The significance of lysosome in the diagnosis and subclassification of Alzheimer's disease

Background: Alzheimer's disease (AD) is a heterogeneous disease with complex pathophysiological characteristics. Lysosomes are the main organelles of degradation in eukaryotic cells, and their dysfunction is closely related to AD. Therefore, our goal is to identify the lysosomal induced molecular subtype of AD and further explore the possible mechanisms. Methods: : The dataset was downloaded from the GEO database. By differential expression analysis, 50 differentially expressed lysosomal genes in AD were identified. R-package "ROCR" was used to plot and calculate ROC curves and AUC values for differential lysosomal genes. The expression data of the above genes with AUC greater than 0.7 in the AD group were extracted and the R package "ConsensusClusterPlus" was used for consistent clustering of the AD data set. The contents of 28 kinds of immune cells in all samples (cluster1:28, cluster2:28) of the AD dataset were calculated using the R-package "GSVA". The R package "limma" was used to analyze the differences of autophagy genes in 56 AD data sets based on consistent clustering. R package "WGCNA" carried out weighted co-expression network analysis of the differential genes between cluster1 and cluster2, and extracted the related genes of the two modules with the highest positive and negative correlation. GO and KEGG functional enrichment of the above module genes was performed. Results: : Two lysosomes subtypes (Cluster1:28, Cluster2: 28) with different outcomes were identified in AD cohort by unsupervised clustering of lysosome diagnostics molecular, known as cluster 1/2. The results showed that 13 immune cells were significantly different between cluster1 and cluster2. A total of 76 differentially expressed autopaghy genes were identified. It indicated autopaghy heterogeneity between lysosome subtypes. The enrichment analysis of the key module genes of the lysosome subtype showed that the key module genes were mainly concentrated in the gene set associated with the synapses. Conclusions: : According to the heterogeneity of lysosomes, we identified two different AD subtypes based on different lysosome gene expressions, preliminarily revealing that the heterogeneity of AD may be mainly caused by lysosomes. The role of lysosomes may be related to autophagy and synapses.