Sex differences in associations between APOE ε2 and longitudinal cognitive decline

Madeline E Wood; Lisa Y Xiong; Yuen Yan Wong; Rachel F Buckley; Walter Swardfager; Mario Masellis; Andrew S P Lim; Emma Nichols; Renaud La Joie; Kaitlin B Casaletto; Raj G Kumar; Kristen Dams-O'Connor; Priya Palta; Kristen M George; Claudia L Satizabal; Lisa L Barnes; Julie A Schneider; Alexa Pichette Binet; Sylvia Villeneuve; Judy Pa; Adam M Brickman; Sandra E Black; Jennifer S Rabin; ADNI and Prevent-AD Research Groups

doi:10.1002/alz.13036

Sex differences in associations between APOE ε2 and longitudinal cognitive decline

Alzheimers Dement. 2023 Oct;19(10):4651-4661. doi: 10.1002/alz.13036. Epub 2023 Mar 30.

Authors

Madeline E Wood^{1

2}, Lisa Y Xiong^{1

3}, Yuen Yan Wong^{1

3}, Rachel F Buckley^{4

5

6}, Walter Swardfager^{1

3}, Mario Masellis^{1

7}, Andrew S P Lim^{1

7}, Emma Nichols⁸, Renaud La Joie⁹, Kaitlin B Casaletto⁹, Raj G Kumar¹⁰, Kristen Dams-O'Connor^{10

11}, Priya Palta¹², Kristen M George¹³, Claudia L Satizabal^{14

15}, Lisa L Barnes¹⁶, Julie A Schneider¹⁶, Alexa Pichette Binet¹⁷, Sylvia Villeneuve^{18

19

20}, Judy Pa²¹, Adam M Brickman²², Sandra E Black^{1

7}, Jennifer S Rabin^{1

2

7

23}; ADNI and Prevent-AD Research Groups

Affiliations

¹ Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, Ontario, Canada.
² Rehabilitation Sciences Institute, University of Toronto, Toronto, Ontario, Canada.
³ Department of Pharmacology & Toxicology, University of Toronto, Toronto, Ontario, Canada.
⁴ Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
⁵ Florey Institute, University of Melbourne, Parkville, Victoria, Australia.
⁶ Melbourne School of Psychological Sciences, University of Melbourne, Parkville, Victoria, Australia.
⁷ Division of Neurology, Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada.
⁸ Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
⁹ Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, California, USA.
¹⁰ Department of Rehabilitation and Human Performance, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹¹ Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹² Departments of Medicine and Epidemiology, Columbia University Irving Medical Center, New York, New York, USA.
¹³ Department of Public Health Sciences, University of California Davis School of Medicine, Davis, California, USA.
¹⁴ Department of Population Health Science and Biggs Institute for Alzheimer's and Neurodegenerative Diseases, UT Health San Antonio, San Antonio, Texas, USA.
¹⁵ Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, USA.
¹⁶ Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, USA.
¹⁷ Clinical Memory Research Unit, Faculty of Medicine, Lund University, Lund, Sweden.
¹⁸ Centre for Studies on Prevention of Alzheimer's Disease (StoP-AD), Douglas Mental Health University Institute, Centre for Studies on the Prevention of Alzheimer's Disease (StoP-AD), Montreal, Quebec, Canada.
¹⁹ Department of Psychiatry, McGill University, Montreal, Quebec, Canada.
²⁰ McConnell Brain Imaging Centre, Montreal Neurological Institute, Montreal, Quebec, Canada.
²¹ Mark and Mary Stevens Neuroimaging and Informatics Institute, Department of Neurology, University of Southern California, Los Angeles, California, USA.
²² Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
²³ Harquail Centre for Neuromodulation, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.

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.

Keywords: APOE; Alzheimer's disease; cognitive decline; race/ethnicity; sex differences.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Apolipoprotein E2* / genetics
Apolipoprotein E3 / genetics
Apolipoproteins E / genetics
Cognitive Dysfunction* / genetics
Female
Genotype
Humans
Male
Sex Characteristics*

Substances

Apolipoprotein E2
Apolipoprotein E3
Apolipoproteins E
ApoE protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding