Search for risk genes in Alzheimer's disease

Alzheimer's disease (AD) is the most common form of neurodegenerative dementia. The susceptibility to AD is determined by a complex interaction between genetic, epigenetic, and environmental factors. Herein, the risk that can be attributed to genetic factors is high (up to 80%). While most AD patients are sporadic, in rare families Mendelian mode of inheritance can be observed. In these rare familial cases, full penetrant mutations have been identified in APP, PSEN1, and PSEN2. Mutations in these three genes are however rarely found in sporadic AD. For over 20 years, the only known genetic risk factor in sporadic AD cases was the APOE-epsilon 4 allele, which increases susceptibility to AD by approximately threefold. Unfortunately, none of these genes explain the frequency of AD. Identification of additional genetic factors was propelled by the advent of genomic approaches such as genome-wide association studies, which has already led to the characterization of 26 novel genetic risk factors. Interestingly, several of these genetic signals cluster in biological pathways including cholesterol, lipid metabolism, immune response, and endocytic trafficking. An additional impulse in genetic research came from the development of novel sequencing technologies. For example, the whole exome sequencing approach has identified an association between the risk of AD and rare coding variants (minor allele frequency < 1%) located in genes such as TREM2, SORL1, and ABCA7. Thus, progress from genetic research has significantly increased our understanding of the disease mechanisms operating in AD. However, even though our knowledge of the genetics of sporadic forms of AD has progressed markedly over the last years, it is still far from complete. Additional research is needed to complete the genetic architecture of AD.