@article {pmid42320779,
year = {2026},
author = {Wang, M and Galvin, VC and Joyce, MKP and Datta, D and Yang, S and Disney, AA and Arnsten, AFT},
title = {Distinctive Molecular Mechanisms in Higher Cortical Circuits Confer Vulnerability to Mental Disorders.},
journal = {Biological psychiatry},
volume = {},
number = {},
pages = {},
pmid = {42320779},
issn = {1873-2402},
support = {F32 EY034772/EY/NEI NIH HHS/United States ; R01 EY029663/EY/NEI NIH HHS/United States ; R01 MH130538/MH/NIMH NIH HHS/United States ; RF1 AG083090/AG/NIA NIH HHS/United States ; },
abstract = {In this article, we review the molecular differences across the cortical hierarchy in primates that expand in the dorsolateral prefrontal cortex (dlPFC) to generate working memory and top-down control but also confer vulnerability in mental disorders. Research on molecular mechanisms early in the primate cortical hierarchy, e.g., in the primary visual cortex (V1), are often in concert with rodent, e.g., neurotransmission relies greatly on AMPA receptors (AMPARs), while modulation with attention involves NMDA receptors (NMDARs) and cholinergic mechanisms. However, there are also significant differences in cortical specializations and cholinergic receptor localization between the rodent and the primate V1. In contrast to V1, the recurrent excitatory microcircuits in layer III of the primate dlPFC that generate working memory express many distinct mechanisms; neurotransmission depends on NMDARs and acetylcholine (and thus arousal state), not AMPARs; extended neuronal firing underlying working memory depends on magnified calcium signaling in spines; however, excessive cytosolic calcium reduces firing, with powerful mechanisms to take the dlPFC offline during uncontrollable stress and/or inflammation, e.g., opening potassium channels on spines to rapidly weaken connections. Regulation of these powerful mechanisms is lost due to inflammation and/or genetic insults (e.g., gain-of-function mutations in CACNA1C, loss of function in GRM3), which may interact to induce loss of dendritic spines and/or tau pathology, cognitive impairments, and reduced top-down control. Many of the genetic risks for schizophrenia weaken layer III dlPFC spine connections, suggesting that multiple genotypes would produce a shared phenotype. The review also suggests new therapeutic targets that can act to reduce inflammation, regulate calcium, and strengthen synaptic efficacy in the primate dlPFC.},
}

@article {pmid42605784,
year = {2026},
author = {Xue, JS and Niu, M and Song, XY and Deng, XM},
title = {Schisandrin A, a dietary lignan from Schisandra chinensis, ameliorates cognitive deficits in AlCl3/D-galactose-treated mice.},
journal = {Nutritional neuroscience},
volume = {},
number = {},
pages = {1-14},
doi = {10.1080/1028415X.2026.2714516},
pmid = {42605784},
issn = {1476-8305},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder with limited disease-modifying therapies. Chronic aluminum exposure, a well-recognized environmental risk factor, exacerbates AD pathogenesis by driving oxidative stress and neuroinflammation. Schisandrin A (SchA), a bioactive lignan from the medicinal and edible plant Schisandra chinensis, exhibits promising antioxidant and anti-inflammatory properties, yet its nutritional relevance for AD intervention remains undefined. This study evaluated SchA's neuroprotective potential in an AlCl3/D-galactose-induced cognitive impairment model. We found that SchA significantly ameliorated learning and memory impairments in Morris water maze, novel object recognition, open field and Y-maze tests, alleviated neuronal damage in the hippocampus and cortex, and reduced cerebral amyloid-β (Aβ) production in AlCl3/D-galactose-treated mice. Mechanistically, SchA mitigated neuroinflammation via inhibiting the IKK/NF-κB/iNOS pathway, and alleviated oxidative stress through activating the Nrf2/HO-1 axis. Our findings demonstrate that SchA exerts neuroprotective effects in AlCl3/D-galactose-treated mice, accompanied by modulation of inflammatory and oxidative-stress-related signalling, supporting its potential as a nutritional intervention for AD.},
}

@article {pmid42605813,
year = {2026},
author = {Al Hasan, MS and Shahria, N and Emon, Y and Alshahrani, MY and Mia, E and Altemani, FH and Suma, RB and Sumaya, UH and Uddin, MB and Islam, MT},
title = {Paeonol as a Multi-Target Therapy for Neurological Disorders: Mechanistic Insights Into Neuroprotection.},
journal = {Immunity, inflammation and disease},
volume = {14},
number = {8},
pages = {e70494},
doi = {10.1002/iid3.70494},
pmid = {42605813},
issn = {2050-4527},
mesh = {Humans ; Animals ; *Neuroprotective Agents/therapeutic use/pharmacology ; *Acetophenones/therapeutic use/pharmacology ; Oxidative Stress/drug effects ; *Nervous System Diseases/drug therapy/metabolism ; Antioxidants/therapeutic use/pharmacology ; Neuroprotection/drug effects ; *Neurodegenerative Diseases/drug therapy ; Anti-Inflammatory Agents/therapeutic use/pharmacology ; },
abstract = {BACKGROUND: Neurological disorders are a major global health challenge in the current era, and they need new therapeutic treatments.

AIMS: This review evaluates the neurobiological activity of Paeonol (PNL) focusing on its antioxidant, anti-inflammatory, and cognitive enhancing effects in various neurodegenerative disorders.

METHODS: A literature search (up to March 2025) was conducted via PubMed, ScienceDirect, Scopus, and other databases using MeSH terms related to PNL's pharmacology and neuroprotection. Inclusion criteria encompassed preclinical studies (in vitro and in vivo) and clinical trials, while exclusion criteria eliminated non-English papers and non-neurodegenerative research.

RESULTS: PNL, a bioactive phenolic compound from Paeonia suffruticosa, has shown antioxidative, anti-inflammatory, and neuroprotective effects. PNL reduces oxidative stress by boosting the activity of superoxide dismutase (SOD) and glutathione (GSH) while decreasing reactive oxygen species (ROS) and lipid peroxidation. It also reduces neuroinflammation by inhibiting key pathways such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), toll-like receptor 4 (TLR4), and mitogen-activated protein kinase (MAPK), and it affects apoptosis-related proteins like B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein (Bax). In Alzheimer's disease (AD) models, PNL reduces amyloid-β plaques and some pro-inflammatory cytokines like interleukin-1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α), improving cognitive function. For ischemic stroke, it reduces infarction volume and microglial activation by targeting TLR2/4 and NF-κB. PNL has anticonvulsant effects in epilepsy and protects dopaminergic neurons in Parkinson's disease (PD). It also demonstrates anxiolytic and antidepressant properties by modulating Brain-Derived Neurotrophic Factor (BDNF), Nerve Growth Factor (NGF), and oxidative stress markers. PNL is quickly absorbed with moderate bioavailability and low blood-brain barrier permeability. It effectively treats unstable angina but is less effective for osteoarthritis pain. Though safe at therapeutic doses, high concentrations can be cytotoxic.

CONCLUSION: Further clinical research is needed to confirm its neurotherapeutic potential.},
}

Humans
Animals
*Neuroprotective Agents/therapeutic use/pharmacology
*Acetophenones/therapeutic use/pharmacology
Oxidative Stress/drug effects
*Nervous System Diseases/drug therapy/metabolism
Antioxidants/therapeutic use/pharmacology
Neuroprotection/drug effects
*Neurodegenerative Diseases/drug therapy
Anti-Inflammatory Agents/therapeutic use/pharmacology

@article {pmid42606055,
year = {2026},
author = {Subramanian, L and Wu, CY and Bai, WZ and Lin, YC and Wu, KC and Chung, RJ},
title = {Clioquinol-Loaded UiO-66(Ce) Metal-Organic Frameworks for Dual Reactive Oxygen Species Scavenging and Metal Chelation in Alzheimer's Disease.},
journal = {ACS applied bio materials},
volume = {9},
number = {16},
pages = {7629-7636},
doi = {10.1021/acsabm.6c01023},
pmid = {42606055},
issn = {2576-6422},
support = {NSTC 112-2221-E-027-038-MY3//National Science and Technology Council/ ; NSTC 112-2321-B-A49-008//National Science and Technology Council/ ; NSTC 113-2314-B-182A-128//National Science and Technology Council/ ; },
mesh = {*Clioquinol/chemistry/pharmacology ; *Reactive Oxygen Species/metabolism/antagonists & inhibitors ; Animals ; *Alzheimer Disease/drug therapy/metabolism ; PC12 Cells ; *Chelating Agents/chemistry/pharmacology/chemical synthesis ; *Metal-Organic Frameworks/chemistry/pharmacology ; Amyloid beta-Peptides/metabolism/antagonists & inhibitors ; Rats ; *Biocompatible Materials/chemistry/pharmacology/chemical synthesis ; Materials Testing ; Cerium/chemistry/pharmacology ; Cell Survival/drug effects ; *Free Radical Scavengers/pharmacology/chemistry/chemical synthesis ; Particle Size ; Molecular Structure ; Surface Properties ; Phthalic Acids ; },
abstract = {Alzheimer's disease (AD) is a major neurodegenerative disorder associated with amyloid-β (Aβ) aggregation and oxidative stress, often linked to metal ion dyshomeostasis. In this study, we developed a clioquinol (CQ)-loaded UiO-66(Ce), a cerium-based metal-organic framework (MOF), as a potential dual-functional platform. The system is designed to combine reactive oxygen species (ROS) scavenging via Ce(III)/Ce(IV) redox cycling with the metal-chelating capability of CQ, aiming to modulate multiple AD-related pathological factors. The material was synthesized and characterized, and its biological performance was preliminarily evaluated in PC-12 cells using an Aβ-Cu2+ model system. The results suggest that UiO-66(Ce)-CQ exhibits acceptable biocompatibility and is associated with reduced intracellular ROS levels, improved cell viability, and modulation of Aβ aggregation behavior. Compared with its individual components, UiO-66(Ce)-CQ showed enhanced overall performance under the tested conditions. While this study is limited to initial in vitro evaluation, the findings provide a preliminary proof of concept for integrating ROS-scavenging and metal-chelating functionalities within a single MOF-based platform, which may offer a potential strategy for AD-related applications.},
}

*Clioquinol/chemistry/pharmacology
*Reactive Oxygen Species/metabolism/antagonists & inhibitors
Animals
*Alzheimer Disease/drug therapy/metabolism
PC12 Cells
*Chelating Agents/chemistry/pharmacology/chemical synthesis
*Metal-Organic Frameworks/chemistry/pharmacology
Amyloid beta-Peptides/metabolism/antagonists & inhibitors
Rats
*Biocompatible Materials/chemistry/pharmacology/chemical synthesis
Materials Testing
Cerium/chemistry/pharmacology
Cell Survival/drug effects
*Free Radical Scavengers/pharmacology/chemistry/chemical synthesis
Particle Size
Molecular Structure
Surface Properties
Phthalic Acids

@article {pmid42606153,
year = {2026},
author = {Paudel, A and Galik, E and Murphy, TE and Boltz, M},
title = {Content Validity of the Quality of Interactions Inventory (QUALII) in Assisted Living.},
journal = {Alzheimer disease and associated disorders},
volume = {},
number = {},
pages = {},
pmid = {42606153},
issn = {1546-4156},
abstract = {BACKGROUND/AIM: To promote staff and resident well-being in Assisted Living (AL), it is essential to enhance daily care interactions between staff and older adults with Alzheimer disease and related dementias (ADRD). There is currently no comprehensive instrument that can both guide the process of improving care interactions and appraise the impact of such improvements in AL. We developed a comprehensive instrument, the Quality of Interactions Inventory (QUALII), that accomplishes both tasks. Here, we evaluate its content validity.

METHODS: An eDelphi study with a convenience sample of N=10 clinical/academic experts in ADRD care and communication. Item-Content Validity Index (I-CVI) and Scale-Content Validity Index (S-CVI) were computed using quantitative ratings; item revisions were based on content analysis of qualitative comments.

RESULTS: Following 3 rounds of eDelphi survey, QUALII was reduced to a 19-item tool with I-CVI=0.90 to 1.00 for item relevance, I-CVI=0.80 to 1.00 for item clarity, and S-CVI=0.93 for the overall scale.

CONCLUSION AND IMPLICATIONS: QUALII demonstrated excellent content validity and will be used for pilot testing in AL communities. Upon pilot testing, QUALII could emerge as a valid, reliable, and comprehensive tool for promoting positive care interactions in ADRD care.},
}

@article {pmid42606290,
year = {2026},
author = {Uchida, K and Sugimoto, T and Nakagawa, T and Noguchi, T and Komatsu, A and Ono, R and Yokoyama, Y and Onoyama, A and Sakurai, T and Saito, T},
title = {Relationship between body composition and mortality in older patients with mild cognitive impairment and Alzheimer's disease: NCGG-STORIES.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261476079},
doi = {10.1177/13872877261476079},
pmid = {42606290},
issn = {1875-8908},
abstract = {BackgroundAlthough a lower body mass index (BMI) has been identified as a prognostic risk factor among older adults with cognitive impairment, it remains unclear which body composition are associated with prognosis.ObjectiveThis study investigated the relationship between body composition and mortality in older adults with mild cognitive impairment (MCI) and Alzheimer's disease (AD).MethodsThis longitudinal study, using data from a memory clinic in Japan, included patients aged ≥65 years who were clinically diagnosed with MCI or AD. Mortality data (date and cause of death) were obtained using a proxy questionnaire. Body composition (muscle mass, fat-free mass, fat mass, %FM) was measured using bioelectrical impedance analysis, and muscle mass index (MMI), fat-free mass index (FFMI) and fat mass index (FMI) were calculated. Body composition index was divided into tertiles (lowest, middle, and highest). To evaluate associations between body composition and mortality, we conducted survival analyses using Cox proportional hazards model (ref. lowest group).ResultsA total of 1575 patients were included in the analysis (mean age, 78.2 years; 63.2% women). The highest FMI and %FM groups had a lower risk of mortality than that in the lowest group (hazard ratio [95% confidence interval]: FMI, 0.55 [0.37-0.81]; %FM, 0.49 [0.33-0.71]), and this association was significant in women with MCI and AD. No significant associations were observed between MMI, FFMI, and mortality.ConclusionsLower FM may be a potential risk factor for poor prognosis, emphasizing the need to monitor it from an early stage of cognitive decline.},
}

@article {pmid42606294,
year = {2026},
author = {Nam, GE and Liu, J and Thoma, M and Kobayashi, LC and Koenen, KC and Kunicki, ZJ and Hayes-Larson, E},
title = {Stress sensitization: Does childhood adversity modify trauma effects on memory?.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261476095},
pmid = {42606294},
issn = {1875-8908},
abstract = {BackgroundTrauma across the lifecourse is implicated in adverse health outcomes, yet whether earlier adversity shapes vulnerability to effects of later trauma on cognitive decline, an important contributor to Alzheimer's disease, remains unclear.ObjectiveWe examined the impact of adult incident traumatic experiences (ITEs) on late-life memory decline, and whether this association is modified by childhood adversity.MethodsWe leveraged 2006-2020 data from the Health and Retirement Study, a longitudinal cohort of US adults aged ≥50 years. ITEs were self-reported stressful or life-threatening experiences in 2006-2012 (any versus none). Childhood adversity (any versus none) included retrospective reports of abuse, neglect, or household dysfunction before age 18. Memory was assessed biennially from 2010-2020 using standardized scores. Linear mixed-effects models estimated associations between ITEs and decline in memory z-score, adjusted for demographics, childhood socioeconomic status, and self-rated health. Stratified analyses examined effect modification by childhood adversity.ResultsAmong 2971 participants, mean baseline age was 67.3 years (SD 9.2); 60% were female and 86% were White. Individuals with ITEs experienced a faster memory decline than those without ITEs (β= -0.014 SD units/year, 95% CI -0.024, -0.003). Childhood adversity did not modify this association. Findings were consistent across sensitivity analyses using alternative exposure and outcome definitions.ConclusionsITEs were associated with accelerated memory decline in later life, and childhood adversity did not modify this relationship. Identifying resilience factors that mitigate the cognitive effects of adult traumatic experiences may inform prevention strategies for Alzheimer's disease.},
}

@article {pmid42606297,
year = {2026},
author = {Zhang, YX and El Hamamy, A and Iqbal, Z and Ranjan, A and Sumani, D and De Souza, KA and Lee, J and Marrelli, S and McCullough, LD and Li, J},
title = {Impact of stroke on respiratory function and amyloid-β pathology in Tg-2576 mice.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261476022},
doi = {10.1177/13872877261476022},
pmid = {42606297},
issn = {1875-8908},
abstract = {BACKGROUND: Stroke is a well-established risk factor for dementia, and many patients with Alzheimer's disease exhibit mixed neuropathology that includes both ischemic injury and amyloid-β (Aβ) accumulation. Breathing disturbances, such as apnea, have also been linked to cognitive dysfunction and accelerated dementia progression.

OBJECTIVE: We hypothesized that stroke aggravates respiratory dysfunction and cognitive impairment in Tg-2576 mice.

METHODS: Female Tg-2576 mice (13-17 months old) underwent permanent distal middle cerebral artery occlusion (pd-MCAO), with age- and sex-matched wild-type and sham-operated controls. Cognitive performance was assessed using the Barnes maze. Respiratory parameters were quantified by whole-body plethysmography. Immunofluorescence was performed to measure Aβ deposition in hippocampus and cortex, astrocyte reactivity in retrotrapezoid nucleus (RTN) using GFAP, and LYVE1 in deep cervical lymph nodes (dCLNs). Aβ levels in cerebrospinal fluid were also assessed as a readout related to clearance-associated changes.

RESULTS: Compared with wild-type controls, Tg-2576 mice exhibited increased apnea frequency and impaired cognitive performance. Following pd-MCAO, Tg-2576 mice showed a further increase in apnea events and prolonged escape latencies in the Barnes maze. Stroke was also associated with enhanced astrocyte reactivity in the RTN, increased Aβ deposition in the hippocampus and cortex, and reduced Aβ levels in cerebrospinal fluid, along with decreased LYVE1-positive lymphatic area in dCLNs, suggesting compromised glymphatic-lymphatic clearance.

CONCLUSIONS: Collectively, these findings indicate that stroke worsens respiratory dysfunction, impairs Aβ clearance pathways, and accelerates cognitive decline in Tg-2576 mice. Targeting post-stroke respiratory abnormalities may represent a therapeutic avenue to mitigate dementia-related comorbidity after ischemic injury.},
}

@article {pmid42606634,
year = {2026},
author = {Cheng, L and Gong, P and Su, X and Fang, Y and Wang, T},
title = {miR-584-5p suppresses Aβ1-42-induced apoptosis in Alzheimer's disease cell model via targeting of HDAC1.},
journal = {Acta neurologica Belgica},
volume = {},
number = {},
pages = {},
pmid = {42606634},
issn = {2240-2993},
abstract = {BACKGROUND: Alzheimer's disease (AD) represents a profoundly detrimental neurodegenerative disorder, and early diagnosis coupled with effective treatment remains a major clinical challenge. MicroRNAs (miRNAs) have emerged as key regulators associated with pathological processes in AD.

AIM: This study aimed to explore the expression pattern and the likely diagnostic value of miR-584-5p in AD, as well as its molecular mechanism of action in regulating β-amyloid (Aβ)-induced apoptosis.

METHODS: Peripheral blood samples from 90 AD patients and age- and sex-matched controls were examined using RT-qPCR. Correlation analyses of miR-584-5p expression with key AD biomarkers (Aβ42, tTau, pTau) were performed in AD patients. Following exposure to 5 µM Aβ1-42, SH-SY5Y cells were employed in subsequent functional experiments. Bioinformatics analysis, a dual-luciferase reporter assay, and negative correlation analysis of plasma samples were conducted to verify the target gene of miR-584-5p.

RESULTS: miR-584-5p was significantly downregulated in AD patients, and its expression correlated with Aβ42 (r = 0.665), total tau (tTau, r = -0.642), phosphorylated tau (pTau, r = -0.576), and Mini-Mental State Examination (MMSE) scores (r = 0.618), yielding an AUC of 0.864 in this single-center cohort. miR-584-5p overexpression inhibited 5 µM Aβ1-42-induced apoptosis in SH-SY5Y cells, an effect that was reversed by concurrent HDAC1 overexpression. Mechanistically, by targeting HDAC1, miR-584-5p modulates p53 acetylation and the Bcl-2/Bax pathway at the protein level.

CONCLUSIONS: miR-584-5p exerted neuroprotective effects via the miR-584-5p/HDAC1 axis, offering new insights into AD pathogenesis and suggesting this axis as a candidate for further preclinical investigation.},
}

@article {pmid42606643,
year = {2026},
author = {Mansor, MR},
title = {Elevated MicroRNA-146a in Alzheimer's Disease and Its Diagnostic Potential.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42606643},
issn = {1559-1182},
mesh = {Humans ; *Alzheimer Disease/diagnosis/genetics/blood ; *MicroRNAs/genetics/blood ; Female ; Male ; Aged ; Biomarkers/blood ; ROC Curve ; Case-Control Studies ; },
abstract = {Alzheimer's disease (AD) is a progressive neurological condition marked by memory impairment and cognitive deterioration. Early diagnosis remains difficult due to the absence of reliable peripheral biomarkers. Circulating microRNAs (miRNAs) have recently gained attention as non-invasive indicators measurable in blood. Among these, microRNA-146a is of particular interest because of its role in inflammatory signaling and its altered expression in AD. This article highlights the diagnostic potential and biological function of microRNA-146a as a peripheral biomarker for Alzheimer's disease. The current study aimed to examine the expression and clinical relevance of microRNA-146a and to assess its possible influence on disease progression in Alzheimer's disease patients. Blood samples were collected after obtaining signed informed consent (No. 3912/2022 MRB) from 50 AD patients and from 50 healthy controls (HC); the miRNA content was screened by RT-PC. The expression of miRNA-146a is significantly greater in the Alzheimer's disease group (4.369 ± 3.168 -fold change) than in the control group (1.056 ± 0.702) (p < 0.001). In order to evaluate miR146a expression efficiency, a receiver operating characteristic (ROC) curve showed miR146a exhibited strong discriminative capability, with an AUC of 0.906 (95% CI 0.83-0.98). At a threshold of 2.21, the sensitivity was 90% and the specificity was 92%, demonstrating exceptional diagnostic efficacy. Logistic regression showed a strong inverse association trend (B = -6.803, OR = 0.001), with borderline statistical significance (p = 0.09). Cross-tabulation with Chi-square test confirmed a highly significant association between miR-146a expression and disease status (p < 0.001). A decision tree using Exhaustive CHAID further supported the finding, achieving 90% classification accuracy with a split point at 2.195. Collectively, these results demonstrate the robustness of miR-146a as a potential biomarker for distinguishing Alzheimer's patients from healthy individuals. An increase was found in the content of expression of microRNA-146a in AD patients compared with HC. Level of microRNA-146a, and correlated with disease; might be used as a biomarker reflecting AD.},
}

Humans
*Alzheimer Disease/diagnosis/genetics/blood
*MicroRNAs/genetics/blood
Female
Male
Aged
Biomarkers/blood
ROC Curve
Case-Control Studies

@article {pmid42606694,
year = {2026},
author = {Jaiswal, C and Singh, I and Singh, AK},
title = {Fisetin Attenuates Amyloid-Beta-Induced Neurotoxicity in Human Neuroblastoma SH-SY5Y Cells: Integrating In Silico Target Prediction and In Vitro Validation.},
journal = {Journal of biochemical and molecular toxicology},
volume = {40},
number = {9},
pages = {e71076},
doi = {10.1002/jbt.71076},
pmid = {42606694},
issn = {1099-0461},
support = {CRG/2022/006612//Anusandhan National Research Foundation/ ; },
mesh = {Humans ; Flavonols ; *Amyloid beta-Peptides/toxicity/metabolism ; *Flavonoids/pharmacology/chemistry ; *Neuroblastoma/metabolism/pathology/drug therapy ; Cell Line, Tumor ; *Peptide Fragments/toxicity ; *Neuroprotective Agents/pharmacology ; Oxidative Stress/drug effects ; Molecular Docking Simulation ; },
abstract = {The accumulation of amyloid beta (Aβ) and tau tangles in the brain leads to Alzheimer's disease (AD). Fisetin, a natural flavonoid, is an antioxidant molecule, and its neuroprotective effects are not clearly understood. Therefore, attempts have been made to evaluate the neuroprotective effects of fisetin using in silico methods and an Aβ1-42-induced neurotoxicity model in human neuroblastoma SH-SY5Y cells. In silico studies demonstrated that fisetin binds strongly and with high stability to different proteins, such as ULK1 (autophagy marker), p21 (senescence/cell cycle marker), and synaptophysin (synaptic marker), which are responsible for maintaining brain health and are implicated in AD. Moreover, Aβ1-42 was also found to bind to these protein targets, indicating that Aβ1-42 and fisetin both target common binding sites. In vitro studies on SH-SY5Y cells further confirmed that fisetin promotes cell survival under the toxic effects of Aβ1-42. It reduced oxidative stress and restored the activities of ion channels, which were impaired by Aβ1-42 treatment. Fisetin increased antioxidant defense and restored the activity of molecules that control brain signals. Overall, fisetin acts on multiple targets to protect neurons by reducing oxidative damage, supporting ion channel activity, and inducing the autophagy process.},
}

Humans
Flavonols
*Amyloid beta-Peptides/toxicity/metabolism
*Flavonoids/pharmacology/chemistry
*Neuroblastoma/metabolism/pathology/drug therapy
Cell Line, Tumor
*Peptide Fragments/toxicity
*Neuroprotective Agents/pharmacology
Oxidative Stress/drug effects
Molecular Docking Simulation

@article {pmid42606732,
year = {2026},
author = {Irfan, M and Zeeshan, U and Haider, and Abbas, A},
title = {Redox-modulating metallic nanoparticles: mechanistic insights into pharmacological activity and cellular therapeutics.},
journal = {Naunyn-Schmiedeberg's archives of pharmacology},
volume = {},
number = {},
pages = {},
pmid = {42606732},
issn = {1432-1912},
abstract = {Redox imbalance refers to abnormal production of reactive oxygen species (ROS) and reactive nitrogen species (RNS), which causes cellular dysfunction and damage, playing a critical role in the onset and progression of many diseases including cancer, cardiovascular disorders, and neurodegenerative conditions such as Alzheimer's and Parkinson's disease. While many previous reviews have covered individual systems of nanoparticles (NP) or single disease applications separately, there is a missing link that has not been adequately summarized regarding the ability of the same metallic core to act as an antioxidant or pro-oxidant, depending on dose, local pH, and surface chemistry. This review addresses that gap by tracing redox modulation from physicochemical origins through intracellular signaling to clinical translation across oncology, infectious diseases, and neurodegeneration. Metallic NPs such as gold, silver, copper, zinc oxide, iron oxide, and cerium-based systems have emerged as transformative tools in modern pharmacology due to their unique physicochemical properties including high surface-to-volume ratio. NPs act as redox modulators by scavenging excess oxidants through enzyme-mimetic activities like superoxide dismutase and catalase or selectively causing cytotoxicity in pathological environments. NPs interact with intracellular organelles and affect signaling pathways like Nrf2, NF-κB, and MAPK. Transition metal nanoparticles catalyze Fenton reactions that generate toxic hydroxyl radicals in the acidic and glutathione-rich tumor microenvironment, leading to programmed cell death through apoptosis, ferroptosis, and cuproptosis. Green synthesis of NPs using plant extracts and microorganisms reduces toxic byproducts and improves biocompatibility and stability. Redox-modulating metallic NPs have shown promise in preclinical models for tumoricidal, anti-inflammatory, and antibacterial uses. Although agents such as Ferumoxytol and Hensify have reached clinical application, challenges regarding long-term toxicity, immunogenicity, and systemic clearance remain. Future directions in this field emphasize the development of stimuli-responsive nanoplatforms for scientifically controlled and reproducible cargo release and the integration of computational tools to predict biological interactions. These advances are expected to provide deeper mechanistic insights into pharmacological activity at the nano-bio interface.},
}

@article {pmid42606899,
year = {2026},
author = {Singh, B and Singh, S and Banerjee, S and Bhargava, S and Subramaniyan, V and Singh, TG},
title = {Aquaporin-4 Mediated Glymphatic Dysfunction and Neuroinflammatory Signaling in Neurodegenerative Disorders.},
journal = {The International journal of neuroscience},
volume = {},
number = {},
pages = {1-29},
doi = {10.1080/00207454.2026.2719591},
pmid = {42606899},
issn = {1563-5279},
abstract = {Aquaporin channels are the predominant fluid regulating channel found in the central nervous system (CNS) and plays a pivotal role in maintaining fluid and ion homeostasis, as well as regulating neuroinflammation, neurodegeneration, and blood-brain barrier (BBB) disruption. This protein is primarily located at astrocytes endfeet within the blood cerebral barrier and other central nervous system (CNS) junctions, facilitating the movement of water in both directions, buffering potassium levels, and aiding in the clearance of interstitial solutes, along with toxic metabolites such as amyloid-β, via the glymphatic system. Changes in the expression or polarization of AQPs are implicated in neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease, epilepsy, and ischemic stroke. Impaired functionality of AQPs is involved in a number of pathological processes including heightened oxidative stress, disruption of the blood-brain barrier, and neuroinflammation. Such pathways are targeted by transcription factors, including nuclear factor κB (NFκB), and signaling pathways, including p38 MAPK, that increase AQPs expression following the action of stressors. Furthermore, impairment of AQPs polarity suppresses glymphatic clearance and promotes toxic protein accumulation, one of the key features of Alzheimer 's disease. AQPs structural features, including its six transmembrane helices and conserved NPA motifs, are critical for function, positioning it as a putative therapeutic target. Preclinical data support the notion that modulation of AQPs activity may offer neuroprotection through restoration of homeostasis and reduction of inflammation in neurodegenerative disease. This review describes the mechanistic links between AQPs dysfunction and neurodegenerative disease, highlighting its potential and limitations as a therapeutic target for the prevention of CNS disorders.},
}

@article {pmid42607070,
year = {2026},
author = {Cheng, ST and Lam, LCW},
title = {Beyond disruptive behaviors and caregiving burden: the role of family dynamics in potentially harmful behaviors by dementia informal caregivers.},
journal = {Aging & mental health},
volume = {},
number = {},
pages = {1-10},
doi = {10.1080/13607863.2026.2691371},
pmid = {42607070},
issn = {1364-6915},
abstract = {OBJECTIVES: Invoking the perspective that unpleasant behaviors can be transmitted within a family through social learning, emotional mimicry, and emotional displacement, the primary study objective is to examine whether negative family exchanges induce potentially harmful behaviors (PHB) by caregivers. The secondary objective is to clarify the causal relationship between burden and (care-recipient) challenging behaviors on the one hand, and PHB on the other, in light of the lack of longitudinal evidence.

METHODS: 99 Alzheimer family caregivers participated in a 6-month 2-wave longitudinal survey. Ten items tapping psychological and physical domains were used to assess PHB. The quality of exchanges with each familial network member was measured using the social convoy questionnaire.

RESULTS: Controlling for baseline PHB in multiple regression, BPSD did not predict PHB at follow-up, but burden did. However, the effect of burden was reduced to nonsignificance after including family exchange variables. In the final model, only negative family exchanges significantly predicted PHB (f[2] = 0.05), and this effect was not mediated by burden.

CONCLUSION: Negative family exchanges contribute to caregivers' PHB over and above burden, underscoring the need to address the broader family dynamics in which caregiving is embedded in dementia care.},
}

@article {pmid42607409,
year = {2026},
author = {Xu, A and Zheng, H and Kong, Z and Wang, X and Dong, H and Lv, Y and Xu, M and Zhou, Y},
title = {A self-powered photoelectrochemical sensor with ultra-low background based on ZnIn2S4@CdS photoanode and Bi2WO6 photocathode for BACE1 detection.},
journal = {Biosensors & bioelectronics},
volume = {313},
number = {},
pages = {119128},
doi = {10.1016/j.bios.2026.119128},
pmid = {42607409},
issn = {1873-4235},
abstract = {Self-powered photoelectrochemical (PEC) sensing features no external power supply, fast response, strong anti-interference and high sensitivity, providing a powerful strategy for ultrasensitive detection of β-site amyloid precursor protein cleaving enzyme 1 (BACE1), a key biomarker for early Alzheimer's disease (AD). In this work, a dual-photoelectrode self-powered PEC biosensor with ultralow background signal was constructed. ZnIn2S4 was grown in situ on fluorine-doped tin oxide (FTO) via hydrothermal reaction, and CdS quantum dots were loaded through successive ionic layer adsorption and reaction to fabricate ZnIn2S4@CdS/FTO photoanode. The obtained photoanode delivered a photocurrent of 279 μA, which was 2.3 times higher than pure ZnIn2S4/FTO, benefiting from superior visible light absorption and charge separation capacity. Bi2WO6@polydopamine (Bi2WO6@PDA) probes were anchored on peptide substrates in 96-well plates. When BACE1 existed, enzymatic cleavage released Bi2WO6@PDA heterojunction probes onto bare FTO photocathode to generate obvious photocurrent. In the absence of BACE1, the photocathode remained equivalent to bare FTO without Bi2WO6@PDA probe. Under visible light and zero bias, the sensor realized sensitive BACE1 detection with a linear range of 1 fg mL[-1]-500 pg mL[-1] with a limit of detection of 0.30 fg mL[-1]. The biosensor possessed favorable selectivity and stability with serum sample recoveries of 96.9%-102.5%, and it could be applied to screen BACE1 inhibitors. This self-powered biosensor with near-zero background shows great application prospect in early AD clinical diagnosis.},
}

@article {pmid42607731,
year = {2026},
author = {Mehta, N and Jo, S and Smirnou, S and Thinakaran, G and Mastrianni, JA},
title = {PrP[C] limits APP delivery to the plasma membrane and alters its processing to facilitate aβ release.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107576},
doi = {10.1016/j.nbd.2026.107576},
pmid = {42607731},
issn = {1095-953X},
abstract = {Several lines of evidence suggest that the cellular isoform of prion protein (PrP[C]) plays one or more roles in Alzheimer's Disease (AD). We previously found, in mouse neuroblastoma N2a cells that express human APP carrying the Swedish mutation (N2a-APPswe), that PrP[C] expression correlated with the secretion of Aβ42 peptide, the product of proteolytic processing of the amyloid precursor protein (APP) that is central to AD. To determine whether PrP[C] modulates APP processing to affect Aβ42 release and if any effect of PrP[C] is selective for APPswe, we applied the MesoScale Discovery (MSD) platform to assess APP processing and Aβ secretion before and after siRNA-induced knockdown of PrP[C] in APPswe and wild-type APP (APPwt) N2a cells. We found that PrP[C] knockdown reduced the major isoforms of secreted Aβ peptides in both cell lines (with the exception of Aβ42 in N2a-APPwt cells) in the absence of a reduction in either APP expression or enhanced Aβ degradation. Additionally, the soluble ectodomain of β-secretase cleavage (sAPPβ) was reduced in both cell lines whereas the ectodomain of α-secretase cleavage (sAPPα) was increased only in N2a-APPwt cells. PrP[C] overexpression led to an increase in Aβ42 in HEK cells and sAPPβ in both N2a cells and HEK cells expressing APPswe, confirming that PrP[C] promotes the amyloidogenic processing pathway independent of cell type. Biotinylation and immunofluorescence studies in the N2a cell lines revealed an increase in APP labeling at the plasma membrane, an increase in APP endocytosis, and an accumulation of APP C-terminal fragments (CTFs) after PrP[C] knockdown. We propose that PrP[C] limits delivery of APP to the plasma membrane, which acts to promote the amyloidogenic pathway by increasing its exposure to BACE1 within early secretory compartments.},
}

@article {pmid42607758,
year = {2026},
author = {Indumathi, J and Arulappan, A and Ramasamy, S},
title = {Comment on "Nutritional Interventions for Preventing Cognitive Decline in Patients with Mild Cognitive Impairment and Alzheimer's Disease: A Comprehensive Network Meta-Analysis and Mendelian Randomization Study".},
journal = {Clinical nutrition ESPEN},
volume = {},
number = {},
pages = {105030},
doi = {10.1016/j.clnesp.2026.105030},
pmid = {42607758},
issn = {2405-4577},
}

@article {pmid42607896,
year = {2026},
author = {Li, X and Chen, Z and Guan, J and Yu, H and Wang, J},
title = {Oral Administration of Melatonin Modulates Macrophage Polarization via Modulating the Vegf Signaling Pathway and Ameliorates Alzheimer's Disease in APP/PS1 Mice.},
journal = {Brain research bulletin},
volume = {},
number = {},
pages = {112088},
doi = {10.1016/j.brainresbull.2026.112088},
pmid = {42607896},
issn = {1873-2747},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder with a global prevalence, currently lacking effective treatments and posing a major public health challenge due to the burden it places on healthcare systems while affecting millions of people. Melatonin is a hormone with considerable potential for treating various neurodegenerative disorders, including AD. The mechanisms responsible for melatonin's therapeutic benefits in Alzheimer's disease (AD) require further elucidation. This study was designed to investigate the mechanisms by which melatonin exerts its effects in APP/PS1 mice.

METHODS: The Morris water maze was used to assess the performance of melatonin-treated APP/PS1 mice. Haematoxylin&Eosin and Nissl staining were conducted to observe the integrity of hippocampal neurons. Transcriptomic sequencing of hippocampal tissue was performed to identify differentially expressed genes, which were subjected to Gene Ontology (GO) term and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Immunofluorescence analysis was used to detect the levels of Cd16, Cd32, Cd68 and Cd206 in APP/PS1 mice. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR), immunoblotting, and immunohistochemistry were employed to validate the relative expression of Vegf, Flt1, and Kdr proteins.

RESULTS: In the Morris water maze, melatonin-treated APP/PS1 mice demonstrated a marked increase in platform crossings. Improved neuronal integrity in the hippocampus was observed through Haematoxylin&Eosin and Nissl staining. Transcriptomic sequencing of hippocampal tissue revealed 295 differentially expressed genes, which were significantly associated with 1091 GO terms and 30 KEGG pathways. Immunofluorescence analysis indicated that melatonin treatment notably reduced Cd16 and Cd32 levels while elevating Cd68 and Cd206 in APP/PS1 mice. Subsequent analyses via RT-qPCR, immunoblotting, and immunohistochemistry validated the increased relative expression of Vegf, Flt1, and Kdr proteins.

DISCUSSION: Melatonin attenuates AD pathogenesis in APP/PS1 mice by promoting macrophage polarization via the Vegf signaling pathway, revealing a novel mechanism for AD prevention and treatment.},
}

@article {pmid42608285,
year = {2026},
author = {Zheng, H and Zheng, J},
title = {Tau-targeting pharmacological strategies in neurodegenerative disease.},
journal = {Trends in pharmacological sciences},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.tips.2026.07.008},
pmid = {42608285},
issn = {1873-3735},
abstract = {Pathological tau accumulation underlies a spectrum of neurodegenerative diseases collectively known as tauopathies. Although reducing tau remains the prevailing therapeutic strategy, indiscriminate tau reduction may compromise physiological functions and has demonstrated limited clinical efficacy. Growing evidence indicates disease- and stage-specific tau heterogeneity-spanning post-translational modifications (PTMs), aggregation states, and vulnerable cell populations-highlighting the necessity for improved targeting selectivity for pathological tau species. In this review, we discuss tau-targeting therapeutic modalities, including nucleic acids to suppress tau expression, immunotherapies and chimeric degraders to facilitate tau protein clearance, inhibitors of aggregation, and emerging strategies for tau PTM-editing and cellular-level interventions for neurofibrillary tangle-bearing neurons.},
}

@article {pmid42608377,
year = {2026},
author = {Chakraborty, P},
title = {Editorial for "Deep Learning-Based Enhancement of Already Diagnostic-Quality MRI for Alzheimer's Disease Classification: Effects on Model Performance and Training Data Requirements".},
journal = {Journal of magnetic resonance imaging : JMRI},
volume = {},
number = {},
pages = {},
doi = {10.1002/jmri.70501},
pmid = {42608377},
issn = {1522-2586},
}

@article {pmid42608531,
year = {2026},
author = {Wu, YL and Xu, QQ and Qin, ZH and Wu, X and Hu, Z and Yang, W and Ren, PY and Tian, YY and Lin, ZX and Xian, YF},
title = {Oxyberberine-nanoparticle attenuates the cognitive deficits in a transgenic mouse model of Alzheimer's disease via modulating gut microbiota through suppressing CXCL10/CXCR3 pathway.},
journal = {Acta pharmacologica Sinica},
volume = {},
number = {},
pages = {},
pmid = {42608531},
issn = {1745-7254},
abstract = {Oxyberberine (OBB) has good potential neuroprotective effects. However, the poor water solubility of OBB poses a challenge to its therapeutic effects. In this study, OBB-hydroxypropyl-β-cyclodextrin (OBB-β-CD) was prepared to increase the water solubility and improve bioavailability of OBB. The neuroprotective effects of OBB-β-CD against AD were investigated using 3×Tg transgenic AD mouse model. OBB-β-CD exhibited dual regulatory capabilities in improving both behavioral deficits and pathological features of AD. OBB-β-CD was more effective than OBB in modulating the amyloid precursor protein (APP) processing and inhibiting the hyperphosphorylation of Tau protein. OBB-β-CD was effective in reducing both the concentration of beta-amyloid 42 (Aβ42) and the deposition of Aβ plaques in 3×Tg mouse models. OBB-β-CD also suppressed neuroinflammation by promoting microglial polarization from an M1-like to an M2-like phenotype. Furthermore, OBB-β-CD restored the gut dysbiosis and inhibited the activation of the C-X-C motif chemokine receptor 3 (CXCR3) and the level of C-X-C motif chemokine ligand 10 (CXCL10) in the brain and colon tissues of 3×Tg mice. Simultaneously, the effect of OBB that suppressed microglial M1 and promoted M2 polarization to improve the neuronal micro-environment was verified in vitro using BV-2 cells. Importantly, OBB-β-CD showed similar anti-AD effects of knockdown of CXCR3 in 3×Tg mice, but no synergistic effects were observed in the shCXCR3 + OBB-β-CD group compared to the shCXCR3 group. Furthermore, the results of molecular docking and surface plasmon resonance (SPR) assay indicated that CXCR3 could bind with OBB. Additionally, the fecal microbiota transplantation (FMT) of fecal microbiota from the OBB-β-CD-treated 3×Tg mice (OBB-β-CD-FMT) significantly alleviated the cognitive deficits in the pseudo-germ-free 3×Tg mice via markedly suppressing the hyperphosphorylation of Tau protein, Aβ level and the activation of CXCR3 in the brain of 3×Tg mice. OBB-β-CD has good potential for further development into a therapeutic agent for AD treatment.},
}

@article {pmid42608580,
year = {2026},
author = {Rutt, S and Tegethoff, P and Taute, M and Neziraj, F and Hufnagel, A and Perneczky, R and Kurz, C and Rauchmann, BS},
title = {Diagnostic accuracy of a self-administered digital cognitive test battery for differentiating early Alzheimer's disease from controls.},
journal = {European archives of psychiatry and clinical neuroscience},
volume = {},
number = {},
pages = {},
pmid = {42608580},
issn = {1433-8491},
abstract = {BACKGROUND: Paper-pencil assessments face limitations in accessibility, lengthy administration, and interrater reliability. Digital tools may overcome these by offering user-friendly, non-verbal, and scalable assessments. This study investigated the diagnostic accuracy of BraincheX, a novel digital test battery focused on accessibility and usability, by comparing its subtest performance to CERAD-Plus equivalents.

METHODS: Fifty-six participants with early AD and amyloid negative cognitively healthy controls were recruited from the LMU hospital memory clinic. Diagnostic groups were defined by amyloid positivity and clinical expert consensus according to the IWG-2 criteria. Participants completed the BraincheX digital battery and CERAD-Plus. BraincheX total score was calculated by summing standardized subtest scores. Data were analyzed using ROC analysis and the Youden Index. Correlations between subtests were examined, and group differences analyzed via ANOVA.

RESULTS: ROC analysis revealed strong diagnostic accuracy for the BraincheX total score in differentiating between early AD and controls (AUC = 0.86; optimal cut-off = - 1.51), with high sensitivity of 89.7% and moderate specificity of 68.0%. BraincheX total scores correlated with CERAD total scores (r = .73, p < .001). BraincheX demonstrated good internal consistency (Cronbach's α = 0.84). ANOVA confirmed significant group differences across all BraincheX subtests (p < .01). Individual subtests showed strong correlations with CERAD-Plus equivalents.

CONCLUSIONS: Findings suggest BraincheX as a promising, accessible digital screening tool for cognitive decline, offering automated scoring, immediate feedback, and reduced examiner bias. Future research is required to validate BraincheX in larger and more diverse populations and to establish BraincheX's clinical applicability.

TRIAL REGISTRY: This analysis was conducted within the framework of the prospectively registered German SCD-Q validation study (NCT06711952). The registered study protocol included digital cognitive testing as part of the assessment protocol. The present manuscript reports a secondary analysis focusing on the diagnostic performance of BraincheX.},
}

@article {pmid42608584,
year = {2026},
author = {Zhang, PF and Juan, Z and Han, J and Wang, Y and Zhu, T and Pang, D and Zheng, X and Lu, Z},
title = {Transcriptome-wide association analysis of Alzheimer's disease: construction and clinical validation of transcriptomic risk scores.},
journal = {European archives of psychiatry and clinical neuroscience},
volume = {},
number = {},
pages = {},
pmid = {42608584},
issn = {1433-8491},
support = {82272414//the National Natural Science Foundation of China/ ; },
abstract = {Early identification of individuals at high risk for Alzheimer's disease (AD) is crucial for disease prevention and intervention. This study aims to develop AD-specific transcriptomic risk scores (TRSs) through multi-tissue transcriptome-wide association study (TWAS) and to evaluate its clinical utility in AD diagnosis and risk prediction. Using GWAS summary statistics combined with expression quantitative trait loci (eQTL) data from 14 tissues, a multi-tissue TWAS approach was applied to identify AD-associated genes. Peripheral blood RNA expression data from the ADNI and GEO databases were used to construct the AD-specific TRSs. The associations of TRSs with AD pathological features and cognitive function were assessed in two independent cohorts. Furthermore, the diagnostic performance, differential diagnostic capability, and risk prediction efficiency of TRSs were evaluated. The TWAS identified 131 genes significantly associated with AD. The TRSs were significantly elevated in patients with AD and mild cognitive impairment (MCI) compared to cognitively normal (CN) individuals, and showed significant correlations with AD pathological markers and cognitive performance. When combined with APOE4 status, the TRSs demonstrated robust diagnostic ability for AD and MCI. When combined with age, the TRSs showed good diagnostic performance in distinguishing AD from frontotemporal dementia (FTD) (AUC = 0.86). Additionally, the TRSs effectively predicted the risk of progression to AD in non-AD individuals (HR = 1.74). The AD-specific TRSs developed in this study shows promising clinical utility in AD diagnosis, differential diagnosis, and risk prediction, providing valuable translational medical evidence for early screening and precision prevention of Alzheimer's disease.},
}

@article {pmid42608660,
year = {2026},
author = {Shinagawa, S and Nagata, T},
title = {Toward Precision Neuropsychiatry of Dementia: Neuropsychiatric Symptoms as Multidimensional Clinical Phenotypes.},
journal = {Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society},
volume = {26},
number = {5},
pages = {e70209},
doi = {10.1111/psyg.70209},
pmid = {42608660},
issn = {1479-8301},
support = {24K10690//Japan Society for the Promotion of Science/ ; JP24wm0625505//Japan Agency for Medical Research and Development/ ; },
mesh = {Humans ; *Dementia/psychology/diagnosis ; Phenotype ; *Neuropsychiatry/methods ; *Precision Medicine/methods ; Sleep Wake Disorders ; },
abstract = {Neuropsychiatric symptoms (NPS) are the most clinically consequential manifestations of dementia, yet they are frequently underestimated as secondary behavioural complications. This review introduces a precision neuropsychiatry framework that conceptualises NPS-including apathy, agitation, psychosis, depression, and sleep disturbances-as multidimensional clinical phenotypes. These phenotypes bridge neurodegeneration, biological aging, brain network disruption, psychosocial context, functional decline, and caregiver burden. We trace the conceptual evolution from dementia to neurocognitive disorders, and from behavioural and psychological symptoms of dementia (BPSD) to NPS and mild behavioural impairment (MBI). Precision neuropsychiatry stratifies NPS based on disease background, clinical stage, neural networks, biological aging, physical vulnerability, and psychosocial context to optimise differential diagnosis, prognostic prediction, and targeted interventions. Although conventional symptom-based classification remains practically useful, it must be complemented by biological, functional, and contextual stratification; identical symptom labels often arise from distinct mechanisms and express differently based on personality, life history, environmental mismatch, and available resources. Emerging evidence from MBI, neuroimaging, brain-age paradigms, frailty, neuroinflammation, Alzheimer's disease (AD) biomarkers, and international consensus criteria supports this multidimensional shift. Future research should advance from cross-sectional symptom descriptions toward longitudinal, mechanism-informed, and context-sensitive models to translate these findings into real-world psychogeriatric care.},
}

Humans
*Dementia/psychology/diagnosis
Phenotype
*Neuropsychiatry/methods
*Precision Medicine/methods
Sleep Wake Disorders

@article {pmid42608702,
year = {2026},
author = {Swane, V and Biering-Sørensen, B},
title = {Posterior cortical atrophy with initial psychiatric presentation: a case report.},
journal = {Journal of medical case reports},
volume = {20},
number = {1},
pages = {},
pmid = {42608702},
issn = {1752-1947},
mesh = {Humans ; Male ; Aged ; Atrophy ; Magnetic Resonance Imaging ; *Cerebral Cortex/pathology/diagnostic imaging ; *Neurodegenerative Diseases/diagnostic imaging/psychology ; Electroencephalography ; Alzheimer Disease ; Neuropsychological Tests ; },
abstract = {BACKGROUND: Posterior cortical atrophy (PCA) is a rare neurodegenerative syndrome most commonly associated with atypical Alzheimer's disease. It is characterized by progressive visuospatial and visuoperceptual deficits with relative sparing of memory and language in early stages. Diagnosis is frequently delayed or missed due to clinical heterogeneity, subtle early symptoms, and limited sensitivity of routine cognitive screening tools. Psychiatric symptoms may further obscure the underlying neurological disorder. This case highlights the diagnostic challenges posed by PCA presenting in the context of prominent psychiatric symptoms, combined with a rapid clinical decline.

CASE PRESENTATION: A 68-year-old white Danish male presented with suicidal ideation and was initially admitted to a psychiatric ward. He had a remote history of a suicide attempt and a family history of suicide but no known neurodegenerative disease. Within a short period, severe cognitive and functional impairment became evident, dominated by visuospatial deficits, apraxia, simultanagnosia, optic ataxia, and features of Gerstmann and Balint syndromes, with relative preservation of memory and language. Neuroimaging revealed marked posterior cortical atrophy and parieto-occipitotemporal hypometabolism with sparing of the posterior cingulate cortex. Cerebrospinal fluid analysis showed mildly reduced amyloid-β1-42 and markedly elevated neurofilament light chain levels. Electroencephalography demonstrated focal posterior slowing without epileptiform activity. Extensive evaluation excluded autoimmune, epileptic, metabolic, and prion-related causes. Based on the clinical syndrome, characteristic neuroimaging findings, and supportive CSF biomarkers, a diagnosis of posterior cortical atrophy likely related to underlying Alzheimer's disease pathology was made. Disease-specific treatment was discussed but not initiated due to patient preference.

CONCLUSIONS: This case illustrates how posterior cortical atrophy may be overlooked, particularly when psychiatric symptoms dominate the initial presentation. It underscores the importance of considering neurodegenerative disorders in older patients with atypical psychiatric presentations or unexplained functional decline. Early recognition of PCA is crucial for accurate diagnosis, appropriate counseling, and tailored supportive care.},
}

Humans
Male
Aged
Atrophy
Magnetic Resonance Imaging
*Cerebral Cortex/pathology/diagnostic imaging
*Neurodegenerative Diseases/diagnostic imaging/psychology
Electroencephalography
Alzheimer Disease
Neuropsychological Tests

@article {pmid42608731,
year = {2026},
author = {Long, W and Yuan, M and Wang, S and Tan, X and Gao, LC},
title = {The mitophagy-inflammasome axis: a shared pathological hub in Alzheimer's and Parkinson's diseases.},
journal = {Translational neurodegeneration},
volume = {15},
number = {1},
pages = {},
pmid = {42608731},
issn = {2047-9158},
support = {2025JJ80178//the Hunan Provincial Natural Science Foundation of China/ ; kq2502334//the Changsha Natural Science Foundation of China/ ; },
mesh = {Humans ; *Mitophagy/physiology ; *Inflammasomes/metabolism ; *Parkinson Disease/pathology/metabolism ; *Alzheimer Disease/pathology/metabolism ; Animals ; Mitochondria/metabolism/pathology ; alpha-Synuclein/metabolism ; Amyloid beta-Peptides/metabolism ; },
abstract = {Alzheimer's disease (AD) and Parkinson's disease (PD) represent the most prevalent chronic neurodegenerative disorders, characterized by progressive loss of neurons as a core pathological feature. Despite discrepancies in their clinical phenotypes and signature pathological proteins, accumulating evidence has validated a common molecular pathogenic mechanism: dysfunctional bidirectional crosstalk between mitophagy and inflammasomes. As the central hub of neuronal energy metabolism, mitochondrial impairment triggers the release of damage-associated molecular patterns such as reactive oxygen species and mitochondrial DNA, which in turn activate inflammasomes (e.g., NLRP3) to elicit chronic neuroinflammation. Conversely, excessive inflammasome activation suppresses mitophagy, exacerbating the accumulation of damaged mitochondria and pathological protein aggregates, and forming a pathological mitochondrial damage-inflammatory activation-autophagy inhibition cycle. Microglia and astrocytes, key immunocompetent cells of the central nervous system, act as a hub within this regulatory network. Therapeutic strategies targeting the mitophagy-inflammasome axis have achieved remarkable advancements, including mitophagy agonists, inflammasome inhibitors, and dual-target modulators. This review summarizes recent findings regarding the pathogenic roles of β-amyloid and α-synuclein in AD and PD, as well as the protective effects offered by regulating mitophagy and inflammasome activity. Furthermore, the major directions and potential hurdles in the development of targeted therapeutics are discussed, in the aim of providing insights into the novel therapeutic avenues for the treatment of both disorders.},
}

Humans
*Mitophagy/physiology
*Inflammasomes/metabolism
*Parkinson Disease/pathology/metabolism
*Alzheimer Disease/pathology/metabolism
Animals
Mitochondria/metabolism/pathology
alpha-Synuclein/metabolism
Amyloid beta-Peptides/metabolism

@article {pmid42608759,
year = {2026},
author = {Talukdar, G and Cvetanovic, M},
title = {Relationship of polyglutamine expansion and loss of ataxin-1 function in neurological diseases.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-01950},
pmid = {42608759},
issn = {1673-5374},
abstract = {Ataxin-1 (ATXN1) was originally identified as a gene in which abnormal expansion of glutamine encoding CAG repeats causes inherited neurodegenerative disease spinocerebellar ataxia type 1. Spinocerebellar ataxia type 1 is characterized by alterations in movement, cognition, and mood, with severe pathology in the cerebellum and brain stem. Studies in spinocerebellar ataxia type 1 mouse models indicated that CAG expansion predominantly causes pathogenic ATXN1 gain-of-function in the cerebellum. Conversely, mice lacking ATXN1 are severely impaired in cognitive tests and exhibit abnormalities in cortical functions. Subsequent genetic and functional studies have associated ATXN1 with intelligence and several neurological conditions, including Alzheimer's disease, amyotrophic lateral sclerosis, schizophrenia, and multiple sclerosis. In some conditions, association is found with CAG expansions in ATXN1 and in others with the loss of ATXN1 expression. Additionally, recent studies indicate the role of ATXN1 in glial cells. Here, we review current genetic and functional evidence of how ATXN1 CAG expansion and loss of ATXN1 function contribute to brain dysfunction in spinocerebellar ataxia type 1, Alzheimer's disease, and multiple sclerosis, with an emphasis on glial cells.},
}

@article {pmid42608768,
year = {2026},
author = {Zhao, Q and Liu, T and Xing, J and Kong, Z and Hu, D and Xia, M and Li, H and Chen, Z and Fei, L and Wang, X and Liu, B and Yang, F},
title = {Exosome research and neuroimaging techniques: Visualization analysis of development trends and research hotspots.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-26-00586},
pmid = {42608768},
issn = {1673-5374},
abstract = {In recent years, neuroimaging and exosome research have become increasingly integrated, providing new perspectives for elucidating the mechanisms of central nervous system diseases, developing non-invasive diagnostic tools, and advancing targeted therapeutic strategies. However, research in this field remains fragmented, and a systematic overview of the overall knowledge structure and cutting-edge hotspots is lacking. A total of 594 English-language articles from the Web of Science Core Collection were selected for bibliometric analysis performed using CiteSpace and VOSviewer software, to elucidate the current application status, development trends, and core hotspots of neuroimaging technology in exosome research. The overall publication volume in this field shows an increasing trend over time. China ranks first in the number of publications (209 articles), while the United States has the highest citation count (9623 citations) and serves as a core country in the international collaboration network. The University of California is the institution with the most publications (29 articles). High-frequency keywords include "extracellular vesicles," "exosomes," "brain," and "Alzheimer's disease," with neuroimaging primarily serving as an assessment and validation tool. The knowledge foundation focuses on mechanisms of exosome traversal across the blood-brain barrier, in vivo imaging validation (e.g., tracking using gold nanoparticle labeling), and complementary validation of exosome biomarkers with imaging (e.g., consistency between peripheral blood exosomal proteins and amyloid positron emission tomography imaging). The field has evolved from exploring drug carriers and standardizing biomarkers toward understanding mechanisms and engineering applications. High-impact application hotspots in neuroimaging include magnetic resonance imaging and computed tomography tracing targeting the blood-brain barrier, multimodal dynamic monitoring with positron emission tomography and magnetic resonance imaging, early diagnosis that combines imaging technology with exosomal biomarkers (e.g., microRNA), high-resolution detection of single exosomes (e.g., imaging flow cytometry), novel imaging probes (e.g., molecular beacons and photoacoustic probes), and deep learning-assisted automatic analysis of exosomal morphology. These findings confirm that neuroimaging is gradually being recognized as an important in vivo visualization validation tool in exosome research. Current research hotspots are highly focused on targeted imaging of exosome traversal across the blood-brain barrier, multimodal molecular imaging tracing, combined diagnosis based on exosomal biomarkers and neuroimaging, highresolution imaging at the single-vesicle level, and deep learning-assisted morphological characterization of exosomes. These findings provide crucial in vivo imaging evidence for exosome-based neural repair strategies. This evidence, in turn, can accelerate the clinical translation of exosomes in neuroregenerative medicine research.},
}

@article {pmid42608950,
year = {2026},
author = {Yañez, O and Bustos, D and Bravo, D and Zuñiga-Bustos, M and Osorio, MI},
title = {Structural Determinants of Zn[2+] Potentiation of Gingipain B Inhibition of Porphyromonas gingivalis by Compounds With the Benzamidine Group: A Computational Study.},
journal = {Proteins},
volume = {},
number = {},
pages = {},
doi = {10.1002/prot.70167},
pmid = {42608950},
issn = {1097-0134},
support = {11241091//Fondo Nacional de Desarrollo Científico y Tecnológico/ ; 1251871//Fondo Nacional de Desarrollo Científico y Tecnológico/ ; 11220444//Fondo Nacional de Desarrollo Científico y Tecnológico/ ; },
abstract = {Gingipain B is a protease released by Porphyromonas gingivalis, which contributes to the development of diseases such as periodontitis, Alzheimer's disease, rheumatoid arthritis and cancer. Therefore, it could be a key target for the design of inhibitors that could be used in new drug therapies. In this search for inhibitors, it is interesting to study their potentiation by Zn[2+], mainly because this divalent cation can be a common additive in toothpastes or mouthwashes. To understand this potentiation process, the structural aspects that determine the effect of Zn[2+] on the different potentiation of gingipain B inhibition by three inhibitors with benzamidine group were studied. For this purpose, molecular dynamics simulations of the enzyme/inhibitor complex, in the presence or absence of Zn[2+], were performed to identify the residues involved in the interaction with the inhibitor or with the cation. From the simulations it is observed that the compounds that are potentiated by Zn interact with the ion via water molecules, which are oriented towards the carbonyl functional group. In addition, a higher solvent exposure of the catalytic site and a lower flexibility of a region adjacent to cysteine 244, which participates in catalysis, are observed in the simulations. The structural and dynamic results obtained through molecular dynamics simulations support the hypothesis that the potentiation of gingipain B inhibition by Zn[2+] is associated with ion-mediated ligand stabilization, leading to a decrease in the number of water molecules in the second hydration shell, as well as polarization of the molecules in the vicinity of Zn[2+]. Taken together, these findings open new avenues for the design of inhibitors whose activity can be modulated or enhanced by the presence of Zn[2+], with potential applications in the development of innovative therapeutic strategies.},
}

@article {pmid42608956,
year = {2026},
author = {Hawas, Y and Abouzid, M and Gadelmawla, AF and Ewis, DK and Khatatbeh, A and Negida, Y and Negida, A},
title = {The Neuroprotective Potentials of Dual GIP/GLP1-RA (Tirzepatide): From Preclinical Experiments to Clinical Trials: A Scoping Review.},
journal = {Brain and behavior},
volume = {16},
number = {8},
pages = {e71702},
doi = {10.1002/brb3.71702},
pmid = {42608956},
issn = {2162-3279},
mesh = {*Tirzepatide/pharmacology ; *Neuroprotective Agents/pharmacology ; Humans ; Animals ; *Neurodegenerative Diseases/drug therapy ; },
abstract = {BACKGROUND: Tirzepatide (TZP), the first approved dual glucagon-like peptide 1 (GLP-1)/glucose-dependent insulinotropic polypeptide (GIP) agonist, has shown neuroprotective effects in preclinical models and early observational studies. This review maps and appraises current preclinical and clinical evidence on TZP's potential neuroprotective effects in neurodegenerative diseases (Alzheimer's and Parkinson's disease), neuroinflammation, cerebrovascular outcomes, neurovestibular disorders, brain tumor response, and idiopathic intracranial hypertension.

METHODS: PubMed, Scopus, Web of Science, Embase, and Elton B. Stephens Company (EBSCO) were searched through September 30, 2025. Eligible sources included original preclinical or clinical studies reporting neurological or neuroprotective effects of TZP. Quality was assessed using SYstematic Review Centre for Laboratory animal Experimentation (SYRCLE) and Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies (CAMARADE) for in vivo studies, toxicological data reliability assessment tool (ToxRTool) for in vitro, Newcastle-Ottawa scale (NOS) for cohorts, and Joanna Briggs Institute (JBI) for case reports.

RESULTS: Twenty-two studies met inclusion criteria as follows: 11 preclinical investigations, 3 retrospective cohorts, and 8 case reports. Preclinical studies demonstrated mitochondrial stabilization (adenosine triphosphate [ATP] restoration; PINK1/Parkin), anti-oxidative and anti-inflammatory signaling, synaptic support (PSD-95/synaptophysin), and blood-brain barrier reinforcement (claudin-1), alongside behavioral improvements. Retrospective cohorts reported reduced cerebrovascular and neurodegenerative disease incidence, papilledema, and headaches, though one cohort identified higher risk of central vertigo and vestibular neuronitis. Case reports documented compression neuropathies, autoimmune encephalitis, hypoglycemia-related seizures, psychiatric reactions, and rhabdomyolysis, most resolving with dose adjustment or discontinuation. Risk-of-bias appraisal revealed frequent "unclear" ratings in animal studies, "reliable with restrictions" in vitro, and high NOS scores for cohorts.

CONCLUSIONS: TZP exhibits biologically plausible neuroprotective mechanisms preclinically. Prospective trials with standardized neurological endpoints, active-comparator designs, and structured safety monitoring are warranted.},
}

*Tirzepatide/pharmacology
*Neuroprotective Agents/pharmacology
Humans
Animals
*Neurodegenerative Diseases/drug therapy

@article {pmid42608972,
year = {2026},
author = {Wu, LL and Huang, XC and Bi, JJ and He, PY},
title = {Efficacy and Evidence Certainty of High-Frequency rTMS for Cognitive Impairment Across Neuropsychiatric Disorders: An Umbrella Review.},
journal = {Brain and behavior},
volume = {16},
number = {8},
pages = {e71695},
doi = {10.1002/brb3.71695},
pmid = {42608972},
issn = {2162-3279},
support = {2021121//Chengdu Medical Research Project/ ; },
mesh = {Humans ; *Transcranial Magnetic Stimulation/methods ; *Cognitive Dysfunction/therapy ; Alzheimer Disease/therapy ; Schizophrenia/therapy/complications ; Major Depressive Disorder/therapy/complications ; *Mental Disorders/therapy/complications ; Parkinson Disease/therapy/complications ; Attention Deficit Disorder with Hyperactivity/therapy ; },
abstract = {BACKGROUND: High-frequency repetitive transcranial magnetic stimulation (HF-rTMS) is a promising intervention for cognitive impairment across neuropsychiatric disorders. However, existing evidence remains fragmented within disease-specific reviews, lacking cross-disorder synthesis and rigorous evaluation of evidence certainty.

OBJECTIVE: This umbrella review systematically evaluates the efficacy of HF-rTMS on cognitive function across six neuropsychiatric disorders with sufficient meta-analytic evidence on cognitive outcomes, including Alzheimer's disease, vascular cognitive impairment, Parkinson's disease, schizophrenia spectrum disorders, major depressive disorder, and attention-deficit/hyperactivity disorder-and assesses the certainty of evidence.

METHODS: We systematically searched CNKI, Cochrane Library, Embase, PubMed, and Web of Science from inception to March 1, 2026, for systematic reviews or meta-analyses reporting cognitive outcomes. Re-meta-analyses were performed using a random-effects model to calculate standardized mean differences (SMDs) with 95% confidence intervals (CIs). Study quality was appraised via AMSTAR-2, and evidence certainty was graded using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework. The corrected covered area (CCA) was calculated to quantify overlap of primary studies across reviews.

RESULTS: Twenty-nine meta-analyses comprising 54 outcome indicators met the inclusion criteria. Pooled analysis indicated that HF-rTMS significantly improved global cognitive function (SMD = 0.68, 95% CI: 0.53-0.83, p < 0.001), though with substantial heterogeneity (I[2] = 88.5%). Subgroup analyses highlighted distinct disease-specific effects: the most robust benefits were observed in Alzheimer's disease (SMD = 0.91) and vascular cognitive impairment (VCI) (SMD = 0.81). We found small-to-moderate effects in schizophrenia spectrum disorders (SSD) and Attention-Deficit/Hyperactivity Disorder (ADHD), but no significant improvements for Parkinson's disease or major depressive disorder. Domain-specific analyses showed that VCI patients benefited across attention, memory, and executive function, whereas SSD patients primarily improved in memory and executive domains. While sensitivity analyses and publication bias adjustments slightly attenuated effect sizes, the overall conclusions remained stable. Notably, the GRADE assessment revealed a paucity of high-quality evidence (1.9%), with 40.7% of outcomes rated as very low quality, largely due to inconsistency (substantial unexplained heterogeneity, I[2] > 50%), risk of bias (methodological limitations including lack of protocol registration and inadequate assessment of primary study bias), and imprecision (wide confidence intervals crossing the null). Overlap across reviews was low (CCA = 4.08%).

CONCLUSION: HF-rTMS appears to provide consistent cognitive benefits in Alzheimer's disease and VCI, whereas its efficacy in other neuropsychiatric disorders remains uncertain. Given the low certainty of evidence and substantial heterogeneity, findings should be interpreted with caution. Future large-scale, multicenter randomized controlled trials with standardized protocols are needed to confirm efficacy and support clinical implementation.},
}

Humans
*Transcranial Magnetic Stimulation/methods
*Cognitive Dysfunction/therapy
Alzheimer Disease/therapy
Schizophrenia/therapy/complications
Major Depressive Disorder/therapy/complications
*Mental Disorders/therapy/complications
Parkinson Disease/therapy/complications
Attention Deficit Disorder with Hyperactivity/therapy

@article {pmid42609045,
year = {2026},
author = {Comitato, A and Neri, A and Cossarizza, A},
title = {Active Vaccination Strategies for Alzheimer's Disease: An Expanded Review.},
journal = {European journal of immunology},
volume = {56},
number = {8},
pages = {e70250},
doi = {10.1002/eji.70250},
pmid = {42609045},
issn = {1521-4141},
support = {//supported/ ; },
mesh = {*Alzheimer Disease/immunology/therapy/prevention & control ; Humans ; Animals ; *tau Proteins/immunology ; *Amyloid beta-Peptides/immunology ; *Alzheimer Vaccines/immunology/therapeutic use ; *Vaccination/methods ; },
abstract = {Alzheimer's disease (AD) is pathologically defined by extracellular β-amyloid (Aβ) aggregates and intracellular hyperphosphorylated Tau, which collectively drive synaptic failure, neuroinflammation and progressive neuronal degeneration. Since current therapies provide predominantly symptomatic relief without halting disease progression, the development of robust disease-modifying interventions remains a critical unmet medical need. Here, we discuss the most recent advances in active immunisation strategies targeting pathological Aβ and Tau species and their potential to meaningfully modify the AD trajectory. Early vaccines such as AN1792 demonstrated proof-of-concept but were limited by T-cell-mediated adverse events. Second-generation approaches, including CAD106, UB-311, ABvac40 and ACI-24, improved safety and immunogenicity through short peptide fragments and liposomal formulations. Next-generation platforms such as MultiTEP and SupraAntigen, alongside nucleic acid-based vaccines, further optimise immune responses, overcoming immunosenescence and selectively targeting toxic oligomers while sparing physiological proteins. Tau-targeted vaccines, including AADvac1, ACI-35 and AV-1980R, show selective reduction of pathological Tau with promising preclinical and early clinical results. Combined Aβ/Tau vaccination demonstrates synergistic effects in preclinical models, supporting multi-target strategies. Future directions focus on preventive vaccination, alternative delivery routes and biomarker-driven personalisation, collectively supporting a shift towards integrated multi-target immunotherapy capable of modulating AD pathology and potentially altering its long-term clinical course.},
}

*Alzheimer Disease/immunology/therapy/prevention & control
Humans
Animals
*tau Proteins/immunology
*Amyloid beta-Peptides/immunology
*Alzheimer Vaccines/immunology/therapeutic use
*Vaccination/methods

@article {pmid42609050,
year = {2026},
author = {Abrahamson, EE and Kofler, JK and Lopez, OL and Cohen, AD and Gogola, A and Aizenstein, HJ and Karikari, TK and Mufson, EJ and Villemange, VL and Ikonomovic, MD},
title = {Characterization of [[18]F]SMBT-1 binding substrates in Alzheimer's disease and related disorders: A postmortem biochemical and immunohistochemical study.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71685},
doi = {10.1002/alz.71685},
pmid = {42609050},
issn = {1552-5279},
support = {P01 AG025204/NH/NIH HHS/United States ; P01 AG014449/NH/NIH HHS/United States ; U24 NS141780/NH/NIH HHS/United States ; P30 AG066468/P50 AG005133/NH/NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/pathology/metabolism/diagnostic imaging ; Female ; *Brain/metabolism/pathology/diagnostic imaging ; Male ; Aged, 80 and over ; Aged ; Monoamine Oxidase/metabolism ; Positron-Emission Tomography ; Thiazoles/pharmacokinetics ; Aniline Compounds ; Fluorine Radioisotopes ; Autoradiography ; Amyloid beta-Peptides/metabolism ; Immunohistochemistry ; *Tauopathies/pathology/metabolism/diagnostic imaging ; Glial Fibrillary Acidic Protein/metabolism ; tau Proteins/metabolism ; *Quinolines ; Radiopharmaceuticals ; },
abstract = {INTRODUCTION: Neuroimaging studies report associations of amyloid beta (Aβ) positron emission tomography (PET) with [[18]F](S)-(2-methylpyrid-5-yl)-6-[(3-fluoro-2-hydroxy)propoxy]quinoline ([[18]F]SMBT-1), a novel reactive astrogliosis surrogate radiotracer with high affinity for monoamine oxidase B (MAO-B) in Alzheimer's disease (AD). Postmortem association of [[18]F]SMBT-1 binding with pathology of AD and non-AD tauopathies is undefined.

METHODS: [[18]F]SMBT-1 binding, [[3]H]Pittsburgh compound B ([[3]H]PiB) binding, and MAO-B activity assays in brain homogenates, with [[18]F]SMBT-1 autoradiography and MAO-B immunoreactivity in relation to glial fibrillary acidic protein (GFAP), major histocompatibility complex II (MHC-II), Aβ, phosphorylated tau, cyano-Pittsburgh compound B (cyano-PiB), and X-34 on brain sections from AD, non-AD tauopathies, and nondemented controls.

RESULTS: [[18]F]SMBT-1 binding correlated with MAO-B activity and [[3]H]PiB binding, with highest levels in AD. [[18]F]SMBT-1 autoradiography corresponded to MAO-B/GFAP-immunoreactive astrocytes associated with Aβ deposits in plaques and vasculature, more closely than to tau pathology. [[18]F]SMBT-1 binding and MAO-B activity in non-AD tauopathies partially overlapped controls and AD, with MAO-B/GFAP-immunoreactive astrocytes in areas with tau pathology.

DISCUSSION: [[18]F]SMBT-1 is a promising biomarker of MAO-B reactive astrocytes in AD and non-AD tauopathies.},
}

Humans
*Alzheimer Disease/pathology/metabolism/diagnostic imaging
Female
*Brain/metabolism/pathology/diagnostic imaging
Male
Aged, 80 and over
Aged
Monoamine Oxidase/metabolism
Positron-Emission Tomography
Thiazoles/pharmacokinetics
Aniline Compounds
Fluorine Radioisotopes
Autoradiography
Amyloid beta-Peptides/metabolism
Immunohistochemistry
*Tauopathies/pathology/metabolism/diagnostic imaging
Glial Fibrillary Acidic Protein/metabolism
tau Proteins/metabolism
*Quinolines
Radiopharmaceuticals

@article {pmid42609152,
year = {2026},
author = {Kimura, K},
title = {[Immune Checkpoint Tim-3 Regulates Microglial Function in Alzheimer's Disease].},
journal = {Brain and nerve = Shinkei kenkyu no shinpo},
volume = {78},
number = {8},
pages = {931-937},
doi = {10.11477/mf.188160960780080931},
pmid = {42609152},
issn = {1881-6096},
mesh = {*Alzheimer Disease/immunology/metabolism ; *Microglia/metabolism/immunology ; Animals ; *Hepatitis A Virus Cellular Receptor 2/metabolism ; Humans ; Signal Transduction ; },
abstract = {Microglia are resident immune cells of the central nervous system and play a central role in the pathogenesis of Alzheimer's disease (AD). Emerging evidence indicates that their functional state critically influences amyloid-β (Aβ) clearance, neuroinflammation, and disease progression. Tim-3, an immune checkpoint molecule, is highly expressed in microglia and functions as a key regulator of microglial homeostasis through the transforming growth factor-β (TGF-β)-Smad2 signaling pathway. Microglia-specific deletion of Tim-3 enhances phagocytic activity. Moreover, microglia-specific Tim-3 deficiency results in reduced Aβ deposition, decreased neurotoxicity, and improved cognitive performance in the 5xFAD mouse model of AD. These effects are not mediated by changes in Aβ production but rather by enhanced microglial clearance and remodeling of Aβ plaques into less toxic forms. Furthermore, single-cell analyses reveal that Tim-3 deficiency promotes a microglial state characterized by increased phagocytic capacity and reduced pro-inflammatory signaling. These findings suggest that Tim-3 acts as a functional checkpoint that limits beneficial microglial responses in AD and that targeting Tim-3 may therefore represent a promising therapeutic strategy for reprogramming microglia and improving disease outcomes.},
}

*Alzheimer Disease/immunology/metabolism
*Microglia/metabolism/immunology
Animals
*Hepatitis A Virus Cellular Receptor 2/metabolism
Humans
Signal Transduction

@article {pmid42609160,
year = {2026},
author = {Nübling, G and Marth, L and Sandkühler, K and Stockbauer, A and Wlasich, E and Jäck, A and Wagemann, O and Kustermann, J and Halbgebauer, S and Tumani, H and Höglinger, G and Levin, J},
title = {Frailty in Adults With Down Syndrome: Cognitive, Functional and Biomarker Associations.},
journal = {Journal of intellectual disability research : JIDR},
volume = {},
number = {},
pages = {},
doi = {10.1111/jir.70162},
pmid = {42609160},
issn = {1365-2788},
support = {2022_EKEA.133//Else Kröner-Fresenius-Stiftung/ ; EXC 2145 SyNergy-ID 390857198//Deutsche Forschungsgemeinschaft/ ; R01 AG081394/NH/NIH HHS/United States ; },
abstract = {BACKGROUND: Down syndrome (DS) entails widespread age-related functional decline affecting multiple organ systems, including genetically determined early-onset Alzheimer disease (DSAD), resulting in an increased vulnerability to frailty early in life. We investigated the relationship between frailty, cognition and intellectual disability (ID) in adults with DS and explored biomarkers associated with frailty.

METHODS: This cross-sectional study investigated 148 consecutive patients at a DSAD outpatient clinic. We applied correlation analyses and hierarchical linear models to determine associations of the Frailty Index for people with Intellectual Disabilities-short form (ID-FISF) with measures of cognition (Cambridge cognitive assessment, CAMCOG-DS), adaptive function (short adaptive behaviour scale, SABS), motor function (SPES/SCOPA), a screening tool (dementia screening questionnaire in individuals with intellectual disabilities, DSQIID-G) for dementia-related change in ADL (activities of daily living) performance, and ID severity (DSM-5). Patients were stratified as cognitively healthy, DS-MCI, DSAD dementia, secondary cognitive decline (CD) or CD of unknown cause. Exploratory analyses included blood biomarkers, bioimpedance measurements and indirect calorimetry.

RESULTS: Both baseline ID severity (β = 0.093, p = 0.014) and cognitive performance (CAMCOG-DS, β = -0.0033, p < 0.001) were independently associated with ID-FISF scores. Acquired cognitive decline was associated with (pre)frailty irrespective of aetiology. After adjustment for ID severity and cognition, ID-FISF scores were associated with adaptive function (SABS: β = -0.0033, p < 0.001), motor function (SPES-SCOPA: β = 0.015, p < 0.001), change in ADL performance (DSQIID-G: β = 0.0061, p < 0.001) and medication burden (β = 0.016, p < 0.001). Exploratory biomarker analyses identified associations with ID-FISF scores for markers of neurodegeneration, inflammation, body composition, cardiac function and cellular stress signalling.

CONCLUSIONS: Frailty in DS is associated with both ID severity and acquired cognitive decline. Future studies should determine whether severe baseline ID increases susceptibility to frailty or primarily influences frailty measurement through lower baseline functional abilities, potentially necessitating ID-adapted frailty thresholds. Biomarker associations further support a multifactorial model of frailty involving neurodegeneration, inflammation and sarcopenia-related processes.},
}

@article {pmid42609354,
year = {2026},
author = {Jackson, BL},
title = {A locus coeruleus-centric framework for novelty, salience, and gamma oscillations: implications for neurostimulation, aging, and disease.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1895931},
pmid = {42609354},
issn = {1663-4365},
abstract = {Neuromodulation techniques in the gamma frequency range, such as chronic 40 Hz sensory stimulation, have gained attention for their potential to impact and preserve cognitive function in the context of neurodegenerative disorders such as Alzheimer's disease (AD). This hypothesis and theory article aims to examine the overlap in biological phenotypes between gamma stimulation techniques and to propose a theoretical mechanism of action that may help to inform future empirical investigations. In Part 1, we provide a neuromodulatory framework related to a multifaceted novelty/salience circuit consisting of phasic activation of hind-, mid-, and basal forebrain nuclei, especially the locus coeruleus (LC); the release of norepinephrine (NE); the activation of cholinergic, dopaminergic, and serotonergic nuclei; and downstream modulation of the neurogliavascular unit through astrocyte-dependent pathways in order to reduce neuroinflammation, increase blood and glymphatic flow, promote synaptic plasticity and myelination, and improve hippocampal-dependent memory. We suggest various falsifiable experiments and testable modifications to stimulation paradigms based on this hypothesis. In Part 2, we review and explore the role of these hind- and midbrain nuclei and neuromodulators in terms of learning, allostatic load, consciousness, and sleep. To strengthen the initial hypothesis and highlight the significance of this proposed circuit, we cite observations of altered gamma oscillations across a variety of neuropsychiatric disorders, as well as speculate on the role of brainstem nuclei in current and potential treatments. This portion aims to emphasize the critical importance of the neural circuit proposed, its involvement in conscious experience, and to potentially inform future neuropsychiatric research and disease modeling, as well as indications for LC-NE or gamma frequency-based interventions. Part 3, in order to explain the significant impact of 40 Hz stimulation on Alzheimer's disease and neurodegeneration, explores a hypothetical functional framework for the core role of the LC-NE system in novelty, evolutionary drive, and management of allostatic load, its potential role in vertebrate aging, and a hypothesis for LC-NE dysfunction and depletion as a significant upstream modulator of the development of amyloid plaques and Alzheimer's disease, respectively. The goal of this work is to motivate future empirical investigations into 40 Hz stimulation paradigms and biomarkers proposed, studies assessing the role of the LC-NE system in the conduction of consciousness and alterations in neuropsychiatric disorders discussed, and into the potential role of the LC in vertebrate aging and the development of Alzheimer's disease.},
}

@article {pmid42609405,
year = {2026},
author = {Zhang, X and Zhu, Y and Song, S and Liu, P and Liu, C and Li, H and Zhang, Y and Wang, C and Du, M and Tang, D and Hu, Y},
title = {The role of ECM-PIEZO1-axis-mediated mechanosensation in the central nervous system.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1881955},
pmid = {42609405},
issn = {1664-2295},
mesh = {Humans ; *Ion Channels/metabolism ; Animals ; *Extracellular Matrix/metabolism ; *Central Nervous System/metabolism ; *Mechanotransduction, Cellular/physiology ; *Central Nervous System Diseases/metabolism ; },
abstract = {Central nervous system (CNS) diseases are characterized by high rates of disability and mortality, and their pathological progression is generally accompanied by abnormal remodeling of the extracellular matrix (ECM) composition and mechanical properties. The mechanosensitive cation channel PIEZO1 is widely expressed in neurons, microglia, astrocytes, oligodendrocytes, and endothelial cells of the CNS. It can precisely sense mechanical signals such as ECM stiffness, viscoelasticity, shear stress, and matrix protein cross-linking, and convert them into intracellular calcium signals and downstream biochemical reactions, thereby mediating the mechanobiological crosstalk between the ECM and cells and playing a key role in physiological processes such as neurodevelopment, synaptic plasticity, blood-brain barrier (BBB) homeostasis, neuroimmune regulation, and cell fate determination. In diseases such as Alzheimer's disease (AD), ischemic stroke (IS), and multiple sclerosis (MS), abnormal stiffening or remodeling of the ECM can lead to excessive activation of PIEZO1, which, by regulating pathways such as nuclear factor-kappa B (NF-κB), Yes-associated protein/transcriptional coactivator with PDZ-binding motif (YAP/TAZ), calcium/calmodulin-dependent protein kinase II (CaMKII), and glutathione peroxidase 4 (GPX4), exacerbates neuroinflammation, BBB disruption, myelin destruction, neuronal ferroptosis, and defective axonal regeneration. This article systematically reviews the cellular expression profile of PIEZO1 in the CNS, the ECM-mediated activation mechanisms, and downstream signaling networks. It elucidates the regulatory role of the ECM-PIEZO1 axis in both the physiological functions and typical diseases of the CNS, aiming to provide a theoretical basis and new insights for mechanobiological research into the mechanisms and targeted therapies of CNS diseases.},
}

Humans
*Ion Channels/metabolism
Animals
*Extracellular Matrix/metabolism
*Central Nervous System/metabolism
*Mechanotransduction, Cellular/physiology
*Central Nervous System Diseases/metabolism

@article {pmid42609483,
year = {2026},
author = {Phelps, HE and Reese, MR and Jeyagopal, S and Sahota, A and Pyon, WS and Bizon, JL and Setlow, B and Burns, MR},
title = {Stereological sampling-based estimates of dopaminergic and cholinergic neuron numbers in young adult and aged male and female Fischer 344 × Brown Norway F1 hybrid rats.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1730515},
pmid = {42609483},
issn = {1663-4365},
abstract = {Age is the primary risk factor for neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease, which are characterized by profound loss of midbrain dopaminergic neurons and basal forebrain cholinergic neurons, respectively. In addition, loss of these neurons can occur even in "normal" (i.e., non-pathological) aging, and as a result there is growing recognition of the value of aged animals in studying both normal aging and age-related neurodegenerative disease. The Fischer 344 x Brown Norway F1 hybrid (FBN) rat is commonly used for such purposes and is recommended for use in aging studies by the NIH due to its extended lifespan and more accurate representation of age-related human diseases such as sarcopenia and cognitive decline. Despite the significant value and broad use of this model, dopaminergic and cholinergic neurons have not been well characterized in this strain, and there have been even fewer comparisons between males and females. To address this issue, we used systematic random sampling principles to generate population estimates for dopaminergic neurons in the substantia nigra pars compacta and ventral tegmental area, and cholinergic neurons in the medial septum and vertical limb of the diagonal band of Broca in 5-6.5-month and 20-26-month-old FBN rats of both sexes. Dopaminergic and cholinergic cell bodies were immunolabeled for tyrosine hydroxylase and choline acetyltransferase, respectively. Because the final counts were obtained from full-thickness image stacks using cell-profile inclusion rules and relatively sparse section sampling, these values are presented as stereological sampling-based estimates rather than strict design-based stereological totals. Within these methodological limits, no age differences in dopaminergic or cholinergic neuron-number estimates were detected in any region assessed, nor were there differences between males and females. These data suggest that FBN rats can be used to model induced age-related neurodegenerative disease without the potential confound of a large independent age-associated loss of these dopaminergic or cholinergic neuronal populations.},
}

@article {pmid42609487,
year = {2026},
author = {Huang, J and Li, X and Zhou, K and Liu, B and Wei, Y and Guo, H and Wei, S and Xu, S and Liu, Y and Huang, J and Deng, D and Liang, L},
title = {High-frequency taVNS modulates olfaction-related brain activity in patients with subjective cognitive decline.},
journal = {Frontiers in human neuroscience},
volume = {20},
number = {},
pages = {1888005},
pmid = {42609487},
issn = {1662-5161},
abstract = {BACKGROUND: Subjective cognitive decline (SCD) is considered a high-risk factor for Alzheimer's disease and serves as a critical window of the prevention and treatment. Transcutaneous auricular vagus nerve stimulation (taVNS) has shown therapeutic effects on cognitive impairment, but there is a lack of research on its application in SCD.

PURPOSE: This study aimed to explore the immediate modulatory effects of taVNS at different frequencies on the brain function in patients with SCD.

METHODOLOGY: Seventy SCD and 49 healthy control (HC) were enrolled. Resting-state functional MRI data were collected at baseline and during taVNS with three stimulation conditions: 1 Hz-taVNS, 20 Hz-taVNS, and sham taVNS (staVNS), respectively. Regional homogeneity (ReHo) analysis was used to identify spontaneous neural activity changes in SCD; the abnormal brain regions were then used as seed for subsequent functional connectivity (FC) analysis. In addition, ReHo and FC analyses were performed to assess the immediate modulatory effects of taVNS in SCD.

RESULTS: Compared with HC, SCD showed abnormal ReHo and FC mainly involving olfaction-related brain regions, and the reduced value was positively associated with Shape Trail Test-part B. During taVNS, we found that 20 Hz-taVNS significantly increased ReHo in the bilateral olfactory cortex compared with baseline, and decreased FC between the left medial orbitofrontal cortex and the right precentral and postcentral gyri. No significant ReHo or FC changes were observed during 1 Hz-taVNS and staVNS.

CONCLUSION: These findings suggest that SCD exhibits reduced spontaneous activity and disrupted FC in the olfaction-related brain regions, which may reflect early functional alterations before objective impairment; 20 Hz-taVNS can modulate these cerebral functional abnormalities and may hold potential as a noninvasive neuromodulation strategy in SCD.},
}

@article {pmid42609516,
year = {2026},
author = {Li, T and Zhang, Q and Wu, Y and Huang, R},
title = {Cell Death in Neurodegenerative Diseases: Molecular Mechanisms and Therapeutic Targets.},
journal = {MedComm},
volume = {7},
number = {9},
pages = {e70915},
pmid = {42609516},
issn = {2688-2663},
abstract = {Neurodegenerative diseases (NDs) are marked by selective neuronal vulnerability and progressive failure of neural circuits. Increasing evidence indicates that neuronal loss is not driven by a single terminal event, but emerges from interacting regulated cell death (RCD) programs. These programs are closely coupled to mitochondrial injury, proteostatic collapse, lysosomal stress, metabolic imbalance, glial state transitions, and chronic neuroinflammation. Yet, how distinct death pathways are organized across cell types, disease stages, and disease-specific microenvironments remains unresolved. This review examines RCD as an integrated pathogenic network in major NDs. Caspase and B-cell lymphoma 2 (BCL2) family signaling, receptor-interacting protein kinase 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like protein activation, NOD-like receptor family pyrin domain containing 3 and gasdermin signaling, GPX4-linked lipid peroxidation control, and autophagy lysosomal failure are discussed as convergent stress response modules rather than isolated pathways. Across Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease, these modules shape neuronal fate through disease-specific interactions with mitochondrial dysfunction, iron dyshomeostasis, inflammasome activation, and microglial metabolic remodeling. We further evaluate emerging therapeutic strategies that target cell death crosstalk, restore autophagy lysosomal competence, or improve delivery to the central nervous system, highlighting the importance of molecular selectivity, cellular context, disease stage, and translational feasibility.},
}

@article {pmid42609573,
year = {2026},
author = {Wan, Z and Lin, Z and Liu, Y and Wang, R and Yang, R and Ai, Y},
title = {The application of traditional machine learning and deep learning with EEG for mild cognitive impairment: a bibliometric analysis.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1880346},
pmid = {42609573},
issn = {1663-4365},
abstract = {OBJECTIVE: This study uses bibliometric methods to analyze the status of electroencephalography (EEG) and machine learning applications in mild cognitive impairment (MCI) research.

METHODS: Relevant literature was searched in the four major English databases (Web of Science, PubMed, IEEE Xplore, and Scopus) and the three major Chinese databases (CNKI, Wanfang, and VIP) from their inception to June 2026. After removing duplicates using NoteExpress and screening the literature according to the inclusion and exclusion criteria, the final data were imported into CiteSpace 6.4. R2 and VOSviewer 1.6.20 for analysis of publication trends, geographic distribution, highly co-cited references, keyword clustering, and burst detection.

RESULTS: A total of 547 valid studies were included in the analysis, comprising 523 English-language studies and 24 Chinese core journal articles. The number of publications in this field has shown phased growth. It entered a period of rapid development after 2018. China ranks first globally in terms of English-language publications; however, there is a significant gap between the number of core publications in Chinese and English. Clinical Neurophysiology is the journal with the highest total local citation score (TLS). Four of the top 10 highly co-cited journals are published in the United States. Highly cited literature has jointly contributed to establishing a core body of knowledge in this field. This knowledge encompasses clinical diagnostic guidelines, electrophysiological mechanisms, signal processing methods, and intelligent algorithm models. Traditional machine learning keywords focus on methodological exploration, including feature extraction and support vector machine classification. Deep learning keywords focus on model applications, including convolutional and artificial neural networks. Keyword burst analysis identifies feature selection, decision trees, and neuropsychological assessment as the current frontier topics in this field.

CONCLUSION: Electroencephalography combined with machine learning has become an important research direction for the early identification and assessment of MCI. The research focus has shifted from traditional EEG signal analysis and manual feature engineering to optimization of deep learning models and exploration of multimodal data fusion. Improved algorithm interpretability, refined EEG rhythm and brain region localization, and the combination of neuropsychological assessment and EEG indicators have become a new research trend.},
}

@article {pmid42609863,
year = {2026},
author = {Nair, AA and Wen, Z and Wang, Z and Yan, J and Saykin, AJ and Huang, H and Thompson, PM and Davatzikos, C and Shen, L},
title = {Staging and Pseudotime Inference of Alzheimer's Disease Progression using Multimodal Imaging Data.},
journal = {Proceedings. IEEE International Conference on Healthcare Informatics},
volume = {2026},
number = {},
pages = {331-340},
pmid = {42609863},
issn = {2575-2626},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline, driven by the accumulation of amyloid-beta plaques, tau tangles, and neuronal atrophy. This study analyzes three imaging modalities corresponding to the three hallmark biomarkers of AD: amyloid PET, tau PET, and structural MRI. Using cortical measurements from the ADNI dataset, we apply PHATE (Potential of Heat-diffusion for Affinity-based Trajectory Embedding), a dimensionality reduction technique, to uncover continuous trajectories of disease progression. We derive pseudotime values from PHATE embeddings via Slingshot, a principal-curve-based pseudotime inference algorithm. In parallel, we apply SuStaIn (Subtype and Stage Inference), a machine learning model that uncovers distinct biomarker event sequences and assigns subjects to discrete disease stages. We observe strong correspondence between SuStaIn-predicted stages and PHATE-derived pseudotimes, indicating temporal coherence across modeling frameworks. SuStaIn further reveals non-overlapping, modality-specific sequences of biomarker abnormalities, consistent with prior neuropathological models. We validate these sequences using pseudotime-aligned kernel density models and clinical measures. Together, our results support the integrative use of these approaches for evaluating AD progression. Future steps will focus on anchoring pseudotime to real-world clinical timelines and experimentally validating SuStaIn-predicted biomarker cascades.},
}

@article {pmid42609893,
year = {2026},
author = {Zhuang, F and Yang, S and Aliyeva, D and Wen, Z and Duong-Tran, D and Davatzikos, C and Chen, T and Wang, S and Shen, L},
title = {Interpretable Alzheimer's Diagnosis via Multimodal Fusion of Regional Brain Experts.},
journal = {Proceedings. IEEE International Conference on Healthcare Informatics},
volume = {2026},
number = {},
pages = {311-320},
pmid = {42609893},
issn = {2575-2626},
abstract = {Accurate and early diagnosis of Alzheimer's disease (AD) is critical for effective intervention and requires integrating complementary information from multimodal neuroimaging data. However, conventional fusion approaches often rely on simple concatenation of features, which cannot adaptively balance the contributions of biomarkers such as amyloid PET and MRI across brain regions. In this work, we propose MREF-AD, a Multimodal Regional Expert Fusion model for AD diagnosis. It is a Mixture-of-Experts (MoE) framework that models mesoscopic brain regions within each modality as independent experts and employs a gating network to learn subject-specific fusion weights. Utilizing tabular neuroimaging and demographic information from the Alzheimer's Disease Neuroimaging Initiative (ADNI), MREF-AD achieves competitive performance over strong classic and deep baselines while providing interpretable, modality- and region-level insight into how structural and molecular imaging jointly contribute to AD diagnosis. The source code is available at https://github.com/PennShenLab/mref-ad.},
}

@article {pmid42609945,
year = {2026},
author = {Yuan, Y and Li, Z and Wang, R and Zhao, H and Song, J},
title = {Huanglian Jiedu decoction ameliorates Alzheimer's disease by regulating calcium homeostasis via mitochondria-associated endoplasmic reticulum membranes.},
journal = {Iranian journal of basic medical sciences},
volume = {29},
number = {6},
pages = {927-934},
pmid = {42609945},
issn = {2008-3866},
abstract = {OBJECTIVES: Huanglian Jiedu decoction (HLJDD), a classic traditional Chinese medicine formula, is investigated for its protective effects against Alzheimer's disease (AD). This study explored its mechanism in an AD cell model, focusing on calcium ion (Ca[2+]) homeostasis regulation via mitochondria-associated endoplasmic reticulum membranes (MAMs).

MATERIALS AND METHODS: Mouse hippocampal HT22 cells were induced with 10 μmol·L⁻¹ Aβ₁₋₄₂ to establish the AD model, then divided into blank, model, and 15% HLJDD-containing serum intervention groups. Fluorescent dyes, qRT-PCR, western blotting, laser scanning confocal microscopy, and Annexin V-FITC/PI staining were used to detect intracellular reactive oxygen species (ROS), mitochondrial membrane potential, VDAC1/GRP75/IP3R (mRNA/protein levels), MAMs formation, intracellular Ca²⁺, and cell apoptosis, respectively.

RESULTS: Aβ₁₋₄₂ reduced HT22 viability in a concentration-dependent manner, while HLJDD significantly improved viability. Compared to the model group, HLJDD evidently decreased ROS levels (P<0.001), elevated mitochondrial membrane potential (P<0.001), up-regulated GRP75 (mRNA/protein, P<0.05), down-regulated VDAC1/IP3R (mRNA/protein, P<0.05 or P<0.001), reduced MAMs (via lower ER-mitochondria co-localization, P<0.05), alleviated Ca²⁺ overload (P<0.001), and lowered apoptosis.

CONCLUSION: HLJDD exerts protective anti-AD effects likely by reducing MAMs formation to alleviate intracellular Ca²⁺ overload, thereby lessening cell damage and apoptosis.},
}

@article {pmid42609986,
year = {2026},
author = {Hung, KC and Weng, HL and Chen, IW},
title = {Lower Risk of Incident Dementia with SGLT2 Inhibitor Versus DPP-4 Inhibitor Initiation in Patients with Type 2 Diabetes and Prior Traumatic Brain Injury: A Retrospective Cohort Study.},
journal = {Drug design, development and therapy},
volume = {20},
number = {},
pages = {624727},
pmid = {42609986},
issn = {1177-8881},
mesh = {Humans ; *Diabetes Mellitus, Type 2/drug therapy ; Retrospective Studies ; *Brain Injuries, Traumatic/drug therapy/complications ; *Dipeptidyl-Peptidase IV Inhibitors/therapeutic use/administration & dosage/pharmacology ; *Sodium-Glucose Transporter 2 Inhibitors/therapeutic use/administration & dosage/pharmacology ; Male ; Female ; Aged ; *Dementia/drug therapy/epidemiology ; Middle Aged ; Incidence ; Cohort Studies ; },
abstract = {PURPOSE: SGLT2 inhibitors have been associated with reduced dementia risk in patients with type 2 diabetes mellitus (T2DM); however, whether this association extends to patients with traumatic brain injury (TBI) remains unknown.

PATIENTS AND METHODS: We conducted a new-user, active-comparator, retrospective cohort study using the TriNetX Research Network. Adults aged ≥50 years with T2DM and a history of TBI who newly initiated an SGLT2 inhibitor were compared with new users of a DPP-4 inhibitor as the active-comparator group between 2014 and 2023. A 1-year landmark period was applied before the outcome was ascertained. The primary outcome was incident dementia during an analytic window extending from day 365 to up to 10 years after the index date. Secondary outcomes included dementia subtypes (ie, vascular dementia or Alzheimer's disease) and all-cause mortality. Propensity score matching, sensitivity analyses, and multivariable Cox regression were performed.

RESULTS: After matching, 3,877 patients were included in each group. Incident dementia occurred in 129 patients (3.33%) in the SGLT2 inhibitor group and 243 patients (6.27%) in the DPP-4 inhibitor group (HR, 0.71; 95% CI, 0.57-0.88; p = 0.002). In exploratory secondary analyses, associations were observed for vascular dementia (HR, 0.49; p = 0.005) and all-cause mortality (HR, 0.76; p < 0.001), but not for Alzheimer's disease (HR, 0.90; p = 0.654). A similar exploratory association was observed in the code-defined non-concussion intracranial injury subgroup (HR, 0.65; p = 0.004).

CONCLUSION: In this retrospective cohort study, SGLT2 inhibitor use was associated with a lower risk of incident dementia in patients with T2DM and TBI. These hypothesis-generating findings warrant further prospective validation.},
}

Humans
*Diabetes Mellitus, Type 2/drug therapy
Retrospective Studies
*Brain Injuries, Traumatic/drug therapy/complications
*Dipeptidyl-Peptidase IV Inhibitors/therapeutic use/administration & dosage/pharmacology
*Sodium-Glucose Transporter 2 Inhibitors/therapeutic use/administration & dosage/pharmacology
Male
Female
Aged
*Dementia/drug therapy/epidemiology
Middle Aged
Incidence
Cohort Studies

@article {pmid42610018,
year = {2026},
author = {Umbria, M and Exposito, J and Gasol, M and Vallano, A},
title = {A regional registry ensures clinical guideline adherence and economic sustainability of Alzheimer's disease treatment: a 12-year population-based study in Catalonia.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1848809},
pmid = {42610018},
issn = {1663-9812},
abstract = {Population-based registries for Alzheimer's disease pharmacological treatment are essential tools for monitoring clinical guideline adherence and health system sustainability. This retrospective observational study analyzes 12 years of real-world data from the Catalan Registry of Pharmacological Treatment of Alzheimer's Disease (RTFMA) between 2012 and 2024. Analyzing a cohort of over 158,000 patients treated with acetylcholinesterase inhibitors or memantine, we found that the treated population increased by 24.5%, reaching 56,874 individuals in 2024. The implementation of a mandatory registration system was associated with high clinical appropriateness, with 81.9% of treatments initiated at recommended moderate stages (GDS 4-5), while only 8.6% began at mild stages. Despite the aging population and the impact of the COVID-19 pandemic-which caused a transient decline in treatment initiations in 2020-the system demonstrated resilience with a full recovery by 2023. Treatment discontinuation was primarily driven by mortality (95% of known reasons), indicating high persistence until end-of-life. From an economic perspective, Alzheimer's therapies represented a stable 1.9% of the total public pharmaceutical budget in 2023, reflecting effective cost containment through generic drug use. These findings suggest that a centralized, guideline-linked registry optimizes patient selection and maintains the economic viability of Alzheimer's care, providing a robust framework for the future integration of high-cost disease-modifying therapies.},
}

@article {pmid42610081,
year = {2026},
author = {Eldehna, WM and El-Damasy, AK and Lim, J and Hefny, SM and Al-Warhi, T and Elgohary, AS and El-Hamaky, AA and Paik, MJ and Elnagar, MR and Elimam, DM and Omar, YM and Kim, H and Tawfik, HO},
title = {Quinazolinone-triazole hybrids as multi-target-directed ligands for Alzheimer's disease: discovery of potent and selective MAO-B inhibitors with cholinesterase modulating activity.},
journal = {RSC advances},
volume = {},
number = {},
pages = {},
pmid = {42610081},
issn = {2046-2069},
abstract = {A new series of quinazolinone-triazole hybrids (QTHs, 5a-n) was designed, synthesized, and evaluated as potential multi-target-directed ligands for Alzheimer's disease. All synthesized compounds were screened against human monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B). The obtained results revealed pronounced selectivity toward MAO-B, with IC50 values ranging from 0.65 to 7.51 µM, while exhibiting negligible MAO-A inhibition (IC50 > 40 µM). Compounds 5a, 5d, 5g, 5h, and 5m emerged as the most potent and selective MAO-B inhibitors and were subsequently evaluated for inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Among them, compound 5h displayed the most favorable biological profile, showing potent inhibition of MAO-B (IC50 = 0.65 µM), AChE (IC50 = 0.084 µM), and BuChE (IC50 = 0.667 µM). In silico ADMET analysis indicated acceptable drug-like properties for the lead compounds. Furthermore, molecular docking studies against MAO-B and AChE revealed favorable binding interactions, while a 500 ns molecular dynamics simulation confirmed the stability of the 5h-MAO-B complex. Collectively, the present findings identify compound 5h as a promising lead candidate and highlight quinazolinone-triazole hybrids as attractive scaffolds for the development of selective MAO-B inhibitors with additional cholinesterase inhibitory activity for Alzheimer's disease treatment.},
}

@article {pmid42610130,
year = {2026},
author = {Aziz, N and Hussain, G and Abbas, QA},
title = {Role of microRNAs in major brain diseases, focusing on neuroinflammation and neuronal apoptosis.},
journal = {Iranian journal of basic medical sciences},
volume = {29},
number = {6},
pages = {844-869},
pmid = {42610130},
issn = {2008-3866},
abstract = {MicroRNAs are non-coding small RNA molecules that play a significant role in regulating gene expression. Increasing lines of evidence have highlighted the microRNA dysregulation and neuroinflammation-associated apoptosis in common brain diseases, including Parkinson's disease, Alzheimer's disease, epilepsy, traumatic brain injury, depression, and migraine. In fact, microRNAs regulate multiple physiological and pathological processes, thus implicating them in both health and disease. Though studies have suggested that the alterations or modifications in microRNA-associated regulatory pathways might contribute to the disease pathogenesis, the underlying molecular mechanisms and the targeted genes remain exclusively unknown. We hope that the idea of using microRNAs as therapeutic targets for brain disorders is not far from reality, but important issues must be addressed before moving into clinical practice. The aim of this review is to enlighten the molecular mechanisms and targeted genes of microRNA implicated in the multifaceted brain disorders. Moreover, several microRNAs have been reported to be up-regulated following disease, but their targeted pathways have not been elucidated yet. This review also highlighted microRNAs that are expected to warrant further exploration of their mechanism of action. This comprehensive overview of the prediction of microRNAs' functions might be helpful in providing more efficient insight for the development of microRNA-based therapeutic interventions for neuropsychiatric and neurodegenerative diseases.},
}

@article {pmid42610137,
year = {2026},
author = {Gong, G and Liu, X and Jia, X and Long, B and Chen, S and Jiang, T and Luo, Y and Feng, Z and Li, X and Luo, Q and Gong, H and Li, A},
title = {Generalized plaque digitization framework for multi-dimensional mesoscopic images.},
journal = {Biomedical optics express},
volume = {17},
number = {8},
pages = {4198-4215},
pmid = {42610137},
issn = {2156-7085},
abstract = {Fine analysis of the spatial distribution and morphology of Aβ plaques is crucial for understanding the pathological progression of Alzheimer's disease (AD). However, at the whole-brain scale, the enormous number of plaques, wide size range, diffuse morphologies, and complex imaging background pose challenges that existing digitization methods often fail to address comprehensively. To this end, this study developed a Generalized Plaque Digitization Framework (GPDigit). The framework adopts a two-step strategy of detection followed by segmentation: first, a customized object detection network achieves precise spatial localization of plaques; second, adaptive foreground signal segmentation is performed within local regions. This design circumvents the difficulty of global threshold selection and the high annotation cost of segmentation networks. GPDigit supports both 2D and 3D data scenarios, ensures detection accuracy through targeted feature extraction mechanisms, and significantly improves training data preparation efficiency with a self-developed annotation tool and multiple data augmentation strategies. Experimental results demonstrate that GPDigit achieves satisfactory digitization performance under challenging conditions such as dense plaque distribution, severe background interference, and weak signals. Application to whole-brain plaque analysis in 5xFAD mice across multiple key ages revealed, at the fine brain-region scale, the spatiotemporal heterogeneity of plaque density and load development. This study provides a systematic solution for plaque digitization in neuropathological mesoscopic high-resolution images and offers a practical tool to advance AD pathology research.},
}

@article {pmid42610650,
year = {2026},
author = {Hiruta, Y and Jin, Z and Adachi, M and Amer, L and Tjokro, NO and Trujillo, DF and Potempa, J and O'Donoghue, AJ and Chen, C and Jokerst, JV},
title = {Protease-Triggered Chromogenic Release From Peptide-Modified Calcium Carbonate Microspheres Enables Colorimetric Detection of Porphyromonas gingivalis Activity.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e77102},
doi = {10.1002/advs.77102},
pmid = {42610650},
issn = {2198-3844},
support = {//Shiley Foundation/ ; //National Nanotechnology Coordinated Infrastructure/ ; ECCS-2025752//National Science Foundation/ ; 22KK0234//Promotion of Joint International Research (Fostering Joint International Research/ ; 21K06495//Promotion of Joint International Research (Fostering Joint International Research/ ; //Japan Society for the Promotion of Science/ ; //Fukuzawa Memorial Fund/ ; },
abstract = {Porphyromonas (P.) gingivalis is a Gram-negative anaerobic bacterium with exceptionally high pathogenicity among periodontal pathogens. It is associated not only with periodontal disease but also with various systemic diseases, including Alzheimer's disease, rheumatoid arthritis, and atherosclerosis. Therefore, early detection of this bacterium is crucial for enabling subsequent treatment and prevention of such conditions. Herein, we report a chromogenic release-based assay system utilizing calcium carbonate microspheres and a dye-labeled peptide that is selectively cleaved by an Arg-specific protease called gingipain (RgpB) that is secreted by P. gingivalis. By utilizing the reactive anhydride functional groups of poly(isobutylene-alt-maleic anhydride), we simultaneously achieved the conjugation of the dye-labeled peptide and its immobilization onto calcium carbonate microspheres. Through optimization of the peptide sequence and the surface modification density on calcium carbonate microspheres, the assay of RgpB detection with the absorbance of supernatant exhibited a low limit of detection of 0.25 nM, as well as high storage stability and selectivity for P. gingivalis. The measurements obtained with this assay system for clinical gingival crevicular fluid samples showed a high correlation (Pearson's r = 0.79) with qPCR results. This assay system offers an on-site, visual means to monitor P. gingivalis activity without requiring specialized instrumentation.},
}

@article {pmid42610694,
year = {2026},
author = {Song, Y and Wu, F and Wong, A and Clendenen, TV and Koenig, KL and Gu, Y and Zeleniuch-Jacquotte, A and Chen, Y},
title = {Midlife physical activity and late-life subjective cognitive complaints in women.},
journal = {The Gerontologist},
volume = {},
number = {},
pages = {},
doi = {10.1093/geront/gnag200},
pmid = {42610694},
issn = {1758-5341},
abstract = {BACKGROUND AND OBJECTIVES: Alzheimer's disease affects mostly women over 65, who make up nearly two-thirds of cases. Subjective cognitive complaints (SCC) can precede Alzheimer's disease by years. While physical activity supports healthy aging, the long-term impact of midlife physical activity (PA) on late-life SCCs in women is limited.

RESEARCH DESIGN AND METHODS: Using data from 4,397 participants (mean age=46.2 years at baseline; 78.7 years at SCC assessment) in the New York University Women's Health Study (NYUWHS), a prospective cohort of 14,274 women enrolled in 1985-1991, we examined the association between midlife PA and SCC reported nearly 30 years later. PA was assessed at baseline using self-reported weekly hours of mild, moderate, and vigorous activity, converted to metabolic equivalent hours per week (MET-hours/week). Odds ratios and 95% CIs were estimated using unconditional logistic regression, adjusting for demographics and midlife and late-life health conditions. Multiple imputation and inverse probability weighting addressed missing data and potential selection bias.

RESULTS: Women in the highest tertile of total midlife PA had 20% lower odds of reporting ≥2 SCCs compared with those in the lowest tertile (OR = 0.80; 95% CI = 0.68-0.95). The inverse association was stronger among never smokers (OR = 0.68; p for interaction=0.029). The inverse association was consistent for moderate and vigorous, but not mild PA. Findings were consistent across sensitivity analyses using alternative SCC definitions, exclusion criteria, and inverse probably weights.

DISCUSSION AND IMPLICATIONS: Higher level of midlife PA was associated with fewer late-life SCCs, suggesting that midlife PA may be an important behavioral correlate of later-life cognitive health in women.},
}

@article {pmid42610745,
year = {2026},
author = {Aywa, KM and Kappe, C and Ghandour, B and Gao, S and Arenz, C and Hannun, YA and Airola, MV},
title = {Development of a FRET-Based Assay for Human Neutral Sphingomyelinase 2.},
journal = {Biochemistry},
volume = {65},
number = {16},
pages = {2548-2556},
doi = {10.1021/acs.biochem.6c00322},
pmid = {42610745},
issn = {1520-4995},
support = {R35GM118128/GM/NIGMS NIH HHS/United States ; R35GM128666/GM/NIGMS NIH HHS/United States ; AR 376/22-1//Deutsche Forschungsgemeinschaft/ ; },
mesh = {Humans ; *Fluorescence Resonance Energy Transfer/methods ; *Sphingomyelin Phosphodiesterase/metabolism/antagonists & inhibitors/genetics ; Sphingomyelins/metabolism/chemistry ; Benzylidene Compounds/pharmacology/chemistry ; Nitrobenzenes/pharmacology/chemistry ; *Enzyme Assays/methods ; Aniline Compounds/pharmacology/chemistry ; Recombinant Proteins/metabolism/chemistry/genetics ; Enzyme Inhibitors/pharmacology ; High-Throughput Screening Assays/methods ; },
abstract = {Neutral sphingomyelinase 2 (nSMase2) is a membrane-bound enzyme that hydrolyzes sphingomyelin (SM) into ceramide and phosphocholine. By generating the bioactive lipid ceramide, nSMase2 plays a critical role in cell stress responses and in regulating exosomes that package and transfer pathogenic factors, including tau protein and amyloid β. Thus, nSMase2 has been implicated in Alzheimer's disease and other neurological disorders. However, current tools to measure nSMase2 activity are limited, in particular those that could be used in therapeutic development. Here we developed a high-throughput assay to measure human nSMase2 activity. The assay uses a sphingomyelin substrate analogue with a FRET donor and acceptor pair attached to the headgroup and acyl-chain, respectively. Using recombinant human nSMase2, we sensitively detected both wild-type and mutant activity and demonstrated inhibition by the known nSMase2 inhibitor GW4869. The assay captures the major hallmarks of nSMase2 regulation by anionic lipids and displays sensitivity capable of detecting nSMase2 activity from cell lysates. Together, this assay enables rapid screening of nSMase2 inhibitors to support future therapeutic development.},
}

Humans
*Fluorescence Resonance Energy Transfer/methods
*Sphingomyelin Phosphodiesterase/metabolism/antagonists & inhibitors/genetics
Sphingomyelins/metabolism/chemistry
Benzylidene Compounds/pharmacology/chemistry
Nitrobenzenes/pharmacology/chemistry
*Enzyme Assays/methods
Aniline Compounds/pharmacology/chemistry
Recombinant Proteins/metabolism/chemistry/genetics
Enzyme Inhibitors/pharmacology
High-Throughput Screening Assays/methods

@article {pmid42610835,
year = {2026},
author = {Paranhos, T and Du, A and Eckbo, R and Wong, B and Camprodon, JA and Dickerson, BC and Eldaief, M and Touroutoglou, A},
title = {Non-invasive brain stimulation increases default mode network functional connectivity in a patient with Posterior Cortical Atrophy.},
journal = {International review of psychiatry (Abingdon, England)},
volume = {},
number = {},
pages = {1-11},
doi = {10.1080/09540261.2026.2682195},
pmid = {42610835},
issn = {1369-1627},
abstract = {Repetitive transcranial magnetic stimulation (rTMS) has been explored as an intervention in typical amnestic Alzheimer's Disease (AD). However, its effects on episodic and associative memory in atypical forms of AD are less known. Posterior cortical atrophy (PCA) is primarily characterized by visuospatial and visuoperceptual symptoms, although significant episodic memory deficits are often observed. To investigate whether intermittent theta burst (iTBS, a form of rTMS), guided by individualized functional imaging, can modulate functional networks and improve associative memory in a patient with PCA presenting with memory impairments. A stimulation target in the left caudal middle frontal gyrus (cMFG) was selected based on peak functional connectivity with the default mode network (DMN). iTBS was administered to this target in a randomized placebo-controlled paradigm. Primary outcomes were changes in functional connectivity of the stimulation target and associative memory performance. Visuospatial working memory and global cognition were secondary outcomes. Consistent with our hypothesis, active iTBS increased connectivity between the cMFG target and distributed DMN regions. Contrary to our hypothesis, associative memory performance did not improve, but we did observe improvements in visuospatial working memory. This case report supports further controlled clinical trials using functional connectivity guided rTMS in PCA.},
}

@article {pmid42611034,
year = {2026},
author = {Dodart, CA},
title = {The locus coeruleus gateway hypothesis: Noradrenergic integrity as a candidate determinant of amyloid-β clearance efficiency in anti-amyloid immunotherapy for Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261474020},
doi = {10.1177/13872877261474020},
pmid = {42611034},
issn = {1875-8908},
abstract = {Anti-amyloid immunotherapies (lecanemab, donanemab) produce statistically significant but clinically modest slowing of decline in early Alzheimer's disease (AD), with substantial inter-individual response variability that current covariates-antibody titer, baseline amyloid load, apolipoprotein E ε4 (APOE4) status, or tau burden-leave largely unexplained. We propose that a systematically unmeasured upstream variable contributes to this variability: the structural integrity of the locus coeruleus (LC), the principal source of brain norepinephrine (NE), framed as a candidate determinant of amyloid-β (Aβ) clearance efficiency rather than of overall clinical outcome. This hypothesis paper synthesizes three peer-reviewed lines of evidence and derives a hierarchy of falsifiable predictions; no new data are reported. First, tau pathology initiates in LC neurons before any cortical structure, reducing NE output from the earliest preclinical stage. Second, NE governs two complementary Aβ-clearance pathways: glymphatic flow, via aquaporin-4 dynamics driven by slow LC oscillations during non-REM sleep, and microglial phagocytosis, via β2-adrenergic receptor signaling. Third, in Parkinson's disease, the DTI-ALPS index mediates the relationship between LC integrity on neuromelanin-sensitive MRI and cognition. We term this the Locus Coeruleus Gateway Hypothesis (LCGH). Its mediation chain is testable now in ADNI, which holds research-grade diffusion-tensor imaging; its treatment-response prediction requires immunotherapy cohorts that acquire such imaging, not the existing CLARITY-AD or TRAILBLAZER-ALZ 2 archives, whose safety MRI used diffusion-weighted, not tensor, sequences. We state explicitly that Aβ clearance is only one contributor to clinical benefit, and that the LCGH predicts pharmacodynamic efficiency, not that NE restoration treats AD.},
}

@article {pmid42602204,
year = {2026},
author = {Wang, H and Zhang, X},
title = {Bridging the islands of innovation: A machine-assisted Semantic-Bibliometric review and conceptual roadmap for closed-loop digital dementia care.},
journal = {Digital health},
volume = {12},
number = {},
pages = {20552076261479403},
pmid = {42602204},
issn = {2055-2076},
abstract = {BACKGROUND: Artificial intelligence (AI), extended reality (XR), and socially assistive robotics (SAR) are each advancing Alzheimer's disease (AD) research and care at a rapid pace. Yet despite substantial progress within each domain, clinical implementation remains weakly integrated across diagnostic, therapeutic, and care functions, producing islands of innovation rather than coordinated care systems.

METHODS: We conducted a machine-assisted semantic-bibliometric synthesis of 2,636 publications on AI-, immersive technology/VR-, and SAR-enabled approaches to AD diagnosis, intervention, and care published between 2021 and 2025. Available title-abstract metadata were encoded using SBERT embeddings, projected via UMAP, and clustered using K-Means to characterize the functional topology of the field. From this mapped corpus, we selected a semantically central subset of 50 studies for high-fidelity full-text synthesis, preserving cross-domain representativeness while maintaining interpretive tractability.

RESULTS: The mapped landscape suggests a three-part pattern of architectural separation. Precision neuroimaging (Cluster C4, 22%) functions primarily as a state-oriented diagnostic domain. Immersive therapeutics (Cluster C2, 48%), the largest cluster, increasingly incorporate adaptive personalization but remain weakly connected to biomarker-based stratification. Embodied robotic care (Cluster C5, 10%) addresses behavioral stabilization with little longitudinal coupling to upstream sensing. Across all three domains, high component-level sophistication coexists with limited evidence of cross-layer coordination.

CONCLUSION: Contemporary digital solutions for AD remain predominantly siloed and state-oriented rather than longitudinally integrated. We synthesize these observations into a conceptual Closed-Loop Architecture, proposed as a roadmap for future integrated digital dementia care. Advancing this agenda will depend on interoperable infrastructure, longitudinal modeling, and prospective cross-layer evaluation-not solely on further isolated gains in classification accuracy.},
}

@article {pmid42602264,
year = {2026},
author = {Tarbiat, S and Kantarci-Carsibasi, N},
title = {Dual inhibitory potential of N-methylcytisine against GSK-3β and AChE: implications for Alzheimer's disease treatment.},
journal = {Open life sciences},
volume = {21},
number = {1},
pages = {20251363},
pmid = {42602264},
issn = {2391-5412},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by memory loss and irreversible cognitive decline. Glycogen synthase kinase 3β (GSK-3β) is significant in tau hyperphosphorylation and neurodegeneration. The cholinergic hypothesis of AD links cognitive impairment to reduced synaptic acetylcholine (ACh). Increased acetylcholinesterase (AChE) activity exacerbates this issue. To search for a potential dual GSK-3β/AChE inhibitor, we focused on N-methylcytisine. This natural cytisine-derived alkaloid has not been studied for its various biological effects on the prevention of AD. The in vitro results indicated that N-methylcytisine displayed promising activity against GSK-3β and AChE with IC50 values of 11 and 22.7 µM, respectively. GSK-3β kinetic study according to the varying substrate or ATP concentrations at different N-methylcytisine levels revealed mixed-type inhibition. The results of the integrated in silico workflow indicate that N-methylcytisine exhibited favorable binding to AChE (docking score -9.6 kcal/mol; MM-GBSA -70.2 kcal/mol), comparable to the reference inhibitor galantamine (-10.8 kcal/mol; -70.6 kcal/mol). In contrast, its interaction with GSK-3β was more moderate (-5.3 kcal/mol; -50.3 kcal/mol) relative to staurosporine (-8.5 kcal/mol; -82.6 kcal/mol), consistent with its smaller scaffold. Overall, the results support a flexible, mixed-type interaction profile and highlight N-methylcytisine as a promising dual-acting candidate for Alzheimer's disease.},
}

@article {pmid42602282,
year = {2026},
author = {Gu, J and Chen, Z and He, Z},
title = {Refining genetic discoveries of group knockoffs via a feature-level filter.},
journal = {Journal of the Royal Statistical Society. Series C, Applied statistics},
volume = {75},
number = {4},
pages = {1067-1090},
pmid = {42602282},
issn = {0035-9254},
abstract = {Identifying variants that carry substantial information on the trait of interest remains a core topic in genetic studies. In analysing the EADB-UKBB dataset to identify genetic variants associated with Alzheimer's disease (AD), however, we recognize that both existing marginal association tests and conditional independence tests using existing knockoff filters suffer either power loss or lack of informativeness, especially when strong correlations exist among variants. To address these limitations, we propose a new feature-versus-group (FVG) filter that seeks balance between the power and precision in identifying important features from a set of strongly correlated features using group knockoffs. In extensive simulation studies, the FVG filter controls the expected proportion of false discoveries and identifies important features in smaller catching sets without large power loss. Applying the proposed method to the EADB-UKBB dataset, we discover important variants from 89 loci (similar to the most powerful group knockoff filter) with catching sets of substantially smaller size and higher purity and verify the biological informativeness of our discoveries.},
}

@article {pmid42602355,
year = {2026},
author = {Yang, G and Xu, X and Xu, Y},
title = {TREM2 as a central immunometabolic hub in Alzheimer's disease: linking microglial states, lipid stress, and disease-stage-specific intervention.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1893545},
pmid = {42602355},
issn = {1664-3224},
mesh = {Humans ; *Alzheimer Disease/metabolism/immunology/pathology ; *Receptors, Immunologic/metabolism/genetics/immunology ; *Microglia/metabolism/immunology ; *Membrane Glycoproteins/metabolism/genetics/immunology ; Animals ; *Lipid Metabolism ; Signal Transduction ; },
abstract = {Triggering receptor expressed on myeloid cells 2 (TREM2) plays a crucial role in regulating microglial function in Alzheimer's disease (AD) and other neurodegenerative disorders. Genetic studies have identified rare coding variants in TREM2 as significant risk factors for late-onset AD (LOAD), highlighting the importance of disrupted microglial signaling in disease pathogenesis. Biochemically, TREM2 acts as a receptor for lipid- and damage-associated molecular patterns, recognizing anionic phospholipids, myelin-derived lipids, apolipoproteins, and aggregated amyloid-β (Aβ). It engages with adaptors like DAP12 and DAP10, activating key signaling pathways, including SYK, PI3K-AKT-mTOR, and PLCγ2, leading to microglial transcriptional and metabolic reprogramming. These processes are essential for the transition of microglia to disease-associated microglia (DAM), influencing amyloid plaque compaction and tau pathology propagation. This review aims to synthesize the latest insights into TREM2 biology, focusing on the role of TREM2 in microglial state transitions, lipid metabolism, and myelin turnover. It also examines the pathophysiological relevance of soluble TREM2 (sTREM2) and AD-associated TREM2 variants. Furthermore, the review explores the therapeutic potential of targeting TREM2, including strategies based on agonistic antibodies and modulation of receptor shedding. Beyond prior descriptive summaries, we organize these findings within a stage-resolved immunometabolic framework that links disease timing, lipid-stress context, and microglial state transitions. This framework is intended to explain why similar TREM2-directed interventions may yield different outcomes across disease stages and pathology compositions. We further highlight stage-specific translational logic, including biomarker-informed (e.g., sTREM2-guided) stratification and monitoring, to support testable and clinically actionable trial designs.},
}

Humans
*Alzheimer Disease/metabolism/immunology/pathology
*Receptors, Immunologic/metabolism/genetics/immunology
*Microglia/metabolism/immunology
*Membrane Glycoproteins/metabolism/genetics/immunology
Animals
*Lipid Metabolism
Signal Transduction

@article {pmid42602413,
year = {2026},
author = {Kim, JW and Yeldesbay, A and Kehm, C and Fassbender, RV and Onur, OA and Rosjat, N and Fink, GR and Daun, S},
title = {Microstates and connectivity states reveal task-related network reorganization in Alzheimer's disease patients.},
journal = {Clinical neurophysiology practice},
volume = {11},
number = {},
pages = {664-676},
pmid = {42602413},
issn = {2467-981X},
abstract = {OBJECTIVE: Microstates derived from EEG amplitude and connectivity states from EEG phase examine distinct aspects of the brain's dynamic organization. However, it is unclear how sensitive they are to changes in functional connectivity in Alzheimer's disease (AD). We examined pre- and post-task alterations of brain activity in AD patients to compare the ability of microstates and connectivity states to capture disease-related network dysfunction.

METHODS: Resting-state EEG (RS-EEG) was recorded before and after a memory task in fifteen patients with AD and fifteen healthy controls. During the memory task, either low-intensity repetitive transcranial magnetic stimulation (rTMS) over the parieto-occipital region or sham stimulation was applied. We quantified microstates and phase-based connectivity states in the alpha frequency range from the RS-EEG.

RESULTS: While microstates showed task-related alterations in healthy controls only, connectivity states were more sensitive to alterations in the AD group. rTMS appeared to reduce these task-related alterations in connectivity states. Connectivity states indicated a shift towards lower, more diffuse connectivity in AD patients. Connectivity states were correlated with memory task performance and amyloid-beta levels in the AD group.

CONCLUSIONS: Connectivity states indicated decreased task-related network stability in AD patients, which correlated with memory task performance. The findings support the neural efficiency hypothesis, which states that more efficient brain network optimization during tasks is linked to better performance.

SIGNIFICANCE: Given the progressive decline of alpha power in AD patients, phase-based connectivity states provide valuable complementary information to microstates and may serve as a biomarker for assessing large-scale network alterations in relation to disease progression.},
}

@article {pmid42602524,
year = {2026},
author = {Dwivedi, AK and Imbimbo, BP and Abanto, J and Espay, AJ},
title = {Comparison of double-blind and open-label decline rates in lecanemab and donanemab trials in Alzheimer's disease.},
journal = {BMJ neurology open},
volume = {8},
number = {2},
pages = {e001649},
pmid = {42602524},
issn = {2632-6140},
abstract = {BACKGROUND: Phase 3 trials of the anti-amyloid monoclonal antibodies lecanemab and donanemab in Alzheimer's disease demonstrated modest slowing of cognitive decline over 18 months. Subsequent open-label extensions (OLE) suggested greater long-term benefit based on comparisons with historical untreated cohorts, which are vulnerable to selection and attrition bias.

METHODS: We simulated longitudinal Clinical Dementia Rating-Sum of Boxes trajectories using mixed-effects models calibrated to reproduce published means, variances and attrition patterns from the Clarity-AD and TRAILBLAZER-ALZ 2 trials, separately for early- and delayed-start cohorts and in combined analyses. Observed annualised slopes were also directly compared between double-blind (DB) and OLE phases. Placebo effects were estimated by comparing DB placebo arms with matched untreated historical cohorts derived from published natural history data.

RESULTS: Simulations closely reproduced reported trajectories. In both trials, the early-start cohorts showed significantly faster annualised decline during OLE than during DB treatment (lecanemab ∆=0.53; 95% CI 0.40 to 0.66; donanemab ∆=0.66; 95% CI 0.41 to 0.91), whereas delayed-start cohorts showed no meaningful phase-related differences. OLE decline rates approximated those observed in DB placebo groups. In the lecanemab trial, DB placebo participants declined more slowly than matched untreated controls; decline in the donanemab trial varied by baseline severity.

CONCLUSIONS: Despite selective retention favouring slower progressors, both lecanemab and donanemab accelerated cognitive decline during OLE phases and paralleled placebo-level declines.},
}

@article {pmid42602880,
year = {2026},
author = {Murugadoss, K and Venkatakrishnan, AJ and Soundararajan, V},
title = {GLP-1-based incretin therapy is associated with lower incident Alzheimer's disease and cardiorenal events in adults with documented neuropsychiatric, cognitive, or sensory risk.},
journal = {Biology methods & protocols},
volume = {11},
number = {1},
pages = {bpag043},
pmid = {42602880},
issn = {2396-8923},
abstract = {Alzheimer's disease (AD) develops over years, creating an opportunity for interventions that target modifiable risk factors before the onset of clinical dementia. Here we applied a federated electronic health record (EHR) system encompassing over 29 million de-identified patients toward a target-trial emulation framework involving 153,412 adults aged 50 years or older with at least one documented AD risk factor. New users of glucagon-like peptide-1 (GLP-1)-based incretin therapy were compared with new users of non-GLP-1 antidiabetic medications after a 12-month washout, with 1:1 propensity-score matching on 30 baseline variables and additional exact matching on index year of therapy initiation and 5-year age band. In the primary matched cohort, 28,901 patients per arm, incretin initiation was associated with lower first recorded AD diagnosis (hazard ratio [HR] 0.46, 95% confidence interval [CI] 0.29-0.73, q = 0.003), all-cause dementia (HR 0.66 [0.55-0.79], q < 0.001), and all-cause mortality (HR 0.46 [0.37-0.58], q < 0.001), with directionally-lower Mild Cognitive Impairment (HR 0.76 [0.61-0.94], q = 0.135) and Alzheimer's-related medication initiation (HR 0.82 [0.65-1.03], q = 0.217). The AD diagnosis mitigation signal was independently reproduced for semaglutide (HR 0.56; N = 23,675 per arm; q = 0.02), with the directionally consistent tirzepatide point estimate (HR 0.60) not reaching significance. GLP-1 RA initiation was also associated with substantially lower (all q < 0.001) incidence of heart failure (HR 0.50 [0.45-0.55]), cardiomyopathy (HR 0.38 [0.31-0.47]), major adverse cardiovascular events (HR 0.74 [0.67-0.82]), acute kidney injury (HR 0.67 [0.67-0.74]), and chronic kidney disease (HR 0.68 [0.62-0.75]). Negative-control outcomes showed no significant separation (all q > 0.45), including allergic rhinitis (HR 0.96 [0.87-1.07]), hemorrhoids (HR 1.07 [0.95-1.21]), and inguinal hernia (HR 1.39 [0.89-2.18]). Stricter two-code ICD definitions supported lower first recorded AD diagnosis in the incretin arm (HR 0.51 [0.29-0.89], q = 0.018) and lower first recorded all-cause dementia diagnosis (HR 0.68 [0.54-0.85], q = 0.003). In 12-month landmark analyses among semaglutide initiators, ≥5% weight-loss responders had lower 3-year AD cumulative incidence than non-responders after matching (0.07% vs. 0.40%; incidence ratio 5.76; P = .036), although this was not significant in the hazard-ratio model (HR 0.54, P = .39). Sustained-dose stratification showed no comparable gradient (high-dose vs. low-dose 0.30% vs. 0.14%; HR 2.77; P = .38), with ≤12 AD events per group. The weight-loss-specific pattern did not extend to all-cause dementia: weight-loss responders and non-responders had similar 3-year cumulative incidence (1.54% vs. 1.70%; HR 0.87, P = .53). Initiation of GLP-1 receptor agonist therapy in adults with documented AD risk factors was associated with lower recorded incidence of AD, dementia, mortality, and multiple cardiovascular and renal outcomes in this observational target-trial emulation. These findings support the hypothesis that earlier incretin therapy may contribute to AD risk modification through upstream cardiometabolic pathways, while prospective randomized prevention studies will be required to determine causality, underlying biological mechanisms, and optimal treatment timing.},
}

@article {pmid42602999,
year = {2026},
author = {Rauhala, E and Johansson, J and Karrasch, M and Eskola, O and Tolvanen, T and Rajander, J and Rinne, JO},
title = {Change in brain glucose metabolism and cognition in amnestic MCI patients in relation to amyloid accumulation: A 3-year follow-up study.},
journal = {Aging brain},
volume = {10},
number = {},
pages = {100165},
pmid = {42602999},
issn = {2589-9589},
abstract = {Our aim was to investigate the change in brain glucose metabolism with [[18]F]fluorodeoxyglucose positron emission tomography ([[18]F]FDG PET) in amyloid beta positive and negative amnestic mild cognitive impairment (aMCI) patients. We investigated associations between change in [[18]F]FDG uptake and cognitive functioning in aMCI patients over up to 3 years. Twenty patients underwent [[18]F]FDG PET (15 men and 5 women, mean age 73.0 years, SD 6.3 at baseline) within a short time interval from [[18]F]Flutemetamol PET. The patients were classified as amyloid positive vs. negative based on the amyloid PET marker [[18]F]Flutemetamol uptake. Patients were examined with brain MRI and cognitive tests at baseline and after 3-year follow-up or earlier if the patient had converted to probable Alzheimer's disease. [[18]F]FDG data was analysed with automated region-of-interest analysis and voxel-based statistical parametric mapping (SPM). [[18]F]FDG uptake nor change of [[18]F]FDG uptake over time differed between amyloid positive and negative groups. However, the amyloid positive patients exhibited significant decline in MMSE scores over three years while the amyloid negative patients maintained stable MMSE level over time. The amyloid positive group had poorer episodic memory scores at baseline and follow-up, and significantly slower processing speed at follow-up as well as significantly more negative change over time in language functions compared to amyloid negative patients. Moreover, we found that [[18]F]FDG uptake was positively associated with cognition in the whole aMCI patient group. Together, our results suggest that brain glucose metabolism in aMCI is independent of amyloid pathology, and probably reflects other brain degenerative processes.},
}

@article {pmid42603243,
year = {2026},
author = {Anwer, T and Verma, A and Asiri, A and Alaklobie, M and Albaqami, A and Alshahrani, F and Aly, K and Sharma, M and Siddiqui, S and Alam, N and Alam, MF},
title = {Restoration of Neuronal Metabolism and Memory in Alzheimer's Disease by Reprogramming the Exosomal microRNA Network.},
journal = {Journal of molecular neuroscience : MN},
volume = {76},
number = {3},
pages = {},
pmid = {42603243},
issn = {1559-1166},
mesh = {Humans ; *Alzheimer Disease/metabolism/genetics ; *MicroRNAs/metabolism/genetics ; *Exosomes/metabolism/genetics ; Animals ; *Neurons/metabolism ; Neuronal Plasticity ; *Memory ; },
abstract = {Historically the development of amyloid-β plaques and tau neurofibrillary tangles have been used as the hallmarks of Alzheimer's disease (AD). However, there is increasing evidence suggests that these pathological hallmarks are secondary to deeper metabolic defect in the brain. AD is progressively being recognized as a metabolic synaptic disorder characterized by insulin resistance, impaired cellular energy homeostasis, mitochondrial dysfunction, and synaptic degeneration. Synaptic plasticity is closely linked to the insulin-sensitive system of glucose utilization, mitochondrial activity, and local protein synthesis that render the synapses highly sensitive to the malfunction of the metabolic system. Recent discoveries highlight the important role of exosomes in mediating communication between neural cells by transferring regulatory miRNAs across neuronal networks. Exosomal miRNAs regulate insulin signaling, synaptic gene expression, mitochondrial function, and neuroinflammation. In AD, exosomal miRNA profiles are significantly altered, with enrichment of miR-29, miR-34a, miR-146a, and miR-21, alongside depletion of synapse-supporting miR-132. These changes contribute to insulin resistance, impaired glucose transporter trafficking, dendritic spine destabilization, and reduced expression of synaptic proteins such as PSD-95 and synaptophysin, ultimately leading to cognitive decline. Importantly, neuron-derived exosomes can cross the blood-brain barrier, making their miRNA cargo promising biomarkers and therapeutic targets for early AD diagnosis and precision treatment.},
}

Humans
*Alzheimer Disease/metabolism/genetics
*MicroRNAs/metabolism/genetics
*Exosomes/metabolism/genetics
Animals
*Neurons/metabolism
Neuronal Plasticity
*Memory

@article {pmid42603367,
year = {2026},
author = {Besser, LM and Mitsova, D and Carmichael, O and Bateman, JR and Lovasi, GS and Tourelle, M and Galvin, JE and Chang, LC and DeCarli, C and Morris, JC and Meyer, OL},
title = {Neighborhood greenspace and brain imaging outcomes in older adults without dementia from three US Alzheimer's Disease Research Centers.},
journal = {Health & place},
volume = {101},
number = {},
pages = {103731},
doi = {10.1016/j.healthplace.2026.103731},
pmid = {42603367},
issn = {1873-2054},
abstract = {Although mounting evidence supports that neighborhood greenspaces (e.g., trees and parks) may benefit cognitive health in older age, fewer studies have investigated benefits to brain health measured via magnetic resonance imaging (MRI). We used data on 892 older adults without dementia from three Alzheimer's Disease Research Centers, examining whether neighborhood greenspace (i.e., greenness and percentage park space) is associated with white matter hyperintensity (WMH) and hippocampal volumes from MRI. We also examined whether associations varied by sex, racial group, urbanicity, or apolipoprotein E genotype (genetic risk factor for Alzheimer's disease). Linear regression models that accounted for neighborhood clustering controlled for demographics, research center, cognitive function, neighborhood deprivation, and comorbidities (e.g., hypertension, diabetes, obesity). Interaction terms (e.g., greenness×sex) were added to the models to evaluate potential effect modification. Living in greener neighborhoods was associated with fewer WMH and greater hippocampal volume in the overall sample. In stratified analyses, the beneficial greenness-WMH association was restricted to Black (not White) participants (i.e., significant interaction). In contrast, an adverse association between park space and lower hippocampal volumes was detected among Black (not White) participants (i.e., significant interaction). Overall, this study suggests associations between living in neighborhoods with more greenspace and MRI biomarkers of lower cerebrovascular and dementia risk, although results were mixed for Black individuals. Our findings need replication in other cohorts that are ethnoracially diverse and that represent different geographic regions, and future studies are needed explain the counterintuitive associations between park space and hippocampal volume among Black older adults.},
}

@article {pmid42603521,
year = {2026},
author = {Ma, J and Hua, Z and Zhao, B and Xu, J and Bao, K and Guo, R},
title = {Generation of a human induced pluripotent stem cell line (HEBHMUi019-A) from a 67-year-old male Alzheimer's patient with APOE-ε4/ε4 genotype.},
journal = {Stem cell research},
volume = {95},
number = {},
pages = {104082},
doi = {10.1016/j.scr.2026.104082},
pmid = {42603521},
issn = {1876-7753},
abstract = {Apolipoprotein E (apoE), encoded by the polymorphic APOE gene, plays a key role in lipid transport and metabolism. The three major APOE alleles are ε2, ε3, and ε4, with ε4 being the strongest genetic risk factor for late-onset Alzheimer's disease. We generated human induced pluripotent stem cells from peripheral blood mononuclear cells of a 67-year-old male patient with Alzheimer's disease carrying the APOE ε4/ε4 genotype. The generated cell line displayed typical iPSC morphology, a normal karyotype, trilineage differentiation potential, and pluripotency-marker expression, providing a resource for investigating APOE ε4-associated disease mechanisms and preclinical therapeutic screening.},
}

@article {pmid42603526,
year = {2026},
author = {Wang, M and Guo, M and Li, S and Song, L and Wu, M and Zhao, J and Xu, T and Zhou, Y},
title = {Kaempferol attenuates microglial activation in Alzheimer's disease via inhibiting the cytosolic HK2-mediated NF-κB signaling pathway.},
journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology},
volume = {160},
number = {},
pages = {158708},
doi = {10.1016/j.phymed.2026.158708},
pmid = {42603526},
issn = {1618-095X},
abstract = {INTRODUCTION: Kaempferol (KAE), a natural flavonoid with substantial anti-inflammatory activity, has demonstrated efficacy against Alzheimer's disease (AD). However, the fundamental mechanisms are not yet fully understood.

OBJECTIVES: The objective of this study was to elucidate the role of KAE in alleviating microglia-mediated neuroinflammation in AD and its underlying mechanisms.

METHODS: The 3 × Tg-AD mice and LPS-stimulated BV2 microglial cells were employed as in vivo and in vitro model respectively. The HK-TAT peptide was utilized to induce mitochondrial dissociation of HK2, and 3-BP was applied as a HK2 inhibitor. Transcriptomic and metabolomic analyses were performed to discover the inhibitory effect of KAE on HK2. Immunofluorescence and Western blotting were employed to explore the suppressive role of KAE in cytosolic HK2-mediated NF-κB signaling. Additionally, the interaction between KAE and HK2 was investigated through molecular docking, validated by SPR, and confirmed via CETSA.

RESULTS: Our findings demonstrated that KAE significantly attenuated LPS-induced microglial activation, along with the release of pro-inflammatory factors and enhanced glycolytic activity. In vivo, KAE partially rescued cognitive impairment and neuronal damage in 3 × Tg-AD mice. Microglial activation was also markedly suppressed. Mechanistically, we revealed that dissociation of HK2 from mitochondria to the cytosol was sufficient to induce microglial activation, and this process was consequently constrained by the suppression of HK2 level and activity using 3-BP. By reducing HK2 levels, KAE suppressed cytosolic HK2-mediated IκBα phosphorylation and subsequent nuclear translocation of NF-κB. Furthermore, KAE not only downregulated HK2 transcription but also bound to HK2, promoting its ubiquitination-mediated degradation.

CONCLUSION: Our data indicate that KAE alleviates microglia-mediated neuroinflammation in AD, which correlates with the suppression of HK2 and the modulation of cytosolic HK2-dependent NF-κB activation.},
}

@article {pmid42603539,
year = {2026},
author = {Dişli, A and Tan, B and Adem, Ş and Akdoğan, N and Rawat, R and Eyüpoğlu, V},
title = {Phenothiazine-tetrazole hybrids as potent cholinesterase inhibitors: Integrated experimental and computational insights for Alzheimer's therapy.},
journal = {Bioorganic chemistry},
volume = {181},
number = {},
pages = {110350},
doi = {10.1016/j.bioorg.2026.110350},
pmid = {42603539},
issn = {1090-2120},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by neuronal loss and cognitive decline. A key pathological feature of AD is the reduction of acetylcholine (ACh) levels resulting from the enzymatic activity of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Therefore, inhibition of these enzymes remains a well-established therapeutic strategy for AD management. In this study, a novel series of phenothiazine-tetrazole hybrids was designed and synthesized as potential cholinesterase inhibitors. Their inhibitory activities against AChE and BChE were evaluated in vitro, and IC50 values were determined in the micromolar range. Among the tested derivatives, Compound E3a (IC50 = 10.664 μM) and Compound E5b (IC50 = 10.315 μM) exhibited the strongest AChE inhibition, whereas Compound D5b showed the highest activity toward BChE (IC50 = 18.734 μM). Enzyme kinetic analysis revealed that E5b and E3a act as competitive AChE inhibitors, with Ki values of 1.313 ± 0.032 μM and 1.520 ± 0.033 μM, respectively. To elucidate the molecular basis of inhibition, molecular docking studies were performed, followed by 500 ns molecular dynamics simulations, MM-PBSA binding free energy calculations, and free energy landscape analyses. The computational results revealed that Compound E3a forms a more dynamically and thermodynamically stabilized complex with AChE, primarily driven by favorable van der Waals interactions. ADMETlab 3.0 predictions further indicated acceptable preliminary drug-like features, although lipophilicity, solubility, CYP liability, and toxicity-related endpoints require further optimization and experimental validation. Collectively, these findings highlight phenothiazine-tetrazole hybrids as promising scaffolds for the rational development of next-generation cholinesterase inhibitors for Alzheimer's therapy.},
}

@article {pmid42603633,
year = {2026},
author = {Choi, HS and Jeon, SH and Liu, H and Kim, M and Yu, JS and Yoo, SS and Son, DJ and Han, SB and Yeo, IJ and Lim, SC and Hong, JT},
title = {p53 deficiency increases vulnerability to chronic stress-induced anxiety- and depression-like behaviors: Role of calcium dysregulation and BDNF signaling.},
journal = {Behavioural brain research},
volume = {},
number = {},
pages = {116437},
doi = {10.1016/j.bbr.2026.116437},
pmid = {42603633},
issn = {1872-7549},
abstract = {The tumor suppressor protein p53 is a known modulator of neurodegenerative disease (ND) processes. Although p53 expression is increased in the brains of patients with Alzheimer's disease, Parkinson's disease, and ischemic stroke, its role in mood disorders such as anxiety and depression remains unclear. To investigate the role of p53 in behavioral responses to chronic stress, we examined behavioral and molecular alterations in p53 knockout (p53[-/-]) mice and wild type mice. In p53[-/-] mice, increased vulnerability to chronic unpredictable mild stress (CUMS)-induced anxiety- and depression-like behaviors was observed following CUMS exposure. In parallel with these behavioral changes, BDNF expression was reduced, whereas glutamate levels were elevated in the prefrontal cortex of p53[-/-] mice. Increased calcium-associated staining and NMDAR2B expression were observed together with increased neuronal injury- and cell death-related markers. In primary cortical neurons derived from p53[-/-] mice, corticosterone treatment resulted in greater increases in glutamate levels, NMDAR2B expression compared to wild-type controls. Cell death markers (cleaved caspase-3, p-p38, p-JNK) were upregulated, while neuroprotective signals (BDNF, p-Akt, p-ERK, p-CREB) were suppressed in p53[-/-] mice, and corticosterone-treated primary neuronal cells from p53[-/-] mice. These findings indicate that p53 deficiency is associated with enhanced vulnerability to CUMS-induced anxiety- and depression-like behaviors and is accompanied by alterations in calcium handling, glutamate homeostasis, neuronal injury-related markers, and BDNF-associated neuroprotective signaling.},
}

@article {pmid42603674,
year = {2026},
author = {Motoyoshi, M and Nagai, J},
title = {Astrocyte engineering.},
journal = {Neuroscience research},
volume = {},
number = {},
pages = {105103},
doi = {10.1016/j.neures.2026.105103},
pmid = {42603674},
issn = {1872-8111},
abstract = {Tiling across the central nervous system, astrocytes contact synapses, blood vessels and other glial cells through highly specialised processes, allowing them to regulate local brain environments across multiple spatial and temporal scales. These anatomical and signalling features make astrocytes attractive substrates for modulating brain function and repair. Here, we frame "astrocyte engineering" as the intentional design of molecular access, sensing and effector modules in astrocytes to interrogate or modify local brain states. This Review focuses on how astrocyte interface biology can be converted into engineering logic, from genetic access and signalling perturbation to emerging sensor-effector designs. We first outline how astrocyte morphology, diversity and intercellular interactions shape the logic of cell-specific targeting. We then summarise tools for astrocyte-specific gene delivery and signalling control, including adeno-associated virus (AAV)-based strategies and G-protein coupled receptor (GPCR) signalling modulation approaches that can alter disease-relevant phenotypes. Further, we discuss recent proof-of-concept studies that equip astrocytes with new recognition or effector functions, including chimeric antigen receptor (CAR) astrocytes, synNotch-based systems, and trophic-factor delivery. We propose that future astrocyte engineering should be guided by omics-based design principles that link cell state, molecular access, input recognition, and effector selection.},
}

@article {pmid42603776,
year = {2026},
author = {Tang, FL and Huang, LJ and Wang, YX and Wang, SM and Ji, WS and Gao, F and Sun, L and Xu, JB},
title = {Novel C3-Aminated Galantamine Derivatives as Selective Butyrylcholinesterase Inhibitors With Neuroprotective Effects.},
journal = {ChemMedChem},
volume = {21},
number = {16},
pages = {e70431},
pmid = {42603776},
issn = {1860-7187},
support = {82404470//National Natural Science Foundation of China/ ; 2025ZNSFSC1731//Natural Science Foundation of Sichuan Province/ ; 2682026CX101//Fundamental Research Funds for the Central Universities/ ; },
mesh = {*Cholinesterase Inhibitors/pharmacology/chemistry/chemical synthesis ; *Galantamine/pharmacology/chemistry/chemical synthesis/analogs & derivatives ; *Neuroprotective Agents/pharmacology/chemistry/chemical synthesis ; *Butyrylcholinesterase/metabolism ; Humans ; Structure-Activity Relationship ; Molecular Docking Simulation ; Molecular Structure ; Hydrogen Peroxide/pharmacology/antagonists & inhibitors ; Apoptosis/drug effects ; Dose-Response Relationship, Drug ; Cell Line, Tumor ; Oxidative Stress/drug effects ; Molecular Dynamics Simulation ; },
abstract = {To explore natural-inspired novel anti-AD bioactive molecules, a series of galantamine derivatives 6a-6u were synthesized via Pd-catalyzed Buchwald-Hartwig cross-coupling, with various nitrogen-containing functional groups installed at the C3 position of galantamine. Compared with galantamine, these compounds showed greatly enhanced selective BChE inhibition activity, suggesting that the C3 position of galantamine might be a key modifiable site for developing new selective BChE inhibitors. Among them, the derivative 6l which contained a 3,5-difluoroaniline structure moiety exhibited promising selective inhibitory activity against eqBChE, with an IC50 of 0.88 μM and a selectivity index of 26.2. Molecular docking and molecular dynamics simulations were performed to elucidate the interaction model between compound 6l and BChE. Moreover, 6l also showed favorable neuroprotection potency against H2O2 injured SH-SY5Y cells. Preliminary mechanistic study revealed that compound 6l could mitigate oxidative stress and suppress cellular apoptosis. This work not only offers a novel galantamine analog with promising in vitro cholinesterase inhibitory and neuroprotective effects for further anti-AD study, but also provides new insights into the structure optimization of natural drug galantamine.},
}

*Cholinesterase Inhibitors/pharmacology/chemistry/chemical synthesis
*Galantamine/pharmacology/chemistry/chemical synthesis/analogs & derivatives
*Neuroprotective Agents/pharmacology/chemistry/chemical synthesis
*Butyrylcholinesterase/metabolism
Humans
Structure-Activity Relationship
Molecular Docking Simulation
Molecular Structure
Hydrogen Peroxide/pharmacology/antagonists & inhibitors
Apoptosis/drug effects
Dose-Response Relationship, Drug
Cell Line, Tumor
Oxidative Stress/drug effects
Molecular Dynamics Simulation

@article {pmid42603781,
year = {2026},
author = {Kaleem, M and Raza, A and Kalpina, FNU and Fatima, M and Batool, SJ and Haider, B and Rashid, H and Jamal, M and Turkmani, M and Khan, U},
title = {Rising Comorbid Alzheimer's and Hypertension Mortality in Older Adults in the United States: Trends and Disparities From a 21-Year CDC WONDER Analysis (1999-2019).},
journal = {Journal of clinical hypertension (Greenwich, Conn.)},
volume = {28},
number = {8},
pages = {e70348},
pmid = {42603781},
issn = {1751-7176},
mesh = {Humans ; United States/epidemiology ; *Alzheimer Disease/mortality/epidemiology ; Female ; Aged ; *Hypertension/mortality/epidemiology/complications ; Male ; Aged, 80 and over ; Risk Factors ; Comorbidity/trends ; },
abstract = {Hypertension, affecting nearly half of US adults, is a significant modifiable risk factor for Alzheimer's disease (AD), the fifth leading cause of death among Americans aged 65 and older. Hypertension contributes to AD through microvascular damage, reduced cerebral perfusion and neuroinflammation, leading to cognitive decline and dementia. This study examines US national trends and disparities in mortality due to comorbid AD and hypertension in older adults (≥65 years) using CDC WONDER data from 1999-2019. Age-adjusted mortality rates (AAMRs) per 100 000 individuals and crude rates (CRs) were determined. Joinpoint regression was used to calculate Annual Percentage Changes (APCs) and Average Annual Percentage Changes (AAPCs). A total of 372 839 deaths occurred, increasing from 4948 to 27 257 annually (1999-2019). AAMRs rose from 14.51 to 53.13, with an AAPC of 6.16%. Females (47.09) had higher AAMRs than males (33.80). Non-Hispanic Blacks experienced the highest mortality rates (54.82), while NH Asians had the lowest (28.14); Hispanics experienced the highest AAPC (6.81). The 85+ age group bore the greatest mortality burden (AAPC: 6.84%). Most deaths (60.05%) occurred in hospice/nursing facilities. Mortality was highest in the West (AAMR: 50.28) and lowest in the Northeast (27.00). Mississippi had the highest, Massachusetts the lowest state-level mortality burden. Non-metropolitan areas exceeded metropolitan AAMRs (47.89 vs. 41.28). Targeted interventions are needed to counter observed trends, addressing hypertension as a key manageable risk factor for AD prevention.},
}

Humans
United States/epidemiology
*Alzheimer Disease/mortality/epidemiology
Female
Aged
*Hypertension/mortality/epidemiology/complications
Male
Aged, 80 and over
Risk Factors
Comorbidity/trends

@article {pmid42604096,
year = {2026},
author = {Bayly, H and Salvati, L and Lenio, S and Mez, J and Alosco, ML and Tripodis, Y},
title = {Evaluating inclusion of continuous multivariable cognitive scores for operational enrichment of preclinical Alzheimer's disease trials: a retrospective emulation study.},
journal = {JAR life},
volume = {15},
number = {},
pages = {100081},
pmid = {42604096},
issn = {2534-773X},
abstract = {BACKGROUND: Prevention trials for Alzheimer's Disease face significant challenges due to the slow and uncertain rate of cognitive decline in asymptomatic, amyloid-positive individuals. Biomarker positivity alone does not guarantee clinically meaningful progression, often leaving studies underpowered.

OBJECTIVES: Evaluate model-based operational trial enrichment within an amyloid-positive, cognitively normal subgroup.

METHODS: Trained on a small cohort from the National Alzheimer's Coordinating Center (N = 113), with external validation using baseline data of a similar small cohort from the Alzheimer's Disease Neuroimaging Initiative (N = 161). Gradient-boosted decision trees estimated progression risk and projected power under alternative enrollment strategies. Predictors included neuropsychological scores, demographics, medical history, and ApoE ε4 genotype. The primary outcome was clinical progression to cognitive impairment within 1- and 3-year follow-up windows.

RESULTS: In the independent testing set, the model successfully increased the effective prevalence of the outcome. The Positive Predictive Value for the 1-year window was 0.27 (a 35% relative increase over the 0.20 baseline prevalence) and 0.43 for the 3-year window (a 23% relative increase over the 0.35 baseline). Power simulations for an emulated trial (N = 500) demonstrated that this enrichment strategy consistently increased statistical power, potentially reducing the required sample size to achieve 80% power by up to 32% for small treatment effect sizes.

CONCLUSIONS: This operational methodology functions as a screening filter to optimize event rates within a highly specific, preselected trial population.},
}

@article {pmid42604767,
year = {2026},
author = {Furuta, M and Ohara, T and Sakata, S and Shibata, M and Oishi, E and Furuta, Y and Kageyama, S and Asakawa, M and Shimazaki, Y and Takeshita, T and Ninomiya, T},
title = {Periodontal Status and the Risk of All-Cause Dementia, Alzheimer's Disease and Vascular Dementia in a Community: The Hisayama Study.},
journal = {Journal of clinical periodontology},
volume = {},
number = {},
pages = {},
doi = {10.1111/jcpe.70185},
pmid = {42604767},
issn = {1600-051X},
support = {24K13242//Japan Society for the Promotion of Science/ ; 23FA1022//Health and Labor Sciences Research Grants of the Ministry of Health, Labor and Welfare of Japan/ ; },
abstract = {AIM: This study examined the associations of periodontal status with incident dementia and its subtypes in a Japanese community.

MATERIALS AND METHODS: The 1396 participants aged ≥ 60 years without dementia were followed for 10 years. Periodontal status at baseline and 5 years was assessed using mean probing pocket depth (PPD), clinical attachment level (CAL) and percentage of bleeding on probing (%BOP), categorized into quartiles. Cox proportional hazards and time-varying Cox models were used.

RESULTS: During follow-up, 267 participants developed dementia; 194 and 51 had Alzheimer's disease (AD) and vascular dementia (VaD), respectively. Compared with the lowest quartile, the highest quartiles of PPD, CAL and %BOP at baseline were associated with increased dementia risk (hazard ratio 1.72 [95% confidence interval 1.18-2.46], 1.59 [1.07-2.38] and 1.56 [1.09-2.22], respectively, all p for trend < 0.05). Elevated %BOP was associated with AD risk (p for trend = 0.023). Higher PPD tended to be associated with VaD (p for trend = 0.076). Similar associations for all-cause dementia were observed in time-varying Cox analyses.

CONCLUSIONS: Poor periodontal status was associated with dementia in older Japanese adults. These findings highlight the potential public health importance of preventing periodontitis to reduce the risk of dementia.},
}

@article {pmid42604943,
year = {2026},
author = {Molnar, FJ},
title = {Those Debating Alzheimer Disease Modifying Therapies Should Review the Seminal JAGS Dementia Minimal Clinically Important Difference Article.},
journal = {Journal of the American Geriatrics Society},
volume = {},
number = {},
pages = {},
doi = {10.1111/jgs.70657},
pmid = {42604943},
issn = {1532-5415},
}

@article {pmid42604981,
year = {2026},
author = {Falcone, C and Arckens, L and Baiula, M and Bedini, A and Bocchi, R and Broadhead, MJ and Caprini, M and Cavaliere, F and Cesca, F and Chowdhury, HH and Ciuba, K and Civiero, L and Escartin, C and Ferroni, S and Formaggio, F and Frasca, A and Gratton, R and Holt, M and Iraci, N and Kreft, M and Leggio, L and Lia, A and Malik, AR and Min, R and Müller, FE and Murat, C and Pereira, MJ and Pekowska, A and Petrelli, F and Ramos-Gonzalez, P and Sanchez-Mico, MV and Smole, Z and Sokolova, D and Solas, M and Soldano, A and Szewczyk, LM and Torazza, C and Severino, FPU and Urrestizala-Arenaza, N and Zeug, A and Zhou, J and Zonta, M and Zorec, R and Verkhratsky, A and Gunhanlar, N},
title = {Written in the Stars: Astrocyte Biology From Evolution to Disease.},
journal = {Acta physiologica (Oxford, England)},
volume = {242},
number = {9},
pages = {e70289},
doi = {10.1111/apha.70289},
pmid = {42604981},
issn = {1748-1716},
support = {CNS2025-166813//MICIU/AEI (Ministerio de Ciencia, Innovación y Universidades/Agencia Estatal de Investigación, Spain)/ ; RYC2021-033202-I//MICIU/AEI (Ministerio de Ciencia, Innovación y Universidades/Agencia Estatal de Investigación, Spain)/ ; PID2023-146385NA-I00//MICIU/AEI (Ministerio de Ciencia, Innovación y Universidades/Agencia Estatal de Investigación, Spain)/ ; PID2024-160537OB-I00//MICIU/AEI (Ministerio de Ciencia, Innovación y Universidades/Agencia Estatal de Investigación, Spain)/ ; 951923//European Commission (H2020)/ ; //European Union - NextGenerationEU/PRTR/ ; 2023.17564.ICDT//FCT (Fundação para a Ciência e a Tecnologia, Portugal)/ ; UMO-2018/01/H/NZ4/00001//National Science Centre (NCN, Poland)/ ; UMO-2021/43/B/NZ2/02934//National Science Centre (NCN, Poland)/ ; UMO-2021/42/E/NZ2/00392//National Science Centre (NCN, Poland)/ ; UMO-2023/51/D/NZ3/02998//National Science Centre (NCN, Poland)/ ; 2024/54/E/NZ4/00134//National Science Centre (NCN, Poland)/ ; 2024/53/B/NZ4/03058//National Science Centre (NCN, Poland)/ ; A2023021F//BrightFocus Foundation/ ; 2023.00418.BD//Fundação para a Ciência e a Tecnologia (FCT) doctoral fellowship/ ; G0C9922N//KU Leuven Research Council (C14/20/071) and the Research Foundation Flanders (FWO), Belgium/ ; },
mesh = {Humans ; *Astrocytes/physiology/pathology ; Animals ; *Biological Evolution ; *Brain ; *Neurodegenerative Diseases/metabolism/pathology ; *Nervous System Diseases ; },
abstract = {In the 21st century, neuroglial research has entered a period of Renaissance, extending the views of prominent neuroanatomists and neurologists of the 19th and early 20th centuries, who assigned to glial cells numerous physiological functions and highlighted their fundamental role in the pathophysiology of nervous system diseases. Astrocytes are highly diversified in structure and function; they control brain homeostasis, support synaptic connectivity, and enable information processing in neural networks. Evolutionary diversification of astrocytes, initially emerging as supportive cells of primitive sensory organs, drove a continuous expansion of astroglial complexity and functional versatility, ultimately making them indispensable neuroprotectors and homeostatic regulators. The large, morphologically elaborate astrocytes of the human brain arguably reflect an evolutionary response to increased neuronal homeostatic demands. Astrocytes are indispensable for synaptic function, serving as the principal regulators of neurotransmitter turnover and neuronal excitability. Astrocytes also govern brain energy metabolism, mitochondrial dynamics, and calcium signaling, thereby actively shaping cortical plasticity and circuits. Astrocytes are fundamental elements of the pathophysiology of neurological, neuropsychiatric, and neurodegenerative diseases, including Alzheimer's and Parkinson's disease, amyotrophic lateral sclerosis, Rett syndrome, genetic astrocytopathies, and neurotrauma, where they demonstrate complex reactive changes directed at tissue preservation and regeneration, but which can also contribute to disease progression. Advances in single-cell transcriptomics, calcium imaging, chemogenetics, and iPSC-based models have transformed our understanding of astrocyte diversity and disease-specific dysfunction, opening new avenues of investigation. Given that no CNS disorder is known to occur without astrocyte involvement, multiple astrocyte-specific molecules represent compelling targets for cell-directed therapeutic strategies.},
}

Humans
*Astrocytes/physiology/pathology
Animals
*Biological Evolution
*Brain
*Neurodegenerative Diseases/metabolism/pathology
*Nervous System Diseases

@article {pmid42605027,
year = {2026},
author = {Duijkers, S and Ter Huurne, DBG and Blom, M and Bodde, HE and Dobbe, JHM and Van der Flier, W and Jansen, WJ and Olde Rikkert, M and Papma, JM and Verhey, FRJ and Ramakers, IHGB},
title = {Current Practice and Long-Term Developments in Multidisciplinary Dutch Memory Clinics.},
journal = {Journal of geriatric psychiatry and neurology},
volume = {},
number = {},
pages = {8919887261478290},
doi = {10.1177/08919887261478290},
pmid = {42605027},
issn = {1552-5708},
abstract = {ObjectivesMemory Clinics (MCs) have a central role in multidisciplinary diagnostics and care of cognitive disorders and dementia. This study describes current clinical practice and developments of Dutch MCs since their start in 1986.MethodsA survey was sent to all Dutch hospital-based MCs in 1998, 2004, 2009, 2017 and 2023. Topics included: organization, patient characteristics, scales and questionnaires, neuropsychological assessment, additional assessments, novel biomarkers, disclosure of diagnosis and treatment. 74 out of the total of 89 MCs completely or partially filled out the questionnaire.ResultsThe number of MCs increased to 89. The number of patients seen increased substantially (per MC/year: 1998: 130; 2023: 324; total: 1998: 1560; 2023: 28,848). The proportion of patients diagnosed with dementia decreased from 80% in 1998 to 47% in 2023. Most commonly available assessments were neuroimaging (100%), routine laboratory testing of blood (98%) and neuropsychological assessment (NPA; 98%). Thirty-one percent indicated infrastructure needed to be changed before prescribing monoclonal antibody treatments for Alzheimer's disease.ConclusionsMCs showed substantial development in number, number of patients and geographical distribution within the country. Nowadays, MCs are central care facilities for the timely and multidisciplinary diagnosis and treatment of people with cognitive disorders and dementia.},
}

@article {pmid42605139,
year = {2026},
author = {Javed, MN and Khan, SM and Mustafa, S and Mujtaba, A and Amin, H and Azhar, N and Hameed, A and Zayed, A and Khalid, M and Hussain, JM},
title = {Gantenerumab for Early Alzheimer's Disease: An Updated Systematic Review and Meta-Analysis.},
journal = {Brain and behavior},
volume = {16},
number = {8},
pages = {e71643},
doi = {10.1002/brb3.71643},
pmid = {42605139},
issn = {2162-3279},
mesh = {Humans ; *Alzheimer Disease/drug therapy ; *Antibodies, Monoclonal, Humanized/therapeutic use/pharmacology ; Randomized Controlled Trials as Topic ; Amyloid beta-Peptides ; },
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with limited treatment options. Gantenerumab, a β-amyloid-targeting monoclonal antibody, has shown mixed clinical results. With new trial data available, this updated systematic review and meta-analysis re-evaluates its efficacy and safety in early AD.

METHODS: Registered on PROSPERO (CRD420251082463) under PRISMA guidelines, we searched PubMed, Cochrane Library, and Google Scholar from inception to October 2025 for randomized trials in early AD comparing gantenerumab with placebo. A random-effects model assessed pooled outcomes with heterogeneity (I[2]) and sensitivity analyses. Additionally, meta-regression and certainty of evidence using Gradepro were performed. Risk of bias was evaluated using the Cochrane tool. An Institutional Review Committee (IRC) and its Ethical Review Board (ERB) approval was not required.

RESULTS: Six trials (3103 participants: 1718 gantenerumab; 1385 placebo) were included. Gantenerumab showed no significant effect on CDR-SB (MD = -0.07; 95% CI: -0.34-0.20; p = 0.62; I[2] = 16%) but produced small improvements in FAQ (MD = -0.73; 95% CI: -1.30 to -0.17; p = 0.01; I[2] = 0%) and Amyloid-PET score (MD = -45.67; 95% CI: -88.09 to -3.24; p = 0.03; I[2] = 99%). While significant statistical improvement was seen in the ADAS-Cog13 score (MD = -0.95; 95% CI: -1.76 to -0.13; p = 0.02; I[2] = 0%), the effect sizes for both FAQ and ADAS-Cog13 fell below established MCID thresholds. MMSE and ADCS-ADL showed no significant differences. Safety analysis revealed higher risks of ARIA-E (RR = 5.51), ARIA-H (RR = 1.73), and injection site reactions (RR = 2.15), with no differences in other adverse events.

CONCLUSION: Gantenerumab significantly reduces amyloid and statistically improves select functional (FAQ) and cognitive (ADAS-Cog13) measures in early AD; however, these changes remain below accepted MCID thresholds, indicating a lack of true clinical meaningfulness. Combined with its failure to enhance global cognition and an increased ARIA risk, routine clinical use is not supported.},
}

Humans
*Alzheimer Disease/drug therapy
*Antibodies, Monoclonal, Humanized/therapeutic use/pharmacology
Randomized Controlled Trials as Topic
Amyloid beta-Peptides

@article {pmid42605141,
year = {2026},
author = {Wang, J},
title = {Comment on 'Predicting cognitive function in Alzheimer's clinical trials via amyloid β-protein biomarkers'.},
journal = {British journal of clinical pharmacology},
volume = {},
number = {},
pages = {},
doi = {10.1002/bcp.70790},
pmid = {42605141},
issn = {1365-2125},
support = {//Zhejiang Chinese Medical University/ ; },
}

@article {pmid42605248,
year = {2026},
author = {Demura, M and Gregory, P and Fukuda, N and Lo, EH and Arai, K},
title = {Exercise and Circadian Rhythm Regulation: Mechanisms, Resilience, and Therapeutic Potential for Neurological Diseases.},
journal = {CNS neuroscience & therapeutics},
volume = {32},
number = {8},
pages = {e71035},
doi = {10.1002/cns.71035},
pmid = {42605248},
issn = {1755-5949},
support = {R01NS113556/NH/NIH HHS/United States ; //Takeda Science Foundation/ ; },
mesh = {Humans ; *Circadian Rhythm/physiology ; Animals ; *Nervous System Diseases/therapy/physiopathology ; *Exercise/physiology ; Alzheimer Disease/physiopathology/therapy ; },
abstract = {BACKGROUND: Circadian rhythms regulate sleep-wake cycles, hormonal secretion, metabolism, and immune responses. Disruption of these rhythms is linked to the onset and progression of various neurological diseases. Emerging evidence suggests that exercise, a non-photic zeitgeber, can modulate circadian function at both central and peripheral levels by regulating core clock gene expression, synchronizing hormonal and metabolic rhythms, and reducing neuroinflammation. Through these mechanisms, exercise enhances the amplitude, stability, and phase alignment of circadian rhythms and may promote physiological resilience.

REVIEW: This review summarizes the molecular and systemic mechanisms through which exercise supports circadian homeostasis and discusses their relevance to stroke and Alzheimer's disease. In both conditions, circadian misalignment contributes to pathological processes including oxidative stress, neuroinflammation, and impaired neurovascular repair. By restoring circadian alignment, appropriately timed exercise may improve neurological outcomes through effects on neuroplasticity, immune regulation, and metabolic synchronization.

SUMMARY: Taken together, current evidence may suggest that exercise can be a promising non-pharmacological strategy to enhance circadian resilience, reduce disease vulnerability, and support neurological recovery.},
}

Humans
*Circadian Rhythm/physiology
Animals
*Nervous System Diseases/therapy/physiopathology
*Exercise/physiology
Alzheimer Disease/physiopathology/therapy

@article {pmid42602062,
year = {2026},
author = {Bréchet, L and Bouhour, C and Rochas, V and Mekrom, VA and Eshmawey, M and Unschuld, PG},
title = {Personalized, home-based transcranial alternating current stimulation for memory improvement in mild cognitive impairment: randomized, sham-controlled clinical trial protocol.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1882406},
pmid = {42602062},
issn = {1663-4365},
abstract = {BACKGROUND: Mild cognitive impairment (MCI) is a prodromal stage of Alzheimer's disease (AD) and represents a critical window for interventions aimed at slowing neurodegenerative progression. Disruptions in neural oscillatory activity are key contributors to memory dysfunction in MCI and AD. Transcranial alternating current stimulation (tACS) is a non-invasive neuromodulation technique that entrains neural oscillations at specific frequencies, potentially restoring network dynamics underlying memory.

METHODS: The MemStim study is a randomized, sham-controlled, parallel-arm, double-blind clinical trial evaluating the efficacy of personalized, home-based gamma-frequency tACS over the left angular gyrus, delivered 5 days a week for 4 weeks, in individuals with MCI. Safety and tolerability are monitored throughout the intervention. Forty participants aged ≥55 years with clinically diagnosed MCI will be recruited at the Geneva University Hospitals and randomized to active or sham stimulation. All participants undergo baseline and post-stimulation assessments, including cognitive testing, structural MRI, and high-density EEG (hdEEG). Individual MRI-based electric-field modeling personalizes stimulation montages targeting the left angular gyrus, a key node of the memory network.

OUTCOMES: The primary outcome is the change in global cognitive function measured by the Montreal Cognitive Assessment (MoCA) from baseline to post-intervention. Secondary outcomes include changes in gamma-band oscillatory power measured with hdEEG. Exploratory EEG analyses will examine spectral, temporal, and spatial brain dynamics. Cognitive assessments are repeated 3 months post-intervention to evaluate persistence of effects.

DISCUSSION: This trial investigates whether personalized gamma-frequency tACS can modulate hdEEG measures of resting-state brain activity and improve memory function in MCI. By integrating individualized stimulation targeting, electrophysiological biomarkers, and remotely supervised home-based delivery, the MemStim study aims to advance personalized neuromodulation as a scalable therapeutic strategy for early intervention in cognitive decline.

CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, identifier NCT05708001.},
}

@article {pmid42602177,
year = {2026},
author = {Azimzadeh, M and Ababzadeh, S and Kahaki, AG and Babaei, SMH and Seyedebrahimi, R and Farsani, ME},
title = {The Gut-Brain Axis in Neurodegeneration: Mechanistic Links Between Dysbiosis and Neuropathology.},
journal = {Iranian journal of pathology},
volume = {21},
number = {4},
pages = {507-522},
pmid = {42602177},
issn = {1735-5303},
abstract = {BACKGROUND & OBJECTIVE: The gut-brain axis is essentially a two-way communication system that physically connects the brain and the intestinal tract. The connection is mediated through a series of pathways, including neural, endocrine, and immune pathways. Gut dysbiosis, which is explained as an imbalance in the microbial community, has been linked to the causation of various neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis. However, the pathological mechanisms in the brain are only partially known. The present review outlines the process of gut dysbiosis and neurodegeneration, detailing the roles of protein aggregation, neuroinflammation, barrier disruption, and neuroglial dysfunction. Then, extending the comparison to a range of neurodegenerative diseases, we discuss the possibility of common pathway therapeutics and actual microbiome-based treatment options planning from the standpoint of microbiome-directed interventions.

CONTENT/FINDINGS: Gut dysbiosis triggers a definable cascade, starting with the disruption of the intestinal barrier and increased permeability (leaky gut), which allows bacterial products (lipopolysaccharides, bacterial amyloids) and pro-inflammatory cytokines to enter systemic circulation. Such peripheral changes weaken the blood-brain barrier and thus allow these factors to access the CNS, where they lead to neuroglial dysfunction (microglial priming, astrocytic reactivity, and oligodendrocyte injury) by disruption of glial homeostasis. CNS glial cell malfunction leads to the development of proteinopathies characteristic of each disease: amyloid and tau hyperphosphorylation in Alzheimer's disease through BACE1 upregulation and kinase activation; synuclein in Parkinson's disease via molecular mimicry, oxidative stress, and impaired clearance; and demyelination in multiple sclerosis through oligodendrocyte apoptosis. Oral bacteria such as Porphyromonas gingivalis aggravate this inflammatory loop through the direct invasion of the CNS and proteolytic cleavage of amyloid and tau. The vagus nerve is yet another pathway through which gut-derived inflammatory signals and pathological synuclein can be transmitted to the brain.

CONCLUSION: The gut microbiome is more than just a correlate of neurodegeneration; it actively promotes neurodegenerative diseases through pathways that can be mechanistically defined. Microbiome-targeted interventions such as dietary changes, precision probiotics, fecal microbiota transplantation, and anti-inflammatory agents offer a measure of hope for changing these pathological processes. Future studies need to be directed at determining the time sequence of cause and effect, finding dependable microbiota-based biomarkers, and formulating tailored strategies that can account for individual microbial composition variability, genetic susceptibility, and environmental exposures. A deeper understanding of the gut-brain axis from this mechanistic perspective could eventually lead to the prevention or postponement of neurodegeneration.},
}

@article {pmid42598783,
year = {2026},
author = {Liu, M and Gong, K and Chen, Y and Heo, G and Xu, Y and Timsina, J and Western, D and Budde, J and Morris, JC and Marco, G and Holtzman, DM and Hinson, J and Levin, S and Ashton, N and Denkinger, M and Schindler, SE and Das, K and Ali, M and Cruchaga, C},
title = {A plasma-based protein signature combining NPTXR, ACHE, and p-tau217 predicts progression to symptomatic Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71748},
pmid = {42598783},
issn = {1552-5279},
support = {R01-AG058501/NH/NIH HHS/United States ; //Cure Alzheimer's Fund/ ; },
mesh = {Humans ; *Alzheimer Disease/blood/diagnosis ; Disease Progression ; *tau Proteins/blood ; Biomarkers/blood ; Female ; Male ; *Acetylcholinesterase/blood ; *Nerve Tissue Proteins/blood ; Aged ; Longitudinal Studies ; Aged, 80 and over ; },
abstract = {INTRODUCTION: We recently identified a plasma-based seven-protein model with strong performance for Alzheimer's disease (AD) classification. Here, we evaluated whether these proteins, alone or combined with plasma phosphorylated tau 217 (p-tau217), predict progression from cognitively unimpaired to symptomatic AD.

METHODS: Using longitudinal data from Knight-ADRC (Alzheimer's Disease Research Center) with replication in Alzheimer's Disease Neuroimaging Initiative (ADNI), we modeled time to progression using Cox regression. Models included p-tau217, the seven-protein panel, and their combination.

RESULTS: The p-tau217 alone showed similar progression prediction (hazard ratio [HR] = 4.08) than the seven-protein model (HR = 4.85). Integrating the seven-protein model with ptau217 significantly improved risk, identifying a high-risk group (HR = 11.15) with two intermediate-risk groups. Simplified models retained prognostic value, with top-performing ratios, Complexin-2/Synaptic vesicle membrane protein VAT-1 homolog (CPLX2/VAT1) and Acetylcholinesterase/Neuronal pentraxin receptor (ACHE/NPTXR) also lead to a significantly better risk stratification than p-tau217 alone.

DISCUSSION: Integrating p-tau217 with targeted plasma proteins enables graded risk stratification and identifies individuals at highest risk of progression, supporting clinically scalable approaches for early risk assessment.},
}

Humans
*Alzheimer Disease/blood/diagnosis
Disease Progression
*tau Proteins/blood
Biomarkers/blood
Female
Male
*Acetylcholinesterase/blood
*Nerve Tissue Proteins/blood
Aged
Longitudinal Studies
Aged, 80 and over

@article {pmid42599498,
year = {2026},
author = {Zhang, P and Guo, X and Yang, M and Cai, Y and Wang, L and Gao, Y},
title = {Photo/Copper-Catalyzed Oxidative Direct Diphosphorothiolation of Indolin-2-ones with P(O)SH Compounds.},
journal = {The Journal of organic chemistry},
volume = {91},
number = {32},
pages = {11141-11147},
doi = {10.1021/acs.joc.6c01443},
pmid = {42599498},
issn = {1520-6904},
support = {22201242//National Natural Science Foundation of China/ ; 22271285//National Natural Science Foundation of China/ ; 2025J09053//Natural Science Foundation of Fujian Province/ ; XYBSKYZZ201926//Xinxiang Medical University/ ; 505527//Research Foundation for Distinguished Professor?s Team of Xinxiang Medical University/ ; },
abstract = {A visible-light-promoted cross-dehydrogenative coupling (CDC) of indolin-2-ones with S-hydrogen phosphorothioates via 4H elimination has been developed, providing 3,3-diphosphorothiolated oxindoles in good yields with broad functional group tolerance. The protocol was also extended to monophosphorothiolation and late-stage diversification of drug-derived substrates. Notably, the products displayed potent and selective butyrylcholinesterase (BuChE) inhibitory activity, suggesting potential as leads for Alzheimer's disease.},
}

@article {pmid42599532,
year = {2026},
author = {Raj, SN and Natnan, ME and Lou, WP and Mediani, A and Tencomnao, T and Baharum, SN},
title = {Unravelling the phytochemical complexity of neuroprotective plants: a metabolomics approach to Alzheimer's disease.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42599532},
issn = {1573-4978},
support = {GGP-2020-043//Universiti Kebangsaan Malaysia/ ; },
mesh = {*Alzheimer Disease/metabolism/drug therapy ; *Metabolomics/methods ; Humans ; *Neuroprotective Agents/pharmacology/therapeutic use/metabolism ; *Phytochemicals/metabolism/therapeutic use/pharmacology ; *Plants, Medicinal/metabolism/chemistry ; Animals ; Metabolome ; Drug Discovery/methods ; },
abstract = {Metabolomics is a comprehensive study of organisms at the metabolite level. The emergence of metabolomics as one of the 'omics' in systems biology perspectives has gained significance in relation to disease research. The use of metabolomics pipeline to unravel the potential of bioactive compounds in medicinal plants for benefiting mankind has become a powerful strategy for drug discovery. While traditional metabolite profiling has mainly classified medicinal plants according to broad biological activities, such as anti-inflammatory, anticancer, anti-diabetic and atherosclerosis effects, the non-targeted and targeted metabolomics offer a comprehensive approach for characterizing novel or previously unknown secondary metabolites providing a far more detailed approach. These advanced methodologies allow researchers to expand current research by providing deeper insight into how these compounds work and their underlying mechanisms at the molecular level. To investigate these metabolic shifts particularly in neurodegenerative diseases model, studies frequently use advanced analytical platform, such as nuclear magnetic resonance (NMR), gas chromatography-mass spectrometry (GC-MS), and liquid chromatography-mass spectrometry (LC-MS) to analyze metabolites in biofluids like blood, urine, and cerebrospinal fluid (CSF). This review will highlight recent metabolomics discoveries on unravelling the complex phytochemical composition of selected medicinal plants in producing neuroprotective bioactive compounds and therapeutic potential to combat neurodegenerative related disease especially Alzheimer's disease (AD).},
}

*Alzheimer Disease/metabolism/drug therapy
*Metabolomics/methods
Humans
*Neuroprotective Agents/pharmacology/therapeutic use/metabolism
*Phytochemicals/metabolism/therapeutic use/pharmacology
*Plants, Medicinal/metabolism/chemistry
Animals
Metabolome
Drug Discovery/methods

@article {pmid42599667,
year = {2026},
author = {Wang, Y and Gu, Z and Zhang, H and Bi, X and Chen, L and Lu, J},
title = {Multimodal MRI insights into hippocampal pathological changes across the Alzheimer's disease continuum: advances and challenges.},
journal = {Japanese journal of radiology},
volume = {},
number = {},
pages = {},
pmid = {42599667},
issn = {1867-108X},
support = {82371495//National Natural Science Foundation of China/ ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder, with early and progressive hippocampal pathology serving as a hallmark across the AD continuum, including subjective cognitive decline, mild cognitive impairment, and AD dementia. Single-modal MRI fails to fully capture multilevel hippocampal neuropathology, hindering accurate early diagnosis and prognostic prediction of AD. This narrative review summarizes recent advances in structural MRI, diffusion tensor imaging, magnetic resonance spectroscopy, quantitative susceptibility mapping, arterial spin labeling, and functional MRI for evaluating hippocampal and medial temporal lobe abnormalities in AD. These techniques provide a multifaceted characterization of AD-associated hippocampal alterations, including macroscopic atrophy, microstructural degeneration, metabolic dysregulation, aberrant iron deposition, hemodynamic dysfunction, and abnormal neuronal activity. Hippocampal damage in AD exhibits distinct subfield specificity, hemispheric asymmetry, and stage-dependent progression, modulated by Aβ/tau pathology, neuroinflammation, and apolipoprotein E ε4 genotype. Notably, multimodal imaging fusion integrated with machine learning outperforms single-modal biomarkers, significantly improving the accuracy of AD early screening, differential diagnosis, and prognostic prediction. Nevertheless, existing studies are hampered by inadequate pathological validation, limited sample sizes, unsatisfactory reproducibility, and multicenter technical heterogeneity. Multimodal MRI offers robust non-invasive evidence for exploring AD hippocampal pathophysiology. Future large-scale multicenter longitudinal studies combining artificial intelligence will advance precision diagnosis and targeted therapy for AD by clarifying the interplay among AD pathology, genetics, and heterogeneous hippocampal injury.},
}

@article {pmid42599691,
year = {2026},
author = {Wang, S and Zou, S and , },
title = {Cerebrospinal fluid glial cell line-derived neurotrophic factor levels interact with APOE ε4 genotype to influence cognitive decline in older adults without dementia.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261477047},
doi = {10.1177/13872877261477047},
pmid = {42599691},
issn = {1875-8908},
abstract = {BackgroundAlthough both apolipoprotein E (APOE) ε4 and glial cell line-derived neurotrophic factor (GDNF) are implicated in the pathogenesis of Alzheimer's disease (AD), it remains unclear whether they interact to affect cognitive decline among older adults without dementia.ObjectiveThis study aimed to examine the interactive effects of APOE ε4 and GDNF on longitudinal cognitive decline.MethodsA total of 543 individuals (mean age 73 [±7] years; 43% female) with cognitively unimpaired (CU) or mild cognitive impairment (MCI) were included from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Linear mixed-effects models were used to examine the contributions of cerebrospinal fluid (CSF) GDNF levels and APOE ε4 status to longitudinal changes in cognitive measures, including the Mini-Mental State Examination (MMSE), the Clinical Dementia Rating - Sum of Boxes (CDR-SB), the 13-item Alzheimer's Disease Assessment Scale - Cognitive subscale (ADAS-Cog-13), and the Rey Auditory Verbal Learning Test (RAVLT) total score.ResultsWe found that the 3-way interaction (APOE ε4 × GDNF × time) was significant for MMSE, CDR-SB, and ADAS-Cog-13, and of marginal significance for RAVLT total score, after adjusting for age, sex, and education. Specifically, individuals who were APOE ε4 carriers with low CSF GDNF levels showed the fastest rate of cognitive decline among the four groups (Low/APOE4-, High/APOE4-, Low/APOE4+, and High/APOE4+).ConclusionsAPOE ε4 appears to interact with CSF GDNF levels to affect longitudinal cognitive decline among older adults without dementia.},
}

@article {pmid42599695,
year = {2026},
author = {Alavi, A and Gujral, J and Gandhi, OH and Amanullah, AA and Ayubcha, C and Patil, S and Werner, TJ and Høilund-Carlsen, PF},
title = {The case for FDG-PET and NaF-PET in risk stratification of mild cognitive impairment.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261477750},
doi = {10.1177/13872877261477750},
pmid = {42599695},
issn = {1875-8908},
abstract = {According to a recent study, integrating amyloid-PET, structural MRI, carotid Doppler ultrasound, cognitive testing, and APOE genotyping improves estimation of dementia progression in patients with mild cognitive impairment, with carotid plaque burden emerging as a dominant predictor in amyloid-β-negative cases. We agree that vascular pathology is crucial but suggest that future models consider supplementing amyloid-PET with FDG-PET, a well-validated functional marker of neuronal injury, and carotid Doppler with [18]F-sodium fluoride (NaF)-PET which can detect and quantify early, active microcalcification. This could further improve risk stratification while facilitating detection of potentially modifiable disease processes.},
}

@article {pmid42599799,
year = {2026},
author = {Liu, R and Zhang, Y and Lai, M and Davydzenka, V and Moffitt, C and England, N and Barbera, G and Chen, R and Lin, DT and Li, Y},
title = {Graph theory identifies altered prefrontal microcircuit organization in Shank3 mice, a mouse Model of autism.},
journal = {Cell reports},
volume = {45},
number = {8},
pages = {117852},
doi = {10.1016/j.celrep.2026.117852},
pmid = {42599799},
issn = {2211-1247},
abstract = {Graph theory provides unique tools to assess complex networks. It has been previously used with functional magnetic resonance imaging (fMRI) datasets to quantify macroscopic-scale connections among different brain regions, readily capturing brain network changes in subjects with Alzheimer's disease. Here, we apply graph theory to miniscope calcium imaging data recorded from the prefrontal cortex of freely behaving wild-type (WT) and Shank3[fx] mice (a mouse model of autism) during social behavior tasks to compare microscopic-scale functional connections among individual neurons. We demonstrate that Shank3[fx] mice display reduced population-level neural activity and a less-integrated and rigid prefrontal microcircuit. Furthermore, we employ machine learning to predict genotypes and behavioral differences between WT and Shank3[fx] mice using graph-theoretic metrics extracted from prefrontal microcircuits. Our results indicate strong links between altered prefrontal microcircuits and social behavior deficits in the Shank3[fx] mice, highlighting prefrontal microcircuitry as a potential diagnostic and therapeutic target for autism.},
}

@article {pmid42599802,
year = {2026},
author = {Bhatta, S and Grzybowski, A and Ortiz, G and DiStasio, M},
title = {TTN[+] macrophages are enriched in the human choroid plexus in Alzheimer's disease.},
journal = {Cell reports},
volume = {45},
number = {8},
pages = {117859},
doi = {10.1016/j.celrep.2026.117859},
pmid = {42599802},
issn = {2211-1247},
abstract = {The choroid plexus (ChP) regulates cerebrospinal fluid homeostasis and immune surveillance, but its cellular organization and response to Alzheimer's disease (AD) remain incompletely defined. Here, we integrate single-nucleus RNA sequencing with spatial transcriptomics to generate a high-resolution atlas of the adult human ChP. We identify all major epithelial, stromal, and immune populations and resolve heterogeneity within macrophages, including a distinct subset expressing the giant protein TTN. These TTN[+] macrophages exhibit coordinated cytoskeletal, stress-response, and phagocytic gene programs and localize to perivascular and stromal niches. In AD, we observe broad, cell type-specific transcriptional remodeling across epithelial, endothelial, mesenchymal, and immune compartments, with expansion of TTN[+] macrophages and increased senescence signatures. Spatial and ligand-receptor analyses reveal altered tissue organization and macrophage interaction patterns with neighboring cells. Combined with in situ validations, these findings provide evidence of TTN expression by macrophages, and reveal a broader AD-associated contextual shift in human ChP immune function in which TTN[+] macrophages are enriched.},
}

@article {pmid42599805,
year = {2026},
author = {Zou, ZM and Wang, D and Tang, WJ and Chen, XL and Li, HJ and Li, GL and Xiao, R and Xu, LH and Si, WK and Chen, ZY},
title = {GLUT4 plasma translocation in lateral septum GABAergic neurons supports neuronal activation and social familiarity.},
journal = {Cell reports},
volume = {45},
number = {8},
pages = {117854},
doi = {10.1016/j.celrep.2026.117854},
pmid = {42599805},
issn = {2211-1247},
abstract = {Social interaction regulates neuronal excitability and behavior, and the lateral septum (LS) plays an important role in social behavior. However, the molecular mechanisms that support LS-dependent social responses remain unclear. Here, we show that neuronal activity-driven glucose transporter 4 (GLUT4) plasma translocation in LS GABAergic neurons supports social familiarity. Neuronal activation triggers CaMKIIα-mediated phosphorylation of GLUT4 at Ser243 and Ser254, which enhances Rab10 binding, GLUT4 surface insertion, and glucose uptake. A cell-permeable TAT-GLUT4(2D) peptide disrupts GLUT4-Rab10 binding, blocks activity-dependent GLUT4 translocation, and impairs social familiarity. LS GLUT4 knockdown disrupts social novelty preference, and this deficit is rescued by wild-type GLUT4 but not trafficking- or transport-deficient mutants. In 5xFAD mice, GLUT4 plasma translocation is reduced during social novelty preference. Selective expression of plasma-localized GLUT4 in LS GABAergic neurons restores neuronal activation and social familiarity impairments, identifying GLUT4 trafficking as a potential target for Alzheimer's disease-related social impairments.},
}

@article {pmid42600000,
year = {2026},
author = {Chae, H and Park, Y and Kim, Y and Yoon, E and Kim, KW and Yoo, S},
title = {Wearable transparent OLED glasses for cognitive stimulation: Enhancing brain connectivity through gamma entrainment.},
journal = {Science advances},
volume = {12},
number = {33},
pages = {eaee5504},
pmid = {42600000},
issn = {2375-2548},
mesh = {Humans ; *Wearable Electronic Devices ; *Cognition/physiology ; *Brain/physiology ; *Gamma Rhythm/physiology ; Cognitive Enhancement ; },
abstract = {Gamma wave entrainment is a promising approach for improving cognitive function, particularly in the early stages of Alzheimer's disease. However, for everyday treatment, a light source system that maintains visibility while delivering effective stimulation is essential for patient comfort and practicality. To address this need, we developed organic light-emitting diode (OLED) glasses with optimized large-area transparent OLEDs for gamma wave entrainment. The optimization involved all layers of the device, including encapsulation, to achieve high luminous transmittance (75%), uniformity (over 90%), and electrical performance, ensuring suitability for wearable applications. Under real-world conditions (see-through visibility and ambient light present), the transparent OLED glasses successfully induced gamma rhythm entrainment, enhancing brain connectivity between the occipital and frontal regions. They also notably reduced visual discomfort and showed a trend of enhanced connectivity compared to nontransparent OLEDs. These results highlight the potential of this noninvasive wearable technology for early cognitive intervention, providing comfortable therapeutic light stimulation.},
}

Humans
*Wearable Electronic Devices
*Cognition/physiology
*Brain/physiology
*Gamma Rhythm/physiology
Cognitive Enhancement

@article {pmid42600372,
year = {2026},
author = {Rudroff, T},
title = {Sex composition as an unaddressed confound in FDG-PET predictive models of Alzheimer's disease conversion.},
journal = {The journal of nutrition, health & aging},
volume = {30},
number = {10},
pages = {100955},
doi = {10.1016/j.jnha.2026.100955},
pmid = {42600372},
issn = {1760-4788},
}

@article {pmid42600466,
year = {2026},
author = {Kumar, N and Khan, I and Singh, J and Kumar, K and Kushwaha, VK and Ojha, S and Raman, SK and Shankar, G},
title = {Recent developments in donepezil-based hybrid molecules as multi-target therapeutics for Alzheimer's disease: A paradigm shift beyond symptomatic treatment.},
journal = {Bioorganic chemistry},
volume = {181},
number = {},
pages = {110361},
doi = {10.1016/j.bioorg.2026.110361},
pmid = {42600466},
issn = {1090-2120},
abstract = {Alzheimer's disease (AD) is a progressive age-related neurodegenerative disorder characterized by the gradual loss of cholinergic neurons, leading to cognitive impairment, synaptic dysfunction, and irreversible neuronal degeneration. The multifactorial nature of AD, involving cholinergic deficits, amyloid-β (Aβ) aggregation, tau hyperphosphorylation, oxidative stress, mitochondrial dysfunction, neuroinflammation, and metal dyshomeostasis, has limited the clinical success of single-target therapeutic strategies. Although donepezil (DPZ), a clinically approved acetylcholinesterase (AChE) inhibitor, remains one of the most widely prescribed agents for symptomatic management, it does not alter the underlying neurodegenerative processes. Consequently, DPZ has emerged as an attractive medicinal chemistry scaffold for the development of multi-target-directed ligands (MTDLs) that simultaneously modulate multiple interconnected pathological pathways implicated in AD. This review provides a comprehensive and critically organized overview of recent advances in DPZ-based hybrid molecules, emphasizing rational design strategies, hybridization approaches, structure-activity relationships (SAR), molecular mechanisms, and pharmacological profiles. To facilitate a mechanistic understanding, the reported hybrids are systematically classified according to structural modifications of the indanone moiety, the benzylpiperidine moiety, or simultaneous modification of both pharmacophoric regions. Comparative analysis reveals how scaffold engineering, linker optimization, and strategic incorporation of complementary pharmacophores influence cholinesterase inhibition, anti-amyloid activity, antioxidant capacity, neuroprotection, metal chelation, monoamine oxidase inhibition, and blood-brain barrier permeability. Importantly, this review critically examines the current translational landscape, highlighting that despite encouraging in vitro and in vivo findings, no DPZ-based hybrid has yet advanced to clinical evaluation. Key challenges, including pharmacokinetic optimization, metabolic stability, safety, target engagement, and clinical translatability, are discussed together with future medicinal chemistry directions. Rather than presenting DPZ-based hybrids as established disease-modifying therapies, the available evidence supports their role as promising multifunctional lead compounds and valuable molecular platforms for the rational design of next-generation anti-Alzheimer agents. By integrating emerging SAR trends with critical translational perspectives, this review provides a contemporary framework to guide future development of clinically relevant multifunctional therapeutics for AD.},
}

@article {pmid42600613,
year = {2026},
author = {Brioschi, S and Belk, JA and Storck, SE and Wu, Y and Wang, Z and Feng, Z and van Olst, L and Emery, JL and Sudan, R and Wu, J and Du, S and Genua, M and La Terza, F and Edwards, AJ and Nguyen, KM and Sanford, J and Lee, DD and Bugatti, M and Federico, AJ and Chen, Y and Wang, Z and Penati, S and Rodrigues, PF and Antonova, AU and Loo, HQ and Smirnov, I and Gilfillan, S and Halabi, CM and Ponce, J and Yan, J and Chang, HY and Randolph, GJ and Vermi, W and Cella, M and Meers, M and Ostuni, R and Gate, D and Nguyen, AT and Cruchaga, C and Hu, S and Kipnis, J and Colonna, M},
title = {Brain perivascular macrophages regulate endothelial cell function via a cMAF-dependent transcriptional program in mouse and human.},
journal = {Cell},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.cell.2026.07.043},
pmid = {42600613},
issn = {1097-4172},
abstract = {Brain perivascular macrophages maintain brain physiology, yet their transcriptional regulators and functions in health and disease remain unclear. Using single-cell multi-omics and functional experiments, we identify cellular musculoaponeurotic fibrosarcoma oncogene (cMAF) as a key transcription factor for brain perivascular macrophages, and conditional deletion of cMAF disrupts their phenotype in vivo. Functionally, cMAF drives insulin-like growth factor-1 (IGF1) expression in perivascular macrophages, enabling communication with endothelial cells. Consistently, cMAF deletion in perivascular macrophages causes transcriptional alterations in cerebral arteries, affecting vascular functions. Notably, cMAF emerges as the main transcription factor for human perivascular macrophages, suggesting conservation of this transcriptional module. During Alzheimer's disease (AD), human perivascular macrophages upregulate cMAF and IGF1 to enhance communication with vascular cells, and this response is abrogated in APOE4 carriers. Lastly, we explore an uncharacterized polymorphism in cMAF, providing evidence that the cMAF program is protective against AD. Targeting cMAF in perivascular macrophages may offer new therapeutic strategies for neurodegenerative and cerebrovascular diseases.},
}

@article {pmid42600734,
year = {2026},
author = {Sharma, T and Sharma, P and Bashir, B and Singh, SK and Vishwas, S},
title = {Small nucleolar RNAs: Emerging therapeutic and diagnostic frontiers in Alzheimer's disease.},
journal = {Drug discovery today},
volume = {},
number = {},
pages = {104771},
doi = {10.1016/j.drudis.2026.104771},
pmid = {42600734},
issn = {1878-5832},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder for which effective therapeutic interventions remain scarce, highlighting the urgent need for new molecular approaches. Small nucleolar RNAs (snoRNAs), classically known for directing ribosomal modifications, have recently emerged as multifunctional regulators of gene expression, stress responses and neuronal homeostasis. Emerging evidence shows snoRNA dysregulation in the biofluids and brain tissue of patients with AD, positioning them as promising diagnostic biomarkers and therapeutic targets. This review outlines the structural, functional and translational potential of snoRNAs, with a particular focus on their ability to modulate AD pathology while also addressing key challenges in their clinical translation, including delivery barriers, biological stability and target specificity.},
}

@article {pmid42600807,
year = {2026},
author = {Fereidouni, A and Nematollahi, S and Mathew, KT and Favennec, V and Liceran, L and Aldenhoff-Kelly, C and Valdivieso, MA and Trent, S and Moradikor, N},
title = {Allosteric modulation of ionotropic and G protein-coupled receptors in Alzheimer's disease: A neuroprotective strategy and therapeutic implications.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {154063},
doi = {10.1016/j.ijbiomac.2026.154063},
pmid = {42600807},
issn = {1879-0003},
abstract = {Alzheimer's disease (AD) is the leading cause of dementia and still lacks an effective treatment that can slow or stop disease progression. In addition to amyloid-β and tau pathology, AD involves major disturbances in calcium balance, neurotransmission, and synaptic plasticity. Conventional orthosteric drugs provide limited symptomatic benefit and often interfere with physiological receptor function, underscoring the need for more selective therapeutic strategies. This review explores allosteric modulation of neurotransmitter receptors as a potential neuroprotective strategy in AD, with an emphasis on mechanisms that restore synaptic integrity, regulate calcium homeostasis, and engage disease-relevant intracellular signaling pathways. The review synthesizes preclinical and clinical evidence on allosteric modulators targeting key ionotropic receptors, including NMDA, AMPA, GABA-A, nicotinic acetylcholine, and P2X7 receptors, and G protein-coupled receptors (GPCRs) such as M1 muscarinic receptors, metabotropic glutamate receptors, and the calcium-sensing receptor. Particular attention is given to receptor selectivity, signaling bias, and translational relevance. Allosteric modulation of ionotropic receptors can influence excitability and synaptic plasticity and may preserve endogenous neurotransmission, with circuit-stabilizing effects reported mainly in preclinical studies. GPCR-directed allosteric modulators can affect AD-related processes, including amyloid- and tau-associated toxicity, excitotoxicity, and neuroinflammation, although evidence for these effects is largely preclinical and clinical translation remains challenging. Convergent pathways, such as Ca[2+]-dependent signaling, ERK/CREB, PI3K/Akt, and cAMP/PKA, may represent shared mediators of disease-relevant effects. Allosteric modulation may offer a more refined, receptor-specific framework for therapeutic investigation in AD. Ionotropic and GPCR-targeted agents may each produce symptomatic or preclinical disease-relevant effects, but their capacity to slow disease progression in patients remains unproven and will require current pharmacological and translational challenges to be addressed.},
}

@article {pmid42600874,
year = {2026},
author = {Xiao, J and Lan, Z and Zhang, R and Zhang, J and Hu, Z and Jia, B and Tang, H and Xu, T and Bao, X and Xu, Y and Yu, L and Ji, SL and Zhu, X},
title = {Novel natural inhibitor Rubimaillin targets NLRP3 R167/Y381 to ameliorate inflammatory and neurodegenerative diseases.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {122293},
doi = {10.1016/j.jep.2026.122293},
pmid = {42600874},
issn = {1872-7573},
abstract = {Rubia cordifolia L. is traditionally used in Chinese medicine for treating arthritic and inflammatory conditions by cooling blood and activating circulation. Gouty arthritis, one of the disease models investigated in this study, falls within this traditional anti-arthritic application. This study investigates whether rubimaillin (Rub), a naphthoquinone from Rubia cordifolia, selectively inhibits NLRP3 inflammasome activation and exerts therapeutic effects in relevant disease models. The NLR family pyrin domain-containing 3 (NLRP3) inflammasome is a key driver of various inflammatory, metabolic, and neurodegenerative disorders; yet, no clinically approved inhibitor is currently available. Rubia cordifolia L. is a traditional medicinal herb, and Rubimaillin (Rub), a naphthoquinone isolated from this herb, has potential anti-inflammatory properties, but its role and mechanism in regulating NLRP3 activation remain unclear.

AIM OF STUDY: This study aimed to determine whether Rubimaillin (Rub), a naphthoquinone isolated from Rubia cordifolia L., can selectively inhibit NLRP3 inflammasome activation and yield therapeutic effects in relevant NLRP3-driven disease models.

MATERIALS AND METHODS: Mouse primary microglia, bone marrow-derived macrophages (BMDMs), and the human macrophage cell line THP-1 were primed with lipopolysaccharide (LPS) for 3 h, then stimulated with Nigericin or ATP to induce NLRP3 inflammasome assembly and pyroptosis. Caspase-1 activation, apoptosis-associated speck-like protein containing a CARD (ASC) speck formation, interleukin-1β (IL-1β) release, and lactate dehydrogenase (LDH) secretion were quantified. Mutagenesis studies were conducted to identify critical residues required for Rub's binding to NLRP3. The in vivo therapeutic potential of Rub was assessed in three murine models of NLRP3-driven inflammation: LPS-induced sepsis, monosodium urate crystal (MSU)-induced gouty arthritis, and the APP/PS1 double-transgenic Alzheimer's disease (AD) mouse model. Mice received intraperitoneal Rub or vehicle, and disease severity was evaluated by histopathology, cytokine profiling, and behavioral tests.

RESULTS: Rub significantly reduced pyroptosis and IL-1β release in mouse primary microglia, BMDMs, and THP-1 cells in a dose-dependent manner, without affecting Absent in melanoma 2(AIM2) or NLR family CARD domain containing 4 (NLRC4) pathways. Mechanistically, Rub directly bound to NLRP3, thereby blocking the oligomerization of both NLRP3 and ASC, as well as preventing caspase-1 activation and gasdermin D (GSDMD) cleavage. Furthermore, mutagenesis studies identified arginine 167 and tyrosine 381 as critical residues for Rub's binding to NLRP3. In vivo, Rub treatment significantly prolonged survival and attenuated lung injury in the sepsis model, reduced paw swelling and bone erosion in the gout model, and ameliorated cognitive deficits and neuroinflammation in the AD model, respectively.

CONCLUSION: Collectively, these findings demonstrate that Rub selectively targets the NLRP3 inflammasome and exerts therapeutic effects on NLRP3-driven diseases including sepsis, gout, and AD. This study provides a molecular basis for the traditional application of Rubia cordifolia L. and highlights Rub as a promising natural lead compound for the treatment of NLRP3-driven disorders.},
}

@article {pmid42600903,
year = {2026},
author = {Wu, X and Ye, Q and Zi, M and Jiang, H and Meng, S and Zheng, J and Zeng, S and Ma, C and Hu, X and Zhao, B and Li, H},
title = {Pyroptosis in Alzheimer's disease: Mechanisms and neuroinflammatory networks.},
journal = {Molecular and cellular neurosciences},
volume = {},
number = {},
pages = {104113},
doi = {10.1016/j.mcn.2026.104113},
pmid = {42600903},
issn = {1095-9327},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder pathologically characterized by amyloid-β (Aβ) deposition, tau protein hyperphosphorylation, neuronal loss, and sustained neuroinflammation. In recent years, pyroptosis, a gasdermin-mediated form of inflammatory programmed cell death, has been recognized as a potential mechanism linking innate immune activation to neurodegenerative injury. This review summarizes the major molecular pathways of pyroptosis, including the canonical inflammasome-caspase-1-GSDMD pathway, the noncanonical caspase-4/5/11-GSDMD pathway, and alternative pathways involving caspase-3/GSDME and caspase-8, with a focus on their roles in the initiation, amplification, and propagation of neuroinflammation in AD. Current evidence suggests that AD-related stimuli, including Aβ aggregation, tau pathology, mitochondrial dysfunction, oxidative stress, and lysosomal damage, can induce inflammasome activation, gasdermin cleavage, and inflammatory mediator release, thereby sustaining chronic neuroinflammation. Concurrently, microglia, neurons, astrocytes, and oligodendrocytes may exhibit varying degrees of pyroptosis-related responses, contributing to impaired Aβ clearance, neuronal injury, glial dysfunction, and myelin pathology, respectively. This review further summarizes potential therapeutic strategies targeting the NLRP3 inflammasome, caspases, gasdermins, natural bioactive compounds, and the gut-brain axis. Overall, pyroptosis provides a novel framework for understanding the interplay between neuroinflammation and neurodegeneration in AD; however, its cell-type-specific roles, stage-dependent effects, and translational potential remain to be fully elucidated.},
}

@article {pmid42601004,
year = {2026},
author = {Shanehbandpour-Tabari, F and Golchoobian, R and Pourabdolhossein, F},
title = {Hippocampal Klotho Expression Is Associated with the Neuroprotective Effects of Metformin Against ICV-STZ-Induced Cognitive Deficits.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {179245},
doi = {10.1016/j.ejphar.2026.179245},
pmid = {42601004},
issn = {1879-0712},
abstract = {Alzheimer's disease (AD) is characterized by progressive cognitive decline, amyloid-β (Aβ) accumulation, oxidative stress, and neuroinflammation. Increasing evidence links metabolic dysfunction to AD, suggesting that antidiabetic drugs such as metformin may exert neuroprotective effects. This study investigated the effects of long-term metformin pretreatment on cognitive function, hippocampal pathology, and neuroprotective gene expression in an intracerebroventricular streptozotocin (ICV-STZ) rat model of AD. Adult male Sprague-Dawley rats were assigned to Sham, STZ, Metformin, and STZ+Metformin groups. Metformin (2 g/L in drinking water) was administered for 12 weeks before ICV-STZ injection. Spatial learning and memory were assessed using the Morris water maze. Hippocampal pathology was evaluated by H&E, Nissl, and Congo red staining, and gene expression was analyzed by quantitative PCR. ICV-STZ induced cognitive impairment, hippocampal Aβ deposition, neuronal loss, and increased expression of pro-inflammatory and oxidative stress markers. Metformin pretreatment significantly improved spatial learning and memory, reduced amyloid burden, and preserved neuronal integrity in the CA1 and CA3 regions. Metformin increased hippocampal Klotho mRNA expression, enhanced antioxidant defenses (Nrf2 and HO-1), suppressed TNF-α, IL-1β, and iNOS expression, and increased IL-10 levels. Although BDNF mRNA expression showed an upward trend, the change was not statistically significant. No significant changes in blood glucose levels were observed. In conclusion, long-term metformin pretreatment attenuated STZ-induced AD-like pathology and cognitive deficits. Its neuroprotective effects were associated with increased hippocampal Klotho expression and reduced oxidative stress and neuroinflammation, supporting further investigation of metformin and the Klotho pathway as potential preventive strategies for AD.},
}

@article {pmid42601176,
year = {2026},
author = {Koh, H and Choi, S and Sung, JE},
title = {Verb-Semantic Feature Analysis for Alzheimer's Dementia in a verb-final language: evidence from Korean.},
journal = {Neuropsychological rehabilitation},
volume = {},
number = {},
pages = {1-25},
doi = {10.1080/09602011.2026.2715712},
pmid = {42601176},
issn = {1464-0694},
abstract = {This study examined the effects of Verb-Semantic Feature Analysis (Verb-SFA) on verb naming, noun retrieval, sentence comprehension, and discourse production in individuals with Dementia of the Alzheimer's Type (DAT). Given the lexical-semantic degradation characteristic of DAT and the central role of verbs in Korean, a verb-final language, this study evaluated whether Verb-SFA facilitates treatment, near-transfer, and far-transfer effects. Three male participants, aged 60 or older with 16 years of education, completed 17 sessions: pre-treatment (4 sessions), treatment (10 sessions), and post-treatment (3 sessions). Treatment effects were assessed using 45-item probe sets derived from the Korean Item Selection Naming Test. Results showed significant improvement in naming accuracy for treated verbs, with a robust interaction between treatment sessions and treated items. No significant near-transfer effects were found for untreated verbs in the probe set or on the Action Naming Test. However, significant near-transfer effects were observed for noun retrieval on the Korean-Boston Naming Test, although verbal fluency tasks showed no improvement. Far-transfer effects emerged in sentence comprehension, suggesting strengthened verb-semantic processing supports higher-level linguistic abilities. No measurable gains were observed in discourse production. Overall, Verb-SFA treatment enhanced verb naming and sentence comprehension in individuals with DAT.},
}