APOE ε4 and the Influence of Sex, Age, Vascular Risk Factors, and Ethnicity on Cognitive Decline

Author:

Makkar Steve R1ORCID,Lipnicki Darren M1,Crawford John D1,Kochan Nicole A1,Castro-Costa Erico2,Lima-Costa Maria Fernanda2,Diniz Breno Satler34,Brayne Carol5ORCID,Stephan Blossom6ORCID,Matthews Fiona6,Llibre-Rodriguez Juan J7,Llibre-Guerra Jorge J89ORCID,Valhuerdi-Cepero Adolfo J10,Lipton Richard B11,Katz Mindy J11,Wang Cuiling11,Ritchie Karen1213,Carles Sophie1415,Carriere Isabelle1213,Scarmeas Nikolaos1617,Yannakoulia Mary18,Kosmidis Mary19,Lam Linda20,Chan Wai Chi20,Fung Ada21,Guaita Antonio22,Vaccaro Roberta22,Davin Annalisa22,Kim Ki Woong2324,Han Ji Won23,Suh Seung Wan23,Riedel-Heller Steffi G25,Roehr Susanne25ORCID,Pabst Alexander25,Ganguli Mary26,Hughes Tiffany F27,Snitz Beth28,Anstey Kaarin J2930,Cherbuin Nicolas30,Easteal Simon31,Haan Mary N32ORCID,Aiello Allison E3334,Dang Kristina32,Pin Ng Tze35,Gao Qi35,Zin Nyunt Ma Shwe35,Brodaty Henry136,Trollor Julian N137,Leung Yvonne38,Lo Jessica W1,Sachdev Perminder136ORCID

Affiliation:

1. Centre for Healthy Brain Ageing, University of New South Wales, Sydney, Australia

2. Instituto René Rachou da Fundaçaõ Oswaldo Cruz, Rio de Janeiro, Brazil

3. Department of Psychiatry, Faculty of Medicine University Toronto, Ontario, Canada

4. Geriatric Psychiatry Division, Center for Addiction and Mental Health, Toronto, Ontario, Canada

5. Department of Public Health and Primary Care, Cambridge University, UK

6. Institute of Health and Society, Newcastle University, Newcastle upon Tyne, UK

7. Finlay-Albarrán Faculty of Medical Sciences, Medical University of Havana, Cuba

8. Institute of Neurology and Neurosurgery, Havana, Cuba

9. Memory and Aging Center, UCSF, San Francisco, California

10. Medical University of Matanzas, Matanzas, Cuba

11. Saul R. Korey Department of Neurology, Albert Einstein College of Medicine, Yeshiva University, New York City, New York

12. Inserm, U1061 Neuropsychiatry: Epidemiological and Clinical Research, La Colombière Hospital, Montpellier Cedex 5, France

13. Université de Montpellier, Montpellier, France

14. Inserm, UMR1153 Epidemiology and Biostatistics Sorbonne Paris Cité Center (CRESS), Paris, France

15. Paris Descartes University, Paris, France

16. 1st Department of Neurology, Aiginition Hospital, National and Kapodistrian University of Athens, Medical School, Athens, Greece

17. Taub Institute for Research in Alzheimer’s disease and the Aging Brain, Gertrude H Sergievsky Center, Department of Neurology, Columbia University, New York city, New York

18. Department of Nutrition and Dietetics (M.Y.), Harokopio University, Athens, Greece

19. Laboratory of Cognitive Neuroscience, School of Psychology, Aristotle University of Thessaloniki, Thessaloniki, Greece

20. Department of Psychiatry, The Chinese University of Hong Kong

21. Department of Applied Social Sciences, The Hong Kong Polytechnic University

22. Golgi Cenci Foundation, Abbiategrasso, Italy

23. Department of Neuropsychiatry, Seoul National University Bundang Hospital, Seongnam, Korea

24. Department of Psychiatry, Seoul National University, College of Medicine, Seoul, Korea

25. Institute of Social Medicine, Occupational Health and Public Health (ISAP), Medical Faculty, University of Leipzig, Leipzig, Germany

26. Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania

27. Department of Sociology, Anthropology, and Gerontology, Youngstown State University, Youngstown, Ohio

28. Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania

29. Neuroscience Research Australia, Sydney, Australia

30. Centre for Research on Ageing, Health and Wellbeing, College of Health and Medicine, The Australian National University, Canberra, Australia

31. John Curtin School of Medical Research, College of Health and Medicine, The Australian National University, Canberra, Australia

32. University of California, School of Medicine, Department of Epidemiology and Biostatistics, San Francisco, California

33. Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, North Carolina

34. Carolina Population Center, Chapel Hill, North Carolina

35. Gerontology Research Programme, Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

36. Dementia Collaborative Research Centre, University of New South Wales Sydney, Sydney, Australia

37. Department of Developmental Disability Neuropsychiatry, School of Psychiatry, University of New South Wales, Australia

38. School of Psychology, University of Nottingham Malaysia, Semenyih, Malaysia

Abstract

Abstract We aimed to examine the relationship between Apolipoprotein E ε4 (APOE*4) carriage on cognitive decline, and whether these associations were moderated by sex, baseline age, ethnicity, and vascular risk factors. Participants were 19,225 individuals aged 54–103 years from 15 longitudinal cohort studies with a mean follow-up duration ranging between 1.2 and 10.7 years. Two-step individual participant data meta-analysis was used to pool results of study-wise analyses predicting memory and general cognitive decline from carriage of one or two APOE*4 alleles, and moderation of these associations by age, sex, vascular risk factors, and ethnicity. Separate pooled estimates were calculated in both men and women who were younger (ie, 62 years) and older (ie, 80 years) at baseline. Results showed that APOE*4 carriage was related to faster general cognitive decline in women, and faster memory decline in men. A stronger dose-dependent effect was observed in older men, with faster general cognitive and memory decline in those carrying two versus one APOE*4 allele. Vascular risk factors were related to an increased effect of APOE*4 on memory decline in younger women, but a weaker effect of APOE*4 on general cognitive decline in older men. The relationship between APOE*4 carriage and memory decline was larger in older-aged Asians than Whites. In sum, APOE*4 is related to cognitive decline in men and women, although these effects are enhanced by age and carriage of two APOE*4 alleles in men, a higher numbers of vascular risk factors during the early stages of late adulthood in women, and Asian ethnicity.

Funder

National Health and Medical Research Council

National Institute on Aging

Dementia Momentum Fund

National Institutes of Health

Brazilian Ministry of Health

Brazilian Ministry of Science and Technology

Minas Gerais State Research Foundation

Medical Research Council

Wellcome Trust

Cuban Ministry of Public Health

Leonard and Sylvia Marx Foundation

Czap Foundation

Alzheimer's Association

ESPA-EU

European Social Fund

Greek National resources

Ministry for Health and Social Solidarity

Mei Family Trust

Korean Health Technology R&D Project

Ministry of Health and Welfare

Centre for Clinical Research

U.S. Department of Health and Human Services

Carolina Population Center, University of North Carolina at Chapel Hill

CPC NICHD-NRSA Population Research Training

Biosocial Training Grant

Agency for Science Technology and Research

Biomedical Research Council

National Medical Research Council

Publisher

Oxford University Press (OUP)

Subject

Geriatrics and Gerontology,Aging

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