APOE-3 and TOMM-40 Haplotypes Determine Inheritance of Alzheimer's Disease Independently of APOE-4 Risk

Noting that estimates for the heritability of apolipoprotein E-4 (APOE-4) for late-onset Alzheimer’s disease (ranging from 58-79%) and the population-attributable risk due to the APOE-4 allele (ranging from 20-70%) suggest that “other genetic variants or interactions between variants incur additional risk and modify age of onset distributions.” Also taking into account the “extraordinary association” for AD with the linkage disequilibrium (LD) region containing APOE, and that TOMM-40, the “protein translocase of the outer mitochondrial membrane,” is also in high LD with APOE, Allen D. Roses, of Duke University and the Deane Drug Discovery Institute, and colleagues sought to identify new haplotypes with this LD region that may increase estimates of heritability. They studies the TOMM-40/APOE-4 LD region in 66 patients with AD and 66 age-matched controls. They found that “unique and distinct inherited families of different TOMM-40 variants are located on the same genetic interval as APOE-3,” but not on the APOE-4 genetic region. These variants can “either increase or decrease the age of risk distribution of AD.” They concluded that “the genetic inheritance of these TOMM-40 variants is independent of the inheritance of APOE-4, providing a differentiation of two distinct forms of APOE-3: those linked to TOMM-40 haplotypes that increase risk and decrease age of onset, and those that decrease risk.”