Identification of Blood Biomarkers for Alzheimer's Disease Through Computational Prediction and Experimental Validation

Abstract

Background: Alzheimer's disease (AD) is the major cause of dementia in population aged over 65 years, accounting up to 70% dementia cases. However, validated peripheral biomarkers for AD diagnosis are not available up to present. In this study, we adopted a new strategy of combination of computational prediction and experimental validation to identify blood protein biomarkers for AD.Methods: First, we collected tissue-based gene expression data of AD patients and healthy controls from GEO database. Second, we analyzed these data and identified differentially expressed genes for AD. Third, we applied a blood-secretory protein prediction program on these genes and predicted AD-related proteins in blood. Finally, we collected blood samples of AD patients and healthy controls to validate the potential AD biomarkers by using ELISA experiments and Western blot analyses.Results: A total of 2754 genes were identified to express differentially in brain tissues of AD, among which 296 genes were predicted to encode AD-related blood-secretory proteins. After careful analysis and literature survey on these predicted blood-secretory proteins, ten proteins were considered as potential AD biomarkers, five of which were experimentally verified with significant change in blood samples of AD vs. controls by ELISA, including GSN, BDNF, TIMP1, VLDLR, and APLP2. ROC analyses showed that VLDLR and TIMP1 had excellent performance in distinguishing AD patients from controls (area under the curve, AUC = 0.932 and 0.903, respectively). Further validation of VLDLR and TIMP1 by Western blot analyses has confirmed the results obtained in ELISA experiments.Conclusion: VLDLR and TIMP1 had better discriminative abilities between ADs and controls, and might serve as potential blood biomarkers for AD. To our knowledge, this is the first time to identify blood protein biomarkers for AD through combination of computational prediction and experimental validation. In addition, VLDLR was first reported here as potential blood protein biomarker for AD. Thus, our findings might provide important information for AD diagnosis and therapies.

Spermidine in dementia

“…Validated peripheral biomarkers for Alzheimer's disease (AD) diagnosis are Bivariate correlation between serum spermidine levels and age. Pearson correlation coefficient between spermidine level and age is -0.512 (p < 0.001) not available at present [15]. Further work needs to be done to evaluate the qualification of spermidine as a biomarker.…”

Alzheimer’s Disease, and Breast and Prostate Cancer Research: Translational Failures and the Importance to Monitor Outputs and Impact of Funded Research

“…Furthermore, next-generation sequencing, omics, integrated computer modelling, systems biology, and imaging technologies are already used to study pathways of diseases, identify new biomarkers, and evaluate the molecular (genetic and epigenetic) effects of new treatments, as reported for cancer [31,200] and AD [32,201,202].…”

Advantages and Pitfalls in Fluid Biomarkers for Diagnosis of Alzheimer’s Disease

“…In order to investigate novel protein and their capacity to predict AD, an early study analyzed 120 plasma proteins and discovered 18 signaling proteins, which showed 90% of accuracy in diagnosis for AD patients and 91% for MCI patients [86]. Further studies have been reported a total of 1590 AD-related proteins, including 296 proteins encoded with 115 up-regulated and 181 down-regulated genes, and supposed to be blood-secretory proteins involved in the pathogenesis of AD [87]. It was suggested that around 35 AD-related proteins are consistent, including four key proteins (APP, apolipoprotein E, PSEN-1, and PSEN-2) involved in AD pathology [87].…”

“…Further studies have been reported a total of 1590 AD-related proteins, including 296 proteins encoded with 115 up-regulated and 181 down-regulated genes, and supposed to be blood-secretory proteins involved in the pathogenesis of AD [87]. It was suggested that around 35 AD-related proteins are consistent, including four key proteins (APP, apolipoprotein E, PSEN-1, and PSEN-2) involved in AD pathology [87]. Synaptic proteins such as synaptosomal-associated protein 25 (SNAP-25) and synaptotagmin-1 (SYT1) were found to be significantly increased in the CSF of AD dementia and prodromal AD patients; however, SNAP-25 and SYT1 were specified to decline in cortical areas [88,89].…”