Genomics of Alzheimer’s disease

Abstract Alzheimer’s disease (AD) is a complex genetic disorder caused by a combination of genetic effects and environmental factors. In genome-wide complex trait analysis studies, it was found that over half of AD phenotypic variance can be explained by genetics, but only one-third of the genetic variance can be explained by known AD single nucleotide polymorphisms (SNPs). The authors note that the higher unexplained genetic variance is due to a significant increase of markers used in the study and unknown SNP’s in regions close to known AD SNP’s as well as in regions not related to AD SNP’s. These unknown variants in the known AD risk regions are not detectable and contribute, therefore, significantly to variance in AD risk. The classic genotype to phenotype relationship is best illustrated by causal genetic mutations/risk variants and their corresponding alterations in the metabolism of amyloid β protein (Aβ). This chapter will primarily focus on Aβ as a phenotypic readout corresponding to genetic variants and showcase an important Aβ-based approach in developing active DNA Aβ42 immunotherapy for the treatment of AD.