Unlocking the Memory Component of Alzheimer's Disease: Biological Processes and Pathways across Brain Regions

Abstract

Alzheimer's Disease (AD) is a neurodegenerative disorder characterized by a progressive loss of memory and a general cognitive decline leading to dementia. AD is characterized by changes in the behavior of the genome and can be traced across multiple brain regions and cell types. It is mainly associated with β-amyloid deposits and tau protein misfolding, leading to neurofibrillary tangles. In recent years, however, research has shown that there is a high complexity of mechanisms involved in AD neurophysiology and functional decline enabling its diverse presentation and allowing more questions to arise. In this study, we present a computational approach to facilitate brain region-specific analysis of genes and biological processes involved in the memory process in AD. Utilizing current genetic knowledge we provide a gene set of 265 memory-associated genes in AD, combinations of which can be found co-expressed in 11 different brain regions along with their functional role. The identified genes participate in a spectrum of biological processes ranging from structural and neuronal communication to epigenetic alterations and immune system responses. These findings provide new insights into the molecular background of AD and can be used to bridge the genotype-phenotype gap and allow for new therapeutic hypotheses.

Keywords: Alzheimer’s Disease; co-expression; computational; functional analysis; memory.

Figure 1

Visual representation of the methodological steps taken. Rectangles with a white background encase the tools utilized.

Figure 2

(A) Venn diagram representing the intersection between the memory related genes from various neurodegenerative disorders and the general Alzheimer’s Disease genes. Thei cross-section is called the Memory in Alzheimer’s Disease gene set (MADgs). (B) Protein–Protein Interaction network produced by the MADgs (blue nodes = MADgs genes).

Figure 3

Intersections of the MADgs genes found co-expressed in 11 brain regions.

Figure 4

Co-expression networks of the MADgs genes in 11 different brain regions. Blue nodes are our input genes from MADgs (seeds).

Figure 5

Venn diagrams representing the intersection of co-expressed genes in different brain regions and combinations of them.

Figure 6

Selected results of biological functions involved in structural development and neurotransmission.

Figure 7

Selected results of biological functions involved in cellular signaling and regulation, metabolism, inflammation, perception and the epigenome.