Sex differences in APOE effects on cognition are domain‐specific
Authors: Contreras Alex G , Walters Skylar , Mukherjee Shubhabrata , Lee Michael L. , Choi Seo‐Eun , Scollard Phoebe , Trittschuh Emily H. , Mez Jesse B. , Bush William S. , Engelman Corinne D. , Lu Qiongshi , Fardo David W. , Widaman Keith F. , Buckley Rachel F. , Mormino Elizabeth C. , Kunkle Brian W. , Naj Adam C. , Clark Lindsay R. , Gifford Katherine A. ,   The Alzhemer's Disease Neuroimaging Initiative (ADNI),   Alzheimer’s Disease Genetics Consortium (ADGC),   The Alzheimer's Disease Sequencing Project (ADSP), Cuccaro Michael L. , Cruchaga Carlos , Pericak‐Vance Margaret A. , Farrer Lindsay A. , Wang Li‐San , Schellenberg Gerard D. , Haines Jonathan L. , Jefferson Angela L. , Johnson Sterling C. , Kukull Walter A. , Albert Marilyn S. , Keene C Dirk , Saykin Andrew J. , Larson Eric B , Sperling Reisa A. , Mayeux Richard , Thompson Paul M , Martin Eden R. , Bennett David A , Barnes Lisa L. , Schneider Julie A , Crane Paul K. , Hohman Timothy J. , Dumitrescu Logan 
Published: December 2022

Background

Two‐thirds of Alzheimer’s disease (AD) patients are women and there are well‐established sex differences in the association between APOE and cognitive impairment in AD. However, it is not clear whether sex‐specific cognitive consequences of APOE emerge across all cognitive domains or in a domain‐specific manner.

Method

Data were obtained from 38,386 participants in four longitudinal studies of aging and AD. The average age of participants at baseline was 75±8 years (10% AD, 42% male, 12% African American [AA], 12% APOE‐ε2 carriers, and 36% APOE‐ε4 carriers). Based on detailed neuropsychological exams, harmonized composite scores for memory, executive function, and language were generated using latent variable modeling. Linear regression assessed APOE*sex interactions on each baseline cognitive domain score. Mixed‐effects regression models assessed sex interactions with APOE on cognitive trajectories, including fixed and random effects for both the intercept and the slope (years from baseline). All models adjusted for age at baseline, sex, and race/ethnicity. Exploratory analyses of the potential effect of race/ethnicity were also performed using an APOE*sex*race interaction term in the model.

Result

As expected, APOE‐ε4 was associated with worse cognitive performance, and APOE‐ε2 was associated with better performance in all domains, both at baseline and longitudinally (p<0.001). At baseline, we observed a significant sex*APOE‐ε4 interaction on memory (β=‐0.06, p<0.001) and significant sex*APOE‐ε2 interaction on memory (β=0.05, p=0.03). In both cases, the association between APOE and memory was significantly stronger in females compared to males. Notably, despite the large sample size, no interactions were observed in the two other cognitive domains or in the longitudinal analysis. Additionally, we observed a significant interaction between sex*APOE‐ε2*race on baseline memory (β=‐0.19, p=0.02), whereby the APOE‐ε2*sex interaction was significant in non‐Hispanic whites (β=0.06, p<0.01) but not in AA (β=‐0.11, p=0.10).

Conclusion

We provide new evidence that the sex difference in APOE in cognition is most pronounced in relation to memory performance and is particularly driven by differences in baseline performance rather than trajectories of performance over time. Future work will examine intersections with clinical diagnosis to better differentiate sex differences in APOE associations in the context of normal aging and neurodegenerative disease.