Associations of Sex, Race, and Apolipoprotein E Alleles With Multiple Domains of Cognition Among Older Adults

Medientyp: E-Artikel
Titel: Associations of Sex, Race, and Apolipoprotein E Alleles With Multiple Domains of Cognition Among Older Adults
Beteiligte: Walters, Skylar; Contreras, Alex G.; Eissman, Jaclyn M.; Mukherjee, Shubhabrata; Lee, Michael L.; Choi, Seo-Eun; Scollard, Phoebe; Trittschuh, Emily H.; Mez, Jesse B.; Bush, William S.; Kunkle, Brian W.; Naj, Adam C.; Peterson, Amalia; Gifford, Katherine A.; Cuccaro, Michael L.; Cruchaga, Carlos; Pericak-Vance, Margaret A.; Farrer, Lindsay A.; Wang, Li-San; Haines, Jonathan L.; Jefferson, Angela L.; Kukull, Walter A.; Keene, C. Dirk; Saykin, Andrew J.; [...]
Erschienen: American Medical Association (AMA), 2023
Erschienen in: JAMA Neurology
Sprache: Englisch
DOI: 10.1001/jamaneurol.2023.2169
ISSN: 2168-6149
Schlagwörter: Neurology (clinical)
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Beschreibung: <jats:sec id="ab-noi230045-4"><jats:title>Importance</jats:title><jats:p>Sex differences are established in associations between apolipoprotein E (<jats:italic>APOE</jats:italic>) ε4 and cognitive impairment in Alzheimer disease (AD). However, it is unclear whether sex-specific cognitive consequences of <jats:italic>APOE</jats:italic> are consistent across races and extend to the <jats:italic>APOE</jats:italic> ε2 allele.</jats:p></jats:sec><jats:sec id="ab-noi230045-5"><jats:title>Objective</jats:title><jats:p>To investigate whether sex and race modify <jats:italic>APOE</jats:italic> ε4 and ε2 associations with cognition.</jats:p></jats:sec><jats:sec id="ab-noi230045-6"><jats:title>Design, Setting, and Participants</jats:title><jats:p>This genetic association study included longitudinal cognitive data from 4 AD and cognitive aging cohorts. Participants were older than 60 years and self-identified as non-Hispanic White or non-Hispanic Black (hereafter, White and Black). Data were previously collected across multiple US locations from 1994 to 2018. Secondary analyses began December 2021 and ended September 2022.</jats:p></jats:sec><jats:sec id="ab-noi230045-7"><jats:title>Main Outcomes and Measures</jats:title><jats:p>Harmonized composite scores for memory, executive function, and language were generated using psychometric approaches. Linear regression assessed interactions between <jats:italic>APOE </jats:italic>ε4 or <jats:italic>APOE</jats:italic> ε2 and sex on baseline cognitive scores, while linear mixed-effect models assessed interactions on cognitive trajectories. The intersectional effect of race was modeled using an <jats:italic>APOE</jats:italic> × sex × race interaction term, assessing whether <jats:italic>APOE</jats:italic> × sex interactions differed by race. Models were adjusted for age at baseline and corrected for multiple comparisons.</jats:p></jats:sec><jats:sec id="ab-noi230045-8"><jats:title>Results</jats:title><jats:p>Of 32 427 participants who met inclusion criteria, there were 19 007 females (59%), 4453 Black individuals (14%), and 27 974 White individuals (86%); the mean (SD) age at baseline was 74 years (7.9). At baseline, 6048 individuals (19%) had AD, 4398 (14%) were <jats:italic>APOE </jats:italic>ε2 carriers, and 12 538 (38%) were <jats:italic>APOE </jats:italic>ε4 carriers. Participants missing <jats:italic>APOE</jats:italic> status were excluded (n = 9266). For <jats:italic>APOE </jats:italic>ε4, a robust sex interaction was observed on baseline memory (β = −0.071, SE = 0.014; <jats:italic>P</jats:italic> = 9.6 × 10<jats:sup>−7</jats:sup>), whereby the <jats:italic>APOE </jats:italic>ε4 negative effect was stronger in females compared with males and did not significantly differ among races. Contrastingly, despite the large sample size, no <jats:italic>APOE </jats:italic>ε2 × sex interactions on cognition were observed among all participants. When testing for intersectional effects of sex, <jats:italic>APOE </jats:italic>ε2, and race, an interaction was revealed on baseline executive function among individuals who were cognitively unimpaired (β = −0.165, SE = 0.066; <jats:italic>P</jats:italic> = .01), whereby the <jats:italic>APOE </jats:italic>ε2 protective effect was female-specific among White individuals but male-specific among Black individuals.</jats:p></jats:sec><jats:sec id="ab-noi230045-9"><jats:title>Conclusions and Relevance</jats:title><jats:p>In this study, while race did not modify sex differences in <jats:italic>APOE </jats:italic>ε4, the <jats:italic>APOE</jats:italic> ε2 protective effect could vary by race and sex. Although female sex enhanced ε4-associated risk, there was no comparable sex difference in ε2, suggesting biological pathways underlying ε4-associated risk are distinct from ε2 and likely intersect with age-related changes in sex biology.</jats:p></jats:sec>

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