloid-β and MPP[+]-Induced Neurotoxicity in SH-SY5Y Cells: An Antioxidant, Molecular Orbital, and ADMET Study.},
journal = {International journal of molecular sciences},
volume = {27},
number = {14},
pages = {},
pmid = {42511444},
issn = {1422-0067},
support = {Grant No. 634/2568//Srinakharinwirot University/ ; },
abstract = {Alzheimer's disease (AD) and Parkinson's disease (PD) are the two main neurodegenerative diseases and cause disability and death in patients worldwide. Neurodegeneration is characterized by a progressive loss of neuronal function and structure, causing enormous impairment in cognitive-motor function. Magnolol and honokiol are isomeric biphenyl neolignans and have exhibited neuroprotective activity in previous studies. Hence, we assessed and compared honokiol, magnolol, and mixtures of honokiol and magnolol in honokiol/magnolol molar ratios of 1:3, 1:1, and 3:1 in terms of their neurotoxicity, using the cell counting kit-8 (CCK-8) assay, and of their neuroprotective effect on intracellular reactive oxygen species (iROS) against amyloid-beta (Aβ)- and 1-methyl-4-phenylpyridinium ion (MPP[+])-induced neurotoxicity in SH-SY5Y cells, using the 2',7'-dichlorodihydrofluorescein diacetate (H2DCF-DA) assay. The results showed that honokiol (H) and magnolol (M) at 0.1 μM and the mixtures of honokiol and magnolol in H/M ratios of 1:3, 1:1, and 3:1 at 0.0001 μM exhibited a significant neuroprotective effect of reducing iROS in SH-SY5Y cells where neurotoxicity was induced by Aβ- and MPP[+] (p-value with respect to Aβ-treated cells < 0.005 and p-value with respect to MPP[+]-treated cells < 0.0001). Moreover, magnolol and honokiol possess antioxidant properties according to computational molecular analysis with Highest Occupied Molecular Orbital (HOMO)- Lowest Unoccupied Molecular Orbital (LUMO) prediction, 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), 2,2-diphenyl-1-picrylhydrazyl (DPPH), and Ferric Reducing Antioxidant Power (FRAP) assays. The mixtures of honokiol and magnolol exerted synergistic neuroprotective ability at all ratios while showing better antioxidation ability than that of pure magnolol alone but comparable to that of pure honokiol alone. Drug-likeness, Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) prediction, and toxicity profiles showed that both compounds are promising neuroprotective agents and that one of the possible targeting mechanisms is the ROS-mediated oxidative stress pathway. Additional neuronal cell lines and in vivo models are required to determine similar effects or other protective mechanisms involving the neuroprotective ability of honokiol and magnolol.},
}

@article {pmid42511465,
year = {2026},
author = {Alshamari, AK and Magdy, N and Basiony, EA and Hassan, NA and Alshammari, OAO and Abdel-Rahman, AA and Alsaif, NOS and Alshammari, MZ and Elrashedy, AA and Hassan, AA},
title = {Synthesis, Biological Evaluation, Molecular Docking and Molecular Dynamics of Substituted Thieno[2,3-d]pyrimidine Derivatives as Potential Anti-Alzheimer Agents.},
journal = {International journal of molecular sciences},
volume = {27},
number = {14},
pages = {},
pmid = {42511465},
issn = {1422-0067},
support = {RG-23 108//University of Ha'il/ ; },
abstract = {Thienopyrimidine derivatives are emerging as potent scaffolds for cholinesterase inhibition in Alzheimer's disease therapy. In this work, a novel series of substituted thieno[2,3-d]pyrimidines was synthesized via Gewald's reaction, followed by cyclization and functionalization through nucleophilic substitution and hydrazone formation. Structural confirmation was achieved using spectroscopic techniques, and biological evaluation was performed against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), with donepezil and rivastigmine as reference drugs. Compound 4 emerged as the most potent and selective AChE inhibitor (IC50 = 0.58 µM), while compound 7 also showed strong AChE inhibition (IC50 = 0.63 µM). Notably, compound 9 exhibited superior BChE inhibition (IC50 = 3.05 µM) compared to donepezil (IC50 = 8.41 µM). Dual inhibitory activity was observed for compounds 5, 6, and 11, highlighting their multitarget potential. Molecular dynamics simulations (200 ns) and MM/GBSA binding free energy calculations provided mechanistic insights. Compound 4 showed the most favorable binding energy (ΔGbind = -59.16 kcal/mol), driven by hydrogen bonds with Tyr121 and Glu199 and π-π stacking with Trp83. Residue-level decomposition identified Tyr121, Trp83, Glu199, and Tyr338 as critical contributors to binding stability. Structure-activity relationship analysis confirmed that nitrogen-containing substituents and cyclic amino moieties enhance potency, whereas bulky aromatic groups reduce activity. These findings establish thieno[2,3-d]pyrimidine derivatives as promising candidates for the development of next-generation anti-Alzheimer agents.},
}

@article {pmid42511496,
year = {2026},
author = {Cha, S and Kim, J and Kim, J and Kim, D and Song, H and Lim, KS and Chae, S},
title = {Spatial Transcriptomics for Dissecting Cellular and Molecular Heterogeneity in the Aging and Diseased Brain.},
journal = {International journal of molecular sciences},
volume = {27},
number = {14},
pages = {},
pmid = {42511496},
issn = {1422-0067},
support = {RS-2024-00441289//National Research Foundation of Korea/ ; RS-2025-00512586//National Research Foundation of Korea/ ; RS-2023-00301850//Ministry of Education/ ; },
abstract = {The brain is a spatially organized tissue where the molecular characteristics of each cell are closely linked to its anatomical location. However, conventional bulk and single-cell RNA sequencing lose this spatial context during the tissue separation process. Spatial transcriptomics (ST) overcomes these limitations by measuring gene expression while preserving the positional information of cells within intact tissues, making it a powerful approach for elucidating the cellular and molecular heterogeneity that defines brain structure and disease. This review summarizes the two main types of ST technology: next-generation sequencing (NGS)-based platforms (Visium, Stereo-Seq, Slide-Seq) and in situ platforms (MERFISH, seqFISH+, Xenium). NGS-based platforms provide unbiased whole-transcriptome profiling across extensive tissue regions, while in situ platforms offer subcellular resolution within individual cells. We aim to assist in platform selection by comparing the principles, advantages, and limitations of each platform. Next, we focus on how spatial sequencing (ST) has been utilized to analyze the spatial heterogeneity of aging and diseased brains, and examine region- and cell-type changes observed in brain aging, the lesion-related microenvironments of Alzheimer's and Parkinson's diseases, and the spatially isolated tumor cell states and immunosuppressive environments of glioblastoma. We also introduce the key brain ST data resources that underpin these studies. Collectively, ST is emerging as an essential tool for understanding the spatial logic of brain function and pathology, demonstrating increasingly greater potential in the field of precision medicine.},
}

@article {pmid42511504,
year = {2026},
author = {Post, WM and Widomska, J and Oosterwijk, E and De Witte, W and Tiemessen, DM and Klemann, CJHM and Ruisch, IH and Coenen, MJH and Janssen, DAW and Martens, F and Carnes, MU and Marks, JA and Page, GP and Richter, HE and Cartwright, R and Minassian, VA and Thomas, LF and Skogholt, AH and Stafne, SN and Hveem, K and Kluivers, KB and Poelmans, G},
title = {Amyloid Precursor Protein Processing Links Female Urgency Urinary Incontinence with Alzheimer's Disease: Implications for Treatment.},
journal = {International journal of molecular sciences},
volume = {27},
number = {14},
pages = {},
pmid = {42511504},
issn = {1422-0067},
support = {PROJ00787 (DIABIP)//European Fund for Regional Development (EFRD)/ ; },
abstract = {Urgency urinary incontinence (UUI) and Alzheimer's disease (AD) are highly comorbid conditions in women, but the underlying molecular mechanisms are largely unknown. Therefore, we used network enrichment analyses and an elaborate literature search to integrate the most significant genes from four genome-wide association studies (GWASs) and other genetic, expression and functional evidence into a molecular landscape of female UUI. This molecular landscape centers around local, i.e., bladder-based, processing of the AD-associated amyloid precursor protein (APP). To further elucidate how APP processing is implicated in the comorbidity between UUI and AD, we conducted polygenic risk score (PRS)-based analyses, which showed that genetic risk factors associated with AD and a decreased amyloid beta 42/40 blood level ratio (also) contribute to UUI susceptibility. In conclusion, APP processing constitutes a putative molecular link between UUI and AD, adding further weight to their clinical comorbidity and having implications for the treatment (and prevention) of both traits.},
}

@article {pmid42511534,
year = {2026},
author = {Naso, F and Gandaglia, A and Sturaro, G and Lepore, A and Arcaro, A and Gentile, F and Di Costanzo, A and Angiolillo, A},
title = {Anti-Alpha-Gal Antibodies Against Gangliosides: Preliminary Data on a New Autoimmune Target in Alzheimer's Disease Patients.},
journal = {International journal of molecular sciences},
volume = {27},
number = {14},
pages = {},
pmid = {42511534},
issn = {1422-0067},
support = {//Fondazione Anticorpi Antifosfolipidi Onlus/ ; //National Plan for NRRP Complementary Investments D∧3 4 Health/ ; },
abstract = {Human anti-αGal antibodies (Abs), known for their marked polyreactivity, have been detected bound to the gray matter of the brains of Alzheimer's disease (AD) patients, although their targets were unclear. Since αGal is a strictly xenogenic antigen absent in humans, this observation raised questions regarding the nature of the structures recognized by these antibodies. In this study, we investigated their potential interaction with gangliosides-glycan structures that are highly abundant in the central nervous system. Using a competitive inhibition ELISA, serum profiles of anti-αGal Abs isotypes and their indirect cross-reactivity with selected soluble gangliosides were analyzed in AD patients and healthy subjects (HSs). AD patients showed reduced levels of anti-αGal IgG and IgM, but increased IgA compared to HSs. Notably, pre-incubation with GM1, GM2, or GD1b did not reduce αGal-HSA binding in HS sera. In contrast, in AD sera, pre-incubation with GD1b reduced residual αGal-HSA binding for all antibody isotypes; additionally, GM1 inhibited IgM binding, and GM2 inhibited IgA binding. These results should therefore be interpreted as competitive inhibition patterns consistent with ganglioside-associated cross-reactivity rather than as direct evidence of antibody binding to immobilized gangliosides. Overall, the findings provide preliminary evidence that, in AD sera, a fraction of αGal-HSA-reactive antibodies can be competitively inhibited by selected gangliosides. This observation supports the presence of an altered humoral anti-carbohydrate signature in AD and identifies neuronal gangliosides as plausible candidate autologous targets that may help explain the previously reported binding of anti-αGal Abs to gray matter. However, given the indirect nature of the assay, these data should be considered hypothesis-generating and require confirmation by direct binding approaches.},
}

@article {pmid42511539,
year = {2026},
author = {Nguyen, LTH and Nguyen, HT and Nguyen, TU},
title = {Investigation of the Potential Neuroprotective Mechanisms of Acalypha indica Against Alzheimer's Disease by Integrated Bioinformatics Analysis.},
journal = {International journal of molecular sciences},
volume = {27},
number = {14},
pages = {},
pmid = {42511539},
issn = {1422-0067},
abstract = {Alzheimer's disease (AD) is one of the most common neurodegenerative disorders; however, available treatments majorly offer symptomatic relief without delaying disease progression and are associated with various adverse effects, highlighting the need for development of alternative therapies. Acalypha indica has previously showed neuroprotective effects in aging-related animal models, yet its mechanisms against AD were not fully understood. In this study, we employed an integrated bioinformatics approach combining network pharmacology, transcriptomic analysis, and molecular docking to investigate the anti-AD potential of this herb. A total of 282 overlapping targets between A. indica compounds and AD were identified. Network pharmacology analysis indicated chrysin, daidzein, galangin, kaempferol, and quercetin as the key bioactive components. Enrichment analyses suggested that targets of these compounds are mainly associated with phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) and mitogen-activated protein kinase (MAPK) signaling pathways. Protein-protein interaction (PPI) analysis identified AKT1, epidermal growth factor receptor (EGFR), interleukin 6 (IL6), tumor necrosis factor (TNF), and p53 protein (TP53) as crucial hub targets. These targets were significantly upregulated in AD brain samples and were closely associated with pathways related to neurodegeneration, inflammation, as well as alterations in immune cell infiltration. Among the compounds, quercetin exhibited the strongest binding affinity to these target proteins. Overall, these findings provide a strong foundation for the multi-target therapeutic potential of A. indica in AD.},
}

@article {pmid42511649,
year = {2026},
author = {Kiss, E and Kirsch, J and Kins, S and Kuhse, J},
title = {Synaptic vs. Non-Synaptic Glycine Receptors: Physiological Role and Implications in Alzheimer's Disease Pathology.},
journal = {International journal of molecular sciences},
volume = {27},
number = {14},
pages = {},
pmid = {42511649},
issn = {1422-0067},
support = {PN-III-P4-PCE-2021-1089//Ministry of Research and Innovation/ ; },
abstract = {Strychnine-sensitive glycine receptors (GlyRs) are pentameric ligand-gated chloride channels that mediate fast inhibitory neurotransmission in the central nervous system (CNS), with high expression in the spinal cord, brainstem, cerebellum, and retina. Beyond traditional postsynaptic phasic inhibition, emerging evidence highlights the importance of extrasynaptic GlyRs-expressed in both neuronal and non-neuronal cells-in mediating tonic inhibition by sensing ambient glycine levels, including in the forebrain. These non-synaptic receptors display high agonist affinity, unique subunit compositions, and distinct pharmacodynamics. Notably, recent studies have begun to implicate aberrant GlyR signaling in Alzheimer's disease (AD) pathology; however, its functional role in this specific neurodegenerative context remains only poorly understood. This review synthesizes the molecular properties and functional significance of these diverse GlyR populations, emphasizing their involvement in calcium signaling, inhibitory tone, and neural circuit modulation, while critically evaluating their emerging therapeutic potential in AD.},
}

@article {pmid42511671,
year = {2026},
author = {Khan, MS and Zafar, I and Bopassa, JC},
title = {Phytochemicals in Alzheimer's Disease Prevention and Management: Molecular Mechanisms, Therapeutic Potential, Translational Challenges, and Emerging Research Directions.},
journal = {International journal of molecular sciences},
volume = {27},
number = {14},
pages = {},
pmid = {42511671},
issn = {1422-0067},
abstract = {Alzheimer's disease (AD) is the most common neurodegenerative disorder and a leading cause of dementia worldwide, characterized by progressive cognitive decline, memory impairment, and neuronal loss. The pathological hallmarks of AD include extracellular accumulation of amyloid-β (Aβ) plaques, intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein, chronic neuroinflammation, oxidative stress, mitochondrial dysfunction, and synaptic degeneration. Current symptomatic therapies provide modest clinical benefits, while recently approved amyloid-targeting monoclonal antibodies, such as lecanemab and donanemab, can slow decline in selected early-stage AD patients but do not cure the disease and are associated with safety, access, and cost concerns. This narrative review summarizes mechanistic evidence from in vitro and in vivo studies and distinguishes preclinical promise from validated clinical utility. Phytochemicals, including polyphenols, flavonoids, alkaloids, terpenoids, and carotenoids, demonstrate neuroprotective effects through antioxidant activity, anti-inflammatory modulation, inhibition of amyloid aggregation, regulation of tau phosphorylation, and support of mitochondria and synapses. Evidence from experimental models suggests that several phytochemicals may help slow AD pathology and improve cognitive function, but clinical translation remains limited due to poor bioavailability, inadequate blood-brain barrier (BBB) penetration, and a lack of large-scale clinical trials. This review highlights critical research gaps and emerging strategies to facilitate phytochemical-based preventive and therapeutic approaches in AD.},
}

@article {pmid42511680,
year = {2026},
author = {Podshivalova, ES and Kutsev, SI and Shestopalov, AV},
title = {The Kynurenine Pathway: Unraveling Its Role in Neurological Disorders via Mammalian Cellular Models.},
journal = {International journal of molecular sciences},
volume = {27},
number = {14},
pages = {},
pmid = {42511680},
issn = {1422-0067},
abstract = {The kynurenine pathway (KP) constitutes the primary route of tryptophan catabolism, generating a spectrum of neuroactive metabolites that profoundly influence central nervous system function. Dysregulation of the KP is increasingly recognized as a critical pathogenic mechanism underlying diverse neuropathological conditions. This review critically evaluates the most widely cited mammalian cellular models currently utilized to delineate the causal role of KP alterations in neurological disease. Specifically, this article examines primary cell cultures, immortalized and tumor-derived cell lines, stem cell-derived systems, and ex vivo organotypic brain slices and tissues, highlighting their distinct methodological advantages, translational limitations, and specific enzymatic profiles. Across the described cellular systems, a recurring mechanistic theme emerges: quinolinic acid-driven mitochondrial dysfunction, oxidative stress, and NAD+ depletion converge in neurodegenerative conditions such as Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. Conversely, kynurenic acid exhibits disorder-dependent-and at times opposing-roles, attenuating dopaminergic neurotoxicity in Parkinson's disease models while contributing to synaptic pruning deficits in schizophrenia models. Furthermore, cellular models demonstrate that IDO1/TDO induction and downstream metabolite shifts are frequently cell type- and species-dependent, complicating direct extrapolation to human pathology. Because no single experimental system achieves complete physiological fidelity, elucidating the complex dynamics of the KP and identifying novel therapeutic targets requires the integration of data across complementary platforms.},
}

@article {pmid42511717,
year = {2026},
author = {Sümer, A and Şahin, S and Menteşe, A},
title = {Carbonic Anhydrase I and II as Biomarkers and Therapeutic Targets in Human Disease: From Physiology to Clinical Translation.},
journal = {International journal of molecular sciences},
volume = {27},
number = {14},
pages = {},
pmid = {42511717},
issn = {1422-0067},
abstract = {Carbonic anhydrases (CAs) are zinc-containing metalloenzymes that catalyze the reversible conversion of carbon dioxide and water into bicarbonate and protons, contributing to acid-base balance, pH regulation, and ion transport. Among human cytosolic isoforms, carbonic anhydrase I (CA I) and carbonic anhydrase II (CA II) are abundant and clinically relevant, yet their distinct roles are often obscured within broader discussions of the CA family. This narrative review evaluates CA I and CA II as biomarkers and therapeutic targets in glaucoma, atherosclerosis and vascular calcification, anemia, epilepsy, Alzheimer's disease, obstructive sleep apnea, obesity-related metabolic dysfunction, and selected cancers. CA II emerges as the more established pharmacological target, particularly in glaucoma, with acetazolamide and sultiame showing therapeutic potential in obstructive sleep apnea and possible contributions to epilepsy and neurodegeneration through pH regulation, bicarbonate-dependent signaling, and mitochondrial function. CA I instead appears more valuable as a disease-associated biomarker, especially in disorders involving erythrocyte turnover, inflammation, anemia, and malignancy, though circulating CA I may be confounded by hemolysis and altered erythrocyte dynamics. Clinical translation requires isoform-selective modulators, tissue-targeted delivery, standardized biomarker assays, and mechanistic models distinguishing primary CA involvement from secondary disease-related changes.},
}

@article {pmid42511728,
year = {2026},
author = {Malaplate, C and Oster, T},
title = {Special Issue "Molecular Insight into Alzheimer's Disease".},
journal = {International journal of molecular sciences},
volume = {27},
number = {14},
pages = {},
pmid = {42511728},
issn = {1422-0067},
abstract = {Alzheimer's disease (AD) remains one of the greatest biomedical challenges of our time, mostly because it appears to result from a complex interplay of several determinants [...].},
}

@article {pmid42511787,
year = {2026},
author = {Sun, D and Wang, S and Meng, Q and Wang, X and Amiri, M and Unnithan, RR and French, C},
title = {Large-Scale Neural Recording Technologies for Investigating Circuit Dysfunction and Functional Biomarker Discovery in Animal Models of Alzheimer's Disease.},
journal = {International journal of molecular sciences},
volume = {27},
number = {14},
pages = {},
pmid = {42511787},
issn = {1422-0067},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder associated with amyloid beta accumulation, tau pathology, and neuronal loss. Increasing evidence suggests that AD is associated with disruptions in large-scale circuit activity across multiple disease animal models, even before clear cognitive decline. These findings highlight the need for functional biomarkers that capture dynamic changes in neuronal network activity, rather than relying solely on molecular or anatomical measures. Recent advances in neural recording technologies now allow AD-related network dysfunction to be examined with greater spatial and temporal resolution. This review summarises recent progress in large-scale neural recording technologies, including miniaturized fluorescence microscopy, voltage-sensitive optical recording, high-density probe electrophysiology, and high-density CMOS microelectrode array systems. These techniques provide improved characterization of large network-level abnormalities in AD animal models. Although they are unlikely to serve directly as routine clinical biomarkers, their translational value lies in clarifying circuit-level disease mechanisms, identifying functional features that may inform candidate clinical biomarkers, and supporting preclinical evaluation of therapeutic interventions.},
}

@article {pmid42511940,
year = {2026},
author = {Victoria-Martínez, J and Martín-Nieto, J},
title = {Exploring Alzheimer Disease from a Retinal and Ocular Perspective.},
journal = {Biomedicines},
volume = {14},
number = {7},
pages = {},
doi = {10.3390/biomedicines14071465},
pmid = {42511940},
issn = {2227-9059},
support = {Grants VIGROB24-237, UADIF24-81 and UAUSTI24-14, awarded to J.M.-N.//University of Alicante/ ; },
abstract = {Alzheimer disease (AD) is a neurodegenerative disorder currently recognized as the leading cause of dementia worldwide. It is characterized by a progressive cognitive decline, which can be studied and diagnosed through the use of various brain biomarkers. The retina, being part of the central nervous system, shares numerous structural and functional features with the brain. In this light, a wide range of alterations have been found in the retina with significant potential as biomarkers for AD diagnosis, even at early stages of its manifestation in the brain, and for monitoring disease progression within this organ. Furthermore, the detection of such alterations in the eye and retina is feasible through non-invasive, relatively simple and cost-effective techniques, such as optical coherence tomography, scanning laser ophthalmoscopy and electroretinography. Using these methods, numerous studies have identified molecular, morphological and functional changes associated with AD in the retina and other ocular elements, including the choroid, cornea, lens, intraocular humors and tear fluid. This review addresses the main anomalous changes identified to date in the retina and other eye structures in patients with AD, highlighting their potential utility as biomarkers for the diagnosis of this disease and their possible extrapolation to its prognosis in the brain.},
}

@article {pmid42511997,
year = {2026},
author = {Apostol, A and Kuzubova, E and Radchenko, A and Chaprov, K and Shcheblykina, O and Lebedev, P and Korokina, L and Pokrovskii, M and Sedinova, V and Khizeva, A and Ninkina, NN and Korokin, M},
title = {Traumatic Brain Injury Modulates Synuclein-Associated Transcription, Amyloid Plaque Morphology and Cognitive Performance in APPswe/PS1dE9/Blg Mice.},
journal = {Biomedicines},
volume = {14},
number = {7},
pages = {},
doi = {10.3390/biomedicines14071524},
pmid = {42511997},
issn = {2227-9059},
support = {This work was supported by the Ministry of Science and Higher Education of the Russian Federation, agreement No. 075-15-2025-558.//The Ministry of Education and Science of the Russian Federation/ ; The Federal Scientific-technical Programme for Genetic Technologies Development for 2019-2030, agreement N◦ 075-15-2025-558//The Ministry of Education and Science of the Russian Federation/ ; },
abstract = {Background/Goals: Traumatic brain injury (TBI) is increasingly recognised as an important risk factor for delayed neurodegeneration and has been implicated in the modulation of Alzheimer's disease (AD)-related amyloid pathology. However, experimental evidence remains equivocal, suggesting that the effects of TBI on amyloidogenesis are context-dependent and influenced by factors including disease stage, injury severity, and the pre-existing neurodegenerative background. This study aimed to comprehensively assess the effects of TBI on cognitive function, synuclein-family gene expression, neuroinflammatory gene expression and amyloid plaque morphology in APPswe/PS1dE9/Blg mice. Methods: Wild-type and APP/PS1 mice were assigned to four experimental groups: WT, WT-TBI, APP/PS1 and APP/PS1-TBI. TBI was induced at 6 months of age using a controlled cortical impact device (precision impactor). Behavioural assessments were conducted at two post-injury time points to evaluate locomotor activity, object recognition memory, short-term spatial memory and spatial learning. Cortex and hippocampus samples were analysed by qRT-PCR to evaluate synuclein-family gene expression and neuroinflammation-related markers. Amyloid plaque pathology was evaluated in Congo red-stained brain sections using QuPath-based image analysis. Results: TBI did not induce a consistent increase in amyloid plaque burden in APP/PS1 mice. Instead, TBI was associated with changes in plaque-size distribution, particularly at the later post-injury time point. Behavioural assessments revealed early trauma-associated cognitive impairmen; whereas, impairments observed at later stages appeared to be driven predominantly by progression of the APP/PS1 phenotype. Gene expression analysis revealed region- and genotype-dependent alterations in synuclein-family transcripts and inflammatory markers with the most pronounced changes observed in the cortex. Conclusions: These findings indicate that TBI does not uniformly accelerate β-amyloid deposition in APP/PS1 mice with established amyloid pathology. Rather, TBI appears to modify the temporal progression and morphological characteristics of amyloid pathology while interacting with genotype-dependent transcriptional responses involving synuclein-family genes and neuroinflammatory pathways. These results highlight the complex interplay between traumatic injury and pre-existing neurodegenerative processes and warrant further studies at the protein-level and over extended follow-up periods to elucidate the underlying mechanisms.},
}

@article {pmid42512037,
year = {2026},
author = {Bagda, V and Farooz, ZH and Knuckey, NW and South, SM and Gribble, SK and Tomar, M and Bharadwaj, P and Ariyath, A and Taddei, K and Martins, RN and Meloni, BP},
title = {The Poly-Arginine Peptide R18D Inhibits Amyloid-Beta (Aβ) Aggregation and Aβ-Induced Cytotoxicity, Reduces Intracellular Tau Aggregation, and Exhibits Oral Bioavailability.},
journal = {Biomedicines},
volume = {14},
number = {7},
pages = {},
doi = {10.3390/biomedicines14071564},
pmid = {42512037},
issn = {2227-9059},
support = {N/A//Perron Institute for Neurological and Translational Science/ ; N/A//Argenica Therapeutics/ ; },
abstract = {Background/Objectives: Effective disease-modifying therapies targeting pathogenic proteins associated with Alzheimer's disease (AD) remain limited. This study investigated the therapeutic potential of the neuroprotective, cationic arginine-rich peptide R18D to mitigate the pathogenic effects of amyloid-beta (Aβ) and tau associated with AD. Methods: R18D was examined for its ability to inhibit Aβ aggregation in a cell-free assay, attenuate Aβ-induced cytotoxicity in MC65 cells, and suppress intracellular tau aggregation in two neural cell models. Intracellular tau aggregation was quantified using a homogeneous time-resolved fluorescence assay. Additionally, a pilot pharmacokinetic study of R18D was conducted in mice following oral gavage administration. Results: In the cell-free assay, R18D inhibited Aβ aggregation by up to 65%. In human MC65 cells induced to overexpress APP-C99 and accumulate Aβ, treatment with R18D inhibited cellular toxicity by as much as 100%. Preformed tau seeds were applied to human SH-SY5Y cells and rat primary cortical neurons to induce intracellular tau aggregation, and tau levels were quantified after 48 h. Exposure to tau seeds induced robust tau aggregation in both cellular models, which was significantly attenuated by R18D treatment, reducing aggregation by 34.8% in SH-SY5Y cells and 49.9% in cortical neurons. Pharmacokinetic studies demonstrated that R18D was detectable in plasma at 30 and 60 min following oral administration in mice. Conclusions: Together, these results demonstrate that R18D can modulate both Aβ and tau pathologies in vitro and is orally bioavailable, supporting its further evaluation as a therapeutic candidate for AD and other tau-associated neurodegenerative disorders.},
}

@article {pmid42512081,
year = {2026},
author = {Che Mohd Nassir, CMN and Vishnumukkala, T and Kalerammana Gopalakrishna, P and Jagadeesan, S and Mohd Nor, NH and Mehat, MZ and Mohd Moklas, MA and Hein, ZM and Kamaruzzaman, MA},
title = {Rodent Models of Alzheimer's Disease: Bridging the Translational Gap Through Systems-Level Integration.},
journal = {Biomedicines},
volume = {14},
number = {7},
pages = {},
doi = {10.3390/biomedicines14071609},
pmid = {42512081},
issn = {2227-9059},
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder and a leading cause of dementia worldwide, yet effective disease-modifying therapies remain elusive. Rodent models have been indispensable for elucidating key pathological mechanisms, including amyloid-beta (Aβ) deposition, tau pathology, neuroinflammation, and synaptic dysfunction. However, despite decades of preclinical success, the translation of therapeutic findings from rodent studies to clinical efficacy in humans has been largely unsuccessful, highlighting critical limitations in current modelling approaches. This narrative review provides a comprehensive and critical evaluation of rodent models of AD, encompassing transgenic, chemically induced, metabolic, inflammatory, and lesion-based paradigms. Rather than presenting these models in isolation, we propose a systems-level framework that categorizes them based on their ability to recapitulate distinct domains of AD pathology, including genetic, environmental, and systemic contributors. By synthesising existing research, highlighting critical gaps, and proposing a tiered minimum-criteria framework for the development of next-generation models, we offer a definitive operational roadmap instead of merely a list of deficiencies. We highlight that most existing models predominantly reflect familial and reductionist aspects of the disease, while failing to capture the complexity of sporadic AD, aging processes, vascular dysfunction, and whole-body interactions. Importantly, we emphasize emerging dimensions that are underrepresented in current rodent models, including glymphatic dysfunction, cerebral small vessel disease, and the microbiota-gut-brain axis, all of which play crucial roles in AD pathogenesis. We further discuss how integrating these factors into next-generation models may improve translational relevance and therapeutic predictability. By synthesizing current evidence and identifying key gaps, we provide a strategic roadmap for the development of more physiologically relevant and translationally robust rodent models. Advancing toward integrative, systems-based approaches will be essential for bridging the persistent gap between preclinical discoveries and clinical success in AD.},
}

@article {pmid42512434,
year = {2026},
author = {Yang, Y and Kwak, YT},
title = {Behavioral Complexity in Alzheimer's Disease: A Diversity-Based Analysis of Neuropsychiatric Symptoms.},
journal = {Brain sciences},
volume = {16},
number = {7},
pages = {},
doi = {10.3390/brainsci16070659},
pmid = {42512434},
issn = {2076-3425},
abstract = {Background and Objectives: To quantify behavioral complexity in probable Alzheimer's disease (AD), compare complexity phenotypes, and determine whether behavioral complexity provides clinically meaningful information beyond total neuropsychiatric burden. We also explored whether global amyloid extent and lobar amyloid topography added explanatory value. Methods: In this cross-sectional retrospective study, we analyzed 245 psychotropic drug-naïve patients with probable AD, positive [18]F-FC119S amyloid positron emission tomography (PET), and complete neuropsychiatric, cognitive, functional, and regional PET data. Behavioral complexity was derived from 12 Korean Neuropsychiatric Inventory domains using symptom count, normalized Shannon entropy of the frequency × severity profile, and a composite index. Patients were classified into tertiles. Multivariable regression and burden-stratified analyses examined associations with cognition, dementia severity, function, and amyloid measures. Results: Higher behavioral complexity was associated with lower Korean Mini-Mental State Examination (K-MMSE) scores and higher Clinical Dementia Rating (CDR) and Global Deterioration Scale (GDS) stages. In multivariable analysis, higher CDR, higher GDS, and lower Barthel Index independently predicted greater complexity, whereas amyloid extent did not. After adjustment for total neuropsychiatric burden, higher CDR remained independently associated with the composite complexity index and normalized entropy, while amyloid extent remained non-significant. Complexity-related clinical differences were most evident in the lowest burden stratum and attenuated at higher burden levels. Regional amyloid analyses yielded only selective signals. Conclusions: Behavioral complexity is a clinically meaningful neuropsychiatric phenotype in AD. Although strongly related to total neuropsychiatric burden, it is not fully reducible to it, with its clearest independent association seen for global dementia severity, particularly at lower overall burden.},
}

@article {pmid42512440,
year = {2026},
author = {Wang, B},
title = {WGTMM: WGAN with Transformer Feature Matching for Generating fMRI Data in MCI Patients.},
journal = {Brain sciences},
volume = {16},
number = {7},
pages = {},
doi = {10.3390/brainsci16070665},
pmid = {42512440},
issn = {2076-3425},
support = {62306268//National Natural Science Foundation of China/ ; },
abstract = {BACKGROUND: The emergence of generative adversarial networks has laid the groundwork for data augmentation, addressing challenges of missing training data in various research scenarios. However, simulating functional magnetic resonance imaging (fMRI) data remains particularly challenging, especially for populations with varying degrees of mild cognitive impairment (MCI). Effectively characterizing and capturing the mechanisms of brain function variations poses a critical issue in cognitive neuroscience. This study aims to simulate and analyze synthetic fMRI blood-oxygen-level-dependent (BOLD) signals across four cognitive stages: healthy control (HC), early MCI (EMCI), late MCI (LMCI), and Alzheimer's disease (AD).

METHODS: We propose WGTMM, an innovative method that integrates the Vision Transformer for fMRI (VTFF) into a generative adversarial network architecture. Crucially, WGTMM directly generates fMRI time-series data from pink noise rather than modeling in a latent space, thereby preserving rich temporal dynamics. The framework incorporates a Wasserstein GAN (WGAN) with feature matching to enhance generation quality and mitigate mode collapse.

RESULTS: demonstrate that WGTMM-generated fMRI data exhibit lower Kullback-Leibler (KL) divergence compared to traditional GAN and WGAN models, indicating a closer resemblance to real datasets from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Furthermore, when applied to data augmentation, the synthetic data substantially improve multi-class classification performance.

CONCLUSIONS: WGTMM not only enriches training datasets but also provides new insights into spatial biomarkers of cognitive decline. By leveraging VTFF to investigate class token attention patterns across 360 brain regions, this study reveals monotonic weight variations along disease stages in key cortical areas, including the rostral Area 6, the primary sensory cortex, and PFm near Wernicke's area, offering a fine-grained exploration of disease progression.},
}

@article {pmid42512442,
year = {2026},
author = {Crisci, V and Sagliano, L and Ferrara, A and Salzillo, A and Trojano, L and Panico, F},
title = {Qualitative Analysis of Constructional Errors in Neurodegenerative Conditions: A Systematic Review.},
journal = {Brain sciences},
volume = {16},
number = {7},
pages = {},
doi = {10.3390/brainsci16070667},
pmid = {42512442},
issn = {2076-3425},
abstract = {Background/Objectives: Constructional apraxia (CA) is an impairment in combining simple elements into coherent spatial configurations without basic motor deficits. Although common in neurodegenerative disorders, the qualitative features of visuo-constructional errors and their role in differentiating dementia types remain unclear. This systematic review aimed to synthesize patterns of visuo-constructional errors in dementia and mild cognitive impairment (MCI), exploring distinctive qualitative features associated with different neurodegenerative conditions. Methods: A systematic literature search was conducted in PubMed, Scopus, and Web of Science for studies published between January 1990 and January 2026, following PRISMA guidelines. Studies on adults with dementia or MCI assessing drawing/copying abilities through standardized tasks and qualitative error analysis were included. Reviews, meta-analyses, case reports, non-English articles, and studies not explicitly assessing constructional apraxia were excluded. The quality of evidence was assessed using an adapted version of the Newcastle-Ottawa Scale. Results: A total of 25 studies were included, showing heterogeneous and condition-specific visuo-constructional deficits. Spatial errors and simplifications were the most common across disorders, while perseverations, rotations, and closing-in phenomena were less frequent. Alzheimer's disease was mainly associated with spatial disorganization, omissions, and conceptual errors linked to temporo-parietal dysfunction; frontotemporal dementia with executive deficits such as perseverations and planning impairments; Lewy body and Parkinson's disease dementias with visuospatial and attentional alterations; and Huntington's disease with simplifications and executive dysfunction related to fronto-striatal involvement. Conclusions: No single error pattern was pathognomonic, but qualitative assessment of constructional errors may provide clinically useful information when integrated with the broader neuropsychological profile.},
}

@article {pmid42512450,
year = {2026},
author = {Yogi, S and Singh, A},
title = {Molecular Mechanisms of Neurodegenerative Diseases: Emerging Biomarkers and Therapeutic Targets.},
journal = {Brain sciences},
volume = {16},
number = {7},
pages = {},
doi = {10.3390/brainsci16070675},
pmid = {42512450},
issn = {2076-3425},
abstract = {Neurodegenerative diseases (NDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), involve the gradual loss of structure or function of neurons in the nervous system and are an increasing threat to the aging population worldwide. Although these disorders have different clinical features which affect cognition, movement and other vital body functions, they share key underlying molecular and cellular processes. This starts with protein misfolding and aggregation, mitochondrial dysfunction, oxidative stress, dysregulated protein homeostasis, neuroinflammation, and disrupted cell death pathways. Recent findings have added disease-specific processes, like amyloid-β and tau aggregates in AD, α-synuclein aggregation and mitophagy failure in PD's, TDP-43-related impaired RNA metabolism in ALS, and mutant huntingtin causing transcription aberrations in HD. Protein interactome network analysis showed mechanistic crosstalk between pathogenic proteins of AD and PD. New evidence highlights how lysosomal dysfunction, endoplasmic reticulum stress, and microglial activation, act as a common axis in neurodegeneration. Advancements in genomics and epigenomics have found shared genetic risk loci and regulatory processes that affect how diseases develop and progress. Simultaneously, new biomarkers like circulating microRNAs, exosome-related pathological proteins, neurofilament light chain, inflammatory cytokines, and microglial activation markers are powering early diagnosis tools and disease variations. New imaging techniques also allow for the identification of protein aggregations before symptoms appear. Overall, these findings are accelerating targeted treatments and personalized medicine aimed at disease progression. This review highlights current insights into the molecular mechanisms of NDs and discusses new biomarkers and treatment targets that help future diagnostic and treatment strategies.},
}

@article {pmid42512462,
year = {2026},
author = {Siarkos, K and Politis, AM and Politis, AA and Smyrnis, N and Papageorgiou, C and Prentakis, A and Gournellis, R and Katirtzoglou, E and Theleritis, C},
title = {Non-Pharmacological Interventions for Managing Apathy in Older Adults with Neurocognitive Disorders: A Systematic Review of Randomized Controlled Trials.},
journal = {Brain sciences},
volume = {16},
number = {7},
pages = {},
doi = {10.3390/brainsci16070687},
pmid = {42512462},
issn = {2076-3425},
abstract = {BACKGROUND/OBJECTIVES: Apathy is among the most common neuropsychiatric features of late-life neurocognitive disorders and predicts functional decline and greater caregiver burden. As no treatment is formally established, identifying effective interventions is a priority. We systematically reviewed non-pharmacological randomized controlled trials (RCTs) targeting apathy in older adults with neurocognitive disorders.

METHODS: We searched PubMed/MEDLINE, PsycInfo, the Cochrane Library, and Google Scholar (final search 23 March 2026). Eligible studies were non-pharmacological RCTs reporting an apathy outcome. Evidence levels were graded with OCEBM and quality with PEDro; two reviewers mapped PEDro items onto Cochrane risk-of-bias domains. Reporting followed PRISMA 2020.

RESULTS: Sixty-two RCTs were included. Physical exercise and music-based interventions showed the most consistent benefit, whereas technology-based and brain stimulation approaches remained experimental. Only 30 trials (48%) showed a significant between-group effect on apathy-most were null, within-group, or had apathy as a secondary outcome. Marked heterogeneity precluded meta-analysis. Most trials were of moderate to high quality, though near-universal performance bias arose from the inability to blind participants and providers.

CONCLUSIONS: Managing apathy in these populations remains challenging, and the certainty of the evidence is limited. Purpose-built, apathy-focused trials reporting effect sizes and durability are needed before disease-specific recommendations can be made.},
}

@article {pmid42512531,
year = {2026},
author = {Phutirat, A and Culevski, KA and Mach, H and Kwon, J and Tan, H and Koh, G and Marzban, C and Mourad, PD},
title = {Low-Intensity Focused Ultrasound Alters Alzheimer's Disease Pathology, In Vivo, as a Function of Ultrasound Dose and Age.},
journal = {Brain sciences},
volume = {16},
number = {7},
pages = {},
doi = {10.3390/brainsci16070757},
pmid = {42512531},
issn = {2076-3425},
support = {W81XWH-20-1-0479//Congressionally Directed Medical Research Programs/ ; },
abstract = {BACKGROUND/OBJECTIVES: Alzheimer's Disease (AD) and vascular dementia contribute up to ~75% of dementia cases, as determined via autopsy. AD arises in part due to the buildup of aberrant proteins (amyloid beta (Aβ) and Tau); vascular dementia is caused by reduced cerebral blood flow. Each dementia mechanisms damages brain. Bobola et al. found that their low-intensity focused ultrasound (FUS) protocol applied to the brains of the 5XFAD mouse model of AD reduced Aβ by 50% through activation of microglia. Eguchi et al. found that their own FUS protocol applied to the brains of the same mouse model reduced Aβ by 15% and increased cerebral blood flow by 50% through an increase in endothelial nitric oxide synthase (eNOS). Here, we sought to test a combined version of those two FUS protocols, expecting both a decrease in Aβ burden and an increase in eNOS.

METHODS: Using a diagnostic ultrasound probe, we applied our combined FUS protocol primarily to the left hippocampus of anesthetized 5XFAD mice, for an hour a day, for three days for younger mice and for five days for older mice. On day three or five, respectively, we harvested their brains and performed histological analysis to assess Aβ burden, microglial activation and their co-localization with Aβ, as well as the burden of eNOS within neuronal nuclei (here called intra-neuronal eNOS) and outside of neurons.

RESULTS: Relative to untreated mice, the treated younger mice had more activated microglia co-localized with Aβ and reduced Aβ burden for large plaques, as well as no change in each measure of eNOS. In contrast, the treated older AD mice had no change in activated microglia co-localized with Aβ, and no change in Aβ burden. However, relative to untreated older AD mice, FUS decreased total and extra-neuronal eNOS and increased intra-neuronal eNOS.

CONCLUSIONS: The ability of our FUS protocol to reduce Aβ burden and alter the eNOS distribution depends critically upon the age of the AD mice (more Aβ plaques for a comparable number of microglia for older mice relative to younger mice) and duration of the treatment. The observed decrease in extra-neuronal eNOS distribution in older AD mice caused by FUS raises the concern that our protocol may increase ischemia, while the increase in intra-neuronal eNOS may counteract that effect via protection of synaptic function. These findings also identify two candidate therapeutic windows for our FUS treatment protocol, each requiring more research before translation to humans. One window is early intervention to maximize Aβ plaque removal via activation of microglia. The second is later intervention to protect synaptic function if it is possible to mitigate the potential ischemic risk caused by the differential effects of FUS on eNOS.},
}

@article {pmid42512540,
year = {2026},
author = {Manzo, J and Hernández-Aguilar, ME},
title = {Autism and Neurodegeneration: Distinct Disorders or a Shared Biological Continuum?.},
journal = {Brain sciences},
volume = {16},
number = {7},
pages = {},
doi = {10.3390/brainsci16070766},
pmid = {42512540},
issn = {2076-3425},
abstract = {BACKGROUND/OBJECTIVES: Autism spectrum disorder (ASD) is traditionally classified as a neurodevelopmental condition, whereas neurodegenerative diseases are defined by progressive neuronal decline in later life. This separation has shaped research and clinical practice, yet emerging evidence suggests potential biological overlap. This review aims to evaluate whether ASD and neurodegenerative disorders represent distinct entities or are linked through shared mechanisms operating across the lifespan.

METHODS: This narrative review synthesizes findings from genetic, molecular, cellular, circuit-level, and epidemiological studies examining ASD and major neurodegenerative conditions, including Alzheimer's disease, Parkinson's disease, and Amyotrophic lateral sclerosis. Emphasis is placed on identifying convergent pathways and evaluating evidence within a lifespan-oriented framework.

RESULTS: Across multiple levels of analysis, ASD and neurodegenerative diseases share partially overlapping biological mechanisms, including mitochondrial dysfunction, impaired proteostasis, neuroimmune alterations, and network-level instability. Genetic and molecular data reveal pleiotropic pathways influencing both early neurodevelopment and later neuronal resilience. Circuit-level studies highlight shared principles of network vulnerability, including cerebellar involvement and excitation-inhibition imbalance. Epidemiological data further indicate increased risk of dementia and parkinsonian features in autistic adults. These convergences suggest that early neurodevelopmental alterations may establish latent vulnerabilities that, under specific conditions, intersect with neurodegenerative processes later in life.

CONCLUSIONS: ASD and neurodegenerative diseases are best understood as distinct clinical conditions that share partially overlapping biological substrates. Rather than implying a deterministic progression, the evidence supports a model of lifespan convergence in which timing, context, and individual susceptibility shape outcomes. This framework highlights the need for integrated research and clinical approaches that consider brain health as a continuous process from development through aging.},
}

@article {pmid42512898,
year = {2026},
author = {Kannenieks, D and Priede, Z and Millers, A and Velins, KK},
title = {Development and External Validation of a Machine Learning Model for Classification of Mild Cognitive Impairment and Dementia Using Clinical Data.},
journal = {Medicina (Kaunas, Lithuania)},
volume = {62},
number = {7},
pages = {},
doi = {10.3390/medicina62071356},
pmid = {42512898},
issn = {1648-9144},
abstract = {Background and Objectives: As society ages, the number of patients with cognitive impairment is increasing. Machine learning methods that use structured clinical and cognitive-assessment data during routine diagnostic work-up may support and monitor structured classifications of cognitive status. This kind of approach can improve early screening, reduce physicians' workload and develop greater support for personalized treatment. To develop an XGBoost-based machine learning model using the National Alzheimer's Coordinating Center (NACC) dataset and to evaluate the model's precision with clinician-assigned diagnosis in a Latvian retrospective cohort study. Materials and Methods: The research was designed as a retrospective external validation cohort study that used two data sources. Firstly, the National Alzheimer's Coordination Center (NACC) longitudinal dataset was used to train the ML model. Secondly, medical records gathered from Pauls Stradins Clinical University Hospital dating from 2020 to May 2025 were used to evaluate the algorithm's precision. Results: In the NACC study, the weighted four-class model achieved an overall accuracy of 84.0% and a balanced accuracy of 70.9%, but the SCD class remained poorly classified. After reframing the model to a three-class model the performance grew stronger for normal cognition, mild cognitive impairment (MCI) and dementia. Class distribution in the Latvian cohort consisted of dementia (n = 138); MCI (n = 13); and subjective cognitive decline (SCD) (n = 2). Dementia was identified most strongly-124/138 (sensitivity-89.9%). MCI was correct in 9/13 cases (sensitivity-69.2%). SCD cases were excluded. Overall, the model agreed with the neurologist-assigned diagnoses in 88.1% of the cases (133/151). Conclusions: The ML classification model has high precision when comparing with neurologist-assigned diagnoses, but it struggles to separate adjacent early-stage diagnoses, meaning that it did not reliably identify SCD. These findings support further methodological development and the implementation of prospective research. Nevertheless, this technology has high potential for being integrated in the future to aid triage and early screening, especially when advanced diagnostics are limited.},
}

@article {pmid42513102,
year = {2026},
author = {Zhu, BT},
title = {Cholesterol at the Center of Alzheimer's Disease: A Unifying Hypothesis on the Pathogenic Mechanism.},
journal = {Molecules (Basel, Switzerland)},
volume = {31},
number = {14},
pages = {},
doi = {10.3390/molecules31142418},
pmid = {42513102},
issn = {1420-3049},
abstract = {It is hypothesized that in most cases of sporadic late-onset Alzheimer's disease (LOAD), the abnormally elevated cholesterol level in brain neurons represents a critical causative factor that drives the pathogenic processes of LOAD. Specifically, it is hypothesized that the abnormally elevated neuronal cholesterol will disrupt mitochondrial structure and metabolic activity, resulting in ATP deficiency as well as reduced formation of neuroactive metabolic intermediates (such as mevalonate and geranylgeraniol) along the cholesterol synthesis pathway in brain neurons. In addition, the abnormally elevated neuronal cholesterol will cause direct neuronal damage as well as other pathogenic changes in the brain, including increased formation and deposition of amyloid β (Aβ) plaques. It is speculated that Aβ accumulation and plaque formation in most LOAD cases only represent characteristic secondary pathological changes and are usually not the main force driving the pathogenesis of LOAD. As discussed in detail in this paper, abnormally elevated neuronal cholesterol in conjunction with ATP deficiency and lack of neuroactive metabolic intermediates will not only cause learning and memory impairment, but will also induce tauopathy and reduce the formation of cholinergic vesicles. It is expected that these pathogenic changes are more readily seen initially in ischemia-sensitive neurons in hippocampus and posterior parietal cortex, which are then followed by neurodegenerative and atrophic changes in other brain regions along with progressive cognitive decline. As explained in this paper, ApoE4 is a major risk factor in LOAD because it has a drastically reduced ability than ApoE2 and ApoE3 to efflux excess cholesterol out of neurons. Overall, there is a large body of direct, indirect and circumstantial clinical and experimental evidence which jointly offers strong support for the cholesterol-centered hypothesis on the etiology and pathogenesis of LOAD. Considerable efforts are made to apply the proposed hypothesis to offer a better mechanistic explanation for many of the poorly understood experimental and/or clinical observations related to AD (mostly LOAD).},
}

@article {pmid42513287,
year = {2026},
author = {Ben Ayed, I and Makni, E and Ammar, A and Brahim, MB and Elloumi, M},
title = {Criterion-Referenced Sex-Specific Six-Minute Walk Distance Cut-Offs for Staging Alzheimer's Disease.},
journal = {Journal of clinical medicine},
volume = {15},
number = {14},
pages = {},
pmid = {42513287},
issn = {2077-0383},
abstract = {Background: Functional decline emerges early in Alzheimer's disease (AD) and may support clinical staging. However, criterion-referenced thresholds for interpreting the six-minute walk distance (6MWD) across AD stages are lacking. This study aims to derive sex-specific 6MWD cut-off values to differentiate mild cognitive impairment (MCI) from moderate AD dementia. Methods: In this cross-sectional study, 233 community-dwelling adults (128 women) were consecutively recruited from a neurology department and classified using IWG-2 criteria (MCI: MMSE ≥ 26; moderate AD dementia: MMSE 10-19). All participants completed a standardized 6 min walk test (6MWT) following American Thoracic Society guidelines. Receiver operating characteristic (ROC) analyses were performed overall and by sex, optimal thresholds were selected using Youden's index, and diagnostic indices such as area under the curve (AUC), sensitivity, specificity, 95% confidence intervals (CI), likelihood ratios (LR) and odds ratio (OR) were computed. Results: Overall, participants with moderate AD dementia exhibited substantially lower 6MWD values than those with MCI (313.7 ± 46.5 m vs. 461.2 ± 60.1 m, p < 0.001). The optimal overall threshold was 390 m, yielding an AUC of 0.97, sensitivity of 98.0%, and specificity of 79.4%. Sex-specific thresholds were 389 m in men (AUC = 0.96, sensitivity = 96.4%, specificity = 79.3%) and 367 m in women (AUC = 0.98, sensitivity = 97.8%, specificity = 87.7%). Conclusions: The 6MWD demonstrates strong discriminatory ability between MCI and moderate AD dementia in this sample. Sex-specific thresholds may support functional staging and monitoring but require internal and external validation before clinical implementation.},
}

@article {pmid42513614,
year = {2026},
author = {Çetinkaya, K and Ünsal, Y},
title = {The Glymphatic System and Neurosurgery: A Comprehensive Narrative Review of Current Concepts and Future Directions.},
journal = {Journal of clinical medicine},
volume = {15},
number = {14},
pages = {},
pmid = {42513614},
issn = {2077-0383},
abstract = {The glymphatic system is a recently defined perivascular waste elimination pathway responsible for the efficient clearance of metabolic waste and neurotoxic proteins in the central nervous system. This system facilitates the entry of cerebrospinal fluid (CSF) into the brain parenchyma via arterial perivascular spaces and its interaction with interstitial fluid (ISF) via glial cell-associated aquaporin-4 (AQP4) channels. It functions particularly actively during sleep. Impairment of glymphatic flow contributes to nerve cell damage and neuroinflammation in various pathologies such as Alzheimer's disease, Parkinson's disease, traumatic brain injury, subarachnoid hemorrhage, and neurological tumors. In neurosurgical practice, surgical positioning, anesthesia regimen, and intracranial pressure changes play a decisive role in glymphatic function, and perioperative modulation of the system can affect postoperative recovery and cognitive outcomes. Today, non-invasive imaging techniques and molecular biological approaches are deepening our understanding of the functioning of the glymphatic system in humans, and this system is emerging as a potential target in the diagnosis and treatment of neurological diseases. This review comprehensively addresses the basic anatomical and physiological principles of the glymphatic system, its role in pathological processes, and its clinical significance in neurosurgical applications.},
}

@article {pmid42514123,
year = {2026},
author = {Malkov, A and Proshchina, A and Krivova, Y and Kharlamova, A and Godovalova, O and Gulimova, V and Saveliev, S},
title = {Neuroglia Alterations in the Olfactory Bulbs in Patients with Schizophrenia: An Exploratory Postmortem Study.},
journal = {Life (Basel, Switzerland)},
volume = {16},
number = {7},
pages = {},
doi = {10.3390/life16071053},
pmid = {42514123},
issn = {2075-1729},
support = {FURG-2025-0031//Russian Scientific Center of Surgery/ ; Charitable donation//Helicon Ltd./ ; },
abstract = {The human olfactory bulb is a promising structure for the investigation of central nervous system disorders, including dementias of various etiologies. In Alzheimer's disease, anosmia is among the earliest clinical manifestations. Although olfactory disturbances have also been reported in schizophrenia, alterations within the olfactory system remain insufficiently studied. The aim of this study was to identify changes in the olfactory bulbs of patients with schizophrenia. Olfactory bulbs obtained from patients with schizophrenia (n = 23) and individuals without identified nervous system pathology (n = 23) were examined. Patients with schizophrenia demonstrated a statistically significant decrease in the immunoreactive area of myelin basic protein and a significant increase in the immunoreactive area of glial fibrillary acidic protein compared with the control group. In addition, the thickness of the layer of incoming olfactory nerve fibers was significantly reduced in the schizophrenia group. Overall, our findings demonstrate neuroglial alterations in the human olfactory bulb in schizophrenia. Together with observations from other brain regions, these results may indicate that the identified changes are systemic rather than localized in nature.},
}

@article {pmid42514192,
year = {2026},
author = {Freij, KW and Akbar, A and Domoyeri, P and Polycarp, N and Higginbotham, DR and Arora, I and Aroke, EN},
title = {Epigenetic Regulation of Modulatory Neurotransmitter System Integrity in the Aging Brain: A Scoping Review Across the Lifespan.},
journal = {Life (Basel, Switzerland)},
volume = {16},
number = {7},
pages = {},
doi = {10.3390/life16071122},
pmid = {42514192},
issn = {2075-1729},
abstract = {Age-related changes in neurotransmitter systems contribute to declines in cognitive, emotional, and motor function, yet the biological mechanisms linking these changes to aging are not completely understood. Epigenetic regulation offers a promising framework to bridge this gap. DNA methylation-based biomarkers of biological aging (i.e., epigenetic clocks) capture cumulative and dynamic aspects of biological aging that may reflect vulnerability in neural systems beyond chronological age. However, whether these indices track with the integrity of neurotransmitter systems has not been systematically examined. This scoping review synthesizes evidence across human studies to evaluate how epigenetic aging processes influence neurotransmitter gene regulation and system function across the lifespan. We included 109 studies spanning 2005-2026. GABAergic genes (GAD1, GABRA2) showed the most consistent and reproducible age-related promoter hypermethylation across the cortex, inversely correlated with mRNA expression and corroborated by MRS evidence of cortical GABA decline. Dopaminergic and serotonergic evidence during normative aging was sparse; most epigenetic data in these systems came from disease cohorts. Histone modifications converged on neurotransmission and synaptic-plasticity loci, predominantly in Alzheimer's disease tissue. Subcortical and brainstem nuclei central to monoaminergic and cholinergic systems remain under-investigated for normative aging epigenetic processes. Environmental and social determinants, socioeconomic status, childhood adversity, and chronic stress, were consistently associated with accelerated peripheral epigenetic aging, but brain-specific data are scarce.},
}

@article {pmid42514209,
year = {2026},
author = {Rodríguez-Escobar, ML and Singh Raj, V and Martínez-Peinado, N and Fuentes, AF and Maldonado, C and Gabaldón-Figueira, JC and Alonso-Padilla, J and Bastida, J and Tallini, LR and Torras-Claveria, L},
title = {Phytochemical Characterization and Evaluation of the Anticholinesterase and Anti-Trypanosoma cruzi Potential of Andean Amaryllidaceae from Bolivia: (Pyrolirion boliviense and Stenomesson miniatum).},
journal = {Life (Basel, Switzerland)},
volume = {16},
number = {7},
pages = {},
doi = {10.3390/life16071139},
pmid = {42514209},
issn = {2075-1729},
abstract = {The Amaryllidaceae family is a rich source of structurally diverse alkaloids with recognized neuroactive and antiparasitic properties. This study provides the first phytochemical and biological characterization of Pyrolirion boliviense and wild Stenomesson miniatum from Bolivia. Alkaloid extracts from bulbs and leaves were analysed by GC-MS and evaluated for acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and Trypanosoma cruzi inhibitory activities. Thirty-two Amaryllidaceae alkaloids were identified, with P. boliviense exhibiting greater alkaloid diversity (25 compounds) and S. miniatum a higher total alkaloid content (227.86 vs. 138.92 μg Gal/100 mg DW). P. boliviense bulb extracts showed the strongest cholinesterase inhibition (AChE IC50 = 6.07 ± 0.47 μg·mL[-1]; BuChE IC50 = 30.93 ± 1.17 μg·mL[-1]), whereas S. miniatum extracts displayed weaker AChE inhibition and no detectable BuChE activity. In anti-T. cruzi assays, bulb extracts were the most active, with S. miniatum showing an IC50 of 0.90 ± 0.15 μg·mL[-1] (SI = 20.12) and selective anti-amastigote activity (IC50 = 1.42 ± 0.66 μg·mL[-1]; SI = 12.77). These findings identify Bolivian Andean Amaryllidaceae as promising sources of bioactive alkaloids with potential applications for Alzheimer's disease and Chagas disease drug discovery.},
}

@article {pmid42514272,
year = {2026},
author = {Lai, C and Xia, H and Zhang, Y and He, Y and Wu, X and Ye, B and Yang, H and Zhang, B},
title = {A Comprehensive Review on the Pharmacological Activities and Biosynthetic Strategies of Protocatechuic Acid.},
journal = {Life (Basel, Switzerland)},
volume = {16},
number = {7},
pages = {},
pmid = {42514272},
issn = {2075-1729},
support = {20252BAC220041//Jiangxi Provincial Department of Science and Technology/ ; 32360021//National Natural Science Foundation of China/ ; 32160016//National Natural Science Foundation of China/ ; },
abstract = {Protocatechuic acid (PCA) is a simple natural phenolic acid widely distributed in plants. It is recognized as an active constituent of numerous traditional herbal medicines and serves as an important metabolic intermediate of polyphenolic compounds such as anthocyanins and proanthocyanidins. At present, PCA production relies on plant extraction and microbial fermentation. Among these, microbial fermentation has emerged as an attractive approach for industrial development owing to its process controllability, environmentally benign nature, and potential for high productivity. This review systematically summarizes the major pharmacological properties of PCA, including its antioxidant, anti-inflammatory, antimicrobial, antiviral, anti-aging, neuroprotective, and hepatoprotective activities. It further highlights the therapeutic potential of PCA in the prevention and management of various chronic diseases, such as cancer, diabetes, Alzheimer's disease, and hypertension. Furthermore, this review summarizes the representative microbial biosynthetic pathways for PCA and discusses recent progress in metabolic engineering strategies aimed at enhancing its microbial production. These strategies include reinforcing precursor supply, redirecting metabolic flux toward the shikimate pathway, blocking PCA degradation routes, relieving intracellular feedback regulation, improving host tolerance, and optimizing fermentation processes to achieve higher PCA productivity and yield. Finally, the major bottlenecks limiting PCA biomanufacturing are discussed, and prospective directions for future research are proposed.},
}

@article {pmid42514407,
year = {2026},
author = {Gaffney, M and Ryan, M and Loetscher, T and Singh, B and Murphy, KJ},
title = {Modification of Visual Contrast in the Dining Environment and Its Impact on Dietary Intake in Older Adults-A Systematic Review.},
journal = {Nutrients},
volume = {18},
number = {14},
pages = {},
doi = {10.3390/nu18142338},
pmid = {42514407},
issn = {2072-6643},
abstract = {Background/Objectives: Malnutrition among older adults, particularly those in aged care, is a major contributor to morbidity and healthcare costs. Reduced visual contrast sensitivity, common with ageing and dementia, may impair the ability to distinguish food from tableware, potentially leading to decreased intake. This systematic review examined whether enhancing visual contrast in the dining environment improves dietary intake in older adults. Methods: Following PRISMA guidelines, five databases were searched from inception to March 2025. Studies were eligible if they involved adults aged ≥65 years and used visual contrast interventions (e.g., coloured tableware, lighting adjustments) aimed at improving food or fluid intake. A narrative synthesis was conducted, and study quality was assessed using the Mixed Methods Appraisal Tool. Results: Of 2901 records screened, four studies (five reports) met the inclusion criteria, involving a total of 64 participants. All studies implemented visual contrast enhancements, including high-contrast dishware and environmental modifications. Most reported increases in food or liquid intake, though statistical significance varied. Some studies also evaluated mealtime behaviours, functional abilities, and food waste, with mixed findings. Methodological limitations, including small sample sizes, short interventions, and inconsistent reporting limited the strength of evidence. Conclusions: Limited and low-quality evidence suggests a possible effect of modifying the dining environment to improve visual contrast for enhancing dietary intake in older adults, with visual contrast sensitivity, particularly those with dementia. However, the evidence gap is large and remains inconclusive. Future well-powered trials with standardised interventions and outcome measures are needed to determine whether these strategies can meaningfully reduce malnutrition in aged care settings.},
}

@article {pmid42514574,
year = {2026},
author = {Karageçili, H and Bingöl, Z and Yılmaz, MA and Fidan, M and Karaismailoğlu, MC and Akıncıoglu, H and Gulcin, İ},
title = {Integrated Assessment of Bioactive Properties of Nine Thlaspi Species: Antioxidant Activity, Enzyme Inhibition and LC-MS/MS Polyphenolic Characterization.},
journal = {Plants (Basel, Switzerland)},
volume = {15},
number = {14},
pages = {},
doi = {10.3390/plants15142207},
pmid = {42514574},
issn = {2223-7747},
abstract = {Brassicaceae plants, among the most widely consumed vegetables worldwide, are recognized as rich sources of biologically active compounds. In this study, nine species belonging to the cruciferous genus Thlaspi were investigated, including T. alliaceum, T. arvense, T. violascens, T. aghricum, T. cataonicum, T. annuum, T. watsonii, T. cariense, and T. elegans. In the past, pennycress species were consumed to alleviate hunger and provide nutritional support during periods of food scarcity. To evaluate the antioxidant capacities of methanol and water extracts obtained from Thlaspi species, several complementary assays were employed, including 2,2'-azino-bis-3-ethylbenzthiazoline-6-sulphonic acid radical (ABTS[•+]) scavenging, 1,1-diphenyl-2-picrylhydrazyl free radicals (DPPH[•]) scavenging, N,N-dimethylphenylenediamine radicals (DMPD[•+]) scavenging, Fe[3+]-2,4,6-tris(2-pyridyl)-s-triazine (TPTZ)-reducing, Fe[3+] ion-reducing, and Cu[2+] ion-reducing assays. The IC50 values of both methanol and water extracts from the aerial parts of Thlaspi species for ABTS[•+], DPPH[•], and DMPD[•+] scavenging activities were studied compared with antioxidant standards, including α-tocopherol, Trolox, butylated hydroxytoluene (BHA), and butylated hydroxyanisole (BHT). The total phenolic and flavonoid contents of the extracts ranged from 8.29 to 49.14 mg gallic acid equivalent (GAE)/g extract and from 2.33 to 74.66 mg quercetin equivalent (QE)/g extract, respectively. Furthermore, the inhibitory effects of water and methanol extracts of Thlaspi species against α-amylase, acetylcholinesterase (AChE), and carbonic anhydrase (CA II) enzymes were evaluated. The IC50 values were determined to range from 122.4 to 245.9 μg/mL for α-amylase, from 17.3 to 24.1 μg/mL for AChE, and from 41.9 to 256.5 μg/mL for CA II inhibition. In addition, the phenolic profiles of Thlaspi species were comprehensively characterized by LC-MS/MS analysis using 53 reference standards. The findings demonstrated that the aerial parts of Thlaspi species are rich in polyphenolic antioxidants and may serve as promising natural sources with potential applications in the management of diabetes, Alzheimer's disease (AD), glaucoma, epilepsy, and cancer.},
}

@article {pmid42514879,
year = {2026},
author = {Osmanlioglu Dag, SR and Alagoz, MA},
title = {Dual Targeting of AChE Inhibition and GPX4 Binding by Plant-Derived Compounds for the Treatment of Alzheimer's Disease: Insights from Molecular Docking and Molecular Dynamics Simulations.},
journal = {Pharmaceutics},
volume = {18},
number = {7},
pages = {},
doi = {10.3390/pharmaceutics18070798},
pmid = {42514879},
issn = {1999-4923},
support = {TSA-2025-4366.//Inonu University/ ; },
abstract = {Background/Objectives: Alzheimer's disease (AD) is primarily characterized by cholinergic dysfunction, for which acetylcholinesterase (AChE) inhibition remains the mainstay of symptomatic treatment. However, additional hypotheses such as ferroptosis-an iron-dependent form of regulated cell death-have gained prominence in explaining disease progression. Glutathione peroxidase 4 (GPX4), a critical antioxidant enzyme, plays a protective role by suppressing ferroptotic pathways. In this context, identifying phytochemicals capable of inhibiting AChE and exhibiting activator-like binding toward GPX4 may provide a dual therapeutic benefit. This study aimed to identify such dual-acting compounds through a structure-based virtual screening approach. Methods: A total of 3014 natural compounds were collected from three curated databases: NPACT, HIT, and HIM. Molecular docking was performed against GPX4 (7U4I) and AChE (7D9Q). Compounds demonstrating high affinity for both targets were shortlisted. Z-score normalization and statistical ranking were used to select the best two dual-target compounds. Results: Out of 3014 compounds, 68 showed dual-binding potential. Among these, NPACT00189 (docking scores: -6.720 kcal/mol for GPX4; -8.983 kcal/mol for AChE) and NPACT01210 (docking scores: -5.813 kcal/mol for GPX4; -9.640 kcal/mol for AChE) were identified as top candidates based on docking scores. Molecular dynamics (MD) simulations were conducted for both compounds for 250 ns on the AChE binding site and the allosteric site of GPX4. The results indicated that NPACT00189 maintained stable interactions throughout the simulation period at both targets, indicating its dual-targeting potential. Conclusions: NPACT00189 represents a promising dual-target candidate for further investigation in AD therapy. Its potential requires confirmation through comprehensive in vitro and in vivo studies.},
}

@article {pmid42514962,
year = {2026},
author = {Chen, C and Leung, C and Zhai, Z and Wang, G and Yang, R and Hu, Q and Yue, X and Yao, Z and Zhao, Z and Zhang, X},
title = {Feasibility Study of Nose-to-Brain Delivery of Galantamine for Alzheimer's Disease: Enhancing Olfactory-Region Deposition to Improve Therapeutic Efficacy.},
journal = {Pharmaceutics},
volume = {18},
number = {7},
pages = {},
doi = {10.3390/pharmaceutics18070885},
pmid = {42514962},
issn = {1999-4923},
support = {2025A1515010639//Natural Science Foundation of Guangdong Province/ ; },
abstract = {Background: Alzheimer's disease (AD) is the seventh leading cause of death worldwide, posing a substantial global health burden. Although galantamine (GNT) is a first-line clinical drug for AD treatment, its therapeutic efficacy is constrained by inefficient brain delivery across the blood-brain barrier (BBB). Nose-to-brain delivery represents a promising route to bypass the BBB. However, its efficiency remains limited by insufficient drug deposition in the anatomically restricted olfactory region. In this study, we developed a galantamine nasal spray (GNT-NS) with enhanced olfactory region deposition and evaluated its feasibility for nose-to-brain delivery in AD treatment. Methods: We optimized the formulation by systematically investigating the cascade relationship among formulation physicochemical properties, spray performance, and olfactory region deposition. Nasal deposition distribution was quantitatively evaluated using a physiologically realistic 3D-printed human nasal cavity model reconstructed from clinical magnetic resonance imaging (MRI) data. Further, the in vivo biodistribution and therapeutic efficacy of GNT-NS were evaluated in AD rats. Results: The optimized formulation P3 achieved an olfactory region fraction of 23.85%, markedly exceeding that of the unoptimized formulation P0. Subsequent in vivo biodistribution studies showed that P3 produced higher brain drug exposure than both intranasally administered P0 and the commercial oral formulation. Further pharmacodynamic studies demonstrated that GNT-NS significantly improved cognitive and behavioral deficits in AD rats, exhibiting superior therapeutic efficacy over commercially available oral galantamine tablets. Conclusions: Collectively, this study proposes a cascade regulation strategy linking formulation physicochemical properties, spray performance, and olfactory region deposition and demonstrates that optimizing nasal spray properties can enhance olfactory deposition, increase brain exposure and improve therapeutic efficacy. These findings provide a useful reference for the design of nose-to-brain delivery formulations for AD and other central nervous system diseases.},
}

@article {pmid42514986,
year = {2026},
author = {Ziaka, M},
title = {A Comprehensive Review of the Gut-Microbiota-Brain Axis in Alzheimer's Disease: From Pathophysiology to Potential Therapies.},
journal = {Pathogens (Basel, Switzerland)},
volume = {15},
number = {7},
pages = {},
doi = {10.3390/pathogens15070659},
pmid = {42514986},
issn = {2076-0817},
abstract = {The gut-microbiota-brain axis (GMBA), an intricate network connecting the gastrointestinal (GI) tract and the brain, plays a pivotal role in maintaining overall health and influencing disease processes. The human gut microbiota, comprising over 3000 bacterial species, regulates immune responses, hormonal signals, and metabolite production, maintaining homeostasis under normal conditions. Dysbiosis, or microbial imbalance, has been linked to various central nervous system (CNS) disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and autism spectrum disorder (ASD). Given the growing interest in this topic and the limited effectiveness of current therapeutic strategies for managing patients with AD, the purpose of the current narrative review is to analyze the pathophysiological role of the GMBA in the pathogenesis of AD and assess potential therapeutic strategies targeting the GMBA, particularly the microbiome and its metabolites. A comprehensive literature search was conducted using PubMed, Scopus, and Web of Science to identify clinical studies, experimental research, and review articles examining the GMBA in health and AD, as well as related therapeutic strategies. The search terms included "Alzheimer's disease", "neuroinflammation", "amyloid-beta", "tau", "gut-brain axis", "microbiome", "short-chain fatty acids", "probiotics", "prebiotics", and "fecal microbiota transplantation". In AD, altered gut microbiota composition is associated with neuroinflammation, neurodegeneration, and exacerbation of disease progression. Probiotics have shown potential in enhancing cognitive function and reducing neuroinflammation by modulating microbiota composition and influencing brain-derived neurotrophic factor (BDNF) levels. Prebiotics, through their impact on gut microbiota and metabolite production, also offer therapeutic promise by improving cognitive function and mitigating neuroinflammation. With its historical and modern applications, fecal microbiota transplantation (FMT) may represent a potential strategy for addressing dysbiosis and its neurological implications. This manuscript focuses on GMBA and its effects on neuroinflammation, neurodegeneration, and CNS health while emphasizing the need for further research into microbiome-based therapies and the gut-brain relationship in patients with AD.},
}

@article {pmid42515114,
year = {2026},
author = {Penalva-Olcina, R and Franco-Campos, F and Taroncher, M and Ruiz, MJ and Fernández-Franzón, M},
title = {Mechanistic Evidence Mapping Ochratoxin A Toxicity onto Alzheimer's Disease-Relevant Neurodegenerative Pathways: A Systematic Review of Experimental Models.},
journal = {Toxics},
volume = {14},
number = {7},
pages = {},
doi = {10.3390/toxics14070549},
pmid = {42515114},
issn = {2305-6304},
support = {PID2024-160527OB-I00//Ministry of Science and Information/ ; },
abstract = {Ochratoxin A (OTA) is a prevalent foodborne mycotoxin that has been increasingly recognized as a potential environmental contributor to neurodegenerative diseases. Despite extensive research, a systematic integration of how OTA replicates the specific pathological hallmarks of Alzheimer's Disease (AD) is currently lacking. This study provides a comprehensive systematic review of the mechanistic evidence linking OTA exposure to AD-related pathways, utilizing the Adverse Outcome Pathway (AOP) framework to categorize complex toxicological data into biological key events (KEs). A systematic literature search was conducted across PubMed, Scopus, and Web of Science. A total of 24 peer-reviewed articles were selected for synthesis, comprising 14 in vitro studies and 10 in vivo investigations. The integrated evidence demonstrates that OTA exposure triggers a robust toxicological cascade that replicates several key mechanistic pathways associated with AD in experimental models. Early molecular triggers involve significant redox imbalance and mitochondrial bioenergetic failure, which serve as catalysts for sustained neuroinflammation and microglial activation. In vivo data, from multiple animal models, consistently show that these cellular dysfunctions culminate in structural damage. This systematic integration provides a clearer roadmap for future risk assessment and emphasizes the urgent need for refined regulatory guidelines to protect neurological health from chronic mycotoxin exposure.},
}

@article {pmid42515635,
year = {2026},
author = {Lawal, AO and Jacob, IB and Karnik, V and Fan, H and Thangamani, S and Massa, PT and Wang, G},
title = {Neuroinflammation, Pericyte Dysfunction, and Alzheimer's Disease-Associated Gene Expression and Pathway Activation in the Brain of SARS-CoV-2-Infected Mice.},
journal = {Viruses},
volume = {18},
number = {7},
pages = {},
doi = {10.3390/v18070783},
pmid = {42515635},
issn = {1999-4915},
abstract = {SARS-CoV-2 infection leads to extrapulmonary complications in multiple organs, including the brain, both in the short-term and long-term. The neurological manifestation of SARS-CoV-2 infection ranges from benign signs like loss of smell and loss of taste to severe complications like encephalitis, stroke, and exacerbation of Alzheimer's disease (AD) progression. Pericytes are mural cells of the brain vasculature that help maintain the blood-brain barrier (BBB), regulate cerebral blood flow (CBF), modulate neuroinflammation, and clear toxic materials, including amyloid beta. Pericytes express ACE2, the receptor for SARS-CoV-2, and therefore may be targeted by either direct virus infection or virus-induced inflammatory cytokines induced by the virus in the brain. To further study the effects of SARS-CoV-2 on pericytes and BBB integrity, the long-term effects of SARS-CoV-2 infection on brain pericytes, inflammation, and other neuropathological complications were analyzed in mice. K18 (human ACE2 transgenic) mice were infected with 10[3] PFU of SARS-CoV-2 (delta strain), and the brains were analyzed at 6, 14, and 30 days post-infection (dpi). A significant reduction in the weight of infected mice was observed by 6 dpi. Viral nucleocapsid protein and infectious SARS-CoV-2 were observed in the brains of all mice by 6 dpi, and in some mice by 14 dpi, but not at 30 dpi. This observation suggests viral neurotropism with subsequent clearance at later timepoints. Despite virus clearance, the levels of inflammatory mediators, including TNF-α and IFN-γ were significantly elevated up to 30 dpi. We also observed a significant reduction in the level of brain pericytes by 14 dpi up to 30 dpi. Importantly, an increase was observed in the level of Friend Leukemia Integration 1 (FLI-1), a transcription factor known to promote pericyte cell death, from 14 dpi up to 30 dpi. The level of amyloid beta 1-42 was elevated in the brain of infected mice at 6 dpi, and this was maintained up to 30 dpi, and there was a decrease in neuronal density from 14 to 30 dpi. Furthermore, we observed an increased expression of Alzheimer's disease (AD)-associated genes like PSEN1, BACE1, and APP. Furthermore, there was increased activation of several neurodegenerative pathways, including "G alpha (z) signaling pathway", "Apelin muscle signaling pathway", and "G beta-gamma (Gβγ) signaling", in the brains of infected mice compared to control mice. Collectively, the observed neuropathology and unique molecular markers of neurodegenerative disease progression provide a novel mechanism by which COVID-19 may promote dementia/AD by contributing to pericyte loss and BBB dysfunction during infection.},
}

@article {pmid42515671,
year = {2026},
author = {Su, G and Wang, Y and Yao, L},
title = {Research Trends and Emerging Frontiers in Proteolysis Targeting Chimeras (PROTACs): A Bibliometric Analysis of 2630 Publications (2001-2025).},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {19},
number = {7},
pages = {},
doi = {10.3390/ph19070988},
pmid = {42515671},
issn = {1424-8247},
abstract = {Background/Objectives: Proteolysis Targeting Chimeras (PROTACs) are heterobifunctional small molecules that induce ubiquitin-proteasome-mediated degradation of target proteins and have matured from proof-of-concept chemistry to a clinically validated therapeutic modality, with the first Phase 3 readout reported in 2025. A systematic bibliometric analysis covering this pivotal-trial era, however, has been lacking. This study aimed to map the historical trajectory, current research front, and emerging frontiers of PROTAC research. Methods: We analyzed 2630 PROTAC-related publications indexed in the Web of Science Core Collection (WoSCC) from 2001 to 2025 using a combined toolkit of CiteSpace, HistCite, the Alluvial Generator, and R (ggplot2), covering co-occurrence networks, burst detection, keyword clustering, citation historiography, alluvial flow analysis, and reference co-citation timeline visualization. Results: China and the USA led global output, and the Chinese Academy of Sciences, China Pharmaceutical University, and Harvard University were the most productive institutions; the Journal of Medicinal Chemistry was the leading publishing venue, and Alessio Ciulli, Jian Jin, and Craig M. Crews anchored the author network. Keyword burst analysis showed that early research centred on E3 ubiquitin ligase recruitment and small-molecule PROTAC design, whereas the current hotspots, resolved through keyword clustering and co-citation timelines, included structural basis and ternary complex design, EGFR-directed degradation, oral bioavailability optimization, applications in multiple myeloma and Alzheimer's disease, tumour-targeted delivery, and computational/AI-driven design. Conclusions: This study extends the bibliometric record of PROTACs across 2001-2025 and identifies oral bioavailability, E3 ligase repertoire expansion, and CNS-penetrant degrader design as the emerging frontiers likely to shape the next phase of the field.},
}

@article {pmid42515707,
year = {2026},
author = {Mella, J and Vega-Muñoz, A and Soto, M and Moraga, D and Campanini-Salinas, J and Sandoval-Obando, E and Contreras-Barraza, N and Salazar-Sepúlveda, G and Salas-Guzmán, N and Carabantes-Silva, R and Mellado, M},
title = {Evolution of Multitarget Strategies for Alzheimer's Disease: From Cholinergic Inhibition to Network-Oriented Therapeutic Design (2006-2025).},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {19},
number = {7},
pages = {},
doi = {10.3390/ph19071024},
pmid = {42515707},
issn = {1424-8247},
support = {Puente de Investigación UCEN Convocatoria Año 2025 grant CIPPTE202505//Central University of Chile/ ; },
abstract = {Background: Alzheimer's disease (AD) is a complex neurodegenerative disorder and a major global health challenge. The traditional "one drug-one target" paradigm has shown limitations in addressing its multifactorial nature. Multitarget-directed ligands (MTDLs), designed to modulate multiple pathological pathways, have emerged as a promising therapeutic strategy. Objectives: To examine the structural, thematic, and temporal evolution of multitarget strategies for AD treatment between 2006 and 2025. Methods: A total of 1184 Web of Science-indexed articles were analyzed. Publication growth, h-index, author productivity, institutional and national contributions, and keyword co-occurrence networks were evaluated using VOSviewer. Bibliometric laws (Price, Bradford, Zipf, and Lotka) were applied to characterize productivity patterns and thematic organization. Results: Multitarget research shows exponential growth, suggesting a consolidation of the MTDL paradigm. China, India, the United States, Italy, and Spain were the most productive countries. Early studies focused on cholinesterase inhibition, particularly acetylcholinesterase-based hybrids. The field expanded to include β-amyloid aggregation, oxidative stress, metal chelation, and blood-brain barrier permeability. Recent trends emphasize integration of computational approaches, including molecular docking, molecular dynamics, virtual screening, and network pharmacology, alongside targets such as BACE1 and GSK-3β. Conclusions: Multitarget strategies have evolved toward a systems-oriented framework. Despite advances, challenges remain in reducing cholinesterase dependency and improving translational validation. This study provides a framework to interpret therapeutic evolution and guide future network-based drug design.},
}

@article {pmid42515735,
year = {2026},
author = {Rosiak, N and Stojceski, F and Maroni, G and Piontek, B and Cielecka-Piontek, J},
title = {Integrative Network Pharmacology and Molecular Docking Analysis Reveals the Multitarget Mechanisms of Pterostilbene in Neurodegenerative Diseases.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {19},
number = {7},
pages = {},
doi = {10.3390/ph19071053},
pmid = {42515735},
issn = {1424-8247},
support = {UMO-2020/37/B/NZ7/03975//National Science Centre/ ; },
abstract = {Background: Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), differ in etiology but share several convergent pathological mechanisms. Pterostilbene (PTR) is a natural stilbene with reported antioxidant, anti-inflammatory, and neuroprotective properties. This study aimed to prioritize putative PTR-associated targets and biological processes potentially relevant to shared neurodegenerative mechanisms. Methods: An integrative in silico workflow combining network pharmacology, protein-protein interaction (PPI) analysis, GO Biological Process (GO BP) enrichment, molecular docking, and molecular dynamics (MD) simulations was applied. GO BP terms were filtered, focused on neurodegeneration- and neuroprotection-related processes, and subjected to REVIGO-based redundancy reduction. Selected targets were further evaluated by docking and 500 ns MD simulations. Results: A total of 181, 165, 128, and 109 shared PTR-disease targets were identified for AD, PD, HD, and ALS, respectively. Redundancy-reduced GO BP analysis indicated associations with neuroinflammation, oxidative stress and reactive oxygen species-related responses, programmed cell death, MAPK/ERK- and PI3K/AKT-related signaling, ion and calcium transport, and lipid-, steroid-, or hormone-associated regulation. PPI topology prioritized SRC, ESR1, and HSP90AA1 as recurrent hub-bottleneck proteins, whereas MD-based structural interpretation focused on ESR1 and HSP90AA1. MD analyses indicated stable PTR interactions with both proteins, with ESR1 showing the most favorable predicted interaction profile. Conclusions: These findings suggest that PTR may interact with shared neurodegeneration-relevant molecular systems, particularly through ESR1- and HSP90AA1-associated mechanisms. However, the results are exclusively computational and should be interpreted as hypothesis-generating, requiring further experimental validation.},
}

@article {pmid42515744,
year = {2026},
author = {Takomthong, P and Waiwut, P and Kongkiatpaiboon, S and Phemphunananchai, K and Boonyarat, C},
title = {Multi-Targeted Anti-Alzheimer's Effects of Tri-Sannibat-Phol: Biological Evaluation, Behavioral Validation, and LC-MS/MS Phytochemical Profiling.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {19},
number = {7},
pages = {},
doi = {10.3390/ph19071063},
pmid = {42515744},
issn = {1424-8247},
support = {B13F680065//NSRF via the Program Management Unit for Human Resources & Institutional Development, Research and Innovation, Thailand/ ; B38G670003//Program Management Unit for Human Resources & Institutional Development, Research and Innovation, Thailand/ ; //Faculty of Pharmaceutical Sciences, Khon Kaen University/ ; //Ubon Ratchathani University/ ; //BCG Economy and Sustainable Development Network through Center of Excellence Consortium under the Reinventing University System (Khon Kaen University),Visiting Professor Program 2025, Thailand/ ; },
abstract = {Background: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by oxidative stress, cholinergic dysfunction, and amyloid-β (Aβ) aggregation. Tri-Sannibat-Phol (TSB), a classical Thai polyherbal formulation comprising Piper retrofractum fruit, Ocimum tenuiflorum root, and Piper nigrum root, has been traditionally used for its medicinal properties, yet its anti-AD potential has never been scientifically evaluated. Methods: The therapeutic potential of TSB was investigated through in vitro bioassays including antioxidant, acetylcholinesterase (AChE) inhibitory, and anti-Aβ aggregation assays, alongside neuroprotective evaluation in H2O2-induced SH-SY5Y neuroblastoma cells. Acute oral toxicity was assessed in male ICR mice in accordance with OECD Guideline 420. Cognitive-enhancing effects were evaluated using the modified Y-maze, Novel Object Recognition, and Morris Water Maze tests in a scopolamine-induced amnesic mouse model. LC-MS/MS analysis was performed for phytochemical characterization and chemical standardization of the formulation. Results: TSB demonstrated significant antioxidant activity, AChE inhibitory activity, and anti-Aβ aggregation effects, with P. nigrum and O. tenuiflorum identified as the primary contributing components. Neuroprotective effects were confirmed in H2O2-induced SH-SY5Y cells, where TSB significantly improved cell viability across concentrations of 1-100 µg/mL. Acute oral toxicity assessment revealed an LD50 exceeding 2000 mg/kg, indicating a favorable safety profile. In vivo behavioral studies demonstrated that TSB at medium-to-high doses significantly reversed scopolamine-induced cognitive deficits across all three behavioral tests. LC-MS/MS analysis identified thirteen piperidine alkaloids, with piperine as the dominant constituent at 17.61 ± 0.80% w/w, proposed as the primary bioactive driver and chemical marker for future quality standardization. Conclusions: These findings suggest that TSB exerts multi-targeted anti-AD effects through complementary mechanisms, supporting its potential as a traditional medicine-based therapeutic candidate for further preclinical and clinical investigation.},
}

@article {pmid42515760,
year = {2026},
author = {Yeysin, L and Akın, D and Çalışkan, S and Hasanoğlu Özkan, E and Hashem, H and Akocak, S and Bräse, S and Çete, S},
title = {Recent Advances in Pyrazole-Based Cholinesterase Inhibitors: Medicinal Chemistry Perspectives from 2020 to 2025.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {19},
number = {7},
pages = {},
doi = {10.3390/ph19071079},
pmid = {42515760},
issn = {1424-8247},
abstract = {Pyrazole derivatives have attracted considerable interest in medicinal chemistry as adaptable frameworks for developing cholinesterase inhibitors, owing to their advantageous physicochemical properties and structural flexibility. The heteroaromatic characteristics of the pyrazole core allow for various substitution patterns, promoting selective interactions with both the catalytically active site (CAS) and the peripheral anionic site (PAS) of cholinesterase enzymes. These attributes enable pyrazole-based drugs to be viable candidates for the therapy of cognitive disorders, especially Alzheimer's disease. This study aims to systematically describe medicinal chemistry studies on pyrazole-based cholinesterase inhibitors conducted from 2020 to 2025. The focus is on structural alterations of the pyrazole core and their impact on the inhibitory action against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) using structure-activity relationship (SAR) analysis. Recent advancements in in vitro enzymatic inhibition studies, molecular docking, kinetic analysis, ADME predictions, and multi-target-directed ligand (MTDL) techniques are rigorously evaluated to elucidate trends in potency, selectivity, and drug-like characteristics based on information retrieved from three search engines: Scopus, PubMed, and Google Scholar. This review addresses significant challenges in pharmacokinetics, blood-brain barrier permeability, and safety while delineating prospects for integrating rational design, computational modeling, and biological validation to expedite the development of clinically relevant pyrazole-based cholinesterase inhibitors for Alzheimer's disease.},
}

@article {pmid42515850,
year = {2026},
author = {Valletta, M and Vetrano, DL and Laukka, EJ and Kalpouzos, G and Oltra, J and Rizzuto, D and Canevelli, M and Fredolini, C and Qiu, C and Winblad, B and Fratiglioni, L and Grande, G},
title = {Blood Biomarkers of Alzheimer's Disease and Patterns of Structural Brain Changes in the Community.},
journal = {Annals of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/ana.78309},
pmid = {42515850},
issn = {1531-8249},
abstract = {OBJECTIVE: We aimed to investigate the associations between Alzheimer's disease (AD)-related blood biomarkers and changes in brain volumes and cerebrovascular burden in community-dwelling older adults.

METHODS: We included 361 dementia-free participants with a Mini-Mental State Examination (MMSE) score ≥ 27 and without prior cerebrovascular events from a Swedish population-based study. Blood phosphorylated-tau217 (p-tau217), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) were measured at baseline. Brain magnetic resonance imaging (MRI) was performed at baseline and after 3 and/or 6 years. Linear mixed models were used to examine associations between AD-related blood biomarkers and changes in volumes of total brain tissue (TBTV), lateral ventricles, hippocampus, amygdala, and white matter hyperintensities (WMHs).

RESULTS: During the follow-up, higher p-tau217 was associated with faster volume loss in the hippocampus (β*year = -0.047, 95% confidence interval [CI] = -0.077 to -0.018) and in the amygdala (β*year = -0.064, 95% CI = -0.105 to -0.022). Elevated GFAP was linked to faster TBTV decline (β*year = -0.040, 95% CI = -0.059 to -0.021), ventricular enlargement (β*year = 0.028, 95% CI = 0.013 to 0.042), and hippocampal shrinkage (β*year = -0.038, 95% CI = -0.064 to -0.013). Participants with higher NfL showed steeper TBTV decline, ventricular enlargement, hippocampal and amygdala shrinkage, and faster WMH accumulation. Results remained largely consistent after excluding participants with mild cognitive impairment at baseline.

INTERPRETATION: In cognitively unimpaired older adults, elevated blood p-tau217 was linked to faster shrinkage in AD-specific brain regions, whereas NfL and GFAP were associated with more widespread atrophy, with NfL also associated with accelerated WMH accumulation. These findings suggest that AD-related blood biomarkers may capture different dementia-related structural brain changes already at early stages. ANN NEUROL 2026.},
}

@article {pmid42515851,
year = {2026},
author = {Luo, P and Yang, X and Gao, K and Le, J and Xian, S and Zheng, M and Cai, J and Wang, M and Liang, H and Xiao, Z and Cui, W and Sun, Q},
title = {Subacute Toxicological Evaluation of 9-Methylfascaplysin, a Marine-Derived Neuroprotective Compound, via an Integrated Multiomics Approach.},
journal = {Journal of applied toxicology : JAT},
volume = {},
number = {},
pages = {},
doi = {10.1002/jat.70364},
pmid = {42515851},
issn = {1099-1263},
support = {2023YFFO724802//National Key Research and Development Program of China/ ; 2026C02A1153//Zhejiang Provincial Applied Basic Research Program/ ; 82271443//National Natural Science Foundation of China/ ; LMS25H090007//Natural Science Foundation of Zhejiang Province/ ; 2024Z191//Ningbo Key Science and Technology Development Program/ ; 2025Z184//Ningbo Key Science and Technology Development Program/ ; 2025HY1010//Zhejiang Provincial Health Industry Science and Technology Plan/ ; //Li Dak Sum Yip Yio Chin Kenneth Li Marine Biopharmaceutical Development Fund/ ; //K. C. Wong Magna Fund in Ningbo University/ ; },
abstract = {9-Methylfascaplysin (9-MF) is a novel marine-derived neuroprotective compound with potential for the development as a therapeutic agent for Alzheimer's disease and ischemic stroke. However, its systematic toxicological profile remains to be fully characterized. In this study, the subacute toxicity of 9-MF was evaluated in male and female Sprague-Dawley rats following 14 consecutive days of intravenous administration. 9-MF at 1-5 mg/kg did not induce significant alterations in body weight, food consumption, motor function, or anxiety-like behavior. Sex-dependent sensitivity to 9-MF-induced hepatotoxicity was observed. Furthermore, 9-MF induced mild hepatic inflammation, red pulp hemorrhage in the spleen, inflammatory cell infiltration, and alveolar septal thickening in the lung, as well as mild neuronal degeneration and structural loosening in the dentate gyrus region of the brain. Integrated transcriptomic, proteomic, and metabolomic analyses further revealed that 5 mg/kg 9-MF regulated 6-pyruvoyltetrahydropterin synthase-centered biopterin metabolism, arachidonate 15-lipoxygenase-centered linoleate metabolism, and the mTOR pathway in the brain, as well as SMPD4/phytosphingosine-centered sphingolipid metabolism, PLA2G2A-centered arachidonic acid metabolism, and GMPR-centered porphyrin metabolism in the blood, contributing to the observed abnormalities. These findings not only provided a toxicological basis for the further drug development of 9-MF but also served as an example of a toxicological study integrating traditional assessments with multiomics strategies.},
}

@article {pmid42515874,
year = {2026},
author = {Ruankham, P and Thiankhaw, K and Chattipakorn, N and Chattipakorn, SC},
title = {Targeting the Adipose-Brain Axis: Adipokines as Key Modulators of Cognitive Dysfunction.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X483381260714095824},
pmid = {42515874},
issn = {1875-6190},
abstract = {INTRODUCTION: Adipose tissue is an active endocrine organ that secretes adipokines capable of modulating brain function through metabolic, inflammatory, vascular, and neurotrophic pathways. Emerging evidence suggests that dysregulated adipokine signaling contributes to cognitive decline and neurodegeneration by impairing neuronal energy metabolism, mitochondrial function, insulin signaling, and synaptic plasticity, while amplifying oxidative stress and neuroinflammation. Therefore, this review aimed to summarize and discuss the potential roles of adipokines in brain health, particularly cognitive function, based on findings from preclinical and clinical studies.

METHODS: The search strategy incorporated combinations of keywords and MeSH terms, including: "adipokine*", "leptin", "adiponectin", "resistin", "brain", "cognition", "cognitive decline", "dementia", "Alzheimer's disease", "aging", and "metabolic dysfunction".

RESULTS: Preclinical studies demonstrate the neuroprotective effects of adipokines such as leptin, adiponectin, and C1q/TNF-Related Protein-3 (CTRP3), which act through AMPK, PI3K/Akt, sirtuin, and anti-inflammatory signaling pathways to preserve neuronal survival and cognitive function. In contrast, adipokines including resistin, Dipeptidyl Peptidase-4 (DPP-4), Angiopoietin-like protein 4 (ANGPTL4), and visfatin may exacerbate neurodegeneration by promoting insulin resistance, amyloidogenic processing, mitochondrial dysfunction, oxidative stress, and chronic inflammation. However, clinical studies in aging populations have reported paradoxical associations between elevated circulating adipokine levels and worse cognitive outcomes, potentially reflecting compensatory upregulation, adipokine resistance, altered body composition, or age-related metabolic dysregulation.

CONCLUSION: This review highlights mechanistic and clinical evidence supporting adipokines as promising biomarkers and therapeutic targets for modulating the adipose-brain axis to prevent or slow cognitive decline.},
}

@article {pmid42515891,
year = {2026},
author = {Jia, J},
title = {Glycogen Synthase Kinase-3β in Alzheimer's Disease: Targets for Therapy and Imaging.},
journal = {Current topics in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115680266497019260720045602},
pmid = {42515891},
issn = {1873-4294},
abstract = {Glycogen synthase kinase-3β (GSK-3β) is a key regulator of the pathogenesis of Alzheimer's disease (AD), capable of simultaneously modulating core pathological processes such as amyloid-β (Aβ) deposition, tau protein hyperphosphorylation, synaptic damage, and neuroinflammation. Therefore, it has become one of the core druggable molecular nodes for AD intervention. This review is mainly divided into two parts. The first part focuses on the GSK-3β inhibitors that have been validated in AD-related cell and animal models. These inhibitors are specifically classified into four categories: metal ion-based compounds, adenosine triphosphate (ATP)-competitive inhibitors, non-ATP-competitive inhibitors, and multi-target inhibitors. The second part focuses on GSK-3β-specific positron emission tomography (PET) radioligands, which can non-invasively monitor GSK-3β enzyme activity in vivo, providing quantitative in vivo molecular imaging tracers for the study of AD pathogenesis and quantitative assessment of treatment effects. This review systematically summarizes GSK-3β-related inhibitors and PET radioligands in AD, thereby providing key references for the rational design of next-generation AD therapeutic drugs and diagnostic agents.},
}

@article {pmid42515906,
year = {2026},
author = {Mailavaram, RP and Chaudhari, Y and S Tarwani, R and Venugopala, KN and Ghosh, M and Maity, P and Deb, PK},
title = {A Comprehensive Review of Phosphodiesterases 4 (PDE4) Inhibitors in Clinical Trials.},
journal = {Current pharmaceutical design},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113816128436242260714073027},
pmid = {42515906},
issn = {1873-4286},
abstract = {Phosphodiesterase 4 (PDE4) facilitates the enzymatic breakdown of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), through its four distinct isotypes, namely PDE4A to PDE4D, along with more than 25 splice variants. It plays a crucial role in cancer development, respiratory issues such as asthma and chronic obstructive pulmonary disease (COPD), autoimmune diseases like psoriasis, and neurological disorders such as Alzheimer's disease. Various methods are being developed to enhance clinical efficacy and reduce side effects. Some of these methods include drug delivery via inhalation and the development of non-emetic PDE4 inhibitors and mixed PDE inhibitors. These inhibitors offer several advantages over traditional formulations, including selectivity for specific inhibitors, targeted tissue distribution, and oral effectiveness. All these efforts have led to the emergence of novel PDE4 inhibitors, with some having progressed to clinical trial stages and others approved as medications. This review summarises PDE4 inhibitors currently in clinical trials, highlighting their therapeutic potential, limitations, and future prospects.},
}

@article {pmid42515913,
year = {2026},
author = {Liu, C and Liu, BP and Pan, F and Larbi, A and Ng, TP and Lu, Y},
title = {Depression and Risk of Alzheimer's Disease: A Mendelian Randomization Study.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050477354260714063740},
pmid = {42515913},
issn = {1875-5828},
abstract = {INTRODUCTION/BACKGROUND: Recent studies show that depression often occurs years before Alzheimer's disease onset in many older adults. However, it is unclear whether this link reflects a causal relationship.

MATERIALS AND METHODS: Summary statistics from Genome-Wide Association Studies (GWAS) of depression and Alzheimer's disease were utilized. Data associated with broad depression included up to 407,746 Europeans, and data associated with major depression disorder included up to 480,359 Europeans; the corresponding Alzheimer's disease associations from consortia included up to 488,285 European participants in the UK Biobank. Two-sample Mendelian randomization analyses served as our primary approach, with additional three-sample analyses performed to validate the findings.

RESULTS: In the sample of 407,746 participants, genetically predicted levels of broad depression showed no significant association with Alzheimer's disease risk (odds ratio, 1.00007; p = 0.908). As for the sample of 480,359 participants associated with major depressive disorder, the result was consistent (odds ratio, 0.99918, p = 0.138) with findings from broad depression. Secondary analyses present consistent results with primary findings. Statistically significant bias from pleiotropy or genetic confounding was not detected in sensitivity analyses.

DISCUSSION: The study's findings do not support a causal role of depression in AD and are more consistent with depression reflecting early disease processes or shared mechanisms.

CONCLUSION: This study's Mendelian randomization approach revealed no causal relationship between depression and Alzheimer's disease, consistent with depression reflecting early disease manifestations rather than a direct causal factor, and hinting at possible shared pathological processes in both conditions.},
}

@article {pmid42515916,
year = {2026},
author = {Saini, M and Hooda, T and Dar, MO and Kumar, S and Khatri, R and Lather, A},
title = {Network Pharmacology-guided Target Evaluation of Nefopam for Alzheimer's Disease: Insights from Docking and Molecular Dynamics Simulations.},
journal = {Current computer-aided drug design},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115734099474093260712091739},
pmid = {42515916},
issn = {1875-6697},
abstract = {INTRODUCTION: Amyloid-β accumulation, aberrant tau protein, neuroinflammation, and oxidative stress are some of the main pathogenic characteristics of Alzheimer's disease (AD), a degenerative illness characterized by cognitive deterioration. The majority of current AD therapies provide symptomatic alleviation with significant adverse effects, highlighting the urgent need for novel therapeutic approaches.

OBJECTIVE: This study examines nefopam, a centrally acting analgesic with NMDA antagonist and monoaminergic properties, as a potential treatment for AD using in silico methods like Network Pharmacology, Docking, and Molecular Dynamics Simulation studies.

RESULTS: Using network pharmacology, 90 molecular targets shared by the AD and nefopam pathways were identified. Following the selection of important hub proteins for further analysis, eight proteins with accessible 3D structures were put through molecular docking and MMGBSA computations. Nefopam demonstrated significant binding affinities, especially to 5HTR2A, GRIN1, 5HTR2C, SLC6A4, SLC6A3, and MAOB, whereas OPRM1 displayed weaker interactions, consistent with its lower MM-GBSA value (-37.04 kcal/mol) and docking score (-2.963). Molecular dynamics simulations of particular complexes over 100 ns revealed stable contacts and minimal structural changes for SLC6A3, SLC6A4, and 5HTR2A, suggesting strong and long-lasting binding.

DISCUSSION: The findings suggest that nefopam exhibits significant multi-target interactions with several proteins involved in AD pathogenesis, particularly those associated with neurotransmission, neuroprotection, and neuroinflammatory pathways. Its stable binding behavior and favorable interaction profiles support its potential role in modulating disease progression beyond symptomatic management.

CONCLUSION: Overall, this computational analysis confirms that nefopam can target multiple proteins linked to AD. These results show that more experimental research is necessary to validate nefopam's therapeutic potential and provide positive support for its repositioning in AD treatment.},
}

@article {pmid42516019,
year = {2026},
author = {Tijms, BM and van Harten, AC and Carillo, MC and Scheltens, P and Vijverberg, EGB},
title = {Analytical framing of Amyloid beta monoclonal antibody trials in Alzheimer's disease can obscure clinical effects.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71646},
doi = {10.1002/alz.71646},
pmid = {42516019},
issn = {1552-5279},
support = {//ZonMW VIDI/ ; 101171721//HORIZON EUROPE European Research Council/ ; },
abstract = {Cochrane Reviews are widely regarded as the gold standard for evidence synthesis, yet analytical framing influences interpretation. A recent Cochrane review of amyloid beta-targeting monoclonal antibodies pools mechanistically and biologically heterogenous interventions. These antibodies differ in biological targets and clinical effects, making a class-level estimate difficult to interpret. Pooling effects across these studies risks obscuring meaningful differences between interventions and may produce conclusions that do not reflect the underlying data, with important consequences for the evaluation of disease-modifying therapies in Alzheimer's disease.},
}

@article {pmid42516031,
year = {2026},
author = {Snyder, HM and Tampi, MP and Aisen, PS and Allegri, R and Apostolova, LG and Atri, A and Aurora, S and Caramelli, P and Crivelli, L and Cummings, J and de Strooper, B and Fox, NC and Grinberg, LT and Hardy, J and Lamb, BT and Levey, A and Lopez, O and Mummery, C and Nitrini, R and Pahlke, S and Petersen, RC and Pike, KJ and Porsteinsson, AP and Rabinovici, GD and Rafii, M and Raman, R and Sabbagh, MN and Salloway, SP and Scheltens, P and Schott, JM and Selkoe, DJ and Sevlever, G and Sperling, R and Tansey, MG and van Dyck, C and Zetterberg, H and Carrillo, MC},
title = {Recent Cochrane review has serious flaws: A perspective of clinicians and researchers from around the world.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71696},
pmid = {42516031},
issn = {1552-5279},
abstract = {In response to a Cochrane review (published in April 2026) on the clinical trials of monoclonal antibodies targeting beta amyloid, this perspective outlines a number of critiques. The scientists, methodologists, subject-matter experts, and clinicians on this perspective strongly recommend that the Cochrane editorial board consider a call for editorial response, correction of press materials, or commissioned reply to this review for four overarching reasons: (1) decision to pool antibodies that do and do not clear beta amyloid, (2) decision to include studies from a time when biomarkers of Alzheimer's disease were not available, (3) analytical and methodological limitations of the approach used, (4) conflating the distinct roles and methodological processes of systematic review and guideline methodologies, (5) contextualizing the present critique within the existing evidence-synthesis literature, and (6) mechanistic inference beyond the scope of the presented analyses. Conclusions that may not accurately reflect treatment-specific effects could cause significant downstream clinical and psychosocial harm to those currently undergoing treatment and their family members as well as individuals considering participation in Alzheimer's clinical trials.},
}

@article {pmid42516127,
year = {2026},
author = {Vieira, GH and Braga, VHG and Mesquita, IM and Rodrigues, SS and Maia, SD and Araújo, GO and Sousa, IMS and de Moura, ALD},
title = {Matrix-assisted laser desorption/ionization mass spectrometry (MALDI) in Alzheimer's disease: a scoping review of proteomic alterations in neurological tissues.},
journal = {Dementia & neuropsychologia},
volume = {20},
number = {},
pages = {e20250437},
pmid = {42516127},
issn = {1980-5764},
abstract = {Matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) has become a valuable tool for molecular mapping in neurological disorders. This scoping review synthesized current evidence on its use in proteomic analysis of neural tissues in Alzheimer's disease (AD). From 1,419 screened records, 26 studies met the inclusion criteria. Findings highlight MALDI-MS's capacity to detect beta-amyloid (Aβ) proteoforms, and tau protein post-translational modifications linked to AD. Its high spatial resolution enables region-specific molecular profiling, enhancing understanding of AD pathophysiology and supporting early biomarker discovery. The review underscores the translational potential of MALDI-MS in advancing targeted therapeutic development.},
}

@article {pmid42516270,
year = {2026},
author = {Rodríguez-Millan, L and Angarita-Rodríguez, A and Vargas-López, V and Pinzón, A and Tarifeño-Saldivia, E and González, J},
title = {Comparative evaluation of reference-free transcriptomic deconvolution highlights the importance of biological validation in astrocytes across Alzheimer's disease.},
journal = {Frontiers in bioinformatics},
volume = {6},
number = {},
pages = {1858866},
pmid = {42516270},
issn = {2673-7647},
abstract = {INTRODUCTION: Astrocytes are central regulators of neuronal energy metabolism and redox homeostasis-processes that become progressively disrupted across the Alzheimer's disease (AD) continuum. However, bulk transcriptomic data obscure cell-type-specific signals, and existing reference-free deconvolution methods often prioritize either statistical robustness or quantitative accuracy without fully integrating both dimensions.

METHODS: Here, we present a comparative framework evaluating two complementary unsupervised approaches, CDSeq and DECODER, to reconstruct astrocyte-associated transcriptomic profiles from human hippocampal samples spanning control, mild cognitive impairment (incipient and moderate), and AD (severe) stages (GSE28146; n = 30). The inferred profiles were functionally contextualized through integration into a genome-scale metabolic model of human astrocytes, enabling the assessment of system-level metabolic alterations associated with disease progression.

RESULTS: Our results reveal consistent dysregulation of key astrocytic pathways, including impairment of the astrocyte-neuron lactate shuttle, disruption of glutamine metabolism, and reduced glutathione-mediated an oxidant capacity. Methodological benchmarking showed distinct yet complementary performance profiles: DECODER achieved higher accuracy in reconstructing global expression magnitudes, whereas CDSeq exhibited greater stability and preservation of gene-gene relationships. Crucially, external validation using independent single-nucleus RNA-seq astrocyte data demonstrated that CDSeq-derived profiles achieve moderate but robust concordance with reference signatures (r ≈ 0.43-0.44), substantially exceeding DECODER-derived concordance (r ≈ 0.19-0.23), with higher concordance with astrocyte-associated signatures, alongside preservation of canonical astrocyte markers and enrichment of astrocyte-specific pathways, indicating superior biological coherence.

DISCUSSION: Together, these findings demonstrate that technical accuracy does not necessarily translate into biological validity and highlight CDSeq as the method that more reliably captures astrocyte-specific transcriptional programs in this context. While DECODER remains valuable for detecting absolute expression changes, CDSeq provides a more consistent recovery of astrocyte-associated transcriptional patterns. More broadly, our results support the incorporation of biological validation alongside statistical benchmarking when selecting deconvolution methods for downstream systems biology and metabolic modeling applications. This framework establishes a reproducible strategy for evaluating deconvolution methods and their functional consequences, advancing the interpretation of bulk transcriptomic data in neurodegenerative disease.},
}

@article {pmid42516384,
year = {2026},
author = {Giacovazzo, G and Latina, V and Yurtsever, ZN and Piccolino, I and Iannuzzi, F and Bossù, P and Amadoro, G and Coccurello, R},
title = {Prenatal immune activation and adult Poly(I:C) re-challenge promote neuroimmune priming and AD-related behavioural, cellular and molecular alterations in wild-type mice.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1845312},
pmid = {42516384},
issn = {1664-3224},
abstract = {OBJECTIVE: Alzheimer's Disease (AD) is neurodegenerative disorder characterized by deposition of Aβ plaques, tau-positive neurofibrillary tangles, neuroinflammation and clinical dementia. Epidemiological and experimental evidence suggest that peripheral immune inflammation is a risk factor for age-related neurodegeneration but whether its sustained activation is sufficient to drive behavioural, molecular and cellular changes consistent with AD-associated neurodegenerative vulnerability remains unclear. Here we investigated whether prenatal immune stimulation followed by an adult systemic re-challenge with Polyinosinic-polycytidylic acid (Poly(I:C)) induces persistent cognitive/motivational/social deficits and hippocampal neurodegeneration in wild-type mice, consistent with long-lasting neuroimmune priming mechanism(s).

METHODS: Pregnant C57Bl/6J dams received intravenously Poly(I:C) at gestational day 17 and male offspring received intraperitoneal Poly(I:C) at 9 months (single- or double-hit design) and were analyzed at 12 months. Recognition memory, working memory, reward-related learning, and social interaction were assessed followed by hippocampal Western blotting and immunofluorescence.

RESULTS: Poly(I:C)-exposed mice exhibited impaired recognition and working memory, reduced palatable food-induced conditioned place preference, and blunted social investigation. These behavioral abnormalities were accompanied by increased amyloidogenic APP processing (BACE1/PSEN1 upregulation and β-CTF accumulation), tau dysregulation (AT8 hyperphosphorylation), microglial activation (Iba1/CD68 upregulation and process retraction), synaptic alterations (α-synuclein reduction), and bioenergetic impairment (reduced mitochondrial and glycolytic markers) in the hippocampus.

CONCLUSION: Overall, these findings indicate that repeated prenatal and postnatal peripheral activation of innate immunity may act as a contributing factor to neurodegenerative phenotype with features relevant to AD-related susceptibility, paving the way for the development of next-generation therapeutical interventions affecting systemic-to-brain inflammatory signaling.},
}

@article {pmid42516522,
year = {2026},
author = {Haye, S and Jacobson, M and Zissimopoulos, J},
title = {Heterogeneous responses to risk-adjustment reform: evidence from dementia diagnosis in Medicare Advantage.},
journal = {Health affairs scholar},
volume = {4},
number = {7},
pages = {qxag167},
pmid = {42516522},
issn = {2976-5390},
abstract = {INTRODUCTION: In 2020, Alzheimer's disease and related dementias (ADRD) diagnoses were reintroduced into the Medicare Advantage (MA) risk-adjustment model creating financial incentives that may increase diagnostic coding and plan payments. This effect may vary across plans depending on provider integration, administrative capacity, and geographic context, with implications for payments and potential "upcoding."

METHODS: Using 100% Medicare data from 2016-2021, we estimated event study and difference-in-differences models comparing adjusted trends in incident ADRD diagnoses in MA relative to traditional Medicare before and after the policy change.

RESULTS: Incident dementia diagnoses increased in MA relative to traditional Medicare, despite an overall downward trend in diagnosis rates. Increases were larger among enrollees in MA health maintenance organization plans (20.8%) than in preferred provider organization plans (7.6%) and varied across insurers, ranging from 7.2% (United Healthcare) to 21.6% (Kaiser Permanente). Increases were more pronounced in urban than in rural areas.

CONCLUSION: Reintroducing ADRD into the MA risk-adjustment model was associated with increased diagnostic coding, with substantial variation across plan types, insurers, and geographic contexts. Because ADRD diagnoses increase risk-adjusted payments, larger increases across some plans may reflect coding practices rather than true disease prevalence, highlighting the need for closer monitoring.},
}

@article {pmid42516540,
year = {2026},
author = {Passalacqua, E and Barberi, G and Amico, P and Di Martino, S and De Rosa, M},
title = {Peptide-drug conjugation: a strategy to address blood-brain barrier limitations in central nervous system diseases.},
journal = {RSC medicinal chemistry},
volume = {},
number = {},
pages = {},
pmid = {42516540},
issn = {2632-8682},
abstract = {Central nervous system diseases are among the most challenging to treat, mainly due to the blood-brain barrier, which restricts the entry of most therapeutics into the brain, preventing them from reaching pharmacological concentrations. Moreover, the multifactorial causes of these diseases require targeting diverse key processes. In this context, peptide-drug conjugates represent a promising strategy and offer a multitargeting regimen platform. In this work, we describe the latest developments of peptide-drug conjugates for glioma, Alzheimer's, and Parkinson's diseases, highlighting how conjugating payloads to specific peptides can offer several therapeutic advantages over conventional approaches. Particular emphasis was given to the chemical nature of the conjugation bonds and to the synthetic reactions to underscore the versatility of the methods used.},
}

@article {pmid42516760,
year = {2026},
author = {Lee, HW and Choi, Y and Lee, S and Kim, JE and Jeon, MT and Jo, M and Park, G and Park, JS and Kim, DG and Cheon, M and Kim, HJ},
title = {Identification of a robust multitarget protein panel for Parkinson's disease via absolute quantification and large-scale external replication.},
journal = {Brain communications},
volume = {8},
number = {4},
pages = {fcag282},
pmid = {42516760},
issn = {2632-1297},
abstract = {This study aimed to identify and validate a robust, generalizable panel of plasma protein biomarkers to improve diagnostic precision in Parkinson's disease. We analysed plasma samples from 12 patients with [[18]F]-FP-CIT PET-confirmed Parkinson's disease and 15 healthy controls using the Olink Target 96 Inflammation Panel to identify differentially expressed proteins. Candidate biomarkers were subsequently validated through absolute quantification using Luminex and Olink Flex platforms in an independent cohort of 46 patients with Parkinson's disease and 33 amyloid-negative and cognitively normal control participants. To assess generalizability, the findings were replicated across multiple heterogeneous populations using large-scale datasets from the UK Biobank and Global Neurodegeneration Proteomics Consortium (GNPC) cohorts. Markers of neurodegeneration [neurofilament light chain (NfL)] and Alzheimer's disease [phosphorylated tau (pTau181), amyloid β [Aβ]42, Aβ40] co-pathology were measured using the single molecule array platform. Our analyses revealed elevated levels of interleukin (IL)-10 and IL-17C and reduced levels of urokinase plasminogen activator (uPA) and neurotrophin-3 (NTF3) in patients with Parkinson's disease. These findings were confirmed in the validation cohort. Multitarget models demonstrated superior diagnostic performance over individual markers, with the combination of IL-17C and uPA achieving the highest discrimination (area under the curve = 0.780). External validation in the UK Biobank and GNPC datasets confirmed consistent directional changes of three candidates (IL-17C, NTF3 and uPA), reinforcing the biological relevance of these markers. Notably, while NfL levels were significantly elevated in Parkinson's disease, no significant differences were observed for pTau181 levels or Aβ42/Aβ40 ratios. These findings identify a specific plasma protein panel, particularly the combination of IL-17C and uPA, as a robust and generalizable diagnostic signature that captures fundamental pathophysiological aspects of Parkinson's disease and enhances diagnostic precision alongside established biomarkers.},
}

@article {pmid42516873,
year = {2026},
author = {Bago Rožanković, P and Šimić, G},
title = {Emerging biomarkers for Parkinson's disease in biological fluids.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1835751},
pmid = {42516873},
issn = {1663-4365},
abstract = {Early and accurate diagnosis of Parkinson's disease (PD) remains a challenge, hindering the efficient recruitment of patients into clinical trials aimed at disease modification. This underscores the urgent need for validated and clinically applicable biomarkers. Research continues to expand our knowledge of fluid biomarkers for detecting and monitoring PD progression. Cerebrospinal fluid α-synuclein (α-syn) seed amplification assays (SAA) have emerged as highly sensitive and specific biomarkers for the diagnosis of PD. The development of less invasive procedures using biological fluids such as serum or saliva would be more practical for routine clinical use. Recent data demonstrate the presence of pathogenic α-synuclein in the serum of PD patients compared with healthy controls, detected using real-time quaking-induced conversion (RT-QuIC) assays. Elevated ratios of pS129-α-syn and/or oligomeric α-syn to total α-syn have also been reported in PD. Future research should clarify differences in protein aggregate formation across various synucleinopathies. Promising advances toward a clinically useful blood-based diagnostic test for PD include the quantification of proteins released from neural-derived extracellular vesicles (NDEVs), such as oligomeric and phosphorylated α-syn, tau, and disease-associated microRNAs. Given the role of neuroinflammation in PD pathogenesis, inflammatory biomarkers, including interleukin (IL)-6, IL-10, tumor necrosis factor-α(TNF-α), glial fibrillary acidic protein (GFAP), chitinase-3-like protein 1 (YKL-40), and monocyte chemoattractant protein-1 (MCP-1), are under active investigation. Furthermore, fluid biomarkers associated with Alzheimer's disease pathology are being explored for their potential to predict motor and cognitive decline in PD and related synucleinopathies. Salivary EVs hold promise as a non-invasive source of PD biomarkers; however, robust validation in large, well-characterized cohorts is essential to improve the diagnostic and prognostic accuracy of PD.},
}

@article {pmid42516875,
year = {2026},
author = {Tropea, MR and Aceto, G and Trovato, RC and Nicitra, E and Santuccio, N and Intili, G and D'Ascenzo, M and Puzzo, D},
title = {Dopamine D3 receptor blockade restores hippocampal synaptic plasticity and rescues memory deficits in Alzheimer's disease mouse models.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1840697},
pmid = {42516875},
issn = {1663-4365},
abstract = {INTRODUCTION: Early synaptic failure is widely considered a primary driver of cognitive decline in Alzheimer's disease (AD), and previous studies have suggested that dopaminergic signaling may contribute to hippocampal synaptic dysfunction. Among dopaminergic receptors, dopamine D3 receptors (D3Rs) have emerged as important modulators of synaptic plasticity and cognitive processes, but their role in AD-related synaptic impairment remains unclear. The aim of this study was to determine whether pharmacological blockade of D3Rs could restore memory deficits and hippocampal synaptic dysfunction in preclinical models of AD.

METHODS: Behavioral studies, including novel object recognition (NOR), novel object location (NOL), and open-field tests, were performed to evaluate recognition memory, spatial memory, locomotor activity, and anxiety-related behavior in two mechanistically distinct mouse models of AD: triple-transgenic 3xTg-AD mice and α7 nicotinic acetylcholine receptor knockout (α7KO) mice. Electrophysiological recordings in hippocampal slices were used to assess AMPA/NMDA ratio, basal synaptic transmission, and long-term potentiation (LTP). qPCR and western blot analyses were performed to evaluate hippocampal D3R mRNA and protein expression, respectively. Pharmacological treatments included the selective D3R antagonist NGB-2904 and cariprazine, a clinically approved antipsychotic with high affinity for D3Rs.

RESULTS: Recognition and spatial memory deficits were rescued by NGB-2904 and cariprazine in both AD models, without affecting locomotor activity or anxiety-related behavior. No sex-dependent differences were observed in the behavioral response to treatment. Electrophysiological recordings revealed a reduced AMPA/NMDA ratio and impaired LTP in both models, while basal synaptic transmission was selectively reduced in 3xTg-AD mice. D3R-targeting compounds restored synaptic transmission and plasticity. Inhibition of PKA prevented the rescue of LTP induced by D3R blockade, suggesting the involvement of the cAMP/PKA signaling pathway. Both models displayed reduced hippocampal D3R mRNA expression and protein levels, suggesting that the residual population of D3Rs might represent a viable target.

CONCLUSION: Together, these findings demonstrate that D3R-targeting compounds rescue synaptic plasticity and memory deficits in two mechanistically distinct AD models. These results support a role for dopaminergic signaling in early synaptic dysfunction and highlights D3R modulation as a relevant pathway for further investigation in AD-related cognitive impairment.},
}

@article {pmid42516878,
year = {2026},
author = {Jalloh, MB and Fadlu Deen, G and Bah, O and Bah, I and Suma, AA and Abiri, OT and Thompson, MC and Tejan, E and Jalloh, F and Foray, FM and Faulkner, MMJ and Gaye, B},
title = {Rising burden of Alzheimer's disease and other dementias in Sierra Leone, 1990-2023: analysis of Global Burden of Disease 2023 estimates.},
journal = {BMJ neurology open},
volume = {8},
number = {2},
pages = {e001507},
pmid = {42516878},
issn = {2632-6140},
abstract = {BACKGROUND: Dementia is an increasing cause of disability and mortality worldwide. Primary dementia surveillance data remain limited in many low-income settings, including Sierra Leone.

OBJECTIVE: To describe trends in Burden of Disease (GBD) 2023 modelled estimates for Alzheimer's disease and other dementias in Sierra Leone from 1990 to 2023, and to decompose the change in estimated deaths into demographic and age-specific mortality components.

METHODS: We conducted a secondary analysis of GBD 2023 estimates for the cause category 'Alzheimer's disease and other dementias' in Sierra Leone. We analysed estimated counts and age-standardised rates for prevalence, deaths, years of life lost, years lived with disability and disability-adjusted life years (DALYs) stratified by age and sex. Temporal trends were described with log-linear regression to estimate annual per cent change, and a three-component decomposition attributed changes in deaths to population growth, ageing and age-specific mortality.

RESULTS: GCD 2023 estimated that dementia deaths in Sierra Leone increased from 188 in 1990 to 474 in 2023, an absolute increase of 286 estimated deaths (152% relative increase). Estimated DALYs increased from 3703 to 7440. The modelled age-standardised death rate rose 26.8% (16.3 to 20.7 per 100 000) and the age-standardised DALY rate 13.4% (293.7 to 333.2 per 100 000). Estimated prevalent cases increased from 5647 to 8887, while the modelled age-standardised prevalence rate declined from 430.7 to 404.0 per 100 000 population. The log-linear annual percentage change was +1.02% for age-standardised death rates, +0.60% for DALY rates and -0.18% for prevalence rates. Decomposition attributed 62% of the increase in estimated deaths to changes in age-specific mortality, 30% to population growth and 8% to population ageing.

CONCLUSIONS: GBD 2023 estimates show a rising absolute burden of dementia in Sierra Leone, against a background of limited local surveillance and mortality ascertainment.},
}

@article {pmid42517390,
year = {2026},
author = {Guo, X and Jiang, T and Ma, W and Cao, D and Mao, X},
title = {Targeting Ferroptosis-associated Histone Acylation for Amelioration of Neurological Disease.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X479697260707073238},
pmid = {42517390},
issn = {1875-6190},
abstract = {Ferroptosis is an iron-dependent, lipid peroxidation-driven form of programmed cell death. There is substantial evidence supporting the critical role of ferroptosis in multiple neurological diseases, including stroke, Alzheimer's disease, Parkinson's disease, epilepsy, and traumatic brain injury. Histone acylation, an important epigenetic mechanism, effectively regulates ferroptosis. To date, the regulation of ferroptosis by histone acylation in neurological diseases has rarely been summarized. Therefore, this review discusses the key mechanisms by which histone acylation regulates ferroptosis, including iron metabolism, antioxidant defense, and lipid peroxidation. Additionally, we summarize the latest advances in understanding the role of histone acylation in ferroptosis and its relation to the emerging hallmarks of neurological diseases. Furthermore, we provide the prospect of targeting key regulatory factors of histone acylation, such as writers, erasers, and readers, for potential therapeutic strategies to ameliorate neurological diseases.},
}

@article {pmid42517391,
year = {2026},
author = {Wei, M and Sui, Y and Xia, X},
title = {Mechanisms and Applications of Transcranial Ultrasound Stimulation in Neurological Disorders and Psychiatric Conditions.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X495837260717044104},
pmid = {42517391},
issn = {1875-6190},
abstract = {Transcranial ultrasound stimulation (TUS) is an emerging non-invasive neuromodulation strategy with high spatial precision and the ability to target both cortical and deep brain regions. This review summarizes recent progress in low-intensity, non-thermal TUS in representative neurological and psychiatric disorders, including Parkinson's disease, Alzheimer's disease, epilepsy, ischemic stroke, depression, anxiety disorders, and schizophrenia. Current preclinical evidence suggests that TUS may alleviate disease-related pathological and functional abnormalities by regulating neurotransmitter release, enhancing neurotrophic factor expression, promoting synaptic plasticity, modulating neural oscillations and circuit connectivity, improving cerebral blood flow, suppressing neuroinflammation and oxidative stress, and facilitating blood-brain barrier opening when combined with microbubbles. These biological effects may act across molecular, cellular, synaptic, circuit, and system levels, ultimately contributing to improvements in motor, cognitive, and emotional dysfunction. This review also discusses the marked heterogeneity of acoustic parameters in preclinical and clinical studies, as well as current evidence on safety. With further standardization of stimulation parameters, deeper mechanistic understanding, and stronger clinical evidence, TUS may develop into a safe, precise, and clinically translatable neuromodulation strategy.},
}

@article {pmid42517395,
year = {2026},
author = {Chen, Y and Zhang, C and Yu, X and Ma, S and Zhai, Y and Zhao, C and Li, C and He, K and Shang, Y},
title = {Bioinformatics-Guided Mechanistic Insights into Scutellaria Barbata Flavonoids Improving CREB Signaling-Related Cognitive Dysfunction through ERK-RSK-CREB Cascade Modulation.},
journal = {Current medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0109298673429444260629063831},
pmid = {42517395},
issn = {1875-533X},
abstract = {INTRODUCTION: There is evidence showing that cognitive dysfunction is a typical characteristic in Alzheimer's Disease (AD) patients. CREB signaling-related neuronal dysfunction through ERK-RSK-CREB is a subtype of the pathological mechanism of AD. The present study aimed to investigate whether Scutellaria Barbata Flavonoids (SBFs) ameliorate the rats' cognitive impairment by targeting the ERK-RSK-CREB signaling pathway, utilizing the CREB indirect inhibition model by a specific ribosomal S6 kinase (RSK) inhibitor BI-D1870 application.

METHODS: Bioinformatics analysis was conducted to identify key pathways involved in AD. Based on this, an in vivo memory impairment model of related-AD was established in rats by indirect inhibition of CREB via intraperitoneal injection of the RSK inhibitor BI-D1870. Following successful memory impairment model of related-AD rats screening with the Morris water maze, the successful model rats were treated with SBFs (140 mg/kg) or the CREB activator Rolipram (0.5 mg/kg). Spatial and short-term memory were assessed using the Barnes maze and the Passive Avoidance Test, respectively. NeurN and Nissl body for neuronal integrity and the expression of ERK-RSK-CREB pathway-related molecules (p-CREB-Ser133/Ser142, RSK, CREB, EGR-1) were evaluated by histological staining, immunohistochemistry, and molecular biology techniques.

RESULTS: Bioinformatics analysis identified the MAPK signaling pathway as a key pathway for further investigation. Experimentally, SBFs administration significantly improved both spatial and short-term memory deficits induced by BI-D1870. This cognitive recovery was associated with the restoration of neuronal Nissl bodies and NeuN expression. Mechanistically, SBFs upregulated the phosphorylation of CREB at Ser133 and the expression of RSK, CREB, and EGR-1 mRNA and/or protein, while concurrently downregulating the elevated phosphorylation of CREB at Ser142, which demonstrated the bidirectional regulatory mechanism of SBFs on CREB phosphorylation of the ERK-RSK-CREB pathway.

DISCUSSION: This study demonstrates that BI-D1870 can cause the rats' memory deficits, and SBFs can mitigate BI-D1870-induced memory deficits by enhancing ERK-RSK-CREB signaling, similar to Rolipram. SBFs restored neuronal integrity (Nissl bodies, NeuN) and upregulated p- CREB-Ser133, RSK, CREB, and EGR-1, suggesting SBFs' neuroprotection. These findings highlight SBFs as a potential therapeutic agent for memory disorders via CREB pathway modulation. However, our research has some limitations. Bioinformatics identified the key signaling pathway involved in AD, but the BI-D1870 model merely estimates AD-related cognitive dysfunction; it does not recapitulate the full spectrum of AD pathology. Future studies should validate the efficacy, mechanisms, bioactive substances, and metabolized root of SBFs in more etiologically relevant transgenic AD models.

CONCLUSION: Our findings indicate that SBFs exert neuroprotective effects against CREB indirect inhibitor-induced cognitive dysfunction, likely through the modulation of the ERK-RSK-CREB pathway. This suggests SBFs as a potential candidate for mitigating memory deficits associated with CREB dysregulation.},
}