Sex hormones and ApoE4: beyond steroids.

The accompanying paper by Burkhardt and colleagues [2] highlights the complexity of the estrogen/Alzheimer’s disease (AD) connection. One possible explanation of these interesting results is that there is a link between particular estrogen receptor polymorphisms and apolipoprotein E (ApoE) polymorphisms. While there are conflicting reports in the literature, several studies have suggested an increased risk of AD in women with particular estrogen receptor polymorphisms [1]. There is a well established physiologic relationship between estrogen and apolipoproteins due to the fact that estrogen is a reproductive steroid hormone formed from cholesterol, the primary source of which is ApoE. Considering the importance of estrogen in regulation of reproductive function, it is easy to imagine that individuals with ApoE4 might be more fertile if they possessed a particular estrogen receptor polymorphism. Alternatively, the ApoE polymorphism dependent differential effect of estrogen on cognition might be explained by the finding that there appears to be a “critical period” during which hormone replacement therapy (HRT) must be initiated in order to have a protective effect on cognition [4]. One possible explanation for the finding that estrogen exposure had no effect on cognition in individuals possessing an ApoE4 gene relates to this “critical period” hypothesis. Since published data suggests that the possession of an ApoE4 allele is associated with an earlier onset of cognitive decline [3], it may be that the “critical period” for patients positive for ApoE4 begins before it does for ApoE4 nega-