Taken together, these results demonstrate how specific the protective effects of e2 are (e.g., they seem specific to tau 3R/4R found in AD and prevent tangles); it may also be the case that despite some evidence for a direct effect on tau, most of e2’s protective associations with tau in AD are via amyloid mediation, but this would not explain e2 as a risk allele. This evidence concerns the gene MAPT and Alzheimer disease.