@article {pmid42934100,
year = {2026},
author = {Chen, L and Long, Y and Huang, D and Zheng, G and Meng, X},
title = {[Lead exposure aggravates Aβ1-42-induced microglial activation through mitochondrial calcium uniporter-mediated mitochondrial calcium accumulation].},
journal = {Nan fang yi ke da xue xue bao = Journal of Southern Medical University},
volume = {46},
number = {10},
pages = {2384-2392},
pmid = {42934100},
issn = {1673-4254},
support = {82473665//National NaturalScience Foundation of China/ ; },
mesh = {*Microglia/drug effects/metabolism ; *Amyloid beta-Peptides ; *Calcium Channels/metabolism ; Animals ; Mice ; *Peptide Fragments ; *Calcium/metabolism ; *Mitochondria/metabolism ; *Lead/toxicity ; Cell Line ; Oxidative Stress ; Nitric Oxide Synthase Type II/metabolism ; Alzheimer Disease ; },
abstract = {OBJECTIVES: To investigate the role of mitochondrial calcium uniporter (MCU) in lead (Pb)‑potentiated microglial activation induced by amyloid β‑protein (1-42) (Aβ1-42) and the regulatory mechanism by which Pb exacerbates Alzheimer disease (AD)-like pathology.

METHODS: Cultured BV2 cells treated with 10 μmol/L Aβ1-42 for 12 h (Aβ1-42 group), 10 μmol/L Pb for 12 h (Pb group), or 10 μmol/L Aβ1-42 for 1 h followed by 10 μmol/L Pb for 12 h (Aβ1-42+Pb group) were examined for changes in intracellular calcium levels using ICP-MS. Morphological changes of the treated cells were observed, and iNOS release and oxidative stress were assessed with immunofluorescence staining. The changes in cellular MCU protein expression was determined with Western blotting, and cell viability was evaluated using CCK-8 assay.

RESULTS: Compared with Aβ1-42-treated cells, the cells with the combined treatment showed significantly elevated mitochondrial Ca²⁺ content and increased MCU protein expression. Downregulation of MCU expression obviously alleviated the reduction of viability of HT22 cells treated with the supernatant from BV2 cells co-treated with Pb and Aβ1-42. The combined treatment with lead and Aβ1-42 caused activation of BV2 cells, manifested by increased cell volume and number of protrusions and intensified fluorescence signals of both Iba1 and iNOS. Downregulation of MCU expression significantly suppressed activation of BV2 cells in the siMCU+Aβ1-42+Pb group, and obviously lowered oxidative stress level, mitochondrial calcium overload, and membrane potential level in the cells.

CONCLUSIONS: Pb exposure exacerbates neuronal injury mediated by Aβ1-42-activated microglia through upregulation of MCU expression, which causes mitochondrial calcium accumulation to trigger oxidative stress.},
}

*Microglia/drug effects/metabolism
*Amyloid beta-Peptides
*Calcium Channels/metabolism
Animals
Mice
*Peptide Fragments
*Calcium/metabolism
*Mitochondria/metabolism
*Lead/toxicity
Cell Line
Oxidative Stress
Nitric Oxide Synthase Type II/metabolism
Alzheimer Disease

@article {pmid42934111,
year = {2026},
author = {Ruan, Y and Cui, C and Li, J and Wang, Y and Wang, X},
title = {[Jiaotaiwan improves lipid metabolism abnormalities in a mouse model of Alzheimer disease by regulating the AMPK signaling pathway].},
journal = {Nan fang yi ke da xue xue bao = Journal of Southern Medical University},
volume = {46},
number = {10},
pages = {2509-2517},
pmid = {42934111},
issn = {1673-4254},
mesh = {Animals ; *Alzheimer Disease/metabolism/drug therapy ; Male ; *Lipid Metabolism/drug effects ; *Signal Transduction/drug effects ; Mice ; *AMP-Activated Protein Kinases/metabolism ; *Drugs, Chinese Herbal/pharmacology ; Mice, Inbred C57BL ; Mice, Transgenic ; Disease Models, Animal ; Brain/metabolism ; PC12 Cells ; },
abstract = {OBJECTIVES: To explore whether Jiaotaiwan ameliorates Alzheimer disease (AD) by regulating lipid metabolism via the AMPK pathway.

METHODS: Twenty 3-month-old male transgenic APP/PS1 mice were randomized equally into two groups for treatment with Jiaotaiwan or normal saline via gavage for 4 weeks, with 10 saline-treated wild-type C57BL/6J mice as the control group. Brain lipid deposition, plasma and brain TC, TG and NEFA levels, and expressions of BACE1, Aβ, p-Tau, ZO-1, occludin, AMPK/p-AMPK, SREBP1, ACC, ATGL, and APOE in the brain tissues were detected. In the in vitro experiment, PC12 cell co-cultured with mature adipocytes were treated with Jiaotaiwan, AICAR, or both, and the intracellular lipid droplets, TG, NEFA, AMPK activity, and ACC expression were measured.

RESULTS: In the AD mouse models, Jiaotaiwan significantly reduced brain lipid deposits, lowered plasma TC and TG levels, increased plasma NEFA level, and decreased brain TG and NEFA expressions without affecting TC expression. Jiaotaiwan treatment also significantly lowered the expressions of cerebral Aβ and p-Tau, increased cerebral occludin expression and p-AMPK/AMPK ratio, and reduced ACC, SREBP1 and APOE expressions without affecting ATGL expression in the mouse models. In the co-cultured cells, Jiaotaiwan obviously alleviated cellular lipid accumulation, lowered cellular TG and NEFA levels, reduced supernatant TG content, and enhanced NEFA release. In both the AD mouse model and co-cultured cell model, Jiaotaiwan significantly lowered Aβ level, increased AMPK activity and p-AMPK/AMPK expression, and lowered the expressions of ACC. Jiaotaiwan combined with AICAR produced a synergistic effect for enhancing p-AMPK/AMPK expressions in the co-cultured cells.

CONCLUSIONS: In the APP/PS1 mouse model of AD, Jiaotaiwan alleviates AD-related lipid deposition and dysregulation by activating AMPK and modulating the downstream lipogenic effectors, providing also protective effects on the blood-brain barrier and neural cells.},
}

Animals
*Alzheimer Disease/metabolism/drug therapy
Male
*Lipid Metabolism/drug effects
*Signal Transduction/drug effects
Mice
*AMP-Activated Protein Kinases/metabolism
*Drugs, Chinese Herbal/pharmacology
Mice, Inbred C57BL
Mice, Transgenic
Disease Models, Animal
Brain/metabolism
PC12 Cells

@article {pmid42934178,
year = {2026},
author = {Liang, J and Cao, H and Ren, X and Sha, N and Han, X and Jiang, L and Liu, B and Zhao, W},
title = {Histone Modifications at the Intersection of Aging, Neuroinflammation and Metabolism in Alzheimer's Disease.},
journal = {Aging cell},
volume = {25},
number = {11},
pages = {},
pmid = {42934178},
issn = {1474-9726},
support = {LH2023H073//Natural Science Foundation of Heilongjiang Province/ ; 2026yjscx001//Innovative Research Project for Postgraduate Students of Heilongjiang University of Chinese Medicine/ ; },
mesh = {Humans ; *Alzheimer Disease/metabolism/pathology/genetics ; *Aging/metabolism ; Animals ; *Histones/metabolism ; *Neuroinflammatory Diseases/metabolism ; *Inflammation/metabolism ; Protein Processing, Post-Translational ; Microglia/metabolism ; },
abstract = {Aging, neuroinflammation and metabolic dysfunction are tightly intertwined in Alzheimer's disease (AD), but how transient pathological signals become persistent cellular states remains poorly understood. Histone post-translational modifications (PTMs) provide a dynamic interface between extracellular stimuli, cellular metabolism and chromatin state. This Review examines how canonical histone modifications and emerging metabolite-derived acylations regulate inflammatory and stress-responsive programmes across microglia, astrocytes and neurons during aging and AD. We discuss how amyloid-β, tau pathology, metabolic dysfunction and innate immune signaling converge on histone-modifying machinery, and how reciprocal interactions between metabolism and chromatin may stabilize disease-associated cell states. Particular attention is given to cellular senescence and neuroimmune memory, while emphasizing the context dependence of individual histone marks across cell types, genomic regions and disease stages. We further evaluate evidence for causality using three criteria: perturbation, persistence and reversibility. This framework distinguishes chromatin states that accompany ongoing pathology from those capable of sustaining pathological cell states beyond their initiating signals. Finally, we consider therapeutic strategies targeting histone-modifying enzymes, chromatin readers and metabolic inputs to restore chromatin plasticity and promote resolution of chronic neuroinflammation.},
}

Humans
*Alzheimer Disease/metabolism/pathology/genetics
*Aging/metabolism
Animals
*Histones/metabolism
*Neuroinflammatory Diseases/metabolism
*Inflammation/metabolism
Protein Processing, Post-Translational
Microglia/metabolism

@article {pmid42934374,
year = {2026},
author = {Rao, A and Anwar, M and Rao, AR and Painkra, B and Kiruthika, S and Kumar, S and Yadav, Y and Dey, AB and Dey, S and Chatterjee, P},
title = {Serum neurofilament light protein as a biomarker across the cognitive decline continuum: a cross-sectional study from an Indian cohort.},
journal = {Aging clinical and experimental research},
volume = {38},
number = {1},
pages = {},
pmid = {42934374},
issn = {1720-8319},
mesh = {Humans ; *Neurofilament Proteins/blood ; Biomarkers/blood ; Male ; Aged ; *Cognitive Dysfunction/blood/diagnosis ; India ; Cross-Sectional Studies ; Female ; *Alzheimer Disease/blood/diagnosis ; Case-Control Studies ; ROC Curve ; Middle Aged ; Cohort Studies ; },
abstract = {BACKGROUND: The Alzheimer's disease (AD) continuum spans from healthy aging to subjective cognitive decline (SCD), mild cognitive impairment (MCI), and dementia. Serum Neurofilament Light Protein (NfL) is a potential non-invasive biomarker for neurodegeneration. This study evaluates serum NfL across the cognitive decline continuum in an Indian cohort.

AIMS: To assess serum NfL as a biomarker for early and progressive neurodegeneration, including its diagnostic utility in SCD, MCI, and AD.

METHODS: This case-control study included 129 participants: 28 cognitively normal older adults (HC), 32 with SCD, 33 with MCI, and 36 with AD. Serum NfL levels were measured using Simoa[®] technology. The association of NfL with cognitive decline was analyzed using a Generalized Linear Model (GLM) adjusted for age and sex, and receiver operating characteristic (ROC) curves assessed diagnostic performance.

RESULTS: Serum NfL median levels progressively increased across groups: HC (21.1 pg/mL), SCD (28.94 pg/mL), MCI (35.5 pg/mL), and AD (48.64 pg/mL). Compared to HC, NfL levels were significantly higher in SCD (adjusted coefficient: 0.59, p = 0.004), MCI (0.72, p = 0.001), and AD (1.13, p < 0.001). ROC analysis showed good discrimination: AUC was 0.795 for SCD vs. HC, 0.908 for MCI vs.HC, and 0.941 for AD vs. HC.

DISCUSSION: The study demonstrates a clear association between rising serum NfL levels and advancing cognitive decline.

CONCLUSIONS: Serum NfL demonstrated potential as a sensitive and non-invasive biomarker for early detection and staging of cognitive decline. The establishment of population-specific cut-offs within an Indian cohort contributes to global efforts toward standardizing blood-based biomarkers for AD.},
}

Humans
*Neurofilament Proteins/blood
Biomarkers/blood
Male
Aged
*Cognitive Dysfunction/blood/diagnosis
India
Cross-Sectional Studies
Female
*Alzheimer Disease/blood/diagnosis
Case-Control Studies
ROC Curve
Middle Aged
Cohort Studies

@article {pmid42934377,
year = {2026},
author = {Wu, Y and Zhang, X and Gao, C and Zhang, Z and Liao, X and Kang, Y},
title = {The cGAS-STING Pathway in Neuroinflammation and Neurological Disease: Mechanisms, Disease Contexts, and Periphery-to-Brain Communication.},
journal = {Cellular and molecular neurobiology},
volume = {46},
number = {1},
pages = {},
pmid = {42934377},
issn = {1573-6830},
support = {2024MZFS007//Research Grant of Key Laboratory of Anesthesiology and Resuscitation, Ministry of Education/ ; 82272199//National Natural Science Foundation of China/ ; 2022YFC2504500//Key Technologies Research and Development Program/ ; },
mesh = {Humans ; Animals ; cGAS-STING Signaling Pathway ; *Nucleotidyltransferases/metabolism ; *Nervous System Diseases/metabolism/pathology ; *Brain/metabolism/pathology ; *Neuroinflammatory Diseases/metabolism/pathology ; *Membrane Proteins/metabolism ; Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase ; STING Protein ; Signal Transduction ; Inflammation/metabolism/pathology ; },
abstract = {Neurodegenerative disorders involve a strong inflammatory component, yet the underlying inflammatory mechanisms may be heterogeneous across disease stage, cell type, and systemic context. A key unresolved question is how cellular and systemic stress is converted into sustained neuroinflammation. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is an innate DNA-sensing hub that translates mislocalized self-DNA - derived from mitochondrial stress and mtDNA leakage, nuclear envelope instability, micronuclei formation, or impaired nucleic-acid disposal - into type I interferon, NF-kB, autophagy-related, and senescence-associated inflammatory programs. Rather than treating cGAS-STING as a universal disease-defining pathway, this review frames it as a context-dependent amplifier that becomes pathogenic when DNA-DAMP burden, defective mitochondrial quality control, neurovascular "leakage", and glial priming converge. We synthesize cell-type-specific evidence in microglia, astrocytes, neurons, and the neurovascular unit; compare mechanistic involvement across Alzheimer's disease, Parkinson's disease dementia and Lewy body disease, amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD), vascular and acute brain injury, and systemic inflammatory encephalopathies; and organize periphery-to-brain communication axes using an explicit evidence-grading framework. A distinctive contribution of this review is a two-hit model in which systemic inflammatory stressors and barrier dysfunction first lower cognitive resilience, followed by brain-resident mitochondrial/DNA damage programs that lock in complement-linked synaptopathy. We also evaluate pharmacological and lifestyle-based modulation, emphasizing biomarker-enriched trial design, CNS exposure, compartment-specific target engagement, and immune-safety constraints. This framework aims to clarify when, where, and in whom cGAS-STING modulation may preserve synapses and cognition without unacceptable immune trade-offs.},
}

Humans
Animals
cGAS-STING Signaling Pathway
*Nucleotidyltransferases/metabolism
*Nervous System Diseases/metabolism/pathology
*Brain/metabolism/pathology
*Neuroinflammatory Diseases/metabolism/pathology
*Membrane Proteins/metabolism
Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
STING Protein
Signal Transduction
Inflammation/metabolism/pathology

@article {pmid42934475,
year = {2026},
author = {Lázár, T and Radics, E and Engh, MA and Turkel, C and Tóth, R and Kói, T and Hegyi, P and Kéri, S and Horváth, AA},
title = {How well do dementia risk scores predict dementia? A systematic review and meta-analysis.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {42934475},
issn = {2509-2723},
abstract = {In our systematic review and meta-analysis, we aimed to assess the predictive accuracy and clinical applicability of ten dementia risk assessment scores for incident dementia in cohort studies. Three of 10 risk scores had sufficient, comparable data for a meta-analysis. We analyzed the Cardiovascular Risk Factors Ageing and Dementia (CAIDE), Lifestyle for brain health (LIBRA), and Alzheimer's Disease Risk Index (ANU-ADRI) in middle- and older-aged baseline populations with short, medium, and long follow-up durations, starting free from dementia, with or without other health conditions. A total of 29 studies met our inclusion criteria; 13 were included in the meta-analyses. CAIDE performed best, particularly among middle-aged participants at baseline, with longer follow-up periods, yielding pooled areas under the curves (AUCs) of 0.74-0.76. ANU-ADRI showed stable, moderate predictive accuracy with AUCs of approximately 0.65-0.71. The original LIBRA showed the lowest discrimination, with AUCs ranging from 0.51 to 0.60, whereas the modified LIBRA performed better, with AUCs of 0.65-0.67 at short follow-up and a pooled AUC of 0.70 (95% CI 0.66-0.74) at medium follow-up. Dementia risk assessment scales show variable predictive performance across scores, baseline age, and follow-up duration, and may be useful for dementia risk stratification in clinical practice. As a substantial proportion of dementia risk is linked to potentially modifiable factors, identifying high-risk individuals may help guide timely risk-reduction strategies. Further prospective validation is needed across different populations and clinical settings.},
}

@article {pmid42934585,
year = {2026},
author = {Mastaglio, E and Egleston, B and Lee, KT and Fetzer, D and Brown, S and Domchek, SM and Fleisher, L and Yi-Wen, K and Wagner, L and Roberts, S and Cacioppo, C and Christiansen, J and Howe, S and Wood, EM and Weinberg, M and Karpink, K and Selmani, E and Feng, J and John, S and Schweickert, K and McLeod, B and Bradbury, AR},
title = {A Randomized Hybrid Type I Effectiveness-Implementation Study of an eHealth Delivery Alternative for Cancer Genetic Testing for Hereditary Cancer (eREACH2): study protocol.},
journal = {BMC cancer},
volume = {26},
number = {1},
pages = {},
pmid = {42934585},
issn = {1471-2407},
support = {U01CA243702/CA/NCI NIH HHS/United States ; },
mesh = {Humans ; *Genetic Testing/methods ; *Genetic Counseling/methods ; Female ; Telemedicine ; Genetic Predisposition to Disease ; Adult ; Return of Individual Research Results ; *Neoplasms/genetics/diagnosis ; Male ; },
abstract = {BACKGROUND: Germline cancer genetic testing has become a standard evidence-based practice, with established risk reduction and cancer screening guidelines for genetic carriers. There are also targeted treatments for some genetic carriers with cancers such as breast and ovarian cancer. Yet, many at-risk patients do not have access to genetic services, leaving many genetic carriers unidentified. The eREACH 2 study (A Randomized Hybrid Type I Effectiveness-Implementation Study of an eReach Delivery Alternative for Cancer Genetic Testing for Hereditary Cancer) evaluates whether an interactive, patient-centered digital alternative for genetic education and disclosure of results is non-inferior compared to the traditional model of pre- and post-test counseling with a genetic counselor.

METHODS: This is a Hybrid Type 1 effectiveness implementation study in which participants are randomized using a 2 × 2 design to test a self-directed, patient-informed, digital intervention to deliver clinical genetic testing versus the traditional pre-test (visit 1) and post-test (visit 2: disclosure) counseling delivered by a genetic counselor. The 4 arms include (A) genetic counselor for visit 1 and visit 2, (B) genetic counselor for visit 1 and digital intervention for visit 2, (C) digital intervention for visit 1 and genetic counselor for visit 2, and (D) digital intervention for both visits. Participants are adults who meet National Comprehensive Cancer Network and/or American Society of Clinical Oncology guidelines for germline genetic testing and are recruited from both community and medical sites across the United States by way of clinician referral as well as patient self-referral. The primary outcomes are non-inferiority in uptake of genetic testing and change in genetic knowledge and general anxiety from baseline to post-disclosure.

DISCUSSION: With many barriers to accessing genetic services, innovative delivery models are needed to address these gaps and increase uptake of genetic services. The eREACH2 study evaluates the effectiveness of an interactive patient-centered digital intervention to deliver clinical genetic testing. We expect this work will inform evidence-based guidelines and the standard-of-care for delivery of genetic testing and is designed to be broadly applicable and easily adaptable for other populations and settings even beyond oncology (e.g. Alzheimer's disease).

TRIAL REGISTRATION: This protocol was registered at clinicaltrials.gov (NCT05427240) on 6/7/2022.},
}

Humans
*Genetic Testing/methods
*Genetic Counseling/methods
Female
Telemedicine
Genetic Predisposition to Disease
Adult
Return of Individual Research Results
*Neoplasms/genetics/diagnosis
Male

@article {pmid42934592,
year = {2026},
author = {Atri, A and Curiale, GG and Aisen, P and Barakos, J and Purcell, D and Bracoud, L and Haeberlein, SB and Grassi, C and Hughes, R and Smirnakis, K},
title = {Spectrum of amyloid-related imaging abnormalities associated with aducanumab treatment: a case series report.},
journal = {BMC neurology},
volume = {26},
number = {1},
pages = {},
pmid = {42934592},
issn = {1471-2377},
mesh = {Humans ; *Antibodies, Monoclonal, Humanized/adverse effects/therapeutic use ; Female ; Magnetic Resonance Imaging ; Male ; Aged ; *Alzheimer Disease/drug therapy/diagnostic imaging ; *Brain/diagnostic imaging/drug effects/pathology ; Middle Aged ; Aged, 80 and over ; },
abstract = {BACKGROUND: Amyloid-related imaging abnormalities (ARIA) observed on magnetic resonance imaging (MRI) are known adverse events associated with beta-amyloid plaque-lowering monoclonal antibodies. A spectrum of radiographic and clinical presentations of ARIA have been observed. ARIA-E refer to vasogenic edema in the brain parenchyma and/or leptomeningeal/subpial sulcal effusion; ARIA-H refer to hemosiderin deposits including cerebral microhemorrhage and localized superficial siderosis. With clinical availability of anti-amyloid therapies for treatment of early clinical stage Alzheimer's disease, there is an important need for better awareness of ARIA and education among a diversity of clinicians and practice settings.

METHODS: To illustrate the wide spectrum of ARIA, we present the clinical history, course, and MRI findings as well as summarize learnings and implications of 10 ARIA-E cases from the aducanumab phase 3 clinical trials EMERGE and ENGAGE (ClinicalTrials.gov identifiers NCT02484547 and NCT02477800). Monitoring and management of ARIA, including criteria and timing of MRI, and drug dosing actions were defined per protocol and based upon radiographic severity and clinical symptoms associated with ARIA. ARIA were detected by MRI performed at pre-specified intervals or in response to symptoms or for safety follow-up reasons.

RESULTS: The majority of ARIA-E events were asymptomatic. Most ARIA-E events occurred within the first 8 aducanumab doses and generally resolved within 3-4 months whether dosing was continued (i.e. when ARIA-E was asymptomatic and of mild radiographic severity) or whether dosing was suspended or discontinued. Occasionally, ARIA-E were recurrent. ARIA-H (microhemorrhages and superficial siderosis) most commonly occurred concurrently with ARIA-E. However, ARIA-H without ARIA-E, termed isolated ARIA-H, occurred at a similar frequency in aducanumab- and placebo-treated groups. 10% of participants with ARIA in the 10 mg/kg group had accompanying symptoms. When present, symptoms of ARIA most frequently included headache, nausea, fatigue, dizziness, confusional state, and visual disturbance. Serious symptoms associated with ARIA were uncommon (occurring in 0.3% of the participants treated with the 10 mg/kg dose regimen).

CONCLUSIONS: These illustrative cases provide learnings into the nature and factors associated with ARIA that can increase knowledge for clinicians and trialists regarding the varied radiographic and clinical presentations and evolution of ARIA.

TRIAL REGISTRATION: Clinical Trials NCT02484547, registered June 18, 2015, https://clinicaltrials.gov/study/NCT02484547 . Clinical Trials NCT02477800, registered June 18, 2015, https://clinicaltrials.gov/study/NCT02477800 .},
}

Humans
*Antibodies, Monoclonal, Humanized/adverse effects/therapeutic use
Female
Magnetic Resonance Imaging
Male
Aged
*Alzheimer Disease/drug therapy/diagnostic imaging
*Brain/diagnostic imaging/drug effects/pathology
Middle Aged
Aged, 80 and over

@article {pmid42934641,
year = {2026},
author = {Li, S and Gu, J and Xu, Z and He, C and Yu, C},
title = {Advances in modified anti-Aβ antibodies for the treatment of Alzheimer's disease.},
journal = {BMC medicine},
volume = {24},
number = {1},
pages = {},
pmid = {42934641},
issn = {1741-7015},
support = {82460264//the National Natural Science Foundation of China/ ; },
mesh = {*Alzheimer Disease/therapy/drug therapy/immunology ; Humans ; *Amyloid beta-Peptides/immunology/antagonists & inhibitors ; Animals ; Antibodies, Bispecific/therapeutic use ; *Antibodies, Monoclonal/therapeutic use ; Blood-Brain Barrier/metabolism ; Immunotherapy/methods ; Immunoconjugates/therapeutic use ; },
abstract = {Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disorder, the treatment of which remains a major clinical challenge. In recent years, significant progress has been made in the immunotherapy of AD. Notably, monoclonal antibodies targeting amyloid-β (Aβ) have already been applied in clinical practice. However, as macromolecular therapeutics, antibodies face substantial challenges in crossing the blood-brain barrier (BBB) efficiently. Systemic administration typically requires high dosages to achieve the therapeutic level of brain exposure, which may trigger adverse events such as amyloid-related imaging abnormalities (ARIA) and thus restrict their widespread clinical application. To resolve this problem, various engineering strategies for modifying anti-Aβ antibodies have been developed. This review summarizes four major modification categories: BBB-penetrating bispecific antibodies (BsAbs), glycosylation engineering, antibody-drug conjugates (ADCs), and chimeric antigen receptor (CAR)-based cell therapies (including CAR-macrophages, CAR-T cells, and CAR-astrocytes). We provide an in-depth discussion of their delivery efficiency, targeting capability, and safety, aiming to lay a foundation for developing safer and more effective next-generation anti-Aβ antibody therapeutic strategies.},
}

*Alzheimer Disease/therapy/drug therapy/immunology
Humans
*Amyloid beta-Peptides/immunology/antagonists & inhibitors
Animals
Antibodies, Bispecific/therapeutic use
*Antibodies, Monoclonal/therapeutic use
Blood-Brain Barrier/metabolism
Immunotherapy/methods
Immunoconjugates/therapeutic use

@article {pmid42934778,
year = {2026},
author = {Shitrit, A and Khattib, A and Khatib, S},
title = {Cannabis flower extracts as a multi-target agent in Alzheimer's disease: Inhibition of AChE, BChE, and BACE1 with cell-protective effects in a PC12 cell model.},
journal = {Journal of cannabis research},
volume = {8},
number = {1},
pages = {},
pmid = {42934778},
issn = {2522-5782},
support = {2022//Jewish Colonization Association (JCA) in Israel/ ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder marked by progressive cognitive decline. Despite extensive research, its multifactorial nature continues to challenge the development of effective therapies. Current treatments, including anticholinergic agents and amyloid β-targeted drugs, alleviate symptoms but fail to halt disease progression and often produce side effects. Therefore, novel multi-target strategies are urgently needed. Cannabis (Cannabis sativa L.) has long been recognized for its medicinal properties, yet its potential in AD therapy has only recently gained attention. Previous studies have mainly focused on single cannabinoids or endocannabinoid system modulation. In this study, we investigated whole cannabis flower extracts, rich in diverse active compounds, for their ability to inhibit key AD-related enzymes: acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and β-secretase (BACE1), using spectrophotometric assays. Fractionation of one extract further identified components with potent inhibitory activity against both BChE and BACE1. Additionally, the extracts were evaluated for their cell-protective potential in PC12 cells exposed to hydrogen peroxide (H2O2) and amyloid β (Aβ1-42), mimicking AD-like oxidative stress conditions. Cannabis extracts showed stronger inhibition of cholinergic enzymes compared to Galantamine, with efficacy depending on extract composition. Importantly, this study is among the first to reveal significant BACE1 inhibition by cannabis extracts. Moreover, the extracts enhanced PC12 cell viability under oxidative stress, indicating cell-protective effects. Overall, these findings suggest that multi-component cannabis extracts may interact with several AD-related molecular targets in vitro and may serve as promising leads for further mechanistic and preclinical investigation.},
}

@article {pmid42934801,
year = {2026},
author = {Chen, Y and Tang, F and Li, X},
title = {MSC-derived extracellular vesicle-associated miRNAs in CNS diseases: mechanisms of microglial polarization and therapeutic implications.},
journal = {Stem cell research & therapy},
volume = {17},
number = {1},
pages = {},
pmid = {42934801},
issn = {1757-6512},
support = {2025ZNSFSC0674//Natural Science Foundation of Sichuan Province/ ; 82071353//National Natural Science Foundation of China/ ; 2021YFS0029 and 2020YFS0104//Key R&D Projects of the Science and Technology Department of Sichuan Province/ ; },
mesh = {Humans ; *MicroRNAs/metabolism/genetics ; *Extracellular Vesicles/metabolism/genetics ; *Mesenchymal Stem Cells/metabolism ; *Central Nervous System Diseases/therapy/genetics/metabolism/pathology ; *Microglia/metabolism/pathology ; Animals ; },
abstract = {Microglia-mediated neuroinflammation contributes to the pathogenesis of many central nervous system (CNS) diseases. After injury or infection, microglia can adopt pro-inflammatory programs that amplify neuronal damage. By contrast, reparative microglial states support inflammatory resolution, tissue repair and regeneration. Strategies that redirect harmful microglial activation toward reparative programs therefore have therapeutic relevance. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs), particularly small EV-enriched preparations, are increasingly studied as low-immunogenicity carriers of regulatory cargo. EV-associated microRNAs (miRNAs) are among the major payloads implicated in immunomodulation. This review synthesizes how MSC-EV-associated miRNAs regulate microglial polarization and neuroinflammation through TLR/NF-κB, MAPK, JAK/STAT, PI3K/Akt and Wnt/β-catenin signaling. We discuss evidence from ischemic stroke, traumatic brain injury, spinal cord injury, Alzheimer's disease and sepsis-associated encephalopathy, and highlight EV terminology, donor source, species context and translational comparability as key barriers for future development.},
}

Humans
*MicroRNAs/metabolism/genetics
*Extracellular Vesicles/metabolism/genetics
*Mesenchymal Stem Cells/metabolism
*Central Nervous System Diseases/therapy/genetics/metabolism/pathology
*Microglia/metabolism/pathology
Animals

@article {pmid42934846,
year = {2026},
author = {Tang, L and Chen, X and Zhang, L and Fan, L and Chen, N and Li, C and Cai, Z and Chen, G and Chen, H and Ye, M and Zheng, H and Li, Q and Ke, Z and Hu, Z and Cao, M and Yang, D and Xu, S and Xie, C and Li, X and Xu, X and Yu, M and Lian, X and Hu, H and Li, H and Cai, X and Chen, H and Xu, W and Cui, G and Zhao, Y and Dong, J and Zhang, L and Zhu, X and Zhao, H and Xu, Y},
title = {Real-world clinical, biomarker, and imaging outcomes of lecanemab in Alzheimer's disease: a multicenter longitudinal cohort study in Jiangsu, China.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {},
pmid = {42934846},
issn = {1552-5279},
support = {2022ZD0211800//STI2030-Major Projects/ ; 82130036 82471454 U25A2064//National Natural Science Foundation of China/ ; ZDXK202216//Jiangsu Province Key Medical Discipline/ ; ZKX23026//Nanjing Key Medical Science and Technology Development Project/ ; //the Nanjing Key Medical Science and Technology Development Project/ ; },
mesh = {Humans ; *Alzheimer Disease/drug therapy/diagnostic imaging/blood ; Female ; Biomarkers/blood ; Male ; Longitudinal Studies ; Amyloid beta-Peptides/blood ; tau Proteins/blood ; China ; Aged ; Peptide Fragments/blood ; Cognitive Dysfunction/drug therapy ; Cohort Studies ; Positron-Emission Tomography ; Magnetic Resonance Imaging ; },
abstract = {INTRODUCTION: Real-world data on lecanemab's efficacy and the longitudinal dynamics of plasma biomarkers are scarce in Chinese patients with Alzheimer's disease (AD).

METHODS: In this multicenter cohort study, 181 AD patients received biweekly lecanemab. Disease-stage-specific Clinical Dementia Rating-Sum of Boxes meaningful within-patient change defined response at Months 3, 6, and 12. We used penalized models, receiver operating characteristic analysis, attrition comparisons, and exploratory Month 3 plasma biomarker analysis.

RESULTS: Cognitive response emerged at Month 6 and intensified by Month 12, largely restricted to mild cognitive impairment and mild dementia due to AD. Repeated five-fold cross-validated areas under the curve across the follow-up timepoints were 0.560, 0.747, and 0.773, with apolipoprotein E ε4 positivity and more severe cognitive impairment linked to lower response odds. Plasma phosphorylated tau 217 (p-tau217) and amyloid beta (Aβ) 42/40 altered as early as Month 3. Month 3 Aβ42/40 showed modest exploratory discrimination. The incidence of amyloid-related imaging abnormalities was 7.2%, all asymptomatic.

DISCUSSION: Lecanemab is effective and safe in AD over 6 to 12 months. Early biomarker changes (p-tau217, Aβ42/40) precede clinical improvement, serving as scalable response indicators.},
}

Humans
*Alzheimer Disease/drug therapy/diagnostic imaging/blood
Female
Biomarkers/blood
Male
Longitudinal Studies
Amyloid beta-Peptides/blood
tau Proteins/blood
China
Aged
Peptide Fragments/blood
Cognitive Dysfunction/drug therapy
Cohort Studies
Positron-Emission Tomography
Magnetic Resonance Imaging

@article {pmid42934953,
year = {2026},
author = {Peshoff, MM and Hambardzumyan, D and Wu, LJ},
title = {TREM2: friend or foe in glioma?.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag369},
pmid = {42934953},
issn = {1460-2156},
abstract = {Triggering receptor expressed on myeloid cells 2 (TREM2) is a neuroimmune signaling hub involved in key cellular processes including microglial phagocytosis, chemotaxis, and inflammation. Dysregulation of TREM2 has been implicated in a variety of diseases, most notably in the innate immune response to neurodegenerative disorders and cancer. The TREM2 pathway plays a significant role in governing microglia phenotypic transitions in Alzheimer's disease, as well as in regulating tumor-associated macrophages' ability to modulate cytotoxic activity. However, TREM2's role can be dependent on experimental parameters and disease contexts. Due to its intricate involvement in related disorders and the myeloid-dominated microenvironment in brain tumors, TREM2 has emerged as a vital player to better understand neuroimmune contributions to central nervous system malignancies. This review critically evaluates TREM2's controversial function in gliomas, analyzes experimental and biological variables that may underlie divergent findings, and outlines important considerations for future investigations.},
}

@article {pmid42935028,
year = {2026},
author = {Khuman, YM and Kapadiya, YM and Maru, JJ},
title = {Synthetic Insights on Donepezil: An Anti-Alzheimer Drug.},
journal = {Archiv der Pharmazie},
volume = {359},
number = {10},
pages = {},
doi = {10.1002/ardp.70364},
pmid = {42935028},
issn = {1521-4184},
mesh = {*Donepezil/chemical synthesis/pharmacology/chemistry/therapeutic use ; Humans ; *Alzheimer Disease/drug therapy ; *Cholinesterase Inhibitors/chemical synthesis/pharmacology/chemistry ; *Nootropic Agents/chemical synthesis/pharmacology ; Animals ; Molecular Structure ; },
abstract = {Alzheimer's disease is a severe condition that poses significant global health concerns to international health agencies and remains a major threat to public health. As there is no cure for Alzheimer's disease, various anti-Alzheimer's medications are used to manage its symptoms. Donepezil is one of the most highly marketed drugs, known for its positive effects on cognition, function, behaviour and overall patient condition, making it a standout treatment option. Various synthetic methods have been developed to produce more efficient pathways that minimise by-products and maximise yield. This review summarises the reported literature on various synthetic routes for producing Donepezil. We have also made an effort to highlight the advantages and limitations of prior literature, which may lead to potential improvements for future research. This work will serve as a foundation for upcoming researchers, ultimately benefiting the well-being of Alzheimer's patients and human society as a whole.},
}

*Donepezil/chemical synthesis/pharmacology/chemistry/therapeutic use
Humans
*Alzheimer Disease/drug therapy
*Cholinesterase Inhibitors/chemical synthesis/pharmacology/chemistry
*Nootropic Agents/chemical synthesis/pharmacology
Animals
Molecular Structure

@article {pmid42935251,
year = {2026},
author = {Haricharan, PB and El-Amier, N and Nicolau, B and Feine, J and de Souza, RF},
title = {Is There Evidence That Dental Care Modifies Cognitive Decline? Insights from a Scoping Review.},
journal = {JDR clinical and translational research},
volume = {},
number = {},
pages = {23800844261491617},
doi = {10.1177/23800844261491617},
pmid = {42935251},
issn = {2380-0852},
abstract = {BACKGROUND: Emerging research suggests that poor oral health, manifested as tooth loss, periodontal disease, or edentulism, may contribute to cognitive impairment and dementia in older adults. However, the role of dental care interventions in modifying this risk remains unclear.

OBJECTIVE: To systematically map and evaluate the evidence on whether dental care utilization and specific dental interventions are associated with cognitive function or cognitive decline in middle-aged and elderly populations.

METHODS: A scoping review was conducted using PRISMA-ScR guidelines. Four databases (MEDLINE, Embase, CINAHL, and PsycINFO) were searched from inception to April 11, 2025. Eligible studies examined the association between dental care and cognitive outcomes in adults aged 45 y or older with tooth loss or other oral conditions. Dental care exposures were grouped into 4 domains: dental care utilization, removable prosthodontic rehabilitation, fixed prosthodontic rehabilitation, and periodontal therapy.

RESULTS: Fifty-three studies were included. Most studies on dental care utilization found that regular dental visits were associated with lower dementia risk, although some showed null associations. Removable prosthodontic rehabilitation, especially with well-fitting or implant-supported dentures, was associated with improved cognitive function, likely mediated by chewing efficiency and nutrition. Fixed prosthodontic rehabilitation, such as implants and crowns, was consistently linked to better cognitive scores. Periodontal therapy showed the most consistent benefit, reducing systemic inflammation and dementia risk. However, evidence remains predominantly observational and marked by substantial heterogeneity across study designs, definitions of dental exposures, and cognitive outcome measures.

CONCLUSION: Maintaining oral health via regular dental care appears to support cognitive resilience in middle-aged and older adults. However, standardized methodologies and prospective studies are needed to clarify causal pathways and inform clinical guidelines.Knowledge Transfer Statement:This scoping review maps the current evidence on whether dental care utilization and common oral health interventions are associated with cognitive outcomes in adults. The findings may guide future translational research and integrated care pathways to reduce cognitive decline through optimized dental care.},
}

@article {pmid42935328,
year = {2026},
author = {Klimov, NA and Orlov, DS and Grishina, TV and Leonova, LE and Shamova, OV},
title = {[Prospects of application of peptide preparations in therapy of Alzheimer's disease.].},
journal = {Advances in gerontology = Uspekhi gerontologii},
volume = {39},
number = {4},
pages = {502-511},
doi = {10.34922/AE.2026.39.4.002},
pmid = {42935328},
issn = {1561-9125},
mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism/physiopathology ; *Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; *Peptides/pharmacology ; },
abstract = {Alzheimer's disease (AD) is a serious kind of pathology that mainly affects older adults and significantly reduces the quality of their life. Despite decades of research, the pathogenesis of AD, the causes and the trigger mechanism of its occurrence remain the subject of debate. This review examines hypotheses of the pathogenesis of AD, including the involvement of amyloid-β peptide and hyperphosphorylated tau protein fragments in neuroinflammation and neurodegeneration. It also discusses potential therapies for AD based on peptides that target various aspects of the disease's pathogenesis.},
}

Humans
*Alzheimer Disease/drug therapy/metabolism/physiopathology
*Amyloid beta-Peptides/metabolism
tau Proteins/metabolism
*Peptides/pharmacology

@article {pmid42935350,
year = {2026},
author = {van de Veen, D and Smeets, B and Peetoom, K and de Vugt, M and Bakker, C and Koopmans, R},
title = {The influence of caregivers' lived experiences in decision-making processes on care transitions in young-onset dementia.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261498377},
doi = {10.1177/13872877261498377},
pmid = {42935350},
issn = {1875-8908},
abstract = {BackgroundCaregivers of people with young-onset dementia (YOD) hold diverse perspectives on the caregiving trajectory, reflecting the heterogeneity of underlying etiologies and the life stages of these people, who are often in the midst of employment, child-rearing, and other social responsibilities. Post-diagnostic care and services are often suboptimal and caregivers tend to be hesitant to initiate formal care and support services. We refer to movements of persons between different levels of care or physical locations as care transitions.ObjectiveTo improve caregiver support, this study aimed to provide insights into caregivers' perspectives on the decision-making process regarding care transitions and associated barriers and facilitators.MethodsSeventeen interviews with six caregivers of people with YOD were analyzed. Inductive content analysis was used to generate codes, followed by constant comparative analysis to create categories and themes describing caregivers' experiences.ResultsBarriers and facilitators influencing the decision-making process related to the initiation of care transitions were identified at two themes: individual and contextual level. Six categories and 23 sub-categories emerged. Individual-level categories included the character traits of the caregiver, the caregiver's need for support, impacts on the quality of the caregiver's relationship, and the burden experienced by the caregiver. Contextual-level categories included the social environment and the caregivers' experiences with healthcare professionals.ConclusionsCaregivers' decision-making regarding care transitions is shaped by thinking processes, character traits and contextual aspects. Healthcare professionals should strengthen collaboration and communication with caregivers. Acknowledging grief and supporting caregivers'sense of control are essential to providing adequate support.},
}

@article {pmid42935558,
year = {2026},
author = {Sattari, N and Dave, A and Chen, IY and Lui, KK and Chappel-Farley, MG and Berisha, DE and Sprecher, KE and Riedner, BA and Jones, S and Bendlin, BB and Mander, BA and Benca, RM},
title = {Sex differences in sleep and memory relationships in older adults at risk for Alzheimer's disease.},
journal = {Frontiers in endocrinology},
volume = {17},
number = {},
pages = {1930177},
pmid = {42935558},
issn = {1664-2392},
mesh = {Humans ; *Alzheimer Disease/physiopathology/genetics ; Female ; Male ; Aged ; *Memory/physiology ; Polysomnography ; *Sleep/physiology ; *Sex Characteristics ; Apolipoprotein E4/genetics ; Electroencephalography ; Risk Factors ; Aged, 80 and over ; Sex Factors ; Sleep Stages ; },
abstract = {INTRODUCTION: Biological sex is an important modifier of aging and Alzheimer's disease risk, yet the sleep-related mechanisms through which sex and genetic risk interact to influence memory remain poorly understood. We examined whether associations among non-rapid eye movement sleep physiology, overnight memory retention, and apolipoprotein E ϵ4 (APOE ϵ4) status, a genetic risk factor for Alzheimer's disease, differed by sex in cognitively unimpaired older adults enriched for Alzheimer's disease risk.

METHODS: Eighty participants completed overnight polysomnography with high-density electroencephalography, and 65 also completed an evening encoding/immediate recall and morning delayed recall word-pair memory task.

RESULTS: Overnight memory retention did not differ by sex. However, exploratory analyses of the proportional overnight retention measure suggested a sex × APOE ϵ4 interaction, such that female APOE ϵ4 carriers may exhibit reduced overnight forgetting relative to female non-carriers and male carriers. Although counterintuitive, this pattern may reflect compensatory or resilience-related sleep-memory mechanisms in cognitively unimpaired women at genetic risk for Alzheimer's disease rather than a protective effect of APOE ϵ4 itself. Women spent more time in N3 sleep and had higher non-rapid eye movement delta and slow sigma power than men. Sleep-memory associations also differed by sex: greater N2 duration was more strongly associated with better overnight retention in men, whereas greater frontal slow sigma power and fronto-central fast sigma power were positively associated with retention in women. Exploratory APOE-stratified analyses suggested sex-specific differences in sleep stage-memory relationships, with more positive N2-memory associations in male than female APOE ϵ4 carriers and more positive N3-memory associations in female than male carriers; both differences remained significant after FDR correction. TFCE-corrected analyses further identified positive associations between NREM delta and sigma activity and overnight memory retention in female APOE ϵ4 carriers.

DISCUSSION: These findings highlight sex-specific patterns in NREM sleep physiology and sleep-memory relationships in cognitively unimpaired older adults at risk for Alzheimer's disease. More broadly, the results suggest that sex and APOE ϵ4 status may jointly shape the neurophysiological pathways linking sleep and memory, underscoring the importance of considering sex as a biological variable when studying sleep, cognitive aging, and Alzheimer's disease vulnerability.},
}

Humans
*Alzheimer Disease/physiopathology/genetics
Female
Male
Aged
*Memory/physiology
Polysomnography
*Sleep/physiology
*Sex Characteristics
Apolipoprotein E4/genetics
Electroencephalography
Risk Factors
Aged, 80 and over
Sex Factors
Sleep Stages

@article {pmid42935632,
year = {2026},
author = {Bae, YJ and Daily, JW and Park, S},
title = {Gut Microbiota as a Mechanistic Nexus between Type 2 Diabetes and Alzheimer's Disease: Insulin Resistance, Neuroinflammation, and Functional Food Strategies.},
journal = {Preventive nutrition and food science},
volume = {31},
number = {5},
pages = {},
pmid = {42935632},
issn = {2287-1098},
abstract = {Type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) share substantial pathological overlap, including brain-specific insulin resistance driven by impaired insulin receptor substrate-1/phosphoinositide 3-kinase/protein kinase B signaling, glycogen synthase kinase-3β dysregulation, tau hyperphosphorylation, and amyloid-β accumulation. Brain-insulin resistance is a key mechanistic link between peripheral metabolic dysfunction and neurodegeneration, although the upstream regulatory pathways remain incompletely defined. Gastrointestinal depletion of butyrate-producing microbial taxa and enrichment of pro-inflammatory genera have been independently documented in T2DM and AD. Gut microbiota dysbiosis propagates insulin resistance through at least five pathways: short-chain fatty acid depletion, lipopolysaccharide (LPS)-mediated endotoxemia, bile acid dysregulation, tryptophan-kynurenine imbalance, and vagus nerve disruption. Critically, LPS translocation and kynurenine-driven neurotoxicity propagate AD-relevant neuroinflammation independently of peripheral metabolic dysfunction, implicating a bidirectional gut-brain mechanism. These risks are amplified in Asian populations, who exhibit a lower pancreatic β-cell mass and attenuated insulin secretion that confer disproportionate vulnerability to glucotoxic cycling and its neurological complications. Such a population-specific dimension remains largely absent from reviews. Against this backdrop, traditional Asian fermented foods (chungkookjang, kimchi, and natto) and plant-derived functional ingredients (Eucommia ulmoides, gooseberry, and black garlic) have a preclinical capacity to restore microbial balance, attenuate insulin resistance, and exert neuroprotection. This review integrates these strands into a unified mechanistic and translational framework, positioning gut microbiota modulation through culturally grounded dietary strategies as a tractable approach to reducing the converging burdens of T2DM and AD in Asians.},
}

@article {pmid42935657,
year = {2026},
author = {Hussain, A and Bokhari, SAI},
title = {Mechanistic insights of Artemisia-derived therapeutics in Alzheimer's disease (AD): from crude botanical extracts to artemisinin and derivatives.},
journal = {3 Biotech},
volume = {16},
number = {11},
pages = {479},
pmid = {42935657},
issn = {2190-572X},
abstract = {Alzheimer's disease (AD) is characterized by several pathological processes including amyloid-β (Aβ) accumulation, Tau hyperphosphorylation, oxidative stress, synaptic dysfunction, neuroinflammation, mitochondrial impairment and loss in neuronal stability. This review assessed the reported neuroprotective potential of crude extracts of different Artemisia species and artemisinin with its derivatives in AD. It focuses on targets, mechanisms, observational markers and functional effects validated by Artemisia extracts and compounds like artemisinin, artemisinin B, artemether, artesunate and dihydroartemisinin in experimental AD models. A comprehensive review of studies was conducted including in vitro, in vivo and in silico research on Artemisia extracts and derivatives focusing on their effects on various pathological processes related to brain. Results showed crude extracts from 17 Artemisia species, which have been reported with considerable neuroprotective effects. Artemisinin and derivatives deliver neuroprotection via targeted mechanisms and effecting observational markers with varying functional outcomes. However, differences in AD models, administration routes, doses, extract composition and outcomes limit direct efficacy comparisons. Hence, direct comparisons of efficacy among Artemisia extracts, artemisinin and its derivatives should be interpreted cautiously. Future inquiries should highlight standardized preparations, brain exposure and pharmacokinetics, mechanistic validation, long-term safety and well-designed comparative and clinical trials to evaluate their potential for AD treatment.},
}

@article {pmid42935659,
year = {2026},
author = {Timsina, J and Chen, Y and Liu, M and Mu, R and Gong, K and Budde, J and Wang, G and Li, Y and Schindler, SE and Morris, JC and Holtzman, DM and Bateman, RJ and Hohman, TJ and Cruchaga, C},
title = {Symmetric Centipolar Normalized Score (SCeNS): A standardization framework for fluid marker cross-comparability in Alzheimer's disease.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {4},
pages = {e70516},
pmid = {42935659},
issn = {2352-8729},
abstract = {INTRODUCTION: Multiple platforms measure Alzheimer's disease fluid biomarkers, such as amyloid beta (Aβ) and p-tau, leading to heterogeneous data. Existing harmonization methods are difficult to interpret as they still provide specific cut-offs and biomarker values are not commaptible between different biomarkers.

METHODS: We propose a standardization approach, Symmetric Centipolar Normalized Score (SCeNS), which uses Gaussian mixture model-derived cutoffs to rescale biomarker z-scores onto a -100 to 100 scale, with a constant cut-off to derive biomarker status, that can be applied to fluid as well as imaging biomakers. The sign (plus or minus) reflects sample's biomarker status. We present the calculation steps and demonstrate how SCeNS enables direct comparison across cohorts, platforms, and tissue types. We also demonstrate a use case of the approach using real-world data from individuals treated with lecanemab.

RESULTS: SCeNS were calucated using cerebrospinal and plasma AD biomarkers measured in mutliple platforms, demostrating that the SCeNS methods provide a consistent and easy to understand biomarker level. We applied the SCeNS method to the lecanmab-treated cohort, where we demostrated the SCeNS previde easy to interpert biomkaer changes as p-tau217 showed highest unit of change, while p-tau181 had highest conversion (7.57%) to biomarker negative.

DISCUSSION: SCeNS provides a simple, interpretable biomarker metric across platforms.},
}

@article {pmid42935768,
year = {2026},
author = {Tian, J and Huang, W and Wen, Y and Liang, Y},
title = {Application of large language models in early screening of Alzheimer's disease: a scoping review.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1906641},
pmid = {42935768},
issn = {1663-4365},
abstract = {OBJECTIVE: To systematically map the current applications of large language models (LLMs) in the early screening of Alzheimer's disease (AD) and to provide evidence to inform future research and nursing practice.

METHODS: This scoping review was conducted in accordance with the Joanna Briggs Institute (JBI) methodological framework. A comprehensive search was performed in PubMed, Web of Science, Embase, Cochrane Library, ProQuest, and Scopus from database inception to April 20, 2026. Eligible studies were screened, selected, and synthesized according to predefined inclusion criteria.

RESULTS: A total of 25 studies were included. The LLMs applied in these studies mainly consisted of general-purpose generative models, multimodal models, and medical-specific models. Data sources primarily included public databases, along with real-world clinical data and simulated data. LLMs were mainly applied for cognitive impairment identification, data augmentation, automated cognitive assessment, and clinical decision support, with cognitive impairment identification being the predominant application direction. Several studies employed prompting strategies including zero-shot prompting, few-shot prompting, chain-of-thought prompting, and agent-based prompting. Multimodal integration and agent-based collaborative reasoning have emerged as important research directions in recent years.

CONCLUSION: Large language models provide a novel technological approach for early AD screening and demonstrate potential for supporting cognitive assessment and risk identification. Future research should strengthen real-world studies, multicenter validation, and the development of model safety and ethical governance frameworks to facilitate the standardized application of LLMs in early AD screening.},
}

@article {pmid42935792,
year = {2026},
author = {Puri, BK and Preyer, R and Lee, GS and Monaghan, L and Schwarzbach, A},
title = {Prefrontal Planning Latency Associated With Age and Serological Evidence of Microbial Exposure.},
journal = {Chronic diseases and translational medicine},
volume = {},
number = {},
pages = {},
pmid = {42935792},
issn = {2589-0514},
abstract = {BACKGROUND: It has been hypothesized that certain cognitive disorders characterized by frontal executive dysfunction, such as Alzheimer's disease (a neurodegenerative conformational proteinopathy involving amyloid-β and tau), may be associated with prior exposure to infectious agents. This study aimed to test the hypothesis that serological markers of microbial exposure are associated with frontal lobe activity in humans.

METHODS: Executive planning latency was measured in 53 adult participants in this cross-sectional study. A venous blood sample was collected from each participant. Assays for the serological markers of bacterial and viral exposure were performed in a blinded manner.

RESULTS: Generalized linear modeling (likelihood ratio χ [2] = 27.76, df = 5, p = 0.0001) included five statistically significant independent variables. Among these, age (|t| = 4.360, p = 0.0001), Borrelia burgdorferi lymphocyte function-associated antigen-1 (| t | = 3.260, p = 0.002), and Ehrlichia chaffeensis and Anaplasma phagocytophilum assays (| t | = 3.138, p = 0.003) were highly significant.

CONCLUSION: This study supports the hypothesis that frontal lobe executive function, as indexed by prefrontal cortical planning latency, is associated with serological evidence of exposure to several bacterial genera, particularly Borrelia and Ehrlichia/Anaplasma, as well as with age.},
}

@article {pmid42935795,
year = {2027},
author = {Oliveira, GM and Nunes, BP and Lam, K and Lima-Costa, MF and Torres, JL and Macinko, J and Moreira, BS and Avelino-Silva, TJ and Gonçalves, VAD and Fortes-Filho, SQ and de Castro, TF and Batista, SRR and Ferriolli, E and Aliberti, MJR},
title = {Primary care effectiveness, multimorbidity, and hospital use in public and private health-care systems in Brazil: a cross-sectional analysis of data from the 2019-2021 Brazilian longitudinal study of aging.},
journal = {Lancet regional health. Americas},
volume = {66},
number = {},
pages = {101680},
pmid = {42935795},
issn = {2667-193X},
abstract = {BACKGROUND: Whether patient-reported experiences in primary care modify the association between multimorbidity and emergency department (ED) visits and hospitalizations remains unclear. We examined these associations across public and private health system sectors among Brazilians aged ≥50 years.

METHODS: This cross-sectional study used nationally representative data from the 2019-2021 Brazilian Longitudinal Study of Aging. Multimorbidity was defined as the presence of ≥2 of 13 chronic conditions. A 12-item patient-reported primary care effectiveness index captured access, continuity, communication, and coordination with participants' usual source of healthcare. Primary outcomes were ED visits and hospitalizations in the past 12 months. Poisson regression models estimated associations with the outcomes, and assessed interactions among multimorbidity, primary care effectiveness, and health system sectors.

FINDINGS: Among 9058 participants (mean age = 66.3 ± 9.9 years; females = 55.3%; White race/ethnicity = 46.4%), 38.0% had multimorbidity. Overall, 12.5% reported an ED visit and 6.0% ≥ 1 hospitalization in the past 12 months. Multimorbidity was associated with approximately twice the prevalence of ED visits and three times the prevalence of hospitalizations. Primary care effectiveness modified these associations across health system sectors (three-way interaction p = 0.04 for ED visits and p < 0.001 for hospitalization). In the public system, higher primary care effectiveness attenuated the association between multimorbidity and hospitalization (interaction prevalence ratio [PR] = 0.74, 95% confidence interval [CI] = 0.63-0.87). In contrast, in the private system, higher primary care effectiveness strengthened the associations of multimorbidity with ED visits (interaction PR = 1.40, 95% CI = 1.18-1.66) and hospitalization (interaction PR = 1.75, 95% CI = 1.22-2.50).

INTERPRETATION: Associations between multimorbidity and healthcare use varied according to patient-reported primary care experiences and health system sector.

FUNDING: The Brazilian National Council for Scientific and Technological Development, the Alzheimer's Association, and the National Institute on Aging.},
}

@article {pmid42935819,
year = {2026},
author = {Zhao, H and Qin, B and Zou, Z and Wen, P},
title = {Explainable machine learning for identifying high-risk Alzheimer's disease and key health characteristics among community-dwelling adults.},
journal = {Frontiers in public health},
volume = {14},
number = {},
pages = {1943300},
pmid = {42935819},
issn = {2296-2565},
mesh = {Humans ; *Alzheimer Disease/diagnosis/epidemiology ; Male ; Female ; *Machine Learning ; Aged ; *Independent Living/statistics & numerical data ; Random Forest ; Middle Aged ; Risk Assessment/methods ; Risk Factors ; Health Surveys ; Aged, 80 and over ; Predictive Learning Models ; },
abstract = {OBJECTIVE: To develop an interpretable machine learning model to identify individuals with AD8-defined high-risk status for Alzheimer's disease among community-dwelling adults, identify key health characteristics and their association patterns with high-risk status, and to inform community-based cognitive health promotion.

METHODS: Based on health survey data from 6,267 community-dwelling adults, AD8-defined high-risk status for Alzheimer's disease was assessed using the Alzheimer's Disease Screening Scale (AD8). LASSO logistic regression, random forest, and decision tree models were constructed, and SHapley Additive exPlanations (SHAP) was used to analyze the importance of key health characteristics and their association patterns.

RESULTS: A total of 6,267 community-dwelling adults were included, of whom 1,454 (23.2%) were classified into the AD8-defined high-risk group. The random forest model showed the highest discriminative performance among the three models. SHAP analysis indicated that fruit intake, age, snoring, mean grip strength, and sleep duration were important health characteristics associated with AD8-defined high-risk status for Alzheimer's disease. SHAP dependence plots further revealed a graded negative association between fruit intake and high-risk status, a U-shaped association for sleep duration, a U-shaped association for mean grip strength, and a positive graded association between snoring frequency and high-risk status.

CONCLUSIONS: Random forest combined with SHAP identified key health characteristics associated with AD8-defined high-risk status among community-dwelling adults and revealed non-linear association patterns involving health behaviors and physical function. These findings may provide useful information for community-based risk stratification and targeted cognitive health promotion.},
}

Humans
*Alzheimer Disease/diagnosis/epidemiology
Male
Female
*Machine Learning
Aged
*Independent Living/statistics & numerical data
Random Forest
Middle Aged
Risk Assessment/methods
Risk Factors
Health Surveys
Aged, 80 and over
Predictive Learning Models

@article {pmid42936480,
year = {2026},
author = {Ding, JA and Samvelian, D and Ying, Z and Diamante, G and Ahn, IS and Palafox-Sanchez, V and Wang, SS and Gomez-Pinilla, F and Yang, X},
title = {Hippocampal and hypothalamic cell-type specific mechanisms underlying nutritional and metabolic modulation of Alzheimer's disease.},
journal = {iScience},
volume = {29},
number = {11},
pages = {117920},
pmid = {42936480},
issn = {2589-0042},
abstract = {To understand the potential of modulating metabolism for therapeutic development for Alzheimer's disease (AD), we investigated the effects of high fructose consumption as a potential risk, and docosahexaenoic acid (DHA) and nicotinamide riboside (NR) as potentially beneficial, on cell type-specific transcriptomic responses in the hippocampus and hypothalamus of the 5xFAD mouse model. Fructose increased the expression of C3, encoding complement component 3, in ependymal cells and inflammatory genes in microglia, which were normalized by DHA and NR. NR and DHA reversed Aβ-associated transcriptional signatures across cell types, but the effects were modified by fructose. DHA and NR treatments reversed the AD-associated decrease in hippocampal oligodendrocytes, with DHA further reducing hippocampal microglia and increasing hypothalamic astrocytes, and NR further increasing hippocampal neuronal proportions. Our study supports the impact of metabolic regulation of AD-associated cell types and pathways and provides molecular support for utilizing nutritional modulators for AD intervention.},
}

@article {pmid42936906,
year = {2026},
author = {Valentim, C and Denecke, J and Frerich, S and Betthauser, TJ and Li, Y and Ahmadi, R and Franzmeier, N and , and Malik, R and Ewers, M},
title = {Pathway-specific polygenic risk scores modify the association between amyloid and tau PET accumulation in patients with Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {},
pmid = {42936906},
issn = {1552-5279},
support = {//European Union's Horizon/ ; 01KU2203//Bundesministerium für Bildung und Forschung/ ; 2525FSB005//Bundesministerium für Gesundheit/ ; 570971002//Deutsche Forschungsgesellschaft/ ; /ALZ/Alzheimer's Association/United States ; //Joachim Herz Foundation/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics/diagnostic imaging/metabolism/pathology ; Female ; Positron-Emission Tomography ; Genetic Risk Score ; *tau Proteins/metabolism ; Genome-Wide Association Study ; Male ; Aged ; Polymorphism, Single Nucleotide ; Brain/metabolism/diagnostic imaging ; *Amyloid beta-Peptides/metabolism ; Cross-Sectional Studies ; Aged, 80 and over ; Genetic Predisposition to Disease ; },
abstract = {BACKGROUND: Genome-wide association studies (GWASs) identified multiple genetic variants associated with Alzheimer's disease (AD) risk, yet the biological pathways linking these to amyloid and tau pathology remain unclear.

METHODS: We conducted a meta-analysis of recent GWASs to identify independent genome-wide significant single nucleotide polymorphisms which were mapped via gene-set enrichment to derive pathway-specific polygenic risk scores (pPRSs). Analyses included 441 amyloid-positive participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI; 224 with longitudinal tau positron emission tomography [PET]) and 250 amyloid-positive participants from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) study (113 with longitudinal tau PET). Robust linear regressions tested cross-sectional and longitudinal pPRS-by-amyloid chronicity interactions on tau PET.

RESULTS: Four pPRSs were identified including adaptive immune response, leukocyte activation, transport, and intracellular signaling. Only the transport pPRS strengthened amyloid-tau coupling cross-sectionally across all Braak stages in ADNI (p < 0.05) and at Braak I in A4 (p < 0.05), with stronger effects observed in females; in ADNI, these associations persisted longitudinally only at the higher Braak stages.

DISCUSSION: Genetic variation in transport pathways modulates amyloid-driven tau accumulation, revealing mechanisms shaping AD progression, beyond apolipoprotein E.},
}

Humans
*Alzheimer Disease/genetics/diagnostic imaging/metabolism/pathology
Female
Positron-Emission Tomography
Genetic Risk Score
*tau Proteins/metabolism
Genome-Wide Association Study
Male
Aged
Polymorphism, Single Nucleotide
Brain/metabolism/diagnostic imaging
*Amyloid beta-Peptides/metabolism
Cross-Sectional Studies
Aged, 80 and over
Genetic Predisposition to Disease

@article {pmid42937271,
year = {2026},
author = {Wang, D and Zhao, Z and Ding, Y},
title = {Relaxin-2 protects synaptic integrity via hippocampal NLRP3-mTOR-autophagy pathways in an age-dependent Alzheimer-like model.},
journal = {Acta pharmaceutica (Zagreb, Croatia)},
volume = {},
number = {},
pages = {},
doi = {10.2478/acph-2026-0023},
pmid = {42937271},
issn = {1846-9558},
abstract = {Alzheimer disease (AD) is associated with age-related synaptic degeneration, neuroinflammation, and impaired autophagy. The present study aimed to investigate the age-dependent neuroprotective effects of relaxin-2 (RLN2) in amyloid-beta 1-42 (Aβ1 - 42)-induced AD-like pathology and hypothesised that RLN2 would provide greater therapeutic benefit in young than aged mice. Young (3-4 months) and aged (12-14 months) mice were intracerebrally (i.c.) injected with amyloid-β (Aβ1 - 42) to develop an AD-like phenotype and treated with RLN2 or a control. Western blot analysis of hippocampal tissues was performed to assess the expression levels of ionised calcium-binding adaptor molecule 1 (Iba1) (microglial activation marker), NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome components, and mechanistic target of rapamycin (mTOR) pathway activity. Neuroinflammation was determined by interleukin-1 beta (IL-1β) and tumour necrosis factor-alpha (TNF-α), while synaptic integrity was assessed by synaptophysin and PSD-95. The Morris Water Maze (MWM) and Novel Object Recognition (NOR) tests were used to measure cognitive and memory performance. Neuroinflammation markers IL-1β and TNF-α were significantly elevated in Aβ1 - 42-injected mice, with aged mice showing a greater increase than young mice. RLN2 treatment markedly reduced IL-1β and TNF-α levels in young mice, whereas the reduction was limited in aged mice. RLN2 treatment had a significant inhibitory effect on hippocampal NLRP3 signalling, reduced mTOR signalling, modulated autophagy-related protein expression, preserved synaptic proteins, and improved cognitive and memory performance (decrease in the MWM escape latency and increase in the NOR discrimination index). RLN2 was not effective in the aged mice, and there was persistent inflammatory activation, impaired autophagy, minimal improvement in synaptic recovery, and a moderate improvement in cognition. These findings suggest that RLN2 could be a potential therapeutic candidate for early-stage AD by targeting neuroinflammation, mTOR-mediated autophagy-related dysregulation, and synaptic loss, while also potentially providing a basis for age-based stratification of treatment responsiveness; however, further studies are required to determine its utility as a biomarker of treatment response or disease progression. Overall, RLN2 exerted neuro-protective effects in i.c. Aβ1 - 42-induced AD-like pathology in an age-dependent manner.},
}

@article {pmid42937433,
year = {2026},
author = {Choi, A and Haystead, A and D'Cunha, R and Hsu, J and Zhu, M and Johnson, KG and Whitson, H and Grewal, DS and Fekrat, S},
title = {Longitudinal Multimodal Retinal Imaging in Cognitively Normal Apolipoprotein E4 Carriers and Noncarriers.},
journal = {Translational vision science & technology},
volume = {15},
number = {10},
pages = {45},
doi = {10.1167/tvst.15.10.45},
pmid = {42937433},
issn = {2164-2591},
mesh = {Humans ; Female ; Tomography, Optical Coherence/methods ; *Apolipoprotein E4/genetics ; Male ; *Multimodal Imaging/methods ; Heterozygote ; *Cognition/physiology ; *Retina/diagnostic imaging ; Middle Aged ; Longitudinal Studies ; Aged ; Retinal Vessels/diagnostic imaging ; Retinal Ganglion Cells/pathology ; Follow-Up Studies ; },
abstract = {PURPOSE: To evaluate longitudinal retinal structural and microvascular changes in cognitively normal apolipoprotein E (APOE) ε4 carriers compared with noncarriers.

METHODS: Cognitively normal adults with known APOE genotype underwent multimodal retinal imaging at baseline and follow-up visits. Optical coherence tomography (OCT) metrics included macular central subfield thickness (CST), ganglion cell-inner plexiform layer (GC-IPL) thickness, and retinal nerve fiber layer (RNFL) thickness. OCT angiography (OCTA) parameters included vessel and perfusion density across 3-mm and 6-mm circles and rings, peripapillary capillary perfusion density (CPD), and capillary flux index (CFI). Annual rates of change were estimated using linear mixed-effects models adjusted for age and sex. A subgroup analysis was performed in participants with ≥5-year follow-up.

RESULTS: This study analyzed 871 eyes from 439 participants (230 APOE ε4 noncarriers and 209 carriers). Baseline retinal parameters did not differ significantly between groups. Carriers demonstrated nominally slower annual RNFL decline (β = 0.334; P = 0.023) and attenuated peripapillary CPD decline (β = 0.0010; P = 0.014) versus noncarriers; neither survived false discovery rate (FDR) correction (P = 0.18). In the ≥5-year subgroup (n = 58), carriers demonstrated nominally higher peripapillary CPD than noncarriers (P = 0.011; FDR-adjusted P = 0.17), although rates of change did not differ significantly between groups.

CONCLUSIONS: Cognitively normal APOE ε4 carriers demonstrated nominally slower peripapillary CPD and RNFL decline over longitudinal follow-up, with carriers maintaining higher CPD at ≥5 years despite comparable baseline imaging.

TRANSLATIONAL RELEVANCE: Longitudinal peripapillary and RNFL changes may reflect early retinal findings associated with APOE ε4 carrier status prior to cognitive decline, supporting further investigation of longitudinal retinal imaging as a potential noninvasive biomarker in preclinical Alzheimer's disease.},
}

Humans
Female
Tomography, Optical Coherence/methods
*Apolipoprotein E4/genetics
Male
*Multimodal Imaging/methods
Heterozygote
*Cognition/physiology
*Retina/diagnostic imaging
Middle Aged
Longitudinal Studies
Aged
Retinal Vessels/diagnostic imaging
Retinal Ganglion Cells/pathology
Follow-Up Studies

@article {pmid42937842,
year = {2026},
author = {Peng, L and Li, Q and Li, Z and Bai, G and Tian, Y and Zhou, S},
title = {Blood-Brain Barrier-Permeable Macrocyclic Chimeras (BmTACs) for Targeted Protein Degradation in the Aging Brain.},
journal = {Journal of the American Chemical Society},
volume = {148},
number = {38},
pages = {41137-41150},
doi = {10.1021/jacs.6c11943},
pmid = {42937842},
issn = {1520-5126},
support = {2682025ZTPY051//Fundamental Research Funds for the Central Universities/ ; 2023JDRC0028//Department of Science and Technology of Sichuan Province/ ; 2024NSFTD0002//Department of Science and Technology of Sichuan Province/ ; 52495011//National Natural Science Foundation of China (NSFC)/ ; 52633003//National Natural Science Foundation of China (NSFC)/ ; U22A20161//National Natural Science Foundation of China (NSFC)/ ; },
mesh = {Animals ; *Blood-Brain Barrier/metabolism ; *Proteolysis/drug effects ; *Macrocyclic Compounds/chemistry/metabolism/pharmacology ; *Aging/metabolism ; Mice ; *Brain/metabolism ; Humans ; Death-Associated Protein Kinases/metabolism ; Reactive Oxygen Species/metabolism ; Proteolysis Targeting Chimera ; },
abstract = {Targeted protein degradation has emerged as a transformative therapeutic strategy, yet its application to neurodegenerative diseases remains fundamentally constrained by the blood-brain barrier (BBB) and lesion specificity. Critically, the BBB undergoes age-dependent functional remodeling, further exacerbating the difficulty of therapeutic intervention. Here we report BBB-permeable macrocyclic chimeras (BmTACs), a modular degradation platform for selective elimination of activated death-associated protein kinase 1 (DAPK1) in the aging brain. BmTACs harness a macrocyclic peptide shuttle that exploits age-upregulated caveolae-mediated transcytosis in brain endothelial cells to achieve efficient BBB traversal and neuron-targeting. A reactive oxygen species (ROS)-responsive caging group on the von Hippel-Lindau ligand enables conditional PROTAC activation exclusively within the high-ROS microenvironment of Alzheimer's disease lesions, minimizing off-target degradation. Systemic administration of BmTACs in aged APP/PS1 mice achieved potent degradation of activated DAPK1, attenuated amyloid-β deposition and Tau hyperphosphorylation, and improved cognition. This work establishes a modular, senescence-adapted paradigm for targeted protein degradation in the aging central nervous system.},
}

Animals
*Blood-Brain Barrier/metabolism
*Proteolysis/drug effects
*Macrocyclic Compounds/chemistry/metabolism/pharmacology
*Aging/metabolism
Mice
*Brain/metabolism
Humans
Death-Associated Protein Kinases/metabolism
Reactive Oxygen Species/metabolism
Proteolysis Targeting Chimera

@article {pmid42938023,
year = {2026},
author = {Ghosh, S and Siddharth, KS and Wagalgave, SM and George, SJ},
title = {Bio-Inspired Chain Capping Selectively Inhibits Elongation to Direct Secondary Pathways in Supramolecular Polymers.},
journal = {Journal of the American Chemical Society},
volume = {148},
number = {37},
pages = {40120-40130},
doi = {10.1021/jacs.6c12274},
pmid = {42938023},
issn = {1520-5126},
support = {NA//Council of Scientific and Industrial Research, India/ ; ANRF/2025/02766//Science and Engineering Research Board/ ; NA//Jawaharlal Nehru Centre for Advanced Scientific Research/ ; },
mesh = {*Polymers/chemistry/chemical synthesis ; Polymerization ; *Amyloid beta-Peptides/chemistry/metabolism ; Macromolecular Substances/chemistry/chemical synthesis ; },
abstract = {Amyloid β aggregation in Alzheimer's disease proceeds via fibril elongation and toxic oligomer generation through secondary nucleation. In biology, molecular chaperones selectively modulate these competing pathways to control aggregate formation and toxicity. Replicating such pathway selectivity in synthetic supramolecular polymerization─differentiating elongation from secondary nucleation─remains a major challenge. Here, we introduce a unique bioinspired small-molecule based inhibition strategy that achieves selective modulation of these pathways in seeded supramolecular polymerization. The rationally designed capper selectively binds fibril ends, suppressing elongation via the end-capping mechanism while preserving fibril surfaces for secondary nucleation. This redirects monomer flux from elongation to surface-catalyzed nucleation, dramatically enhancing branching and yielding hierarchical superstructures. In contrast to conventional seeded polymerization, which yields linear architectures dominated by elongation, this tunable kinetic switch establishes a synthetic analogue of chaperone-mediated regulation, providing a general framework for programming pathway selection in supramolecular polymerization to access complex hierarchical materials.},
}

*Polymers/chemistry/chemical synthesis
Polymerization
*Amyloid beta-Peptides/chemistry/metabolism
Macromolecular Substances/chemistry/chemical synthesis

@article {pmid42938161,
year = {2026},
author = {Santa, NA and Daza-Santacoloma, G and Serna, WS},
title = {Predicting MCI-to-Alzheimer's Conversion: A Systematic Benchmark of Classical, Machine Learning, and Deep Survival Models.},
journal = {Diagnostics (Basel, Switzerland)},
volume = {16},
number = {20},
pages = {},
pmid = {42938161},
issn = {2075-4418},
support = {790-2023//Technological University of Pereira/ ; },
abstract = {Background/Objectives: Predicting time-to-conversion from mild cognitive impairment (MCI) to Alzheimer's disease (AD) is a critical clinical challenge. Most survival analyses rely on static baseline variables, ignoring the temporal dynamics of serial neuroimaging. We benchmark seven survival model families using a novel temporal MRI descriptor pipeline on ADNI. Methods: A cohort of 661 MCI patients (250 conversion events, 37.8%, median follow-up 42.0 months) was constructed from ADNI. FreeSurfer volumetrics of six brain regions were summarised into three time-based descriptors each (atrophy rate, trajectory variability σ, and time-weighted cumulative mean μ) under strict anti-leakage constraints, yielding 18 neuroimaging features which, combined with six clinical variables (age, sex, education, MMSE, ADAS-13, and APOE-ε4), form a 24-dimensional covariate vector. Cox PH, Weibull AFT, Exponential, RSF, GBST, DeepSurv, and DeepHit were evaluated under stratified 5-fold cross-validation and assessed on an independent OASIS-3 cohort (n=78) as an exploratory analysis. Results: All seven models achieved C-index 0.853-0.863 (Δ=0.010), with Cox PH reaching 0.863±0.027 using only routine structural MRI. Time-dependent AUC ranged from 0.856 (12 months) to 0.938 (48 months). Risk stratification by quartile yielded highly separated Kaplan-Meier curves (log-rank p<0.001). On OASIS-3 (n=78, exploratory), classical models showed preliminary cross-cohort consistency (Weibull AFT 0.760±0.063, RSF 0.759±0.049), while deep learning degraded substantially (DeepSurv 0.551±0.116); these results are hypothesis-generating and should not be interpreted as confirmatory given the small per-fold sample size (EPV ≈ 1). Conclusions: The temporal MRI descriptor pipeline achieves a C-index of 0.863 using only routine structural MRI, without PET or CSF biomarkers, demonstrating strong discriminative performance on ADNI MCI-to-AD conversion. The narrow performance band (Δ=0.010) suggests that, within this feature-engineering paradigm, no clear performance separation was observed among the evaluated model architectures; this convergence may reflect feature-level rather than architecture-level constraints, although the underlying cause cannot be established from discriminative performance alone. Classical models showed more stable cross-cohort behaviour under data-scarce conditions; prospective validation on larger cohorts with full covariate parity is required before clinical translation can be considered.},
}

@article {pmid42938304,
year = {2026},
author = {Yamada, H and Yanaizu, M and Iwai, N and Kato, M and Suzuki, H and Wakai, M and Araki, M and Kino, Y},
title = {Identification of RNA-Binding Proteins Regulating the Alternative Splicing of TREM2 Exon 4.},
journal = {Genes},
volume = {17},
number = {10},
pages = {},
pmid = {42938304},
issn = {2073-4425},
support = {19K07982//Japan Society for the Promotion of Science/ ; 20K07876//Japan Society for the Promotion of Science/ ; 23K14763//Japan Society for the Promotion of Science/ ; },
mesh = {*Membrane Glycoproteins/genetics/metabolism ; Humans ; *Receptors, Immunologic/genetics/metabolism ; *Alternative Splicing/genetics ; Exons ; HEK293 Cells ; *RNA-Binding Proteins/genetics/metabolism ; *Alzheimer Disease/genetics ; CELF Proteins/genetics/metabolism ; Nerve Tissue Proteins/genetics/metabolism ; },
abstract = {BACKGROUND/OBJECTIVES: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline. Most AD cases are sporadic, with both environmental and genetic factors contributing to disease onset and progression. TREM2, an AD susceptibility gene, encodes a receptor protein expressed on the plasma membrane of microglia and macrophages. In addition to membrane-bound TREM2, soluble TREM2 (sTREM2) is also present in the brain. sTREM2 can be generated through two distinct mechanisms: proteolytic shedding of membrane-bound TREM2 and alternative splicing of TREM2 exon 4. Because the mechanisms regulating the latter pathway remain unclear, we investigated the molecular mechanisms underlying TREM2 exon 4 alternative splicing, with a particular focus on RNA-binding proteins (RBPs).

METHODS: We designed guide RNAs (gRNAs) targeting sequences within exon 4. The gRNAs and an exon 4 splicing reporter were transfected into HEK293-based cells with inducible dCasRx expression to identify regions containing cis-regulatory elements involved in exon 4 splicing. RBPs interacting with the candidate region were subsequently identified by RNA pulldown followed by LC-MS/MS analysis.

RESULTS: We identified regions within exon 4 containing putative cis-regulatory elements involved in its alternative splicing and found that CELF1, CELF2, and DDX41 interact with RNA containing one of these regions. Knockdown experiments indicated that these RBPs differentially regulate exon 4 splicing.

CONCLUSIONS: Our findings suggest that TREM2 exon 4 alternative splicing is regulated by multiple cis-regulatory elements and RBPs, including CELF1, CELF2, and DDX41. Together with our previous identification of CELF1 and CELF2 as regulators of TREM2 exon 3 splicing, these findings suggest that CELF1 and CELF2 play complex roles in the regulation of TREM2 alternative splicing.},
}

*Membrane Glycoproteins/genetics/metabolism
Humans
*Receptors, Immunologic/genetics/metabolism
*Alternative Splicing/genetics
Exons
HEK293 Cells
*RNA-Binding Proteins/genetics/metabolism
*Alzheimer Disease/genetics
CELF Proteins/genetics/metabolism
Nerve Tissue Proteins/genetics/metabolism

@article {pmid42938334,
year = {2026},
author = {Tian, X and Xue, X},
title = {Associations of Blood Lipid Traits with Cognitive-Related Outcomes and Their Sensitivity to APOE-Region Instrumental Variables: A Mendelian Randomization and Colocalization Study.},
journal = {Genes},
volume = {17},
number = {10},
pages = {},
pmid = {42938334},
issn = {2073-4425},
support = {2025-JYB-JBGS-007//Fundamental Research Funds for the Central Universities/ ; 2021-ZXFZJJ-044//University-Level Vertical Scientific Research Development Fund/ ; 2024-HXFZJJ-008//Horizontal Scientific Research Development Fund/ ; },
mesh = {Humans ; Mendelian Randomization Analysis ; *Apolipoproteins E/genetics ; *Lipids/blood/genetics ; Cholesterol, HDL/blood/genetics ; *Cognition ; *Alzheimer Disease/genetics/blood ; Female ; *Dementia/genetics/blood ; Male ; Phenotype ; },
abstract = {Background: Neurodegenerative, cognitive, and cerebrovascular outcomes are central to brain health. Previous studies have linked blood lipid traits to these outcomes, but associations differ across lipid components and outcome types. However, the contribution of APOE remains unclear. We compared these patterns, quantified their dependence on APOE, and identified shared signals outside the region. Methods: We used two-sample Mendelian randomization to examine associations between four blood lipid traits from the Global Lipids Genetics Consortium and seven cognitive-related outcomes from FinnGen R11, followed by regional colocalization analysis. We stratified instruments into APOE and non-APOE regions and compared region-specific estimates. Robust non-APOE signals supported by colocalization were further assessed using UK Biobank BIG40 imaging-derived phenotypes. Results: Genetically predicted high-density lipoprotein cholesterol (HDL-C) was inversely associated with the FinnGen composite endpoint of stroke excluding SAH and with cerebrovascular sequelae. Total cholesterol (TC) was positively associated with Alzheimer disease (AD) and dementia.Colocalization supported shared regional signals for TC-AD near TSBP1/TSBP1-AS1, LDL-C-AD within the extended HLA region, and HDL-C-stroke excluding SAH near ILRUN. Estimates for AD, dementia, and memory loss were sensitive to APOE-region exclusion, whereas the HDL-C-stroke estimate was materially unchanged. In separate exploratory analyses of 13 BIG40 imaging phenotypes, HDL-C colocalized with left lateral and right medial orbitofrontal gray-white matter intensity contrast. Conclusions: Lipid-related genetic effects differ across brain outcomes. AD and dementia estimates were sensitive to APOE-region instruments, whereas the HDL-C-associated signal for the composite stroke endpoint persisted after their exclusion. Exploratory imaging results nominate orbitofrontal intensity contrast as an HDL-C correlate.},
}

Humans
Mendelian Randomization Analysis
*Apolipoproteins E/genetics
*Lipids/blood/genetics
Cholesterol, HDL/blood/genetics
*Cognition
*Alzheimer Disease/genetics/blood
Female
*Dementia/genetics/blood
Male
Phenotype

@article {pmid42938377,
year = {2026},
author = {Zhong, S and Xie, G and Zhang, Z},
title = {Multi-Cohort Transcriptomic Integration Identifies Overlapping Immune and Antigen-Presentation Features in Alzheimer's Disease and Hashimoto's Thyroiditis.},
journal = {Genes},
volume = {17},
number = {10},
pages = {},
pmid = {42938377},
issn = {2073-4425},
support = {82371191//National Natural Science Foundation of China/ ; },
mesh = {Humans ; *Hashimoto Disease/genetics/immunology/pathology ; *Alzheimer Disease/genetics/immunology/pathology ; *Transcriptome/genetics ; *Antigen Presentation/genetics ; Female ; Male ; Thyroid Gland/immunology/metabolism ; Cohort Studies ; Gene Expression Profiling ; Brain/immunology/metabolism ; },
abstract = {BACKGROUND: Thyroid disorders and Alzheimer's disease (AD) have been linked epidemiologically, but whether AD brain tissue and thyroid tissue affected by Hashimoto's thyroiditis (HT) share molecular features remains unclear.

METHODS: Differential expression was estimated in AD (GSE122063) and HT (GSE138198) discovery cohorts using limma, with donor-level blocking and adjustment for age, sex and post-mortem interval where available. Shared genes were tested against chance within the genes measured in both cohorts, separately for each direction of change; characterized by enrichment analysis; related to marker-based cell-state scores; and evaluated in two AD cohorts, three thyroid cohorts including one with concurrently collected normal thyroid (GSE165724), and a single-nucleus AD dataset (GSE138852).

RESULTS: The discovery analyses identified 3593 AD- and 3806 HT-associated genes. The overlap was direction-specific: genes upregulated in both diseases exceeded chance (117 vs. 83.2 expected; p = 8.9 × 10[-5]), whereas the other direction combinations did not. Co-upregulated genes were enriched for MHC class II antigen presentation (FDR = 0.004), complement (FDR = 0.002), microglial activation (FDR = 0.017) and T-cell activation (FDR = 1.7 × 10[-4]), and recurred in two independent thyroid datasets and the within-study LT+ versus LT- comparison, with less consistent, region-dependent recurrence in AD cohorts. This shared component tracked immune cell-state signals-glial/myeloid activation in AD and lymphocytic infiltration in HT. Fourteen co-upregulated genes, including ITGAX, CD22 and BST2, met prespecified recurrence and detectability criteria.

CONCLUSIONS: AD brain tissue and thyroid tissue affected by HT exhibit a co-upregulated immune and antigen-presentation transcriptional program that reflects immune activation in both tissues. These overlapping features are associative and do not establish a causal relationship between AD and HT.},
}

Humans
*Hashimoto Disease/genetics/immunology/pathology
*Alzheimer Disease/genetics/immunology/pathology
*Transcriptome/genetics
*Antigen Presentation/genetics
Female
Male
Thyroid Gland/immunology/metabolism
Cohort Studies
Gene Expression Profiling
Brain/immunology/metabolism

@article {pmid42938969,
year = {2026},
author = {Nguyen, T and Woods, C and Liu, J and Wang, C and Lin, AL and Cheng, J},
title = {APOEFormer: A Multimodal AI Model for APOE4 Carrier Status Prediction and Phenotype Characterization in Alzheimer's Disease.},
journal = {Bioengineering (Basel, Switzerland)},
volume = {13},
number = {10},
pages = {},
pmid = {42938969},
issn = {2306-5354},
support = {//University of Missouri/ ; },
abstract = {The apolipoprotein E ε4 (APOE4) allele is the strongest genetic risk factor for late-onset Alzheimer's disease (AD), the most common form of dementia. APOE4 carriers exhibit cerebrovascular and metabolic dysfunction, structural brain alterations, and gut microbiome changes decades before the onset of clinical symptoms. Better understanding of the early manifestation of these physiological changes is critical for development of timely AD interventions and risk reduction protocols. Multi-modal datasets encompassing a wide range of APOE ε4 and AD associated biomarkers provide a valuable opportunity to gain insight into the APOE4 phenotype; however, these datasets often present analytical challenges due to small sample sizes and high heterogeneity. Here, we propose a two-stage multimodal AI model (APOEFormer) that integrates blood metabolites, brain vascular and structural MRI, microbiome profiles, and other clinical and demographic data to predict APOE4 allele status. In the first stage, modality-specific encoders are used to generate initial representations of input data modalities, which are aligned in a shared latent space via self-supervised contrastive learning during pretraining. The contrastive learning objective encourages learning of informative and consistent representations across modalities through leveraging cross-modality relationships. In the second stage, the pretrained representations are used as inputs to a multimodal transformer that integrates information across modalities to predict a key AD-risk genetic variant (APOE4). Across 10 repeated experimental runs with different train-validation-test splits, APOEFormer predicts whether an individual carries an APOE4 allele with an average prediction accuracy of 75%, demonstrating robust performance under limited sample sizes. Post hoc perturbation analysis of the predictive model revealed valuable insights into the driving components of the APOE4 phenotype-including key blood biomarkers and brain regions strongly associated with APOE4.},
}

@article {pmid42939079,
year = {2026},
author = {Cantillo-Negrete, J and Rodríguez-García, ME and Carrillo-Mora, P and Méndez-Gómez, DD and Carino-Escobar, RI},
title = {Brain-Computer Interfaces for Cognitive Rehabilitation: A Narrative Review.},
journal = {Bioengineering (Basel, Switzerland)},
volume = {13},
number = {10},
pages = {},
pmid = {42939079},
issn = {2306-5354},
abstract = {Cognitive diseases/disorders are a major cause of disability affecting millions of people worldwide due to pathologies or conditions such as Alzheimer's disease, Parkinson's disease, vascular cognitive impairment, and attention deficit/hyperactivity disorder. The effects of these diseases/disorders can range from subjective cognitive complaints to mild cognitive impairment and even dementia that can affect multiple cognitive domains, causing disability and alterations in daily functioning and quality of life. Cognitive training has been researched as a potential therapeutic option for treating cognitive disability. In particular, cognitive training delivered using brain-computer interfaces (BCIs) represents a promising technology for cognitive rehabilitation. For this reason, this work presents a narrative review aimed at bridging the clinical aspects of cognition performance and the technical features of BCI systems. Additionally, it reports on the current advances of BCIs for cognitive rehabilitation in the pathologies/conditions that are the main contributors of cognitive impairment globally. Specifically, Alzheimer's disease, Parkinson's disease, mild cognitive impairment, cerebrovascular diseases, and attention-deficit/hyperactivity disorder were included in the review; other pathologies that can also cause cognitive impairment such as multiple sclerosis, traumatic brain injury, brain tumors, infectious diseases, and psychiatric conditions such as schizophrenia or autism spectrum disorder, or drug or toxin-related causes were outside the scope of the present review. Across the literature, studies have reported that BCI cognitive training can improve cognition performance for mild cognitive impairment, stroke, and attention-deficit/hyperactivity disorder, showcasing its feasibility as a complementary therapy. However, the amount of evidence is still scarce, with few reported randomized controlled clinical trials and all of the applications comprising non-invasive systems using electroencephalography, while invasive or other non-invasive approaches remain largely unassessed. Therefore, further research regarding the design of BCIs for targeting specific cognitive domains is necessary to allow for the future introduction of these types of systems into clinical rehabilitation environments, rather than only demonstrating their feasibility, as has been mainly done to date.},
}

@article {pmid42939080,
year = {2026},
author = {Omidi, S and Bacsu, JR and Absher, JR and Babaieasl, F and Kooshiar, H and Imani, SM and Ebrahimi, N and Smith, ML and Rahemi, Z},
title = {Generative Artificial Intelligence in Health Research and Care: A Narrative Review of Applications and Implications for Alzheimer's Disease and Related Dementia.},
journal = {Bioengineering (Basel, Switzerland)},
volume = {13},
number = {10},
pages = {},
pmid = {42939080},
issn = {2306-5354},
support = {Grant K01AG081485/AG/NIA NIH HHS/United States ; Grant 24AARG-D-1242910/ALZ/Alzheimer's Association/United States ; //Clemson University/ ; },
abstract = {The advent of generative artificial intelligence (AI), particularly large language models (LLMs) and deep generative networks, is transforming the landscape of Alzheimer's disease and related dementia (ADRD) research and care. This narrative review aims to synthesize current applications of generative AI in ADRD research and care, highlight ethical and implementation challenges, and propose strategies for responsible integration into clinical practice. We conducted a narrative review of literature, regulatory documents, program reports, and relevant sources published between 2016 and 2026, with a specific focus on cognitive screening, synthetic data generation, digital twin modeling, and caregiver support. Techniques discussed include generative adversarial networks (GANs), variational autoencoders (VAEs), diffusion models, multimodal transformers, and LLM-powered chatbots. Generative AI enables applications such as virtual patient companions, remote cognitive assessments via conversational agents, multimodal image-to-text tools, synthetic data augmentation, disease progression simulation, and improved caregiver communication. Challenges include model explainability, clinical validation, regulatory compliance, privacy, data bias, hallucination risk, patient autonomy, and global disparities. Responsible development requires transparent reporting, stakeholder co-design, rigorous clinical and economic validation, and continuous post-deployment monitoring to support fairness and effectiveness in real-world settings.},
}

@article {pmid42939267,
year = {2026},
author = {Gatto, RG and Youssef, H and Uruk, G and Carlos, AF and Reichard, RR and Lowe, VJ and Whitwell, JL and Josephs, KA},
title = {Pilot Multimodal Imaging Assessment of Neuropathological Iron Deposition and Molecular PET in Frontotemporal Lobar Degeneration.},
journal = {Brain sciences},
volume = {16},
number = {10},
pages = {},
pmid = {42939267},
issn = {2076-3425},
support = {5RF1NS112153-26/NH/NIH HHS/United States ; 5R01DC012519-26/NH/NIH HHS/United States ; 5R01NS089757-25/NH/NIH HHS/United States ; },
abstract = {BACKGROUND/OBJECTIVES: The role of iron in Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD) has been debated. However, the effects of iron on protein burden in these diseases remain poorly elucidated. We hypothesized that there is an association between iron deposition and tau and beta-amyloid deposition in deep grey matter (GM) regions in FTLD.

METHODS: Neuropathological samples were collected from two control subjects and 10 disease subjects. This included 12 subjects, with several pathological subgroups represented by only one or two cases. Of the 10 disease subjects, one had low-level AD neuropathology (L-AD), and one had high-level AD neuropathology (H-AD), whereas the remaining eight subjects had FTLD-tau pathology, including progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), globular glial tauopathy (GGT), and Pick's disease (PiD). Neuropathological samples were stained for iron with Prussian blue (PB) and ferritin, tau, and beta-amyloid in the basal ganglia (BG). All 12 subjects had also undergone diffusion MRI, amyloid-PET (PiB-PET), and Tau-PET (flortaucipir) before death. Diffusion tensor imaging mean diffusivity (MD) from BG was examined in each subject. Spearman's rank correlations between imaging and histology were calculated.

RESULTS: Increased BG iron was observed in PSP subjects. Prussian blue and ferritin measures were associated with higher tau- and β-amyloid pathological burden. Tau-PET uptake correlated with iron in the BG.

CONCLUSIONS: The results of this exploratory study suggest associations between iron burden and tau- and β-amyloid-related measures within basal ganglia regions that may help to explain increased PET signals in AD and FTLD-Tau. Our findings should be considered to be hypothesis-generating and require validation. These preliminary findings require validation in larger cohorts.},
}

@article {pmid42939269,
year = {2026},
author = {Dong, H and Wang, W and Zeng, W and Zou, Q and Lu, W and Chen, C and Yao, J and Li, Y},
title = {Acupuncture in Aging-Related Brain Diseases: From Mitochondrial Homeostasis to Clinical Signals.},
journal = {Brain sciences},
volume = {16},
number = {10},
pages = {},
pmid = {42939269},
issn = {2076-3425},
support = {82405582//National Natural Science Foundation of China/ ; GZB20240087 and 2024M750285//China Postdoctoral Science Foundation/ ; },
abstract = {Mitochondria play a key role in maintaining cellular homeostasis through energy metabolism, ROS regulation, calcium handling, and apoptosis control. Mitochondrial dysfunction contributes to neurological vulnerability in the aging brain, where neuronal energy demand, axonal transport, synaptic activity, and neurovascular repair depend on mitochondrial integrity. Animal studies in chronic brain disease and acute brain-injury models have examined acupuncture-related changes in phenotypic outcomes and mitochondrial measures, including behavioral, physiological, and molecular readouts. Their findings span mitochondrial ultrastructure, biogenesis, dynamics, mitophagy, and downstream signaling. Clinical studies have examined acupuncture in Parkinson's disease, stroke, and Alzheimer's disease. Animal studies report acupuncture-related changes in mitochondrial structure and indices of quality control alongside improvements in neurological, behavioral, or injury-related outcomes. These mitochondrial changes may influence oxidative stress, calcium regulation, apoptosis, mitochondrial transport, and intercellular mitochondrial support. Clinical studies mainly report symptom and functional outcomes, while a small number of imaging studies also describe changes in cerebral glucose metabolism or neural activity. These preliminary clinical and metabolic signals may inform further investigation into whether mitochondrial processes are associated with clinical responses to acupuncture. Current experimental work also has important limitations: most studies focus on a limited set of mitochondrial quality-control markers, while the mitochondrial unfolded protein response, axonal mitochondrial trafficking, and dynamic mitochondrial transfer are rarely assessed. Future clinical studies should pair neurological outcomes with feasible measures of mitochondrial function and energy metabolism. Tracking these measures over time may help clarify how changes in mitochondrial function and energy metabolism during acupuncture treatment relate to functional recovery.},
}

@article {pmid42939317,
year = {2026},
author = {Kumar, P},
title = {Editorial: Advances in Memory and Cognitive Decline Associated with Aging and Alzheimer's Disease.},
journal = {Brain sciences},
volume = {16},
number = {10},
pages = {},
pmid = {42939317},
issn = {2076-3425},
abstract = {Alzheimer's disease is a progressive neurodegenerative disease in the elderly population [...].},
}

@article {pmid42939320,
year = {2026},
author = {Macoir, J},
title = {Numerical Cognition in Neurodegenerative Disorders: A Systematic Review of Patterns of Preservation and Impairment.},
journal = {Brain sciences},
volume = {16},
number = {10},
pages = {},
pmid = {42939320},
issn = {2076-3425},
abstract = {BACKGROUND/OBJECTIVES: Numerical cognition comprises multiple processes supporting the representation, comprehension, production, and manipulation of numerical information. Although numerical impairments have been described in neurodegenerative diseases, findings remain fragmented across disorders and numerical domains. This systematic review aimed to characterize patterns of preserved and impaired core numerical abilities across neurodegenerative disorders and to examine their implications for cognitive models and clinical assessment.

METHODS: PubMed, Web of Science, and PsycINFO were systematically searched for original empirical studies in English or French examining core numerical cognition in adults with neurodegenerative disorders or mild cognitive impairment. Reference lists were additionally screened. Methodological quality was appraised using design-specific Joanna Briggs Institute critical appraisal tools. Forty-seven studies published between 1989 and 2026 met the eligibility criteria. Findings were synthesized qualitatively because of substantial heterogeneity in study designs, clinical populations, and numerical measures.

RESULTS: Numerical profiles varied considerably across disorders, individuals, and disease stages, but several broad patterns emerged. Basic number comprehension and magnitude processing were often relatively preserved, whereas greater vulnerability was observed for processes requiring transformation, retrieval, or manipulation of numerical information. Arithmetic fact knowledge showed variable preservation, including dissociations between stored knowledge and its retrieval. Calculation procedures and complex calculation were among the most consistently affected abilities. Evidence was strongest for Alzheimer's disease and semantic variant primary progressive aphasia and remained limited for several other neurodegenerative disorders.

CONCLUSIONS: Numerical cognition is differentially affected across neurodegenerative diseases, supporting its multicomponent organization. These findings suggest the potential value of multidomain assessment rather than reliance on isolated calculation tasks. However, methodological heterogeneity, variation in methodological strength across studies, and the limited evidence available for several disorders reduce confidence in the generalizability of these patterns and currently preclude defining reliable disease-specific numerical signatures.

REGISTRATION: OSF, 10.17605/OSF.IO/DU2Y9.

FUNDING: None.},
}

@article {pmid42939322,
year = {2026},
author = {Bodria, M and Daini, E and Pioli, S and Piemontese, M and Vandini, E and Ottani, A and Zoli, M and Giuliani, D and Vilella, A},
title = {Chronic Inhalation of Sulphureous Water Mitigates Early Amyloid Pathology and Associated Microglial Changes in 5XFAD Mice.},
journal = {Brain sciences},
volume = {16},
number = {10},
pages = {},
pmid = {42939322},
issn = {2076-3425},
support = {//Fondazione per la Ricerca Scientifica Termale/ ; //MIUR Dipartimenti di Eccellenza 2018-2022/ ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a chronic neurodegenerative disorder characterized by progressive cognitive decline and behavioral impairments. Hydrogen sulfide (H2S) is an endogenous gasotransmitter that exerts pleiotropic neuromodulatory, anti-inflammatory, cytoprotective, and trophic effects within the central nervous system. Objectuves: This study investigated whether chronic inhalation of naturally H2S-rich sulphureous water, a non-invasive and clinically applicable intervention, exerts neuroprotective effects in 5XFAD mice, a transgenic model of severe AD pathology.

METHODS: Two-month-old male and female wild-type and 5XFAD mice underwent daily inhalation of saline or sulphureous water for eight weeks. Sulphureous water exposure was well tolerated and did not impair baseline learning or memory in either genotype. A detailed analysis of swim trajectories revealed selective enhancement of spatially accurate navigation strategies in sulphureous water-exposed 5XFAD female mice, with nearly a threefold increase in effective search behaviors, whereas male mice showed no treatment-specific effects. In addition, sulphureous water inhalation significantly reduced the number and area of 6E10[+] and 11A1[+] amyloid-β plaques in corticohippocampal regions and decreased cortical microglia number. Transcriptional profiling of cortical tissue revealed strong genotype-dependent upregulation of microglial, inflammatory, and stress-response genes. Sulphureous water exposure selectively modulated inflammatory and stress-response genes, including Cd11b, Cst, Sod1, Tgfb1, and Hsp90a, with distinct genotype-dependent interactions.

RESULTS: Overall, chronic inhalation of naturally H2S-rich sulphureous water during the prodromal phase of AD-like pathology mitigated early amyloid burden, reduced cortical microgliosis, and improved qualitative aspects of spatial navigation, particularly in female mice.

CONCLUSIONS: These findings warrant further translational investigation of sulphureous water inhalation as a potential preventive or disease-modifying strategy for AD in humans.},
}

@article {pmid42939332,
year = {2026},
author = {Gu, D and Lei, Y and Lu, J and Yi, W and Zhang, Q and He, Y and Wang, C and Cai, Z},
title = {Age-Stratified Serum Biomarkers for Discriminating Clinically Defined Cognitive Impairment in Neurological Inpatients: A Cross-Sectional Study.},
journal = {Brain sciences},
volume = {16},
number = {10},
pages = {},
pmid = {42939332},
issn = {2076-3425},
abstract = {Background: With the aging of the global population and the increasing prevalence of cognitive dysfunction worldwide, early identification of cognitive impairment has become an important public health issue. This study aims to investigate the correlation between peripheral serum neurodegenerative biomarkers and age, as well as the discriminative efficacy of cognitive impairment across different age cohorts. Notably, subjects were grouped by clinical cognitive assessment without pathological confirmation via amyloid/tau PET or cerebrospinal fluid testing to define Alzheimer's disease pathology. Methods: A cross-sectional study enrolled 425 inpatients from the neurology department. Nonparametric tests were used to explore the correlation between age and peripheral serum biomarkers, as well as intergroup differences in biomarker levels among different cognitive statuses. Age-stratified logistic regression models were constructed to evaluate the association between biomarkers and cognitive impairment, with odds ratios (OR) and 95% confidence intervals (CI) calculated. Receiver operating characteristic (ROC) curves and corresponding area under the curve (AUC) were adopted to assess the discriminative performance of each indicator. In this study, cognitive impairment was defined clinically based on MoCA and clinical assessment, not biomarker-confirmed Alzheimer's disease pathology. Results: Except for glial fibrillary acidic protein (GFAP) (r = 0.062, p = 0.207), all detected biomarkers were significantly correlated with age. Among them, p-Tau181 (r = 0.288, p < 0.001), p-Tau217 (r = 0.275, p < 0.001), Aβ1-42 (r = 0.132, p = 0.007), Aβ1-40 (r = 0.254, p < 0.001), and NfL (r = 0.200, p < 0.001) were positively associated with age, while Aβ42/40 ratio was negatively correlated with age (r = -0.253, p < 0.001). After age-based grouping, phosphorylated tau protein (p-Tau)181 showed relatively better discriminative performance in the <65 years group (AUC = 0.6212, 95% CI: 0.537-0.705); GFAP (AUC = 0.7776, 95% CI: 0.718-0.837) and NfL (AUC = 0.7329, 95% CI: 0.670-0.796) showed higher AUC values among participants aged ≥65 years. Conclusions: The correlation and discriminative efficacy of peripheral serum biomarkers for clinically defined cognitive impairment showed differences across age groups in this exploratory analysis. Within this inpatient cohort, p-Tau181 showed relatively better discriminative performance in the <65 years group, while GFAP and NfL showed numerically higher AUC values in the ≥65 years group. These exploratory findings suggest age-related differences in biomarker performance patterns that warrant further investigation in independent cohorts. The modest AUC (0.6212) for p-Tau181 in the younger group suggests that while it offers a statistical advantage, its clinical utility as a standalone screening tool remains limited, reinforcing the need for comprehensive clinical evaluation. Our results provide exploratory evidence for age-stratified minimally invasive serum-based assessment of clinically defined cognitive impairment in neurological inpatients, and cannot be directly generalized to community populations or used for definite Alzheimer's disease pathological screening; rather, our results serve as a reference for age-stratified screening in clinical inpatient settings rather than standalone diagnostic criteria.},
}

@article {pmid42939346,
year = {2026},
author = {Alfaro-Rodríguez, A and Cortes-Altamirano, JL and Reyes-Long, S and Bonilla-Jaime, H and Avila-Camacho, FJ and Moreno-Villalba, LM and Herrera-López, ME and González-Maciel, A and Pérez-Guille, B and Soriano-Rosales, RE and Calderon-Guzman, D and Juaréz-Olguín, H},
title = {Glial Contributions to Pain in Neurodegenerative Disease Models: A Systematic Review of Microglial and Astrocytic Evidence.},
journal = {Brain sciences},
volume = {16},
number = {10},
pages = {},
pmid = {42939346},
issn = {2076-3425},
abstract = {Background/Objectives: Pain is a common and disabling non-motor manifestation of neurodegenerative disorders, but the contribution of glial cells to nociceptive processing remains incompletely understood. This systematic review evaluated evidence from preclinical models of neurodegenerative diseases linking microglial and astrocytic activity to pain. Methods: The protocol was prospectively registered in PROSPERO (CRD420251084310), and reporting followed PRISMA 2020. We conducted the original electronic search in PubMed/MEDLINE; during major revision, we conducted supplementary searches in Scopus and Web of Science Core Collection. Across the three sources, we identified 2248 records. After hierarchical deduplication by DOI, PMID, and normalized title, 1567 unique records were screened. Eligible in vivo studies assessed microglial and/or astrocytic alterations together with pain- or nociception-related outcomes. Risk of bias was independently evaluated by two investigators using the SYRCLE tool, and findings were synthesized qualitatively. Results: Twenty-six studies met the eligibility criteria: sixteen examined multiple sclerosis/experimental autoimmune encephalomyelitis (61.5%), seven Parkinson's disease (26.9%), two Alzheimer's disease-related models (7.7%), and one Huntington's disease model (3.8%); no eligible amyotrophic lateral sclerosis study was identified. Pain-related alterations involved inflammatory, neuroimmune, synaptic, and astrocyte-associated pathways, but the evidence was strongly model-dependent. Findings based on individual studies, including early astrocytic contributions in experimental autoimmune encephalomyelitis and altered inflammatory allodynia in an Alzheimer's disease model, are interpreted as study-specific observations requiring replication. Conclusions: The available evidence supports context-dependent associations between glial responses and nociceptive processing; however, marker specificity, EAE predominance, sex and age imbalance, and incomplete reporting of bias control procedures limit causal and cross-disease generalization.},
}

@article {pmid42939350,
year = {2026},
author = {Li, X and Xiao, W and Hu, M and Li, L and Lin, L},
title = {The Iron-Mitochondria-Oligodendrocyte Axis: An Emerging Metabolic Framework for Alzheimer's Disease.},
journal = {Brain sciences},
volume = {16},
number = {10},
pages = {},
pmid = {42939350},
issn = {2076-3425},
support = {2026ZD0555304//National Science and Technology Major Project of China/ ; 2026AFC0861//Key project of Innovation and Development Joint Found of Natural Science Foundation of Hubei Province/ ; 2023AFD123//Key project of Innovation and Development Joint Found of Natural Science Foundation of Hubei Province/ ; },
abstract = {With the accelerating process of global aging, Alzheimer's disease (AD) has become an enormous public health burden worldwide. However, its pathogenesis is still not fully understood beyond the classic amyloid-β (Aβ) and tau hypotheses. This review aims to fill this critical knowledge gap by proposing the "Iron-Mitochondria-Oligodendrocyte Axis (IMOA)" as a novel metabolic paradigm for deciphering the complex biological mechanisms underlying AD. Specifically, we explicitly aim to address whether this axis functions as a causal, permissive, or modulatory pathway during the early and progressive stages of the disease. We systematically summarize the reciprocal regulatory interactions within this axis, with a focus on how brain iron dyshomeostasis preferentially impacts mitochondria in oligodendrocytes, which are characterized by high metabolic demand. Notably, the IMOA framework highlights disordered iron metabolism as a potential modulatory factor of neurodegeneration by linking iron imbalance to impaired energy metabolism. Excessive intracellular iron induces mitochondrial dysfunction, insufficient energy supply, and reactive oxygen species (ROS) overproduction, thereby triggering oligodendrocyte ferroptosis and myelin degeneration. These events further aggravate neuronal energy depletion, forming a potentially self-sustaining pathological cascade that may operate synergistically with or upstream of Aβ and tau pathologies. This framework not only bridges the logical disconnect between protein accumulation and neuronal degeneration in the Aβ and tau hypothesis but also provides promising targets for multi-target therapeutic strategies. The IMOA offers valuable insights for improving the temporal and spatial precision of AD diagnosis and intervention. Collectively, targeting the IMOA may represent a transformative strategy for developing precision diagnostics and combination therapies to halt or delay the progression of AD.},
}

@article {pmid42939371,
year = {2026},
author = {Nakanishi, T and Fukuchi, M},
title = {Prostaglandin E2 in Brain Inflammation: Roles and Dynamics.},
journal = {Brain sciences},
volume = {16},
number = {10},
pages = {},
pmid = {42939371},
issn = {2076-3425},
abstract = {Background/Objectives: Prostaglandin E2 (PGE2) is a known inflammatory mediator. It is produced by cyclooxygenase (COX)-1/2 during inflammation via four distinct G protein-coupled receptors (EP1-EP4). PGE2 is involved in the development of brain diseases induced by acute and chronic stresses, although the mechanisms regulating PGE2 concentration remain unclear. This review summarizes the mechanisms in relation to the activity of PGE2, focusing on membrane transporters in neuroinflammation and central nervous system (CNS) disorders. Methodology: A literature search was conducted using the PubMed database to evaluate the roles and dynamics of PGE2 in the central nervous system (CNS) under acute and chronic stress conditions. Results: PGE2 produced during inflammation acts via four receptors (EP1-EP4). These receptors mediate diverse and complex pathways in neurons and glial cells (microglia and astrocytes), influencing pathologies involving acute and chronic inflammation such as cerebral ischemia, Alzheimer's disease, Parkinson's disease, and neuropathic pain. EP1, EP2, and EP3 generally promote neurotoxicity, inflammation, and blood-brain barrier disruption, whereas EP4 predominantly exerts anti-inflammatory and neuroprotective effects. Furthermore, membrane transporters, particularly SLCO2A1 (also known as PGT) and MRP4 (encoded by ABCC4), regulate local PGE2 concentrations and facilitate its clearance across the blood-brain and blood-cerebrospinal fluid barriers. Understanding these transporters and receptors provides insights into controlling PGE2 dynamics in CNS diseases. Conclusions: Growing evidence indicates that membrane transporters play critical roles in regulating these levels in the brain, and elucidating the expression profiles of functional PG transporters may offer novel therapeutic strategies for refractory inflammation-based CNS diseases.},
}

@article {pmid42939380,
year = {2026},
author = {Pebe-Muñoz, CDP and Alzola, P and Díez-Villoria, E and Contador, I},
title = {Cerebral Hemodynamic Patterns in People with Subjective Cognitive Decline: A Systematic Review Based on Functional Near-Infrared Spectroscopy.},
journal = {Brain sciences},
volume = {16},
number = {10},
pages = {},
pmid = {42939380},
issn = {2076-3425},
abstract = {Background/Objectives: Subjective cognitive decline (SCD) has been proposed as an early symptomatic manifestation of dementia/Alzheimer's disease. However, its associated brain patterns are not yet fully characterized. In recent years, functional near-infrared spectroscopy (fNIRS) has emerged as a cost-effective technique to detect hemodynamic changes associated with cognitive decline. Therefore, fNIRS may be a valuable tool to investigate SCD neural underpinnings. This systematic review synthesizes current fNIRS evidence regarding the hemodynamic correlates of SCD during both resting-state and cognitive task conditions. Methods: Following PRISMA guidelines, we searched Scopus, PubMed, and Web of Science databases for studies combining keywords ('subjective cognitive decline', 'cognitive complaints', 'memory complaints', 'fNIRS', and 'near-infrared spectroscopy') with Boolean operators. Results: We identified 181 records, of which 10 studies fulfilled the inclusion and exclusion criteria. All studies were cross-sectional. Furthermore, 33% lacked a healthy control group, 56% lacked a standardized SCD identification protocol, 55% used small or imbalanced samples, and 66% did not clearly differentiate prefrontal subregions. In both resting-state and task conditions, SCD individuals showed heterogeneous hemodynamic responses in prefrontal areas. The severity of SCD and the difficulty of the tasks may be useful moderators of these associations. Conclusions: The limited evidence and methodological differences prevent identifying a specific hemodynamic pattern for SCD. Adopting longitudinal, well-powered, and well-controlled designs will be essential to evaluate fNIRS-derived hemodynamic responses in SCD.},
}

@article {pmid42939406,
year = {2026},
author = {Angelopoulou, E and Stamelos, I and N Sampatakakis, S and Papageorgiou, S and Scarmeas, N and Hatzimanolis, A and Proukakis, C and Villa, C},
title = {Polygenic Risk Scores in Alzheimer's Disease: A Cross-Scale View from Genes to Brain and Behavior.},
journal = {Biology},
volume = {15},
number = {20},
pages = {},
pmid = {42939406},
issn = {2079-7737},
abstract = {Alzheimer's disease (AD) is a genetically complex disorder in which inherited susceptibility is distributed across rare high-impact variants, the apolipoprotein E (APOE) locus, and a broad polygenic background of common risk alleles. Polygenic risk scores (PRSs) provide a quantitative framework for summarizing this distributed genetic liability and have become increasingly important tools for risk stratification, cohort enrichment, and biological interpretation. In this review, we synthesize evidence on AD PRSs across multiple biological and clinical scales, moving from genes and molecular pathways to biomarkers, brain structure and function, cognition, behavior, and clinical translation. Genome-wide PRSs capture aggregate inherited risk, whereas pathway-, tissue-, cell-type-, and biomarker-specific PRSs may help clarify the biological routes through which genetic susceptibility is expressed, including amyloid and tau metabolism, lipid homeostasis, endosomal trafficking, immune regulation, glial activation, proteostasis, and mitochondrial quality control. Evidence indicates that AD PRSs are most consistently associated with amyloid-related biomarkers, while associations with tau, neurodegeneration, brain atrophy, functional connectivity, cognitive decline, and neuropsychiatric manifestations are more heterogeneous and often depend on APOE, disease stage, biomarker context, and variable computation methodologies. Although PRSs show promise for research enrichment and mechanistic stratification, their individual-level clinical utility remains limited by modest predictive performance, ancestry-related transferability, calibration challenges, and ethical considerations. Future progress will require multi-ancestry cohorts, integration of common and rare variation, multi-omic annotation, longitudinal modeling, and multimodal prediction frameworks. Ultimately, PRSs are best viewed not as stand-alone diagnostic tools, but as cross-scale instruments for linking inherited susceptibility to the heterogeneous biological and clinical manifestations of AD.},
}

@article {pmid42939431,
year = {2026},
author = {Wang, J and Rong, M and Cui, J and Guo, H and Xu, J and Guo, Y},
title = {A Docking-Guided Strategy Prioritizes Parishin B as a Potential Anti-Alzheimer's Constituent of Gastrodia elata Blume.},
journal = {Biology},
volume = {15},
number = {20},
pages = {},
pmid = {42939431},
issn = {2079-7737},
support = {22177054//National Natural Science Foundation of China/ ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder with limited treatment options. Phosphodiesterase 4B (PDE4B) is a key regulator of neuroinflammation and has been implicated in AD pathology. Using molecular docking against PDE4B as a screening anchor, we analyzed constituents from G. elata water extract and identified Parishin B as a top-ranked candidate. Parishin B directly inhibited recombinant PDE4B, reducing activity to 22.1% of control at 100 μM. In an Al[3+]-induced zebrafish AD model, both the crude extract and purified Parishin B significantly rescued behavioral deficits; Parishin B at 100 μM showed no statistical difference from the donepezil group, while the crude extract was effective at 30 μg/mL. Mechanistically, Parishin B protected SH-SY5Y neurons against H2O2-induced oxidative stress by reducing ROS and apoptosis and suppressed LPS-induced neuroinflammation in BV-2 microglia via downregulation of iNOS and COX-2. These results suggest that Parishin B is a chemically traceable constituent with dual neuroprotective actions, validating the docking-guided screening strategy and supporting further investigation of G. elata as a source of AD-relevant bioactive compounds.},
}

@article {pmid42939494,
year = {2026},
author = {Zhu, F and Shao, X},
title = {Research Advances and Perspectives on Gut Microbiota Regulating Alzheimer's Disease.},
journal = {Biology},
volume = {15},
number = {20},
pages = {},
pmid = {42939494},
issn = {2079-7737},
support = {81771767, 81801580//National Natural Science Foundation of China/ ; },
abstract = {Alzheimer's disease is a neurodegenerative disease characterized by progressive cognitive impairment. One of the primary reasons for the significant challenges in its clinical management is that the pathogenesis of Alzheimer's disease has not been fully elucidated and effective intervention methods remain lacking. Therefore, it is crucial to explore relevant peripheral risk factors and novel therapeutic targets. The gut-microbiota-brain axis is a complex bidirectional regulatory network that integrates neural, endocrine, immune, and metabolic pathways. As the core of this axis, the gut microbiota modulates neuroinflammation, synaptic plasticity, and protein homeostasis. Specifically, metabolites such as short-chain fatty acids can cross the blood-brain barrier to regulate microglia activation, while microbial-mediated immunomodulatory effects directly influence the deposition of amyloid-β and the phosphorylation of tau protein. Existing studies have confirmed that Alzheimer's disease patients exhibit gut microbiota imbalance, typically manifested as a decreased abundance of beneficial bacteria and the proliferation of potential proinflammatory bacteria. The dysbiosis is closely related to the accumulation of core pathological markers and the severity of cognitive impairment. This article aims to elucidate the interaction and underlying mechanisms between the gut microbiota and Alzheimer's disease, offering an integrated analysis and research prospects to facilitate the development of novel intervention strategies.},
}

@article {pmid42939505,
year = {2026},
author = {López-Landa, A and González-Sánchez, E and Pérez-Villavicencio, J and Serrano García, N and García-Hernández, C and Lee, Á and Rubio-Osornio, M and Rubio, C},
title = {Ozone as a Catalyst for Alzheimer's Disease and Sleep Disorders: Implications for Neurodegeneration Induced by Air Pollution.},
journal = {Biology},
volume = {15},
number = {20},
pages = {},
pmid = {42939505},
issn = {2079-7737},
abstract = {Tropospheric ozone, a highly reactive air pollutant, has emerged as a potential environmental risk factor for Alzheimer's disease (AD) and its associated sleep disturbances, yet a comprehensive synthesis of the underlying mechanisms has remained limited. This narrative review summarizes experimental and epidemiological evidence on ozone exposure, neurodegeneration and disrupted sleep, organized around one working hypothesis: ozone generates a systemic oxidative-inflammatory signal that reaches the central nervous system, with sleep/circadian disruption and AD-related pathology as downstream outcomes that may reinforce each other. In experimental models, ozone is associated with oxidative stress, mitochondrial dysfunction, blood-brain barrier disruption, glial activation and neuroinflammation, overlapping with β-amyloid accumulation and tau hyperphosphorylation, and with reduced REM sleep and altered neurotransmitters; clock-gene changes have been shown mainly in peripheral tissue. Circadian disruption is a candidate effector, and current data cannot distinguish mediation from co-occurrence. Epidemiological evidence for ozone-specific associations with cognitive decline remains inconsistent at the population level compared with other pollutants such as PM2.5 or NO2, although some cohorts report pollutant-specific effects and modulation by the apolipoprotein E ε4 (APOE4) genotype. Most experimental studies use concentrations well above regulatory ambient standards. Overall, ambient ozone is a biologically plausible, but not yet epidemiologically confirmed, candidate risk factor for AD and sleep disorders. Future work should prioritize exposure-graded longitudinal studies and clarification of the dose-response relationship, including the effects of controlled medical ozone.},
}

@article {pmid42939619,
year = {2026},
author = {Bagyinszky, E and An, SSA},
title = {Brain Blindness Versus Eye Blindness: Genetic and Molecular Connections Between Alzheimer's Disease and Visual Impairment.},
journal = {Current issues in molecular biology},
volume = {48},
number = {10},
pages = {},
pmid = {42939619},
issn = {1467-3045},
abstract = {Visual dysfunctions were observed among Alzheimer's disease (AD) patients, including posterior cortical degeneration, retinal abnormalities, or coexisting ocular disease. Posterior cortical atrophy (PCA) is a clinical syndrome characterized by progressive higher-order visual impairment and is most frequently associated with AD pathology, although other neurodegenerative causes may be possible. Pathogenic variants in PSEN1 and PSEN2 were reported in individual cases of PCA and may support a possible monogenic contribution to selected early-onset posterior phenotypes. By contrast, variants and common AD risk genes, including GRN, MAPT, TREM2, BIN1, PICALM, ABCA7, and APOE E4 allele, represented broader genetic associations whose specific contribution to posterior cortical vulnerability remains incompletely defined. These forms of evidence should be interpreted separately. Genome-wide association studies identified overlapping loci associated with AD and glaucoma, including loci on chromosome 11 involving MTCH2, NDUFS3, and SPI1. This overlap reflected shared genetic susceptibility, pleiotropy, or putative convergent biological pathways involving mitochondrial function, immune regulation, and cellular stress. However, shared loci and pathway associations did not establish direct signaling, anatomical communication, or a causal relationship between brain and ocular tissues. The opposing tissue-specific effects reported for APOE further indicated that data in the brain may not be extrapolated to the retina. Future studies should clarify the cell-specific effects, causal direction, and clinical significance of shared genetic factors using well-characterized cohorts and tissue-specific experimental models. Overall, current evidence supported the partially overlapping genetic and cellular mechanisms in AD and selected ocular disorders, while further studies should be needed on the biological relationship between the brain and eye.},
}

@article {pmid42939638,
year = {2026},
author = {Lee, H and Park, SH and Chae, HJ},
title = {Minor Phytocannabinoids as Candidate Multi-Target Modulators of Endoplasmic Reticulum Stress-Linked Proteostasis Failure in Alzheimer's Disease: A Mechanistic Review.},
journal = {Biomolecules},
volume = {16},
number = {10},
pages = {},
pmid = {42939638},
issn = {2218-273X},
support = {National University Development Project//Jeonbuk National University/ ; },
mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism/pathology ; *Cannabinoids/pharmacology/therapeutic use/chemistry ; *Proteostasis/drug effects ; *Endoplasmic Reticulum Stress/drug effects ; Animals ; Unfolded Protein Response/drug effects ; Oxidative Stress/drug effects ; Proteotoxic Stress ; },
abstract = {Alzheimer's disease (AD) involves pathological processes that may limit single-target therapeutic strategies. Endoplasmic reticulum (ER) stress and unfolded protein response (UPR) dysregulation may contribute to proteostasis failure. This review examines whether minor phytocannabinoids from Cannabis sativa L.-cannabigerol (CBG), cannabichromene (CBC), cannabinol (CBN), cannabidivarin (CBDV), and tetrahydrocannabivarin (THCV)-warrant investigation as modulators of ER stress-linked proteostasis failure in AD. Evidence is organized around calcium dyshomeostasis, mitochondrial dysfunction and oxidative stress, neuroinflammation, and autophagic impairment as processes that may converge on ER stress, and limited direct evidence for UPR marker changes is evaluated separately. These compounds show overlapping but distinct target profiles involving cannabinoid receptors, transient receptor potential (TRP) channels, peroxisome proliferator-activated receptor γ, mitochondrial and redox pathways, and inflammatory signaling. Available evidence associates CBN primarily with mitochondrial stress pathways, while its involvement in ER-mitochondria signaling remains hypothetical. CBG has been associated with oxidative and inflammatory pathways, THCV with inflammatory signaling, and CBC and CBDV with TRP-related calcium signaling and autophagic pathways. CBDV and CBG have been associated with UPR marker changes in non-neuronal cells, although their functional direction and relevance to AD remain uncertain. Minor phytocannabinoids may serve as pharmacological probes for ER stress-linked proteostasis in AD, and validation in AD-relevant neuronal, organoid, in vivo, and pharmacokinetic studies is required before therapeutic potential can be established.},
}

Humans
*Alzheimer Disease/drug therapy/metabolism/pathology
*Cannabinoids/pharmacology/therapeutic use/chemistry
*Proteostasis/drug effects
*Endoplasmic Reticulum Stress/drug effects
Animals
Unfolded Protein Response/drug effects
Oxidative Stress/drug effects
Proteotoxic Stress

@article {pmid42939687,
year = {2026},
author = {Dou, W and Chen, X and Hong, H and Liu, Q and Xiao, S and Li, L and Yu, J and Tang, C},
title = {Integrated Multi-Omics Analysis Reveals ACO2 as an Oxidative-Stress-Related Biomarker in Alzheimer's Disease.},
journal = {Biomolecules},
volume = {16},
number = {10},
pages = {},
pmid = {42939687},
issn = {2218-273X},
support = {2025Z146 and 2025Z212//"Science and Technology Innovation Yongjiang 2035" Key Research and Development Plan in 2025/ ; 2024C03101//One health Interdisciplinary Research Project, Institute of One Health Science, Ningbo University, Zhejiang Province Leading Geese Plan/ ; D16013//National 111 Project of China/ ; 2023YFC3304203//National key research and development program/ ; 2023CSJGG1800//Yangtze River Delta Science and Technology Innovation Community Joint Research Project/ ; 025C01200(SD2), 2024C03266 and 2024C03101//Key Research and Development Program of Zhejiang Province/ ; 20231203A18//Hangzhou Science and Technology Development Project/ ; 2022Z241, 2023Z132, 2023Z168, 2024Z230, 2024S047and 2023S151//Ningbo Science and Technology Project/ ; },
mesh = {*Alzheimer Disease/genetics/metabolism ; *Oxidative Stress/genetics ; Humans ; Biomarkers/metabolism ; Animals ; Mice ; Hippocampus/metabolism ; Multiomics ; Male ; Proteomics ; Female ; Gene Expression Profiling ; Disease Models, Animal ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and memory impairment. Oxidative stress plays an important role in disease progression in AD. However, the molecular mechanisms underlying oxidative stress in AD remain unclear and reliable biomarkers for its detection have not been identified. In this study, bioinformatics analyses integrating differential expression analysis and weighted gene co-expression network analysis were performed to identify oxidative-stress-related differentially expressed genes. Using machine learning algorithms, ACO2 was identified as a significantly downregulated hub gene associated with AD. Single-cell transcriptomic analysis further showed markedly reduced ACO2 expression levels in hippocampal neurons of patients with AD. To validate these findings, proteomic analysis, quantitative real-time polymerase chain reaction (qPCR), and Western blotting were performed in a mouse model of AD. These results confirmed decreased ACO2 mRNA and protein expression levels in the hippocampus. Consistently, qPCR analysis of peripheral blood samples from patients with AD revealed significantly reduced ACO2 expression levels compared to those in healthy controls. Collectively, these findings identified ACO2 as an oxidative-stress-related biomarker associated with AD and suggested its potential value as an AD-related candidate biomarker.},
}

*Alzheimer Disease/genetics/metabolism
*Oxidative Stress/genetics
Humans
Biomarkers/metabolism
Animals
Mice
Hippocampus/metabolism
Multiomics
Male
Proteomics
Female
Gene Expression Profiling
Disease Models, Animal

@article {pmid42939712,
year = {2026},
author = {Rietmann, ÁJ and Sanchis, I and Spinelli, R and López, JA and Siano, ÁS},
title = {From Amphibian Extracts to Focused Libraries: An Algorithm-Based Strategy to Uncover Potent Multi-Target Anti-Alzheimer Peptides.},
journal = {Biomolecules},
volume = {16},
number = {10},
pages = {},
pmid = {42939712},
issn = {2218-273X},
support = {PICT-GR-150//Consejo Nacional de Investigaciones Científicas y Técnicas/ ; PICT-INVI-282//Consejo Nacional de Investigaciones Científicas y Técnicas/ ; },
mesh = {Animals ; *Cholinesterase Inhibitors/pharmacology/chemistry/isolation & purification ; *Alzheimer Disease/drug therapy ; Algorithms ; *Peptides/chemistry/pharmacology ; Humans ; Acetylcholinesterase/metabolism ; Antioxidants/pharmacology/chemistry ; *Amphibians ; Butyrylcholinesterase/metabolism ; Amino Acid Sequence ; },
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder, driving the search for multitarget-directed ligands (MTDLs) able to modulate multiple pathological pathways. Since amphibians represent a rich source of bioactive peptides, skin extracts from Scinax nasicus and Dendropsophus nanus, classified by sex, developmental stage, and season, were evaluated against key AD-related mechanisms, including cholinesterase inhibition, antioxidant activity, and Fe[2+] chelation. Subsequently, a rational discovery workflow was implemented, integrating extract-level chemical characterization and bioactivity screening with the sequence identification of the main components and a novel in silico algorithm-based prioritization. This strategy, formalized through the Multi-Target Therapeutic Potential Score (MTTP-Score), served as a rational filter to produce a focused synthetic library, significantly minimizing experimental time and cost. Peptides derived from D. nanus (Dn) displayed the most promising multitarget candidates. Dn-7 combined sub-micromolar dual cholinesterase inhibition (IC50 = 0.32 and 1.2 µM for AChE and BChE, respectively) with highly efficient Fe[2+] chelation (EC50 = 39 µM), representing the highest MTDL activity reported for an amphibian peptide. Dn-18 emerged as a moderate butyrylcholinesterase inhibitor with strong metal chelating capacity. Overall, this study establishes a pipeline for the rational discovery of peptide-based MTDL scaffolds for AD.},
}

Animals
*Cholinesterase Inhibitors/pharmacology/chemistry/isolation & purification
*Alzheimer Disease/drug therapy
Algorithms
*Peptides/chemistry/pharmacology
Humans
Acetylcholinesterase/metabolism
Antioxidants/pharmacology/chemistry
*Amphibians
Butyrylcholinesterase/metabolism
Amino Acid Sequence

@article {pmid42939722,
year = {2026},
author = {Morgan, J and Aarons, T and Lace, G and Mukhopadhyay, A},
title = {Chromosome 14 MicroRNA Cluster Members in Brain-Derived Extracellular Vesicles Can Be Genotype-Associated Biomarker Candidates for Alzheimer's Disease and Frontotemporal Dementia.},
journal = {Biomolecules},
volume = {16},
number = {10},
pages = {},
pmid = {42939722},
issn = {2218-273X},
support = {SERA52/ALZS_/Alzheimer's Society/United Kingdom ; },
mesh = {Humans ; *MicroRNAs/genetics/metabolism ; *Frontotemporal Dementia/genetics/metabolism ; *Alzheimer Disease/genetics/metabolism ; *Extracellular Vesicles/metabolism/genetics ; Female ; Biomarkers/metabolism ; *Chromosomes, Human, Pair 14/genetics ; Male ; *Brain/metabolism ; Aged ; Genotype ; Multigene Family ; Middle Aged ; },
abstract = {BACKGROUND: The chromosome 14 microRNA cluster (C14MC) is the second largest microRNA (miRNA) cluster in the human genome, which is tightly regulated during early development and dysregulated in many disease conditions. Members of this cluster are reported to have important temporal and spatial roles in early development, especially in neurogenesis. Although extensively studied as cancer biomarkers, their potential as molecular signatures of neurodegenerative diseases (NDs) remains poorly understood. Given the importance of non-invasive or less-invasive biomarkers of dementia, brain-derived small extracellular vesicles (BDsEVs) represent a promising source of disease-associated miRNAs. BDsEVs can traverse the blood-brain barrier and potentially become a surrogate for molecular changes within the brain in accessible body fluids. We investigated whether BDsEV-associated C14MC miRNAs exhibit shared or disease-specific expression patterns in Alzheimer's disease (AD) and genetically defined subtypes of frontotemporal dementia (FTD).

METHODS: BDsEVs were isolated from post-mortem frontal cortex tissue of neurologically healthy controls, AD, and FTD cases carrying pathogenic GRN, MAPT, or C9orf72 mutations. Seven candidate C14MC miRNAs were quantified by RT-qPCR, while small RNA-sequencing data were analysed to characterise C14MC expression patterns.

RESULTS: Among the RT-qPCR candidates, miR-323a-5p and miR-758-5p showed significant differences between diagnostic groups. MiR-323a-5p demonstrated disease-associated upregulation in FTD-MAPT compared with all other groups (fold change = 6.68, adjusted p < 0.001) in the relative-expression analysis, with ΔCt analysis supporting all comparisons except AD. Exploratory small RNA-sequencing identified nominal expression differences in FTD-MAPT (miR-1197, miR-381-3p, miR-299-3p) and FTD-C9orf72 (miR-485-3p, miR-381-3p) compared to controls, alongside nominal differences observed in AD against FTD mutation groups (miR-1247-5p), with recurrent alterations across multiple comparisons. Further nominal differences were observed between underlying proteinopathies.

CONCLUSIONS: Collectively, these findings identify disease- and genotype-associated patterns of C14MC miRNAs within BDsEVs, although the sequencing findings remain exploratory and require validation in larger independent cohorts. Thus, our results highlight the potential of individual C14MC members as BDsEV-derived molecular signatures and candidate biomarkers for molecular stratification of dementia.},
}

Humans
*MicroRNAs/genetics/metabolism
*Frontotemporal Dementia/genetics/metabolism
*Alzheimer Disease/genetics/metabolism
*Extracellular Vesicles/metabolism/genetics
Female
Biomarkers/metabolism
*Chromosomes, Human, Pair 14/genetics
Male
*Brain/metabolism
Aged
Genotype
Multigene Family
Middle Aged

@article {pmid42939727,
year = {2026},
author = {Kong, Y and Peng, J and Sun, J and Nie, Y},
title = {Cannabidiol Alleviates Aβ1-42-Induced Cognitive Deficits and Neuronal Injury Associated with Modulation of the AEA-FAAH-CB1R Axis and BDNF/TrkB Signaling.},
journal = {Biomolecules},
volume = {16},
number = {10},
pages = {},
pmid = {42939727},
issn = {2218-273X},
support = {JJPY2025006//the Natural Science Foundation Project/ ; },
mesh = {Animals ; *Amyloid beta-Peptides/toxicity/metabolism ; *Cannabidiol/pharmacology ; Brain-Derived Neurotrophic Factor/metabolism ; Rats ; *Peptide Fragments/toxicity ; PC12 Cells ; Receptor, trkB/metabolism ; Signal Transduction/drug effects ; Receptor, Cannabinoid, CB1/metabolism ; Hippocampus/metabolism/drug effects/pathology ; Endocannabinoids/metabolism ; Male ; *Cognitive Dysfunction/drug therapy/metabolism/chemically induced ; Neurons/drug effects/metabolism/pathology ; Neuroprotective Agents/pharmacology ; Arachidonic Acids/metabolism ; Amidohydrolases/metabolism ; Polyunsaturated Alkamides/metabolism ; Alzheimer Disease/drug therapy/metabolism ; },
abstract = {Background: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, synaptic dysfunction, and neuronal injury. Cannabidiol (CBD), a non-psychoactive constituent of Cannabis sativa L., has neuroprotective potential, but its underlying mechanisms remain unclear. Purpose: This study investigated the effects of CBD on Aβ1-42-induced cognitive impairment and hippocampal injury, focusing on endocannabinoid and BDNF/TrkB signaling. Methods: Cognitive function was assessed by Morris water maze and novel object recognition tests; hippocampal pathology and molecular changes were evaluated by H&E staining, immunofluorescence, LC-MS, ELISA, and Western blotting; and CB1R involvement was further examined in Aβ1-42-treated PC12 cells using AM251. Results: CBD improved cognitive performance, attenuated hippocampal histopathological alterations, reduced tau hyperphosphorylation, and partially restored synaptophysin levels. CBD also increased hippocampal AEA levels, reduced FAAH levels, and restored CB1R and BDNF/TrkB-associated signaling. In Aβ1-42-treated PC12 cells, CBD improved cell viability and increased synaptophysin, CB1R, BDNF, and p-TrkB/TrkB levels, whereas AM251 attenuated several CBD-associated effects. Conclusions: These findings suggest that modulation of the AEA-FAAH-CB1R axis and BDNF/TrkB signaling may contribute to the neuroprotective effects of CBD against Aβ1-42-induced cognitive impairment and neuronal injury.},
}

Animals
*Amyloid beta-Peptides/toxicity/metabolism
*Cannabidiol/pharmacology
Brain-Derived Neurotrophic Factor/metabolism
Rats
*Peptide Fragments/toxicity
PC12 Cells
Receptor, trkB/metabolism
Signal Transduction/drug effects
Receptor, Cannabinoid, CB1/metabolism
Hippocampus/metabolism/drug effects/pathology
Endocannabinoids/metabolism
Male
*Cognitive Dysfunction/drug therapy/metabolism/chemically induced
Neurons/drug effects/metabolism/pathology
Neuroprotective Agents/pharmacology
Arachidonic Acids/metabolism
Amidohydrolases/metabolism
Polyunsaturated Alkamides/metabolism
Alzheimer Disease/drug therapy/metabolism

@article {pmid42939748,
year = {2026},
author = {Shi, X and Chen, G and Wang, X and Ma, R and Li, G},
title = {Deubiquitinating Enzymes in Alzheimer's Disease: From Protein Homeostasis to Diverse Pathological Processes.},
journal = {Biomolecules},
volume = {16},
number = {10},
pages = {},
pmid = {42939748},
issn = {2218-273X},
support = {No. 82271230//National Natural Science Foundation of China/ ; },
mesh = {Humans ; *Alzheimer Disease/pathology/metabolism/enzymology ; Animals ; *Proteostasis ; *Deubiquitinating Enzymes/metabolism ; Ubiquitination ; Autophagy ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; Homeostasis ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder involving multiple pathological processes, including amyloid-β (Aβ) accumulation, tau pathology, impaired autophagy, mitochondrial dysfunction, neuroinflammation, and synaptic dysfunction. Deubiquitinating enzymes (DUBs) reverse ubiquitination and regulate protein stability, degradation, and cellular signaling. Although studies of DUBs in AD have largely focused on Aβ metabolism and tau homeostasis, accumulating evidence implicates DUBs in a broader range of AD-related processes, including autophagy, neuroinflammation, mitochondrial function, and synaptic function. Several DUBs have also been implicated in more than one of these processes, although these effects have often been identified in different experimental models. In this review, we summarize current knowledge of DUBs in major AD-related pathological processes and discuss the mechanisms through which individual DUBs may influence different aspects of AD pathology. We also discuss the limitations of current studies and the potential and challenges of targeting DUBs in AD.},
}

Humans
*Alzheimer Disease/pathology/metabolism/enzymology
Animals
*Proteostasis
*Deubiquitinating Enzymes/metabolism
Ubiquitination
Autophagy
Amyloid beta-Peptides/metabolism
tau Proteins/metabolism
Homeostasis

@article {pmid42939867,
year = {2026},
author = {Park, YM and Choi, BK and Park, MG and Kim, M and Won, W and Shin, HJ and Lee, CJ},
title = {K34 (3,3″-Dihydroxy-6'-desmethyl Terphenyllin) Promotes Hemoglobin-Supported H2O2 Decomposition and Attenuates Neurodegenerative Phenotypes in APP/PS1 Mice with Focal GiD.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {15},
number = {10},
pages = {},
pmid = {42939867},
issn = {2076-3921},
support = {IBS-R001-D2//Institute for Basic Science/ ; PKB0012//Korea Institute of Ocean Science and Technology/ ; PEB0010//Korea Institute of Ocean Science and Technology/ ; },
abstract = {Hydrogen peroxide (H2O2) contributes to oxidative stress in Alzheimer's disease (AD), yet conventional antioxidants that directly scavenge H2O2 have shown limited therapeutic efficacy. Here, we investigated K34 (3,3″-dihydroxy-6'-desmethyl terphenyllin), a catechol-bearing para-terphenyl isolated from the marine fungus Penicillium janthinellum 168CLC-17.1, as an indirect H2O2-decomposing agent. Complementary cell-free assays showed that K34 promoted peroxidase-dependent H2O2 decomposition, including Hb-supported H2O2 decomposition, while molecular docking predicted a plausible binding pose near the Hbβ heme pocket. In amyloid-β42 (Aβ42)-stimulated primary astrocytes, K34 reduced intracellular H2O2. In APPswe/PSEN1dE9 (APP/PS1) mice subjected to focal GFAP-inducible diphtheria toxin receptor (fGiD), systemic K34 attenuated memory impairment, preserved NeuN-positive neurons, reduced GFAP immunoreactivity, and improved hippocampal spike probability. K34 also exhibited low passive blood-brain barrier (BBB) permeability and limited inhibition of five major cytochrome P450 (CYP) isoforms under the tested conditions. These findings extend Hb-supported H2O2 decomposition to a structurally distinct marine natural product and support further evaluation of K34 as an antioxidant scaffold for modulating oxidative stress-associated neurodegenerative phenotypes.},
}

@article {pmid42939895,
year = {2026},
author = {Yüksel, M and Schmidt, M},
title = {Circular RNAs in Alzheimer's Disease: Mechanisms, Biomarkers, and EPAC Signalling in Ferroptosis.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {15},
number = {10},
pages = {},
pmid = {42939895},
issn = {2076-3921},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and complex pathogenesis, involving amyloid-β (Aβ) accumulation, tau pathology, and neuroinflammation, driven by microglial shifts toward pro-inflammatory M1-like states, causing neuronal dysfunction and death, particularly by ferroptosis. Current diagnostic and therapeutic strategies remain limited, highlighting the need for novel molecular regulators. Circular RNAs (circRNAs) are covalently closed non-coding RNAs (ncRNAs), representing promising regulatory molecules and peripheral biomarkers. Evidence suggests that circRNAs regulate AD-related pathways, through microRNA (miRNA) sponging, including modulation of NF-κB/BACE1-dependent (nuclear-factor-kappa-B/beta-site APP-cleaving enzyme 1) amyloidogenic APP (amyloid precursor protein) processing and through disruption of NMDA (N-methyl-D-aspartate) receptor-dependent synaptic signaling, exemplified by circRIMS2-driven UBE2K (ubiquitin-conjugating enzyme E2K)-mediated GluN2B (glutamate ionotropic receptor NMDA type subunit-2B) degradation. Additionally, circRNAs represent promising non-invasive diagnostic biomarkers. Plasma hsa_circRNA_050263 showed high diagnostic accuracy for early-stage AD. CircRNAs may offer a therapeutic strategy for modulating cell-death pathways, particularly ferroptosis. Selectively targeting EPAC2 (exchange protein directly activated by cAMP2) may preserve EPAC2-associated neuroprotection, while limiting EPAC1-associated ferroptosis, although challenges such as blood-brain barrier delivery remain to be addressed. This review summarizes circRNA biogenesis, diagnostic potential, and roles in AD pathogenesis, and limitations and AD models, besides investigating the selective circRNA-EPAC axis.},
}

@article {pmid42940012,
year = {2026},
author = {Jiao, Y and Du, C and Ding, Y and Zhou, R and Zhao, A and Liu, J and Deng, Y and For The Alzheimer's Disease Neuroimaging Initiative, },
title = {CSF APOE Secondary Glycosylation Predicts Cognitive Decline in Mild Cognitive Impairment.},
journal = {Biomedicines},
volume = {14},
number = {10},
pages = {},
pmid = {42940012},
issn = {2227-9059},
support = {82201392//National Natural Science Foundation of China/ ; 22YF1425100//Shanghai Sailing Program/ ; },
abstract = {Background: Glycosylation is an important post-translational modification of apolipoprotein E (APOE) and APOE in cerebrospinal fluid (CSF) displays an additional secondary glycosylation that is not present in plasma, suggesting a brain-specific regulatory mechanism. This study investigated whether altered APOE glycosylation is associated with early cognitive decline and progression from mild cognitive impairment (MCI) to AD and further explored its potential biological relevance. Methods: APOE glycosylation levels were measured in participants with MCI and healthy controls (HCs). Analyses were stratified by APOE4 genotype and examined in relation to neuroimaging markers. The data-derived cut-off values were used to assess disease progression. Single-cell transcriptomic data from the SEA-AD cohort were analyzed to characterize glycosylation-related alterations in dementia microglia. Results: The total APOE glycosylation in CSF and plasma did not differ significantly between the MCI and control groups. CSF secondary APOE glycosylation was lower in participants with MCI in the unadjusted analysis. It was not significantly associated with baseline white matter hyperintensity (WMH) or hippocampal volume. In exploratory analyses using a data-derived cut-off, lower CSF secondary glycosylation was associated with faster hippocampal volume decline and shorter time to AD conversion. Donor-level pseudobulk analysis of the SEA-AD cohort showed lower ST6GAL1 expression and higher APOE, LPL, and CD9 expression in donors with dementia; MGAT1 was not significantly altered overall. Conclusions: CSF secondary APOE glycosylation may be associated with early pathological changes and disease progression in MCI. Together with alterations in microglial glycosylation-related pathways, these exploratory findings suggest broader glycosylation dysregulation in APOE-related neurodegeneration.},
}

@article {pmid42940016,
year = {2026},
author = {Uhl, GR and Choi, J and Kannan, B and Henderson, I and Hess, E and Rogers, H and McFarland, D and Dowell, H and Nolan, S and Schultz, K},
title = {Alzheimer's Disease Neurofibrillary Pathophysiology: PTPRD- and Flavonol-Modified Mechanisms, Prevention and Therapeutics.},
journal = {Biomedicines},
volume = {14},
number = {10},
pages = {},
pmid = {42940016},
issn = {2227-9059},
support = {Supplements to U)1DA047713 and UG3DA056039/AG/NIA NIH HHS/United States ; },
abstract = {A variety of evidence now supports two interrelated hypotheses concerning Alzheimer's disease (AD) neurofibrillary pathology (NFT), its prevention and treatment. The first hypothesis: the receptor type protein tyrosine phosphatase D (PTPRD) plays a key role in AD NFT pathogenesis by modulating activities of neuronal glycogen synthase kinase 3s (GSK3s) in hyperphosphorylating tau. The second hypothesis: positive allosteric modulation of PTPRD's downregulation of GSK3s by flavonols and improved flavonol analogs provides a novel path to prevention and treatment of AD. We review the convergence of evidence from human, mouse, in vitro and in silico studies that enhances the likely translational relevance of these hypotheses.},
}

@article {pmid42940037,
year = {2026},
author = {Sahuquillo, J and Al-Nusaif, M and Torrecilla-Vall-Llossera, M and Durduran, T and Poca, MA},
title = {Five Decades of Infusion Testing in Idiopathic Normal-Pressure Hydrocephalus: Resistance to CSF Outflow as a Biomarker in Search of a Gold Standard.},
journal = {Biomedicines},
volume = {14},
number = {10},
pages = {},
pmid = {42940037},
issn = {2227-9059},
support = {PI25/01408//Institute of Health Carlos III/ ; 2021SGR/00810//Agency for Administration of University and Research/ ; 10108144//European Union/ ; SCOSWEAR PID2023-147553OB-I00//Spanish State Research Agency/ ; SAFEICP PLEC2022-009290//Spanish State Research Agency/ ; LitMuscle DTS22/00023//Institute of Health Carlos III/ ; },
abstract = {Idiopathic normal-pressure hydrocephalus (iNPH) is a potentially reversible cause of gait impairment, cognitive decline, and urinary dysfunction in older adults, yet identifying patients most likely to benefit from cerebrospinal fluid (CSF) diversion remains a major diagnostic challenge. For more than five decades, the lumbar infusion test, introduced by Katzman and Hussey in 1970, has served as the principal method for assessing CSF absorptive capacity through measurement of resistance to CSF outflow (Rout). This narrative review examines the historical development, physiological basis, and contemporary clinical application of infusion testing in iNPH, with particular emphasis on the diagnostic and prognostic value of Rout. We critically review the evidence supporting the Rout thresholds recommended by current international, Japanese, and American Academy of Neurology guidelines and reassess their performance using a Bayesian framework. Recalculation of likelihood ratios from published meta-analyses demonstrates that none of the commonly proposed Rout thresholds (10-18 mmHg·min/mL) achieves the prognostic performance typically associated with a strong rule-in or rule-out test. We argue that this limited performance reflects not only methodological heterogeneity in infusion-testing protocols but also a more fundamental problem: the absence of a universally accepted reference standard for iNPH. We further examine the limitations of using postoperative clinical improvement as a surrogate reference standard, including variability in outcome definitions, delayed treatment effects, and the potential for circular reasoning. Finally, we review emerging CSF proteomic biomarkers of neuroinflammation, axonal injury, and concomitant Alzheimer-type pathology that may complement hydrodynamic assessment by capturing the balance between reversible hydrocephalus-related dysfunction and irreversible neurodegenerative burden. We conclude that Rout should be regarded as a valuable but incomplete biomarker and that future progress will likely depend on multimodal, probabilistically interpreted models integrating CSF hydrodynamics, neuroimaging, and molecular biomarkers to improve prognostic stratification and establish more robust diagnostic frameworks for iNPH.},
}

@article {pmid42940120,
year = {2026},
author = {Haq, NU and Irshad, SU and Bibi, Z and Rehman, S and Sohail, S and Irshad, SR and Haider, NU and Mir, S and Shareef, A and Lucke-Wold, B},
title = {The Glymphatic System in Traumatic Brain Injury, Subarachnoid Hemorrhage, and Neurodegeneration: A Unifying Neurobiological Framework.},
journal = {Biomedicines},
volume = {14},
number = {10},
pages = {},
pmid = {42940120},
issn = {2227-9059},
abstract = {Whether glymphatic dysfunction drives or merely follows brain injury and neurodegeneration remains unresolved. The glymphatic system mediates the transport, exchange, and clearance of solutes between cerebrospinal fluid (CSF) and interstitial fluid (ISF) through paravascular CSF influx, polarized aquaporin-4 (AQP4) at astrocytic endfeet, and meningeal lymphatic drainage. This narrative review synthesizes evidence on glymphatic regulation and its role in traumatic brain injury (TBI), subarachnoid hemorrhage (SAH), and neurodegeneration, and appraises imaging, biomarker, and therapeutic approaches. PubMed/MEDLINE and Google Scholar were searched from inception to August 2026, and 128 sources were analyzed. In TBI, mechanical shear and NLR family pyrin domain-containing 3 (NLRP3)-dependent inflammation may alter AQP4 distribution and impair tau and amyloid-beta (Aβ) clearance; however, glymphatic failure has not been established as the causal mediator of later neurodegeneration, which is likely multifactorial. After SAH, blood and fibrin may obstruct perivascular pathways, and hemoglobin, heme, and iron toxicity may further disrupt CSF-ISF exchange; these changes are associated with delayed cerebral ischemia, cortical spreading depolarizations, and post-hemorrhagic hydrocephalus. Impaired clearance of Aβ, phosphorylated tau, and α-synuclein may link glymphatic dysfunction to Alzheimer's and Parkinson's diseases, although causality is unproven. Current imaging tools, including diffusion tensor imaging analysis along the perivascular space (DTI-ALPS), and biomarkers do not yet provide a validated measure of glymphatic function. Sleep optimization is a low-risk strategy, and controlled lumbar drainage has the strongest clinical evidence among CSF-dynamics approaches. Translation requires appropriate animal models and prospective TBI/SAH studies combining serial DTI-ALPS with cognitive follow-up.},
}

@article {pmid42940148,
year = {2026},
author = {Zhao, P and Lai, S and Dai, S and Zhou, C and Li, N and Yu, W},
title = {Profiling Amino Acid Substitutions in Proteomic Datasets of Alzheimer's Disease Reveals Biological Significance.},
journal = {Biomedicines},
volume = {14},
number = {10},
pages = {},
pmid = {42940148},
issn = {2227-9059},
support = {MHP/033/20, ITS/043/23//ITC/ ; 16102422, 16103621, R4012-18, C7015-23G, T12-101/23N//RGC/ ; HzQB-KCZYB-2020083//Hetao Cooperation Zone Project/ ; 3030_009, BGF.001.2023, CSSET24SC01, Z1056, OKT26EG06//Hong Kong University of Science and Technology/ ; },
abstract = {Background: Amino acid (AA) substitutions in Alzheimer's disease (AD) have been studied almost exclusively at the DNA and RNA levels, and the proteome-level substitution landscape remains largely uncharacterized. Methods: We applied an open-search substitutomics pipeline (PIPI-C with Comet re-scoring, 1% PSM-level FDR) to two independent AD brain proteomic datasets, the AMP-AD superior temporal gyrus cohort (244 individuals) and PXD013753, excluding substitutions whose mass shifts coincide with common post-translational modifications. Results: We quantified 789 substitution-bearing peptidoforms from 185 proteins, corresponding to 784 protein-level substitution events. N > M was the most frequent N > X substitution in both datasets. In an institution-stratified case-control meta-analysis, 138 peptidoforms were more and 142 less abundant in AD than in neuropathological controls. Of 774 genome-mappable events, 710 (91.7%) were recorded in neither UniProt nor gnomAD, and only five matched a population variant with allele frequency ≥ 0.1%. The unrestricted search recovered six literature-reported sites in GFAP, ACTG1, and HBB. Conclusions: Proteome-level profiling reveals substitution events in AD brains that catalogued germline variation does not explain; their molecular origin requires orthogonal validation.},
}

@article {pmid42940174,
year = {2026},
author = {Gogu, AA and Axelerad, A and Gogu, AE and Benta, M and Neda-Stepan, O and Bredicean, AC},
title = {MTHFR C677T and Brain MRI Patterns Across Cognitive and Vascular Disorders: A Systematic Review.},
journal = {Biomedicines},
volume = {14},
number = {10},
pages = {},
pmid = {42940174},
issn = {2227-9059},
abstract = {Background: Elevated plasma homocysteine, arising from impaired one-carbon metabolism, has been implicated in cerebral microvascular injury and in neurodegeneration. The methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism is the commonest genetic determinant of homocysteine concentration, but whether it leaves a measurable structural footprint on the brain remains unresolved. We synthesised genotype-stratified structural MRI findings in Alzheimer's disease, mild cognitive impairment, and vascular cognitive disorders. Methods: Four sources (PubMed, Europe PMC, OpenAlex, Semantic Scholar) were searched up to 20 September 2026. Eligible reports gave C677T-stratified structural MRI outcomes in adults with clinically defined cognitive disorders. Quality was appraised with an adapted Newcastle-Ottawa Scale, and exploratory random-effects meta-analyses supplemented a narrative synthesis. Results: Thirteen studies (3880 participants across partly overlapping cohorts) were included. Moderate-to-severe white matter lesions were modestly more frequent in TT homozygotes, consistently across contributing studies, with no consistent excess in heterozygotes. Regional volume findings were inconsistent and largely confined to one cohort, whereas whole-brain atrophy rate, hippocampal and medial temporal measures, lacunes, microbleeds, and diffusion metrics showed no genotype-only association. Homocysteine was higher in T-allele carriers wherever measured. Conclusions: The evidence is more compatible with a modest association with vascular white matter injury than with a reproducible neurodegenerative imaging phenotype and does not support genotype-guided clinical decision-making. Longitudinal, biomarker-characterised cohorts with harmonised imaging, adequately powered genotype groups, and measured nutritional status are the main priorities.},
}

@article {pmid42940213,
year = {2026},
author = {Deng, Y and Chen, D and Yin, H and Lu, Z and Tian, X and Gong, Q and , },
title = {Paired CSF-Plasma Analyte Signal Contrasts Across Alzheimer's Disease Clinical Stages and MCI-to-Dementia Conversion.},
journal = {Biomedicines},
volume = {14},
number = {10},
pages = {},
pmid = {42940213},
issn = {2227-9059},
abstract = {Background: Cerebrospinal fluid (CSF) and plasma biomarkers provide complementary information about Alzheimer's disease (AD), but matched analytes are commonly evaluated separately. We investigated whether relative CSF-plasma analyte signals were associated with AD clinical stage and subsequent conversion from mild cognitive impairment (MCI) to AD dementia. Methods: We analyzed paired CSF and plasma NULISAseq data from 1199 Alzheimer's Disease Neuroimaging Initiative participants. For 125 shared analyte readouts, ΔNPQ was defined as the within-participant difference between CSF and plasma normalized protein quantifications. Clinical-stage associations were evaluated using covariate-adjusted models. In 547 participants with baseline MCI, we examined subsequent dementia conversion and compared matched CSF-only, plasma-only, ΔNPQ, and joint CSF-plasma representations. Results: Fourteen readouts mapping to eight gene-level targets were associated with more advanced clinical stage after false-discovery-rate correction, involving amyloid/tau, synaptic, astroglial, cholinergic, and neuroaxonal processes. During a median follow-up of 3.0 years, 203 participants with MCI converted to AD dementia. A cross-sectionally derived six-analyte ΔNPQ score was associated with subsequent conversion after adjustment for demographic, genetic, and baseline clinical characteristics (hazard ratio per standard deviation, 1.64; 95% confidence interval, 1.38-1.96). The joint CSF-plasma model yielded the largest estimated improvement in discrimination. After additional adjustment for amyloid/tau biomarkers, the association between ΔNPQ and dementia conversion was attenuated. Conclusions: Relative CSF-plasma analyte patterns are associated with AD clinical stage and subsequent dementia conversion in MCI. Paired-biofluid analysis provides a complementary framework for characterizing disease-associated molecular heterogeneity, rather than a demonstrably superior prognostic model.},
}

@article {pmid42940294,
year = {2026},
author = {Wang, X and Wu, S and He, J and Wang, R and Zhao, W and Zhang, Z and Zeng, Z and Zhang, Y and Jiang, Q and Zhao, B and Zhang, M},
title = {Nicotinamide Mononucleotide-Producing Probiotic Strain B12-N Attenuates Aging and Cognitive Decline in a Caenorhabditis elegans Model of Alzheimer's Disease: Efficacy and Underlying Mechanisms.},
journal = {Foods (Basel, Switzerland)},
volume = {15},
number = {20},
pages = {},
pmid = {42940294},
issn = {2304-8158},
support = {2024YFD2100903//National Key Research and Development Program of China/ ; 2024-JSGG-027//National Center of Technology Innovation for Dairy/ ; },
abstract = {Nicotinamide mononucleotide (NMN) is an active component found in probiotics that may help alleviate Alzheimer's disease and the effects of aging. The screened NMN-producing strain, Ligilactobacillus salivarius B12-N, contained 6.25 μg of NMN per 10[9] CFU, as determined by LC-MS analysis of bacterial cell extracts. The results indicate that B12-N showed a slightly greater numerical improvement in chemotactic behavior than purified NMN. However, no significant differences were observed between B12-N and NMN in other AD-related or aging-associated phenotypes examined. Transcriptome analysis revealed that 16 pathways were common to both the NMN group and the B12-N group. Notably, the P450 metabolism pathway, longevity regulation pathway, and autophagy pathway were significantly enriched. These findings indicate partially overlapping phenotypic and transcriptomic responses to B12-N and NMN, suggesting that NMN may contribute to some of the biological effects associated with B12-N.},
}

@article {pmid42941768,
year = {2026},
author = {Procopio, E and Accattatis, A and Stroscio, CA and Guzzi, G and Lavano, A and La Torre, D and Della Torre, A},
title = {Diagnostic and Predictive CSF Biomarkers in Idiopathic Normal Pressure Hydrocephalus (iNPH): A Systematic Review.},
journal = {International journal of molecular sciences},
volume = {27},
number = {20},
pages = {},
pmid = {42941768},
issn = {1422-0067},
mesh = {*Hydrocephalus, Normal Pressure/cerebrospinal fluid/diagnosis ; Humans ; *Biomarkers/cerebrospinal fluid ; Amyloid beta-Peptides/cerebrospinal fluid ; tau Proteins/cerebrospinal fluid ; Peptide Fragments/cerebrospinal fluid ; },
abstract = {Idiopathic normal pressure hydrocephalus (iNPH) is a progressive disorder clinically characterized by Hakim's triad: gait disturbance, cognitive impairment, and urinary incontinence. iNPH treatment consists of neurosurgical implantation of a ventriculoperitoneal CSF diversion, whose outcome depends on an early and correct diagnosis. Currently, there is no specific diagnostic test to perform preoperatively. Still, the combination of neurological examination, gait analysis, neurocognitive evaluation, and the tap test is useful to suggest when surgery is indicated. Our systematic review aims to identify diagnostic and outcome predictor CSF biomarkers (BM) in iNPH. The present systematic review was conducted following PRISMA 2020 guidelines. PubMed, Scopus, and the Cochrane Library databases were first consulted in April 2025 and updated in May 2026. Studies were selected using the terms "idiopathic normal pressure hydrocephalus" and "CSF biomarkers" under Medical Subject Headings (MeSH) as inclusion criteria. The eligibility of a record was defined according to the study title and abstract. The QUADAS-2, QUIPS, ROBINS-I V2, and RobVis tools were used to assess the risk of bias. Ninety-nine records were included in this systematic review. Amyloid proteins (Aβ40-42), followed by tau (τT, τP-181) and neuroinflammatory proteins were the most frequently CSF BM analyzed in patients with iNPH. ELISA was the most used method to measure BM in CSF samples. Forty-seven records investigated the potential diagnostic role of CSF BM; comparisons were frequently made among iNPH, Alzheimer's disease (AD), and healthy control CSF samples. Regarding outcome prediction, 28 records examined CSF BM, with heterogeneous comparisons such as lumbar versus ventricular CSF or shunted versus non-shunted iNPH CSF samples, including healthy controls and iNPH. Seven records proposed both the diagnostic and predictive role of some CSF biomarkers, especially for tau proteins and Aβ42. On the other hand, 17 records concluded that neither a diagnostic nor a predictive role could be proposed for the CSF BM they analyzed. However, these records increased knowledge about an iNPH CSF pattern. Collecting and analyzing CSF samples from iNPH patients can be advantageous in differential diagnosis with other similar neurodegenerative disorders, especially AD, and therefore a predictor of neurosurgical outcomes. Combined biomarker panels should be integrated in standardized protocols, measuring: Aβ42, Aβ42/Aβ40, p-tau, total tau, ADAβ42/p-tau, L-PGDS, NFL and NRGN.},
}

*Hydrocephalus, Normal Pressure/cerebrospinal fluid/diagnosis
Humans
*Biomarkers/cerebrospinal fluid
Amyloid beta-Peptides/cerebrospinal fluid
tau Proteins/cerebrospinal fluid
Peptide Fragments/cerebrospinal fluid

@article {pmid42941852,
year = {2026},
author = {Skinner, SG and Aleman, EG and Berges, AN and Kim, KJ and Kantilal, D and Asatryan, L and Davies, DL},
title = {Dihydromyricetin and Neuroinflammation: Implications for CNS Disorders and Therapeutic Development.},
journal = {International journal of molecular sciences},
volume = {27},
number = {20},
pages = {},
pmid = {42941852},
issn = {1422-0067},
support = {//Timothy M. Chan Professorship in Complementary Therapeutic/ ; //USC Mann School of Pharmacy and Pharmaceutical Sciences/ ; //USC Institute of Addiction Science/ ; //Cai Foundation/ ; },
mesh = {Humans ; *Flavonols/therapeutic use/pharmacology ; Animals ; *Central Nervous System Diseases/drug therapy/metabolism ; *Neuroinflammatory Diseases/drug therapy/metabolism ; *Anti-Inflammatory Agents/therapeutic use/pharmacology ; NF-kappa B/metabolism ; Oxidative Stress/drug effects ; Signal Transduction/drug effects ; },
abstract = {Dihydromyricetin (DHM) is a bioactive polyphenol with broad therapeutic potential, including strong anti-inflammatory activity. Importantly, DHM has been shown to cross the blood-brain barrier (BBB), enabling pharmacological activity within the central nervous system (CNS) and positioning it as a candidate for CNS disorders in which neuroinflammation plays a central role, including Alzheimer's disease, Parkinson's disease, and stroke. Therapeutics such as DHM, which address neuroinflammation, are of increasing interest. Across CNS disease models, DHM's effects show recurring convergence on NF-κB suppression, NLRP3 inflammasome inhibition, and autophagy regulation, alongside context-specific mechanisms involving oxidative stress, ferroptosis, neurotrophic signaling, and peripheral gut-CNS communication. This review examines the evidence for DHM as a neuroinflammatory modulator, focusing on the mechanisms by which it exerts its therapeutic effects. By doing so, we aim to support its translational potential as a natural product for improving human health.},
}

Humans
*Flavonols/therapeutic use/pharmacology
Animals
*Central Nervous System Diseases/drug therapy/metabolism
*Neuroinflammatory Diseases/drug therapy/metabolism
*Anti-Inflammatory Agents/therapeutic use/pharmacology
NF-kappa B/metabolism
Oxidative Stress/drug effects
Signal Transduction/drug effects

@article {pmid42941873,
year = {2026},
author = {Zdunek, J and Grodner, B},
title = {Peptides and Peptide Analogues Targeting Acetylcholinesterase-Associated Mechanisms in Alzheimer's Disease and Dementias: Evidence Gaps, Design Strategies, and Translational Perspectives.},
journal = {International journal of molecular sciences},
volume = {27},
number = {20},
pages = {},
pmid = {42941873},
issn = {1422-0067},
mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism ; *Acetylcholinesterase/metabolism ; Animals ; *Cholinesterase Inhibitors/therapeutic use/pharmacology/chemistry ; *Peptides/therapeutic use/chemistry/pharmacology ; *Dementia/drug therapy/metabolism ; Neuroprotective Agents/therapeutic use/pharmacology/chemistry ; Amyloid beta-Peptides/metabolism ; Drug Design ; },
abstract = {Alzheimer's disease and related dementias involve interacting disturbances in amyloid-β, tau, neuroinflammation, oxidative stress, mitochondrial function, synaptic integrity, and cholinergic neurotransmission. Acetylcholinesterase, in addition to terminating cholinergic signalling through acetylcholine hydrolysis, participates in non-catalytic interactions associated with amyloid-β, providing a mechanistic rationale for multi-target therapeutic strategies. This critical narrative review evaluates natural acetylcholinesterase-inhibitory peptides, amyloid-targeting sequences, D-enantiomeric and retro-inverso analogues, endogenous and neuroprotective peptides, and selected peptidomimetic and multifunctional designs. The literature is considered according to an evidence hierarchy that distinguishes direct acetylcholinesterase/peripheral anionic site target engagement from independently demonstrated secondary mechanisms, cellular activity, central nervous system exposure, in vivo pharmacodynamics, and clinical efficacy. The reviewed evidence indicates that peptides and peptide-derived compounds offer substantial molecular recognition and structural adaptability and may, in principle, be engineered to combine selected cholinergic and disease-relevant functions. Importantly, no single candidate reviewed here has experimentally demonstrated all of the proposed cholinergic, anti-amyloid, anti-inflammatory, antioxidant, mitochondrial, and synaptoprotective activities simultaneously. However, neuroprotective, anti-amyloid, or cognitive effects alone do not establish direct acetylcholinesterase modulation, and many proposed multifunctional candidates lack experimental evidence of acetylcholinesterase/peripheral anionic site engagement. Overall, the available literature supports the feasibility of designing multifunctional peptide-based acetylcholinesterase-directed agents, but the evidence remains insufficient to establish a clinically validated class of multifunctional acetylcholinesterase modulators.},
}

Humans
*Alzheimer Disease/drug therapy/metabolism
*Acetylcholinesterase/metabolism
Animals
*Cholinesterase Inhibitors/therapeutic use/pharmacology/chemistry
*Peptides/therapeutic use/chemistry/pharmacology
*Dementia/drug therapy/metabolism
Neuroprotective Agents/therapeutic use/pharmacology/chemistry
Amyloid beta-Peptides/metabolism
Drug Design

@article {pmid42941929,
year = {2026},
author = {Khibech, O and Abdelfattah, B and Bouhrim, M and Alqahtani, MJ and Alqahtani, JH and Miantezila Basilua, J and Boulouiz, A and Touzani, R},
title = {Multiscale Computational Prioritization of Chromone-Based Acetylcholinesterase Ligands.},
journal = {International journal of molecular sciences},
volume = {27},
number = {20},
pages = {},
pmid = {42941929},
issn = {1422-0067},
support = {ORF-2026-583//King Saud University/ ; },
mesh = {*Acetylcholinesterase/chemistry/metabolism ; *Chromones/chemistry/pharmacology ; Molecular Docking Simulation ; Humans ; Ligands ; *Cholinesterase Inhibitors/chemistry/pharmacology ; Molecular Dynamics Simulation ; Animals ; Torpedo ; Donepezil/chemistry ; Protein Binding ; },
abstract = {Identifying acetylcholinesterase (AChE) ligands for Alzheimer's disease research requires integrating molecular recognition with pharmacokinetic and safety considerations. Here, four designed chromone derivatives (M1-M4) were investigated to determine how conformational sampling and complementary molecular descriptors refine docking-based prioritization. Donepezil redocking in human AChE and cross-docking into Torpedo californica AChE recovered the crystallographic and transferred reference orientations, respectively, with RMSDs of 0.942 and 1.074 Å. Molecular docking was integrated with 800 ns molecular dynamics, MM/PBSA, electronic-structure calculations, and pharmacokinetic/toxicity predictions. M4 achieved the most favorable chromone docking score (-9.6 kcal mol[-1]), whereas M3 yielded the most favorable chromone MM/PBSA estimate within the 775-800 ns window (-23.90 ± 2.31 kcal mol[-1]). Donepezil retained a more favorable MM/PBSA estimate (-41.00 ± 2.75 kcal mol[-1]). M4 exhibited the highest electronic hardness, while predicted toxicity profiles revealed distinct liabilities across the series. The divergence between docking and sampled energetics highlights the value of integrating complementary criteria when selecting compounds for experimental evaluation. These protocol-dependent findings prioritize M3 and M4 as complementary computational candidates requiring experimental confirmation of AChE inhibition, selectivity, and safety.},
}

*Acetylcholinesterase/chemistry/metabolism
*Chromones/chemistry/pharmacology
Molecular Docking Simulation
Humans
Ligands
*Cholinesterase Inhibitors/chemistry/pharmacology
Molecular Dynamics Simulation
Animals
Torpedo
Donepezil/chemistry
Protein Binding

@article {pmid42941947,
year = {2026},
author = {Öztan, G and İşsever, T and İşsever, H},
title = {Integrative Genetic and Transcriptomic Analysis Reveals Candidate Molecular Differences Among Dementia with Lewy Bodies, Alzheimer's Disease, and Parkinson's Disease Dementia.},
journal = {International journal of molecular sciences},
volume = {27},
number = {20},
pages = {},
pmid = {42941947},
issn = {1422-0067},
mesh = {Humans ; *Lewy Body Disease/genetics/metabolism ; *Alzheimer Disease/genetics/metabolism ; *Parkinson Disease/genetics/metabolism ; *Gene Expression Profiling ; *Transcriptome ; Female ; Male ; Aged ; },
abstract = {Dementia with Lewy bodies (DLB) shares substantial clinical and molecular features with Alzheimer's disease (AD) and Parkinson's disease dementia (PDD), complicating the identification of disease-specific molecular alterations. This study aimed to characterize transcriptomic differences among these disorders and to integrate expression findings with published Lewy body dementia (LBD) genetic evidence. Gene-level expression profiles from 42 postmortem prefrontal cortex samples in GSE150696, including controls, AD, DLB, and PDD, were analyzed using age- and sex-adjusted empirical-Bayes models with false discovery rate (FDR) correction, followed by sensitivity analyses, post hoc exploratory candidate selection, and integration with an external LBD multi-omics gene-prioritization dataset. No gene reached FDR < 0.05 in the DLB-versus-AD comparison. In contrast, SLC19A2, VAMP1, and COX5B were lower in DLB than in PDD and were FDR-supported in the primary age- and sex-adjusted model, although their statistical significance was partly model-dependent. A post hoc cross-disease analysis identified 60 exploratory candidates, of which SYT11 was the only gene overlapping with the published LBD-prioritized gene set. The overall 60-gene set was not significantly enriched for LBD-associated genes. These findings did not demonstrate broad robust disease-disease differences and are consistent with substantial molecular overlap, while remaining compatible with limited statistical power. A limited number of transcriptomic candidates, including the exploratory SYT11 overlap, warrant independent validation.},
}

Humans
*Lewy Body Disease/genetics/metabolism
*Alzheimer Disease/genetics/metabolism
*Parkinson Disease/genetics/metabolism
*Gene Expression Profiling
*Transcriptome
Female
Male
Aged

@article {pmid42941959,
year = {2026},
author = {Zhao, X and Zeng, Y and Song, Z and He, J and He, Q and Lin, H and Liu, L and Yu, W and Cheng, S},
title = {EP2 and EP4 in Alzheimer's Disease: Cell-Dependent Signalling and Implications for Selective Targeting.},
journal = {International journal of molecular sciences},
volume = {27},
number = {20},
pages = {},
pmid = {42941959},
issn = {1422-0067},
support = {82074046//National Natural Science Foundation of China/ ; 82575038//National Natural Science Foundation of China/ ; 2024RC1060//the Science and Technology Innovation Leading Talent Program of the Hunan Provincial Department of Science and Technology/ ; 2025JJ90003//the University Joint Fund of the Natural Science Foundation of Hunan Province/ ; Internal Medicine of Traditional Chinese Medicine; Document No. Xiang Wei Yi Fa [2025] 7//the 2025 Hunan Provincial Class A Medical Discipline Construction Project/ ; CX20251181//the Postgraduate Scientific Research Innovation Project of Hunan Province/ ; 2025CX071//Postgraduate Scientific Research Innovation Project of Hunan Province/ ; },
mesh = {*Alzheimer Disease/metabolism/drug therapy/pathology ; Humans ; *Receptors, Prostaglandin E, EP2 Subtype/metabolism/antagonists & inhibitors/genetics ; Animals ; *Receptors, Prostaglandin E, EP4 Subtype/metabolism/antagonists & inhibitors/genetics ; *Signal Transduction ; Amyloid beta-Peptides/metabolism ; Dinoprostone/metabolism ; Microglia/metabolism ; },
abstract = {Prostaglandin E2 (PGE2) signalling influences amyloid-β (Aβ) processing, myeloid function, and neuronal injury in Alzheimer's disease (AD). Although EP2 and EP4 share Gs-cyclic adenosine monophosphate (cAMP) signalling, their cellular effects differ. This review integrates genetic, pharmacological, ageing, and AD-model evidence to assess receptor-selective targeting. EP2 deletion enhances myeloid Aβ handling and reduces microglia-mediated neuronal injury in experimental systems, providing a rationale for selective EP2 inhibition. In aged mice, PGE2-EP2 signalling redirects glucose towards glycogen storage and restricts myeloid mitochondrial respiration; benefits from a predominantly peripheral antagonist suggest that some age-related outcomes may improve without high brain exposure. Chronic antagonist studies in AD models, however, show variable effects on inflammation, amyloid burden, and behaviour. EP4 exhibits contrasting cell-dependent actions: activation supports microglial Aβ uptake and inflammatory control, whereas signalling in some amyloid precursor protein (APP)-expressing cells promotes APP internalisation and Aβ production. Human AD evidence remains mainly tissue-based; EP2 antagonist testing has involved healthy volunteers, not patients with AD. These findings indicate that receptor selectivity alone is insufficient to predict therapeutic outcomes. Further studies should combine cell-specific receptor manipulation, measurements of central and peripheral exposure, and separate assessments of Aβ production, clearance, tissue injury, and functional outcomes.},
}

*Alzheimer Disease/metabolism/drug therapy/pathology
Humans
*Receptors, Prostaglandin E, EP2 Subtype/metabolism/antagonists & inhibitors/genetics
Animals
*Receptors, Prostaglandin E, EP4 Subtype/metabolism/antagonists & inhibitors/genetics
*Signal Transduction
Amyloid beta-Peptides/metabolism
Dinoprostone/metabolism
Microglia/metabolism

@article {pmid42941970,
year = {2026},
author = {Malcampo, M and Hernáez, Á and Hernando-Redondo, J and Ros, E and Corella, D and Martínez-González, MÁ and Salas-Salvadó, J and Estruch, R and Timiraos, J and Gómez-Gracia, E and Fiol, M and Lapetra, J and Serra-Majem, L and Riera-Mestre, A and Pintó, X and Puig-Pijoan, A and Ruiz-Canela, M and Sorlí, JV and Babio, N and Lamuela-Raventós, RM and Khymenets, O and Sala-Vila, A and Castañer, O and Fitó, M},
title = {HDL Functionality, Cholesterol-Related Biomarkers and Incidence of Dementia: A Case-Cohort Study in Older Adults at High Cardiovascular Risk.},
journal = {International journal of molecular sciences},
volume = {27},
number = {20},
pages = {},
pmid = {42941970},
issn = {1422-0067},
support = {PI25/00015, PI17/00214, PI20/00012, PI24/00326//Instituto de Salud Carlos III/ ; },
mesh = {Humans ; Male ; *Biomarkers/blood/metabolism ; Female ; Aged ; *Dementia/epidemiology/blood/metabolism/etiology ; Incidence ; *Cholesterol, HDL/blood/metabolism ; *Cholesterol/blood/metabolism ; *Cardiovascular Diseases/blood/epidemiology ; Alzheimer Disease/epidemiology/blood ; Risk Factors ; Aged, 80 and over ; Case-Control Studies ; Cohort Studies ; Hydroxycholesterols/blood ; Apolipoproteins E/blood ; },
abstract = {Associations of lipid profiles, including qualitative and functional high-density lipoprotein (HDL) traits, and cholesterol-related biomarkers with incident dementia and Alzheimer's disease (AD), remain unclear. In this regard, older adults at high cardiovascular risk are at particularly high risk of developing dementia. The aim is to evaluate whether these biomarkers are associated with the incidence of dementia and AD in older adults at high cardiovascular (CV) risk. In a case-cohort study, we selected 106 incident dementia cases (82 AD) and a random subcohort of 201 non-cases. We quantified (baseline and at one-year), lipid profile; HDL-mediate cholesterol efflux capacity in a model of human neurons; HDL-mediated anti-inflammatory protection in a model of brain endothelial cells; 24S-hydroxycholesterol and apolipoprotein E. Multivariable-adjusted Cox models were addressed. HDL cholesterol was inversely associated, whereas triglycerides directly associated, with dementia and AD incidence. Higher HDL-mediated cholesterol efflux was inversely associated with dementia (HR 0.64, 95% confidence interval (CI) 0.45-0.91) and AD (HR 0.52, 0.35-0.76). Greater HDL-mediated endothelial protection was associated with lower dementia and AD incidence (HR 0.68, 95% CI 0.47 to 0.99 and HR 0.61, 95% CI 0.41 to 0.91, respectively). A one-year increase in 24S-hydroxycholesterol was associated with a higher incidence of any dementia (HR 2.38, 1.33-4.27) and AD (HR 2.24, 1.11-4.53). Enhanced HDL functional properties ex vivo, in preclinical models using human brain cells, together with lower levels of 24S-hydroxycholesterol, are inversely associated with the incidence of dementia and AD, highlighting these factors as promising prognostic targets in older adults at high CV risk.},
}

Humans
Male
*Biomarkers/blood/metabolism
Female
Aged
*Dementia/epidemiology/blood/metabolism/etiology
Incidence
*Cholesterol, HDL/blood/metabolism
*Cholesterol/blood/metabolism
*Cardiovascular Diseases/blood/epidemiology
Alzheimer Disease/epidemiology/blood
Risk Factors
Aged, 80 and over
Case-Control Studies
Cohort Studies
Hydroxycholesterols/blood
Apolipoproteins E/blood

@article {pmid42942001,
year = {2026},
author = {Samorodova, AA and Beletskiy, AP and Balaban, PM and Borodinova, AA},
title = {Differential Regulation of Cholesterol-Related Gene Expression by HDAC Inhibition in Neuron-Enriched and Glia-Enriched Rat Primary Cultures.},
journal = {International journal of molecular sciences},
volume = {27},
number = {20},
pages = {},
pmid = {42942001},
issn = {1422-0067},
support = {No. 24-15-00149//Russian Science Foundation/ ; },
mesh = {Animals ; *Histone Deacetylase Inhibitors/pharmacology ; *Cholesterol/metabolism/genetics ; *Neurons/metabolism/drug effects/cytology ; *Neuroglia/metabolism/drug effects/cytology ; Rats ; Hydroxamic Acids/pharmacology ; *Gene Expression Regulation/drug effects ; Cells, Cultured ; Histone Deacetylases/metabolism ; Epigenesis, Genetic ; },
abstract = {Brain cholesterol homeostasis is a highly sophisticated, epigenetically regulated process where neurons and glia play distinct roles in maintaining metabolic balance. Disruption of this tightly regulated system is a hallmark of many neurological disorders, including Alzheimer's disease. Histone deacetylase (HDAC) inhibitors were shown to regulate transcription of metabolic genes in the brain. However, their influence on cholesterol-related gene expression in functionally different neural cell populations remains insufficiently characterized. In this study, we used a model of rat primary cultures enriched in either neurons or glial cells to compare the culture-specific transcriptional responses induced by the HDAC inhibitor trichostatin A (TSA). Using quantitative PCR, we analyzed the relative mRNA expression of representative genes involved in cholesterol synthesis (Hmgcs1, Mvd, Lss, Dhcr7), transport (Apoe, Apod), uptake (Vldlr, Ldlr), efflux (Abca7, Abcg1), and elimination (Cyp46a1). Our results suggest that HDAC inhibition induces complementary yet distinct and epigenetically tunable transcriptional responses in the neuronal and glial cell cultures maintained under their respective culture-specific conditions. We hypothesize that these transcriptional changes may have functional consequences for cholesterol metabolic pathways, including altered cholesterol accumulation in both cell types and enhanced cholesterol efflux in neurons. However, this requires further experimental validation. Overall, our results provide a framework for understanding how cell-type-specific epigenetic regulation of cholesterol-related genes may shape brain lipid homeostasis. These insights may facilitate the development of cell-targeted epigenetic therapies for neurological disorders associated with metabolic dysfunction.},
}

Animals
*Histone Deacetylase Inhibitors/pharmacology
*Cholesterol/metabolism/genetics
*Neurons/metabolism/drug effects/cytology
*Neuroglia/metabolism/drug effects/cytology
Rats
Hydroxamic Acids/pharmacology
*Gene Expression Regulation/drug effects
Cells, Cultured
Histone Deacetylases/metabolism
Epigenesis, Genetic

@article {pmid42942071,
year = {2026},
author = {De Benedittis, S and Spadafora, P and Greco, BM and Di Palo, A and Gallo, O and Nuzzo, D and Picone, P and Brunelli, E and Sesti, S and Montesanto, A and Passarino, G and Risoleo, K and Ferrise, F and Colao, R and Maletta, R and Marchese, G and Cavalcanti, F},
title = {L1CAM-Enriched Extracellular Vesicle MicroRNAs in Mild Cognitive Impairment and Alzheimer's Disease: An Exploratory Study.},
journal = {International journal of molecular sciences},
volume = {27},
number = {20},
pages = {},
pmid = {42942071},
issn = {1422-0067},
support = {[DM 1557 11.10.2022]//European Union/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics/blood/metabolism ; *Neural Cell Adhesion Molecule L1/metabolism/genetics ; *MicroRNAs/genetics/metabolism/blood ; *Cognitive Dysfunction/genetics/blood/metabolism ; *Extracellular Vesicles/metabolism/genetics ; Female ; Biomarkers/blood ; Male ; Aged ; Gene Expression Profiling ; High-Throughput Nucleotide Sequencing ; },
abstract = {Early diagnosis of Alzheimer's disease (AD) and the identification of reliable molecular biomarkers remain critical clinical needs. In this context, extracellular vesicles (EVs) enriched by L1CAM immunocapture-L1CAM-enriched EVs-a fraction widely used to obtain material of putative neuronal origin, have been proposed as a minimally invasive source of information on brain molecular changes. We conducted next-generation sequencing (NGS) of microRNAs (miRNAs) from L1CAM-enriched EVs isolated from the plasma of 11 AD patients, 11 mild cognitive impairment (MCI) individuals, and 14 healthy controls (CTRs) to identify a candidate molecular signature. Our analysis identified five differentially expressed miRNAs-miR-423-5p, miR-122-5p, miR-151b, miR-16-5p, and miR-149-3p-in MCI individuals. Three of these-miR-423-5p, miR-122-5p and miR-151b-were higher in MCI and lower in AD, a pattern that differentiated the two clinically defined groups. Furthermore, enrichment analysis of the predicted targets of the differentially expressed miRNAs identified processes relevant to neurodegeneration, including synaptic organisation, cytoskeletal dynamics, and protein degradation. Overall, these preliminary findings identify blood-based L1CAM-enriched EV miRNAs as candidates for further evaluation in cognitive impairment. While validation in larger, biomarker-confirmed and independent cohorts is required, this exploratory study provides data that may guide the design of future biomarker studies.},
}

Humans
*Alzheimer Disease/genetics/blood/metabolism
*Neural Cell Adhesion Molecule L1/metabolism/genetics
*MicroRNAs/genetics/metabolism/blood
*Cognitive Dysfunction/genetics/blood/metabolism
*Extracellular Vesicles/metabolism/genetics
Female
Biomarkers/blood
Male
Aged
Gene Expression Profiling
High-Throughput Nucleotide Sequencing

@article {pmid42942089,
year = {2026},
author = {Lv, X and Huang, M and Long, W and Li, X and Hu, Z and Feng, Y and Du, J and Long, Q and Chen, Y and Shi, M and Qin, D},
title = {Epigenetic Mechanisms in Neurodegenerative Diseases: From Genetic Regulation to Therapeutic Potential.},
journal = {International journal of molecular sciences},
volume = {27},
number = {20},
pages = {},
pmid = {42942089},
issn = {1422-0067},
support = {YPKLS2025-029//Yunnan Key Laboratory of Integrated Traditional Chinese and Western Medicine for Chronic Dis-ease in Prevention and Treatment/ ; KUST-KH2022017Y//Kunming University of Science and Technology & the First People's Hospital of Yunnan Province Joint Special Project on Medical Research/ ; 202401AY070001-135//Yunnan Provincial Department of Science and Technology-Kunming Medical University Joint Special Project/ ; },
mesh = {Humans ; *Epigenesis, Genetic ; *Neurodegenerative Diseases/genetics/therapy/metabolism ; Animals ; DNA Methylation ; Gene Expression Regulation ; RNA Methylation ; Biomarkers/metabolism ; Histones/metabolism ; Epitranscriptome ; },
abstract = {Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), are multifactorial disorders in which genetic susceptibility alone cannot account for sporadic onset, clinical diversity, or age-dependent progression. Epigenetic mechanisms-DNA methylation, histone modifications, non-coding RNAs, and m6A RNA methylation-bridge environmental and intracellular cues to stable gene expression changes. Emerging evidence associates epigenetic dysregulation with amyloid-β/tau pathology in AD, α-synuclein pathology in PD, and TDP-43/C9orf72-associated toxicity in ALS, while functional studies suggest that selected epigenetic alterations may contribute to these processes. In this narrative review, we distinguish associative, functional, and mechanistic evidence using claim-specific criteria based on experimental perturbation, direct molecular assessment, and pathway-dependence or rescue testing, while considering the study system. We further evaluate the translational promise of epigenetic biomarkers in liquid biopsies, while emphasizing the major barriers that separate bench findings from bedside application, including poor target specificity, limited blood-brain barrier penetration, and the absence of biomarker-guided patient stratification. By integrating pathological mechanisms, biomarker development, and therapeutic strategies, this review argues that future epigenetic research in neurodegeneration must prioritize causal validation, CNS-penetrant drug development, and prospective trials integrating epigenetic profiling to achieve meaningful clinical impact.},
}

Humans
*Epigenesis, Genetic
*Neurodegenerative Diseases/genetics/therapy/metabolism
Animals
DNA Methylation
Gene Expression Regulation
RNA Methylation
Biomarkers/metabolism
Histones/metabolism
Epitranscriptome

@article {pmid42942122,
year = {2026},
author = {Khan, MA and Chinnappan, R and Andole, S and Akif, M and Mir, TA and Yaqinuddin, A and Pham, PT and Bader, MM},
title = {α-Halogenated Curcumins Enhance the Binding Affinity and Induced Structural Alterations to Amyloid-β Protein in Alzheimer's Disease.},
journal = {International journal of molecular sciences},
volume = {27},
number = {20},
pages = {},
pmid = {42942122},
issn = {1422-0067},
support = {25444//Alfaisal University/ ; },
mesh = {*Amyloid beta-Peptides/metabolism/chemistry ; *Curcumin/chemistry/analogs & derivatives/pharmacology/metabolism ; *Alzheimer Disease/metabolism/drug therapy ; Protein Binding ; Humans ; *Peptide Fragments/metabolism/chemistry ; Thermodynamics ; Circular Dichroism ; Halogenation ; Molecular Docking Simulation ; Protein Structure, Secondary ; Binding Sites ; Spectrometry, Fluorescence ; },
abstract = {Amyloid-β (Aβ) aggregation and associated structural changes are central features of Alzheimer's disease (AD) pathology. In this study, we investigated the binding of α-halogenated curcumins, α-bromocurcumin and α-chlorocurcumin, to Aβ1-42 and examined their effects on the peptide secondary structure using fluorescence spectroscopy and circular dichroism (CD). Both α-halogenated curcumins interacted with Aβ1-42, but their binding properties differed from those of the parent curcumin. α-Chlorocurcumin exhibited a higher binding affinity for Aβ1-42 than curcumin, whereas α-bromocurcumin showed comparatively weaker binding. Temperature-dependent binding studies revealed that the association of α-halogenated curcumins with Aβ1-42 was influenced by temperature, with reduced binding affinity at higher temperatures. Thermodynamic analysis demonstrated favorable free-energy changes for the interactions and revealed that α-halogenation altered the relative enthalpic and entropic contributions to Aβ1-42 binding. CD analysis further showed that binding of the curcumin altered the secondary structure of Aβ1-42. These structural changes were more pronounced in the presence of the α-halogenated derivatives, indicating that halogen substitution influences the interaction and conformational response of Aβ1-42. Molecular docking analysis provided additional insight into the possible binding modes and predicted intermolecular contacts between the α-halogenated curcumin and Aβ1-42. Overall, the findings demonstrate that α-halogenation modulates the binding and structural effects of curcumin derivatives on Aβ1-42, with α-chlorocurcumin exhibiting particularly favorable binding characteristics. These findings provide a basis for further investigation of α-halogenated curcumins as potential modulators of Aβ-related molecular processes associated with AD.},
}

*Amyloid beta-Peptides/metabolism/chemistry
*Curcumin/chemistry/analogs & derivatives/pharmacology/metabolism
*Alzheimer Disease/metabolism/drug therapy
Protein Binding
Humans
*Peptide Fragments/metabolism/chemistry
Thermodynamics
Circular Dichroism
Halogenation
Molecular Docking Simulation
Protein Structure, Secondary
Binding Sites
Spectrometry, Fluorescence

@article {pmid42942133,
year = {2026},
author = {Wang, Q and Wang, S and Xu, Z and Song, L and Yang, K and Zhang, C and Cheng, X},
title = {Aluminum Chloride-Induced Planarian Model with Cognitive Impairments Through Neuronal Damage, Neurotransmitter Imbalance, Apoptosis, and Oxidative Stress.},
journal = {International journal of molecular sciences},
volume = {27},
number = {20},
pages = {},
pmid = {42942133},
issn = {1422-0067},
support = {82374062; 82675239//National Natural Science Foundation of China/ ; YDZX2023137//Central Guidance for Local Science and Technology Development Funds/ ; XZ202601ZY0167//Science and Technology Projects of Xizang Autonomous Region/ ; },
mesh = {Animals ; *Aluminum Chloride/toxicity ; *Oxidative Stress/drug effects ; *Planarians/drug effects/metabolism ; *Apoptosis/drug effects ; *Neurons/metabolism/drug effects/pathology ; Disease Models, Animal ; *Cognitive Dysfunction/chemically induced/metabolism/pathology/drug therapy ; *Neurotransmitter Agents/metabolism ; Alzheimer Disease/metabolism ; },
abstract = {The prevalence of Alzheimer's disease has significantly increased, which will place a heavy burden on families and society. Cognitive impairment is a typical feature of Alzheimer's disease. Rodent models play a key role in AD research, but their considerable expense and slow development pose challenges to the pace of therapeutic discovery. Here, we established a new model of cognitive dysfunction in planarians using AlCl3. After exposure to 50 μM AlCl3 for 48 h, the planarians exhibited cognitive dysfunction in the phototaxis test, dual-stimulus decision test and T-maze test. Immunohistochemical and immunofluorescence experiments confirmed that AlCl3 damaged the neural structure of planarians. Moreover, AlCl3 disrupted the balance of neurotransmitters, leading to cell apoptosis and oxidative stress. Finally, we confirmed that donepezil alleviated the cognitive impairment caused by AlCl3. This indicates that the model we established for cognitive dysfunction in planarians was feasible. However, planarians lack the amyloid-β plaques and tau neurofibrillary tangles typical of AD. Therefore, the planarian model can be considered a promising complementary platform for high-throughput screening of candidate drugs for cognitive impairment.},
}

Animals
*Aluminum Chloride/toxicity
*Oxidative Stress/drug effects
*Planarians/drug effects/metabolism
*Apoptosis/drug effects
*Neurons/metabolism/drug effects/pathology
Disease Models, Animal
*Cognitive Dysfunction/chemically induced/metabolism/pathology/drug therapy
*Neurotransmitter Agents/metabolism
Alzheimer Disease/metabolism

@article {pmid42942158,
year = {2026},
author = {Tekin, E and Koldemir Gündüz, M and Yığman, Z and Aydoğan Kara, B and Küçük, A and Arslan, M},
title = {Safranal, a Natural Neuroprotective Compound, Modulates Plasma Iron Levels, Improves Behavioral Performance, and Demonstrates Dose-Specific Cytoprotection in Alzheimer's Disease Models.},
journal = {International journal of molecular sciences},
volume = {27},
number = {20},
pages = {},
pmid = {42942158},
issn = {1422-0067},
support = {224S564//The Scientific and Technological Research Council of Türkiye/ ; },
mesh = {Animals ; *Alzheimer Disease/drug therapy/blood/pathology ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Iron/blood ; Male ; *Cyclohexenes/pharmacology/therapeutic use ; Rats ; Humans ; *Terpenes/pharmacology/therapeutic use ; Disease Models, Animal ; Amyloid beta-Peptides/metabolism/toxicity ; *Cytoprotection/drug effects ; Behavior, Animal/drug effects ; Cell Line, Tumor ; Apoptosis/drug effects ; Streptozocin ; Cell Survival/drug effects ; Antioxidants ; },
abstract = {Metal dyshomeostasis contributes to Alzheimer's disease (AD) by influencing amyloid aggregation, oxidative imbalance, and impaired clearance mechanisms. Safranal, a bioactive constituent of Crocus sativus, exhibits antioxidant properties, but its metal-modulating actions remain insufficiently understood. This study investigated whether safranal modulates metal (Fe, Cu, Zn) levels in an AD rat model while evaluating its cytoprotective rescue capacity against Aβ1-42 induced neurotoxicity in differentiated SH-SY5Y cells. AD was induced in male rats via intracerebroventricular streptozotocin, followed by a four-week safranal administration (0.5 mg/kg/day, ip). Behavioral performance, plasma metal levels (ICP-MS), and cerebral total antioxidant capacity (FRAP) were evaluated alongside histological assessment. Post-treatment protocols were employed to evaluate the effects of safranal on cell viability and apoptosis in differentiated SH-SY5Y cells exposed to Aβ1-42. Longitudinal analyses revealed that safranal attenuated exploratory deficits and recognition memory impairments in AD rats. Decreased plasma iron levels in the AD group were restored by safranal, accompanied by a return of cerebral antioxidant capacity to normal. Although overt hippocampal histological alterations were absent in this early phase, post-treatment with safranal successfully offered a therapeutic rescue window, preserving cell viability and attenuating Aβ1-42-induced apoptotic features in vitro. Safranal demonstrates beneficial neuroprotective effects in AD models by improving behavioral outcomes, partially correcting plasma iron levels, and mediating cytoprotective rescue windows against Aβ1-42-induced cellular toxicity. These findings suggest that safranal represents a promising natural candidate for reducing behavioral deficits, supporting peripheral iron status, and offering functional cell survival in AD models.},
}

Animals
*Alzheimer Disease/drug therapy/blood/pathology
*Neuroprotective Agents/pharmacology/therapeutic use
*Iron/blood
Male
*Cyclohexenes/pharmacology/therapeutic use
Rats
Humans
*Terpenes/pharmacology/therapeutic use
Disease Models, Animal
Amyloid beta-Peptides/metabolism/toxicity
*Cytoprotection/drug effects
Behavior, Animal/drug effects
Cell Line, Tumor
Apoptosis/drug effects
Streptozocin
Cell Survival/drug effects
Antioxidants

@article {pmid42942270,
year = {2026},
author = {Wood, PL},
title = {Cognitive Reserve: White Matter, Microvascular, Glymphatic and Cholinergic Dysfunction in Alzheimer's Disease.},
journal = {Life (Basel, Switzerland)},
volume = {16},
number = {10},
pages = {},
pmid = {42942270},
issn = {2075-1729},
abstract = {Late-onset Alzheimer's disease (LOAD) is a cognitive disorder that leads to the requirement of full-time care. The ever-increasing growth of the LOAD population demands that more research be dedicated to the discovery/design of effective therapeutics. The two major hypotheses that have been evaluated in the clinic include the cholinergic and the amyloid hypotheses. Unfortunately, the therapeutics that have resulted from research in these areas have minimal clinical impact. These are, respectively, the cholinesterase inhibitors and the anti-amyloid therapies. Clearly, a new path forward is needed. To this end, a number of genetic approaches and biochemical investigations are currently being employed to provide new insights into the pathophysiology of dementia. While there currently is a diverse array of dysfunctions that have been reported in LOAD subjects, white matter (WM) dysfunction may be a nodal point that is critical to the pathophysiology of cognitive decline. In this review, I present our current knowledge of WM dysfunction in LOAD. This addresses the potential contributions of microvascular dysfunction to WM abnormalities and neuronal dysfunction. This knowledge base has the potential to lead to a new approach for treating cholinergic dysfunction in cognitive disorders.},
}

@article {pmid42942327,
year = {2026},
author = {Somangalin Ramanathan, HV and Thompson, C and Goswami, T},
title = {Distributional Characterization of ICV-Normalized Regional Brain Volumes in Alzheimer's Disease.},
journal = {Life (Basel, Switzerland)},
volume = {16},
number = {10},
pages = {},
pmid = {42942327},
issn = {2075-1729},
abstract = {Introduction: Alzheimer's disease (AD) has progressive structural brain changes that can be described using magnetic resonance imaging (MRI). Previous work has used several statistical approaches to compare the volume of brain regions such as the hippocampus, entorhinal cortex, and amygdala. However, many of these approaches assume a Normal or symmetric distribution of regional volumes, which may not fully capture the variance and regional morphological variability of observed brain volumes. This study compares different probability distributions to assess the distributional flexibility needed to characterize brain volumes normalized to intracranial volume (ICV). Method: Six candidate probability distributions were evaluated across 21 FreeSurfer-derived, ICV-normalized regional brain volumes classified by sex and diagnosis group (Female-CN, Male-CN, Female-AD, and Male-AD). After ICV quality control, data were drawn from 3409 T1-weighted 3T MRI scans of 1343 participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI); the primary analysis used one baseline scan per participant. The resulting 84 region-by-group combinations (21 regions × 4 groups) were fitted using maximum likelihood, with all four parameters of the four-parameter Exponentiated Weibull (Weibull4P) estimated by multistart, ridge-stabilized maximum likelihood with identifiability safeguards. Distributions were compared with the Akaike information criterion (AIC), its small-sample correction (AICc) and the Bayesian information criterion (BIC). A distribution was regarded as adequate relative to other candidates when the AIC was within 10 units of the lowest AIC. Absolute fit was assessed with parametric bootstrap goodness-of-fit tests and robustness was assessed with a participant-level bootstrap, five-fold cross-validation of all six distributions and age-stratified refits. Results: The Normal distribution gave the lowest AIC in 40 of the 84 combinations, Gamma in 21, Lognormal in 12, Weibull4P in 10 and the two-parameter Weibull in one. Two or more distributions were within 2 AIC units of the lowest AIC in 51 combinations. Weibull4P was adequate by the relative AIC (ΔAIC < 10) in all 84 combinations, compared with 74 for Gamma, 68 for Normal and 66 for Lognormal; its largest difference from the lowest AIC was 4.9. In the 12 ventricular combinations, Normal was adequate in only one, compared with all 12 for Weibull4P. Weibull4P retained relative AIC support in at least 95% of the 500 participant-bootstrap replicates in 83 combinations and in all three age bands in every combination, including refits that did not meet StablePass. It met the descriptive BIC threshold in 53 combinations and the cross-validation threshold in 55. In the parametric-bootstrap goodness-of-fit tests, Weibull4P was not rejected by the uncorrected Anderson-Darling test in 71 of the 84 combinations, more than any other candidate (Gamma: 60; Normal: 57). Normality was rejected after FDR correction in 21 combinations, including 10 ventricular combinations. Of the 42 sex-specific AD-CN comparisons, 41 were significant after age adjustment and FDR correction. Conclusions: The Normal distribution most often had the lowest AIC and had relative support in most tissue combinations in this ADNI dataset, but rarely in ventricular combinations. The four-parameter Exponentiated Weibull had the lowest AIC in fewer combinations but was the only candidate with relative AIC support across all regions and groups, including the right-skewed ventricular volumes. It was also rejected less often by the Anderson-Darling goodness-of-fit test than any other candidate. However, its additional parameters were less supported by BIC, and its estimated lower bound restricted its out-of-sample performance. These findings support an empirical approach to evaluating distributional form rather than assuming normality, with Exponentiated Weibull as an alternative to consider alongside simpler distributions.},
}

@article {pmid42942335,
year = {2026},
author = {Matei, C and Palade, NA and Dobri-Nicoara, AM and Dumitriu, DO and Mutu, C and Popescu, ASC and Pintea, AL and Atasie, D},
title = {Genetic Risk Architecture of Late-Onset Alzheimer's Disease: Mapping Single-Nucleotide Polymorphisms to Disease-Defining Molecular Pathways.},
journal = {Life (Basel, Switzerland)},
volume = {16},
number = {10},
pages = {},
pmid = {42942335},
issn = {2075-1729},
abstract = {Late-onset Alzheimer's disease (LOAD) is increasingly recognized as a complex, multifactorial disorder driven by the convergence of genetic susceptibility and interconnected molecular pathways, rather than a single linear pathogenic cascade. In this review, we integrate evidence from genome-wide association studies, sequencing analyses, and experimental research to map disease-associated single-nucleotide polymorphisms (SNPs) onto key biological processes underlying LOAD pathogenesis. Converging data consistently implicate a limited number of core domains, including amyloid-β metabolism, tau pathology, neuroinflammation, lipid homeostasis, endosomal-lysosomal trafficking, mitochondrial dysfunction, and synaptic impairment. Importantly, genetic risk variants are not randomly distributed, but cluster within these pathways, exerting coordinated effects across multiple biological systems and supporting a network-based organization of disease. We further examine how these pathways interact at a systems level, highlighting key interfaces such as the amyloid-tau, lipid-immune, inflammation-proteostasis, and mitochondria-synaptic dysfunction axes. These interconnected processes form self-reinforcing feedback loops that amplify neurodegeneration and contribute to disease progression. From a translational perspective, this integrated framework provides a mechanistic basis for the limited efficacy of single-target therapies and supports the development of multi-target and pathway-oriented strategies, as well as precision medicine approaches based on genetic and biomarker integration. Collectively, this review supports a unified model of LOAD as a polygenic network disorder and underscores the importance of pathway convergence in understanding disease heterogeneity and guiding future therapeutic development.},
}

@article {pmid42942573,
year = {2026},
author = {Xu, S and Fu, X and Zuo, L and Wang, M},
title = {The Interplay Between Oophorectomy and Alzheimer's Disease: A Narrative Review.},
journal = {Medicina (Kaunas, Lithuania)},
volume = {62},
number = {10},
pages = {},
pmid = {42942573},
issn = {1648-9144},
mesh = {Humans ; *Alzheimer Disease/etiology/physiopathology ; Female ; *Ovariectomy/adverse effects ; Risk Factors ; Cognitive Dysfunction/etiology ; },
abstract = {Alzheimer's disease (AD) is the leading cause of dementia worldwide and affects women more frequently than men. Although age remains the main risk factor, reproductive aging and changes in ovarian hormone exposure may also contribute to this difference. Premenopausal bilateral oophorectomy causes an abrupt loss of ovarian hormones, including estradiol, progesterone, and testosterone, and several observational studies have associated this change with a higher risk of later cognitive impairment or dementia, particularly when surgery is performed at a younger age. However, these studies have assessed different outcomes, including dementia, mild cognitive impairment, subjective cognitive changes, and AD-related imaging findings, and current evidence does not establish a direct causal relationship between oophorectomy and AD. Possible biological pathways include neuroinflammation, synaptic dysfunction, amyloid-β and tau-related changes, and cerebrovascular dysfunction, although much of the mechanistic evidence remains experimental or indirect. Genetic background, vascular health, age at surgery, and the duration of hormone deprivation may further influence individual risk. Hormone replacement therapy has an established role in the management of premature or early surgical menopause when there is no contraindication, but its effect on long-term AD prevention remains uncertain; the timing of treatment may be important, but current evidence does not confirm a preventive effect. This review summarizes current epidemiological, neuroimaging, and experimental evidence linking oophorectomy with cognitive health and AD, and discusses hormone therapy, pharmacological and non-pharmacological management, emerging research approaches, and remaining knowledge gaps. Future studies with detailed information on surgical timing, hormone exposure, genetic risk, vascular factors, longitudinal cognition, and AD-related biomarkers are needed to better define which women may be most vulnerable after premenopausal oophorectomy.},
}

Humans
*Alzheimer Disease/etiology/physiopathology
Female
*Ovariectomy/adverse effects
Risk Factors
Cognitive Dysfunction/etiology

@article {pmid42942883,
year = {2026},
author = {Abbatecola, AM and Migliara, G and D'Agostino, F and Veronese, N and Giuliani, A and Caponnetto, S and Corbi, G and Signoriello, E and Incalzi, RA and Paolisso, G},
title = {Impact of GLP-1 Receptor Agonists on Cognitive Performance in Adults at Risk of Alzheimer's Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.},
journal = {Nutrients},
volume = {18},
number = {20},
pages = {},
pmid = {42942883},
issn = {2072-6643},
mesh = {Humans ; *Alzheimer Disease/prevention & control/etiology ; *Glucagon-Like Peptide-1 Receptor Agonists ; Randomized Controlled Trials as Topic ; *Cognition/drug effects ; *Diabetes Mellitus, Type 2/drug therapy/complications ; *Cognitive Dysfunction/drug therapy ; Middle Aged ; Aged ; Risk Factors ; Cognitive Enhancement ; Female ; Male ; },
abstract = {Background/Objectives: Type 2 diabetes, a widely recognized risk factor of Alzheimer's disease (AD), is mainly due to the role played by insulin resistance on neuronal degeneration. Mild Cognitive Impairment (MCI) also significantly increases the risk of developing AD by approximately 40%. Epidemiological studies have demonstrated correlations between glucagon-like peptide-1 agonists (GLP-1RAs) on reducing the risk of AD. We synthesize current data from randomized controlled trials (RCTs) to summarize the effects of GLP-1RA treatment in adults with Type 2 diabetes or with MCI on cognitive performance. Methods: We searched databases from inception to 1 January 2026 investigating effects of GLP-1RA(s) on cognition. PubMed, Web of Science and Scopus databases were explored following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). We selected only RCTs in adults investigating GLP-1RA(s) on cognitive performance. Results: Overall mean age was 64.5 yrs with an average follow-up period of 28.4 months. A total of 13,711 participants from five RCTs were included. Following a source-data audit, four randomized controlled trials contributed analytically compatible data to at least one cognitive domain. Cognitive domains were analyzed separately using Hedges' g. Random-effects models used restricted maximum likelihood (REML) estimation with Knapp-Hartung inference when at least two compatible studies contributed. For global cognition, three studies yielded g = 0.014 (95% CI: -0.061 to 0.088; p = 0.515; I[2] = 0%). For attention, two studies yielded g = 0.072 (95% CI: -2.164 to 2.308; p = 0.753; I[2] = 31.1%). For delayed memory, executive function, and verbal function, only one compatible study was available per domain; these were therefore reported as single-study estimates rather than pooled effects. A sensitivity analysis excluding the dominant Cukierman trial yielded an imprecise and non-significant effect estimate for global cognition (g = -0.205, 95% CI: -2.678 to 2.269) indicating that the robustness of the pooled result could not be established. Conclusions: Current randomized evidence is insufficient to establish a consistent beneficial effect of GLP-1RA(s) on cognitive function in adults at risk of AD. The available findings should be considered exploratory and hypothesis-generating because few analytically compatible trials were available within each cognitive domain.},
}

Humans
*Alzheimer Disease/prevention & control/etiology
*Glucagon-Like Peptide-1 Receptor Agonists
Randomized Controlled Trials as Topic
*Cognition/drug effects
*Diabetes Mellitus, Type 2/drug therapy/complications
*Cognitive Dysfunction/drug therapy
Middle Aged
Aged
Risk Factors
Cognitive Enhancement
Female
Male

@article {pmid42942913,
year = {2026},
author = {Dardano, DM and Macrì, R and Serra, M and Altomare, C and Ritorto, G and Ussia, S and Anwar, MMJ and Palma, E and Mollace, V},
title = {A Comprehensive Analysis of Extraction Methods, Phytochemical Characterization and Neuroprotective Potential of Curcumin.},
journal = {Nutrients},
volume = {18},
number = {20},
pages = {},
pmid = {42942913},
issn = {2072-6643},
support = {PON-MIUR 03PE000_78_1//Ministry of Education, Universities and Research/ ; PON-MIUR 03PE000_78_2//Ministry of Education, Universities and Research/ ; },
mesh = {*Curcumin/pharmacology/isolation & purification/pharmacokinetics/chemistry ; *Neuroprotective Agents/pharmacology/isolation & purification/pharmacokinetics/chemistry ; Humans ; Animals ; *Phytochemicals/pharmacology/isolation & purification ; Biological Availability ; Plant Extracts/pharmacology ; Curcuma/chemistry ; },
abstract = {Curcumin, a natural polyphenol derived from Curcuma longa, exhibits multi-targeted anti-inflammatory, antioxidant, and neuroprotective activities. This review aims to evaluate its extraction methodologies, synthetic pathways, and neuroprotective potential across preclinical and clinical paradigms, while addressing bioavailability barriers and commercial adulteration. In cellular models (BV-2, U87), curcumin inhibits TLR4/MyD88/NF-κB and NLRP3 inflammasome signaling, resulting in the downregulation of pro-inflammatory cytokines (IL-1β, TNF-α, IL-6) and enzymes (COX-2, iNOS), while simultaneously activating Nrf2/ARE antioxidant pathways. Moreover, it facilitates the polarization of neuroprotective M2 microglia. In animal models of ischemic stroke, traumatic brain injury, and Parkinson's disease, curcumin reduces neuroinflammation, protects dopaminergic neurons, and maintains the integrity of the blood-brain barrier. Advanced nanocarriers such as PLGA nanoparticles, exosomes, and lipid complexes bypass rapid hepatic metabolism, thereby increasing brain bioavailability. Clinical data demonstrate that bioavailable formulations (Theracurmin, Longvida, CurQfen) could improve memory function and reduce cerebral amyloid and tau deposits in subjects without dementia and with mild cognitive impairment. Conversely, the use of unformulated curcumin results in inconsistent findings in trials for Alzheimer's and Parkinson's diseases owing to its poor systemic absorption. In conclusion, Curcumin might represent a promising multitarget neuroprotective agent; however, addressing pharmacokinetic limitations via bioavailable delivery systems and implementing rigorous quality control to prevent commercial adulteration are essential for effective clinical application.},
}

*Curcumin/pharmacology/isolation & purification/pharmacokinetics/chemistry
*Neuroprotective Agents/pharmacology/isolation & purification/pharmacokinetics/chemistry
Humans
Animals
*Phytochemicals/pharmacology/isolation & purification
Biological Availability
Plant Extracts/pharmacology
Curcuma/chemistry

@article {pmid42943209,
year = {2026},
author = {Zhou, B and Zhong, Y and Meng, X and Xu, B and Jia, L},
title = {Comparative Network Pharmacology and Molecular Docking Analysis of Ursodeoxycholic Acid and Tauroursodeoxycholic Acid in Alzheimer's Disease-Associated Molecular Networks.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {19},
number = {10},
pages = {},
pmid = {42943209},
issn = {1424-8247},
support = {82204562//National Natural Science Foundation of China/ ; 202510228100S//National Innovation Training Program/ ; },
abstract = {Background/Objectives: Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by amyloid- and tau-related pathology, neuroinflammation, metabolic dysregulation, and neuronal loss. Previous studies have shown the potential effects of bile acids, especially ursodeoxycholic acid (UDCA) and tauroursodeoxycholic acid (TUDCA), on neurodegenerative diseases. However, whether UDCA and TUDCA exhibit distinct molecular interaction patterns within an Alzheimer's disease-associated biological context remains unclear. This study aims to compare the relevant targets, enrichment pathways, and docking profiles predicted by UDCA and TUDCA using the computer network pharmacology framework. Methods: The study combined analysis of networks relating to drug action with methods examining how structures bind. We predicted potential targets of UDCA and TUDCA by using public databases and intersected with AD-related genes. Protein-protein interaction network construction, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses, and integrated compound-target-pathway network analysis were performed. Key targets were further evaluated by molecular docking to characterize predicted binding patterns and ligand-target interaction profiles. Results: UDCA and TUDCA share 98 and 103 intersecting genes with AD, respectively, with significant overlapping targets. Functional enrichment analysis showed that UDCA-related targets were significantly enriched in nuclear receptor activity, transcriptional regulation, and metabolic pathways. TUDCA-related targets are more significantly enriched in cell survival, kinase activity and neural activity ligand-receptor interactions. Molecular docking analyses provided target-specific structural information, while same-target docking using GPBAR1 and MAPK14 further revealed ligand-dependent differences in predicted interaction patterns under identical receptor conditions. Results from approaches examining systems and structure both indicate that ursodeoxycholic acid and tauroursodeoxycholic acid show profiles of action that work together. UDCA was associated with predicted upstream regulatory and metabolic-related target profiles, whereas TUDCA showed greater association with intracellular signaling, apoptosis-related, and neuronal survival-related pathways. Conclusions: The two bile acids showed predicted associations with pathways related to cell death regulation, inflammation, and metabolism. These findings provide a methodological basis and testable hypotheses for future experimental validation, but they should not be interpreted as direct evidence of therapeutic efficacy in Alzheimer's disease.},
}

@article {pmid42943215,
year = {2026},
author = {Gatherer, M and Brown, C and Chinezu, L and Manu, D and Williams, A and Pendower, A and Ainslie, J and Walker, L and Attems, J and Kelly, L and Counts, S and Carare, R},
title = {Changes in Adrenergic and Cholinergic Receptors on Human Cerebral Vessels.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {19},
number = {10},
pages = {},
pmid = {42943215},
issn = {1424-8247},
support = {A20201187S//BrightFocus Foundation/ ; 5345//Alzheimer's Research UK/ ; 760108/23.05.2023//European Union/ ; //British Romanian Academic Institute of Neuroscience/ ; },
abstract = {Background/Objectives: Sporadic cerebral amyloid angiopathy (CAA) occurs due to a failure of clearance of amyloid-beta (Aβ) along the walls of capillaries and arteries. Soluble Aβ is eliminated from the brain along the basement membranes of capillaries and arteries as Intramural Periarterial Drainage (IPAD). The motive force for IPAD is provided by the spontaneous contractions of vascular smooth muscle cells, as vasomotion. Cerebrovascular smooth muscle cells receive adrenergic and cholinergic innervation from the Locus Coeruleus and the Nucleus Basalis of Meynert, which are compromised very early in Alzheimer's disease (AD). Here, we tested the hypothesis that adrenergic and cholinergic receptors are histologically preserved in parenchymal and leptomeningeal blood vessels with CAA. Methods: Using immunohistochemistry, we examined the cerebrovascular distribution of muscarinic (M1, M2), nicotinic (α 7 nicotinic acetylcholine receptor), and adrenergic (α1b/2b) receptors in post-mortem brain tissue. We compared receptor distribution across CAA and non-CAA patients, as well as young and old patients without CAA. Results: We found significant differences in the receptor immunoreactivity of α7 nicotinic acetylcholine receptors, as well as α1b and α2b adrenergic receptors. However, there were no differences in the receptor immunoreactivity of M1 or M2 muscarinic receptors between patient groups. Conclusions: As IPAD depends on the functionality of the vascular smooth muscle cells to maintain the integrity of IPAD with aging, based on these histological findings, future therapeutic interventions could focus on agonists of α7 nicotinic acetylcholine and α1b/2b adrenergic receptors.},
}

@article {pmid42943270,
year = {2026},
author = {Kalkan Cakmak, R and Sarikamis Johnson, B and Ercin, N and Besli, N and Beker, M and Celik, U},
title = {Incensole Acetate Regulates the Sirtuin-Insulin Signaling Axis in an Experimental Alzheimer's Disease Model.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {19},
number = {10},
pages = {},
pmid = {42943270},
issn = {1424-8247},
support = {124S487//TÜBİTAK/ ; 2021/068//Scientific Research Projects (BAP) Coordination Unit of the University of Health Sciences Turkey/ ; },
abstract = {Background/Objectives: Alzheimer's disease (AD) is associated with impaired brain insulin signaling, oxidative stress, and neuroinflammation. This study investigated the effects of incensole acetate (IA) on sirtuin-associated insulin-signaling and cellular stress-response pathways using integrated computational and in vitro approaches. Methods: ADMET prediction, molecular docking, molecular dynamics simulations, and MM-PBSA analyses were performed for IA against SIRT1, SIRT3, and SIRT6 and compared with their corresponding reference ligands. An Aβ1-42-induced AD model was established in mesenchymal stem cell-derived neurons. The effects of IA on insulin-signaling components, sirtuins, Aβ, NF-κB, NRF2, and PPARα were evaluated using RT-qPCR, Western blotting, and immunofluorescence. Results: IA showed weaker docking affinities than the corresponding reference ligands for all three sirtuins, whereas trajectory-based analyses revealed target-dependent dynamic behavior. MM-PBSA-derived binding-energy estimates were -35.16 ± 3.32, -30.24 ± 3.63, and -38.26 ± 3.90 kcal/mol for IA with SIRT1, SIRT3, and SIRT6, respectively, with IA showing a more favorable relative energetic profile than 8L9 for SIRT6. In vitro, IA treatment was associated with reduced detectable Aβ levels and modulation of INSR, IRS, AKT, and AS160 expression. IA increased SIRT1 and SIRT6 expression, whereas SIRT3 protein levels were not significantly altered. IA also reduced NF-κB and increased NRF2 and PPARα expression. Conclusions: IA modulated insulin-signaling-related, sirtuin-associated, inflammatory, oxidative-stress, and metabolic markers in an Aβ1-42-induced cellular AD model. Computational analyses support potential IA-sirtuin interactions, particularly a favorable relative MM-PBSA energetic profile for SIRT6; however, direct sirtuin activation or causal sirtuin-mediated signaling was not established.},
}

@article {pmid42943286,
year = {2026},
author = {Sait, AM and Day, PJR},
title = {Targeting Cholinergic Dysfunction and Gingipain Activity in Alzheimer's Disease: A Dual AChE-Kgp Computational Study.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {19},
number = {10},
pages = {},
pmid = {42943286},
issn = {1424-8247},
support = {EP/R513131/1//EPSRC doctoral training partnership grant made to the University of Manchester/ ; },
abstract = {Introduction: Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder for which single-target strategies may be insufficient. This study explored a host-microbial multitarget strategy using a CNS-oriented small molecule predicted to engage both human acetylcholinesterase (AChE) and Porphyromonas gingivalis lysine-specific gingipain K (Kgp). Methods: A CNS-focused library of 116,226 compounds was standardized and filtered to 1000 candidates for sequential AChE/Kgp docking. Refined docking, interaction-guided pose analysis, dual-target ranking, and SwissADME predictions were used for prioritization. ADKGP_0026671 was subsequently evaluated in single 100 ns molecular dynamics trajectories for AChE and Kgp, alongside donepezil and KYT-36 reference complexes, followed by MM/PBSA endpoint energy analysis. Results: ADKGP_0026671 showed docking scores of -11.804 kcal/mol for AChE and -7.345 kcal/mol for Kgp, was predicted to be BBB-permeant and not a P-glycoprotein substrate, and contained no PAINS or Brenk alerts. The single MD trajectories showed continued binding-site association and limited protein backbone deviation over the simulated period, although reproducibility cannot be established without independent replicas. MM/PBSA endpoint estimates were negative for AChE (-18.86 kcal/mol) and Kgp (-15.67 kcal/mol), but less favorable than donepezil and KYT-36, respectively. Conclusions: ADKGP_0026671 showed a balanced computational profile across two mechanistically distinct targets, supporting experimental evaluation of a host-microbial dual-target strategy in AD. These findings remain hypothesis-generating and require biochemical validation and replicated simulations.},
}

@article {pmid42943300,
year = {2026},
author = {Gogu, MR and Mazarianu, I and Stanciu, GD and Tamba, BI and Ciorpac, M and Gorgan, DL},
title = {Microglial Therapeutic Potential in Alzheimer's Disease: From Phenotypic Diversity to Targeted Interventions.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {19},
number = {10},
pages = {},
pmid = {42943300},
issn = {1424-8247},
support = {project number PN-IV-P6-6.1-CoEx-2024-0141, within PNCDI IV//This work was supported by a grant of the Ministry of Education and Research, CCCDI - UEFISCDI/ ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by β-amyloid (Aβ) deposition, tau pathology and cognitive decline. Increasing evidence from genetic, transcriptomic, experimental and clinical studies has identified microglia as key regulators of AD pathogenesis. Under physiological conditions, microglia maintain central nervous system homeostasis through immune surveillance, phagocytosis and neurotrophic support. However, persistent exposure to pathological stimuli promotes a shift toward dysfunctional inflammatory states that contribute to neuroinflammation, synaptic impairment, tau propagation and neurodegeneration. Recent advances have revealed substantial microglial heterogeneity, highlighting the existence of dynamic and disease stage-dependent activation states rather than fixed phenotypes. In early disease stages, microglia can promote Aβ clearance and tissue repair, whereas chronic activation may exacerbate pathological processes. These findings have driven the development of microglia-targeted therapeutic strategies aimed at enhancing protective functions while limiting maladaptive inflammatory responses. This review summarizes current knowledge regarding microglial involvement in AD and discusses emerging therapeutic approaches, ranging from immunomodulation and metabolic reprogramming to gene-based and nanotechnology-driven interventions, with a focus on their translational potential.},
}

@article {pmid42943397,
year = {2026},
author = {Liu, Y and Feng, X and Dong, H and Lan, T and Wu, J and Wang, C and Zhang, X},
title = {Integrated Genetic and Multi-Omic Analyses Reveal Oral Microbial Associations with Brain Structure and Alzheimer's Disease.},
journal = {Microorganisms},
volume = {14},
number = {10},
pages = {},
pmid = {42943397},
issn = {2076-2607},
support = {82470988//National Natural Science Foundation of China/ ; },
abstract = {Oral microbial dysbiosis is linked to systemic inflammatory, vascular, and metabolic perturbations, but species-level relationships with human brain structure remain poorly defined. Using two-sample Mendelian randomization, we mapped 438 of 439 oral species with genome-wide association study instruments to 1325 adult brain imaging-derived phenotypes. In total, 87 associations involving 51 taxa and 79 traits passed Benjamini-Hochberg correction across taxa within each imaging-derived phenotype. The childhood and metabolomic screens identified 196 nominal taxon-volume associations and 1118 candidate metabolite-linked paths, respectively, as exploratory findings. Spatial and single-nucleus transcriptomics localized candidate regional and cell-associated variation in brain-structure gene programs. In total, 35 taxa showed nominal genetic associations with Alzheimer's disease. Integration with full-length oral 16S ribosomal ribonucleic acid gene sequencing from a 51-participant case-control cohort prioritized Selenomonas infelix, Capnocytophaga granulosa, and Dialister pneumosintes. In a secondary exploratory analysis, the three-taxon salivary model incorporating educational attainment yielded a leave-one-out cross-validated area under the receiver operating characteristic curve of 0.843. This post-selection estimate is subject to optimism, and the model remains a proof of concept requiring independent external validation. This cross-scale atlas prioritizes microbial and anatomical targets and provides a translational foundation for mechanistic validation and non-invasive neurodegenerative risk markers.},
}

@article {pmid42943436,
year = {2026},
author = {Lee, H and Min, YW and Kim, TJ},
title = {Genetic Proxies for Helicobacter pylori Serology Are Dominated by HLA Class II Haplotype Structure: Implications for Reported Associations with Neurodegenerative Disease.},
journal = {Microorganisms},
volume = {14},
number = {10},
pages = {},
pmid = {42943436},
issn = {2076-2607},
support = {RS-2024-00437038//Korea Health Industry Development Institute/ ; },
abstract = {Genetic variants that predict anti-Helicobacter pylori immunoglobulin G (IgG) seropositivity lie almost entirely within the major histocompatibility complex (MHC), which also carries established risk loci for several diseases. Mendelian randomisation studies using such variants have reported causal effects of H. pylori infection on neurodegenerative disease, although the phenotype indexed is anti-H. pylori IgG seropositivity, not infection itself. We evaluated 22 candidate variants from a Japanese genome-wide study of anti-H. pylori IgG antibody titre in two-sample Mendelian randomisation analyses across five prespecified genomic proxy sets; the number retained varied by outcome. Higher genetically predicted anti-H. pylori IgG seropositivity was associated with lower Alzheimer's disease risk (odds ratio 0.83, 95% confidence interval 0.73 to 0.95). The association was absent once MHC variants were removed (0.94, 0.78 to 1.12), was strongest using HLA class II variants alone (0.73, 0.59 to 0.91), and traced to two variants near HLA-DRB1 and HLA-DQA1. Those proxies did not predict peptic ulcer disease in an ancestry-matched Japanese study (1.02, 0.92 to 1.13), differing from Parkinson's disease (0.73, 0.55 to 0.97; difference p = 0.029). Colocalisation did not support a shared causal variant for the serological and disease signals, selected proxy associations were attenuated after conditioning on leading class II variants, and the haplotypes tagged by the proxies differed between European and East Asian reference panels, indicating limited cross-ancestry transferability. The behaviour of these proxies is dominated by HLA class II haplotype structure, and they are therefore unsuitable for inferring a protective effect of H. pylori infection on neurodegenerative disease from IgG seropositivity.},
}

@article {pmid42943696,
year = {2026},
author = {Zhao, X and Liang, R and Li, Y and Yan, J and Zhang, J and Su, Z and Liu, Y and Yang, H and Cheng, M},
title = {Hemicyanine-Based Wash-Free Near-Infrared Fluorescent Probe for Imaging Amyloid-β Aggregates in Alzheimer's Disease.},
journal = {Molecules (Basel, Switzerland)},
volume = {31},
number = {20},
pages = {},
pmid = {42943696},
issn = {1420-3049},
support = {2024-MSLH-442//Natural Science Foundation Project of the Joint Program of Science and Technology Planning of Liaoning Province/ ; YQ202306//"OutstandingYouth" Support Plan of Shenyang Pharmaceutical University/ ; NO. LJ212510163020, China//the Scientific Research Funding Project of Education Department of Liaoning Province/ ; },
mesh = {*Alzheimer Disease/metabolism/diagnostic imaging ; Animals ; *Amyloid beta-Peptides/metabolism/chemistry ; *Fluorescent Dyes/chemistry ; Mice ; Humans ; *Carbocyanines/chemistry ; *Protein Aggregates ; Fluorescent Chemosensor Compounds ; Brain/metabolism ; Optical Imaging ; Disease Models, Animal ; },
abstract = {As a key biomarker of Alzheimer's disease (AD), amyloid-β (Aβ) is frequently employed for the diagnosis of AD. Near-infrared fluorescence (NIRF) imaging is a non-invasive, low-cost route for visualizing Aβ in vivo. However, most existing Aβ NIRF probes require tedious washing steps, show modest fluorescence turn-on (<50-fold), and stain normal tissue non-specifically. In this work, by fine-tuning the amphiphilicity of a hemicyanine scaffold to place its log P within the appropriate range, we identified P3 as a wash-free NIRF probe for Aβ aggregates. P3 bound Aβ aggregates with high affinity. In vivo, P3 distinguished AD mice from wild-type mice with a 4.8-fold signal ratio, together with adequate brain uptake (1.5 ± 0.1 ID/g at 20 min) and rapid clearance. Unlike Thioflavin T, which indiscriminately labels Aβ aggregates and normal neurons, P3 specifically labeled Aβ aggregates with negligible background, which enabled wash-free imaging with a signal-to-noise ratio of 80 ± 4. This work provides a wash-free, high-affinity NIRF probe for Aβ imaging.},
}

*Alzheimer Disease/metabolism/diagnostic imaging
Animals
*Amyloid beta-Peptides/metabolism/chemistry
*Fluorescent Dyes/chemistry
Mice
Humans
*Carbocyanines/chemistry
*Protein Aggregates
Fluorescent Chemosensor Compounds
Brain/metabolism
Optical Imaging
Disease Models, Animal

@article {pmid42943733,
year = {2026},
author = {Fantini, J and Lefebvre, M and Aulas, A and Chahinian, H and Yahi, N},
title = {The Disordome Paradigm: How Intrinsic Disorder Encodes Emergent Biological Function.},
journal = {Molecules (Basel, Switzerland)},
volume = {31},
number = {20},
pages = {},
pmid = {42943733},
issn = {1420-3049},
mesh = {*Intrinsically Disordered Proteins/chemistry/metabolism ; Humans ; alpha-Synuclein/chemistry/metabolism ; Protein Folding ; Thermodynamics ; Protein Conformation ; Protein Binding ; Static Electricity ; Gangliosides/metabolism/chemistry ; },
abstract = {Classical structural biology equates function with a fixed three-dimensional fold, a view challenged by intrinsically disordered proteins (IDPs) and regions (IDRs), which populate broad conformational ensembles rather than a unique structure. This article introduces the "disordome" paradigm, extending Uversky's "unfoldome" to describe how function emerges from electrostatic and hydration landscapes that reshape reversibly upon encounter with a partner. Using α-synuclein binding to ganglioside-enriched rafts and IDR-driven liquid-liquid phase separation, we argue that transient folding-upon-binding events, potentially entropically cheap, generate information-rich complexes and condensates that dissolve once conditions change, consistent with the second law of thermodynamics. We trace this logic to overlooked precursors: in 1957 Klotz invoked rubber elasticity to introduce entropy as the driver of protein "disorientation", while in 1962 Bernal described such proteins as chains "coiled in different ways" and formulated a "two-atom rule" whereby bonding constraints fix atomic geometry only up to two atoms apart. We argue that the local under-determination described by this two-atom rule, left unresolved in IDPs by any conserved network of contacts, helps explain why AlphaFold fails on IDPs. A quantum-mechanical pillar (dispersion, OH-π contacts, tunneling) is proposed as underrepresented in IDP research. We discuss implications for the origin of life, cellular regulation via condensates, and a therapeutic logic ("target the target, not the arrow") illustrated by AmyP53, which occupies raft gangliosides rather than disordered amyloid proteins in Alzheimer's and Parkinson's diseases.},
}

*Intrinsically Disordered Proteins/chemistry/metabolism
Humans
alpha-Synuclein/chemistry/metabolism
Protein Folding
Thermodynamics
Protein Conformation
Protein Binding
Static Electricity
Gangliosides/metabolism/chemistry

@article {pmid42943736,
year = {2026},
author = {Chen, S and Li, B and Zhao, T and Huang, Q and Li, C and Ainiwan, Y and Qi, S and Pan, J},
title = {Flocculent Ti3AlC2-Based Two-Dimensional Material Flexible Microneedle Patch for Screening Alzheimer's Disease Animal Biomarkers and In Situ Revealing Spatial Aggregation of Arachidonic Acid.},
journal = {Molecules (Basel, Switzerland)},
volume = {31},
number = {20},
pages = {},
pmid = {42943736},
issn = {1420-3049},
mesh = {Animals ; *Alzheimer Disease/metabolism/diagnosis/blood ; *Biomarkers/metabolism/blood ; Rabbits ; *Arachidonic Acid/metabolism ; Humans ; *Titanium/chemistry ; Brain/metabolism ; Disease Models, Animal ; Needles ; },
abstract = {Efficient diagnosis and pathological elucidation of Alzheimer's disease (AD) are constrained by the lack of technologies for in situ capture of metabolites in living brain tissues. Metabolic disorders in the parietal lobe highly correlate with AD progression, yet existing methods cannot achieve in situ capture and spatial analysis. A petal-like flocculent Ti3AlC2-based flexible microneedle patch was developed for in situ extraction and mass spectrometry of parietal metabolites in AD rabbits. Sodium hydroxide etching and cetyltrimethylammonium bromide (CTAB) self-assembly constructed a flocculent micro-/nanostructure, enhancing enrichment ~4-fold (2.5-fold after etching + 1.6-fold after CTAB). The stretchable substrate enables conformal attachment to the curved parietal lobe. Application to the exposed cortex demonstrates mechanical flexibility, linear glucose response (R[2] = 0.9958) and resistance to salt/protein interference. Serum profiling of 15 AD patients and 15 controls with OPLS-DA shows clear discrimination (top-5 markers combined area under the curve (AUC) = 0.84). Spatial analysis reveals arachidonic acid's unique pattern of centralized aggregation with peripheral gradient diffusion. This novel in situ device enables brain metabolite detection and reveals abnormal arachidonic acid aggregation, providing evidence for lipid-pathway AD interventions.},
}

Animals
*Alzheimer Disease/metabolism/diagnosis/blood
*Biomarkers/metabolism/blood
Rabbits
*Arachidonic Acid/metabolism
Humans
*Titanium/chemistry
Brain/metabolism
Disease Models, Animal
Needles

@article {pmid42943751,
year = {2026},
author = {Qin, Q and Yan, Q and Zhu, K and Miao, J and Yang, M and Wu, Z and Fan, C and Jiang, P and Wu, G and Wang, Q},
title = {Alpiniae oxyphyllae Fructus in Alzheimer's Disease: Multi-Target Mechanisms, Current Evidence, and Future AI-Driven Perspectives.},
journal = {Molecules (Basel, Switzerland)},
volume = {31},
number = {20},
pages = {},
pmid = {42943751},
issn = {1420-3049},
support = {GJPY2026046//High-Level Scientific and Technological Research Project of Ningbo University/ ; 2023YFF0724802//National Key Research and Development Project of China/ ; No.2023ZL150//Zhejiang Provincial Traditional Chinese Medicine Science and Technology Program/ ; },
mesh = {*Alzheimer Disease/drug therapy/metabolism ; *Alpinia/chemistry ; Humans ; Animals ; *Plant Extracts/chemistry/pharmacology/therapeutic use ; Neuroprotective Agents/chemistry/pharmacology/therapeutic use ; *Artificial Intelligence ; Flavonoids/chemistry ; *Drugs, Chinese Herbal/chemistry/therapeutic use/pharmacology ; Fruit/chemistry ; },
abstract = {Alpiniae oxyphyllae Fructus (Zingiberaceae; Alpinia oxyphylla Miq) (AOF) is a traditional Chinese medicinal and edible homologous material rich in bioactive metabolites, including flavonoids, terpenes, and sesquiterpenes. Its multiple metabolites and multi-target nature confer unique advantages for cognitive function and neuroprotection. However, recent advances in extraction techniques, the discovery of AOF effects, and novel ameliorative mechanisms against Alzheimer's disease (AD) require an updated review. This review systematically expands on the botanical features, traditional dietary applications, and quality control of AOF raw materials, as well as its AD-ameliorating effect, in vivo absorption, toxicological safety, and extraction technology optimization strategies. Moreover, we explored the emerging mechanisms underlying the effectiveness of AOF and its bioactive metabolites in improving AD, including effects on glial cell function, the gut-brain axis, brain metal ions, and advanced glycation end products. This review comprehensively summarizes preclinical studies, clinical research, and commercially available products related to AOF and its metabolites. It also expounds upon the potential impetus that artificial intelligence could offer AOF research in the future. In summary, this review provides innovative technologies, in-depth mechanistic analyses, and novel research directions for exploring AOF extracts and their bioactive metabolites to offer strategic guidance for identifying new functional factors and drug candidates to combat AD.},
}

*Alzheimer Disease/drug therapy/metabolism
*Alpinia/chemistry
Humans
Animals
*Plant Extracts/chemistry/pharmacology/therapeutic use
Neuroprotective Agents/chemistry/pharmacology/therapeutic use
*Artificial Intelligence
Flavonoids/chemistry
*Drugs, Chinese Herbal/chemistry/therapeutic use/pharmacology
Fruit/chemistry

@article {pmid42943797,
year = {2026},
author = {Cavalluzzi, MM and Terlizzi, F and Catalano, A and Pannunzio, A and Rotondo, NP and Habtemariam, S and Lentini, G},
title = {Natural Compounds and Their Microbiota-Derived Metabolites as Modulators of the Microbiota-Gut-Brain Axis in Alzheimer Disease: Biochemical Mechanisms and Drug Discovery Insights-A Narrative Review.},
journal = {Molecules (Basel, Switzerland)},
volume = {31},
number = {20},
pages = {},
pmid = {42943797},
issn = {1420-3049},
mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism/microbiology ; Animals ; *Biological Products/pharmacology/therapeutic use ; *Drug Discovery ; *Brain/metabolism/drug effects ; *Gastrointestinal Microbiome/drug effects ; Polyphenols/pharmacology ; },
abstract = {The microbiota-gut-brain axis (MGBA) is a complex signaling network linking the gut microbiota with central nervous system function. Growing evidence suggests that gut microbial dysbiosis contributes to neurodegenerative diseases (NDs) through mechanisms involving oxidative stress, neuroinflammation, disruption of the epithelial barrier, and altered microbial metabolite production. Unfortunately, the currently available therapies for NDs remain predominantly focused on symptomatic relief and do not modify the underlying disease progression. Natural bioactive compounds, particularly polyphenols, have emerged as promising multi-target modulators of the MGBA due to their pleiotropic effects across microbial, epithelial, immune, and neural compartments. This narrative review summarizes the available evidence on natural compounds and their microbial metabolites that target the MGBA, as evaluated in both in vitro and in vivo models. With a focus on Alzheimer disease, the molecular and cellular mechanisms underlying their effects across microbial, epithelial, immune, and neural compartments, as well as their potential therapeutic value through MGBA modulation, are discussed.},
}

Humans
*Alzheimer Disease/drug therapy/metabolism/microbiology
Animals
*Biological Products/pharmacology/therapeutic use
*Drug Discovery
*Brain/metabolism/drug effects
*Gastrointestinal Microbiome/drug effects
Polyphenols/pharmacology