Maria Fernanda Lima-Costa; Erico Castro-Costa. Fundação Oswaldo Cruz. Instituto René Rachou. Belo Horizonte, MG, Brasil.John D. Crawford Centre for Healthy Brain Ageing. University of New South Wales.Sydney, New South Wales, Australia Anbupalam Thalamuthu Centre for Healthy Brain Ageing. University of New South Wales. Sydney, New South Wales, Australia Nicole A. Kochan Centre for Healthy Brain Ageing. University of New South Wales.Sydney, New South Wales, Australia Maria Fernanda Furtado Lima Costa Fundação Oswaldo Cruz. Instituto René Rachou. Belo Horizonte, MG, Brazil Erico Castro Costa Fundação Oswaldo Cruz. Instituto René Rachou. Belo Horizonte, MG, Brazil Cleusa Pinheiro Ferri Universidade Federal de São Paulo. Departamento de Psiquiatria. São Paulo, SP, Brazil Carol Brayne Department of Public Health and Primary Care. Cambridge University. Cambridge, United Kingdom Blossom Stephan Institute of Health and Society. Newcastle University. Newcastle upon Tyne, United Kingdom Juan J. Llibre-Rodriguez Finlay-Albarrán Faculty of Medical Sciences. Medical University of Havana. Havana, Cuba Jorge J. Llibre-Guerra Institute of Neurology and Neurosurgery. Havana, Cuba/ Memory and Aging Center. University of California. San Francisco, San Francisco, California, United States of America Adolfo J. Valhuerdi-Cepero Medical University of Matanzas. Matanzas, Cuba Richard B. Lipton Saul R. Korey Department of Neurology. Albert Einstein College of Medicine. Yeshiva University. New York, New York, United States of America/Department of Epidemiology and Population Health. Albert Einstein College of Medicine. Yeshiva University. New York, New York, United States of America/Department of Psychiatry and Behavioral Medicine. Albert Einstein College of Medicine. Yeshiva University. New York, New York, United States of America Mindy J. Katz Saul R. Korey Department of Neurology. Albert Einstein College of Medicine. Yeshiva University. New York, New York, United States of America Carol A. Derby Saul R. Korey Department of Neurology. Albert Einstein College of Medicine. Yeshiva University. New York, New York, United States of America/Department of Epidemiology and Population Health. Albert Einstein College of Medicine. Yeshiva University. New York, New York, United States of America Karen Ritchie Inserm, U1061 Neuropsychiatry: Epidemiological and Clinical Research. La Colombière Hospital. Montpellier, France/Université de Montpellier. Montpellier, France/Centre for Clinical Brain Sciences. University of Edinburgh. Edinburgh, United Kingdom Marie-Laure Ancelin Inserm, U1061 Neuropsychiatry: Epidemiological and Clinical Research. La Colombière Hospital. Montpellier, France/Université de Montpellier. Montpellier, France Isabelle Carrière Université de Montpellier. Montpellier, France Nikolaos Scarmeas 1st Department of Neurology. Aiginition Hospital, Medical School. National and Kapodistrian University of Athens. Athens, Greece/Taub Institute for Research on Alzheimer’s Disease and the Aging Brain. Gertrude H. Sergievsky Center.Department of Neurology., Columbia University. New York, NY, United States of America Mary Yannakoulia Department of Nutrition and Dietetics. Harokopio University. Athens, Greece Georgios M. Hadjigeorgiou University of Thessaly, Larissa, Greece/Department of Neurology. Medical School. University of Cyprus. Nicosia, Cyprus Linda Lam Department of Psychiatry. Chinese University of Hong Kong. Hong Kong SAR, China Wai-chi Chan Department of Psychiatry. University of Hong Kong. Hong Kong SAR, China Ada Fung Department of Applied Social Sciences. Hong Kong Polytechnic University. Hong Kong SAR, China Antonio Guaita Golgi Cenci Foundation. Milan, Italy Roberta Vaccaro Golgi Cenci Foundation. Milan, Italy Annalisa Davin Golgi Cenci Foundation. Milan, Italy Ki Woong Kim Department of Neuropsychiatry. Seoul National University Bundang Hospital. Seongnam, Korea/Department of Psychiatry. College of Medicine. Seoul National University. Seoul, Korea/Department of Brain and Cognitive Science. College of Natural Sciences. Seoul National University. Seoul, Korea Ji Won Han Department of Neuropsychiatry. Seoul National University Bundang Hospital. Seongnam, Korea Seung Wan Suh Department of Neuropsychiatry. Seoul National University Bundang Hospital. Seongnam, Korea Steffi G. Riedel-Heller Institute of Social Medicine. Occupational Health and Public Health. Medical Faculty. University of Leipzig. Leipzig, Germany Susanne Roehr Institute of Social Medicine. Occupational Health and Public Health. Medical Faculty. University of Leipzig. Leipzig, Germany Alexander Pabst Institute of Social Medicine. Occupational Health and Public Health. Medical Faculty. University of Leipzig. Leipzig, Germany Martin van Boxtel Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience. Maastricht University Medical Center. Maastricht, The Netherlands Sebastian Köhler Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience. Maastricht University Medical Center. Maastricht, The Netherlands Kay Deckers Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience. Maastricht University Medical Center. Maastricht, The Netherlands Mary Ganguli Department of Psychiatry, School of Medicine. University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America/Department of Neurology. School of Medicine. University of Pittsburgh. Pittsburgh, Pennsylvania, United States of America/Department of Epidemiology. Graduate School of Public Health. University of Pittsburgh., Pittsburgh, Pennsylvania, United States of America Erin P. Jacobsen Department of Psychiatry, School of Medicine. University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America Tiffany F. Hughes Department of Sociology, Anthropology, and Gerontology. Youngstown State University. Youngstown, Ohio, United States of America Kaarin J. Anstey School of Psychology.University of New South Wales. Sydney, New South Wales, Australia/ Neuroscience Research Australia. Sydney, New South Wales, Australia/Centre for Research on Ageing. Health and Wellbeing. Australian National University. Canberra, Australian Capital Territory, Australia Nicolas Cherbuin Centre for Research on Ageing. Health and Wellbeing. Australian National University. Canberra, Australian Capital Territory, Australia Mary N. Haan Department of Epidemiology and Biostatistics. School of Medicine, University of California, San Francisco, San Francisco, California, United States of America Allison E. Aiello Department of Epidemiology. Gillings School of Global Public Health. University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America/ Carolina Population Center. University of North Carolina at Chapel Hill. Chapel Hill, North Carolina, United States of America Kristina Dang Department of Epidemiology and Biostatistics. School of Medicine, University of California, San Francisco, San Francisco, California, United States of America Shuzo Kumagai Center for Health Science and Counseling. Kyushu University. Kasuga, Japan Tao Chen Center for Health Science and Counseling. Kyushu University. Kasuga, Japan Kenji Narazaki Faculty of Socio-Environmental Studies. Fukuoka Institute of Technology. Fukuoka, Japan Tze Pin Ng Gerontology Research Programme, Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore Qi Gao Gerontology Research Programme, Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore Ma Shwe Zin Nyunt Department of Psychological Medicine. Yong Loo Lin School of Medicine. National University of Singapore. Singapore Marcia Scazufca Universidade de São Paulo. Faculdade de Medicina. Hospital da Clínicas. Instituto de Psiquiatria e LIM-23. São Paulo, SP, Brazil Henry Brodaty Centre for Healthy Brain Ageing. University of New South Wales.Sydney, New South Wales, Australia/ Dementia Collaborative Research Centre. University of New South Wales. Sydney, New South Wales, Australia Katya Numbers Centre for Healthy Brain Ageing. University of New South Wales.Sydney, New South Wales, Australia Julian N. Trollor Centre for Healthy Brain Ageing. University of New South Wales.Sydney, New South Wales, Australia/ Department of Developmental Disability Neuropsychiatry. School of Psychiatry. University of New South Wales, Sydney. New South Wales, Australia Kenichi Meguro Geriatric Behavioral Neurology. Tohoku University. Sendai, Japan Satoshi Yamaguchi Geriatric Behavioral Neurology. Tohoku University. Sendai, Japan Hiroshi Ishii Geriatric Behavioral Neurology. Tohoku University. Sendai, Japan Antonio Lobo Department of Medicine and Psychiatry, Universidad de Zaragoza. Zaragoza, Spain/Instituto de Investigación Sanitaria Aragón. Zaragoza, Spain/Centro de Investigación Biomédica en Red de Salud Mental. Ministry of Science and Innovation, Madrid, Spain Raul Lopez-Anton Instituto de Investigación Sanitaria Aragón. Zaragoza, Spain/Centro de Investigación Biomédica en Red de Salud Mental. Ministry of Science and Innovation, Madrid, Spain/Department of Psychology and Sociology. Universidad de Zaragoza. Zaragoza, Spain Javier Santabárbara Instituto de Investigación Sanitaria Aragón. Zaragoza, Spain/Centro de Investigación Biomédica en Red de Salud Mental. Ministry of Science and Innovation, Madrid, Spain/Department of Microbiology. Preventive Medicine and Public Health.Universidad de Zaragoza. Zaragoza, Spain Yvonne Leung Centre for Healthy Brain Ageing. University of New South Wales.Sydney, New South Wales, Australia Jessica W. Lo Centre for Healthy Brain Ageing. University of New South Wales.Sydney, New South Wales, Australia Gordana Popovic Centre for Healthy Brain Ageing. University of New South Wales.Sydney, New South Wales, Australia /School of Mathematics and Statistics. University of New South Wales, Sydney. New South Wales, Australia Perminder S. Sachdev Centre for Healthy Brain Ageing. University of New South Wales.Sydney, New South Wales, Australia /Dementia Collaborative Research Centre. University of New South Wales. Sydney, New South Wales, AustraliaBackground: With no effective treatments for cognitive decline or dementia, improving the evidence base for modifiable risk factors is a research priority. This study investigated associations between risk factors and late-life cognitive decline on a global scale, including comparisons between ethno-regional groups. Methods and findings: We harmonized longitudinal data from 20 population-based cohorts from 15 countries over 5 continents, including 48,522 individuals (58.4% women) aged 54–105 (mean = 72.7) years and without dementia at baseline. Studies had 2–15 years of follow-up. The risk factors investigated were age, sex, education, alcohol consumption, anxiety, apolipoprotein E ε4 allele (APOE*4) status, atrial fibrillation, blood pressure and pulse pressure, body mass index, cardiovascular disease, depression, diabetes, self-rated health, high cholesterol, hypertension, peripheral vascular disease, physical activity, smoking, and history of stroke. Associations with risk factors were determined for a global cognitive composite outcome (memory, language, processing speed, and executive functioning tests) and Mini-Mental State Examination score. Individual participant data meta-analyses of multivariable linear mixed model results pooled across cohorts revealed that for at least 1 cognitive outcome, age (B = −0.1, SE = 0.01), APOE*4carriage (B = −0.31, SE = 0.11), depression (B = −0.11, SE = 0.06), diabetes (B = −0.23, SE = 0.10), current smoking (B = −0.20, SE = 0.08), and history of stroke (B = −0.22, SE = 0.09) were independently associated with poorer cognitive performance (p < 0.05 for all), and higher levels of education (B = 0.12, SE = 0.02) and vigorous physical activity (B = 0.17, SE = 0.06) were associated with better performance (p < 0.01 for both). Age (B = −0.07, SE = 0.01), APOE*4 carriage (B = −0.41, SE = 0.18), and diabetes (B = −0.18, SE = 0.10) were independently associated with faster cognitive decline (p < 0.05 for all). Different effects between Asian people and white people included stronger associations for Asian people between ever smoking and poorer cognition (group by risk factor interaction: B = −0.24, SE = 0.12), and between diabetes and cognitive decline (B = −0.66, SE = 0.27; p < 0.05 for both). Limitations of our study include a loss or distortion of risk factor data with harmonization, and not investigating factors at midlife. Conclusions: These results suggest that education, smoking, physical activity, diabetes, and stroke are all modifiable factors associated with cognitive decline. If these factors are determined to be causal, controlling them could minimize worldwide levels of cognitive decline. However, any global prevention strategy may need to consider ethno-regional differences.