Apolipoprotein E ε2 allele promotes longevity and protects patients with Downʼs syndrome from dementia

ALTHOUGH individuals with Downʼs syndrome nearly always develop the clinical and pathological features of Alzheimerʼs disease, some clearly do not become demented despite living into their sixth and seventh decades. Genetic variation at the apolipoprotein E locus has recently been shown to be an important determinant of Alzheimerʼs disease, with the ε4 allele having been shown to be associated with the disease and, at least in some cases, the ε2 allele being negatively associated with the disease. Here we show, in a series of clinically assessed individuals with Downʼs syndrome, that the ε2 allele of ApoE is associated with both longevity and the absence of clinical evidence of dementia. These data show that the clinical phenotype of Downʼs syndrome can be modulated by genes on chromosomes other than chromosome 21. The importance of this observation to the pathogenesis of Alzheimerʼs disease, both in Downʼs syndrome and in general, is discussed.