Dr. Frick was recently awarded one of nine inaugural “Sex and Gender in Alzheimer’s” research grants by the Alzheimer’s Association. Dr. Frick’s project is designed to examine how sex and estrogen treatment interact with the genetic risk factor apolipoprotein E (APOE) to regulate memory and neural function in a mouse model of Alzheimer’s disease. The familiar Alzheimer’s disease mouse model developed by collaborator Dr. Mary Jo LaDu of the University of Illinois at Chicago also expresse human APOE variants APOE3 or APOE4. APOE4 is particularly deleterious for cognition in women, especially those with elevated endogenous or exogenous estrogen levels. Moreover, interactions among APOE genotype, sex, and estrogen significantly contribute to Alzheimer’s risk. Yet the nature of these interactions and underlying mechanisms remains entirely unknown. Thus, the overall objective for this application is to determine the role of APOE in regulating the effects of sex and estrogen on memory consolidation neural function in male and female mice that express human APOE3 and APOE4. The proposal will test the central hypothesis that disrupted neuronal function in APOE4 carriers contributes to sex differences in AD risk (Aim 1) and the detrimental effects of estrogen in female APOE4 carriers (Aim 2).
This research will determine the extent to which APOE genotype contributes to sex differences in memory decline, and compare how the effects of estrogen on memory and brain function differ by APOE genotype. APOE status is an important determinant of the effectiveness of hormone therapy (HT). Thus, identifying which patients may benefit from HT, and developing more effective treatments for those who do not respond to HT, is essential to address the needs of a heterogeneous AD population.