Struble and McAsey propose that apolipoprotein E (APOE) is a pivotal required intermediary in the neuroprotective effects of hormone replacement therapy (HT) not only in dementia but in other chronic neurological diseases. Basic science analyses indicate that 17β-estradiol increases APOE expression, which facilitates neuronal plasticity, neural repair, and could delay progression of several types of neurodegenerative disease. The issue of the APOE4 isoform, which may be a negative regulator of HT outcomes, is considered along with therapeutic implications for either increasing or decreasing its expression. These authors propose that subsequent studies of the impact of HT or selective estrogen receptor modulators on neurological function should include APOE genotyping.