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

• DOI: 10.1001/jamaneurol.2023.2169
• Publication Date: 2023-07-17T15:33:44Z
• Authors: Skylar Walters; Alex G. Contreras; Jaclyn M. Eissman; Shubhabrata Mukhe...; Michael L. Lee; Seo-Eun Choi; Phoebe Scollard; Emily H. Trittschuh; Jesse B. Mez; William S. Bush; Brian W. Kunkle; Adam C. Naj; Amalia Peterson; Katherine A. Gifford; Michael L. Cuccaro; Carlos Cruchaga; Margaret A. Peric...; Lindsay A. Farrer; Li-San Wang; Jonathan L. Haines; Angela L. Jefferson; Walter A. Kukull; C. Dirk Keene; Andrew J. Saykin; Paul M. Thompson; Eden R. Martin; David A. Bennett; Lisa L. Barnes; Julie A. Schneider; Paul K. Crane; Timothy J. Hohman; Logan Dumitrescu; ; Erin Abner; Perrie Adams; Alyssa Aguirre; Marilyn Albert; Roger Albin; Mariet Allen; Lisa Alvarez; Liana Apostolova; Steven Arnold; Sanjay Asthana; Craig Atwood; Gayle Ayres; Robert Barber; Lisa Barnes; Sandra Barral; Jackie Bartlett; Thomas Beach; James Becker; Gary Beecham; Penelope Benchek; David Bennett; John Bertelson; Sarah Biber; Thomas Bird; Deborah Blacker; Bradley Boeve; James Bowen; Adam Boxer; James Brewer; James Burke; Jeffery Burns; William Bush; Joseph Buxbaum; Goldie Byrd; Laura Cantwell; Chuanhai Cao; Cynthia Carlsson; Minerva Carrasquillo; Kwun Chan; Scott Chase; Yen-Chi Chen; Marie-Franciose C...; Nathaniel Chin; Helena Chui; Jaeyoon Chung; Suzanne Craft; Paul Crane; Carlos Cruchaga; Michael Cuccaro; Jessica Culhane; C. Munro Cullum; Eveleen Darby; Barbara Davis; Charles DeCarli; John DeToledo; Dennis Dickson; Nic Dobbins; Ranjan Duara; Nilufer Ertekin-T...; Denis Evans; Kelley Faber; Thomas Fairchild; Daniele Fallin; Kenneth Fallon; David Fardo; Martin Farlow; John Farrell; Lindsay Farrer; Victoria Fernande...; Tatiana Foroud; Matthew Frosch; Douglas Galasko; Adriana Gamboa; Daniel Geschwind; Bernadino Ghetti; Alison Goate; Thomas Grabowski; Neill Graff-Radford; Anthony Griswold; Jonathan Haines; Hakon Hakonarson; Kathleen Hall; James Hall; Ronald Hamilton; Kara Hamilton-Nelson; Xudong Han; John Hardy; Lindy Harrell; Elizabeth Head; Victor Henderson; Michelle Hernandez; Lawrence Honig; Ryan Huebinger; Matthew Huentelman; Christine Hulette; Bradley Hyman; Linda Hynan; Laura Ibanez; Philip De Jager; Gail Jarvik; Suman Jayadev; Lee-Way Jin; Kimberly Johnson; Leigh Johnson; Gyungah Jun; M. Ilyas Kamboh; Moon II Kang; Anna Karydas; Gauthreaux Kathryn; Mindy Katz; John Kauwe; Jeffery Kaye; C. Dirk Keene; Benjamin Keller; Aisha Khaleeq; Ronald Kim; Janice Knebl; Neil Kowall; Joel Kramer; Walter Kukull; Brian Kunkle; Amanda Kuzma; Frank LaFerla; James Lah; Eric Larson; Melissa Lerch; Alan Lerner; Yuk Ye Leung; James Leverenz; Allan Levey; Donghe Li; Andrew Lieberman; Richard Lipton; Oscar Lopez; Kathryn Lunetta; Constantine Lyketsos; Douglas Mains; Jennifer Manly; Logue Mark; David Marquez; Daniel Marson; Eden Martin; Eliezer Masliah; Paul Massman; Arjun Masukar; Richard Mayeux; Wayne McCormick; Susan McCurry; Stefan McDonough; Ann McKee; Marsel Mesulam; Jesse Mez; Bruce Miller; Carol Miller; Charles Mock; Abhay Moghekar; Thomas Montine; Edwin Monuki; Sean Mooney; John Morris; Shubhabrata Mukhe...; Amanda Myers; Adam Naj; Trung Nguyen; Sid O'Bryant; Kyle Ormsby; Marcia Ory; Raymond Palmer; Joseph Parisi; Henry Paulson; Valory Pavlik; David Paydarfar; Victoria Perez; Margaret Pericak-...; Ronald Peterson; Marsha Polk; Liming Qu; Mary Quiceno; Joseph Quinn; Ashok Raj; Farid Rajabli; Vijay Ramanan; Eric Reiman; Joan Reisch; Christiane Reitz; John Ringman; Erik Robertson; Monica Rodriguear; Ekaterina Rogaeva; Howard Rosen; Roger Rosenberg; Donald Royall; Mary Sano; Andrew Saykin; Gerard Schellenberg; Julie Schneider; Lon Schneider; William Seeley; Richard Sherva; Dean Shibata; Scott Small; Amanda Smith; Janet Smith; Yeunjoo Song; Salvatore Spina; Peter St George-H...; Robert Stern; Alan Stevens; Stephen Strittmatter; David Sultzer; Russell Swerdlow; Jeffery Tilson; Giuseppe Tosto; John Trojanowski; Juan Troncoso; Debby Tsuang; Otto Valladares; Jeffery Vance; Vivianna Van Deerlin; Linda Van Eldik; Badri Vardarajan; Robert Vassar; Harry Vinters; Jean Paul Vonsattel; Li San Wang; Sandra Weintraub; Kathleen Welsh-Bo...; Nick Wheeler; Ellen Wijsman; Kirk Wilhelmsen; Scott Williams; Benjamin Williams; Jennifer Williamson; Henrick Wilms; Thomas Wingo; Randall Woltjer; Martin Woon; Steven Younkin; Lei Yu; Yi Zhao; Xiongwei Zhou; Congcong Zhu; Olusegun Adegoke; Paul Aisen; Liana G. Apostolova; Miriam Ashford; Laurel Beckett; Marie Bernard; Haley Bernhardt; Bret Borowski; Yuliana Cabrera; Nigel J. Cairns; Maria Carrillo; Kewei Chen; Mark Choe; Taylor Clanton; Godfrey Coker; Cat Conti; Karen Crawford; Sandhitsu Das; Michael Donohue; Adam Fleisher; Derek Flenneiken; Evan Fletcher; Juliet Fockler; Arvin Forghanian-...; Tatiana M. Foroud; Nick C. Fox; Erin Franklin; Devon Gessert; Hector González; Robert C. Green; Jeffery Gunter; Danielle Harvey; Lindsey Hergesheimer; Carole Ho; Erin Householder; John K. Hsaio; Clifford R. Jack; Jonathan Jackson; William Jagust; Neda Jahanshad; Gustavo Jimenez; Chengshu Jin; David Jones; Kejal Kantarci; Zaven Khachaturian; Alexander Knaack; Robert A. Koeppe; Adrienne Kormos; Susan Landau; Payam Mahboubi; Ian Malone; Donna Masterman; Chet Mathis; Garrett Miller; Tom Montine; Shelley Moore; John C. Morris; Scott Neu; John Neuhaus; Kwangsik Nho; Talia M. Nir; Rachel Nosheny; Kelly Nudelman; Ozioma Okonkwo; Richard J. Perrin; Jeremy Pizzola; William Potter; Michael Rafii; Rema Raman; Robert Reid; Eric R. Reiman; Shannon L. Risacher; Stephanie Rossi Chen; Laurie Ryan; Jennifer Salazar; Andrew J. Saykin; Christopher Schwarz; Matthew Senjem; Elizabeth Shaffer; Leslie M. Shaw; Li Shen; Nina Silverberg; Stephanie Smith; Lisa Taylor-Reinwald; Leon Thal; Sophia I. Thomopo...; Paul Thompson; Arthur W. Toga; Duygu Tosun-Turgut; John Q. Trojanowski; Diana Truran Sacrey; Dallas Veitch; Prashanthi Vemuri; Sarah Walter; Chad Ward; Michael W. Weiner; Kristi Wilmes; Paul A. Yushkevich; Caileigh Zimmerman
• Keywords: Apolipoprotein E

Importance Sex differences are established in associations between apolipoprotein E ( APOE ) ε4 and cognitive impairment Alzheimer disease (AD). However, it is unclear whether sex-specific consequences of consistent across races extend to the ε2 allele. Objective To investigate sex race modify with cognition. Design, Setting, Participants This genetic association study included longitudinal data from 4 AD aging cohorts. were older than 60 years self-identified as non-Hispanic White or Black (hereafter, Black). Data previously collected multiple US locations 1994 2018. Secondary analyses began December 2021 ended September 2022. Main Outcomes Measures Harmonized composite scores for memory, executive function, language generated using psychometric approaches. Linear regression assessed interactions on baseline scores, while linear mixed-effect models trajectories. The intersectional effect was modeled an × interaction term, assessing differed by race. Models adjusted age at corrected comparisons. Results Of 32 427 participants who met inclusion criteria, there 19 007 females (59%), 4453 individuals (14%), 27 974 (86%); mean (SD) 74 (7.9). At baseline, 6048 (19%) had AD, 4398 (14%) carriers, 12 538 (38%) carriers. missing status excluded (n = 9266). For ε4, a robust observed memory (β −0.071, SE 0.014; P 9.6 10 −7 ), whereby negative stronger compared males did not significantly differ among races. Contrastingly, despite large sample size, no cognition all participants. When testing effects sex, ε2, race, revealed function cognitively unimpaired −0.165, 0.066; .01), protective female-specific but male-specific individuals. Conclusions Relevance In this study, could vary sex. Although female enhanced ε4-associated risk, comparable difference suggesting biological pathways underlying risk distinct likely intersect age-related changes biology.