INTRODUCTION
Alzheimer's Disease (AD) is a neurological condition that increases in severity from a gradual start. Previous studies have found an association between long sleep (LS) and AD. To slow its progression, it is important to recognize biomarkers associated with the early stages of both AD and LS.
METHODS
This study aimed to use two-sample Mendelian Randomization (MR) to identify blood and urine biomarkers associated with AD and LS. Thirty-five biomarkers from blood and urine were included as exposures in the MR analysis, while AD and LS were considered the outcomes. The AD dataset included 39,106 patients and 46,828 controls from Europe. Data on sleep duration were obtained from a GWAS in 34,184 cases and 305,742 controls of European ancestry. This study included 35 blood and urine biomarkers across 355,891 participants, including 318,953 white British, 23,582 non-white British, 6,019 African, and 7,338 South Asian participants from the UK Biobank.
RESULTS
Cystatin C, CRP, and Non-Albumin protein showed genetic association with AD and LS. The genetic association results after Bonferroni's correction are significant for Non-Albumin Protein in AD and LS.
DISCUSSION
This study provides further insight into the genetic associations and relationships among AD, LS, and other biomarkers; it also presents several potential candidates for AD and LS diagnosis and treatment. The opposing roles of C-reactive Protein, Cystatin C, and Non-Albumin protein in AD and LS warrant a greater exploration of their differential functions at various ages and in specific brain microenvironments in future studies.
CONCLUSION
This study provides a theoretical basis for the diagnosis and treatment of AD and LS. More experiments are needed in the future to verify this prediction.
Jian-Ran Ma, Zhen Wei, Chunshu Rong et al.· Current Alzheimer Research· 0 citations
INTRODUCTION
The pathogenesis of Alzheimer's disease (AD) is complex, with immune system dysregulation playing a critical role. However, the specific molecular mechanisms linking peripheral immune responses to central pathologies in AD remain unclear. This study aims to systematically screen for reliable plasma biomarkers of AD by integrating transcriptomics, Mendelian randomization (MR) of plasma proteomics, and bioinformatics analyses, and to explore their potential pathogenic mechanisms and therapeutic drugs.
MATERIALS AND METHODS
Transcriptomic sequencing of plasma samples from three AD patients and three healthy controls was first performed to identify differentially expressed genes (DEGs) and perform functional enrichment analyses. The aim of this study is to provide a preliminary indication of gene expression changes based on real patient samples for subsequent MR and bioinformatics analyses, rather than serving as confirmatory evidence. Following this, two-sample MR was performed to explore the potential causal relationship between plasma proteins and AD in genetic prediction, and MR-positive results were intersected with transcriptome DEGs to identify highconfidence targets. After that, protein-protein interaction (PPI) analysis, functional enrichment (GO/KEGG), and transcription factor (TF) target network analysis were conducted. Based on the KEGG pathway analysis, the causal association between antibodies related to Epstein-Barr virus and AD in genetic prediction was further evaluated. In the end, the diagnostic power of core biomarkers was validated in the GEO dataset. Potential therapeutic drugs were screened in the CTD database, followed by verification through molecular docking and molecular dynamics simulation.
RESULT
Our transcriptomic enrichment analysis of DEGs indicates that AD is significantly correlated with viral infection and immune and inflammatory pathways. According to the results of MR analyses, 36 plasma proteins have a causal effect on AD in genetic prediction. Among these 36 targets, two pathways are identified as enriched: "EBV Infection" and "Efferocytosis". Seven core targets are CR2, ICAM1, TAPBP, TNFAIP3, THBS1, SCARF1, and SIRPG. Also, the concentration of antibodies against EBV EBNA-1 and VCA p18 was confirmed by MR analyses to be risk factors for AD. According to drug predictions, molecular docking, and molecular dynamics simulations, resveratrol can stabilize CR2.
DISCUSSION
This study systematically identifies major plasma immune biomarkers associated with AD and proposes a mechanism by which EBV infection regulates plasma proteins CR2, TNFAIP3, and THBS1, which may affect AD risk. Resveratrol is thought to have preventive and protective effects, as predicted computationally.
CONCLUSION
This study systematically identified key plasma markers associated with AD. Resveratrol is likely to become a potentially effective preventive and protective drug in the prevention and treatment of AD, providing new ideas and targets for immune intervention of AD.
Xu Wang, Jinjian Li, Zhen Wei et al.· Current Alzheimer Research· 0 citations
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