New genetic players in late-onset Alzheimer's disease: Findings of genome-wide association studies

Abstract

Late-onset Alzheimer's disease (LOAD) or sporadic AD is the most common form of AD. The precise pathogenetic changes that trigger the development of AD remain largely unknown. Large-scale genome-wide association studies (GWASs) have identified single-nucleotide polymorphisms in multiple genes which are associated with AD; most notably, these are ABCA7, bridging integrator 1 (B1N1), triggering receptor expressed on myeloid cells 2 (TREM2), CD33, clusterin (CLU), complement receptor 1 (CRI), ephrin type-A receptor 1 (EPHA1), membrane-spanning 4-domains, subfamily A (MS4A) and phosphatidylinositol binding clathrin assembly protein (PICALM) genes. The proteins coded by the candidate genes participate in a variety of cellular processes such as oxidative balance, protein metabolism, cholesterol metabolism and synaptic function. This review summarizes the major gene loci affecting LOAD identified by large GWASs. Tentative mechanisms have also been elaborated in various studies by which the proteins coded by these genes may exert a role in AD pathogenesis have also been elaborated. The review suggests that these may together affect LOAD pathogenesis in a complementary fashion.

Keywords: Alzheimer's disease; Heart and Aging Research in Genomic Epidemiology; LOAD; Translational Genomics Research Institute; genome-wide association study; single nucleotide polymorphism.

Fig. 1

Schematic representation of multiple organizations who worked to find new genome-wide association study loci and how different loci are connected with each other. The gene loci found as a result of meta-analyses belong to three broad functional categories: immune response, synaptic function and cholesterol metabolism. GWAS, genome wide association studies; GERAD1, genetic and environmental risk for Alzheimer's disease consortium 1; EADI1, European Alzheimer's disease initiative 1; CHARGE, Cohorts for Heart and Aging research in genomic epidemiology; TGRI, Translational Genomics Research Institute; ADGC, Alzheimer's disease genetic consortium; LOAD, late onset Alzheimer's disease.

Fig. 2

Interconnected responsible pathways to cause amyloid and tau accumulation. Gene involved in AD pathogenesis can be broadly grouped into 3 categories; immune response (CR1, MS4A, TREM2, CD33, EPHA1), cholesterol metabolism (APOE, CLU, ABCA7), synaptic function (PICALM, CD2AP, BIN1). The cumulative effect of all these genes is manifested through the final common pathway of amyloid and tau cascade.