Alzheimer’s Disease Variants with the Genome-Wide Significance are Significantly Enriched in Immune Pathways and Active in Immune Cells

Abstract

The existing large-scale genome-wide association studies (GWAS) datasets provide strong support for investigating the mechanisms of Alzheimer's disease (AD) by applying multiple methods of pathway analysis. Previous studies using selected single nucleotide polymorphisms (SNPs) with several thresholds of nominal significance for pathway analysis determined that the threshold chosen for SNPs can reflect the disease model. Presumably, then, pathway analysis with a stringent threshold to define "associated" SNPs would test the hypothesis that highly associated SNPs are enriched in one or more particular pathways. Here, we selected 599 AD variants (P < 5.00E-08) to investigate the pathways in which these variants are enriched and the cell types in which these variants are active. Our results showed that AD variants are significantly enriched in pathways of the immune system. Further analysis indicated that AD variants are significantly enriched for enhancers in a number of cell types, in particular the B-lymphocyte, which is the most substantially enriched cell type. This cell type maintains its dominance among the strongest enhancers. AD SNPs also display significant enrichment for DNase in 12 cell types, among which the top 6 significant signals are from immune cell types, including 4 B cells (top 4 significant signals) and CD14+ and CD34+ cells. In summary, our results show that these AD variants with P < 5.00E-08 are significantly enriched in pathways of the immune system and active in immune cells. To a certain degree, the genetic predisposition for development of AD is rooted in the immune system, rather than in neuronal cells.

Lymphatics in Neurological Disorders: A Neuro-Lympho-Vascular Component of Multiple Sclerosis and Alzheimer’s Disease?

“…In MS, the involvement of the immune system is evident and remains the primary target of all available treatments to date (Fernandez et al, 2016). In AD, the involvement of the immune system was recently emphasized by GWAS studies, linking immune genes to familiar AD susceptibility (Jiang et al, 2016; Yokoyama et al, 2016). Moreover, recent work suggests the involvement of complement system and microglia in early stage of AD development, before any overt brain amyloid pathology (Hong et al, 2016), and the role of T cells in later stages (Baruch et al, 2016).…”

Secretory Products of the Human GI Tract Microbiome and Their Potential Impact on Alzheimer's Disease (AD): Detection of Lipopolysaccharide (LPS) in AD Hippocampus

“…LPSs, as characteristic components of the outer leaflet of the outer membrane of Gram-negative bacteria shed into the extracellular space, play key roles in host-pathogen interactions and the innate-immune system (Hill and Lukiw, 2015; Zhao et al, 2015; Maldonado et al, 2016). While LPSs contain large and hypervariable oligosaccharide/polysaccharide regions, the relatively conserved lipid region (lipid A) is the endotoxic and biologically active moiety that is largely responsible for septic shock (Jiang et al, 2016; Maldonado et al, 2016). A canonic LPS structure is represented by that of E. coli LPS, one of the most potent neurotoxic lipid A species known, consisting of a 1,4′-biphosphorylated glucosamine disaccharide bearing six fatty acids which are unbranched chains 12–14 methyl(ene) units in length.…”

Bacteroides fragilis Lipopolysaccharide and Inflammatory Signaling in Alzheimer’s Disease

“…Lipopolysaccharides are characteristic components of the outer leaflet of the outer membrane of Gram-negative bacteria shed into the extracellular space that play key roles in host–pathogen interactions of the innate-immune system ( Hill and Lukiw, 2015 ; Zhao et al, 2015 ; Jiang et al, 2016 ; Maldonado et al, 2016 ). While LPSs contain large and hypervariable polysaccharide/oligosaccharide regions, the relatively conserved lipid region (lipid A) is the endotoxic and biologically active moiety that is responsible for septic shock ( Jiang et al, 2016 ; Maldonado et al, 2016 ). A “canonical” LPS structure is represented by that of LPS from E. coli , that contains one of the most potent neurotoxic lipid A species known, consisting of a 1,4′-biphosphorylated glucosamine disaccharide bearing six fatty acids which are unbranched chains 12–14 methyl(ene) units in length.…”