Associations of Sex, Race, and Apolipoprotein E Alleles With Multiple Domains of Cognition Among Older Adults
Authors: 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. , Thompson Paul M. , Martin Eden R. , Bennett David A. , Barnes Lisa L. , Schneider Julie A. , Crane Paul K. , Hohman Timothy J. , Dumitrescu Logan ,   Alzheimer’s Disease Neuroimaging Initiative, Alzheimer’s Disease Genetics Consortium, and Alzheimer’s Disease Sequencing Project, Abner Erin , Adams Perrie , Aguirre Alyssa , Albert Marilyn , Albin Roger , Allen Mariet , Alvarez Lisa , Apostolova Liana , Arnold Steven , Asthana Sanjay , Atwood Craig , Ayres Gayle , Barber Robert , Barnes Lisa , Barral Sandra , Bartlett Jackie , Beach Thomas , Becker James , Beecham Gary , Benchek Penelope , Bennett David , Bertelson John , Biber Sarah , Bird Thomas , Blacker Deborah , Boeve Bradley , Bowen James , Boxer Adam , Brewer James , Burke James , Burns Jeffery , Bush William , Buxbaum Joseph , Byrd Goldie , Cantwell Laura , Cao Chuanhai , Carlsson Cynthia , Carrasquillo Minerva , Chan Kwun , Chase Scott , Chen Yen-Chi , Chesselet Marie-Franciose , Chin Nathaniel , Chui Helena , Chung Jaeyoon , Craft Suzanne , Crane Paul , Cruchaga Carlos , Cuccaro Michael , Culhane Jessica , Cullum C. Munro , Darby Eveleen , Davis Barbara , DeCarli Charles , DeToledo John , Dickson Dennis , Dobbins Nic , Duara Ranjan , Ertekin-Taner Nilufer , Evans Denis , Faber Kelley , Fairchild Thomas , Fallin Daniele , Fallon Kenneth , Fardo David , Farlow Martin , Farrell John , Farrer Lindsay , Fernandez-Hernandez Victoria , Foroud Tatiana , Frosch Matthew , Galasko Douglas , Gamboa Adriana , Geschwind Daniel , Ghetti Bernadino , Goate Alison , Grabowski Thomas , Graff-Radford Neill , Griswold Anthony , Haines Jonathan , Hakonarson Hakon , Hall Kathleen , Hall James , Hamilton Ronald , Hamilton-Nelson Kara , Han Xudong , Hardy John , Harrell Lindy , Head Elizabeth , Henderson Victor , Hernandez Michelle , Honig Lawrence , Huebinger Ryan , Huentelman Matthew , Hulette Christine , Hyman Bradley , Hynan Linda , Ibanez Laura , De Jager Philip , Jarvik Gail , Jayadev Suman , Jin Lee-Way , Johnson Kimberly , Johnson Leigh , Jun Gyungah , Kamboh M. Ilyas , Kang Moon II , Karydas Anna , Kathryn Gauthreaux , Katz Mindy , Kauwe John , Kaye Jeffery , Keene C. Dirk , Keller Benjamin , Khaleeq Aisha , Kim Ronald , Knebl Janice , Kowall Neil , Kramer Joel , Kukull Walter , Kunkle Brian , Kuzma Amanda , LaFerla Frank , Lah James , Larson Eric , Lerch Melissa , Lerner Alan , Leung Yuk Ye , Leverenz James , Levey Allan , Li Donghe , Lieberman Andrew , Lipton Richard , Lopez Oscar , Lunetta Kathryn , Lyketsos Constantine , Mains Douglas , Manly Jennifer , Mark Logue , Marquez David , Marson Daniel , Martin Eden , Masliah Eliezer , Massman Paul , Masukar Arjun , Mayeux Richard , McCormick Wayne , McCurry Susan , McDonough Stefan , McKee Ann , Mesulam Marsel , Mez Jesse , Miller Bruce , Miller Carol , Mock Charles , Moghekar Abhay , Montine Thomas , Monuki Edwin , Mooney Sean , Morris John , Mukherjee Shubhabrata , Myers Amanda , Naj Adam , Nguyen Trung , O'Bryant Sid , Ormsby Kyle , Ory Marcia , Palmer Raymond , Parisi Joseph , Paulson Henry , Pavlik Valory , Paydarfar David , Perez Victoria , Pericak-Vance Margaret , Peterson Ronald , Polk Marsha , Qu Liming , Quiceno Mary , Quinn Joseph , Raj Ashok , Rajabli Farid , Ramanan Vijay , Reiman Eric , Reisch Joan , Reitz Christiane , Ringman John , Robertson Erik , Rodriguear Monica , Rogaeva Ekaterina , Rosen Howard , Rosenberg Roger , Royall Donald , Sano Mary , Saykin Andrew , Schellenberg Gerard , Schneider Julie , Schneider Lon , Seeley William , Sherva Richard , Shibata Dean , Small Scott , Smith Amanda , Smith Janet , Song Yeunjoo , Spina Salvatore , St George-Hyslop Peter , Stern Robert , Stevens Alan , Strittmatter Stephen , Sultzer David , Swerdlow Russell , Tilson Jeffery , Tosto Giuseppe , Trojanowski John , Troncoso Juan , Tsuang Debby , Valladares Otto , Vance Jeffery , Van Deerlin Vivianna , Van Eldik Linda , Vardarajan Badri , Vassar Robert , Vinters Harry , Vonsattel Jean Paul , Wang Li San , Weintraub Sandra , Welsh-Bohmer Kathleen , Wheeler Nick , Wijsman Ellen , Wilhelmsen Kirk , Williams Scott , Williams Benjamin , Williamson Jennifer , Wilms Henrick , Wingo Thomas , Woltjer Randall , Woon Martin , Younkin Steven , Yu Lei , Zhao Yi , Zhou Xiongwei , Zhu Congcong , Adegoke Olusegun , Aisen Paul , Apostolova Liana G. , Ashford Miriam , Beckett Laurel , Bernard Marie , Bernhardt Haley , Borowski Bret , Cabrera Yuliana , Cairns Nigel J. , Carrillo Maria , Chen Kewei , Choe Mark , Clanton Taylor , Coker Godfrey , Conti Cat , Crawford Karen , Das Sandhitsu , Donohue Michael , Fleisher Adam , Flenneiken Derek , Fletcher Evan , Fockler Juliet , Forghanian-Arani Arvin , Foroud Tatiana M. , Fox Nick C. , Franklin Erin , Gessert Devon , González Hector , Green Robert C. , Gunter Jeffery , Harvey Danielle , Hergesheimer Lindsey , Ho Carole , Householder Erin , Hsaio John K. , Jack Clifford R. , Jackson Jonathan , Jagust William , Jahanshad Neda , Jimenez Gustavo , Jin Chengshu , Jones David , Kantarci Kejal , Khachaturian Zaven , Knaack Alexander , Koeppe Robert A. , Kormos Adrienne , Landau Susan , Mahboubi Payam , Malone Ian , Masterman Donna , Mathis Chet , Miller Garrett , Montine Tom , Moore Shelley , Morris John C. , Neu Scott , Neuhaus John , Nho Kwangsik , Nir Talia M. , Nosheny Rachel , Nudelman Kelly , Okonkwo Ozioma , Perrin Richard J. , Pizzola Jeremy , Potter William , Rafii Michael , Raman Rema , Reid Robert , Reiman Eric R. , Risacher Shannon L. , Rossi Chen Stephanie , Ryan Laurie , Salazar Jennifer , Saykin Andrew J. , Schwarz Christopher , Senjem Matthew , Shaffer Elizabeth , Shaw Leslie M. , Shen Li , Silverberg Nina , Smith Stephanie , Taylor-Reinwald Lisa , Thal Leon , Thomopoulos Sophia I. , Thompson Paul , Toga Arthur W. , Tosun-Turgut Duygu , Trojanowski John Q. , Truran Sacrey Diana , Veitch Dallas , Vemuri Prashanthi , Walter Sarah , Ward Chad , Weiner Michael W. , Wilmes Kristi , Yushkevich Paul A. , Zimmerman Caileigh 
Published: July 2023

Importance

Sex differences are established in associations between apolipoprotein E (APOE) ε4 and cognitive impairment in Alzheimer disease (AD). However, it is unclear whether sex-specific cognitive consequences of APOE are consistent across races and extend to the APOE ε2 allele.

Objective

To investigate whether sex and race modify APOE ε4 and ε2 associations with cognition.

Design, Setting, and Participants

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.

Main Outcomes and Measures

Harmonized composite scores for memory, executive function, and language were generated using psychometric approaches. Linear regression assessed interactions between APOE ε4 or APOE 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 APOE × sex × race interaction term, assessing whether APOE × sex interactions differed by race. Models were adjusted for age at baseline and corrected for multiple comparisons.

Results

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 APOE ε2 carriers, and 12 538 (38%) were APOE ε4 carriers. Participants missing APOE status were excluded (n = 9266). For APOE ε4, a robust sex interaction was observed on baseline memory (β = −0.071, SE = 0.014; P = 9.6 × 10−7), whereby the APOE ε4 negative effect was stronger in females compared with males and did not significantly differ among races. Contrastingly, despite the large sample size, no APOE ε2 × sex interactions on cognition were observed among all participants. When testing for intersectional effects of sex, APOE ε2, and race, an interaction was revealed on baseline executive function among individuals who were cognitively unimpaired (β = −0.165, SE = 0.066; P = .01), whereby the APOE ε2 protective effect was female-specific among White individuals but male-specific among Black individuals.

Conclusions and Relevance

In this study, while race did not modify sex differences in APOE ε4, the APOE 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.