The importance of being connected.

In the 17 years since the original report linking the 4 allele of the apolipoprotein E (APOE) gene [1] with late-onset Alzheimer’s disease (LOAD), considerable effort has been expended to elucidate the role that APOE plays in LOAD risk and age of disease onset. LOAD is a genetically complex and heterogeneous disorder. The disease has a strong heritability that is estimated to reach nearly 80% [2], yet only a few genes that account for a proportion of the observed genetic variability have been definitively associated with the disease [3]. The only firmly established genetic risk factor for sporadic AD, and the risk factor with the largest effect size, is the 4 allele of APOE [4]. Carriage of an APOE 4 allele significantly increases the lifetime risk for AD, with the level of risk increasing as the 4 allele dose increases [4, 5], and is associated with lower age of disease onset [4, 6–9]. The APOE gene occurs in an extended linkage region on chromosome 19 that provides an extraordinary genome wide association signal with LOAD. This association signal is generally attributed to the 4 allele of APOE, but other polymorphisms in adjacent genes and the APOE promoter may also contribute to disease pathogenesis. In this commentary, we consider the findings of Lescai et al. [10] in the context of an extensive phylogenetic analysis of the TOMM40-APOE region recently reported by our group [11, 12]. In this issue, Lescai and colleagues identify a haplotype, comprised of a specific allele of an APOE