Untangling the Genetics of a Complex Disease

In contrast to many of the struggles of complex trait linkage analysis, Alzheimer disease (AD) research has provided a shining example of the successes that are possible using the traditional study design that has provided the bulk of the extensive genetic understanding of numerous monogenic diseases such as cystic fibrosis and Huntington disease. In recent years, 4 genes have been identified that are involved in the heritable risk of AD. Mutations in 3 of these 4 (the amyloid precursor protein, presenilin 1, and presenilin 2 genes) cause an extremely rare, early-onset, highly penetrant, dominantly acting form of the disease.^1- 4 Although unlikely to be valuable in screening for AD, these rare mutations provide important revelations about the biological mechanisms of AD. The fourth, the ∊4 allele of the APOE gene,⁵ confers a roughly 3-fold increased risk of developing the common, later-onset form of the disease. Because of its frequency (approximately 15% in the general population), this allele accounts for nearly all of the currently identified genetic risk associated with AD. It is clear, however, that other genetic risk factors for the common form of AD must exist as these 4 factors account for only 50% of the total genetic risk.⁶