Apolipoprotein E variants and cognition in healthy individuals: a critical opinion.

The epsilon4 allele of apolipoprotein E (ApoE) is a well-established risk factor for late onset Alzheimer's disease (AD). This knowledge has generated interest in the role of ApoE variants in normal cognition. Varying degrees of cognitive dysfunction have been described in non-demented individuals with one or two epsilon4 alleles leading to suggestions that the gene plays a role in normal cognition or helps calibrate the aging process. In this paper, these hypotheses are critically evaluated. It is argued that ApoE variants play no role in cognitive development. Given the differential neurocognitive sequelae of normal aging and AD, we also suggest that accelerated aging is unlikely to account for the pattern of deficits observed in non-demented epsilon4 allele carriers. We conclude that the neuropsychological dysfunction reported in non-demented epsilon4 carriers is most likely to be the result of incipient AD.