@article {pmid42134889,
year = {2026},
author = {Chinnathambi, S and Rangappa, N},
title = {Therapeutics immunotargets for Tauopathy.},
journal = {Advances in protein chemistry and structural biology},
volume = {151},
number = {},
pages = {267-302},
doi = {10.1016/bs.apcsb.2025.10.015},
pmid = {42134889},
issn = {1876-1631},
mesh = {Humans ; *Tauopathies/immunology/drug therapy/therapy/pathology/metabolism ; *Alzheimer Disease/immunology/drug therapy/pathology/metabolism ; Animals ; tau Proteins/metabolism/immunology ; Autophagy/drug effects ; Mitochondria/metabolism/drug effects ; Oxidative Stress/drug effects ; },
abstract = {Alzheimer's disease is a multi-factor involved neurodegenerative disease. In Alzheimer's condition, the pathological protein transfer from cell to cell and cause other cells to degenerate, similar to prion like diseases, this pathological protein transfer is exacerbated by neuroinflammation, mitochondrial dysfunction, oxidative stress, autophagy impairment, and cholinergic deficits. Neuroinflammation, driven by chronic microglial activation, produces excessive cytokines that worsen Tau hyperphosphorylation. Mitochondrial dysfunction, characterized by impaired energy metabolism, enzyme deficits in the TCA cycle, and ROS overproduction, leads to oxidative damage to proteins, lipids, and nucleic acids. Oxidative stress further accelerates neuronal damage. Autophagy dysfunction, caused by impaired mTOR signalling, disrupts the clearance of Aβ and Tau, facilitating their accumulation. Additionally, cholinergic deficits, including reduced acetylcholine levels, impair cognitive functions like memory and learning. Therapeutic approaches targeting these interconnected mechanisms, such as modulating inflammation, restoring mitochondrial and autophagy functions, and addressing the amyloid and Tau pathways will offers promising directions for treating Alzheimer's disease by developing an effective intervention to manage this debilitating disorder.},
}

Humans
*Tauopathies/immunology/drug therapy/therapy/pathology/metabolism
*Alzheimer Disease/immunology/drug therapy/pathology/metabolism
Animals
tau Proteins/metabolism/immunology
Autophagy/drug effects
Mitochondria/metabolism/drug effects
Oxidative Stress/drug effects

@article {pmid42134891,
year = {2026},
author = {Chinnathambi, S and Rangappa, N and Chandrashekar, M},
title = {Antioxidants as immunomodulators for Tau and Amyloid-β in Alzheimer's disease.},
journal = {Advances in protein chemistry and structural biology},
volume = {151},
number = {},
pages = {303-365},
doi = {10.1016/bs.apcsb.2025.10.007},
pmid = {42134891},
issn = {1876-1631},
mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism/immunology/pathology ; *Antioxidants/pharmacology/therapeutic use ; *tau Proteins/metabolism/immunology ; *Amyloid beta-Peptides/metabolism/immunology ; Animals ; Oxidative Stress/drug effects ; },
abstract = {Alzheimer's Disease is a progressive neurodegenerative disorder driven by oxidative stress, neuroinflammation, and pathological protein aggregation, such as Tau tangles and Amyloid-beta plaques. These processes disrupt neuronal integrity, contributing to cognitive decline. Dietary antioxidants, including phenolic compounds, omega-3 fatty acids, carotenoids, and isothiocyanates, have shown significant potential in mitigating these pathological mechanisms. They neutralize free radicals, reduce Tau hyperphosphorylation, inhibit Amyloid-beta aggregation, and alleviate inflammation, offering neuroprotection. Nutrient-rich diets, such as the Mediterranean, MIND, and Indian traditional diets, rich in these bioactive compounds, are associated with enhanced brain health and a reduced risk of AD progression. This review highlights the multifaceted role of antioxidants in preventing and managing AD while emphasizing the need for continued research to optimize their therapeutic potential and integration into daily nutrition.},
}

Humans
*Alzheimer Disease/drug therapy/metabolism/immunology/pathology
*Antioxidants/pharmacology/therapeutic use
*tau Proteins/metabolism/immunology
*Amyloid beta-Peptides/metabolism/immunology
Animals
Oxidative Stress/drug effects

@article {pmid42134986,
year = {2026},
author = {King, AJ and Amoah, K and Zhang, L and Bahn, JH and Barney, RM and Quinones-Valdez, G and Xiao, X},
title = {Allele-specific splicing modulates protein isoforms and Alzheimer's risk.},
journal = {Genome research},
volume = {},
number = {},
pages = {},
doi = {10.1101/gr.281117.125},
pmid = {42134986},
issn = {1549-5469},
abstract = {Despite growing catalogs of genetic variation linked to human traits and diseases, the functional impact of most genetic variants remains poorly understood. Alternative splicing, particularly in the human brain, represents a key layer of post-transcriptional regulation that may mediate genetic effects on gene expression and protein diversity. In this study, we systematically map allele-specific alternative splicing (ASAS) events in postmortem brain tissues from the Mount Sinai Brain Bank cohort, identifying hundreds of genetically regulated splicing events across four brain regions. Using a concordance-based method, we nominate more than 500 putative functional SNPs associated with ASAS, many of which overlap splicing QTLs (sQTLs), RNA-binding protein binding sites, and GWAS loci for Alzheimer's disease (AD), brain traits, and immune phenotypes. ASAS events are enriched in genes involved in mitochondrial function and frequently occur in 5' untranslated regions (5' UTRs), in which they are associated with protein quantitative trait loci (pQTLs), alternative start codons, and isoform-specific domain changes, highlighting an underappreciated mechanism through which noncoding variants can influence translation and proteome complexity. Importantly, we also identify a subset of ASAS events exhibiting disease-specific splicing patterns in AD brains, including functional SNPs with opposing splicing effects between AD and control groups in genes implicated in mitochondrial function and neuronal signaling. Together, our results provide a brain-specific, splicing-resolved map of regulatory variation and uncover novel mechanisms linking genetic variation to transcript and protein-level changes in AD. This work highlights the importance of allele-specific splicing analysis for interpreting noncoding variation in complex human disorders.},
}

@article {pmid42135109,
year = {2026},
author = {Yin, X and Zhang, H and Zhang, R and Xue, J and Hou, Y},
title = {Epigenetic noise in the aging brain: tuning neuronal vulnerability to neurodegeneration.},
journal = {Trends in neurosciences},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.tins.2026.04.006},
pmid = {42135109},
issn = {1878-108X},
abstract = {Aging is the predominant risk factor for neurodegenerative diseases, yet the mechanisms linking biological aging to selective neuronal degeneration remain incompletely understood. Accumulating evidence indicates that aging progressively disrupts epigenetic regulation, manifested as increased epigenetic noise in DNA methylation, histone modifications, and chromatin accessibility, which undermines transcriptional precision and the stability of neuronal identity. Recent advances in single-cell and spatial epigenomics further suggest that these age-associated epigenetic alterations are not merely correlative but can actively shape neuronal vulnerability across brain regions and cell types. In this review, we synthesize emerging evidence showing how epigenetic noise contributes to selective neurodegeneration across Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease, and discuss emerging strategies aimed at stabilizing the aging neuronal epigenome.},
}

@article {pmid42135303,
year = {2026},
author = {Han, X and Rosenberg, GM and Kisling, VM and Zhang, T and Lee, CY and Ravi, A and Melnik, M and Bilousova, T and Spina, S and Nana, AL and Grinberg, LT and Seeley, WW and Gylys, KH and Huckins, LM and Raj, T and Brennand, KJ and Rexach, JE},
title = {Single-nucleus epigenomic dysregulation unmasks genetic risk-associated neurodegenerative glia states.},
journal = {Nature communications},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41467-026-73007-1},
pmid = {42135303},
issn = {2041-1723},
support = {R01 AG075802, R01 RF1NS128800//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R21AG082014//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01 AG075802/AG/NIA NIH HHS/United States ; R21AG082014//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; RF1AG065926//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG068030, RF1AG065926, R01AG050986//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01ES033630//U.S. Department of Health & Human Services | NIH | National Institute of Environmental Health Sciences (NIEHS)/ ; },
abstract = {The accumulation of abnormal tau protein selectively affects distinct brain regions and specific populations of neurons and glial cells in tau-related dementias, such as Alzheimer's disease, Pick's disease and progressive supranuclear palsy. Although the three disorders share the feature of tau protein pathology, the regulatory circuitry of non-coding genetic variants underlying risk-associated cell states remains to be elucidated. Using paired single-nucleus profiling of chromatin accessibility and gene expression across the three conditions, we define cell-type-specific cis-regulatory elements across six cell types and fifty subclasses. Comparing disease-dynamic cis-regulatory elements across three disorders, we find that glia overrepresent disorder-specific gene regulation related to dynamic cellular response to stress. We show that human genetic variants affecting microglial gene regulation converge into distinct and co-regulated modules affecting specific cellular functions. Moreover, polygenic risk modifiers are maximally co-accessible in disorder-specific glial states, modifying distinct pathways such as sphingomyelin regulation in Pick's disease. Our study informs glial regulators linked to polygenic modifiers of primary tauopathy, establishing modifiable pathways governing resilience.},
}

@article {pmid42135307,
year = {2026},
author = {Ye, T and Lv, X and Fang, Z and Li, Q and Chen, F and Dong, Y and Xiang, K and Yang, Y and Dai, C and Do, QL and Sun, J and Su, KP and Liu, J},
title = {1-deoxysphinganine promoted microglial glycolytic reprogramming and neuroinflammation in alzheimer's disease.},
journal = {Translational psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41398-026-04093-4},
pmid = {42135307},
issn = {2158-3188},
abstract = {Recent evidence suggests that microglial activation, driven by a metabolic shift towards glycolysis, was involved in the pathogenesis of Alzheimer's disease (AD). Although sphingolipid (SL) dysregulation has been linked to AD, the role of 1-deoxysphinganine (deoxySO), an atypical and neurotoxic SL, on microglial glycolytic reprogramming remains unclear. We measured serum deoxySO levels in AD patients and evaluated their association with cognitive performance. In APP/PS1 mice, we examined cerebral deoxySO level and the effects of deoxySO supplementation on cognitive function, neuropathology, and microglial activation. In vitro, BV2 microglia were used to assess inflammatory and metabolic changes via qPCR, western blot, ELISA, and RNA-seq analyses. The serum deoxySO levels were significantly elevated in AD patients, which was positively correlated with cognitive impairment. APP/PS1 mice exhibited increased cerebral deoxySO level, and supplementation with deoxySO could exacerbate cognitive deficits and Aβ plaque accumulation. Moreover, deoxySO supplementation increased microglial activation and enhanced inflammation in vivo and in vitro AD models. qPCR analysis identified disease-associated microglia (DAM) as a key deoxySO-responsive subpopulation, while RNA-seq revealed significant enrichment of genes related to glycolytic metabolism and inflammatory responses. Subsequently, qPCR confirmed that deoxySO promoted glycolytic metabolic reprogramming, which promoted DAM activation, thereby aggravating AD pathology. These findings identify deoxySO as a critical metabolic driver that links to microglial glycolytic activation and neuroinflammation, suggesting that targeting deoxySO-mediated metabolic pathways may offer a novel therapeutic strategy for AD.},
}

@article {pmid42135537,
year = {2026},
author = {Pak, K and Kim, J and Kim, K and Kim, K and Kim, YJ and Lee, H and Suh, H and Moon, E and Lee, BD and Park, JM and Choi, JH and Lee, YM},
title = {Brain Amyloid Deposition Is Negatively Associated with Cardiac Amyloid Retention in Apo E4 Carriers: A Pilot Study.},
journal = {Molecular imaging and biology},
volume = {},
number = {},
pages = {},
pmid = {42135537},
issn = {1860-2002},
support = {RS-2025-16067714//National Research Foundation of Korea/ ; Clinical research grant 2025//Pusan National University Hospital/ ; },
abstract = {PURPOSE: We investigated the relationship between amyloid deposition in the brain and heart using positron emission tomography (PET) scan with a focus on the influence of the apolipoprotein (Apo) E4 genotype.

PROCEDURE: Twenty-eight participants (12 healthy controls, 11 patients with mild cognitive impairment, and 5 patients with Alzheimer's disease) were recruited. Each subject visited the institution three times on separate days for echocardiography, brain and cardiac [18]F-Florbetaben PET, and brain magnetic resonance imaging. Myocardial tracer retention (MTR, %) was calculated as the change in the myocardial mean standardized uptake value on summed-frame images of the first 5 min and between 15 and 20 min. Brain amyloid deposition was quantified using the Centiloid scale.

RESULTS: The mean MTR of all participants was 24.0%, with no significant difference between Apo E4 carriers and non-carriers. Within this pilot study, an inverse association was identified between MTR and brain amyloid deposition on the Centiloid scale specifically among Apo E4 carriers. In contrast, no significant association was found in Apo E4 non-carriers, consistent with the findings from the full-volume analysis.

CONCLUSION: In this pilot study, an inverse association was observed between brain amyloid β deposition and cardiac amyloid retention in Apo E4 carriers, but not in non-carriers. These findings represent an exploratory clinical observation regarding potential genotype-specific patterns in central and peripheral amyloid dynamics. While the results are hypothesis-generating, they highlight the need for further research into the brain-heart axis in amyloid-related diseases, particularly in genetically at-risk individuals using larger confirmatory cohorts.},
}

@article {pmid42135576,
year = {2026},
author = {Pan, JP and Wang, PJ and Zhang, J and Knapskog, AB and Watne, LO and Wang, HL and Lagartos-Donate, MJ and Lautrup, S and Mao, LP and Wang, Q and Ling, ZP and Zhang, SQ and Schmauck-Medina, T and Ai, R and Edwin, TH and Zhang, T and Saltvedt, I and Eldholm, RS and Smith, A and Veverová, K and Caponio, D and Kobro-Flatmoen, A and Pang, H and Wang, Z and Wang, H and Gao, LJ and Halaas, NB and Wong, G and Vyhnalek, M and Luo, OJ and McEwan, WA and Storm-Mathisen, J and Gan, L and Hu, Z and Zetterberg, H and Witter, MP and Aarsland, D and Selbæk, G and Chen, G and Fang, EF},
title = {Reduced ULK1 links impaired autophagy and mitophagy to Alzheimer's disease pathology.},
journal = {Nature aging},
volume = {},
number = {},
pages = {},
pmid = {42135576},
issn = {2662-8465},
support = {282952//Cure Alzheimer's Fund (Alzheimer's Disease Research Foundation)/ ; 2020001//Ministry of Health and Care Services | Helse Sør-Øst RHF (Southern and Eastern Norway Regional Health Authority)/ ; 2021021//Ministry of Health and Care Services | Helse Sør-Øst RHF (Southern and Eastern Norway Regional Health Authority)/ ; 2023093//Ministry of Health and Care Services | Helse Sør-Øst RHF (Southern and Eastern Norway Regional Health Authority)/ ; 269901//Akershus University College of Applied Science/ ; 261973//Akershus University College of Applied Science/ ; 262960//Akershus University College of Applied Science/ ; 263928//Akershus University College of Applied Science/ ; 390612//Akershus University College of Applied Science/ ; 207819//Kreftforeningen (Norwegian Cancer Society)/ ; },
abstract = {ULK1 (Atg1) initiates macroautophagy and mitophagy, which support neuronal growth and survival, yet how this pathway is disrupted in aging and Alzheimer's disease (AD) remains unclear. Here we report reduced ULK1 in serum and cerebrospinal fluid during aging in cognitively unimpaired participants from the COGNORM study (n = 75) and in patients with AD from the NorCog Memory Clinic Cohort (n = 316). In AD mice, ULK1 overexpression stimulates autophagic flux, reduces AD pathology and delays cognitive decline alongside increased phagocytic degradation of amyloid-β, reduced tauopathy and improved mitochondrial quality. Mechanistically, ULK1 upregulation increases autophagy and PINK1-, FUNDC1- and AMBRA1-associated mitophagy; higher autophagy and mitophagy increase cellular NAD[+], which in turn deacetylates acetylated-Tau174 via the NAD[+]-SIRT1 axis, leading to reduced tauopathy. Using in vitro tau seeding assays and a Caenorhabditis elegans tau model, we validate the efficacy of ULK1 activators in inhibiting tauopathy. We propose that age-related decline in ULK1 leads to autophagy and mitophagy impairment and increases the progression of AD and identify ULK1 as a potential therapeutic target.},
}

@article {pmid42135610,
year = {2026},
author = {Fratto, E and Buonocore, J and Fortunato, F and Sammarra, I and Calomino, C and Vescio, B and Quattrone, A and Gambardella, A and Quattrone, A},
title = {The bidirectional association of epilepsy with Alzheimer's disease and other neurodegenerative dementias: A longitudinal observational study on the UK Biobank.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261450962},
doi = {10.1177/13872877261450962},
pmid = {42135610},
issn = {1875-8908},
abstract = {BackgroundConverging evidence supports a bidirectional link between epilepsy and Alzheimer's disease (AD). Limited data are available regarding the association of epilepsy with frontotemporal dementia (FTD) and dementia with Lewy bodies (DLB).ObjectiveTo estimate the bidirectional association between epilepsy and AD, FTD, and DLB in the UK Biobank, a large, multi-source healthcare dataset.MethodsEpilepsy, AD, FTD, and DLB cohorts were extracted. Cox proportional-hazard models were used to compare the AD risk in the epilepsy cohort against matched controls, and the epilepsy risk in the AD cohort against matched controls. Prevalent association of epilepsy with FTD and DLB was assessed using Chi-squared/Fisher test.ResultsHazard-ratio (HR) for AD in the epilepsy population versus controls was 2.5 (1.8-3.4, p < 0.001); HR increased when epilepsy was diagnosed in the sixth-seventh decade and in individuals with epilepsy carrying the APOE ε4 allele. Conversely, HR for epilepsy in AD versus controls was 14.8 (9.7-22.5, p < 0.001). Epilepsy prevalence was higher in the FTD population compared to controls, with prevalence ratio (PR) of 5.3 (2.4-11.8, p = 0.001). Epilepsy PR in DLB versus controls approached but did not achieve statistical significance (2.4, 1.0-5.7, p = 0.068).ConclusionsOur findings reinforce the notion of a bidirectional association between epilepsy and AD, providing proof-of-concept that epilepsy, especially late-onset, may be successfully integrated into AD risk frameworks. Furthermore, we found a high prevalence of epilepsy in the FTD population. Careful stratification of individuals with epilepsy could offer an opportunity to identify those at higher risk of future or covert AD and neurodegeneration.},
}

@article {pmid42135618,
year = {2026},
author = {Quansah, DNK and Halcrow, PW and Kumar, N and Liang, B and Geiger, JD},
title = {Role of endolysosome iron in amyloid-β protein-induced increases in reactive oxygen species, mitochondrial depolarization, and cytotoxicity.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261449714},
doi = {10.1177/13872877261449714},
pmid = {42135618},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is a neurodegenerative disease characterized pathologically by the presence of extracellular plaques containing amyloid-β (Aβ) protein, and intraneuronal accumulations of neurotoxic proteins including Aβ and hyperphosphorylated tau. Also implicated in AD pathophysiology are increased levels of reactive oxygen species (ROS) and iron dyshomeostasis. Ferrous iron (Fe[2+]) controls generation of ROS via Fenton-like reactions and Aβ42 increases levels of intracellular ROS. Endosomes and lysosomes (endolysosomes) are acidic organelles that contain high levels of readily releasable stores of Fe[2+] and lysosomotropic insults can trigger Fe[2+] release from endolysosomes, which is sufficient to account for increased levels of cytoplasmic Fe[2+] and ROS.ObjectiveWe tested the hypothesis that endolysosome stores of Fe[2+] were sufficient to control Aβ42-induced increases in mitochondrial Fe[2+] and ROS, mitochondrial depolarization, and cell death.MethodsUsing SH-SY5Y human neuroblastoma cells, we investigated the effects of Aβ42 (500 nM) and Aβ40 (500 nM) peptides on endolysosome and mitochondrial stress responses.ResultsAβ42 but not Aβ40 accumulated in and significantly decreased endolysosome Fe[2+] levels. Further, Aβ42 significantly (1) de-acidified endolysosomes, (2) caused endolysosome damage, (3) caused impaired autophagy, (4) increased levels of cytosolic Fe[2+] and ROS, (5) increased levels of mitochondrial Fe[2+] and ROS, (6) decreased mitochondrial membrane potentials, and (7) significantly increased cell death by apoptosis and ferroptosis. These neurotoxic effects were blocked by the endolysosome-specific iron chelator deferoxamine.ConclusionsEndolysosome stores of Fe[2+] appear to be important regulators of Aβ42-induced cytotoxicity and targeting these iron stores may lead to new therapeutics against AD-like pathology.},
}

@article {pmid42135783,
year = {2026},
author = {Wu, Z and Tan, Q and Xue, F and Jiang, Z and Zhao, H and Zhang, Y and Liu, Y and Zhang, Y and Ding, D and Chen, H and Xu, Y and Li, F and Zhang, C},
title = {Cellular state heterogeneity underlying sex differences in Alzheimer's disease based on single-cell transcriptome.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02081-w},
pmid = {42135783},
issn = {1758-9193},
support = {LH2023C062//Natural Science Foundation of Heilongjiang Province/ ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder that disproportionately affects women. However, the molecular mechanisms underlying sex differences in AD remain poorly understood.

METHODS: In this study, we curated 3,302,741 single-nucleus or single-cell profiles from 603 samples (296 female and 307 male samples; 339 AD and 264 normal) across 10 cohorts to investigate sex-specific differences in the brain of individuals with and without AD. Focusing on six major cell types, we applied non-negative matrix factorization at the sample level to identify cell type -specific meta-programs (MPs). These MPs consist of mutually exclusive and functionally orthogonal gene set, representing different functional states of brain cells. Using these MPs, we characterized cellular states (CSs) across four sex-disease groups. We then examined sex differences in both AD and normal brains at the level of cellular states, with emphasis on metabolism, cell-cell communication, senescence, and disease relevance.

RESULTS: Metabolic profiling revealed that inflammatory homeostasis is maintained through distinct metabolic pathways in males and females. Cell-cell communication analysis showed that the same cellular state interaction network is linked to AD pathology through sex-biased ligand-receptor pairs. Disease association analyses further indicated that polygenic risk for AD is not uniformly distributed across cell states, but instead shows sex-biased enrichment in specific neuronal and glial circuits. Senescence analysis suggested that males and females exhibit distinct CS-specific signatures of cellular senescence in AD. Additionally, we identified oligodendrocytes MP13 and excitatory neuron MP1 as sex-biased meta-programs.

CONCLUSIONS: Overall, our study identified sex-biased MPs across six major cell types and revealed that females displayed greater vulnerability to Aβ and tau pathology, while males carry a higher genetic risk burdens. These findings highlight cellular state heterogeneity underlying sex differences in AD.},
}

@article {pmid42135847,
year = {2026},
author = {Sinha, IR and Atkinson, AL and Irwin, KE and Ling, JP and Wong, PC},
title = {TDP-43: [GU]-ardian of the transcriptome.},
journal = {Molecular neurodegeneration},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13024-026-00944-2},
pmid = {42135847},
issn = {1750-1326},
abstract = {TDP-43 is a ubiquitously expressed, primarily nuclear DNA/RNA-binding protein implicated in neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer's disease (AD). In this review, we examine the structure and regulation of TDP-43, how these features influence its localization and functional activity, and how their disruption may contribute to disease. Among TDP-43's diverse functions, splicing repression of nonconserved RNA sequences termed cryptic exons has emerged as especially central to human disease. TDP-43 nuclear depletion and cytoplasmic aggregation are well-established pathological features in affected neurons and glia of neurodegenerative diseases, and accumulating evidence suggests that loss of TDP-43-mediated splicing repression occurs presymptomatically in disease. Advances in RNA-sequencing have enabled systematic identification of cryptic exon inclusion as a sensitive marker of TDP-43 dysfunction. Here, we synthesize current knowledge of TDP-43 biology and curate datasets from human tissues and experimental models, focusing on cryptic splicing to provide a resource for leveraging cryptic exon biology to better understand, detect, and target TDP-43 dysfunction.},
}

@article {pmid42135869,
year = {2026},
author = {Xu, H and Nanda, S and Sun, J and Rudd, M and Gou, L and Marks, H and Williams, CK and Magaki, S and Vinters, HV and Hintiryan, H and Dong, HW},
title = {Investigation of the myelin-amyloid interplay in Alzheimer's disease: insights from novel dsCMA imaging in mouse and human brains.},
journal = {Acta neuropathologica communications},
volume = {},
number = {},
pages = {},
doi = {10.1186/s40478-026-02317-8},
pmid = {42135869},
issn = {2051-5960},
support = {R01AG084036-01 (H.-W.D.)/NH/NIH HHS/United States ; R01AG084036-01 (H.-W.D.)/NH/NIH HHS/United States ; R01AG084036-01 (H.-W.D.)/NH/NIH HHS/United States ; R01AG084036-01 (H.-W.D.)/NH/NIH HHS/United States ; R01AG084036-01 (H.-W.D.)/NH/NIH HHS/United States ; S10OD025017/NH/NIH HHS/United States ; R01AG084036-01 (H.-W.D.)/NH/NIH HHS/United States ; R01AG084036-01 (H.-W.D.)/NH/NIH HHS/United States ; CHE-0722519//National Science Foundation/ ; },
abstract = {Myelin deterioration impairs neural communication and may contribute to neurodegenerative diseases such as Alzheimer's disease (AD). However, the spatiotemporal relationship between myelin degeneration and AD pathology remains unclear. We developed a novel imaging method-double-scan Cyto- and myelo-architecture (dsCMA)-that integrates multi-fluorescent labeling of cytoarchitecture and pathological markers with brightfield myelin staining on the same tissue sections. Coupled with computational tools for automated detection and quantification of amyloid-beta (Aβ) plaques and myelinated axons, dsCMA enables systematic analysis of Aβ-myelin interactions in 5xFAD mice and postmortem human AD tissues. In mice, we identified progressive, region-specific myelin disruption associated with Aβ accumulation, particularly in the hippocampus and cortex. Human samples revealed variable Aβ-myelin spatial relationships across individuals and regions, with evidence supporting a potential myelin origin for some plaques. These findings offer new insights into Aβ-myelin interplay and establish dsCMA as a scalable platform for histopathological analysis in translational and longitudinal AD research.},
}

@article {pmid42135923,
year = {2026},
author = {Mia, E and Hossain, MA and Bristy, AH and Hossan, R and Asif, U and Sherwani, AK and Alshahrani, MY and Selim, S and Rakib, IH and Yana, NT and Akter, K and Hasan, MSA},
title = {Neuroprotective Properties of Litchi chinensis and Its Phytochemicals in Preclinical Models of Alzheimer's Disease.},
journal = {Brain and behavior},
volume = {16},
number = {5},
pages = {e71474},
doi = {10.1002/brb3.71474},
pmid = {42135923},
issn = {2162-3279},
mesh = {*Alzheimer Disease/drug therapy/metabolism ; *Litchi/chemistry ; Animals ; *Neuroprotective Agents/pharmacology ; Disease Models, Animal ; *Phytochemicals/pharmacology ; *Plant Extracts/pharmacology ; Humans ; Rats ; Oxidative Stress/drug effects ; Mice ; Amyloid beta-Peptides/metabolism ; },
abstract = {PURPOSE: Alzheimer's disease (AD) is a progressive neurodegenerative disorder involving amyloid-β deposition, tau hyperphosphorylation, oxidative stress, and neuroinflammation. This review systematically evaluates the neuroprotective effects of Litchi chinensis and its phytochemicals against AD, focusing on modulation of Aβ accumulation, tau pathology, oxidative stress, neuroinflammation, apoptosis, and synaptic dysfunction using available preclinical evidence.

METHOD: A systematic literature search was conducted in PubMed, Scopus, Web of Science, ScienceDirect, and Google Scholar up to August 2025 using relevant keywords. Studies investigating neuroprotective effects of Litchi chinensis extracts or compounds in in vitro or in vivo AD models were included, while unrelated studies, duplicates, abstracts, and non-full-text articles were excluded.

RESULTS: Litchi chinensis extracts and phytochemicals demonstrated broad neuroprotective actions. In triple-transgenic mice, oligonol treatment (0.25-0.50 mg/mL) significantly reduced amyloid precursor protein (APP), β-secretase, and amyloid-β levels, while also decreasing tau hyperphosphorylation. Seed extracts (0.7-2.8 g/kg/day) reduced amyloid-β accumulation and neuronal injury in Sprague-Dawley rats. Anti-inflammatory effects were evident through decreased tumor necrosis factor-α, IL-1β, IL-6, and interferon gamma, alongside increased IL-4. Antioxidant defenses were enhanced via upregulation of antioxidant enzymes such as glutathione peroxidase-1 and superoxide dismutase-2, while apoptosis was suppressed by increasing Bcl-2 and reducing Bax and caspase activity. Synaptic integrity was preserved through upregulation of PSD95, synaptophysin, and serotonin receptor proteins, resulting in improved learning and memory in AD models. Additional benefits included enhanced mitochondrial and proteasomal activity, alleviation of endoplasmic reticulum (ER) stress, and induction of neurotrophic factors like insulin-like growth factor 2 and fibroblast growth factor 21.

CONCLUSION: Litchi chinensis demonstrates a multitargeted neuroprotective role, making it a promising natural therapeutic candidate for Alzheimer's management. However, as most findings are limited to preclinical models, further clinical studies are necessary to validate efficacy, ensure safety, and explore its translational potential.},
}

*Alzheimer Disease/drug therapy/metabolism
*Litchi/chemistry
Animals
*Neuroprotective Agents/pharmacology
Disease Models, Animal
*Phytochemicals/pharmacology
*Plant Extracts/pharmacology
Humans
Rats
Oxidative Stress/drug effects
Mice
Amyloid beta-Peptides/metabolism

@article {pmid42136057,
year = {2026},
author = {Basha, S and Vijeev, A and Nadig, SS and Agarwal, K and Meharchandani, V and Pai, AR and Mahato, KK},
title = {Metabotropic Glutamate Receptor-Dependent Synaptic Plasticity in Age-Related Neurodegenerative Disorders.},
journal = {Neural plasticity},
volume = {2026},
number = {1},
pages = {e3455379},
doi = {10.1155/np/3455379},
pmid = {42136057},
issn = {1687-5443},
support = {//Manipal Academy of Higher Education/ ; 17x(3)/Adhoc/33/2022-ITR//Indian Council of Medical Research/ ; EM/Dev/SG/75/0782/2023//Indian Council of Medical Research/ ; BT/INF/22/SP43065/2021//Department of Biotechnology, Ministry of Science and Technology, India/ ; IF:220005//Department of Science and Technology, Ministry of Science and Technology, India/ ; },
mesh = {Humans ; *Neuronal Plasticity/physiology ; *Receptors, Metabotropic Glutamate/metabolism/physiology ; Animals ; *Neurodegenerative Diseases/metabolism/physiopathology ; *Aging/physiology/metabolism ; *Brain/metabolism/physiopathology ; },
abstract = {Synaptic plasticity is a fundamental property of the nervous system that underpins learning, memory, and adaptive behavior across the lifespan. Disruption of plasticity mechanisms is increasingly recognized as a unifying feature of age-related neurodegenerative and neuropsychiatric disorders. While classical models of long-term potentiation (LTP) and long-term depression (LTD) have primarily emphasized ionotropic glutamate receptors (iGluRs), emerging evidence identifies metabotropic glutamate receptors (mGluRs) as central regulators of synaptic stability, metaplasticity, and activity-dependent translational control. This review synthesizes molecular, synaptic, circuit-level, and translational evidence to position mGluR-dependent plasticity as a context-sensitive signaling framework that governs excitatory-inhibitory balance across cortical and subcortical networks. This review examines subtype-specific contributions of Groups I, II, and III mGluRs to LTP and LTD, highlighting their roles in intracellular calcium dynamics, protein synthesis-dependent plasticity, and neuron-glia interactions. Particular emphasis is placed on receptor localization, intracellular signaling pathways, and region-specific cortical plasticity, which collectively determine how mGluR signaling shapes functional outcomes across distributed brain circuits. This review further discusses how dysregulation of mGluR-mediated plasticity contributes to synaptic and circuit dysfunction in Alzheimer's disease (AD), Parkinson's disease (PD), schizophrenia, autism spectrum disorder (ASD), Fragile X syndrome (FXS), and epilepsy, with attention to disease stage-specific and context-dependent alterations revealed by electrophysiological, molecular, and receptor imaging studies. Finally, emerging translational strategies, including subtype-selective biomarkers, allosteric and pathway-biased modulation, and circuit-targeted interventions, are evaluated for their potential to restore adaptive plasticity while limiting maladaptive network remodeling. Collectively, this review reframes mGluR-dependent synaptic plasticity as a dynamic and integrative regulator of neuronal circuit function in aging and disease, providing a conceptual and mechanistic foundation for the development of precision neuroplasticity-based therapeutics.},
}

Humans
*Neuronal Plasticity/physiology
*Receptors, Metabotropic Glutamate/metabolism/physiology
Animals
*Neurodegenerative Diseases/metabolism/physiopathology
*Aging/physiology/metabolism
*Brain/metabolism/physiopathology

@article {pmid42136096,
year = {2026},
author = {Zou, H and Kaddurah-Daouk, R and Luo, S and , },
title = {Longitudinal Sparse Single-Omics Factor Analysis for High-Dimensional Blood Biomarkers in Alzheimer's Disease.},
journal = {Statistics in medicine},
volume = {45},
number = {10-12},
pages = {e70601},
doi = {10.1002/sim.70601},
pmid = {42136096},
issn = {1097-0258},
support = {R01AG064803/AG/NIA NIH HHS/United States ; P30AG072958/AG/NIA NIH HHS/United States ; },
mesh = {*Alzheimer Disease/blood/diagnosis ; Humans ; *Biomarkers/blood ; Cognitive Dysfunction/blood ; Longitudinal Studies ; *Metabolomics/methods ; Factor Analysis, Statistical ; Lipidomics ; Principal Component Analysis ; Computer Simulation ; Aged ; Algorithms ; Male ; Female ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder whose molecular mechanisms involve multiple biological pathways. Longitudinal blood-based omics data, such as lipidomics and metabolomics profiles, offer promising noninvasive biomarkers for early detection and prognosis, yet they are high-dimensional, sparse, and exhibit complex temporal and cross-feature correlations. The primary goal of this study is to identify which omics data types are most strongly associated with time to dementia onset in patients with mild cognitive impairment (MCI) at baseline. To address this, we propose a longitudinal sparse single-omics factor analysis (LS-SOFA) framework that models each omics view through view-specific latent factors and feature-weight matrices, with temporal dynamics captured by functional principal component analysis (FPCA). The resulting functional principal component (FPC) scores are incorporated into a survival model to test whether each omics view is associated with time to dementia onset. An efficient covariance-based estimation algorithm substantially reduces computational and memory cost, enabling large-scale application in the Alzheimer's Disease Neuroimaging Initiative (ADNI) study. In simulations, LS-SOFA achieves higher longitudinal estimation accuracy and more stable hypothesis testing than competing methods. Applied to five blood-based omics views from ADNI, LS-SOFA identified plasma lipidomics and serum metabolomics from FIA and UPLC as significantly associated with dementia risk after FDR adjustment, with nominal evidence of association for gut microbial metabolomics from serum. The top features within each omics view reveal biologically interpretable metabolic pathways that may serve as blood-based biomarkers for AD progression.},
}

*Alzheimer Disease/blood/diagnosis
Humans
*Biomarkers/blood
Cognitive Dysfunction/blood
Longitudinal Studies
*Metabolomics/methods
Factor Analysis, Statistical
Lipidomics
Principal Component Analysis
Computer Simulation
Aged
Algorithms
Male
Female

@article {pmid42136137,
year = {2026},
author = {Bao, L and Zhao, F and Xu, W and Jiang, P and Zhang, Y and Luo, Y and Guan, W and Li, M and Chen, Q and Zhang, L and Kuang, H and Li, J and Liu, Y},
title = {Pharmacodynamics and mechanisms of triterpene components from the leaves of Astragalus mongholicus Bunge in the treatment of Alzheimer's disease.},
journal = {Natural product research},
volume = {},
number = {},
pages = {1-9},
doi = {10.1080/14786419.2026.2671969},
pmid = {42136137},
issn = {1478-6427},
abstract = {This study investigates the therapeutic potential and underlying mechanisms of triterpenoids (TR) derived from the leaves of Astragalus mongholicus Bunge for the treatment of Alzheimer's disease (AD). Eighteen triterpenoid compounds were identified in the TR fraction using UPLC-Q-TOF-MS. In the 3 × Tg-AD transgenic mouse model, the therapeutic efficacy of TR was assessed using a comprehensive approach that included the Morris water maze, histopathological analysis, transmission electron microscopy, and Western blotting. The findings revealed that TR significantly improved spatial learning and memory impairments, reduced hippocampal neuronal degeneration, and diminished the deposition of phosphorylated Tau (p-Tau) protein. Ultrastructural examination further confirmed that TR preserved mitochondrial integrity. Mechanistic studies showed that TR upregulated key mitophagy-related proteins in both PINK1/Parkin-dependent and -independent pathways. In conclusion, TR exerts neuroprotective effects by activating mitophagy through multiple pathways, highlighting its potential as a promising therapeutic candidate for AD. This study not only provides experimental evidence for the therapeutic potential of natural products targeting mitophagy in Alzheimer's disease but also expands the medicinal development value of the leaves of Astragalus mongholicus Bunge.},
}

@article {pmid42136262,
year = {2026},
author = {Khan, MA and Khan, ZA and Shoeb, F and Siddiqui, Z and Pandey, G and Fatima, G and Khan, RH and Khan, MM},
title = {Role of De Novo Lipogenesis in Neurodegeneration and Neurogenesis Disruption in Alzheimer's Disease and Treatment Perspective.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X423516260216052123},
pmid = {42136262},
issn = {1875-6190},
abstract = {Progressive neurodegeneration, decline in neurogenesis, and cognitive dysfunction alongside amyloid-β plaque and neurofibrillary tangle formation are prominent pathological features of Alzheimer's Disease (AD). Although the underlying mechanism remains unclear, evidence suggests that surplus intracellular lipids/fatty acids could be the primary mediators. In this regard, increased levels of Saturated Fatty Acids (SFAs), Monounsaturated Fatty Acids (MUFAs), their triglyceride and ceramide derivatives have been reported in the brain of patients with AD. Further, converging evidence from basic and clinical studies suggests that de novo lipogenesis could be the main source of lipid/fatty acid accumulation in the brains of patients with AD. Although elevated cholesterol has long been suggested to induce inflammation and neurodegenera-tion in AD, recent evidence suggests that the effects of SFAs and their lipid derivatives, particularly ceramides, could be more detrimental. Consequently, de novo lipogenesis inhibitors could be the potential therapeutic targets for the early intervention in AD. Intriguingly, several studies have shown that treatment with various natural or synthetic compounds, which inhibit de novo lipogenesis, effectively reduced neurodegeneration, cognitive dysfunction, and inflammation in the model animals of AD. These compounds also increased neurogenesis while reducing lipid/fatty acid accumulation, suggesting that blocking lipid/fatty acid biosynthesis by inhibiting de novo lipogenesis could be an effective strategy in treating AD. Thus, while the study discusses the effects of various FDA-approved AD drugs and selected natural and synthetic inhibitors of de novo lipogenesis on neurodegeneration and neurogenesis in model animals, the doors are open for conducting clinical trials in patients with AD.},
}

@article {pmid42136266,
year = {2026},
author = {Gupta, S and Nihal, PM and Jawaid, T and Ashesh, AM and Bhise, MR and Rawat, M and Lohidasan, S and Wal, P and Kumar, A and Kumar, D and Gasmi, A},
title = {Exploring Mitochondrial Dysfunction and Protective Therapeutic Approaches to Counteract Its Role in Alzheimer's Disease Progression.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X419571260226033536},
pmid = {42136266},
issn = {1875-6190},
abstract = {Alzheimer's disease (AD) is the primary cause of dementia, characterized by a progres-sive decrease in mental abilities and the accumulation of amyloid-beta (Aβ) peptides in the brain. The combination of these peptides leads to the development of neuritic plaques and neurofibrillary tangles that disrupt neural communication and eventually lead to the loss of neurons. One of the fac-tors that are involved in the development of AD is mitochondrial dysfunction. Disrupted function-ing of mitochondria leads to the production of less energy by the cells, increased oxidative stress, and accelerates the neurodegeneration process. Neurons that carry out their mitochondrial functions normally are required to keep the balance of calcium, in a reasonable energy production, and in the survival of the cells. Mitophagy, which guarantees the clearing of damaged mitochondria, is im-paired in AD. Cholinesterase blockers and NMDA receptor blockers are currently used as treat-ments, but these are not aimed at the underlying pathophysiology of the condition. New treatment approaches that are aimed at enhancing mitochondrial health, in contrast, are viable at providing a potential to decelerate or alter mitochondrial AD progression. The goals of these approaches include enhancement of the mitophagy process, alleviation of oxidative stress, and preservation of mito-chondrial health, which may disrupt major pathological events such as Aβ aggregation and tau hy-perphosphorylation. By concentrating on the replacement of mitochondria, scientists are moving in the right direction to develop therapies that will not only help control the symptoms but also cure the disease.},
}

@article {pmid42136267,
year = {2026},
author = {Saraswati, BD and Wicaksono, AW and Valles, SL and Poeggeler, B and Singh, SK},
title = {Exploring the Gut Microbiome as a Promising Frontier in Alzheimer's Disease Therapy.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X444975260408044214},
pmid = {42136267},
issn = {1875-6190},
abstract = {Alzheimer's Disease (AD) is a major global health challenge, particularly in ageing populations, and current therapies offer limited modification of disease progression. Emerging evidence indicates that the gut microbiome contributes to AD pathogenesis through metabolic, immune, and neuroendocrine mechanisms. Microbial metabolites, including Short-Chain Fatty Acids (SCFAs), bile acids, and trimethylamine-N-oxide (TMAO), regulate neuronal signalling and blood-brain barrier integrity, and dysbiosis has been linked to amyloid-β (Aβ) accumulation, tau hyperphosphorylation, chronic neuroinflammation, oxidative stress, and synaptic dysfunction. Host genetic factors, particularly APOE ε4 and immune-regulatory variants such as TREM2 and CD33, further influence microbial composition and susceptibility to metabolite-driven pathology. This review provides a deeper synthesis of current evidence by integrating findings across multi-omics studies and identifying key unresolved issues in the microbiome-AD field. The discussion evaluates whether microbiome alterations act as early initiators or downstream consequences of neurodegeneration, examines sources of heterogeneity in microbiome-targeted interventions, and considers how inter-individual variability in host genetics and microbial ecology may inform precision therapeutics. Conceptual frameworks presented here, including a two-phase dysbiosis trajectory and a metabolite "tipping-point" network, aim to reconcile conflicting results and support the development of testable mechanistic hypotheses. Microbiome-directed strategies, such as probiotics, prebiotics, dietary modulation, faecal microbiota transplantation, and antiviral therapies, demonstrate promise but require rigorous mechanistic validation and methodological standardisation. Continued advancement in longitudinal, genotype-stratified, and multi-omics research will be essential for translating microbiome science into clinically actionable approaches. Overall, current evidence positions the gut microbiome as a compelling frontier for the development of personalised, diseasemodifying strategies in AD.},
}

@article {pmid42136277,
year = {2026},
author = {Saxena, V and Singh, V and Sanskriti, },
title = {Translational Perspectives on Anti-Inflammatory Interventions for Neurodegenerative Disorders: Evidence from Gut-Brain Axis.},
journal = {Central nervous system agents in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715249430752260407050033},
pmid = {42136277},
issn = {1875-6166},
abstract = {The Gut-Brain Axis (GBA) has a complex role in chronic neuroinflammation, which is increasingly connected to neurodegenerative diseases (NDDs) such as Multiple Sclerosis (MS), Parkinson's Disease (PD), and Alzheimer's Disease (AD). Through neuronal, endocrine, and immunological pathways, the GBA enables twoway communication between the gastrointestinal tract and the central nervous system. According to recent research, the pathophysiology of neuroinflammatory responses in NDDs may be significantly influenced by gut dysbiosis, increased intestinal permeability, and modified microbial metabolites, such as Short-Chain Fatty Acids (SCFAs) and polyphenols. This study summarizes preclinical and clinical data supporting several anti- inflammatory approaches targeting GBA. Probiotics and fecal microbiota transplantation are two examples of microbiota-based treatments that have demonstrated promise in reducing neuroinflammatory responses and enhancing cognitive performance. Mediterranean and polyphenol-rich diets are among the dietary therapies that show promise in modifying the composition of microorganisms, lowering pro-inflammatory signaling, and enhancing neuroprotection. Through microbiota regulation, pharmacological substances such as curcumin, resveratrol, and SCFA mimetics also have anti-neuroinflammatory benefits. However, a number of translational challenges still exist, including limitations in animal models, a lack of standardized therapies, and inter-individual microbiome heterogeneity. In order to provide precise, GBA-targeted therapies, future views place a strong emphasis on integrating multi-omics, artificial intelligence, and personalized medicine. This study highlights a new therapeutic approach to treating neurodegeneration by examining the translational potential of anti- inflammatory therapies targeting GBA. It also emphasizes the necessity of strong clinical studies to confirm these findings.},
}

@article {pmid42136278,
year = {2026},
author = {Sharma, A and Mittal, V and Sharma, D and Deswal, G and Das, A and Guarve, K and Grewal, AS},
title = {Therapeutic Insights into Natural Products for Modulating Neurodegenerative Disease Pathways.},
journal = {Central nervous system agents in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715249405308251210104405},
pmid = {42136278},
issn = {1875-6166},
abstract = {INTRODUCTION: Neurodegenerative Disorders (NDs), such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and Amyotrophic Lateral Sclerosis (ALS), are chronic and progressive conditions marked by the gradual loss of neuronal structure and function. These disorders lead to cognitive, motor, and sensory decline, significantly reducing quality of life and posing a major global health burden due to rising healthcare costs and the absence of curative therapies. This review aims to comprehensively explore the therapeutic potential of natural products in targeting cellular and molecular mechanisms underlying NDs, highlighting their neuroprotective roles and potential for disease modification.

METHODS: A comprehensive literature review was conducted using databases including PubMed, Scopus, Web of Science, and Google Scholar. Peer-reviewed articles, clinical trials, and experimental studies were analyzed to evaluate the therapeutic potential of natural products and their bioactive compounds in the management of NDs.

RESULTS: ND pathogenesis involves oxidative stress, neuroinflammation, mitochondrial dysfunction, and abnormal protein aggregation, ultimately leading to neuronal death. Current therapies largely provide symptomatic relief without altering disease progression. Natural products from plants, fungi, and marine sources demonstrate strong neuroprotective potential through multitargeted mechanisms. Bioactive compounds such as flavonoids, alkaloids, terpenoids, and polyphenols exhibit antioxidant, anti-inflammatory, anti-apoptotic, and neuroprotective activities. Key molecules, including curcumin, resveratrol, luteolin, quercetin, and catechins, modulate signaling pathways such as NF-κB, MAPK, PI3K/AKT, Nrf2, apoptosis, and autophagy, thereby reducing amyloid-beta aggregation, protecting dopaminergic neurons, improving mitochondrial function, and enhancing cognition in preclinical and clinical studies.

DISCUSSION: Natural products represent promising candidates for disease modification in NDs due to their multi-pathway actions and relatively low toxicity. However, major limitations, such as poor bioavailability, pharmacokinetic variability, and the lack of standardized formulations, hinder clinical translation. Innovative strategies, including advanced drug-delivery systems, structural modifications, and synergistic formulations, are needed to overcome these barriers.

CONCLUSION: Natural products hold significant therapeutic potential in managing neurodegenerative diseases by targeting multiple pathological mechanisms. Their integration into ND treatment could provide safer and more effective alternatives, but further well-designed clinical trials are essential to establish their efficacy and facilitate clinical application.},
}

@article {pmid42136280,
year = {2026},
author = {Wal, P and Aziz, N and Srivastava, S and Wal, A and Khan, A and Vijayanandhan, V and Ali, SS and Gasmi, A},
title = {Traditional Chinese Medicine in the Modern Era; Network Pharmacology Exploration of Neuroprotective Mechanisms: A Systematic Review.},
journal = {Current neurovascular research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672026454396260417113611},
pmid = {42136280},
issn = {1875-5739},
abstract = {INTRODUCTION: Alzheimer's Disease (AD) is a multifactorial neurodegenerative disorder characterized by complex molecular dysregulation that cannot be adequately addressed by single-- target therapeutic strategies. Traditional Chinese Medicine (TCM), with its multi-component, multi-target philosophy, has attracted renewed scientific interest through the application of Network Pharmacology (NP). This systematic review aims to critically evaluate and synthesize current evidence on the use of NP to elucidate the neuroprotective mechanisms of TCM in AD.

METHODS: A systematic literature review was conducted using PubMed, Scopus, Web of Science, and Google Scholar to identify studies published between 2005 and March 2025. Eligible studies employed network pharmacology or systems pharmacology approaches to investigate TCM formulations, herbs, or bioactive compounds in the context of AD. Data were extracted on compound-- target interactions, protein-protein interaction networks, pathway enrichment analyses, and literature-reported molecular docking or experimental validation. No new experimental or computational analyses were performed.

RESULTS: The reviewed studies consistently demonstrated that network pharmacology effectively reveals key molecular targets and signaling pathways involved in AD pathogenesis, including PI3K/Akt, mTOR, MAPK, NF-κB, oxidative stress, and neuroinflammatory pathways.

DISCUSSION: These findings highlight NP as a valuable systems-level framework that bridges TCM theory with modern molecular pharmacology. However, limitations such as database dependency, prediction bias, and limited experimental validation remain.

CONCLUSION: This systematic review enhances mechanistic understanding of TCM-based interventions for AD and offers a rational foundation for future experimental, clinical, and drug-discovery studies targeting complex neurodegenerative diseases.},
}

@article {pmid42136282,
year = {2026},
author = {Singh, P and Bhardwaj, S and Nagarajan, K},
title = {Development and Assessment of Phytoconstituents-based Nanoemulsion as a Potent Combined Therapy for Neuroprotection in Scopolamine-induced Alzheimer's Disease Rat Model.},
journal = {Current neurovascular research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672026450795260413103307},
pmid = {42136282},
issn = {1875-5739},
abstract = {INTRODUCTION: Nanoemulsions are increasingly recognized as effective carriers for delivering neuroprotective agents in the management of neurodegenerative conditions like Alzheimer's disease. Alzheimer's Disease (AD) is a chronic and progressive neurological disorder marked by memory impairment, cognitive dysfunction, oxidative damage, and degeneration of neurons. This study focuses on designing and evaluating a nanoemulsion-based drug delivery system combining Resveratrol and Ginkgo biloba to investigate their potential neuroprotective effects in a scopolamine- induced Alzheimer's model in Wistar rats.

METHODS: A total of nine water-in-oil nanoemulsion formulations (F1-F9) were developed using probe sonication and examined for various parameters, including droplet size, zeta potential, polydispersity index (PDI), entrapment efficiency, and in vitro drug release profiles.

RESULTS: Among these, Formulation F2, containing 25 mg of Resveratrol and 25 mg of Ginkgo biloba, showed the most favourable characteristics, including a high entrapment efficiency of 90.13%, maximum drug release of 92.33%, a particle size of 92.83 nm, and a zeta potential of 30.75 mV, suggesting good stability of the formulation. For the in vivo evaluation, rats were divided into six groups: normal control, negative control (scopolamine-treated), standard treatment group (Diazepam 2 mg/kg), and three test groups with different formulations. Behavioural studies using the Y-maze demonstrated that the Test Group 1 (treated with F2 formulation) had significantly improved spontaneous alternation behaviour, indicating enhanced cognitive performance. Biochemical analysis showed reduced malondialdehyde (MDA) levels and increased glutathione (GSH) levels, suggesting potent antioxidant activity. Additionally, histopathological examination of brain tissue revealed that the F2-treated group showed reduced neuronal damage and better preservation of hippocampal structure.

DISCUSSION: In rats treated with scopolamine, the optimized F2 nanoemulsion showed excellent physicochemical stability and markedly enhanced cognitive function. Strong antioxidant and neuroprotective effects of the combination formulation are indicated by decreased MDA levels, increased GSH levels, and intact hippocampus architecture.

CONCLUSION: The Resveratrol-Ginkgo biloba nanoemulsion (F2) successfully reduced oxidative stress and cognitive impairment, indicating its potential as a treatment for early-stage Alzheimer's disease. Additional research is needed to confirm its therapeutic application.},
}

@article {pmid42136286,
year = {2026},
author = {Tiwari, P and Kadiri, SK and Sulakhiya, K},
title = {Hyperprolactinemia and Tau Pathology: Unravelling Neuroendocrine Dysregulation for Therapeutic Targeting.},
journal = {Current neurovascular research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672026467094260417052012},
pmid = {42136286},
issn = {1875-5739},
abstract = {BACKGROUND: Hyperprolactinemia, characterized by persistently elevated serum prolactin levels, is traditionally associated with reproductive and metabolic disturbances. Emerging evidence now implicates hyperprolactinemia in central nervous system dysfunction, particularly in the pathogenesis of neurodegenerative disorders. Chronic elevation of prolactin has been linked to tau pathology, a hallmark of Alzheimer's disease and related tauopathies, through mechanisms that promote tau hyperphosphorylation, microtubule destabilization, and neuronal compromise.

METHODOLOGY: This systematic review assesses the evidence on hyperprolactinemia and tau pathology. The overall literature search was performed in PubMed, Scopus, and Web of Science with the help of certain keywords that included prolactin, tau protein, neuroinflammation, oxidative stress, and dopaminergic signaling. The studies were narrowed down to a set of pre-established inclusion and exclusion criteria (original research, molecular and clinical data, relevance to neuropsychiatric disorders, non-English articles, reviews, animal studies that did not have a translational relevance). A clear study selection procedure was used, with independent screening and consensus-based resolution. The results generalize molecular, transcriptomic, neuroimaging, and clinical data to assess mechanistic connections and treatment prospects.

RESULTS: Neurons susceptible to tau accumulation under hyperprolactinemic states exhibit altered apoptotic signaling, impaired vesicular trafficking, and mitochondrial dysfunction. These disruptions correlate with increased neuroinflammation and oxidative stress, suggesting a mechanistic link between endocrine imbalance and tau-mediated neurotoxicity. Therapeutic agents such as dopamine agonists, selective kinase inhibitors, and prolactin receptor antagonists have the potential to restore neuroendocrine homeostasis and mitigate tau pathology.

DISCUSSION: The findings underscore hyperprolactinemia as a modifiable risk factor for cognitive decline. The neuroendocrine-tau axis represents a critical interface where hormonal dysregulation may precipitate neurodegenerative cascades. Clinical implications in the manuscript include that prolactin may serve as a biomarker of an early neurodegenerative process and that its role in the treatment approach includes dopamine agonists, prolactin receptor antagonists, and kinase inhibitors. This simplified methodology will ensure the highlights are original and have translational implications beyond mere abstract repetition.

CONCLUSION: Hyperprolactinemia-induced tau dysregulation presents novel opportunities for neuroprotective targeting. By bridging molecular mechanisms with clinical relevance, this review advocates for longitudinal studies to assess cognitive outcomes in hyperprolactinemic individuals. Emphasizing endocrine health may enhance cognitive resilience and inform future strategies for diagnosis, risk stratification, and therapeutic intervention in neurodegenerative diseases.},
}

@article {pmid42136293,
year = {2026},
author = {Ramesh, J and Jayanthi, B and Mohan, VK and Srinivasan, S and Vijayalakshmi, MK and Mohan, M},
title = {Targeted Nanotechnology Approaches to Bypass the Blood-brain Barrier in Neurodegenerative Disorders.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273444679260416064255},
pmid = {42136293},
issn = {1996-3181},
abstract = {Neurodegenerative diseases like Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS), and Huntington's disease (HD) are a growing health burden across the world because of the progressive loss of brain cells and the ineffective nature of the available treatment. One significant challenge in the treatment of these conditions is the Blood- -Brain Barrier (BBB), a highly selective interface that limits the access of most therapeutic molecules to the central nervous system. Nanotechnology has become an attractive approach to addressing this difficulty, as it enables the delivery of drugs with high accuracy and actively engages in the repair of the BBB. This review provides an overall synthesis of focused nanotechnology solutions aimed at both circumventing and restoring BBB function in neurodegenerative illnesses. It discusses various nanoparticle (NP) platforms such as polymeric, lipid-based, micellar, metallic, and carbon-derived systems in the light of their physicochemical aspects, transport across the BBB, and therapeutic efficacy. Particular emphasis is put on the receptor-mediated transcytosis, neurovascular unit modulations, and the regulation of Wnt, Shh, and Tie-2 signalling pathways, which are BBB integrity pathways. The review incorporates mechanisms of BBB repair in combination with neuroprotective nanotherapies, rather than focusing solely on end repair. This review covers the role of targeted nanotechnology in the future of therapeutic approaches for neurodegenerative diseases. By connecting materials science, molecular neuroscience, and clinical innovation, it demonstrates how next-generation brain-targeted therapies can be developed using targeted nanotechnology.},
}

@article {pmid42136299,
year = {2026},
author = {Xia, B and Wu, S and Yu, W and Lü, Y},
title = {Research Progress on Intervention Strategies Targeting the Gut-Brain Axis in Alzheimer`s Disease.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273431295251201140053},
pmid = {42136299},
issn = {1996-3181},
abstract = {As the most common neurodegenerative disease in the world, Alzheimer's Disease (AD) is characterized by a complex pathogenesis and a lack of effective treatments. In recent years, breakthroughs in the Gut-Brain Axis (GBA) theory have provided a new direction for AD intervention. Studies have shown that AD patients commonly exhibit gut dysbiosis, accompanied by decreased Short-Chain Fatty Acid (SCFA) levels, endotoxin leakage, and increased systemic inflammation, which accelerate cognitive decline via neuroinflammation, Aβ deposition, and synaptic dysfunction. Based on this, intervention strategies targeting the GBA have emerged as a focus of research for slowing down the pathological process of AD. In this study, we systematically summarize the mechanisms linking gut microbiota dysbiosis to AD pathology. This includes the roles of metabolites (e.g., SCFA, LPS, and TMAO) in modulating neuroinflammation and Blood-Brain Barrier (BBB) permeability, as well as the critical involvement of vagal nerve pathways in gut-brain signaling. We further explored the potential of probiotics to improve cognitive function by restoring microbial homeostasis, enhancing anti-inflammatory effects, and elevating neurotrophic factor levels; dietary interventions (e.g., the Mediterranean and MIND diets) to reduce AD risk by modulating microbial composition and metabolic activity; and Fecal Microbiota Transplantation (FMT) to reduce Aβ plaque deposition and mitigate neuroinflammation. Despite promising findings, challenges persist, including discrepancies between animal models and human subjects, individual variability in microbiota composition, and an incomplete understanding of underlying mechanisms. In the future, it will be necessary to combine multiple technologies to develop personalized intervention protocols and optimize clinical translation processes, providing a theoretical basis for the precise treatment of AD.},
}

@article {pmid42136300,
year = {2026},
author = {Naeem, MU and Khan, Y and Costa, RAD and Khan, SS and Faheem, M},
title = {Re-Profiling and Re-purposing of FDA-Approved AntiViral Agents Against Neurological Targets of Memory and Cognition: Molecular Docking and Simulation Approach.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273422165260215182925},
pmid = {42136300},
issn = {1996-3181},
abstract = {BACKGROUND: Dementia is a prevalent symptom of Alzheimer's Disease (AD), associated with either low levels of acetylcholine or destruction by enzymes. Such enzymes are acetylcholinesterase (AChE) and butyryl-cholinesterase (BuChE). The current research worked on re-purposing of 69 Food and Drug Administration Authority (FDA) approved antiviral agents against targets of AD, including AChE (PDB ID: 4BDT) and BuChE (PDB ID: 5LKT).

METHODS: Targets proteins like AChE (PDB ID: 4BDT) and BuChE (PDB ID: 5LKT), and their PDB IDs were retrieved from the Protein Data Bank (PDB), purified through Discovery Studio Visualizer 2016 (DSV-2016), and saved in PDB format. Data of 69 FDA-approved antiviral agents and standard donepezil were obtained from different published literature, and structures were downloaded from the PubChem structure search tool. DSV-2016 was used for the purification of the targets. PyRx was utilized for the docking of 69 test agents and the standard drug donepezil. DSV-2016 was used for post-docking analysis. In addition, Physio-chemical properties, pharmacokinetics, drug-likeness, and medicinal chemistry analysis of three potential compounds (based on binding affinity) and molecular dynamic simulation (MDS) were performed using SWISSADME and AMBER24 software, respectively.

RESULTS: Docking revealed the binding affinities of Saquinavir (-9.1 kcal.mol-1), paritaprevir (-10.8 kcal.mol-1), and simeprevir (-10.1 kcal.mol-1) with AChE. The recorded binding affinities against BuChE were Saquinavir (-11.7 kcal.mol-1), paritaprevir -11.2 kcal.mol-1), and simeprevir (-11.4 kcal.mol-1). Saquinavir and paritaprevir constructed one hydrogen bond with Threonine (THR38) and Glycine (GLN291), respectively. Simeprevir with Asparagine (ASN283), Valine (VAL282), and Tyrosine (TYR72), granting three hydrogen bonds. The data on lipophilicity was determined in terms of Log Po/w (ILOGP). Water solubility of Saquinavir, Paritaprevir, and Simeprevir demonstrated that the Log S (ESOL) value is much higher, and hence the mentioned three compounds are water insoluble. Saquinavir, paritaprevir, and simeprevir were subjected to molecular dynamics simulations, which showed good interactions of the test agents with BuChE compared to AChE.

DISCUSSION: The study revealed that already approved 69 FDA anti-viral agents showed potential interaction with the selected targets (AChE and BuChE). Three compounds, saquinavir, paritaprevir, and simeprevir, were found with high binding affinities. As they are utilized in human life for various viral infections with known pharmacology and pharmacokinetics data, we can repurpose such a drug to be active against memory loss or cognitive problems.

CONCLUSION: Based on the applied computational techniques on 69 FDA-approved agents, including molecular docking, SWISS-ADME, and MDS, we identified saquinavir, simeprevir, and paritaprevir as potential molecules modulating the action of AChE and BuChE to restore memory and cognition. Hence, it is supposed that these agents may serve as anti-Alzheimer agents. Further investigations are needed to find their therapeutic potential in in vitro and in vivo animal models.},
}

@article {pmid42136304,
year = {2026},
author = {Anjukandan, A and Kaliyaperumal, R},
title = {Challenges in Brain Drug Delivery for Neurodegenerative Disorders and Recent Trends: A Review.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273453002260416115852},
pmid = {42136304},
issn = {1996-3181},
abstract = {INTRODUCTION: Age-related disorders known as neurodegenerative illnesses are defined by uncontrolled neuronal loss that gradually impairs brain function. The majority of age-related neurodegenerative disorders are caused by dementias, in particular. Nowadays, the neurodegenerative disorders are not limited to age and are reported in all age groups. The drug delivery to treat the neurodegenerative disorders is challenging due to the presence of the blood-brain barrier (BBB).

METHOD: A critical literature review has been conducted across databases such as Scopus, Embase, Cochrane, and PubMed. Blood-brain barrier, neurodegenerative disorders, novel drug delivery system, and targeted drug therapy were the search terms.

RESULTS: Neurodegenerative Diseases (NDD) impact the peripheral nervous system, nerve cells, muscles, and the nerve-muscle junction. This term broadly encompasses cognitive disorders, such as Alzheimer's disease, Lewy body dementia, frontotemporal dementia, and vascular dementia. Additionally, other neurodegenerative conditions such as multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease, and spinocerebellar ataxias predominantly impair motor system function and nerves in the limbs. The existing therapeutic approaches to treat neurological diseases exhibit limited efficacy due to the BBB. This highly selective semipermeable membrane permits vital nutrients to enter the brain while blocking the potentially harmful toxins. It makes it very challenging to get medications into the brain. There are several effective approaches to deliver drugs to the brain (nanocarrier systems, intranasal administration, and focused ultrasound) to address the limitations of conventional treatments.

CONCLUSION: This review discusses neurodegenerative disorders, brain anatomy/physiology, barriers to drug delivery, and strategies to overcome these limitations.},
}

@article {pmid42136342,
year = {2026},
author = {Liu, CW and Shan, ZX and Li, WJ and Qu, QW and Hou, XQ},
title = {Potential Therapeutic Effects and Mechanisms of Estrogen on Diabetes, Alzheimer's Disease,and Their Comorbidity:A Review.},
journal = {Zhongguo yi xue ke xue yuan xue bao. Acta Academiae Medicinae Sinicae},
volume = {48},
number = {2},
pages = {328-337},
doi = {10.3881/j.issn.1000-503X.16649},
pmid = {42136342},
issn = {1000-503X},
mesh = {Humans ; *Alzheimer Disease/drug therapy/epidemiology ; *Estrogens/therapeutic use ; *Diabetes Mellitus/drug therapy/epidemiology ; Comorbidity ; },
abstract = {Estrogen is a lipid-soluble steroid hormone and one of the most important female sex hormones.It mainly functions by interacting with estrogen receptors,maintaining normal physiological and pathophysiological functions of the body,and playing a crucial role in regulating blood glucose homeostasis,metabolism,and physiological processes associated with brain learning and memory.Recent studies have shown that estrogen has potential therapeutic effects on diabetes,cognitive impairment and other diseases.It will provide new ideas and treatment strategies for diabetes,Alzheimer's disease,and their comorbidity by regulating the activity of estrogen and the interaction with estrogen receptors to modulate related pathological and physiological processes.This article reviews the latest research progress in the relationship between estrogen and these diseases,providing a new perspective and prospect for the prevention and treatment of diabetes,Alzheimer's disease,and their comorbidity.},
}

Humans
*Alzheimer Disease/drug therapy/epidemiology
*Estrogens/therapeutic use
*Diabetes Mellitus/drug therapy/epidemiology
Comorbidity

@article {pmid42136344,
year = {2026},
author = {Zhang, XT and Chen, SS and Liu, YW and Huang, HR and Yu, Y},
title = {Role of Brain Insulin Resistance in the Pathogenesis of Alzheimer's Disease.},
journal = {Zhongguo yi xue ke xue yuan xue bao. Acta Academiae Medicinae Sinicae},
volume = {48},
number = {2},
pages = {347-354},
doi = {10.3881/j.issn.1000-503X.16614},
pmid = {42136344},
issn = {1000-503X},
mesh = {*Alzheimer Disease/metabolism/etiology/physiopathology/pathology ; *Insulin Resistance ; Humans ; *Brain/metabolism ; },
abstract = {Alzheimer's disease (AD) is the most common type of dementia,in which brain insulin resistance (BIR) plays a key role.BIR affects the response of brain cells to insulin and is associated with cognitive decline and pathological features of AD.This study explores the role of BIR in the pathogenesis of AD and evaluates potential treatment strategies,aiming to provide new directions for the prevention and treatment of AD.},
}

*Alzheimer Disease/metabolism/etiology/physiopathology/pathology
*Insulin Resistance
Humans
*Brain/metabolism

@article {pmid42136452,
year = {2026},
author = {Dias, AL and Rayff da Silva, P and Pires, HFO and Roberta Pimenta Souza, L and Ferreira de Sousa, N and Ferreira Alves, A and Cabral de Andrade, J and Neri, LCD and Ferreira Goncalves, MC and Bezerra Felipe, CF and Graciela da Silva Stiebbe Salvadori, M and Scotti, MT and Scotti, L},
title = {A Review of Pathophysiology and Computational Studies of Isoeugenol Derived Acetamides against Alzheimer's Disease.},
journal = {Current topics in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115680266400065251208095300},
pmid = {42136452},
issn = {1873-4294},
abstract = {Alzheimer's disesase (AD) is a neurodegenerative disorder characterized by a deterioration of cognitive fuction, memory loss, and behavioral changes. The current pharmacotherapy is limited and focuses only on symptom relief. Therefore, this study aimed to review the targets involved in Alzheimer's disease (AD) and evaluate the pharmacokinetics and potential interactions of isoeugenol and nine hybrid acetamides derived from it. The pharmacokinetic profiles of the compounds were assessed using ADMET analysis through Deep-PK. For molecular docking, nine hybrid acetamide derivatives of isoeugenol and molecular targets implicated in AD pathophysiology were selected for consensus analysis. All compounds were predicted to exhibit satisfactory pharmacokinetic properties, including good intestinal absorption and blood-brain barrier penetrability. Regarding the toxicological profile, a few derivatives showed potential toxic effects. According to the molecular docking results, the derivatives exhibited satisfactory interactions with five key targets involved in Alzheimer's disease pathophysiology: apoE4, GABAA, e-NOS, i-NOS, and n-NOS, suggesting potential activity through these pathways. Notably, several compounds showed significant potential activity via the nitric oxide (NO) pathway. The studied compounds demonstrated a favorable pharmacokinetic profile and a high in silico likelihood of modulating Alzheimer's disease-related pathways, highlighting their potential as candidates for further in vitro and in vivo investigations.},
}

@article {pmid42136471,
year = {2026},
author = {Sharma, S and Thakur, A and Paliwal, D and Mondal, R and Saini, S and Sahu, R and Kaushik, N and Tiwari, H},
title = {Exploring the Therapeutic Potential of Coumarin Scaffolds in Alzheimer's Disease: A Comprehensive Review.},
journal = {Mini reviews in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113895575443995260406045449},
pmid = {42136471},
issn = {1875-5607},
abstract = {Alzheimer's disease is a progressive and debilitating form of neurological disorder that affects millions of people across the globe. Alzheimer's disease is essentially defined by the presence of cognitive decline, memory impairments, and behavioral symptoms, and it is also defined by pathological hallmarks such as amyloid plaques, Tau protein inclusions, oxidative stress, & neuroinflammation. However, despite the vast progress made in the field of neuroscience and pharmacology, there is no permanent treatment available for Alzheimer's disease, and the existing treatments are only symptomatic in nature. This has led to the search for new innovative therapeutic approaches based on small molecules with multifunctional pharmacological properties. Among different molecules, Coumarin derivatives have been identified as promising therapeutic agents owing to their high structural diversity and potent ability to bind key molecular targets involved in AD pathogenesis. Coumarin derivatives have been found to have strong potential for modulating oxidative stress, inhibitng cholinesterase, reducing neuroinflammation, and interfering with amyloid-beta aggregation. Recent advancements in the synthesis and design of coumarin derivatives have shown that slight modifications in their structure can yieldsubstantial improvements in their efficacy and selectivity in the treatment of Alzheimer's disease. For coumarin derivatives to be used in the treatment of Alzheimer's disease, they need first to be able to cross the blood-brain barrier. To overcome this limitation, scientists have been working to improve lipophilicity, optimize molecular size and polarity, and design prodrugs. This review provides an updated account of the use of coumarin derivatives in the treatment of Alzheimer's disease. It focuses on their neuroprotective and, symptommodifying effects, and their use in dealing with the multifactorial nature of the disease. Moreover, this paper aims to give recent research findings and discuss the structure-activity relationships of these compounds. The knowledge gained from this review is expected to motivate further research endeavors in the development of stronger and more specific AD drugs.},
}

@article {pmid42136472,
year = {2026},
author = {Shrivastava, N and Husain, A and Haider, K},
title = {Substituted Benzofurans as Potent Anticancer Agents: Advances, Molecular Docking, and SAR Studies.},
journal = {Mini reviews in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113895575435772260422071930},
pmid = {42136472},
issn = {1875-5607},
abstract = {Benzofuran, an oxygen-containing fused heterocyclic aromatic compound, occurs naturally as a secondary metabolite from various plant sources like Rutaceae, Asteraceae, Cyperaceae, and Liliaceae. The derivatives of benzofuran possess a wide range of biological activities, including anticancer, anti-inflammatory, antioxidant, antibiotic, analgesic, anti-Alzheimer's, and immunosuppressive effects. Various synthetic methods are currently used to prepare various benzofuran derivatives. Its therapeutic significance is highlighted by the presence of the benzofuran core in several FDA-approved drugs. Due to the development of resistance in existing anticancer therapies, there is an urgent need for novel, effective, and safe therapeutic approaches. Many heterocyclic moieties and their structural hybrids have been explored for their potential biological activity and have attracted considerable attention as anticancer agents. Substituted benzofuran derivatives are emerging as lead candidates to meet the global challenges of cancer and its available treatment. Benzofuran has the chemical formula C8H6O. Structurally, it consists of a fused ring system: a benzene ring fused to a five-membered furan ring (with one oxygen). Both benzene and furan contribute to its aromatic character. Benzofuran heterocycle plays an important role in drug design and drug discovery due to its versatile nature. The current review summarizes the recent progress in the design, development, drug discovery, and pharmacological actions of benzofuran derivatives as anticancer agents; their molecular docking studies; and structure-activity relationships reported over the past five to six years, emphasizing fused heterocyclic analogues and their prospects to develop as lead molecules. A thorough understanding of the structure-activity relationship will provide a valuable framework for novel drug discovery and design.},
}

@article {pmid42136945,
year = {2026},
author = {Quartarone, M and Forte, L and Calabrese, L and Brigiano, M and Annini, A and Trolese, S and Vella, G and Vaienti, F and Boschetti, M and Chattat, R},
title = {Spontaneous conversations as data in young-onset dementia research: a qualitative study.},
journal = {Frontiers in dementia},
volume = {5},
number = {},
pages = {1805579},
pmid = {42136945},
issn = {2813-3919},
abstract = {BACKGROUND: Young-onset dementia (YOD), defined by symptom onset before the age of 65, profoundly impacts personal identity, work, and family life. Despite growing interest in the psychosocial dimensions of YOD, the direct voices of people living with the condition remain underrepresented. Existing qualitative research has mainly relied on structured interviews, which can constrain spontaneity and the emergence of authentic meanings. This study adopts an innovative approach by analyzing spontaneous conversations as a naturalistic form of data, enabling a more ecological understanding of living experience.

METHODS: An exploratory qualitative study was conducted at an Italian Meeting Center for people with YOD. Eleven participants (aged 55-68) took part in 14 naturally occurring group conversations, recorded between October 2024 and February 2025. Transcripts were analyzed using the General Inductive Approach. Themes were co-developed through iterative coding and later validated in a participatory feedback session involving all participants.

FINDINGS: Four overarching themes were identified: (1) Living with Alzheimer's: between awareness and "broad shoulders"-redefining identity and meaning in everyday life; (2) Significant relationships: between closeness, misunderstanding, and new balances-navigating relational change and finding belonging in peer groups; (3) The struggle to be believed: between invisible illness and judging gazes-confronting stigma, disbelief, and social invisibility; (4) Support that makes a difference: between resources and ideas for living better-valuing respectful, personalized, and co-designed support. Participants collectively emphasized the need to move from a "for" to a "with" logic in dementia care and research:"It is not enough to do something for us. We need to build it together."

CONCLUSIONS: Spontaneous conversations offer a powerful lens to capture the nuanced, relational, and participatory aspects of living with young-onset dementia. This approach complements traditional qualitative methods by restoring authenticity to the voices of people with dementia, fostering inclusion, and informing the co-construction of more responsive psychosocial and community interventions.},
}

@article {pmid42137339,
year = {2026},
author = {Tang, H and Li, Y and Pu, Y and Wang, L and Yang, Y and Liu, L and Bai, X},
title = {Investigating the therapeutic mechanism of Puerarin in vascular dementia: an integrated approach combining network pharmacology and experimental validation.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1796295},
pmid = {42137339},
issn = {1663-9812},
abstract = {BACKGROUND: Vascular dementia (VaD) is the second most common type of dementia after Alzheimer's disease. Puerarin (PUE) is a natural compound isolated from Puerariae Lobatae Radix, plays an important role in treating neurodegenerative and neurovascular diseases. Studies have confirmed that Puerarin can reduce neuroinflammation and protect the blood-brain barrier (BBB). However, the precise mechanism by which PUE treats VaD remains to be elucidated.

OBJECTIVE: To investigate the therapeutic effect of Puerarin on VaD and its underlying molecular mechanisms.

MATERIALS AND METHODS: Cognitive performance was assessed using the behavioral testing. Hematoxylin and Eosin staining (H&E) and Nissl staining were employed to assess neuronal morphology in the hippocampus. Additionally, network pharmacology (NP) was used to identify putative bioactive compounds in PUE and candidate targets associated with VaD. Transmission electron microscopy (TEM), enzyme-linked immunosorbent assay (ELISA), quantitative PCR (qPCR), and Western blotting were used for experimental validation. To further interrogate pathway involvement, lipopolysaccharide (LPS), a Toll-like receptor 4 (TLR4) agonist, was administered, followed by repeated behavioral testing and molecular analyses.

RESULTS: Behavioral testing showed that PUE mitigated two-vessel occlusion (2VO)-induced cognitive deficits and reduced hippocampal neuronal injury. NP identified 17 putative active compounds and 100 overlapping targets between PUE and VaD. GO and KEGG enrichment analyses indicated that these targets were enriched in Toll-like receptor and NF-κB signaling, implicating an anti-neuroinflammatory mechanism. Experimental assays showed that PUE reduced TLR4 and myeloid differentiation primary response 88 (MyD88) expression, decreased nuclear factor-kappa-B p65 (NF-κB p65) phosphorylation, and lowered pro-inflammatory mediator levels. Importantly, the administration of the TLR4 agonist LPS effectively counteracted the therapeutic effects of Puerarin.

CONCLUSION: Puerarin improves learning and cognitive abilities in VaD rats by inhibiting the TLR4/MyD88/NF-κB signaling pathway, thereby attenuating pathological alterations in the hippocampus, protecting the BBB integrity from cerebral ischemic damage, and exerting anti-neuroinflammatory effects.},
}

@article {pmid42137345,
year = {2026},
author = {Chen, H and Xing, X and Ding, X and Xiang, G and Li, J and Yang, Y and Liu, Q and Xu, K and Lei, Q and Li, P},
title = {Serum metabolomics identifies GPC depletion in hepatic encephalopathy and its therapeutic potential for cognitive impairment.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1807444},
pmid = {42137345},
issn = {1663-9812},
abstract = {BACKGROUND: Hepatic encephalopathy (HE), a common neurological complication in end-stage cirrhosis, is a complex disorder whose molecular pathogenesis has yet to be fully elucidated. Metabolomics studies provide novel insights into elucidating the pathological mechanisms of HE. This study aims to screen serum differential metabolites in cirrhosis and HE patients using metabolomics technology, with particular focus on validating the therapeutic effects of key metabolites on HE-associated cognitive dysfunction and its underlying mechanisms.

METHODS: This study was designed to first enroll 20-30 subjects per group (including healthy controls, cirrhosis patients, and HE patients) for serum untargeted metabolomic analysis using liquid chromatography-tandem mass spectrometry technology, combined with multivariate statistical analysis and pathway enrichment methods to identify key metabolites. This study established five experimental rat groups and developed a HE rat model via modified common bile duct ligation to evaluate the effects of key metabolite supplementation on cognitive function, while simultaneously assessing therapeutic outcomes through histopathological examination and ultrastructural observations.

RESULTS: A total of 2,375 metabolites were identified by metabolomic analysis. Comprehensive analysis screened five differentially expressed metabolites (including sn-glycero-3-phosphocholine (GPC)) significantly associated with disease progression, with GPC prioritized for subsequent validation of its effects on cognitive function in HE. The results demonstrated that GPC supplementation notably improved HE rats' spatial working memory and motor ability, while alleviating hepatic inflammatory infiltration and blood-brain barrier damage.

CONCLUSION: This study is the first to discover and confirm the protective effect of GPC in improving cognitive dysfunction in HE, and the mechanism may be related to preserving the integrity of the blood-brain barrier.},
}

@article {pmid42137421,
year = {2026},
author = {Aguerd, A and Bennis, F and Chegdani, F},
title = {PathoAnalyzer-I: An Integrative Bioinformatics Platform for Chronic Disease Analysis.},
journal = {Bioinformatics and biology insights},
volume = {20},
number = {},
pages = {11779322261433663},
pmid = {42137421},
issn = {1177-9322},
abstract = {Chronic diseases impose a global health burden, contributing to high mortality and economic costs. Even with the recent surge in molecular data, these conditions remain largely incurable due to their biological complexity, data fragmentation, and analysis challenges, hindering early diagnosis, mechanistic understanding, and therapy. To address this, we developed PathoAnalyzer-I, an in silico platform that combines bioinformatics and machine learning to decipher chronic diseases. The tool requires no programming skills and provides a user-friendly interface for pathological analysis within a single framework. PathoAnalyzer-I uses a dataset of molecular data for 531 chronic diseases, from databases including the GWAS Catalog, PubChem, and STRING-db, enriched with machine learning-based predictions. Its dual-prediction system enhances molecular insights: one model imputes missing risk alleles with 77.6% accuracy, while a second predicts novel SNP-disease associations with 89.3% accuracy, providing avenues for future research. Applied to Alzheimer's disease, the platform identified diagnostic biomarkers (e.g. rs6733839T), core genes in disease mechanisms (e.g. BIN1, APOE, SLC24A4, ABCA7, PTK2B), major pathological mechanisms like amyloid processing, synaptic dysfunction, and cellular vulnerability, as well as therapeutic molecules including Beta-Lapachone and preventive compounds such as curcumin. With its features, PathoAnalyzer-I enables scientists, regardless of their resources, to conduct in-depth in silico studies of chronic diseases.},
}

@article {pmid42137472,
year = {2026},
author = {Al-Karmalawy, AA and Attia, MI and Alnajjar, R and El-Shiekh, RA and Al Khatib, AO and Yousef, TA and Abdel-Sattar, E},
title = {Discovery of Caralluma-derived pregnane glycosides as potent and selective cholinesterase inhibitors: integrated in silico and in vitro evaluation.},
journal = {RSC advances},
volume = {16},
number = {27},
pages = {24903-24915},
pmid = {42137472},
issn = {2046-2069},
abstract = {Alzheimer's disease (AD) is the fourth leading cause of death among elderly people worldwide. It has a complex pathogenesis, making multitarget-directed ligands (MTDLs) a key therapeutic strategy. This study evaluated pregnane glycosides isolated from Caralluma species (Apocynaceae) as potential cholinesterase inhibitors targeting acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes for AD treatment. In silico molecular docking against AChE (PDB: 4EY7) and BuChE (PDB: 8CGO) identified caratuberside E and awdelioside B as top AChE binders (-11.09 and -11.49 kcal mol[-1], outperforming the cocrystal inhibitor at -9.52 kcal mol[-1]). For BuChE, caratuberside G and penicilloside C showed superior scores (-10.94 and -11.55 kcal mol[-1] vs. -8.89 kcal mol[-1] for the cocrystal). These results were validated by 200 ns molecular dynamics simulations (stable RMSD values) and MM-GBSA binding free-energy calculations, confirming strong interactions and favourable energetics. In vitro assays (using donepezil as reference) demonstrated potent inhibition: caratuberside E was most active against AChE (IC50 = 0.69 ± 0.07 µM), followed by awdelioside B (IC50 = 18.99 ± 0.06 µM); caratuberside G (IC50 = 1.59 ± 0.16 µM) and penicilloside C (IC50 = 12.38 ± 0.51 µM) excelled against BuChE. Collectively, these pregnane glycosides from Caralluma show promise as selective cholinesterase inhibitors and potential MTDLs for AD therapy.},
}

@article {pmid42137642,
year = {2026},
author = {Wang, Y and Li, H and Wang, Y and Wang, Y and Dong, Z and Lu, Y},
title = {Classification and prediction of Alzheimer's disease stages and conversion from mild cognitive impairment based on multimodal data fusion.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1802842},
pmid = {42137642},
issn = {1663-4365},
abstract = {OBJECTIVE: This study aimed to develop multimodal prediction models based on real-world clinical data for classifying different stages of Alzheimer's disease (AD) and for predicting the conversion from mild cognitive impairment (MCI) to AD.

METHODS: A single-center retrospective real-world cohort study was conducted. A total of 658 individuals aged ≥50 years were included and classified into cognitively normal (CN), MCI, and AD groups. Demographic characteristics, neurocognitive assessment results, conventional magnetic resonance imaging (MRI) features, and blood-based biomarkers were collected. Logistic regression was used to construct pairwise classification models for disease stages and prediction models for MCI-to-AD conversion. Model performance was evaluated through stepwise integration of multimodal features. Discrimination ability was assessed using the area under the receiver operating characteristic curve (AUC), together with calibration curves and decision curve analysis. In a sub-cohort with thin-slice MRI data, the additional value of hippocampal volume was further examined.

RESULTS: Significant differences were observed among disease stages in cognitive function, imaging markers, and blood biomarkers (all p < 0.05). Multimodal fusion models achieved the best performance in disease stage classification (CN vs. AD: AUC = 0.96 ± 0.01; MCI vs. AD: AUC = 0.86 ± 0.03). The conversion prediction model integrating multimodal features showed good discrimination (AUC = 0.87) and satisfactory calibration. In the thin-slice MRI sub-cohort, inclusion of hippocampal volume increased the AUC to 0.88.

CONCLUSION: Multimodal prediction models based on real-world clinical data improved the accuracy of AD stage classification and the prediction of MCI-to-AD conversion risk. These models demonstrated good clinical feasibility. High-resolution structural imaging markers further enhanced predictive performance in selected populations.},
}

@article {pmid42137644,
year = {2026},
author = {Fairof, MHZ and Muhammad, H and Abdullah, AHA and Ibrahim, FW and Ooi, TC and Md Nasir, NL and Poo, CL and Ab Dullah, SS and Abd Rahman, MRA and Ibnu Rasid, EN and Mat Ludin, AF and Rajab, NF},
title = {Chrono-combined aerobic-resistance exercises as therapeutic approach to reverse neurodegeneration in rat model: a detailed protocol.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1775321},
pmid = {42137644},
issn = {1663-4365},
abstract = {The global increase in neurodegenerative disorders such as Alzheimer's disease has prompted the search for effective non-pharmacological interventions. Chrono-exercise which is the physical training aligned with circadian rhythms has emerged as a novel strategy to strengthen cognitive resilience. This study explores the impact of chrono-exercises, incorporating aerobic, resistance, and combined modalities, performed at the early dark (ZT13) and early light (ZT1) phases in an aluminum chloride (AlCl3)-induced rat model of neurodegeneration. One hundred male Wistar rats aged 2-3 months will undergo structured exercise interventions following AlCl3 exposure. Neurobehavioural assessments including novel object recognition and open-field tests along with grip strength analysis, biochemical profiling and histological evaluations of brain and muscle tissues will be conducted. We hypothesize that the timing of combined aerobic-resistance exercise critically influences neuroplasticity and cognitive performance. Findings are expected to guide circadian-based exercise prescriptions to counter cognitive decline and enhance brain health in aging populations.},
}

@article {pmid42137842,
year = {2026},
author = {Faradilla, MA and Anastasya, KS and Yastani, D and Yohana, Y and Tungka, EX and Suweino, S},
title = {Oxidative stress as a converging mechanism of aging and neurodegeneration: From molecular pathways to therapeutic targets.},
journal = {Narra J},
volume = {6},
number = {1},
pages = {e3042},
pmid = {42137842},
issn = {2807-2618},
mesh = {Humans ; *Oxidative Stress/physiology ; *Aging/metabolism/physiology ; *Neurodegenerative Diseases/metabolism ; Reactive Oxygen Species/metabolism ; Antioxidants/therapeutic use ; Mitochondria/metabolism ; Parkinson Disease/metabolism ; Alzheimer Disease/metabolism ; },
abstract = {Aging is the primary risk factor for major neurodegenerative disorders, yet the precise molecular links between biological aging and progressive neuronal loss remain complex. Oxidative stress, defined as an imbalance between the production of reactive oxygen species (ROS) and antioxidant defenses, has emerged as a central converging mechanism driving both processes. This review aims to synthesize current evidence demonstrating how chronic redox imbalance drives cellular senescence and neuronal vulnerability through mitochondrial dysfunction, lipid peroxidation, and oxidative protein damage. These insights underscore how sustained oxidative insults promote the misfolding and aggregation of disease-defining proteins, including amyloid-beta in Alzheimer's disease and α-synuclein in Parkinson's disease, thereby amplifying neuroinflammation, synaptic dysfunction, and bioenergetic failure. Furthermore, antioxidant-based therapeutic strategies are critically reassessed, highlighting a paradigm shift from non-specific radical scavenging toward targeted modulation of endogenous defense systems, particularly NRF2 signaling and mitochondria-directed antioxidants. By integrating molecular mechanisms with translational perspectives, this review integrates molecular, cellular, and translational evidence to explain how oxidative stress links biological aging to neurodegenerative disorders such as Alzheimer's and Parkinson's diseases.},
}

Humans
*Oxidative Stress/physiology
*Aging/metabolism/physiology
*Neurodegenerative Diseases/metabolism
Reactive Oxygen Species/metabolism
Antioxidants/therapeutic use
Mitochondria/metabolism
Parkinson Disease/metabolism
Alzheimer Disease/metabolism

@article {pmid42137879,
year = {2026},
author = {Wang, Z and Zoltán, KJ and Matta, C and Paluska, L and Al-Mnaseer, A and Takács, R and Ducza, L},
title = {A Systems-Level Transcriptomic Framework Identifies Shared Cellular Hubs in Osteoarthritis and Alzheimer's Disease.},
journal = {Computational and structural biotechnology journal},
volume = {35},
number = {1},
pages = {0085},
pmid = {42137879},
issn = {2001-0370},
abstract = {Osteoarthritis (OA) and Alzheimer's disease (AD) are prevalent age-associated disorders that frequently co-occur, yet the molecular basis of their comorbidity remains incompletely understood. To explore potential shared cellular programs, we performed an integrative analysis of publicly available bulk and single-cell transcriptomic datasets derived from human OA cartilage and AD cortex. Cross-disease comparison identified 60 overlapping differentially expressed genes, including 18 consistently up-regulated genes, which we defined as a shared up-regulated gene set (SUGS). Functional enrichment analyses indicated convergence on extracellular matrix remodeling, inflammatory signaling, metabolic stress responses, and immune regulation. Single-cell analysis of OA cartilage revealed expansion of a fibrochondrocyte subpopulation enriched for SUGS activity and extracellular-matrix-associated ligands. In AD cortex, a disease-associated oligodendrocyte subcluster displayed elevated SUGS activity and stress-response gene expression and occupied a prominent-receiver-like position within inferred neuronal-glial communication networks. Ligand-receptor analysis performed independently within each tissue identified collagen-related signaling in OA and neurexin-associated signaling in AD as dominant intratissue pathways. Because the OA and AD datasets are cross-sectional and were derived from independent cohorts and distinct tissues, these analyses do not establish direct inter-organ communication, temporal sequence, or causal directionality. In addition, CellChat-based ligand-receptor inference was performed independently within each tissue and does not itself infer cross-organ communication. The identification of sender-like and receiver-like cellular hubs should therefore be interpreted as a hypothesis-generating, systems-level conceptual framework that may help organize future experimental studies investigating potential links between joint inflammation and neurodegeneration in aging.},
}

@article {pmid42137886,
year = {2026},
author = {Jun, H and Ye, W and Liu, Y and Becker, A and Yin, H and Mattke, S},
title = {Identification of cognitive impairment using the Lancet Commission's risk factors and Medicare administrative data.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {},
pages = {e70363},
pmid = {42137886},
issn = {2352-8729},
abstract = {INTRODUCTION: Prediction models based on administrative data may present a scalable opportunity to identify risk of cognitive impairment, but their accuracy relative to models using richer information is uncertain.

METHODS: We developed and validated models to identify the likelihood of mild cognitive impairment (MCI) and dementia using the Health and Retirement Study linked to Medicare data from 2000 to 2016 (N = 63,740). Predictors covered most risk factors identified by the 2024 Lancet Commission. Model performance was assessed using multiple metrics, including the area under the receiver operating characteristic curve (AUC).

RESULTS: Probit models with demographics and chronic conditions yielded high AUCs of 71.3% (MCI) and 82.1% (dementia). Adding individual level education provided the largest improvement in AUCs, whereas dual eligibility status offered smaller gains (p  <  0.001). Air pollution exposure, obesity, and interaction terms did not enhance prediction.

DISCUSSION: Predictors in administrative data can be used to generate reasonably accurate, well calibrated models predicting likelihood of cognitive impairment.},
}

@article {pmid42137887,
year = {2026},
author = {Burnham, SC and Arora, AK and Iaccarino, L and Kennedy, I and Kotari, V and Wijayawardana, SR and Shaw, LM and Benina, N and Lu, M and Pontecorvo, MJ and Quevenco, FC and Wang, J and , },
title = {Interchangeability of CSF and PET to identify Alzheimer's disease pathology.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {},
pages = {e70288},
pmid = {42137887},
issn = {2352-8729},
abstract = {INTRODUCTION: Establishing interchangeability between cerebrospinal fluid (CSF) and positron emission tomography (PET) for patient identification may improve access to Alzheimer's disease (AD) therapies.

METHODS: Alzheimer's Disease Neuroimaging Initiative participants with mild cognitive impairment or AD dementia and available CSF, florbetapir PET, and/or flortaucipir PET were included. The interchangeability of CSF (per label threshold/method) and PET was evaluated for patient identification.

RESULTS: Fujirebio Lumipulse amyloid beta (Aβ) 42/Aβ40 (N = 288) and Roche Elecsys phosphorylated tau 181 (P-tau181)/Aβ42 (N = 251) Conformité Européene (CE)-marked CSF assays were in high agreement with and non-inferior to florbetapir PET for identifying patients with AD pathology. High agreement was observed between Roche Elecsys CSF P-tau181/Aβ42 (N = 127) and an early (temporal) flortaucipir PET stratification.

DISCUSSION: CSF assays were interchangeable with amyloid PET to identify patients with AD pathology and were in high agreement with elevated early temporal flortaucipir PET. CSF biomarkers may be used as a robust alternative to PET, potentially increasing access to AD diagnosis and disease-modifying treatments.},
}

@article {pmid42138018,
year = {2026},
author = {Chen, CP and Zhang, T and E, ED and Xu, TY and Han, Q and Gao, X and Sun, J and Huang, Y and Yang, JH and Zhang, XQ},
title = {Targeting mGluR2/3 Signaling With LY341495 Restores Dentate Gyrus Function and Cognitive Performance in a Male Mouse Model of Alzheimer's Disease.},
journal = {CNS neuroscience & therapeutics},
volume = {32},
number = {5},
pages = {e70916},
doi = {10.1002/cns.70916},
pmid = {42138018},
issn = {1755-5949},
support = {82201322//National Natural Science Foundation of China/ ; LY24H090001//the Natural Science Foundation of Zhejiang Province/ ; 2024010317//Ningbo Top Medical and Health Research Program/ ; 2022020304//Ningbo Top Medical and Health Research Program/ ; 2023H017//Ningbo Science and Technology Project/ ; 2024L003//Ningbo Clinical Research Center for Emergency and Critical Diseases/ ; },
mesh = {Animals ; Male ; *Alzheimer Disease/drug therapy/pathology/genetics/metabolism/psychology ; *Receptors, Metabotropic Glutamate/antagonists & inhibitors/metabolism ; *Dentate Gyrus/drug effects/metabolism ; Mice, Transgenic ; Mice ; Disease Models, Animal ; *Xanthenes/pharmacology/therapeutic use ; *Amino Acids/pharmacology/therapeutic use ; *Cognition/drug effects ; Signal Transduction/drug effects ; Amyloid beta-Protein Precursor/genetics ; Presenilin-1/genetics ; Mice, Inbred C57BL ; },
abstract = {BACKGROUND: Aberrant metabotropic glutamate receptor 2/3 (mGluR2/3) signaling has been implicated in the synaptic and cognitive deficits observed in Alzheimer's disease (AD), yet the underlying regulatory mechanisms remain unclear. This study investigated the therapeutic potential of LY341495, a selective mGluR2/3 antagonist, in APP/PS1 transgenic mice, a widely used AD model.

METHODS: Male APP/PS1 mice were treated with the selective mGluR2/3 antagonist LY341495. Cognitive performance was evaluated using behavioral tests. Hippocampal dentate gyrus (DG) alterations were examined by immunohistochemistry and electrophysiology, including analyses of mGluR2/3 expression, excitatory synaptic activity, adult neurogenesis, calbindin expression, and amyloid-β plaque burden.

RESULTS: APP/PS1 mice exhibited pathological upregulation of mGluR2/3 in the DG, accompanied by altered presynaptic glutamatergic transmission, reduced neurogenesis, decreased calbindin expression, and deficits in recognition and spatial memory. LY341495 treatment attenuated the aberrant mGluR2/3 upregulation, enhanced excitatory synaptic activity, and improved calbindin levels and neurogenesis in the DG. Importantly, these changes were associated with significant reductions in DG amyloid-β plaque burden and marked improvements in cognitive performance.

CONCLUSIONS: This study highlights the novelty of linking mGluR2/3 inhibition to the restoration of calcium-buffering capacity, as reflected by calbindin expression and neurogenesis, processes critical for DG plasticity and resilience. These findings underscore the therapeutic potential of LY341495 as a novel intervention targeting mGluR2/3 signaling in AD.},
}

Animals
Male
*Alzheimer Disease/drug therapy/pathology/genetics/metabolism/psychology
*Receptors, Metabotropic Glutamate/antagonists & inhibitors/metabolism
*Dentate Gyrus/drug effects/metabolism
Mice, Transgenic
Mice
Disease Models, Animal
*Xanthenes/pharmacology/therapeutic use
*Amino Acids/pharmacology/therapeutic use
*Cognition/drug effects
Signal Transduction/drug effects
Amyloid beta-Protein Precursor/genetics
Presenilin-1/genetics
Mice, Inbred C57BL

@article {pmid42138095,
year = {2026},
author = {García-Alba, J and Molanes-López, EM and Zuluaga, P and Vaquero, L and Bajo, R and Hinojosa, JA and Calvillo-Torres, R and Galván-Román, JM and Bell-Fenellos, C and Alcolea, D and Fortea, J and Lagunas, N and Alfayate, E and García, F and Mateo, G and Modenhauer, F and Fernández, A},
title = {The Combined Role of Cognitive, Plasma, Volumetric and EEG Markers Along the Alzheimer's Disease Continuum in Down Syndrome.},
journal = {Journal of intellectual disability research : JIDR},
volume = {},
number = {},
pages = {},
doi = {10.1111/jir.70120},
pmid = {42138095},
issn = {1365-2788},
support = {PID2019-106772RB-I00//Ministerio de Ciencia e Innovación de España/ ; },
abstract = {BACKGROUND: The validation of noninvasive markers for the early detection of Alzheimer's disease (AD) in Down syndrome (DS) is a crucial goal within this population. DS patients are characterised by their overall vulnerability and, particularly, by their high risk of developing AD due to genetic conditions. Considering this background, in this study, we analysed the benefits that a combination of markers might yield in such detection.

METHODS: Sixty-two participants (35 females, 27 males) with DS (age > 45 years) distributed in three groups (asymptomatic [ADS], prodromal [PDS] and dementia [DDS]) underwent clinical and neuropsychological evaluation, together with the assessment of brain volumetry, plasma (neurofilament light and p-tau217), genetic (APOE4) and EEG markers.

RESULTS: Regression analyses demonstrated the key role of p-tau217 among the studied biomarkers. However, the inclusion of p-tau217 failed to produce any significant improvement in the diagnostic model based on verbal memory tasks. This model correctly classified 88.0% of the ADS patients, 75.0% of the PDS patients and 93.8% of the DDS patients. In addition, a strong correlation was observed between p-tau217, delta power, volumetric scores and memory performance.

CONCLUSIONS: Our findings suggested that, even when controlling the effect of elevated p-tau217 levels, the role of memory markers is essential to assist in AD diagnosis within the DS population. The combination of cognitive and plasma markers for the detection of prodromal AD cases in DS appeared to be highly effective. This is especially relevant after the recent FDA's approval of plasma markers such as ptau-217 for the diagnosis of AD.},
}

@article {pmid42138134,
year = {2026},
author = {Dereschuk, KJ and Asay, CC and Espiridion, ED},
title = {Depression and Anxiety in Stroke-Related and Alzheimer Disease-Related Pseudobulbar Affect: A TriNetX Retrospective Cohort Study.},
journal = {Alzheimer disease and associated disorders},
volume = {},
number = {},
pages = {},
doi = {10.1097/WAD.0000000000000727},
pmid = {42138134},
issn = {1546-4156},
abstract = {INTRODUCTION: Pseudobulbar affect (PBA) is a disorder of emotional expression associated with neurological diseases, including stroke and Alzheimer disease. Depression and anxiety frequently co-occur, but whether psychiatric outcomes differ by neurological etiology remains unclear.

OBJECTIVE: To compare the risk and timing of depressive episodes and anxiety disorders in stroke-associated versus Alzheimer disease-associated PBA.

METHODS: We conducted a retrospective cohort study using the TriNetX Global Health Research Network (2020 to 2025). Two mutually exclusive cohorts were identified: PBA with stroke and PBA with Alzheimer disease. Outcomes were depressive episode (ICD-10-CM F32) and anxiety disorder, unspecified (ICD-10-CM F41.9), occurring after PBA diagnosis. One-to-one propensity score matching was performed for age, sex, race, and ethnicity. Kaplan-Meier analyses and Cox proportional hazards models assessed risk and timing.

RESULTS: After matching, 1074 patients per cohort were included for depression analysis. Depression occurred in 68.7% of Alzheimer disease-PBA versus 34.7% of stroke-PBA (absolute risk difference 34.0%, P<0.001; HR=2.52, 95% CI: 2.22-2.86). For anxiety (n=946 per cohort), rates were 48.8% versus 24.9% (absolute risk difference 23.9%, P<0.001; HR=1.98, 95% CI: 1.70-2.30).

CONCLUSION: Alzheimer disease-associated PBA confers a higher and earlier risk of depression and anxiety, supporting enhanced psychiatric screening in neurodegenerative disease.},
}

@article {pmid42138177,
year = {2026},
author = {Rashwan, EH and Elashal, M and Khalifa, SAM and Abd El-Wahed, AA and Wang, D and Hussein, WM and Wang, XP and Cheng, G and Al Naggar, Y and Wang, H and Wang, Z and Nahar, L and Guo, Z and El-Seedi, HR},
title = {Alzheimer's disease and apitherapy: the therapeutic effect of various honeybee products.},
journal = {Neurodegenerative disease management},
volume = {},
number = {},
pages = {1-17},
doi = {10.1080/17582024.2026.2664407},
pmid = {42138177},
issn = {1758-2032},
abstract = {Alzheimer's disease (AD) is one of the devastating diseases that has a high incidence without satisfactory preventive and curative strategies. The multi-targeted interventions become a promising alternative to address their complex pathogenesis. This narrative review searched PubMed/MEDLINE, Scopus, and Web of Science (January 2010-December 2025) to assess the therapeutic potential of honeybee products for AD management. The use of bee-derived compounds demonstrated neuroprotective advantages via known mechanisms. For instance, honey polyphenols reduce tau hyperphosphorylation and amyloid beta (Aβ) deposition through anti-inflammatory and antioxidant actions. Pinocembrin a compound of propolis, plays a role in nuclear factor kappa B (NF-B) suppression of microglial activation via its proteolytic degradation and even enhances synaptic plasticity. Phospholipase A2 and melittin inhibited the acetylcholinesterase activity by raising the level of brain-derived neurotrophic factor (BDNF). Royal jelly has a neurotrophic impact, proven to promote neuroprogenitor cell proliferation, while bee pollen enhances cognitive function via extracellular signal-regulated kinase- cyclic adenosine monophosphate response element-binding protein (ERK-CREB) signaling. Apilarnil can protect and stimulate nerves and possesses anti-inflammatory properties. Despite the notion that apitherapy has a promising role in the management of, challenges including standardization, bioavailability, and clinical validation, warrant more attention prior to the implication in the drug discovery field.},
}

@article {pmid42138182,
year = {2026},
author = {Maruff, P and Albala, B and Harvey, D and Saito, N and Kanoria, S and Aisen, P and Petersen, R and Weiner, MW and Beckett, L and , },
title = {Remote, unsupervised assessment of cognitive impairment and decline in Alzheimer's disease using the Cogstate Brief Battery in ADNI-3.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71357},
doi = {10.1002/alz.71357},
pmid = {42138182},
issn = {1552-5279},
support = {/AG/NIA NIH HHS/United States ; U19 AG024904/NH/NIH HHS/United States ; U01AG024904/NH/NIH HHS/United States ; //Northern California Institute for Research and Education/ ; /EB/NIBIB NIH HHS/United States ; /CAPMC/CIHR/Canada ; //Foundation for the National Institutes of Health/ ; },
mesh = {Humans ; *Alzheimer Disease/diagnosis ; *Cognitive Dysfunction/diagnosis ; Male ; Female ; Aged ; *Neuropsychological Tests ; Longitudinal Studies ; Aged, 80 and over ; Middle Aged ; Amyloid beta-Peptides/metabolism ; Reproducibility of Results ; },
abstract = {INTRODUCTION: Remote neuropsychological testing can monitor brain health in individuals with or at risk of Alzheimer's disease (AD). We evaluated acceptability and validity of the Cogstate Brief Battery (CBB) for remote administration.

METHODS: Non-demented adults from the Alzheimer's Disease Neuroimaging Initiative (ADNI) completed the CBB in-clinic under supervision, then remotely every six months, with annual in-clinic reassessments. Groups included cognitively unimpaired (CU) adults with normal amyloid (CU Aβ-) or elevated amyloid (CU Aβ+), and individuals with mild cognitive impairment with or without amyloid (MCI Aβ+, MCI Aβ-). Performance was compared across contexts and longitudinal changes were examined.

RESULTS: At baseline, MCI Aβ+ participants performed worse than CU Aβ-. CBB performance was similar across contexts, with consistent group differences. Over time, MCI Aβ+ participants showed greater decline on remote CBB measures than CU Aβ- adults.

DISCUSSION: Remote unsupervised CBB assessments are valid, reliable, and sensitive to AD-related cognitive impairment.},
}

Humans
*Alzheimer Disease/diagnosis
*Cognitive Dysfunction/diagnosis
Male
Female
Aged
*Neuropsychological Tests
Longitudinal Studies
Aged, 80 and over
Middle Aged
Amyloid beta-Peptides/metabolism
Reproducibility of Results

@article {pmid42138198,
year = {2026},
author = {Wang, X and Song, L and Wang, J and Xie, Q and Wang, Y and Li, C and Wang, T and Du, Y},
title = {miR‑223‑3p promotes microglial lactylation and M1 polarization via the FBXW7/Notch1/Hes1/SIRT1 axis.},
journal = {International journal of molecular medicine},
volume = {58},
number = {1},
pages = {},
doi = {10.3892/ijmm.2026.5849},
pmid = {42138198},
issn = {1791-244X},
mesh = {*MicroRNAs/genetics/metabolism ; *Sirtuin 1/metabolism/genetics ; *Microglia/metabolism/pathology ; *Receptor, Notch1/metabolism/genetics ; *F-Box-WD Repeat-Containing Protein 7/metabolism/genetics ; Humans ; Signal Transduction ; Animals ; *Transcription Factor HES-1/metabolism/genetics ; Alzheimer Disease/genetics/metabolism/pathology ; Mice ; Male ; Cell Polarity ; Female ; },
abstract = {Neuroinflammation is a hallmark of Alzheimer's disease (AD) and is closely linked to microglial M1 polarization. In the present study, miR‑223‑3p was identified as a critical regulator of microglial metabolic reprogramming. Analyses of Gene Expression Omnibus and AD Neuroimaging Initiative datasets revealed significant upregulation of miR‑223‑3p in the brain, blood, and cerebrospinal fluid of patients with AD. The overexpression of miR‑223‑3p promoted M1 polarization and increased reactive oxygen species (ROS) levels. Transcriptomic, metabolomic and Seahorse analyses revealed increased glycolysis, lactate production and lactylation, whereas inhibition of lactylation reduced M1 polarization and ROS accumulation. Mechanistically, miR‑223‑3p suppressed SIRT1 expression and directly targeted FBXW7, leading to activation of the Notch1/Hes1 pathway and further suppression of SIRT1. In summary, these findings demonstrate that miR‑223‑3p drives microglial lactylation‑mediated M1 polarization through the FBXW7/Notch1/Hes1/SIRT1 signaling axis. The present study provides new insight into the role of lactylation in neuroinflammation and highlights miR‑223‑3p as a potential therapeutic target for AD.},
}

*MicroRNAs/genetics/metabolism
*Sirtuin 1/metabolism/genetics
*Microglia/metabolism/pathology
*Receptor, Notch1/metabolism/genetics
*F-Box-WD Repeat-Containing Protein 7/metabolism/genetics
Humans
Signal Transduction
Animals
*Transcription Factor HES-1/metabolism/genetics
Alzheimer Disease/genetics/metabolism/pathology
Mice
Male
Cell Polarity
Female

@article {pmid42138358,
year = {2026},
author = {Wang, S and Cao, G and Huang, Y},
title = {Empowering classification for multivariate functional data with simultaneous feature selection.},
journal = {Statistical methods in medical research},
volume = {},
number = {},
pages = {9622802261449366},
doi = {10.1177/09622802261449366},
pmid = {42138358},
issn = {1477-0334},
abstract = {The opportunity to utilize multivariate functional data types for conducting classification tasks is emerging with the growing availability of imaging data. Inspired by the extensive data provided by the Alzheimer's Disease Neuroimaging Initiative, we introduce a novel classifier tailored for multivariate functional data. Each observation in this framework may be associated with numerous functional processes, varying in dimensions, such as curves and images. Each predictor is a random element in an infinite-dimensional function space, and the number of functional predictors can potentially be much greater than the sample size. By adopting a sparse deep rectified linear unit network architecture and incorporating the LassoNet algorithm, the proposed functional Bayesian information criterion deep neural network performs feature selection and classification simultaneously, in contrast to existing functional data classifiers. This approach addresses the challenge of complex inter-correlation structures among multiple functional processes without requiring distributional assumptions. A simulation study and a real data application demonstrate its favorable performance.},
}

@article {pmid42138465,
year = {2026},
author = {Gomes, FCA and Matias, I},
title = {Astrocytes in Brain Aging and Neurodegeneration: Cellular Mechanisms and Interventional Strategies.},
journal = {Journal of neurochemistry},
volume = {170},
number = {5},
pages = {e70459},
doi = {10.1111/jnc.70459},
pmid = {42138465},
issn = {1471-4159},
support = {//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; //Ministério da Saúde/ ; //Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro/ ; //Instituto Nacional de Ciência e Tecnologia da Glia/ ; },
mesh = {Humans ; *Astrocytes/pathology/metabolism ; *Aging/pathology/metabolism ; Animals ; *Brain/pathology/metabolism ; *Neurodegenerative Diseases/pathology/metabolism ; Cellular Senescence/physiology ; },
abstract = {Aging is characterized by progressive changes in the physiology of brain cells, which may contribute to cognitive decline, ultimately leading to dementia and impaired quality of life. The increase in senescent cells, including glial cells in the brain, is a general feature of normal aging and has been associated with age-related pathologies. Although recent evidence suggests that astrocytes undergo senescence in these conditions, little is known about the molecular, and cellular mechanisms underlying this event. This mini review, prepared as part of the special issue Neurochemistry in Latin America, provides a focused overview of astrocyte dysfunction in physiological aging and neurodegenerative conditions, integrating findings from the field alongside recent contributions from our group. We discuss how astrocyte aging contributes to cognitive decline and highlight emerging evidence on how targeting astrocytes, both genetically and pharmacologically, may rescue cognitive decline associated with aging and neurodegenerative diseases. Astrocytes produce several molecules that control synapse formation and function, which are decreased in the aging brain and in Alzheimer's disease models. In this context, recent studies indicate that astrocytes undergo significant molecular and functional remodeling during aging. Notably, astrocyte senescence has been associated with loss of lamin-B1, nuclear alterations, impaired synaptogenic and neuritogenic capacity, altered glutamate metabolism, and mitochondrial dysfunction, all of which may contribute to reduced neuronal support and circuit integrity. In parallel, recent advances have shown that astrocyte responses during aging also include diverse reactive states that vary according to brain region, microenvironment, and disease stage. Importantly, senescence-associated and reactive features are not mutually exclusive and may coexist or interact, further contributing to synaptic dysfunction and increased vulnerability to neurodegeneration. Finally, we discuss emerging therapeutic strategies aimed at modulating astrocyte function, including targeting astrocyte-derived synaptogenic factors and metabolic pathways, as potential approaches to mitigate cognitive decline. Together, current evidence indicates that astrocyte dysfunction in aging reflects a complex and dynamic spectrum of cellular states that play a central role in brain vulnerability and represent promising targets for intervention in aging and neurodegenerative diseases.},
}

Humans
*Astrocytes/pathology/metabolism
*Aging/pathology/metabolism
Animals
*Brain/pathology/metabolism
*Neurodegenerative Diseases/pathology/metabolism
Cellular Senescence/physiology

@article {pmid42138642,
year = {2026},
author = {Weitzel, M and Walendzik, A and Giebel, GD and Raszke, P and Wasem, J and Levin, J and Nübling, G and Wagemann, O and Wlasich, E and Pantel, J and Tesky, VA and Schall, A and Ruhnke, T and Dröge, P and Hüer, T},
title = {(Alzheimer's) dementia in adults with Down syndrome in Germany: Administrative prevalence based on a claims data analysis.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261449417},
doi = {10.1177/13872877261449417},
pmid = {42138642},
issn = {1875-8908},
abstract = {BackgroundPeople with Down syndrome (DS) have a significantly increased risk of developing early-onset Alzheimer's disease. For example, a longitudinal study by McCarron et al. (2017) found that 97% of a cohort of 77 DS patients aged 35 years and older developed dementia. Despite this high risk, administrative data on dementia prevalence in this population remain limited.ObjectiveThis study examines whether the diagnosed prevalence is lower than expected based on epidemiological data and explores differences compared to the general population.MethodsA comparative analysis of administrative dementia prevalence (2010-2019) was conducted using claims data for adults with and without DS. Prevalence rates were calculated by age and sex. Chi-square tests were applied to assess significance (p < 0.05), with Cramér's V and Phi as measures of association. Odds ratios were calculated to evaluate group differences.ResultsTotal administrative dementia prevalence was significantly higher in adults with DS (Mean Value (MV) 9.2% ± 1.7% (Standard Deviation (SD))) than those without DS (MV 3.2% ± 0.3% (SD)). Age- and sex-specific analyses also revealed notable differences. For example, in the 56-60 years age group, prevalence was MV 28.7% ± 4.6% (SD) in adults with DS versus MV 0.7% ± 0.1% (SD) in those without DS.ConclusionsAlthough administrative dementia prevalence is higher among adults with DS than those without DS, observed rates appear lower than expected based on existing epidemiological data. This suggests a potential underdiagnosis of dementia in the DS population in Germany.},
}

@article {pmid42139078,
year = {2026},
author = {Huang, YS and Wu, SD and Chen, HC and Lu, KC and Ka, SM and Wu, CC},
title = {Melatonin Receptor Signaling in Human Pathologies: From Molecular Mechanisms to Therapeutic Targets.},
journal = {Function (Oxford, England)},
volume = {},
number = {},
pages = {},
doi = {10.1152/function.011.2026},
pmid = {42139078},
issn = {2633-8823},
abstract = {The Melatonin Receptor 1A (MTNR1A), a highly conserved G protein-coupled receptor (GPCR), mediates crucial physiological functions. Its structure features an N-terminus responsible for melatonin binding and a C-terminus that initiates downstream signaling pathways to modulate target gene expression. Given MTNR1A's ability to form homodimers or heterodimers with other GPCRs, its expression levels are critical for the precise control of cellular signaling. This review article provides a comprehensive update on MTNR1A, highlighting recent developments concerning its expression distribution, gene regulation, protein motifs, and mediated signaling pathways. We also discuss the clinical relevance of single nucleotide polymorphisms (SNPs) associated with the MTNR1A receptor and the range of diseases linked to its dysfunction. Current understanding and future perspectives regarding the gene regulation and stimulation of MTNR1A expression are critically addressed. Furthermore, we investigate the role of MTNR1A genetic variants in idiopathic osteoporosis and the association between decreased MTNR1A expression and membranous nephropathy. The systemic involvement of MTNR1A downregulation in cancer, fetal growth restriction, type 2 diabetes, and Parkinson's and Alzheimer's diseases is further underlined by its established biological functions. In conclusion, targeting MTNR1A-related downregulation and developing specific agonists or modulators offers a promising avenue for advancement in therapeutic medicine.},
}

@article {pmid42139159,
year = {2026},
author = {Carvalho, MS and Barssotti, L and Santos, LMBD and Rosa, LRO and Gomes-Marcondes, MCC and Carneiro, EM and Barbosa, HCL and Zangerolamo, L},
title = {Tauroursodeoxycholic acid (TUDCA) ameliorates age-related skeletal muscle loss.},
journal = {The Journal of physiology},
volume = {},
number = {},
pages = {},
doi = {10.1113/JP290683},
pmid = {42139159},
issn = {1469-7793},
support = {2021/13917-6//Fundação de Amparo à Pesquisa do Estado de São Paulo/ ; },
abstract = {Ageing leads to changes in body composition, including increased adiposity and reduced skeletal muscle mass and force. The alterations in ageing skeletal muscle result from impaired proteostasis driven by factors such as chronic inflammation, hormonal changes and reduced nutrient absorption. Those age-related changes in body composition and skeletal muscle compromise mobility and increase the risk of falls, fractures and metabolic disorders. Tauroursodeoxycholic acid (TUDCA), a bile acid with known benefits in chronic diseases, has been shown by our group to improve cognition and metabolic homeostasis in ageing and Alzheimer's disease mouse models. Interestingly, in previous studies, TUDCA treatment was also associated with increased skeletal muscle mass in ageing mice, leading us to hypothesize that TUDCA could target skeletal muscle to reduce age-related muscle loss. To explore this, we treated 18-month-old C57BL/6 mice with TUDCA or vehicle for 20 days, using 3-month-old mice as a young control group. We demonstrate that TUDCA treatment decreases body weight while increasing skeletal muscle mass, restores muscle fibre size and preserves functional integrity. Additionally, TUDCA enhances skeletal muscle insulin sensitivity through increased AKT activation and reduces tissue inflammation. Such improvements collectively support the restoration of skeletal muscle proteostasis, as indicated by increased protein synthesis and phosphorylation of key anabolic signalling pathways, including ribosomal protein S6 kinase beta-1 (P70S6K) and eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1). These findings contribute to a better understanding of TUDCA's actions on skeletal muscles of ageing mice and highlight its role as a promising strategy against age-related muscle loss. KEY POINTS: Tauroursodeoxycholic acid (TUDCA) treatment attenuates skeletal muscle loss in ageing mice. TUDCA improves skeletal muscle insulin sensitivity and restores AKT signalling. TUDCA exerts an anti-inflammatory effect in skeletal muscle of ageing mice. TUDCA emerges as a potential therapy for age-related skeletal muscle loss.},
}

@article {pmid42139283,
year = {2026},
author = {Ge, L and Guo, Y and Xu, X and Xu, J and Hu, M},
title = {Association between hemoglobin glycation index and cognitive function: Evidence in the elderly.},
journal = {PloS one},
volume = {21},
number = {5},
pages = {e0338613},
doi = {10.1371/journal.pone.0338613},
pmid = {42139283},
issn = {1932-6203},
mesh = {Humans ; Male ; Female ; Aged ; *Cognition/physiology ; Cross-Sectional Studies ; *Glycated Hemoglobin/metabolism ; *Cognitive Dysfunction/blood ; Nutrition Surveys ; Middle Aged ; Aged, 80 and over ; },
abstract = {BACKGROUND: Cognitive impairment has been a major public health challenge. This study aims to estimate the association of hemoglobin glycation index (HGI) with cognitive function in U.S. older adults.

METHODS: In this cross-sectional study, data from the National Health and Nutrition Examination Survey (NHANES, 2011-2014) was obtained. Cognitive function was assessed based on the three scales [Digit Symbol Substitution Test (DSST), Animal Fluency Test (AFT), and Consortium to Establish a Registry for Alzheimer's disease (CERAD)], along with a composite Z-score derived from the sum of the Z-scores of these three assessments. We used weighted univariate and multivariate linear regression to estimate the unstandardized β coefficient and 95% confidence interval (CI) of the association between HGI levels and cognitive function.

RESULTS: Our study comprised a total of 1,406 subjects. As compared with the second tertile of HGI, the lowest tertile had a lower Z-score [β = -0.13 (95% CI: -0.25, -0.01)] and CERAD score [β = -1.07 (95% CI: -1.93, -0.21)] in the fully adjusted model. For the highest tertiles of HGI (vs. second tertile), Z-score and DSST decreased by 0.16 (95%CI: -0.31, -0.01) and 3.09 (95%CI: -6.00, -0.18), respectively. Females in the lowest HGI tertile (vs. second HGI tertile) exhibited a decline in cognitive function scores (Z-score, CERAD, AFT; all P < 0.05), while males in the highest tertile of HGI (vs. second HGI tertile) showed decreased cognitive function scores (Z-score, DSST; all P < 0.05). In addition, Z-score and CERAD scores also decreased (all P < 0.05) in the highest HGI tertile (vs. second HGI tertile) among non-users of antidiabetic drugs.

CONCLUSION: Both lower and higher HGI levels are associated with cognitive decline. Lower HGI is related to poorer learning and memory, while higher HGI is associated with executive function impairment. Future longitudinal studies are need to verify whether changes in HGI levels can be used as an early warning indicator for cognitive decline.},
}

Humans
Male
Female
Aged
*Cognition/physiology
Cross-Sectional Studies
*Glycated Hemoglobin/metabolism
*Cognitive Dysfunction/blood
Nutrition Surveys
Middle Aged
Aged, 80 and over

@article {pmid42139290,
year = {2026},
author = {Jhaldiyal, A and Kumari, M and Guttman, LC and Tripathi, T and Khan, MR and Wang, J and Biswas, D and Pasupuleti, A and Aggarwal, A and Pandya, S and Chou, SC and Panicker, N and Monghekar, A and Albert, M and Bekris, LM and Leverenz, JB and Kam, TI and Dawson, TM and Dawson, VL},
title = {PARP1 deficiency mitigates amyloid pathology, neurodegeneration, and cognitive decline in a familial Alzheimer's disease model.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {123},
number = {20},
pages = {e2525028123},
doi = {10.1073/pnas.2525028123},
pmid = {42139290},
issn = {1091-6490},
support = {NS067525//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; AG085688//HHS | NIH | National Institute on Aging (NIA)/ ; U19AG033655//HHS | NIH | National Institute on Aging (NIA)/ ; n/a//Edward N. and Della L. Thome Memorial Foundation (Thome Memorial Foundation)/ ; Zenith Award//Alzheimer's Association (AA)/ ; },
mesh = {*Alzheimer Disease/pathology/genetics/metabolism ; Animals ; *Poly (ADP-Ribose) Polymerase-1/genetics/deficiency/metabolism/cerebrospinal fluid ; *Cognitive Dysfunction/pathology/genetics/metabolism ; Humans ; Mice ; Amyloid beta-Peptides/metabolism ; Disease Models, Animal ; Mice, Knockout ; Male ; Female ; Amyloid Precursor Protein Secretases/metabolism ; Plaque, Amyloid/pathology ; DNA Damage ; Aspartic Acid Endopeptidases/metabolism ; Mice, Transgenic ; },
abstract = {Poly(ADP-ribose) (PAR) polymerase 1 (PARP1) has been implicated in DNA damage responses and neuroinflammation in Alzheimer's disease (AD), yet its role in amyloid-beta (Aβ) pathology remains unclear. Here, we show that PARP1 activation drives Aβ pathology and neurodegeneration. Using a sensitive enzyme-linked immunosorbent assay, we observed significantly elevated PAR levels in the cerebrospinal fluid (CSF) of patients with mild cognitive impairment (MCI) and AD compared to controls. In vitro, oligomeric Aβ1-42 activated PARP1 and induced DNA damage, while genetic or pharmacological inhibition of PARP1 conferred neuroprotection. In vivo, PARP1 knockout in the 5XFAD mouse model of amyloidosis led to reduced amyloid plaque burden, preserved synaptic and neuronal integrity, attenuated glial activation and neuroinflammation, and rescued cognitive deficits. Mechanistically, PARP1 deficiency decreased amyloid precursor protein and BACE1 levels, altered γ-secretase complex composition, and enhanced Aβ degradation via neprilysin. These findings position PARP1 as a critical mediator of Aβ toxicity and neurodegeneration, suggesting its inhibition as a promising therapeutic strategy for AD.},
}

*Alzheimer Disease/pathology/genetics/metabolism
Animals
*Poly (ADP-Ribose) Polymerase-1/genetics/deficiency/metabolism/cerebrospinal fluid
*Cognitive Dysfunction/pathology/genetics/metabolism
Humans
Mice
Amyloid beta-Peptides/metabolism
Disease Models, Animal
Mice, Knockout
Male
Female
Amyloid Precursor Protein Secretases/metabolism
Plaque, Amyloid/pathology
DNA Damage
Aspartic Acid Endopeptidases/metabolism
Mice, Transgenic

@article {pmid42139611,
year = {2026},
author = {Rhabneh, L and Ababneh, R and Al-Muhtaseb, A and Aloqaily, M},
title = {Effects of angiotensin converting enzyme inhibitors versus angiotensin receptor blockers on cognitive decline: A retrospective real-world database study.},
journal = {Wiadomosci lekarskie (Warsaw, Poland : 1960)},
volume = {79},
number = {4},
pages = {736-744},
doi = {10.36740/WLek/216191},
pmid = {42139611},
issn = {0043-5147},
mesh = {Humans ; *Angiotensin-Converting Enzyme Inhibitors/therapeutic use/adverse effects ; *Angiotensin Receptor Antagonists/therapeutic use/adverse effects ; Retrospective Studies ; Male ; Female ; *Cognitive Dysfunction/chemically induced/epidemiology ; Aged ; Middle Aged ; *Heart Failure/drug therapy/complications ; Aged, 80 and over ; Dementia/epidemiology ; },
abstract = {OBJECTIVE: Aim: To compare 5-year cognitive outcomes in patients with HFrEF who receive angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs).

PATIENTS AND METHODS: Materials and Methods: Retrospective cohort study of: 1) 135,873 adults with HFrEF (International Classification of Diseases-10th Revision-Clinical Modification [ICD-10-CM] codes: I50.2 or I50.4) started on ACEI between Aug 1, 2019 and Aug 1, 2024; and 2) 135,873 propensity matched patients receiving ARBs during that time. Data were obtained from the TriNetX Research Network, encompassing 80 health care organizations in the United States. The primary endpoint was the composite of cognitive decline (ICD-10-CM: R41.8), dementia (ICD-10-CM: F01-F03), and Alzheimer's disease (ICD-10- CM: G30).

RESULTS: Results: At 5 years,17,679 patients on ACEI met the primary endpoint vs 16,345 patients on ARBs (5-year incidence: 30.71% vs 28.54%; HR: 1.153; 95% CI: 129-1.178; P < 0.001), with consistently higher rates of cognitive decline (24.94% vs 22.81%; HR: 1.146; 95% CI: 1.119-1.174; P < 0.001), dementia (15.63% vs 13.71%; HR:1.204; 95% CI: 1.168-1.241; P < 0.001), and Alzheimer's disease (4.15% vs 3.51%; HR: 1.202; 95% CI: 1.131-1.277; P < 0.001) in the ACEI cohort.

CONCLUSION: Conclusions: ACEI was associated with higher 5-year rates of neurocognitive disorders when compared to ARBs in patients with HFrEF.},
}

Humans
*Angiotensin-Converting Enzyme Inhibitors/therapeutic use/adverse effects
*Angiotensin Receptor Antagonists/therapeutic use/adverse effects
Retrospective Studies
Male
Female
*Cognitive Dysfunction/chemically induced/epidemiology
Aged
Middle Aged
*Heart Failure/drug therapy/complications
Aged, 80 and over
Dementia/epidemiology

@article {pmid42139766,
year = {2026},
author = {Liu, Y and Huang, Y and Wang, Y and Mao, M and Huang, M},
title = {PTBP1: A master regulator of neural development and transdifferentiation-promise and pitfalls.},
journal = {Biochemical and biophysical research communications},
volume = {823},
number = {},
pages = {153948},
doi = {10.1016/j.bbrc.2026.153948},
pmid = {42139766},
issn = {1090-2104},
abstract = {The polypyrimidine tract-binding protein 1 (PTBP1), a pivotal RNA-binding protein and splicing regulator, is emerging as a master orchestrator of neuronal fate determination, neurodevelopment, and neural function through its central role in alternative splicing. We synthesize current knowledge on PTBP1's multifaceted roles in orchestrating neural tube formation, neuronal migration, and synaptic circuit assembly through precise control of alternative splicing programs. We critically examine the rapidly evolving field of PTBP1-mediated cellular reprogramming, analyzing both supportive evidence and significant controversies surrounding glia-to-neuron conversion across species. We further integrate molecular mechanisms with pathophysiological relevance, highlighting how PTBP1 dysregulation contributes to neurodevelopmental disorders and neurodegenerative conditions including Alzheimer's and Parkinson's diseases. We evaluate emerging therapeutic strategies targeting PTBP1, assessing their mechanistic foundations, technical limitations, and translational potential. Crucially, we highlight key methodological considerations and species-specific regulatory differences that must be addressed to realize PTBP1's therapeutic promise. This synthesis provides a critical framework for future research directions at the intersection of RNA biology, neural development, and regenerative neuroscience.},
}

@article {pmid42139770,
year = {2026},
author = {Bettcher, BM and Ren, S and Wang, Y and Carlson, NE and Lippitt, WL and McConnell, BV and Wilson, EN and Shapiro, ALB and Coughlan, C and Carlisle, TC and Unger, JR and Cook, GG and Bengtson, K and Gorla, L and Ueberheide, BM and Kanshin, E and Potter, H and Schulz, L and Frazer-Abel, A and Pelak, VS},
title = {Relation of blood-based inflammation conditional networks to key immune health status and Alzheimer's biomarkers in aging adults.},
journal = {Neurobiology of aging},
volume = {166},
number = {},
pages = {14-28},
doi = {10.1016/j.neurobiolaging.2026.05.001},
pmid = {42139770},
issn = {1558-1497},
abstract = {Blood inflammatory marker studies in aging and Alzheimer's disease (AD) research have faced numerous interpretative and methodological challenges that have hindered the field's understanding of the relationship between immune network regulation/dysregulation and aging health factors. We examined how blood inflammation markers directly relate to each other in typical aging, cognitively unimpaired adults using a conditional network analytic modeling approach. We further evaluated how blood inflammation networks relate to key aging risk factors by decomposing the networks into eigenvectors with associated hub proteins and then evaluated the associations of the resulting eigenproteins with demographic information, core biomarkers of AD pathobiology in CSF and blood, and immune health history. Networks of blood inflammation markers showed both divergent and convergent relationships with outcomes, including strong associations between a CXCL5-driven blood inflammation network and age, sex, and CSF Aβ42/Aβ40, and an IL-6- and FGF-21-driven network and sex, CSF Aβ42/Aβ40, and Qalb (CSF-serum albumin ratio). An IFN-gamma- and CXCL9-driven network was associated with both age and CSF Aβ42/Aβ40, whereas blood inflammation networks with hub proteins of CXCL11/CXCL9 and CCL19/CCL4, respectively, were associated solely with sex. Finally, an MCP-3-, MCP-4-, and CXCL6-driven network was associated with cumulative surgical procedure exposures. Despite associations between CSF Aβ42/Aβ40 and multiple networks, plasma Aβ42/Aβ40 was not significantly associated with any blood inflammatory network. Our findings highlight the importance and the challenges of inferring immune pathophysiology from blood-based markers; mirroring the complex pleiotropic biology of inflammation, blood inflammatory markers show associations with multiple demographic and salient health factors in aging adults.},
}

@article {pmid42139977,
year = {2026},
author = {Soni, U and Pujari, R},
title = {Gentisic acid confers multimodal neuroprotection in experimental Alzheimer's disease by targeting oxidative stress, neuroinflammation, and protein aggregation.},
journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology},
volume = {156},
number = {},
pages = {158276},
doi = {10.1016/j.phymed.2026.158276},
pmid = {42139977},
issn = {1618-095X},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline associated with oxidative stress, neuroinflammation, cholinergic dysfunction, and accumulation of amyloid-β (Aβ) and hyperphosphorylated tau (p-tau). Given the multifactorial nature of AD, phytochemicals with multi-target pharmacological properties are of growing therapeutic interest. Gentisic acid (GA; 2,5-dihydroxybenzoic acid) possesses established antioxidant and anti-inflammatory activities; however, its potential relevance in AD has not been comprehensively evaluated.

PURPOSE: This study investigated the neuroprotective potential of gentisic acid against Alzheimer-like pathology using integrated in vitro and in vivo experimental models.

STUDY DESIGN: A preclinical experimental study combining cell-based assays and an aluminium chloride (AlCl3) and D-galactose (D-Gal)-induced rat model of AD-like neurodegeneration was conducted.

METHODS: Blood-brain barrier (BBB) permeability of GA was assessed using a PAMPA-BBB assay. Neuroprotective effects were examined in AlCl₃-exposed SH-SY5Y cells. In vivo, Wistar rats received AlCl₃ and D-Gal to induce cognitive and biochemical alterations, followed by oral GA treatment. Behavioral paradigms such as open field, Morris water maze, novel object recognition, elevated plus maze and Y-maze tests were employed to assess spatial learning, recognition memory, and anxiety-like behavior. Oxidative stress markers, antioxidant enzymes, acetylcholinesterase activity, monoaminergic neurotransmitters, brain-derived neurotrophic factor (BDNF), pro-inflammatory cytokines, amyloid beta, and hyperphosphorylated tau protein levels were quantified. Histopathological evaluation of hippocampal and cortical regions was performed.

RESULTS: GA demonstrated adequate BBB permeability and concentration-dependent protection against AlCl₃-induced cytotoxicity in SH-SY5Y cells. In the rat model, GA (10, 30, and 100 mg/kg, per oral (p.o.) improved cognitive performance and attenuated anxiety-like behavior. Treatment with GA reduced lipid peroxidation (malondialdehyde), restored antioxidant defenses (superoxide dismutase, catalase and reduced glutathione), inhibited acetylcholinesterase activity, and normalized monoaminergic neurotransmitters (serotonin and dopamine). GA further elevated BDNF levels and suppressed pro-inflammatory cytokines (tumor necrosis factor-alpha and interleukin-1 beta). Notably, GA decreased cerebral Aβ and p-tau accumulation and preserved hippocampal and cortical architecture.

CONCLUSION: Gentisic acid exerts multi-modal neuroprotective effects, including antioxidant, anti-inflammatory, anti-cholinesterase, and anti-amyloidogenic actions, in experimental models of AD. These findings support its potential as a phytochemical candidate for further development in the prevention or adjunctive management of AD.},
}

@article {pmid42140009,
year = {2026},
author = {Wang, X and Liu, Y and Fu, J and Li, Y and Zhao, M and Tian, Q},
title = {Corrigendum to "Systematic post-translational modification genome wide identifies therapeutic targets for Alzheimer's disease: evidence from multi-cohort analysis" [J Prev Alzheimer Dis, 13 (2026) 100422].},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {6},
pages = {100593},
doi = {10.1016/j.tjpad.2026.100593},
pmid = {42140009},
issn = {2426-0266},
}

@article {pmid42140047,
year = {2026},
author = {Remelli, F and Grande, G and Dekhtyar, S and Laukka, EJ and Trevisan, C and Volpato, S and Fratiglioni, L and Triolo, F},
title = {Neuropsychiatric symptoms and dementia development: a 15-year population-based study.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {7},
pages = {100596},
doi = {10.1016/j.tjpad.2026.100596},
pmid = {42140047},
issn = {2426-0266},
abstract = {BACKGROUND: Mild Behavioral Impairment (MBI) has been proposed to detect neuropsychiatric symptoms (NPS) associated with dementia development, but evidence from population-based settings is limited.

OBJECTIVES: To (i) investigate the association between NPS in late life and the onset of dementia over 15 years in community-dwelling older adults, and (ii) test the interplay of NPS and Cognitive Impairment, No Dementia (CIND) in dementia development.

METHODS: 2597 dementia-free individuals aged 60+ from a longitudinal population-based cohort underwent cognitive assessments over 15 years. Thirty clinically-assessed NPS were mapped into five domains and, within each domain, a z-score was computed from the sum of the NPS's points. MBI was identified when the z-score was above 1.5 standard deviations (SDs) in at least one of 5 neuropsychiatric domains. Based on a cognitive battery, CIND was defined as scoring ≥1.5 SDs below age-specific means in at least one cognitive domain. Dementia was diagnosed by DSM-IV criteria following standardized procedures.

RESULTS: MBI, present in 16.1% of the sample, was associated with a higher hazard of incident dementia over 15 years (multi-adjusted hazard ratio [HR] 1.68, 95% confidence interval [CI] 1.31-2.17). Decreased motivation and social inappropriateness were the domains associated with incident dementia (HR 2.23, 95%CI 1.59-3.14 and HR 3.29, 95%CI 1.83-5.94, respectively). Compared to those with neither, individuals with either MBI (HR 1.37, 95%CI 1.00-1.90) or CIND (HR 2.22, 95%CI 1.73-2.84) had increased dementia incidence, especially when co-occurring (HR 4.41, 95%CI 3.04-6.39).

CONCLUSIONS: Late life NPS, especially with co-occurring cognitive impairment, was associated with a higher dementia incidence.},
}

@article {pmid42140183,
year = {2026},
author = {Shostak, D and Liang, Z and Huang, Y},
title = {Cell-type-specific APOE4 cascade across the Alzheimer's disease continuum.},
journal = {Neuron},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuron.2026.04.024},
pmid = {42140183},
issn = {1097-4199},
abstract = {Apolipoprotein E4 (APOE4) is the leading genetic risk factor and an increasingly recognized causal contributor to Alzheimer's disease (AD). AD progresses along a temporal, pathological, and clinical continuum spanning preclinical, prodromal, and dementia stages. Across this continuum, APOE4 exerts detrimental effects at distinct times and in different cell types, underscoring the need for a model defining not only how but also when and in which cells these effects occur. In this review, we synthesize current findings and propose a temporal model linking cell-type-specific APOE4 expression to AD progression. In this model, age-associated stress upregulates neuronal APOE4 expression, leading to early neuronal deficits characteristic of preclinical AD. Neuronal APOE4-induced damage subsequently triggers a harmful glial response that, alongside glial APOE4, amplifies neurodegeneration and accelerates the onset of prodromal and dementia AD. This model highlights the temporal and cellular dynamics of APOE4 effects and suggests stage- and cell-type-specific therapeutics targeting APOE4-driven mechanisms across the AD continuum.},
}

@article {pmid42140197,
year = {2026},
author = {Ojeda-Juarez, D and Funk, G and McClatchy, DB and Richards, E and Rajic, AJ and Soldau, K and Geschwind, MD and Chen, X and Yates, JR and Gonias, SL and Sigurdson, CJ},
title = {PrP[C]-facilitated cell signaling activates phospholipase Cɣ1 and triggers an Arc/Arg3.1 response in mouse and iPSC-derived human neurons.},
journal = {Stem cell reports},
volume = {},
number = {},
pages = {102924},
doi = {10.1016/j.stemcr.2026.102924},
pmid = {42140197},
issn = {2213-6711},
abstract = {Synapse loss is an early feature of prion disease, yet the underlying drivers are poorly understood. We recently found evidence of neuronal hyperactivity and synaptic loss in prion-infected mice. Herein, we identified increased Arc/Arg3.1 in patients with prion disease, suggesting heightened neuronal activity also occurs in the human prion-affected brain. To determine the signaling events initiated by prion aggregates (PrP[Sc]), we developed a disease model in which human iPSC-derived excitatory neurons are stimulated with a PrP[Sc]-mimetic antibody, POM1, that binds cellular prion protein (PrP[C]). Within 2 h of POM1 exposure, we detected an Arc/Arg3.1 response together with transcriptomic changes previously reported in prion-infected mice. We identified altered phosphorylation of PLC-γ1, ERK1/2, and EGFR as additional PrP[C]-triggered cell signaling events. These results suggest that PrP[C] ligands, including PrP[Sc], trigger rapid signaling events linked to neuronal hyperactivity in human neurons, and indicate PLC-γ1 as a potential therapeutic target.},
}

@article {pmid42140357,
year = {2026},
author = {Recchia, D and Raymond, M and Berticat, C and Artero, S},
title = {Interrelationships between refined carbohydrates, periodontal diseases, and cognitive decline: a narrative review.},
journal = {Advances in nutrition (Bethesda, Md.)},
volume = {},
number = {},
pages = {100657},
doi = {10.1016/j.advnut.2026.100657},
pmid = {42140357},
issn = {2156-5376},
abstract = {Accumulating studies suggest that carbohydrate quality influences both oral and cognitive health. Diets rich in refined carbohydrates promote insulin resistance, oxidative stress, inflammation, and disrupt oral microbiota. These changes contribute to periodontal disease and neurodegeneration. Periodontitis is associated with cognitive decline via inflammation, bacterial translocation, and blood-brain barrier disruption. Although less extensively studied, reverse pathways may also operate. Cognitive decline may alter dietary behavior through neurohormonal changes, increasing preference for sweeter foods, and promote periodontal disease by impairing motor functions essential for oral hygiene. Periodontitis may further shift dietary choices toward softer, more processed foods trough tooth loss, oral pain, and chewing difficulties. These interactions may reinforce a cycle linking diet, oral health, and cognition. To date, no study has comprehensively examined the interrelationships between carbohydrate quality, periodontal disease, and cognitive decline within a unified framework. This narrative review aimed to address this gap by synthesizing findings on each bidirectional dyadic association, examining terminology and methodological approaches, and discussing shared mechanisms and biological pathways. Through this work, insulin resistance, chronic inflammation, oxidative stress, and microbiota dysbiosis were identified as shared integrative pathways, and key research gaps were highlighted to guide future research and inform prevention strategies for aging populations.},
}

@article {pmid42140366,
year = {2026},
author = {Mazor, M and Seghezzi, S and Manohar, S},
title = {Remembering what you did: episodic memory for self-actions.},
journal = {Neuroscience and biobehavioral reviews},
volume = {},
number = {},
pages = {106725},
doi = {10.1016/j.neubiorev.2026.106725},
pmid = {42140366},
issn = {1873-7528},
abstract = {Episodic memory stores not only passively experienced events, but also one's own past actions and decisions. Despite their critical role for learning about the world and about the self, little is known about how such memories for self-actions are stored and retrieved. We argue that memory for self-actions plays three key roles in the cognitive economy: it scaffolds memory for environmental events, enables learning from delayed feedback, and allows individuals to learn about their own abilities and preferences. A synthesis of evidence from behaviour and psychopathology is consistent with an organizing framework: memory for self-actions draws on a generative self-model - a simplified schema of one's own cognition. This framework helps explain why memory for habitual actions is particularly vulnerable to memory distortions, manifesting as confabulations in amnesic patients and obsessive doubt in individuals with OCD. We further propose that an accurate self-model may partially compensate for hippocampal memory loss in Alzheimer's disease. We suggest that much can be learned from studying the cognitive and neural mechanisms underlying the ability to remember one's own decisions and actions, and identify critical questions for advancing our understanding of this important but neglected aspect of human memory.},
}

@article {pmid42140379,
year = {2026},
author = {Raza, SA and de Almeida, PP and Farid, I and Macha, N and Knoll, M and Roser, P and Scherbaum, N and Herring, A and Keyvani, K},
title = {Kallikrein-8 contributes to kallikrein-kinin system dysregulation in Alzheimer's disease.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115834},
doi = {10.1016/j.expneurol.2026.115834},
pmid = {42140379},
issn = {1090-2430},
abstract = {Neuroinflammation is a central feature of Alzheimer's disease (AD), yet the mechanisms linking inflammatory protease systems to disease pathology remain incompletely understood. The kallikrein-kinin system (KKS), a major source of bradykinin, has been associated with AD mainly at the peripheral level, but its regulation within the human brain remains largely unexplored. Here, we investigated KKS activity in human AD tissue and a transgenic mouse model, with a particular focus on serine protease kallikrein-8 (KLK8). We observed that both bradykinin and bradykinin B1 receptor levels are increased in the hippocampus of AD patients, with a pronounced upregulation in females. In the TgCRND8 mouse model of AD, hippocampal bradykinin levels were also elevated, while heterozygous KLK8 knockout ameliorated this pathological effect, supporting a functional contribution of KLK8. Analysis of kallikrein expression revealed a selective increase in KLK8 in the AD hippocampus, whereas the canonical kinin-generating proteases, tissue kallikrein (KLK1) and plasma kallikrein (KLKB1), remained unchanged. In vitro cleavage assays demonstrated that recombinant human KLK8 can process both low- and high-molecular-weight kininogens, and functional assays confirmed that KLK8 increases bradykinin levels in human hippocampal tissue and plasma, an effect that was blocked by a KLK8-neutralizing antibody. Together, these findings identify KLK8 as a previously unrecognized modulator of the KKS in the AD brain. Our data support a model in which elevated KLK8 contributes to dysregulated bradykinin production and B1R signaling, providing a mechanistic link between KLK8 activity and neuroinflammation in Alzheimer's disease.},
}

@article {pmid42140442,
year = {2026},
author = {Puthiyattil, N and Varughese, D and Mani, BM and Babu, RS and Nair, KS and George, RL and Ramitha, PA and Dogra, N and Mathew, M and Varghese, MT and Hof, PR and Mohanakumar, KP and Rajamma, U},
title = {Extracellular Vesicles as Paradigm Shifters: Transformative Roles in Diagnosis and Therapy for Brain Disorders.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103178},
doi = {10.1016/j.arr.2026.103178},
pmid = {42140442},
issn = {1872-9649},
abstract = {Extracellular Vesicles (EVs), the nano-sized extracellular membrane-bound vesicles, facilitate cell-to-cell communication by transporting bioactive molecules like proteins, lipids, and nucleic acids. Their unique cargo, determined by the cell of origin, makes them valuable tools for studying disease pathogenesis and potential drug delivery systems. Research suggests that EVs play a role in the pathogenesis of various diseases, including neurodegenerative and neurodevelopmental disorders. They have been implicated in diseases like Parkinson's disease (PD), Alzheimer's disease (AD), autism spectrum disorder (ASD) and Huntington's disease (HD), where their presence and cargo can contribute to disease progression. EVs can cross physiological barriers, like blood-brain barrier (BBB), and placental barrier, and this unique property makes them promising candidates for therapeutic interventions aimed at neurological disorders. Current investigations explore the utility of EVs as potential drug delivery systems for neurological conditions, with their biocompatibility enhancing their suitability for delivering therapeutic cargo directly to brain cells. EVs have been observed to accumulate in the brains of animal models of neurodevelopmental and neurodegenerative diseases, thus offering valuable insights into underlying pathological mechanisms. The review highlights the growing interest in EVs and brain diseases, focusing on their roles in PD, AD, ASD, and HD, as well as their potential therapeutic applications. Furthermore, the implications of EVs for biomarker discovery and innovative drug delivery strategies in neurodevelopmental and neurodegenerative disorders are discussed, suggesting that they may pave the way for future therapeutic interventions.},
}

@article {pmid42140516,
year = {2026},
author = {Wasim, R},
title = {Nitric Oxide Signaling in Alzheimer's Disease: A Double-Edged Sword.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {178986},
doi = {10.1016/j.ejphar.2026.178986},
pmid = {42140516},
issn = {1879-0712},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory impairment, and behavioral changes, primarily affecting the elderly population. Despite extensive research, the exact pathogenesis of AD remains elusive, with proposed mechanisms involving amyloid-β accumulation, tau protein hyperphosphorylation, oxidative stress, neuroinflammation, and neuronal apoptosis. Nitric oxide (NO), a gaseous signaling molecule synthesized by nitric oxide synthases (NOS), plays dual roles in AD pathophysiology-acting as both a neuroprotective and neurotoxic agent depending on its concentration and cellular context. The NO-cGMP signaling pathway is integral to synaptic plasticity, long-term potentiation, and neurogenesis, processes essential for memory and learning. Conversely, excessive NO generation via inducible NOS contributes to neuroinflammation, oxidative and nitrosative stress, and neuronal damage. NO also modulates cerebral blood flow, neuroplasticity, and myelination, influencing AD progression. Current pharmacological management focuses on symptomatic relief through cholinesterase inhibitors and NMDA receptor antagonists, while emerging NO-based therapies and PDE-5 inhibitors show potential neuroprotective benefits. Additionally, anti-inflammatory agents and herbal compounds targeting NO-mediated pathways, exhibit promising neuroprotective properties. A deeper understanding of NO's dualistic role may provide novel therapeutic strategies for mitigating AD progression and enhancing cognitive resilience.},
}

@article {pmid42140519,
year = {2026},
author = {Edwards, N and Sakata, S and McConnell, G and Bushell, TJ},
title = {Astrocytic reactivity and amyloid load are reduced in a sex-dependent manner in a mouse model of amyloid pathology following protease-activated receptor 2 activation.},
journal = {Neuropharmacology},
volume = {},
number = {},
pages = {111010},
doi = {10.1016/j.neuropharm.2026.111010},
pmid = {42140519},
issn = {1873-7064},
abstract = {Alzheimer's disease is a leading cause of death, but current treatments are limited in their use and primarily offer symptomatic relief. Recent developments targeting amyloid plaques have given some hope, but their true value remains equivocal. Hence, alternative therapeutic targets are required with neuroinflammation, particularly glial cells, been a recent area of interest. Indeed, there has been intense research into the role of reactive astrocytes in neurodegenerative diseases with several studies indicating that reducing their reactivity is beneficial in animal models of disease. Building on our previous work using the blood brain barrier permeable protease-activated receptor 2 (PAR2) activator, AC264613 (AC), we investigate the consequence of AC administration on mouse behaviour, astrocytic reactivity and amyloid plaque load in the 5xFAD mouse model of amyloid pathology. Our data reveal similar behavioural changes in both 5xFAD[-] and 5xFAD[+] mice that are sex-independent. However, AC reduces both GFAP and C3 expression levels, markers for astrocyte reactivity, in female but not male 5xFAD[+] mice. In contrast, AC did not affect Iba1 and CD68 expression levels, markers for microglial activation and function, in mice of either sex. Significantly, AC reduced amyloid plaque load only in female 5xFAD[+] mice similar to that seen with astrocyte reactivity. These data reveal that PAR2 activation can reduce astrocyte reactivity and amyloid plaque load in 5xFAD[+] mice. Our findings add further weight to the proposal that targeting astrocyte reactivity to reduce neuroinflammation in neurodegenerative disorders, in this case using PAR2 activation, may be a viable therapeutic strategy.},
}

@article {pmid42140898,
year = {2026},
author = {Wang, Y and Zhou, Z and Liu, W and Zhang, P and Cheng, Y and Su, Y and Wang, F and Wong, KC and Li, X},
title = {Interpretable modality-aware mapping of gene regulation in single-cell multiomics with scMAGCA.},
journal = {Nature communications},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41467-026-73055-7},
pmid = {42140898},
issn = {2041-1723},
support = {62472195//National Natural Science Foundation of China (National Science Foundation of China)/ ; },
abstract = {Single-cell multi-omics technologies profile multiple molecular layers in individual cells, but existing methods often struggle to integrate transcriptomic, proteomic, and epigenomic measurements into an interpretable representation while preserving relationships among cells. Here, we present the single-cell multi-omics adversarial graph convolutional autoencoder (scMAGCA), which constructs cell graphs and uses adversarial alignment to learn interpretable shared embeddings that capture cellular heterogeneity and regulatory complexity. Across diverse datasets, scMAGCA outperforms existing methods in modality alignment, clustering, and batch correction. In Alzheimer's disease, scMAGCA resolves neuronal subtypes and regulatory programs that are missed by single-modality analyses. In kidney cancer, it identifies tumor-specific epithelial and endothelial populations and uncovers biomarkers validated by quantitative polymerase chain reaction. These results support scMAGCA as an interpretable framework for resolving complex cell states in disease.},
}

@article {pmid42045851,
year = {2026},
author = {Liu, X and Xu, H and Han, X and Zhang, Q},
title = {Association between triglyceride-glucose index and vascular dementia in ICU patients with cerebrovascular disease: a retrospective study based on the MIMIC-IV database.},
journal = {BMC neurology},
volume = {26},
number = {1},
pages = {},
pmid = {42045851},
issn = {1471-2377},
support = {HPYJ202409//Faculty Scientific Research Fund of Heping Hospital Affiliated to Changzhi Medical College/ ; },
abstract = {BACKGROUND: Vascular dementia (VaD) is the second most common type of dementia after Alzheimer’s disease. Previous studies have confirmed a significant correlation between white matter changes and cognitive dysfunction, especially in patients with metabolic syndrome, suggesting that silent vascular risk factors may promote cerebrovascular pathology with advancing age. The Triglyceride-Glucose (TyG) Index, a novel metabolic indicator calculated based on fasting triglyceride and glucose levels, reflects insulin resistance (IR).

METHODS: Our research aimed to analyze data from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database, using logistic regression analysis and constructing restricted cubic spline (RCS) curves to evaluate the association between the TyG index and VaD in patients with cerebrovascular disease (CVD). Subgroup analyses were performed, but no statistically significant associations were observed within individual strata. Additionally, univariate and multivariate logistic regression analyses were conducted to identify factors associated with VaD. Exploratory analyses were also performed.

RESULTS: After the implementation of the inclusion criteria, a total of 1,754 patients with CVD were enrolled. Among them, 13.91% were diagnosed with VaD. Logistic regression showed that patients in the highest TyG quartile had significantly higher odds of VaD compared with the lowest quartile (Model 3: OR = 2.315, 95% CI: 1.437–3.776, p < 0.001). RCS showed a significant linear association (P = 0.046). No statistically significant subgroup effects were observed. Exploratory association analyses were performed, but formal validation was not conducted.

CONCLUSION: Higher TyG levels were independently associated with increased odds of VaD in patients with CVD after adjusting for potential confounders. Future prospective studies are needed to confirm these associations and explore their clinical implications.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12883-026-04915-4.},
}

@article {pmid42079285,
year = {2026},
author = {Phasuk, S and Tooley, KB and Sun, JL and Pagala, V and Palacios, G and Deats, S and Garland, G and Robinson, LL and Wang, X and Belingon, B and Cook, J and Tan, H and Lkhagva, A and Yuan, ZF and Wu, L and Johnson, A and Bradberry, M and Robinson, CG and High, AA and Korstanje, R and Vevea, JD},
title = {APOE is a presynaptic protein that accumulates with age and modulates neurotransmitter release.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
pmid = {42079285},
issn = {2692-8205},
abstract = {The synaptic vesicle (SV) cycle is the fastest membrane trafficking and protein sorting process in biology. It underlies neuronal communication and cognition, yet synaptic function declines during normal aging, increasing vulnerability to neurologic disease. How the SV cycle is maintained across the lifespan of a complex organism remains unclear. Here, we used wild-type mice (C57BL/6J) to define the age- and sex-stratified molecular landscape of SVs and identified apolipoprotein E (APOE) as an abundant presynaptic protein further enriched in aged female samples. Super-resolution imaging, cell-type selective expression, and protease protection assays demonstrate that APOE originates from astroglia and associates with the cytosolic face of SVs. Using iGluSnFR and pHluorin optophysiology, we find that both decreased and increased APOE levels impair neurotransmission during stimulus trains. Together, these findings place APOE at the synapse and establish it as a cell-nonautonomous regulator of the SV cycle.},
}

@article {pmid42128444,
year = {2026},
author = {Atri, A and Apostolova, LG and Iwata, A and Wessels, AM and Atkins, A and Lu, M and Ye, W and Ryan, S and Doty, EG},
title = {Clinical Meaningfulness of Donanemab in Early Symptomatic Alzheimer Disease: Data From the Randomized Phase 3 TRAILBLAZER-ALZ 2 Trial.},
journal = {Neurology. Clinical practice},
volume = {16},
number = {3},
pages = {e200621},
doi = {10.1212/CPJ.0000000000200621},
pmid = {42128444},
issn = {2163-0933},
mesh = {Humans ; *Alzheimer Disease/drug therapy ; Aged ; *Cognitive Dysfunction/drug therapy ; Male ; Female ; *Antibodies, Monoclonal, Humanized/therapeutic use/pharmacology ; Aged, 80 and over ; Disease Progression ; Activities of Daily Living ; *Outcome Assessment, Health Care ; },
abstract = {BACKGROUND AND OBJECTIVES: Understanding the meaningfulness of clinical trial outcomes is essential for people living with Alzheimer disease (AD) and their clinicians to make evidence-based shared treatment decisions in real-world clinical care. Donanemab, a monoclonal antibody targeting the insoluble form of β-amyloid found in plaques, significantly slows cognitive and functional decline of AD in participants with mild cognitive impairment (MCI) or mild AD-related dementia. This analysis reviews the efficacy of donanemab across various clinical outcome assessments, using both published data and new complementary analyses to provide context on its potential benefits for patients and caregivers.

METHODS: We present findings from prespecified and post hoc analyses from the TRAILBLAZER-ALZ 2 trial. Clinical outcomes assessed were Integrated AD Rating Scale (iADRS), comprising the 13-item AD Assessment Scale-Cognitive Subscale (ADAS-Cog13) and AD Cooperative Study-Instrumental Activities of Daily Living (ADCS-iADL); Clinical Dementia Rating (CDR)-Sum of Boxes (CDR-SB) for clinical severity and individual cognitive and functional domains; CDR-Global for clinical severity stage progression; meaningful within-patient change (MWPC); and ADCS-Activities of Daily Living dependence score.

RESULTS: Donanemab reduced the risk of progression from MCI to mild AD by 33% (hazard ratio [HR] = 0.67; 95% CI 0.52-0.87; p = 0.003) and from mild to moderate AD by 50% (HR = 0.50; 95% CI 0.33-0.78; p = 0.002). In addition, donanemab reduced MWPC risk over 76 weeks by 38% for CDR-SB (HR = 0.62; 95% CI 0.52-0.75; p < 0.001) and 30% for iADRS (HR = 0.70; 95% CI 0.58-0.84; p < 0.001). Donanemab-treated participants exhibited significant slowing of clinical progression across multiple ADAS-Cog13 and ADCS-iADL items and all CDR-SB cognitive and functional domains. Donanemab also slowed progression of dependence least-squares mean change difference, -0.14 [95% CI -0.24 to -0.04; p = 0.007]), representing 23% slowing of progression (95% CI 6.17%-40.32%), and reduced risk of progression to requiring in-home support by 27% (HR = 0.74; 95% CI 0.59-0.91; p = 0.005).

DISCUSSION: These results add to the evidence and further support clinically meaningful donanemab-mediated effects on cognition and function for patients and their caregivers and may aid communication of realistic treatment expectations and informed decision-making.

ClinicalTrials.gov NCT04437511. Submitted: June 17, 2020; First patient enrolled: June 19, 2020. clinicaltrials.gov/study/NCT04437511 EudraCT Number 2020-000077-25. Start date of recruitment: June 19, 2020. clinicaltrialsregister.eu/ctr-search/trial/2020-000077-25/results.},
}

Humans
*Alzheimer Disease/drug therapy
Aged
*Cognitive Dysfunction/drug therapy
Male
Female
*Antibodies, Monoclonal, Humanized/therapeutic use/pharmacology
Aged, 80 and over
Disease Progression
Activities of Daily Living
*Outcome Assessment, Health Care

@article {pmid42128467,
year = {2026},
author = {Tan, S and Gourabi, S and Cribbet, MR and Cundiff, JM and McDonough, IM},
title = {Sleep quality is associated with default mode and salience network connectivity differently across age and sex.},
journal = {Neurobiology of aging},
volume = {165},
number = {},
pages = {76-91},
doi = {10.1016/j.neurobiolaging.2026.05.002},
pmid = {42128467},
issn = {1558-1497},
abstract = {Aging and biological sex are critical moderators of sleep quality, which contributes significantly to age-related cognitive decline and Alzheimer's disease (AD) risk. This study investigated how age and sex moderated the relationship between subjective sleep quality and resting-state functional connectivity (rsFC) within networks associated with hyperarousal and cognitive processing. Using an exploratory-confirmatory approach across two datasets (N = 95 and N = 1244), we examined connectivity of the default mode network (DMN), salience network (SN), and amygdala with the rest of the brain. Results revealed distinct age- and sex-dependent patterns: in the DMN, a three-way interaction (Age×Sex×Sleep Quality) showed that poorer sleep quality was associated with reduced DMN-superior parietal lobule (SPL) connectivity in younger women but hyperconnectivity in older women. This hyperconnectivity correlated with poorer episodic memory performance, consistent with patterns observed in preclinical AD. For the SN, an age-dependent interaction showed that poorer sleep was associated with SN-sensorimotor hyperconnectivity in younger adults-supporting the hyperarousal hypothesis-but lower connectivity in older adults, suggesting a shift toward different mechanisms, such as circadian or homeostatic decline, in late life. No significant effects were found for the amygdala or blood-based biomarkers of AD pathology, inflammation, or sex hormones. These findings highlight a selective vulnerability of the DMN to sleep impairments in older women and suggest that the neural correlates of poor sleep shift from hyperarousal in youth to neurodegenerative-like patterns in older age.},
}

@article {pmid42128684,
year = {2026},
author = {Zhang, QT and Wu, WQ and Deng, YH and Dong, L and Xu, YM and Fu, XJ and Jiang, HQ},
title = {[Establishment of reference intervals for plasma p-tau181, Aβ1-42, Aβ1-40, and Aβ1-42/40 ratio and a preliminary study of their correlation with corresponding cerebrospinal fluid reference intervals].},
journal = {Zhonghua yu fang yi xue za zhi [Chinese journal of preventive medicine]},
volume = {60},
number = {5},
pages = {784-790},
doi = {10.3760/cma.j.cn112150-20251227-01232},
pmid = {42128684},
issn = {0253-9624},
mesh = {Humans ; *Amyloid beta-Peptides/cerebrospinal fluid/blood ; *tau Proteins/blood/cerebrospinal fluid ; Cross-Sectional Studies ; *Peptide Fragments/cerebrospinal fluid/blood ; Reference Values ; Alzheimer Disease/blood/cerebrospinal fluid ; Adult ; Biomarkers/cerebrospinal fluid/blood ; Male ; Female ; Middle Aged ; Phosphorylation ; Aged ; },
abstract = {Objective: To establish reference intervals for Alzheimer's disease (AD)-related biomarkers in plasma and cerebrospinal fluid (CSF) of adults in Shanghai using single molecule immune detection. Methods: In this cross-sectional study, which included residual plasma samples from 454 healthy individuals and CSF samples from 106 non-AD patients were collected from the Department of Laboratory Medicine, Huashan Hospital, Fudan University, between March and July 2024. The concentrations of phosphorylated tau protein-181 (p-tau181), amyloid-beta peptide 1-42 (Aβ1-42), and amyloid-beta peptide 1-40 (Aβ1-40) were detected using the AST-Dx90 fully automated fluorescence immunoassay analyzer. After normality testing and outlier removal, reference intervals were determined by the non-parametric method and validated using plasma samples from 20 healthy individuals. Results: Spearman correlation analysis revealed no significant correlations with age for plasma Aβ1-42 (R=0.047, P=0.344), the Aβ1-42/40 ratio (R=-0.050, P=0.326), or for CSF p-tau181 (R=-0.078, P=0.438), Aβ1-42 (R=0.002, P=0.980), Aβ1-40 (R=-0.084, P=0.400), and the Aβ1-42/40 ratio (R=0.173, P=0.083) (|R|<0.2, P>0.05). Although plasma p-tau181 (R=-0.102, P=0.032) and Aβ1-40 (R=0.150, P=0.002) showed statistically significant associations with age (P<0.05), the strength of these correlations was very weak (|R|<0.2).Z-tests indicated that there were no statistically significant differences (Z }

Humans
*Amyloid beta-Peptides/cerebrospinal fluid/blood
*tau Proteins/blood/cerebrospinal fluid
Cross-Sectional Studies
*Peptide Fragments/cerebrospinal fluid/blood
Reference Values
Alzheimer Disease/blood/cerebrospinal fluid
Adult
Biomarkers/cerebrospinal fluid/blood
Male
Female
Middle Aged
Phosphorylation
Aged

@article {pmid42128892,
year = {2026},
author = {Mlinarič, T and Van Den Kerchove, A and Barinaga, ZI and Van Hulle, MM},
title = {Correction: EEG-based classification of alzheimer's disease and frontotemporal dementia using functional connectivity.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {},
doi = {10.1038/s41598-026-49348-8},
pmid = {42128892},
issn = {2045-2322},
}

@article {pmid42129136,
year = {2026},
author = {Huo, Y and Huang, W and Liu, Z and Chen, H and Bai, T and Wang, Y and Wang, K and Zhang, D and Cheng, J and Sun, Y and Ma, G and Zhao, C and Zhang, Z and Shu, N},
title = {Functional system-specific brain aging across the Alzheimer's disease continuum.},
journal = {Translational psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41398-026-04081-8},
pmid = {42129136},
issn = {2158-3188},
support = {82301608, 32271145, 81871425, 210510238//National Natural Science Foundation of China (National Science Foundation of China)/ ; L252087//Natural Science Foundation of Beijing Municipality (Beijing Natural Science Foundation)/ ; },
abstract = {Accelerated brain aging is implicated in Alzheimer's disease (AD). However, the spatial heterogeneity of brain aging patterns across different functional systems along the AD continuum remains largely unexplored. We developed functional system-specific brain age models derived from structural magnetic resonance imaging in a healthy adult cohort (n = 22,672) and applied them to 1478 participants across the AD continuum. Using up to 6 years of retrospective longitudinal data before clinical AD conversion, we quantified predicted age differences (PADs) and their change rates, characterized heterogeneous brain aging trajectories, and examined their associations with AD biomarkers, cognitive performance, and clinical progression. Progressive mild cognitive impairment (MCI) individuals showed early PAD deviations in the default mode network and accelerated changes in attention and control networks. System-wise PAD dynamics mediated the effects of AD-related biomarkers on cognitive decline. Integrating PAD features can improve predictive accuracy of MCI-to-AD conversion (AUC = 0.95). Functional system-specific PADs can be sensitive biomarkers for early detection and monitoring of individualized AD risk.},
}

@article {pmid42129145,
year = {2026},
author = {Pulst, SM and Paul, S and Nguyen, H and Dansithong, W and Figueroa, KP and Gandelman, M and Bonini, NM and Scoles, DR},
title = {A human Staufen1 BAC transgenic mouse exhibits abnormal autophagy and neurodegeneration across the central nervous system.},
journal = {Cell death & disease},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41419-026-08830-x},
pmid = {42129145},
issn = {2041-4889},
support = {R21NS127028//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R01NS137233//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R01NS097903//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R21NS128630//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R61/R33NS124965//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R21NS128630//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R35NS097275//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R56NS033123//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R37NS033123//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R35NS127253//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R61/R33NS124965//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; },
abstract = {RNA-binding proteins (RBPs) play an essential role in development, normal functioning, and human disease. Staufen1 (STAU1) is an RBP that regulates mRNA degradation and subcellular localization, and is part of the ATXN2 protein complex. Previously, we showed that STAU1 is overabundant in patient fibroblasts and in mouse models of Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and spinocerebellar ataxia type 2 (SCA2), where it is associated with impaired autophagic flux due to STAU1-mediated upregulation of mTOR translation. STAU1 overabundance and impaired autophagy cause accumulation of biomolecular condensates and abnormal unfolded protein response (UPR). We generated a mouse model expressing the entire human STAU1 gene (hSTAU1) in a bacterial artificial chromosome (BAC) construct. hSTAU1 in these mice was expressed in cerebral hemispheres, cerebellum, and spinal cord, as well as cultured cortical neurons and cortical and spinal cord astrocytes, and microglia. Expression of hSTAU1 caused dysregulated gene expression, abnormal autophagy, glial activation, and changes in neuronal marker proteins. All of these were significantly improved by reducing STAU1 abundance by RNAi, but exacerbated in BAC-STAU1 mice crossed with Prp-TDP-43(Q331K) transgenic mice. Similar results were also obtained in eye phenotypes in ALS- and SCA2-relevant fly models upon changing staufen-1 dosage. Despite the molecular changes, we observed no overt behavioral changes in mice up to 55 weeks of age, suggesting that STAU1 may function as an epistatic modifier of neuronal degeneration. The BAC-hSTAU1 mouse will be useful for developing therapies targeting the human STAU1 gene.},
}

@article {pmid42129267,
year = {2026},
author = {Wang, Z and Xia, X},
title = {Cytokine gene polymorphisms and serum cytokine levels identify a neuroinflammatory nexus in Alzheimer's disease.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-52911-y},
pmid = {42129267},
issn = {2045-2322},
abstract = {Neuroinflammation, orchestrated by glial cells and mediated by cytokines, is now recognized as a pivotal pathogenic mechanism in Alzheimer's disease (AD). However, the interplay between host genetic variations driving inflammatory responses and the resultant central or peripheral inflammatory milieu in AD susceptibility remains poorly defined. This study aimed to decode the crosstalk between functional polymorphisms in key cytokine genes and their corresponding serum cytokine levels in relation to AD risk. We performed a case-control investigation involving 160 patients with newly diagnosed, sporadic late-onset AD and 280 age- and gender-matched cognitively healthy controls. Four important cytokines from serum were quantified using high-sensitivity ELISA. Functional single nucleotide polymorphisms in the regulatory regions of their genes were genotyped using PCR-RFLP. AD patients exhibited significantly elevated concentrations of all above cytokines (all p < 0.001). Several SNPs were associated with altered AD risk (IL-1β -511 C/T; TNF-α -308 G/A; IL-10 -1082 G/A). This cross-sectional case-control study demonstrates that specific cytokine gene polymorphisms are associated with AD risk in this Chinese cohort, and these genetic variants correlate with altered serum cytokine levels. These findings suggest an association between host genetic variation in inflammatory genes and AD susceptibility, but do not establish causality. The observed elevations in peripheral cytokines may reflect systemic inflammation rather than AD-specific neuroinflammation.},
}

@article {pmid42129367,
year = {2026},
author = {Rickman, NC and Liu, G and Franz, AR and Bernhard, W and Bearer, CF},
title = {The role of choline in neurodevelopment.},
journal = {Pediatric research},
volume = {},
number = {},
pages = {},
pmid = {42129367},
issn = {1530-0447},
abstract = {Choline was first declared to be an essential nutrient in 1998. Current research on choline intake has been sufficient for the Food and Nutrition Board of the National Academies of Science, Engineering & Medicine to establish a loose guideline, but more investigation into healthy choline intakes is necessary to clarify guidelines. Choline is intimately involved in human metabolism, as an essential precursor for cell membrane components such as phosphatidylcholine and sphingomyelin, lipoprotein and fatty acid trafficking, and the neurotransmitter acetylcholine. It plays an essential role in histone, RNA, and DNA methylation, creatine synthesis, and more. Choline-related pathologies have already been implicated in multiple severe developmental diseases, such as schizophrenia, Down syndrome, and neural tube defects, and age-related diseases such as Alzheimer's. Choline supplementation has been shown to alleviate the symptoms of neurodevelopmental diseases, such as Fetal Alcohol Spectrum Disorder and neonatal hyperbilirubinemia. The choline intake by most adults is estimated to be less than the current recommendations. Choline supplementation, particularly for vulnerable populations such as pregnant women, preterm infants, and cystic fibrosis patients, requires further investigation to establish adequate recommendations and to fully elucidate the consequences of malnutrition. Outcomes of choline deficiency and supplementation, such as neurodevelopment, should be measured. IMPACT: What this article adds to the existing literature An up-to-date summary of the metabolism of choline A review of the role of choline in normal and abnormal neurodevelopment A concise description of sources of choline.},
}

@article {pmid42129462,
year = {2026},
author = {Liu, Z and Che, C and He, G and Wu, H and Cai, L and Cui, L and Liang, L},
title = {Mandarin speech-based early detection of SCD: a feature-fusion residual network method.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71460},
pmid = {42129462},
issn = {1552-5279},
support = {//Basic and Applied Basic Research Foundation of Guangdong Province/ ; //2024B1515230001/ ; GDMULCJC2024006//Special Project for Clinical and Basic Sci&Tech Innovation of Guangdong Medical University/ ; LCYJ2021B001//Affiliated Clinical Research Project of Guangdong Medical University/ ; 4SG22307P//Special Project of Songshan Lake Medical-Engineering Integration Innovation Centre at Guangdong Medical University/ ; },
mesh = {Humans ; Male ; Female ; *Cognitive Dysfunction/diagnosis ; Cross-Sectional Studies ; Early Diagnosis ; Aged ; *Alzheimer Disease/diagnosis ; *Speech/physiology ; Middle Aged ; },
abstract = {INTRODUCTION: Alzheimer's disease (AD) poses a global health challenge. Early intervention during the stage of subjective cognitive decline (SCD) - a potential window for delaying disease progression - is crucial. This study aims to assess an exploratory speech-based model for rapid SCD screening.

METHOD: This study included 459 participants, comprising individuals with AD, mild cognitive impairment (MCI), SCD, and normal controls. We used Pic-Talk clips and Mandarin speech with residual network features for SCD screening.

RESULTS: In this cross-sectional study, our model achieved high performance with accuracy, recall, precision, F1, and area under the curve of 81.77 ± 2.78%, 80.53 ± 2.64%, 82.27 ± 2.38%, 81.39 ± 1.85%, and 82.85 ± 2.01%, respectively, outperforming other speech models.

DISCUSSION: This non-invasive exploratory approach to SCD assessment shows potential, revealing acoustic differences at the group level between SCD and other diagnostic groups. It is expected that the future integration of biomarkers will enhance the model's accuracy and expand its applicability.},
}

Humans
Male
Female
*Cognitive Dysfunction/diagnosis
Cross-Sectional Studies
Early Diagnosis
Aged
*Alzheimer Disease/diagnosis
*Speech/physiology
Middle Aged

@article {pmid42129508,
year = {2026},
author = {Liu, W and Shimogori, T},
title = {Spatiotemporal brain transcriptomics reveal risk gene hot-spots in major neuropsychiatric disorders.},
journal = {Communications biology},
volume = {9},
number = {1},
pages = {},
pmid = {42129508},
issn = {2399-3642},
mesh = {Humans ; *Brain/metabolism/growth & development ; *Transcriptome ; *Mental Disorders/genetics ; *Genetic Predisposition to Disease ; Gene Expression Profiling ; Spatio-Temporal Analysis ; Genome-Wide Association Study ; },
abstract = {Brain development is guided by dynamic gene expression programs that vary across brain regions and developmental stages. Although numerous risk genes for neuropsychiatric disorders have been identified, the spatiotemporal contexts in which they act remain unclear. Here we show the spatiotemporal expression patterns of genome-wide risk gene sets across 15 neuropsychiatric traits, including autism, attention deficit hyperactive disorder, obsessive compulsive disorder, major depression, bipolar disorder, schizophrenia, epilepsy, Alzheimer's disease and Parkinson's disease, using bulk and single-cell transcriptomic data from the human brain. We identify trait-specific spatiotemporal enrichment patterns, allowing a classification of disorders into prenatally and postnatally enriched groups that align with known ages of disease onset. Integration with brain imaging datasets and gene co-expression network analysis further identifies synaptic development and function, as well as RNA processing during early brain development, in neuropsychiatric risk. These findings provide a systems-level framework linking genetic risk to neurodevelopmental and neuroanatomical contexts.},
}

Humans
*Brain/metabolism/growth & development
*Transcriptome
*Mental Disorders/genetics
*Genetic Predisposition to Disease
Gene Expression Profiling
Spatio-Temporal Analysis
Genome-Wide Association Study

@article {pmid42129577,
year = {2026},
author = {Stark, M and Wagner, M and Kuhn, E and Roeske, S and Amthauer, H and Bartels, C and Boecker, H and Brosseron, F and Buchert, R and Buerger, K and Daamen, M and Drzezga, A and Düzel, E and Ersözlü, E and Essler, M and Ewers, M and Fliessbach, K and Glanz, W and Hellmann-Regen, J and Incesoy, EI and Janowitz, D and Kafali, K and Kilimann, I and Krause, BJ and Kronmüller, M and Laske, C and Maier, F and Maurer, A and Michely, J and Perneczky, R and Peters, O and Preis, L and Priller, J and Rauchmann, BS and Reimold, M and Rominger, A and Schmid, M and Schneider, A and Sodenkamp, S and Spottke, A and Spruth, EJ and Teipel, S and Wiltfang, J and , and Jessen, F and Kleineidam, L},
title = {Minor neuropsychological deficits and stage 2 of Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71458},
pmid = {42129577},
issn = {1552-5279},
support = {//Gemeinnützige Hertie-Stiftung/ ; BN012//Deutsches Zentrum für Neurodegenerative Erkrankungen/ ; //Life Molecular Imaging/ ; U01AG024904/NH/NIH HHS/United States ; W81XWH-12-2-0012//U.S. Department of Defense/ ; /AG/NIA NIH HHS/United States ; /EB/NIBIB NIH HHS/United States ; //AbbVie/ ; /ALZ/Alzheimer's Association/United States ; //Alzheimer's Drug Discovery Foundation/ ; //Araclon Biotech/ ; //Biogen/ ; //Bristol-Myers Squibb/ ; //CereSpir, Inc./ ; //Cogstate/ ; //Eisai/ ; //Elan Pharmaceuticals, Inc./ ; //Eli Lilly and Company/ ; //EuroImmun Medizinische Labordiagnostika/ ; //F. Hoffmann-La Roche/ ; //Genentech/ ; //Fujirebio/ ; //GE Healthcare/ ; //IXICO Ltd./ ; //Janssen Alzheimer Immunotherapy Research & Development, LLC./ ; //Lumosity/ ; //Lundbeck/ ; //Merck & Co., Inc./ ; //Meso Scale Diagnostics, LLC./ ; //NeuroRx Research/ ; //Neurotrack Technologies/ ; //Novartis Pharmaceuticals Corporation/ ; //Pfizer Inc./ ; //Piramal Imaging/ ; //Servier/ ; //Transition Therapeutics/ ; /CAPMC/CIHR/Canada ; U24 AG072122/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/diagnosis/psychology ; Female ; Aged ; Neuropsychological Tests/statistics & numerical data ; Male ; *Cognitive Dysfunction/diagnosis ; Longitudinal Studies ; Biomarkers ; Aged, 80 and over ; },
abstract = {INTRODUCTION: Subtle symptoms, like subjective cognitive decline (SCD) and minor neuropsychological deficits (MNPD), can improve the risk stratification in preclinical Alzheimer´s disease (AD) but their importance is insufficiently elaborated.

METHODS: We pooled data from cognitively normal individuals participating in three longitudinal cohort studies (N = 13,192, 8,359[63.3%] female, mean [SD] age 71.0[8.4]).

RESULTS: Compared to participants without SCD and MNPD (SCD-/MNPD-), SCD-/MNPD+, SCD+/MNPD-, and SCD+/MNPD+ participants had an increased risk for mild cognitive impairment (MCI) and dementia, including in amyloid-positive individuals. Focusing on SCD+/MNPD+ participants triples the positive predictive value of amyloid biomarker testing for the 5-year prediction of MCI and reduces the required samples size for trials in preclinical AD to one fourth, compared to considering all cognitively normal participants regardless of subtle symptoms.

DISCUSSION: SCD and MNPD offer a powerful approach for risk stratification in preclinical AD, which can improve clinical trial designs, risk counseling, and future case identifications for early treatment.},
}

Humans
*Alzheimer Disease/diagnosis/psychology
Female
Aged
Neuropsychological Tests/statistics & numerical data
Male
*Cognitive Dysfunction/diagnosis
Longitudinal Studies
Biomarkers
Aged, 80 and over

@article {pmid42129676,
year = {2026},
author = {Ning, K and Abdin, E and Asharani, PV and Isvoranu, AM and Epskamp, S and Ng, LL and Chong, SA and Subramaniam, M},
title = {Mapping the network structure of dementia and its associated factors among older adults in Singapore: evidence from two national cross-sectional studies.},
journal = {BMC geriatrics},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12877-026-07535-2},
pmid = {42129676},
issn = {1471-2318},
abstract = {BACKGROUND: Dementia arises from the interplay of multiple sociodemographic, behavioural, physical, and psychosocial factors that often coexist and interact in later life. Traditional epidemiological studies have typically examined these factors in isolation, overlooking their complex interrelations. Network analysis provides an integrative framework to visualise and quantify these interconnections, offering insights into how dementia and its associated factors coexist within a broader system.

METHODS: Data were drawn from two nationally representative cross-sectional surveys of older adults aged ≥60 years in Singapore: the Well-being of the Singapore Elderly (WiSE) 2023 study (n=2010) and the WiSE 2013 study (n=2565). Dementia was assessed using the 10/66 diagnostic criteria. Variables included factors identified by the Lancet Commission on Dementia Prevention, Intervention, and Care, and established indices including the Lifestyle for BRAin health (LIBRA), Cardiovascular Risk Factors, Aging and Incidence of Dementia (CAIDE), Australian National University Alzheimer's Disease Risk Index (ANU-ADRI), and World Health Organization (WHO) guidelines. Network structure was estimated using mixed graphical models. Sensitivity analyses were conducted to assess the robustness of the network.

RESULTS: Across both surveys, dementia showed the strongest conditional associations with age, educational attainment, employment status, being physically active, walking frequency, stroke, daytime sleepiness, and difficulty maintaining friendships. The overall network structures were comparable in the two surveys, indicating stable interconnections among demographic, behavioural, and social domains. Majority of these interconnections were also not found to vary by gender and ethnicity.

CONCLUSIONS: This study highlights the complex web of interrelations linking dementia with social, behavioural, and health-related factors in later life. Rather than implying causal direction, these findings illustrate how multiple factors cluster and coexist within older adults' lives. These interconnections may inform the design of holistic strategies that integrate employment opportunities, physical activity promotion, social participation, sleep health, and cerebrovascular prevention into comprehensive dementia prevention and care frameworks.},
}

@article {pmid42129775,
year = {2026},
author = {Börsch, AL and Riethues, F and Schulte-Mecklenbeck, A and Wang, X and Heming, M and Lu, IN and Müller-Miny, L and Wiendl, H and Gross, CC and Bernard-Valnet, R and Meyer Zu Hörste, G},
title = {A CSF disease-associated macrophage signature defines progressive multiple sclerosis.},
journal = {Journal of neuroinflammation},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12974-026-03861-9},
pmid = {42129775},
issn = {1742-2094},
abstract = {OBJECTIVE: Progression in multiple sclerosis (MS) often corresponds to irreversible disability in MS patients. Cellular changes in the cerebrospinal fluid (CSF) have provided biomarkers and mechanisms in relapsing-remitting MS (RRMS) but remain understudied in primary and secondary progressive MS (summarized herein as PMS).

METHODS: We combined retrospective flow cytometry of CSF cells from RRMS (n = 169), PMS (n = 56), and non-inflammatory controls (n = 74) with prospective CSF single-cell transcriptomics of 35 individuals (11 controls, 12 RRMS, and 12 PMS) and with confirmatory CSF ELISA. Available CSF single-cell data from age-matched and Alzheimer's disease (AD) patients served as additional controls.

RESULTS: Proportions of CD14[+] monocytes in CSF are increased in PMS and correlated with clinical surrogate markers of progression. Transcriptionally, these monocytes resembled border-associated macrophages (BAM)-like cells with a chronically activated antigen-presenting phenotype. Additionally, these monocytes shared some features with disease-associated microglia/macrophages (DAM), previously identified in neurodegeneration. Induction of DAM-associated molecules, including transcribed and soluble TREM2 (sTREM2), characterized secondary progressive MS (SPMS) and supported its differential diagnosis.

INTERPRETATION: We thus identified MS stage-specific CSF signatures and shared cellular features of degeneration detectable in CSF of PMS patients.},
}

@article {pmid42129839,
year = {2026},
author = {Yang, D and Liu, P and Han, M and Ke, Z and Tan, Y and Yu, L and Hu, Z and Mao, C and Cheng, Y and Zhang, H and Zhang, Y and Zhu, X and Xu, Y},
title = {Plasma extracellular vesicle proteins biomarker for cerebral small vessel disease related cognitive impairment.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02078-5},
pmid = {42129839},
issn = {1758-9193},
support = {2023ZD0504902//Noncommunicable Chronic Diseases-National Science and Technology Major Project/ ; 82130036//the National Natural Science Foundation of China/ ; 2022ZD0211800//the STI2030-Major Projects/ ; ZDXK202216//iangsu Province Key Medical Discipline/ ; },
abstract = {BACKGROUND: Cerebral small vessel disease (CSVD) is a major contributor to vascular dementia. Given the absence of effective treatments, the development of blood-based biomarkers for early diagnosis and prediction is paramount to facilitate targeted clinical interventions. We aimed to identified blood-based extracellular vesicle (EV) biomarkers for screening CSVD with normal cognition (CSVD-NC) or cognitive impairment (CSVD-CI), and predicting disease progression.

METHODS: We conducted a multi-center cross-sectional and longitudinal study involving patients with CSVD-NC and CSVD-CI, healthy controls (HCs), and patients with CI due to Alzheimer's disease (AD-CI). Plasma EV proteomics were profiled using LC-MS/MS in a discovery set. Candidate EV biomarkers identified in this phase were subsequently validated in a larger independent set using parallel reaction monitoring. Machine learning was applied to develop and optimize diagnostic combinations for identifying CSVD and predicting disease progression.

RESULTS: Plasma EV proteins exhibiting progressive changes during CSVD progression were predominantly enriched in immune-inflammatory and ribosomal dysfunction. Three plasma EV proteins (ATP6V1F, HNRNPU, and RPL38) demonstrated robust, cross-dataset consistency from HC to CSVD-NC to CSVD-CI continuum, and displayed distinct expression patterns between CSVD-CI and AD-CI (P < 0.001). These EV biomarkers demonstrated high diagnostic accuracy for CSVD with or without CI (AUC = 0.849-0.897), and effectively stratified high-risk versus low-risk populations for CSVD cognitive progression (P = 0.005). Moreover, they were associated with CSVD-related structural injury and specific cognitive functions: EV ATP6V1F with hippocampal atrophy, language, and memory; EV RPL38 with WMH burden and white matter integrity; and EV HNRNPU with visuospatial function and executive function.

CONCLUSION: The identified plasma EV biomarkers reliably reflect CSVD-related vascular injury and cognitive decline, and hold promise as minimally invasive tools for early screening and risk stratification of CSVD-related CI, especially in community settings.},
}

@article {pmid42129847,
year = {2026},
author = {Lu, Y and Abdullah, M and Healy, LR and Yin, T and Yesiltepe, M and D'Adamio, L and Tambini, MD},
title = {Valosin-containing Protein is cargo in Amyloid Precursor Protein extracellular vesicles.},
journal = {Cell communication and signaling : CCS},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12964-026-02936-7},
pmid = {42129847},
issn = {1478-811X},
support = {R01AG063407/AG/NIA NIH HHS/United States ; R00AG065441/AG/NIA NIH HHS/United States ; },
abstract = {The Amyloid Precursor Protein (APP), a genetic cause of Alzheimer's disease (AD), is a type-I transmembrane protein that is metabolized by proteolysis in the endolysomal system. APP and its metabolites are secreted by cells in extracellular vesicles (EVs). To study the function of APP-containing EVs, we isolated App-EVs from rat primary neuronal conditioned media and proteomic analysis identified the Valosin-containing protein (Vcp) as molecular cargo. Pharmacological modulation of Vcp activity was found to alter App processing and global EV secretion in rat primary neurons. AD-associated knock-in App mutations were found to alter the abundance of App-EVs and the trafficking of App metabolites within App-EVs, in a manner related to the epitopes generated by the nonamyloidogenic processing of App.},
}

@article {pmid42130238,
year = {2026},
author = {Lim, HK and Shih, AY and Gust, J},
title = {Leukocyte-endothelial interactions and brain capillary function in neurological diseases.},
journal = {Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism},
volume = {},
number = {},
pages = {271678X261441983},
doi = {10.1177/0271678X261441983},
pmid = {42130238},
issn = {1559-7016},
abstract = {Enhanced leukocyte-endothelial interactions are a hallmark pathological feature in brain disease. Preclinical studies have demonstrated increased leukocyte adhesion at the capillary level as a major contributor to cerebral blood flow (CBF) reductions across diverse neurological disorders, including Alzheimer's disease, ischemic stroke, and epilepsy. Remarkably, even modest levels of capillary obstruction (2%-5%) lead to disproportionate reductions in cerebral perfusion at the network level. Beyond acute perfusion deficits, chronic leukocyte obstruction contributes to long-term consequences such as structural capillary remodeling and altered blood-brain barrier function. This review synthesizes preclinical and clinical evidence across various neurological conditions to establish mechanistic links between leukocyte-driven neuroinflammatory pathology and cerebrovascular dysfunction at the capillary level. We integrate evidence on the structural and molecular basis of leukocyte adhesion, the multiscale impacts of increased leukocyte recruitment on capillary dysfunction, downstream inflammatory cascades, and neurological disease pathology. We address translational implications for therapeutic intervention arising from these mechanistic links.},
}

@article {pmid42130250,
year = {2026},
author = {Akar, S and Alvur, O and Evyapan, G and Ozdem, B and Porsuk Doru, I},
title = {Escin Attenuates Amyloid Beta 1-42-Induced Oxidative Stress, Apoptosis, and Neuroinflammation in Neuron-Like SH-SY5Y Cells.},
journal = {Journal of biochemical and molecular toxicology},
volume = {40},
number = {5},
pages = {e70903},
doi = {10.1002/jbt.70903},
pmid = {42130250},
issn = {1099-0461},
support = {TSA-2023-10713//Van Yuzuncu Yıl University Research Fund/ ; },
mesh = {*Amyloid beta-Peptides/toxicity ; Humans ; *Oxidative Stress/drug effects ; *Apoptosis/drug effects ; *Peptide Fragments/toxicity ; Cell Line, Tumor ; *Neurons/metabolism/pathology/drug effects ; *Escin/pharmacology ; Reactive Oxygen Species/metabolism ; *Neuroprotective Agents/pharmacology ; *Neuroinflammatory Diseases/metabolism/pathology/drug therapy ; Cell Survival/drug effects ; Alzheimer Disease/metabolism/drug therapy/pathology ; NF-kappa B/metabolism ; Inflammation/metabolism ; },
abstract = {The pathogenesis of Alzheimer's disease (AD) involves amyloid beta (Aβ)-induced oxidative stress, apoptotic cell death, and neuroinflammation, contributing to neuronal dysfunction. In our study, a differentiation protocol using retinoic acid was applied to SH-SY5Y cells to generate a neuron-like phenotype, and the neuroprotective efficacy of Escin was investigated by inducing Aβ1-42-mediated cytotoxicity. The experimental protocol involved an initial treatment with 2 µM Escin prior to Aβ1-42 application. Cell viability, intracellular reactive oxygen species (ROS), apoptosis, and inflammatory mediator expression (NF-κB, TNF-α, IL-1β) were assessed by MTT assay, flow cytometry with DCFH-DA, flow cytometry with Annexin V-FITC/7-AAD staining, and RT-qPCR, respectively. In our results, Aβ1-42 exposure was found to significantly reduce cell viability and increase ROS production. Additionally, it was observed to enhance apoptotic cell death and increase pro-inflammatory gene expression. Escin pretreatment was found to significantly mitigate these effects by reducing oxidative stress, apoptosis, and NF-κB-mediated inflammatory signaling. Furthermore, galantamine (10 µM), an approved AD treatment agent, was used as a positive control to compare the effects of Escin and confirmed the experimental model by exhibiting protective effects. In conclusion, these findings demonstrate that Escin is a promising neuroprotective agent and warrant further investigation into its potential to mitigate Aβ-related neuronal damage in AD.},
}

*Amyloid beta-Peptides/toxicity
Humans
*Oxidative Stress/drug effects
*Apoptosis/drug effects
*Peptide Fragments/toxicity
Cell Line, Tumor
*Neurons/metabolism/pathology/drug effects
*Escin/pharmacology
Reactive Oxygen Species/metabolism
*Neuroprotective Agents/pharmacology
*Neuroinflammatory Diseases/metabolism/pathology/drug therapy
Cell Survival/drug effects
Alzheimer Disease/metabolism/drug therapy/pathology
NF-kappa B/metabolism
Inflammation/metabolism

@article {pmid42130394,
year = {2026},
author = {Chen, F and Zhang, H and Huang, Y and Zhu, J and Cui, F and Liang, S and Li, Y and Wang, Y and Xie, X and Liu, R},
title = {Neuronal PRRT3 coordinates amyloidogenic processing and Tau phosphorylation via distinct Ras-ERK-AP-1 and CaMKII/PP2A pathways.},
journal = {Acta biochimica et biophysica Sinica},
volume = {},
number = {},
pages = {},
doi = {10.3724/abbs.2026085},
pmid = {42130394},
issn = {1745-7270},
abstract = {Alzheimer's disease (AD) is characterized by extracellular β-amyloid (Aβ) deposition and intracellular Tau hyperphosphorylation, yet upstream factors that coordinately regulate both pathologies remain poorly understood. Here, we identify proline-rich transmembrane protein 3 (PRRT3) as a previously unrecognized, neuron-enriched upstream regulator of AD dual pathology. PRRT3 expression is elevated in brain tissues from AD patients and exhibits abnormal persistence in APP/ PS1 mice. PRRT3 knockdown markedly reduces APP, PS1, and BACE1 mRNA expressions, thereby decreasing Aβ generation in neuronal cells. Mechanistically, PRRT3 promotes the expressions of these amyloidogenic genes via activation of the activator protein-1 (AP-1) complex, as evidenced by reduced phosphorylation of c-Fos and c-Jun after PRRT3 knockdown. Transcriptomic profiling further reveals broad downregulation of calcium signaling-related receptors and intracellular calcium-handling proteins, accompanied by attenuated calcium signaling and ERK activity. Artificially elevating intracellular calcium with thapsigargin completely reverses the neuroprotective effects of PRRT3 knockdown, restoring both the Ras-ERK-AP-1-dependent amyloidogenic machinery and CaMKII/PP2A-mediated Tau hyperphosphorylation. In parallel, PRRT3 knockdown shifts the balance between the Ca [2+]-dependent Tau kinase CaMKII and the phosphatase PP2A, leading to reduced Tau hyperphosphorylation at multiple AD-relevant sites. Collectively, these findings establish PRRT3 as a neuron-enriched upstream regulator linking calcium dysregulation to both amyloidogenic processing and Tau phosphorylation. Targeting PRRT3 may therefore represent a promising strategy to simultaneously modulate the two core pathological processes in AD.},
}

@article {pmid42130449,
year = {2026},
author = {Suk, K and Lee, WH},
title = {GV1001: repurposing a telomerase-derived peptide for neurological therapeutics.},
journal = {Expert opinion on investigational drugs},
volume = {},
number = {},
pages = {},
doi = {10.1080/13543784.2026.2674652},
pmid = {42130449},
issn = {1744-7658},
abstract = {INTRODUCTION: Neurodegenerative and demyelinating diseases represent major unmet medical needs, with existing therapeutics demonstrating limited efficacy and significant safety concerns. Drug repurposing offers accelerated development timelines and established safety profiles. GV1001, a 16-amino acid telomerase-derived peptide originally developed as a cancer vaccine, has emerged as a promising multi-mechanism neuroprotective agent.

AREAS COVERED: This review examines preclinical evidence demonstrating GV1001 efficacy across Alzheimer's disease, stroke, experimental autoimmune encephalomyelitis, and depression models. Convergent mechanisms include gonadotropin-releasing hormone receptor-mediated neuroprotection, mitochondrial stabilization, modulation of glial functional states away from tissue-damaging inflammation, and promotion of remyelination. Clinical translation through Phase 2 trials in Alzheimer's disease demonstrated statistically significant cognitive improvements consistent with neurotrophic benefit, with excellent safety profiles lacking amyloid-related imaging abnormalities.

EXPERT OPINION: The network pharmacology approach of GV1001-simultaneously addressing multiple pathological processes - positions it as a differentiated alternative to single-target therapeutics. The dual anti-inflammatory and pro-remyelination profile of the peptide addresses critical unmet needs in progressive multiple sclerosis. Phase 3 confirmation, biomarker-driven patient stratification, and combination therapy investigations represent critical development priorities. Successful development may help validate multi-mechanism approaches in neurodegeneration, potentially catalyzing paradigm shifts from reductionist single-target strategies.},
}

@article {pmid42130461,
year = {2026},
author = {Tian, M and Wang, D and Zhang, C and Fan, J and Li, W and Liu, X and Shi, J},
title = {Gut Microbiota Dysbiosis Drives Early Alzheimer's Pathogenesis via Microglial TREM2/SYK/NF-κB Signaling Axis.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.6c00173},
pmid = {42130461},
issn = {1948-7193},
abstract = {Gut microbiota dysbiosis is implicated in Alzheimer's disease (AD), but causal evidence and mechanisms linking it to microglial dysfunction remain unclear. This study aimed to determine whether gut microbiota drives neuroinflammation and cognitive impairment via the microglial TREM2/SYK signaling axis in early AD. Using six-month-old APP/PS1 mice, fecal microbiota transplantation (FMT) was performed between AD and wild-type mice. Cognitive function, gut microbiota composition (16S rRNA sequencing), serum metabolites, hippocampal neuroinflammation, microglial polarization, and TREM2/SYK/NF-κB pathway activity were assessed. BV2 microglial cells were treated with Aβ oligomers, a TREM2 agonist, or a SYK inhibitor for mechanistic validation. AD mice exhibited cognitive decline, reduced microbial diversity (e.g., decreased Bacteroidetes and Lactobacillus), and altered circulating metabolites, including decreased butyrate and elevated LPS. Their hippocampi exhibited heightened glial activation, elevated pro-inflammatory cytokines (TNF-α, IL-1β, IL-6), and a shift toward pro-inflammatory activation markers (M1-associated). At the molecular level, TREM2 expression was downregulated, whereas SYK phosphorylation and NF-κB activation were enhanced, concomitant with synaptic protein loss. Critically, FMT from healthy donors reversed these abnormalities and improved cognition, whereas AD microbiota induced mild pathology in wild-type mice. In vitro, TREM2 activation or SYK inhibition attenuated Aβ-induced M1 polarization and cytokine release in microglia. Gut microbiota dysbiosis promotes early AD pathogenesis by dysregulating the microglial TREM2/SYK/NF-κB pathway, thereby driving neuroinflammation and synaptic dysfunction. Targeting this microbiota-signaling axis may offer novel therapeutic strategies.},
}

@article {pmid42130608,
year = {2026},
author = {Xu, Y and Sachdev, PS and Lennon, MJ},
title = {Vascular cognitive impairment and dementia drug-development pipeline 2025.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {},
pages = {e70263},
pmid = {42130608},
issn = {2352-8737},
abstract = {INTRODUCTION: There are currently no approved medicines for vascular cognitive impairment and dementia (VCID).

METHODS: We reviewed clinical trials across nine registries and included, summarized, and evaluated trials that had not yet published peer-reviewed results by August 22, 2025.

RESULTS: We found 88 clinical trials using 62 drugs. Cardiovascular disease-targeted therapies accounted for 37% (23 drugs). Synthetic and plant-based cognitive function enhancers accounted for 21% (13 drugs) each. Drugs targeting neuropsychiatric symptoms comprised 10% of the pipeline (six agents), biological disease-targeted therapies 5% (three agents), and other drugs 6% (four agents). There were 30 trials assessing 25 drugs in Phase 4, 24 trials assessing 21 drugs in Phase 3, 29 trials assessing 28 drugs in Phase 2, and five trials assessing four drugs in Phase 1.

DISCUSSION: While small relative to Alzheimer's disease (138 drugs, 182 trials in 2025), the drug pipeline for VCID shows some promise and will require further investment.},
}

@article {pmid42130609,
year = {2026},
author = {Gobbi, S and Silvestri, E and Tonietto, M and Klein, G and van den Heuvel, M and Magon, S},
title = {Functional connectome metrics reveal distinct prognostic subtypes in two Phase 3 gantenerumab trials.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {},
pages = {e70259},
pmid = {42130609},
issn = {2352-8737},
abstract = {INTRODUCTION: Alzheimer's disease (AD) heterogeneity poses significant challenges for drug development, identification of individuals at risk, and treatment response prediction. Scientists have leveraged graph theory and resting-state functional magnetic resonance imaging (rs-fMRI) to successfully stratify people with AD. Still, the prognostic value of rs-fMRI graph metrics in AD clinical trials remains unclear.

METHODS: We analyzed rs-fMRI from participants in amyloid-lowering clinical trials. Four graph metrics-global efficiency, clustering coefficient, modularity, and shortest path length-were computed and baseline clusters defined using unsupervised k‑means. We investigated the baseline connectome of each cluster to assess the level of network dysfunction and impairment (i.e., loss of global integration, resulting in disrupted communication between brain regions and reduced global efficiency). These clusters were related to a 116-week change in cognition and brain volume using covariate-adjusted mixed-effects models.

RESULTS: Three clusters emerged with distinct functional connectome efficiency, demographic, and AD-related biomarkers profiles. These baseline differences led to significant variations in disease progression. The most impaired‑connectome cluster declined fastest, whereas the most integrated declined slowest.

DISCUSSION: rs-fMRI graph metrics might effectively stratify participants with AD in clinical trials and serve as potential prognostic biomarkers.},
}

@article {pmid42130716,
year = {2026},
author = {Deau, E and Simon, C and Hogrel, G and Caillette, J and Dairou, J and Herault, Y and Morlet, B and Miyata, Y and Meijer, L and Lindberg, MF},
title = {Mapping the Brain Interaction Network of the Dual-Specificity, Tyrosine Phosphorylation-Regulated Kinase 1A (DYRK1A) Targeted by Leucettinib-21 Using Affinity Chromatography.},
journal = {ACS pharmacology & translational science},
volume = {9},
number = {5},
pages = {1204-1227},
pmid = {42130716},
issn = {2575-9108},
abstract = {Leucettinibs are substituted 2-aminoimidazolin-4-ones inspired by the marine sponge natural product Leucettamine B and developed as pharmacological inhibitors of DYRK1A (dual-specificity, tyrosine phosphorylation-regulated kinase 1A), a therapeutic target for indications such as Down syndrome, Alzheimer's disease, Parkinson's disease, diabetes, myocardial infarction, etc. Leucettinib-21 is currently being tested in a phase 1 clinical trial. In this study, four different affinity chromatography-based approaches were developed to identify the rat brain targets of Leucettinib-21: (1) Leucettinib-21 (and its kinase-inactive isomer as control) immobilized on agarose beads, (2) immobilized metal affinity chromatography, (3) KinAffinity bead competition assays, and (4) immunoprecipitation with DYRK1A-specific antibodies. Altogether, these complementary methods (1) confirm known targets of Leucettinib-21, and identify (2) new protein kinases and nonkinases interacting with Leucettinib-21, (3) potential new partners of DYRK1A, and (4) pathways and cellular mechanisms potentially modulated by Leucettinib-21. These methods can be expanded to various cells and tissues from models of pathologies where Leucettinib-21 demonstrates efficacy.},
}

@article {pmid42130721,
year = {2026},
author = {Kumar, S and Upadhyay, A},
title = {Roles of RNA-Binding Nuclear Proteins in Alzheimer's Disease Pathophysiology.},
journal = {ACS pharmacology & translational science},
volume = {9},
number = {5},
pages = {1055-1067},
pmid = {42130721},
issn = {2575-9108},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder associated with cognitive decline. Pathologically, AD is characterized by the accumulation of amyloid β (Aβ) monomers that may generate oligomers or fibrils in the extracellular space and inside the neurons. With time, the oligomers and fibrils aggregate into insoluble plaques, which may trigger a cascade of molecular events. These include altering gene expression at a broader level, implicating cross-talk with the nuclear machinery, including transcription. There is now emerging evidence implicating the role of RNAs and other nuclear proteins in AD pathogenesis, especially those associated with RNA splicing and ribonucleoproteins, which, along with post-transcriptional modifications, give rise to multiple functional proteoforms. Notably, RBPs themselves exist as multiple proteoforms, adding complexity to the proteome involved in AD. Therefore, in this review, we limit the discussion to the canonical protein forms of RBPs already established to have some role in AD pathophysiology. Recently, our proteomic study identified three such RBPs (SRSF2, hnRNPH1, and hnRNPA2B1) copurifying with amyloid, suggesting a possible interaction with Aβ and contribution to AD pathology. SRSF2 is a splicing factor involved in tau exon splicing, while hnRNPH1 and hnRNPA2B1 are both heterogeneous nuclear RBPs (hnRNPs) involved in mRNA processing. Some of the other hnRNPs have previously been implicated in AD and tau pathology. This review focuses on some of the recent evidence that suggests a possible involvement of RNA-associated nuclear proteins in dysregulation of widespread RNA processing affecting the AD pathogenesis pathways. We discuss how their dysfunction could modulate Aβ and tau-associated changes with an emphasis on understanding the linkage between nuclear RNA machinery and AD pathophysiology. Understanding this crosstalk may offer new insights into our understanding of AD and could provide RNA-centric therapeutic avenues.},
}

@article {pmid42130756,
year = {2026},
author = {von Borcke, N and Purwien, AV and Steiert, A and Hasecke, H and Bouter, Y},
title = {Reduced CB1 Cannabinoid Receptor Expression in Alzheimer's Disease and Transgenic Mouse Models.},
journal = {Aging medicine (Milton (N.S.W))},
volume = {9},
number = {2},
pages = {168-184},
pmid = {42130756},
issn = {2475-0360},
abstract = {OBJECTIVES: Therefore, in the present study, the CB1 receptor (CB1R) expression in the hippocampal and cortical tissue of a clinically and neuropathologically characterized cohort of AD patients was analyzed.

METHODS: Post-mortem brain tissue from patients with sporadic AD and non-demented control subjects was analyzed immunohistochemically, focusing on the hippocampus, medial frontal gyrus, and superior temporal gyrus. CB1R expression levels were measured and correlated with neuropathological hallmarks of AD (amyloid-β and tau pathology), neuroinflammatory markers (GFAP and IBA1), cognitive status (Reisberg scale), ApoE genotype, and age. Complementary analyzes were performed in two AD mouse models (5xFAD and Tg4-42).

RESULTS: CB1R expression was significantly reduced in the hippocampus, medial frontal gyrus, and superior temporal gyrus of AD patients. CB1R levels negatively correlated with both amyloid-β and tau pathology but showed no association with cognitive performance, neuroinflammatory markers, age, or ApoE genotype. Consistent with the human findings, CB1R expression was also reduced in the cortex of 5xFAD mice and in the hippocampus of Tg4-42 mice.

CONCLUSIONS: Our data demonstrate a region-specific downregulation of CB1R in both human AD brains and transgenic mouse models, which correlates with key neuropathological hallmarks of the disease. These findings suggest a potential role for CB1R in AD pathophysiology and support further investigation into its utility as a biomarker or therapeutic target.},
}