Defining the Genetic Architecture of Alzheimer's Disease: Where Next.

BACKGROUND: Late-onset Alzheimer's disease is a genetically complex disorder. For 17 years, APOE was the only known susceptibility gene for disease. Through mostly genome-wide association studies, 25 loci are now known to associate with late-onset Alzheimer's disease. These susceptibility loci are not randomly distributed with respect to their functions. In fact, pathway analysis implicates significant enrichment of immunity, endocytosis, cholesterol metabolism, and ubiquitination in disease.

SUMMARY: Twenty-five loci have now been reliably shown to associate with Alzheimer's disease. However, a significant proportion of genetic variation in disease pathology is yet to be detected. Rare variation is being investigated through exome chip and next-generation sequencing experiments, which have already identified new protective and risk variants. Using a polygenic risk score approach, it is now possible to identify population groups with the greatest and fewest biological susceptibilities to disease. This method has proved more effective in predicting disease status than individual, genome-wide significant variants of small/moderate effect. Future studies will establish the specific functional changes that contribute to disease by piloting novel cellular modelling techniques using reprogrammed induced pluripotent stem cells from individuals with selected risk profiles. This will allow a variety of models to be produced to help understand disease mechanisms and test new drug therapies.

KEY MESSAGES: Alzheimer's disease is a polygenic trait that has been linked to deficits in immunity, endocytosis, cholesterol metabolism and ubiquitination. Future work will focus on identifying rare disease susceptibility loci, unpicking the functional significance of the known risk loci and piloting novel cellular modelling techniques.