Meta-Analysis

. 2023 Aug;19(8):3365-3378.

doi: 10.1002/alz.12962. Epub 2023 Feb 15.

Sex differences in dementia risk and risk factors: Individual-participant data analysis using 21 cohorts across six continents from the COSMIC consortium

Jessica Gong^{1

2}, Katie Harris¹, Darren M Lipnicki³, Erico Castro-Costa⁴, Maria Fernanda Lima-Costa⁴, Breno S Diniz⁵, Shifu Xiao⁶, Richard B Lipton⁷, Mindy J Katz⁷, Cuiling Wang⁸, Pierre-Marie Preux⁹, Maëlenn Guerchet⁹, Antoine Gbessemehlan⁹, Karen Ritchie¹⁰, Marie-Laure Ancelin¹⁰, Ingmar Skoog¹¹, Jenna Najar¹¹, Therese Rydberg Sterner¹¹, Nikolaos Scarmeas^{12

13}, Mary Yannakoulia¹⁴, Mary H Kosmidis¹⁵, Antonio Guaita¹⁶, Elena Rolandi^{16

17}, Annalisa Davin¹⁶, Oye Gureje¹⁸, Stella Trompet¹⁹, Jacobijn Gussekloo^{19

20}, Steffi Riedel-Heller²¹, Alexander Pabst²¹, Susanne Röhr²¹, Suzana Shahar²², Devinder Kaur Ajit Singh²², Nurul Fatin Malek Rivan²², Martin van Boxtel²³, Sebastian Köhler²³, Mary Ganguli²⁴, Chung-Chou Chang²⁴, Erin Jacobsen²⁴, Mary Haan²⁵, Ding Ding²⁶, Qianhua Zhao²⁶, Zhenxu Xiao²⁶, Kenji Narazaki²⁷, Tao Chen²⁸, Sanmei Chen²⁹, Tze Pin Ng³⁰, Xinyi Gwee³⁰, Katya Numbers³, Karen A Mather³, Marcia Scazufca³¹, Antonio Lobo^{32

33

34}, Concepción De-la-Cámara^{32

34}, Elena Lobo^{33

34

35}, Perminder S Sachdev³, Henry Brodaty³, Maree L Hackett^{1

36}, Sanne A E Peters^{1

2

37}, Mark Woodward^{1

2}; Cohort Studies of Memory in an International Consortium (COSMIC)

Affiliations

¹ The George Institute for Global Health, University of New South Wales, Sydney, Australia.
² The George Institute for Global Health, Imperial College London, London, UK.
³ Centre for Healthy Brain Ageing (CHeBA), Discipline of Psychiatry and Mental Health, Faculty of Medicine and Health, UNSW Sydney, Sydney, Australia.
⁴ Center for Studies in Public Health and Aging Rene Rachou Institute, Oswaldo Cruz Foundation, Belo Horizonte, Brazil.
⁵ UConn Center on Aging, Department of Psychiatry, School of Medicine, University of Connecticut Health Center, Farmington, Connecticut, USA.
⁶ Department of Geriatric Psychiatry, Shanghai Mental Health Centre, Shanghai Jiaotong University School of Medicine, Shanghai, China.
⁷ Department of Neurology, Albert Einstein College of Medicine, Bronx, New York, USA.
⁸ Department of Epidemiology and Community Heath, Albert Einstein College of Medicine, Bronx, New York, USA.
⁹ Inserm U1094, IRD U270, Univ. Limoges, CHU Limoges, EpiMaCT - Epidemiology of chronic diseases in tropical zone, Institute of Epidemiology and Tropical Neurology, OmegaHealth, Limoges, France.
¹⁰ INM Institute for Neurosciences of Montpellier, Univ Montpellier, INSERM, Montpellier, France.
¹¹ Department of Psychiatry and Neurochemistry, Center for Ageing and Health (Age Cap), University of Gothenburg, Gothenburg, Sweden.
¹² 1st Department of Neurology, Aiginition Hospital, National and Kapodistrian University of Athens Medical School, Athens, Greece.
¹³ Department of Neurology, Columbia University, New York, New York, USA.
¹⁴ Department of Nutrition and Dietetics, Harokopio University, Athens, Greece.
¹⁵ Lab of Cognitive Neuroscience, School of Psychology, Aristotle University of Thessaloniki, Thessaloniki, Greece.
¹⁶ Golgi Cenci Foundation, Abbiategrasso, Italy.
¹⁷ Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy.
¹⁸ WHO Collaborating Centre for Research and Training in Mental Health, Neurosciences and Substance Abuse, Department of Psychiatry, University of Ibadan, Ibadan, Nigeria.
¹⁹ Section of Gerontology and Geriatrics, Department of Internal Medicine, Leiden University Medical Center, Leiden, the Netherlands.
²⁰ Department of Public Health and Primary Care, Leiden, the Netherlands.
²¹ Institute of Social Medicine, Occupational Health and Public Health (ISAP), University of Leipzig, Leipzig, Germany.
²² Centre for Healthy Ageing and Wellness, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia.
²³ Alzheimer Centrum Limburg, School for Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands.
²⁴ Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
²⁵ Department of Epidemiology and Biostatistics, School of Medicine, University of California, San Francisco, San Francisco, California, USA.
²⁶ Institute of Neurology, National Center for Neurological Disorders, National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, China.
²⁷ Center for Liberal Arts, Fukuoka Institute of Technology, Fukuoka, Japan.
²⁸ Sports and Health Research Center, Department of Physical Education, Tongji University, Shanghai, China.
²⁹ Global Health Nursing, Department of Health Sciences, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
³⁰ Gerontology Research Programme, Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Queenstown, Singapore.
³¹ Instituto de Psiquiátria e LIM-23, Hospital da Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.
³² Department of Medicine and Psychiatry, Universidad de Zaragoza, Zaragoza, Spain.
³³ Instituto de Investigación Sanitaria Aragón (IIS Aragón), Zaragoza, Spain.
³⁴ n°33 CIBERSAM, Madrid, Spain.
³⁵ Department of Public Health, Universidad de Zaragoza, Zaragoza, Spain.
³⁶ Faculty of Health and Wellbeing, University of Central Lancashire, Lancashire, UK.
³⁷ Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.

PMID: 36790027
PMCID: PMC10955774
DOI: 10.1002/alz.12962

Meta-Analysis

Sex differences in dementia risk and risk factors: Individual-participant data analysis using 21 cohorts across six continents from the COSMIC consortium

Jessica Gong et al. Alzheimers Dement. 2023 Aug.

. 2023 Aug;19(8):3365-3378.

doi: 10.1002/alz.12962. Epub 2023 Feb 15.

Authors

Affiliations

¹ The George Institute for Global Health, University of New South Wales, Sydney, Australia.
² The George Institute for Global Health, Imperial College London, London, UK.
³ Centre for Healthy Brain Ageing (CHeBA), Discipline of Psychiatry and Mental Health, Faculty of Medicine and Health, UNSW Sydney, Sydney, Australia.
⁴ Center for Studies in Public Health and Aging Rene Rachou Institute, Oswaldo Cruz Foundation, Belo Horizonte, Brazil.
⁵ UConn Center on Aging, Department of Psychiatry, School of Medicine, University of Connecticut Health Center, Farmington, Connecticut, USA.
⁶ Department of Geriatric Psychiatry, Shanghai Mental Health Centre, Shanghai Jiaotong University School of Medicine, Shanghai, China.
⁷ Department of Neurology, Albert Einstein College of Medicine, Bronx, New York, USA.
⁸ Department of Epidemiology and Community Heath, Albert Einstein College of Medicine, Bronx, New York, USA.
⁹ Inserm U1094, IRD U270, Univ. Limoges, CHU Limoges, EpiMaCT - Epidemiology of chronic diseases in tropical zone, Institute of Epidemiology and Tropical Neurology, OmegaHealth, Limoges, France.
¹⁰ INM Institute for Neurosciences of Montpellier, Univ Montpellier, INSERM, Montpellier, France.
¹¹ Department of Psychiatry and Neurochemistry, Center for Ageing and Health (Age Cap), University of Gothenburg, Gothenburg, Sweden.
¹² 1st Department of Neurology, Aiginition Hospital, National and Kapodistrian University of Athens Medical School, Athens, Greece.
¹³ Department of Neurology, Columbia University, New York, New York, USA.
¹⁴ Department of Nutrition and Dietetics, Harokopio University, Athens, Greece.
¹⁵ Lab of Cognitive Neuroscience, School of Psychology, Aristotle University of Thessaloniki, Thessaloniki, Greece.
¹⁶ Golgi Cenci Foundation, Abbiategrasso, Italy.
¹⁷ Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy.
¹⁸ WHO Collaborating Centre for Research and Training in Mental Health, Neurosciences and Substance Abuse, Department of Psychiatry, University of Ibadan, Ibadan, Nigeria.
¹⁹ Section of Gerontology and Geriatrics, Department of Internal Medicine, Leiden University Medical Center, Leiden, the Netherlands.
²⁰ Department of Public Health and Primary Care, Leiden, the Netherlands.
²¹ Institute of Social Medicine, Occupational Health and Public Health (ISAP), University of Leipzig, Leipzig, Germany.
²² Centre for Healthy Ageing and Wellness, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia.
²³ Alzheimer Centrum Limburg, School for Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands.
²⁴ Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
²⁵ Department of Epidemiology and Biostatistics, School of Medicine, University of California, San Francisco, San Francisco, California, USA.
²⁶ Institute of Neurology, National Center for Neurological Disorders, National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, China.
²⁷ Center for Liberal Arts, Fukuoka Institute of Technology, Fukuoka, Japan.
²⁸ Sports and Health Research Center, Department of Physical Education, Tongji University, Shanghai, China.
²⁹ Global Health Nursing, Department of Health Sciences, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
³⁰ Gerontology Research Programme, Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Queenstown, Singapore.
³¹ Instituto de Psiquiátria e LIM-23, Hospital da Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.
³² Department of Medicine and Psychiatry, Universidad de Zaragoza, Zaragoza, Spain.
³³ Instituto de Investigación Sanitaria Aragón (IIS Aragón), Zaragoza, Spain.
³⁴ n°33 CIBERSAM, Madrid, Spain.
³⁵ Department of Public Health, Universidad de Zaragoza, Zaragoza, Spain.
³⁶ Faculty of Health and Wellbeing, University of Central Lancashire, Lancashire, UK.
³⁷ Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.

PMID: 36790027
PMCID: PMC10955774
DOI: 10.1002/alz.12962

Abstract

Introduction: Sex differences in dementia risk, and risk factor (RF) associations with dementia, remain uncertain across diverse ethno-regional groups.

Methods: A total of 29,850 participants (58% women) from 21 cohorts across six continents were included in an individual participant data meta-analysis. Sex-specific hazard ratios (HRs), and women-to-men ratio of hazard ratios (RHRs) for associations between RFs and all-cause dementia were derived from mixed-effect Cox models.

Results: Incident dementia occurred in 2089 (66% women) participants over 4.6 years (median). Women had higher dementia risk (HR, 1.12 [1.02, 1.23]) than men, particularly in low- and lower-middle-income economies. Associations between longer education and former alcohol use with dementia risk (RHR, 1.01 [1.00, 1.03] per year, and 0.55 [0.38, 0.79], respectively) were stronger for men than women; otherwise, there were no discernible sex differences in other RFs.

Discussion: Dementia risk was higher in women than men, with possible variations by country-level income settings, but most RFs appear to work similarly in women and men.

Keywords: data harmonization; dementia; diversity; risk factor; sex difference.

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Conflict of interest statement

B.S.D. has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from UOL Tecnologia Educacional, Brazil; and participates on a Data Safety Monitoring Board or Advisory Board for Depression treatment and Aβ dynamics: A study of Alzheimer's disease risk (ABD Study) (1 R01 AG070821‐01A1). R.B.L. received funding support from NIH/NIA 2PO1 AG003949 (Einstein Aging Study), S&L Marx Foundation, Czap Foundation; grants from the FDA, the Migraine Research Foundation, and the National Headache Foundation; served as consultant, advisory board member, and received honoraria from or research support from: Abbvie (Allergan), American Academy of Neurology, American Headache Society, Amgen, Biohaven, Biovision, Boston, Dr. Reddy's (Promius), Electrocore, Eli Lilly, eNeura, Equinox, GlaxoSmithKline, Grifols, Lundbeck (Alder), Merck, Pernix, Pfizer, Teva, Vector, and Vedanta; and has stock in Biohaven and Manistee. M.J.K. is supported by NIH/NIA AG03949. C.W. is supported by NIH/NIA AG003949. M.G. is supported by French National Research Agency, AXA Research Fund, and Limoges University Hospital (France). N.S. is supported by Alzheimer's Association grant IIRG‐09‐133014, European Social Fund grants 189 10276/8/9/2011, National Strategic Reference Framework‐EU program Excellence Grant (ARISTEIA), and Greek Ministry of Health grants DY2b/oik.51657/14.4.2009, as well as EPAD—Local PI of recruiting site for multinational, multicenter Innovative Medicines Initiative (IMI) sponsored observational study of prodromal stages of dementia, and NovoNordisc—Local PI of recruiting site for multinational, multicenter industry sponsored phase III treatment trial for Alzheimer's disease; and served on the Chair of Data Safety Monitoring Board for Albert Einstein College of Medicine—NIH funded study. M.Y. is supported by European Social Fund and Ministry of Health, and received fundings from ERASMUS+—European Commission and HORIZON2020 – European Commission; served as the President of the National Nutrition Policy Committee – no fees. M.G. is supported by the National Institute on Aging, NIH, received payments from the University of Connecticut Health Center for honoraria for lectures; participated on a Data Safety Monitoring Board or Advisory Board for Indiana University School of Medicine; and received honorarium payment from the Journal of the American Geriatrics Society. C.C.C. is supported by the NIH (R01 grant: MYHAT study). A.L. and ZARADEMP study was supported by grants from the Fondo de Investigación Sanitaria, Instituto de Salud Carlos III, Spanish Ministry of Economy and Competitiveness, Madrid, Spain (grants 94/1562, 97/1321E, 98/0103, 01/0255, 03/0815, 06/0617, G03/128, 12/02254, 16/00896, 19/01874), and the Fondo Europeo de Desarrollo Regional (FEDER) of the European Union and Gobierno de Aragón, (grant B15_17R). Group #19; A.L. received financial support to attend scientific meeting from Janssen. E.L. has received honorarium from University of Granada. None of these activities was related to the current project. M.W. is supported by Australian NHMRC and EU Horizon 2020, and is a consultant for Amgen and Freeline outside the submitted work; and participated on a Data Safety Monitoring Board or Advisory Board for DMB STAREE trial (no payment). The rest of the authors have no conflicts of interest. C.D.L.C. has received financial support to attend scientific meetings from Janssen, Almirall, Lilly, Lundbeck, Rovi, Esteve, Novartis, Astrazeneca, Pfizer, and Casen Recordati. M.W. has been a consultant for Amgen, Freeline, and Kirin outside the submitted work. Author disclosures are available in the supporting information.

Figures

**FIGURE 1**
Sex‐specific Kaplan–Meier survival curve (and 95% confidence intervals) for survival probability of all‐cause dementia

**FIGURE 2**
Age‐ and education‐adjusted study‐specific and pooled hazard ratios for all‐cause dementia by sex (women vs. men). CI, confidence interval; HR, hazard ratio

**FIGURE 3**
Age‐ and education‐adjusted pooled hazard ratios for sex (women vs. men) in association with all‐cause dementia, stratified by subgroups. *APOE*, apolipoprotein E; CI, confidence interval; HR, hazard ratio

**FIGURE 4**
Age‐ and education‐adjusted women‐to‐men ratio of hazard ratios for all‐cause dementia by risk factor. *APOE*, apolipoprotein E; BMI, body mass index; CI, confidence interval; HDL, high density lipoprotein; HR, hazard ratio; LDL, low density lipoprotein; RHR, ratio of hazard ratios

See this image and copyright information in PMC

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Sex differences in dementia risk and risk factors: Individual-participant data analysis using 21 cohorts across six continents from the COSMIC consortium

Affiliations

Sex differences in dementia risk and risk factors: Individual-participant data analysis using 21 cohorts across six continents from the COSMIC consortium

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical