Abstract
Alzheimer's disease (AD) is a neurodegenerative disorder contributing to a rapid decline in cognitive function and ultimately dementia. Most cases of AD occur in elderly and later years.
There is a growing need for understanding the relationship between aging and AD to identify shared and unique hallmarks associated with the disease in a region and cell-type specific manner.
Although genomic studies on AD have been performed extensively, the molecular mechanism of disease progression is still not clear. The major objective of our study is to obtain a higher-order
network-level understanding of aging and AD, and their relationship using gene expression profiles of young (20–50 years), aging (70–99 years), and AD (70–99 years). Also, these approaches were
used to determine regional vulnerability in aging and AD. Hippocampus (HC) is vulnerable to damage at early stages of AD and altered neurogenesis in the hippocampus is linked to the onset of AD. We combined the weighted gene co-expression network and weighted protein-protein interaction network-level approaches to study the transition from young to aging to AD in HC. We found that modules associated with astrocytes, endothelial cells and microglial cells are upregulated and significantly correlate with both aging and AD. The modules associated with neurons, mitochondria and endoplasmic reticulum are downregulated and significantly correlate with AD than aging. The oligodendrocytes module does not show significant correlation with either aging or disease. Further, we identified aging- and AD-specific interactions/subnetworks by integrating the gene expression with a human protein-protein interaction network. We found dysregulation of genes encoding protein kinases (FYN, SYK, SRC, PKC, MAPK1, ephrin receptors) and transcription factors (FOS, STAT3, CEBPB, MYC, NFKβ, and EGR1) in AD. Further, we found genes that encode proteins with neuroprotective function (14- 3-3 proteins, PIN1, ATXN1, BDNF, VEGFA) to be part of the downregulated AD subnetwork.Further, network analysis on regions Entorhinal Cortex (EC), Post Central Gyrus (PCG) and Superior Frontal Gyrus (SFG) revealed similar cell-types were affected in aging and AD but the
extent of changes is more diverse in aging than AD. Glial and endothelial changes were prominent in aging whereas neuronal changes were prominent in AD. Synaptic transmission, protein
processing, mitochondria energy metabolism, and inflammation were the major processes affected in these regions. In aging, EC showed minimal changes followed by HC and PCG while SFG
showed maximum changes. In AD, EC and HC showed maximum changes while PCG and SFG showed minimal changes. Overall, the network-level analysis showed differences in regional vulnerability to aging and AD. Taken together, our study highlights that simultaneously analyzing aging and AD will help to understand the pre-clinical and clinical phase of AD and aid in developing the treatment strategies.