Sex differences in associations between <i>APOE ε2</i> and longitudinal cognitive decline
Madeline Wood Alexander, Lisa Y. Xiong, Yuen Yan Wong, Rachel F. Buckley, Walter Swardfager, Mario Masellis, Andrew Lim, Emma Nichols, Renaud La Joie, Kaitlin B. Casaletto, Raj G. Kumar, Kristen Dams-O’Connor, Priya Palta, Kristen M. George, Claudia L. Satizábal, Lisa L. Barnes, Julie A. Schneider, Alexa Pichette Binet, Sylvia Villeneuve, Judy Pa, Adam M. Brickman, Sandra E. Black, Jennifer S. Rabin
Abstract
INTRODUCTION: We examined whether sex modifies the association between APOE ε2 and cognitive decline in two independent samples. METHODS: We used observational data from cognitively unimpaired non-Hispanic White (NHW) and non-Hispanic Black (NHB) adults. Linear mixed models examined interactive associations of APOE genotype (ε2 or ε4 carrier vs. ε3/ε3) and sex on cognitive decline in NHW and NHB participants separately. RESULTS: In both Sample 1 (N = 9766) and Sample 2 (N = 915), sex modified the association between APOE ε2 and cognitive decline in NHW participants. Specifically, relative to APOE ε3/ε3, APOE ε2 protected against cognitive decline in men but not women. Among APOE ε2 carriers, men had slower decline than women. Among APOE ε3/ε3 carriers, cognitive trajectories did not differ between sexes. There were no sex-specific associations of APOE ε2 with cognition in NHB participants (N = 2010). DISCUSSION: In NHW adults, APOE ε2 may protect men but not women against cognitive decline. HIGHLIGHTS: We studied sex-specific apolipoprotein E (APOE) ε2 effects on cognitive decline. In non-Hispanic White (NHW) adults, APOE ε2 selectively protects men against decline. Among men, APOE ε2 was more protective than APOE ε3/ε3. In women, APOE ε2 was no more protective than APOE ε3/ε3. Among APOE ε2 carriers, men had slower decline than women. There were no sex-specific APOE ε2 effects in non-Hispanic Black (NHB) adults.