Apolipoprotein E and cognitive decline in Alzheimer's disease

In efforts to explain the phenotypic heterogeneity of Alzheimer's disease (AD), many studies have sought subtypes of this illness. The recent identification of several distinct genes associated with AD provides the first biological means of differentiating such subtypes. Mutations on chromosomes 1, 14, and 21 provoke various forms of early-onset familial AD. Yet, these genes account in aggregate for fewer than 2% of all AD cases. Most AD cases have later onset (i.e., after age 65). To date, the only confirmed genetic marker associated with increased risk of late-onset AD is allele epsilon 4 at APOE, the polymorphic locus on chromosome 19 that encodes apolipoprotein E. The risk for AD is enhanced, and the mean age of symptom onset reduced, as the number of epsilon 4 alleles (0, 1, or 2) increases. These observations suggest epsilon 4 accelerates the neurodegenerative process that underlies the development of AD. A logical prediction from this hypothesis is that cognitive decline in AD should progress more quickly for those whose genotype includes epsilon 4. Three articles in this issue [1-3] address this topic. Contrary to such a prediction, all three studies report that AD patients with epsilon 4 do not show faster cognitive or functional decline than patients without epsilon 4. The clinical series of Growdon et al. [1] and Kurz et al. [3] also failed to replicate the common observation of differences in onset with various APOE genotypes. Although this latter finding may in part reflect limited sample size, it also highlights the difficulties commonly encountered when studying ``population'' characteristics in self-referred clinic samples. To study disease progression, Growdon et al. [1] and Kurz et al. [3] monitored performance on several psychometric measures of cognitive and functional abilities for up to 5.5 years. Growdon et al. estimated that APOE genotype accounted for less …