Genomics and Functional Genomics of Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is a complex and multifactorial neurodegenerative disease. Due to its long clinical course and lack of an effective treatment, AD has become a major public health problem in the USA and worldwide. Due to variation in age-at-onset, AD is classified into early-onset (< 60 years) and late-onset (≥ 60 years) forms with early-onset accounting for only 5-10% of all cases. With the exception of a small number of early-onset cases that are afflicted because of high penetrant single gene mutations in APP, PSEN1, and PSEN2 genes, AD is genetically heterogeneous, especially the late-onset form having a polygenic or oligogenic risk inheritance. Since the identification of APOE as the most significant risk factor for late-onset AD in 1993, the path to the discovery of additional AD risk genes had been arduous until 2009 when the use of large genome-wide association studies opened up the discovery gateways that led the identification of ~ 95 additional risk loci from 2009 to early 2022. This article reviews the history of AD genetics followed by the potential molecular pathways and recent application of functional genomics methods to identify the causal AD gene(s) among the many genes that reside within a single locus. The ultimate goal of integrating genomics and functional genomics is to discover novel pathways underlying the AD pathobiology in order to identify drug targets for the therapeutic treatment of this heterogeneous disorder.

Keywords: Alzheimer’s disease; Functional genomics; Genome-wide association studies; Genomics; SNPs.

Fig. 1

Generation of β-amyloid (Aβ) peptides. The APP amino acid sequence from position 670 to 723 is shown, including the transmembrane region from amino acid 701 to 723. The cleavage sites of α-, β-, and γ-secretases are labelled. Following the generation of APP-C99 by β-secretase, it is cleaved by γ-secretase through its endopeptidase activity (ε-site) to generate Aβ48 or Aβ49 peptide, which is then further cleaved sequentially by the C-terminal peptidase activity of γ-secretase to produce Aβ45, Aβ42, and Aβ38 peptides from Aβ48 (shown at the right bottom end) or Aβ46, Aβ43, and Aβ40 peptides from Aβ49 (shown at the right top end). The full lengths of Aβ40 and Aβ42 peptides are illustrated at the bottom. The start position of APP-C83 following the cleavage with α-secretase is also shown

Fig. 2

Structure of the APOE gene with four exons (top). Non-synonymous mutations at codon 112 (Cys112Arg) and codon 158 (Arg158Cys) in exon 4 code for three common alleles/haplotypes: APOE*2, APOE*3, and APOE*4 (bottom right), resulting in six genotypes (bottom left). The most common APOE*3 allele has Cys at position 112 and Arg at position 158 in the ApoE protein. The amino acid change in APOE*4 at codon 112 is indicated by Arg*, and the amino acid change in APOE*2 at codon 158 is indicated by Cys*

Fig. 3

Timeline of the discovery of AD genes/loci. Red color labelled APP, PSEN1, and PSEN2 genes are for early-onset AD. Green color labelled NFIC and OR2B2 loci were discovered in transethnic GWAS. Purple color labelled IGF1R locus is unique to African Americans and blue color labelled SCARB2 locus is unique to Japanese. The remaining loci were discovered in Europeans/Whites