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

Steve R. Makkar; Darren M. Lipnicki; John D. Crawford; Nicole A. Kochan; Erico Castro-Costa; Maria Fernanda Lima-Costa; Breno Satler Diniz; Carol Brayne; Blossom Stephan; Fiona Matthews; Juan J. Llibre-Rodriguez; Jorge J. Llibre-Guerra; Adolfo J. Valhuerdi-Cepero; Richard B. Lipton; Mindy J. Katz; Cuiling Wang; Karen Ritchie; Sophie Carles; Isabelle Carriere; Nikolaos Scarmeas; Mary Yannakoulia; Mary Kosmidis; Linda Lam; Wai Chi Chan; Ada Fung; Antonio Guaita; Roberta Vaccaro; Annalisa Davin; Ki Woong Kim; Ji Won Han; Seung Wan Suh; Steffi G. Riedel-Heller; Susanne Roehr; Alexander Pabst; Mary Ganguli; Tiffany F. Hughes; Beth Snitz; Kaarin J. Anstey; Nicolas Cherbuin; Simon Easteal; Mary N. Haan; Allison E. Aiello; Kristina Dang; Tze Pin Ng; Qi Gao; Ma Shwe Zin Nyunt; Henry Brodaty; Julian N. Trollor; Yvonne Leung; Jessica W. Lo; Perminder Sachdev; Cohort Studies of Memory in an International Consortium (COSMIC)

doi:10.1093/gerona/glaa116

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

Steve R. Makkar^*, Darren M. Lipnicki, John D. Crawford, Nicole A. Kochan, Erico Castro-Costa, Maria Fernanda Lima-Costa, Breno Satler Diniz, Carol Brayne, Blossom Stephan, Fiona Matthews, Juan J. Llibre-Rodriguez, Jorge J. Llibre-Guerra, Adolfo J. Valhuerdi-Cepero, Richard B. Lipton, Mindy J. Katz, Cuiling Wang, Karen Ritchie, Sophie Carles, Isabelle Carriere, Nikolaos ScarmeasMary Yannakoulia, Mary Kosmidis, Linda Lam, Wai Chi Chan, Ada Fung, Antonio Guaita, Roberta Vaccaro, Annalisa Davin, Ki Woong Kim, Ji Won Han, Seung Wan Suh, Steffi G. Riedel-Heller, Susanne Roehr, Alexander Pabst, Mary Ganguli, Tiffany F. Hughes, Beth Snitz, Kaarin J. Anstey, Nicolas Cherbuin, Simon Easteal, Mary N. Haan, Allison E. Aiello, Kristina Dang, Tze Pin Ng, Qi Gao, Ma Shwe Zin Nyunt, Henry Brodaty, Julian N. Trollor, Yvonne Leung, Jessica W. Lo, Perminder Sachdev, Cohort Studies of Memory in an International Consortium (COSMIC)

^*Corresponding author for this work

Research output: Contribution to journal › Journal article › peer-review

25 Citations (Scopus)

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.

Original language	English
Pages (from-to)	1863-1873
Number of pages	11
Journal	Journals of Gerontology - Series A Biological Sciences and Medical Sciences
Volume	75
Issue number	10
Early online date	12 May 2020
DOIs	https://doi.org/10.1093/gerona/glaa116
Publication status	Published - Oct 2020

Scopus Subject Areas

Medicine(all)

User-Defined Keywords

APOE genotype
Cognitive decline
Epidemiology
Ethnicity
Sex

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10.1093/gerona/glaa116

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Makkar, S. R., Lipnicki, D. M., Crawford, J. D., Kochan, N. A., Castro-Costa, E., Lima-Costa, M. F., Diniz, B. S., Brayne, C., Stephan, B., Matthews, F., Llibre-Rodriguez, J. J., Llibre-Guerra, J. J., Valhuerdi-Cepero, A. J., Lipton, R. B., Katz, M. J., Wang, C., Ritchie, K., Carles, S., Carriere, I., ... Cohort Studies of Memory in an International Consortium (COSMIC) (2020). APOE ε4 and the Influence of Sex, Age, Vascular Risk Factors, and Ethnicity on Cognitive Decline. Journals of Gerontology - Series A Biological Sciences and Medical Sciences, 75(10), 1863-1873. https://doi.org/10.1093/gerona/glaa116

@article{7d2f1443768142fea1d6b9220366836a,

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

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.",

keywords = "APOE genotype, Cognitive decline, Epidemiology, Ethnicity, Sex",

author = "Makkar, {Steve R.} and Lipnicki, {Darren M.} and Crawford, {John D.} and Kochan, {Nicole A.} and Erico Castro-Costa and Lima-Costa, {Maria Fernanda} and Diniz, {Breno Satler} and Carol Brayne and Blossom Stephan and Fiona Matthews and Llibre-Rodriguez, {Juan J.} and Llibre-Guerra, {Jorge J.} and Valhuerdi-Cepero, {Adolfo J.} and Lipton, {Richard B.} and Katz, {Mindy J.} and Cuiling Wang and Karen Ritchie and Sophie Carles and Isabelle Carriere and Nikolaos Scarmeas and Mary Yannakoulia and Mary Kosmidis and Linda Lam and Chan, {Wai Chi} and Ada Fung and Antonio Guaita and Roberta Vaccaro and Annalisa Davin and Kim, {Ki Woong} and Han, {Ji Won} and Suh, {Seung Wan} and Riedel-Heller, {Steffi G.} and Susanne Roehr and Alexander Pabst and Mary Ganguli and Hughes, {Tiffany F.} and Beth Snitz and Anstey, {Kaarin J.} and Nicolas Cherbuin and Simon Easteal and Haan, {Mary N.} and Aiello, {Allison E.} and Kristina Dang and Ng, {Tze Pin} and Qi Gao and Nyunt, {Ma Shwe Zin} and Henry Brodaty and Trollor, {Julian N.} and Yvonne Leung and Lo, {Jessica W.} and Perminder Sachdev and {Cohort Studies of Memory in an International Consortium (COSMIC)}",

note = "This work was supported by a National Health and Medical Research Council of Australia Program Grant (grant number ID 1093083); the National Institute on Aging of the National Institutes of Health under grant number RF1AG057531; and philanthropic contributions to the Dementia Momentum Fund (University of New South Wales Project ID PS38235), which collectively fund the COSMIC consortium. The content of this publication is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or other funders. Funding for the contributing studies is as follows: Bambui: the Brazilian Ministry of Health (Department of Science and Technology); the Brazilian Ministry of Science and Technology (National Fund for Scientific and Technological Development, Funding of Studies, Brazilian National Research Council); and the Minas Gerais State Research Foundation; CFAS: major awards from the Medical Research Council and the Department of Health, UK; CHAS: the Wellcome Trust Foundation (grant numbers GR066133 and GR08002); and the Cuban Ministry of Public Health; EAS: supported in part by National Institutes of Health (grant number NIA 2 P01 AG03949); the Leonard and Sylvia Marx Foundation; and the Czap Foundation; ESPRIT: Novartis; HELIAD: the Alzheimer{\textquoteright}s Association (grant number IIRG-09133014); ESPA-EU program Excellence Grant (ARISTEIA, grant number 189 10276/8/9/2011), which is co-funded by the European Social Fund and Greek National resources; and the Ministry for Health and Social Solidarity (Greece, grant number ΔΥ2β/οικ.51657/14.4.2009); HK-MAPS: the Mei Family Trust; Invece.Ab: financed with own funds; and supported in part by “Federazione Alzheimer Italia,” Milan, Italy; KLOSCAD: the Korean Health Technology R&D Project, Ministry of Health and Welfare, Republic of Korea (grant no. HI09C1379 (A092077)); LEILA75+: the Interdisciplinary Centre for Clinical Research at the University of Leipzig (Interdisziplin{\"a}res Zentrum f{\"u}r Klinische Forschung/IZKF; grant number 01KS9504); MoVIES: National Institute on Aging, National Institutes of Health, United States Department of Health and Human Services (grant number R01AG07562); PATH: National Health and Medical Research Council of Australia (grant numbers 973302, 179805, 157125, and 1002160); SALSA: National Institutes of Health (grant numbers AG12975, T32 AG049663, ES023451); Carolina Population Center (CPC) grant (the P2C Center grant from the National Institutes of Health, grant number P2C HD050924); CPC NICHD-NRSA Population Research Training (the T32 Training grant from the National Institutes of Health, grant number T32 HD007168); and a Biosocial Training Grant (grant number T32 HD091058); SLASI: Agency for Science Technology and Research (A*STAR) Biomedical Research Council (BMRC) (grant numbers 03/1/21/17/214 and 08/1/21/19/567); and the National Medical Research Council (grant number NMRC/1108/2007); Sydney MAS: National Health & Medical Research Council of Australia Program Grant (grant number ID 350833). Publisher Copyright: {\textcopyright} The Author(s) 2020. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved.",

year = "2020",

month = oct,

doi = "10.1093/gerona/glaa116",

language = "English",

volume = "75",

pages = "1863--1873",

journal = "Journals of Gerontology - Series A Biological Sciences and Medical Sciences",

issn = "1079-5006",

publisher = "Gerontological Society of America",

number = "10",

}

Makkar, SR, Lipnicki, DM, Crawford, JD, Kochan, NA, Castro-Costa, E, Lima-Costa, MF, Diniz, BS, Brayne, C, Stephan, B, Matthews, F, Llibre-Rodriguez, JJ, Llibre-Guerra, JJ, Valhuerdi-Cepero, AJ, Lipton, RB, Katz, MJ, Wang, C, Ritchie, K, Carles, S, Carriere, I, Scarmeas, N, Yannakoulia, M, Kosmidis, M, Lam, L, Chan, WC, Fung, A, Guaita, A, Vaccaro, R, Davin, A, Kim, KW, Han, JW, Suh, SW, Riedel-Heller, SG, Roehr, S, Pabst, A, Ganguli, M, Hughes, TF, Snitz, B, Anstey, KJ, Cherbuin, N, Easteal, S, Haan, MN, Aiello, AE, Dang, K, Ng, TP, Gao, Q, Nyunt, MSZ, Brodaty, H, Trollor, JN, Leung, Y, Lo, JW, Sachdev, P & Cohort Studies of Memory in an International Consortium (COSMIC) 2020, 'APOE ε4 and the Influence of Sex, Age, Vascular Risk Factors, and Ethnicity on Cognitive Decline', Journals of Gerontology - Series A Biological Sciences and Medical Sciences, vol. 75, no. 10, pp. 1863-1873. https://doi.org/10.1093/gerona/glaa116

TY - JOUR

T1 - APOE ε4 and the Influence of Sex, Age, Vascular Risk Factors, and Ethnicity on Cognitive Decline

AU - Makkar, Steve R.

AU - Lipnicki, Darren M.

AU - Crawford, John D.

AU - Kochan, Nicole A.

AU - Castro-Costa, Erico

AU - Lima-Costa, Maria Fernanda

AU - Diniz, Breno Satler

AU - Brayne, Carol

AU - Stephan, Blossom

AU - Matthews, Fiona

AU - Llibre-Rodriguez, Juan J.

AU - Llibre-Guerra, Jorge J.

AU - Valhuerdi-Cepero, Adolfo J.

AU - Lipton, Richard B.

AU - Katz, Mindy J.

AU - Wang, Cuiling

AU - Ritchie, Karen

AU - Carles, Sophie

AU - Carriere, Isabelle

AU - Scarmeas, Nikolaos

AU - Yannakoulia, Mary

AU - Kosmidis, Mary

AU - Lam, Linda

AU - Chan, Wai Chi

AU - Fung, Ada

AU - Guaita, Antonio

AU - Vaccaro, Roberta

AU - Davin, Annalisa

AU - Kim, Ki Woong

AU - Han, Ji Won

AU - Suh, Seung Wan

AU - Riedel-Heller, Steffi G.

AU - Roehr, Susanne

AU - Pabst, Alexander

AU - Ganguli, Mary

AU - Hughes, Tiffany F.

AU - Snitz, Beth

AU - Anstey, Kaarin J.

AU - Cherbuin, Nicolas

AU - Easteal, Simon

AU - Haan, Mary N.

AU - Aiello, Allison E.

AU - Dang, Kristina

AU - Ng, Tze Pin

AU - Gao, Qi

AU - Nyunt, Ma Shwe Zin

AU - Brodaty, Henry

AU - Trollor, Julian N.

AU - Leung, Yvonne

AU - Lo, Jessica W.

AU - Sachdev, Perminder

AU - Cohort Studies of Memory in an International Consortium (COSMIC)

N1 - This work was supported by a National Health and Medical Research Council of Australia Program Grant (grant number ID 1093083); the National Institute on Aging of the National Institutes of Health under grant number RF1AG057531; and philanthropic contributions to the Dementia Momentum Fund (University of New South Wales Project ID PS38235), which collectively fund the COSMIC consortium. The content of this publication is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or other funders. Funding for the contributing studies is as follows: Bambui: the Brazilian Ministry of Health (Department of Science and Technology); the Brazilian Ministry of Science and Technology (National Fund for Scientific and Technological Development, Funding of Studies, Brazilian National Research Council); and the Minas Gerais State Research Foundation; CFAS: major awards from the Medical Research Council and the Department of Health, UK; CHAS: the Wellcome Trust Foundation (grant numbers GR066133 and GR08002); and the Cuban Ministry of Public Health; EAS: supported in part by National Institutes of Health (grant number NIA 2 P01 AG03949); the Leonard and Sylvia Marx Foundation; and the Czap Foundation; ESPRIT: Novartis; HELIAD: the Alzheimer’s Association (grant number IIRG-09133014); ESPA-EU program Excellence Grant (ARISTEIA, grant number 189 10276/8/9/2011), which is co-funded by the European Social Fund and Greek National resources; and the Ministry for Health and Social Solidarity (Greece, grant number ΔΥ2β/οικ.51657/14.4.2009); HK-MAPS: the Mei Family Trust; Invece.Ab: financed with own funds; and supported in part by “Federazione Alzheimer Italia,” Milan, Italy; KLOSCAD: the Korean Health Technology R&D Project, Ministry of Health and Welfare, Republic of Korea (grant no. HI09C1379 (A092077)); LEILA75+: the Interdisciplinary Centre for Clinical Research at the University of Leipzig (Interdisziplinäres Zentrum für Klinische Forschung/IZKF; grant number 01KS9504); MoVIES: National Institute on Aging, National Institutes of Health, United States Department of Health and Human Services (grant number R01AG07562); PATH: National Health and Medical Research Council of Australia (grant numbers 973302, 179805, 157125, and 1002160); SALSA: National Institutes of Health (grant numbers AG12975, T32 AG049663, ES023451); Carolina Population Center (CPC) grant (the P2C Center grant from the National Institutes of Health, grant number P2C HD050924); CPC NICHD-NRSA Population Research Training (the T32 Training grant from the National Institutes of Health, grant number T32 HD007168); and a Biosocial Training Grant (grant number T32 HD091058); SLASI: Agency for Science Technology and Research (A*STAR) Biomedical Research Council (BMRC) (grant numbers 03/1/21/17/214 and 08/1/21/19/567); and the National Medical Research Council (grant number NMRC/1108/2007); Sydney MAS: National Health & Medical Research Council of Australia Program Grant (grant number ID 350833). Publisher Copyright: © The Author(s) 2020. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved.

PY - 2020/10

Y1 - 2020/10

N2 - 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.

AB - 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.

KW - APOE genotype

KW - Cognitive decline

KW - Epidemiology

KW - Ethnicity

KW - Sex

UR - http://www.scopus.com/inward/record.url?scp=85087430028&partnerID=8YFLogxK

U2 - 10.1093/gerona/glaa116

DO - 10.1093/gerona/glaa116

M3 - Journal article

C2 - 32396611

AN - SCOPUS:85087430028

SN - 1079-5006

VL - 75

SP - 1863

EP - 1873

JO - Journals of Gerontology - Series A Biological Sciences and Medical Sciences

JF - Journals of Gerontology - Series A Biological Sciences and Medical Sciences

IS - 10

ER -

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

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