The application of functional genomics to Alzheimer’s disease

Abstract

Alzheimer’s disease (AD) is a polygenic/complex disorder in which more than 50 genetic loci are involved. Primary and secondary loci are potentially responsible for the phenotypic expression of the disease under the influence of both environmental factors and epigenetic phenomena. The construction of haplotypes as genomic clusters integrating the different genotype combinations of AD-related genes is a suitable strategy to investigate functional genomics in AD. It appears that AD patients show about 3–5 times higher genetic variation than the control population. The analysis of genotype–phenotype correlations has revealed that the presence of the APOE-4 allele in AD, in conjunction with other loci distributed across the genome, influence disease onset, brain atrophy, cerebrovascular perfusion, blood pressure, β-amyloid deposition, ApoE secretion, lipid metabolism, brain bioelectrical activity, cognition, apoptosis and treatment outcome. Pharmacogenomics studies also indicate that the therapeutic response in AD is genotype-specific and that ∼ 15% of the cases with efficacy and/or safety problems are associated with a defective CYP2D6 gene. Consequently, the understanding of functional genomics in AD will foster productive pharmacogenomic studies in the search for effective medications and preventive strategies in AD.