Apolipoprotein E (ApoE) has three major polymorphic alleles, denoted APOE2, APOE3, and APOE4. Two copies of APOE4 constitutes the strongest genetic risk factor for AD and increases the risk of developing disease by 12 compared with individuals who inherit APOE3. ApoE4 differs from ApoE3 by a single amino acid, this small change alters the conformation of the protein, altering its activity in many biological pathways causing it to make one both more likely to develop AD and more susceptible to the consequences. One consequence of these minor protein variations is that purified ApoE4 is less stable than ApoE3, with ApoE2 being even more stable. Using an assay to measure this instability we have found a small molecule that can make ApoE4 more like ApoE3 and this molecule is also able to impact some of the biological processes which make ApoE4 so detrimental, so called ApoE correctors. However, this compound is not able to enter the brain which is necessary for a drug against AD. Our research plan is to change this molecule in specific ways to find a compound that will both, correct ApoE4 structure and function to make it more like ApoE3 as well as enter the brain. These efforts represent initial steps towards our overall long-term objective, discovering first in class ApoE4 correctors as therapeutics for AD.