Polygenic risk scores for alzheimer’s disease are related to dementia risk in apoe ɛ4 negatives

Jenna Najar; Sven J. van der Lee; Erik Joas; Hanna Wetterberg; John Hardy; Rita Guerreiro; Jose Bras; Margda Waern; Silke Kern; Henrik Zetterberg; Kaj Blennow; Ingmar Skoog; Anna Zettergren

doi:10.1002/dad2.12142

Polygenic risk scores for alzheimer’s disease are related to dementia risk in apoe ɛ4 negatives

Jenna Najar^*
, Sven J. van der Lee
, Erik Joas
, Hanna Wetterberg
, John Hardy
, Rita Guerreiro
, Jose Bras
, Margda Waern
, Silke Kern
, Henrik Zetterberg
, Kaj Blennow
, Ingmar Skoog
, Anna Zettergren

^*Corresponding author for this work

Sahlgrenska Academy
University of Gothenburg
UCL Institute of Neurology
Great Ormond St Hospital for Children NHS Trust
University College London
Hong Kong University of Science and Technology
Van Andel Institute

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

Introduction: Studies examining the effect of polygenic risk scores (PRS) for Alzheimer’s disease (AD) and apolipoprotein E (APOE) genotype on incident dementia in very old individuals are lacking. Methods: A population-based sample of 2052 individuals ages 70 to 111, from Swe-den, was followed in relation to dementia. AD-PRSs including 39, 57, 1333, and 13,942 single nucleotide polymorphisms (SNPs) were used. Results: AD-PRSs (including 39 or 57 SNPs) were associated with dementia (57-SNPs AD-PRS: hazard ratio 1.09, confidence interval 1.01–1.19, P = .03), particularly in APOE ɛ4 non-carriers (57-SNPs AD-PRS: 1.15, 1.05–1.27, P = 4 × 10–3, 39-SNPs AD-PRS: 1.22, 1.10–1.35, P = 2 × 10–4 ). No association was found with the other AD-PRSs. Further, APOE ɛ4 was associated with increased risk of dementia (1.60, 1.35–1.92, P = 1 × 10–7 ). In those aged ≥95 years, the results were similar for the AD-PRSs, while APOE ɛ4 only predicted dementia in the low-risk tertile of AD-PRSs. Discussion: These results provide information to identify individuals at increased risk of dementia.

Original language	English
Article number	e12142
Journal	Alzheimer's and Dementia: Diagnosis, Assessment and Disease Monitoring
Volume	13
Issue number	1
DOIs	https://doi.org/10.1002/dad2.12142
Publication status	Published - 2021

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Alzheimer’s disease
Apolipoprotein E genotype
Dementia
Polygenic risk score
Risk factors in epidemiology

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10.1002/dad2.12142

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Najar, J., van der Lee, S. J., Joas, E., Wetterberg, H., Hardy, J., Guerreiro, R., Bras, J., Waern, M., Kern, S., Zetterberg, H., Blennow, K., Skoog, I., & Zettergren, A. (2021). Polygenic risk scores for alzheimer’s disease are related to dementia risk in apoe ɛ4 negatives. Alzheimer's and Dementia: Diagnosis, Assessment and Disease Monitoring, 13(1), Article e12142. https://doi.org/10.1002/dad2.12142

@article{d63f90c6edf341de8d4920ebd916863e,

title = "Polygenic risk scores for alzheimer{\textquoteright}s disease are related to dementia risk in apoe ɛ4 negatives",

abstract = "Introduction: Studies examining the effect of polygenic risk scores (PRS) for Alzheimer{\textquoteright}s disease (AD) and apolipoprotein E (APOE) genotype on incident dementia in very old individuals are lacking. Methods: A population-based sample of 2052 individuals ages 70 to 111, from Swe-den, was followed in relation to dementia. AD-PRSs including 39, 57, 1333, and 13,942 single nucleotide polymorphisms (SNPs) were used. Results: AD-PRSs (including 39 or 57 SNPs) were associated with dementia (57-SNPs AD-PRS: hazard ratio 1.09, confidence interval 1.01–1.19, P = .03), particularly in APOE ɛ4 non-carriers (57-SNPs AD-PRS: 1.15, 1.05–1.27, P = 4 × 10–3, 39-SNPs AD-PRS: 1.22, 1.10–1.35, P = 2 × 10–4 ). No association was found with the other AD-PRSs. Further, APOE ɛ4 was associated with increased risk of dementia (1.60, 1.35–1.92, P = 1 × 10–7 ). In those aged ≥95 years, the results were similar for the AD-PRSs, while APOE ɛ4 only predicted dementia in the low-risk tertile of AD-PRSs. Discussion: These results provide information to identify individuals at increased risk of dementia.",

keywords = "Alzheimer{\textquoteright}s disease, Apolipoprotein E genotype, Dementia, Polygenic risk score, Risk factors in epidemiology",

author = "Jenna Najar and \{van der Lee\}, \{Sven J.\} and Erik Joas and Hanna Wetterberg and John Hardy and Rita Guerreiro and Jose Bras and Margda Waern and Silke Kern and Henrik Zetterberg and Kaj Blennow and Ingmar Skoog and Anna Zettergren",

note = "Funding Information: Swedish state under the agreement between the Swedish government and the county councils; the Swedish State Support for Clinical Research, Grant/Award Numbers: ALF 716681, ALFGBG-81392, ALFGBG-715986, ALFGBG-720931, ALFGBG-81392, ALF GBG-771071; the Swedish Research Council, Grant/Award Numbers: 11267, 825-2012-5041, 2013-8717, 2015-02830, 2017-00639, 2017-00915, 2018-02532, 2019-01096, 2019-02075, 2018-02532; Swedish Research Council for Health, Working Life and Welfare, Grant/Award Numbers: 2001-2646, 2001-2835, 2001-2849, 2003-0234, 2004-0150, 2005-0762, 2006-0020, 2008-1229, 2008-1210, 2012-1138, 2004-0145, 2006-0596, 2008-1111, 2010-0870, 2013-1202, 2013-2300, 2013-2496; Swedish Alzheimer Foundation, Grant/Award Numbers: AF-742881, AF-930582, AF-646061, AF-741361, AF-842471, AF-737641; Swedish Brain Power, Hj?rnfonden, Sweden, Grant/Award Numbers: FO2016-0214, FO2017-0243, FO2018-0214, FO2019-0163; The Alzheimer?s Association Zenith Award, Grant/Award Number: ZEN-01-3151; The Alzheimer?s Association Stephanie B. Overstreet Scholars, Grant/Award Number: IIRG-00-2159; The Alzheimer?s Association, Grant/Award Numbers: IIRG-03-6168, IIRG-09-131338; The Bank of Sweden Tercentenary Foundation; Stiftelsen S?derstr?m-K?nigska Sjukhemmet; Magnus Bergvalls Stiftelse; Stiftelsen f?r Gamla Tj?narinnor; Handlanden Hjalmar Svenssons Forskningsfond; Fredrik och Ingrid Thurings Stiftelse, Grant/Award Number: 2019-00522; UK Medical Research Council, Alzheimer?s Society and Alzheimer?s Research UK; Medical Research Council, Grant/Award Number: MR/N026004/1; Wellcome Trust Hardy, Grant/Award Number: 202903/Z/16/Z; Dolby Family Fund, National Institute of Health Research University College London Hospitals Biomedical Research Centre; National Institute for Health Research University College London Hospitals Biomedical Research Centre; European Research Council, Grant/Award Number: 81712; Alzheimer Drug Discovery Foundation (ADDF), USA, Grant/Award Number: 201809-2016862; Alzheimer Drug Discovery Foundation, Grant/Award Number: RDAPB-201809-2016615; European Union Joint Program for Neurodegenerative Disorders, Grant/Award Number: JPND2019-466-236T he authors thank the participants in the Prospective Population Study of Women, and the Gothenburg H70 Birth Cohort Study. The authors also thank the members of the study group for their cooperation in data collection and management; UCL Genomics, London, UK, for performing the genotyping; and the Genomic Aggregation Project in Sweden (GAPS), the Karolinska Institute, Stockholm, for help and advice with the QC and imputation. Further, we thank the International Genomics of Alzheimer?s Project (IGAP) for providing summary results data for these analyses. The investigators within IGAP contributed to the design and implementation of IGAP and/or provided data but did not participate in analysis or writing of this report. IGAP was made possible by the generous participation of the control sub-jects, the patients, and their families. The i?Select chips was funded by the French National Foundation on Alzheimer?s disease and related dis-orders. EADI was supported by the LABEX (laboratory of excellence program investment for the future) DISTALZ grant, Inserm, Institut Pasteur de Lille, Universit? de Lille 2 and the Lille University Hospi-tal. GERAD/PERADES was supported by the Medical Research Council (Grant no 503480), Alzheimer?s Research UK (Grant no 503176), the Wellcome Trust (Grant n? 082604/2/07/Z) and German Federal Ministry of Education and Research (BMBF): Competence Network Dementia (CND) grant no 01GI0102, 01GI0711, 01GI0420. CHARGE was partially supported by the NIH/NIA grant R01 AG033193 and the NIA AG081220 and AGES contract N01?AG?12100, the NHLBI grant R01 HL105756, the Icelandic Heart Association, and the Erasmus Medical Center and Erasmus University. ADGC was supported by the NIH/NIA grants: U01 AG032984, U24 AG021886, U01 AG016976, and the Alzheimer?s Association grant ADGC?10-196728. The study was financed by grants from the Swedish state under the agreement between the Swedish government and the county councils, the Swedish State Support for Clinical Research (the ALF-agreement; ALF 716681, ALFGBG-81392, ALFGBG-715986, ALFGBG-720931, ALFGBG-81392, ALF GBG-771071), the Swedish Research Council (no 11267, 825-2012-5041, 2013-8717, 2015-02830, 2017-00639, 2017-00915, 2018-02532, 2019-01096, 2019-02075, 2018-02532), Swedish Research Council for Health, Working Life and Welfare (no 2001-2646, 2001-2835, 2001-2849, 2003-0234, 2004-0150, 2005-0762, 2006-0020, 2008-1229, 2008-1210, 2012-1138, 2004-0145, 2006-0596, 2008-1111, 2010-0870, 2013-1202, 2013-2300, 2013-2496), the Swedish Alzheimer Foundation (AF-742881, AF-930582, AF-646061, AF-741361, AF-842471, AF-737641), Swedish Brain Power, Hj?rnfonden, Sweden (FO2016-0214, FO2017-0243, FO2018-0214, FO2019-0163), The Alzheimer?s Association Zenith Award (ZEN-01-3151), The Alzheimer?s Association Stephanie B. Overstreet Scholars (IIRG-00-2159), The Alzheimer?s Association (IIRG-03-6168, IIRG-09-131338), The Bank of Sweden Tercentenary Foundation, Stiftelsen S?derstr?m-K?nigska Sjukhem-met, Magnus Bergvalls Stiftelse, Stiftelsen f?r Gamla Tj?narinnor, Handlanden Hjalmar Svenssons Forskningsfond, and Fredrik och Ingrid Thurings Stiftelse (2019-00522). John Hardy is supported by the UK Dementia Research Institute, which receives its funding from DRI Ltd and is funded by the UK Medical Research Council, Alzheimer?s Society and Alzheimer?s Research UK, and Medical Research Council (award number MR/N026004/1), Wellcome Trust Hardy (award number 202903/Z/16/Z), Dolby Family Fund, National Institute of Health Research University College London Hospitals Biomedical Research Centre, and supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. Henrik Zetterberg is a Wallenberg Scholar and is further supported by grants from the European Research Council (81712), the Alzheimer Drug Discovery Foundation (ADDF), USA (201809-2016862), and the UK Dementia Research Institute at UCL. Kaj Blennow is further supported by the Alzheimer Drug Discovery Foundation (ADDF), USA (RDAPB-201809-2016615), and European Union Joint Program for Neurodegenerative Disorders (JPND2019-466-236). The funding organizations had no role in design, conduct of the study, or preparation of the manuscript. Funding Information: The authors thank the participants in the Prospective Population Study of Women, and the Gothenburg H70 Birth Cohort Study. The authors also thank the members of the study group for their cooperation in data collection and management; UCL Genomics, London, UK, for performing the genotyping; and the Genomic Aggregation Project in Sweden (GAPS), the Karolinska Institute, Stockholm, for help and advice with the QC and imputation. Further, we thank the International Genomics of Alzheimer{\textquoteright}s Project (IGAP) for providing summary results data for these analyses. The investigators within IGAP contributed to the design and implementation of IGAP and/or provided data but did not participate in analysis or writing of this report. IGAP was made possible by the generous participation of the control subjects, the patients, and their families. The i–Select chips was funded by the French National Foundation on Alzheimer{\textquoteright}s disease and related disorders. EADI was supported by the LABEX (laboratory of excellence program investment for the future) DISTALZ grant, Inserm, Institut Pasteur de Lille, Universit{\'e} de Lille 2 and the Lille University Hospital. GERAD/PERADES was supported by the Medical Research Coun- cil (Grant no 503480), Alzheimer{\textquoteright}s Research UK (Grant no 503176), the Wellcome Trust (Grant n◦ 082604/2/07/Z) and German Federal Ministry of Education and Research (BMBF): Competence Network Dementia (CND) grant no 01GI0102, 01GI0711, 01GI0420. CHARGE was partially supported by the NIH/NIA grant R01 AG033193 and the NIA AG081220 and AGES contract N01–AG–12100, the NHLBI grant R01 HL105756, the Icelandic Heart Association, and the Erasmus Medical Center and Erasmus University. ADGC was supported by the NIH/NIA grants: U01 AG032984, U24 AG021886, U01 AG016976, and the Alzheimer{\textquoteright}s Association grant ADGC–10-196728. The study was financed by grants from the Swedish state under the agreement between the Swedish government and the county councils, the Swedish State Support for Clinical Research (the ALF-agreement; ALF 716681, ALFGBG-81392, ALFGBG-715986, ALFGBG-720931, ALFGBG-81392, ALF GBG-771071), the Swedish Research Council (no 11267, 825-2012-5041, 2013-8717, 2015-02830, 2017-00639, 2017-00915, 2018-02532, 2019-01096, 2019-02075, 2018-02532), Swedish Research Council for Health, Working Life and Welfare (no 2001-2646, 2001-2835, 2001-2849, 2003-0234, 2004-0150, 2005-0762, 2006-0020, 2008-1229, 2008-1210, 2012-1138, 2004-0145, 2006-0596, 2008-1111, 2010-0870, 2013-1202, 2013-2300, 2013-2496), the Swedish Alzheimer Foundation (AF-742881, AF-930582, AF-646061, AF-741361, AF-842471, AF-737641), Swedish Brain Power, Hj{\"a}rnfonden, Sweden (FO2016-0214, FO2017-0243, FO2018-0214, FO2019-0163), The Alzheimer{\textquoteright}s Association Zenith Award (ZEN-01-3151), The Alzheimer{\textquoteright}s Association Stephanie B. Overstreet Scholars (IIRG-00-2159), The Alzheimer{\textquoteright}s Association (IIRG-03-6168, IIRG-09-131338), The Bank of Sweden Tercentenary Foundation, Stiftelsen S{\"o}derstr{\"o}m-K{\"o}nigska Sjukhem-met, Magnus Bergvalls Stiftelse, Stiftelsen f{\"o}r Gamla Tj{\"a}narinnor, Handlanden Hjalmar Svenssons Forskningsfond, and Fredrik och Ingrid Thurings Stiftelse (2019-00522). John Hardy is supported by the UK Dementia Research Institute, which receives its funding from DRI Ltd and is funded by the UK Medical Research Council, Alzheimer{\textquoteright}s Society and Alzheimer{\textquoteright}s Research UK, and Medical Research Council (award number MR/N026004/1), Wellcome Trust Hardy (award number 202903/Z/16/Z), Dolby Family Fund, National Institute of Health Research University College London Hospitals Biomedical Research Centre, and supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. Henrik Zetterberg is a Wallenberg Scholar and is further supported by grants from the European Research Council (81712), the Alzheimer Drug Discovery Foundation (ADDF), USA (201809-2016862), and the UK Dementia Research Institute at UCL. Kaj Blennow is further supported by the Alzheimer Drug Discovery Foundation (ADDF), USA (RDAPB-201809-2016615), and European Union Joint Program for Neurodegenerative Disorders (JPND2019-466-236). The funding organizations had no role in design, conduct of the study, or preparation of the manuscript. Funding Information: ALFGBG-720931, ALFGBG-81392, ALF GBG-771071; the Swedish Research Council, Grant/Award Numbers: 11267, 825-2012-5041, 2013-8717, 2015-02830, 2017-00639, 2017-00915, 2018-02532, 2019-01096, 2019-02075, 2018-02532; Swedish Research Council for Health, Working Life and Welfare, Grant/Award Numbers: 2001-2646, 2001-2835, 2001-2849, 2003-0234, 2004-0150, 2005-0762, 2006-0020, 2008-1229, 2008-1210, 2012-1138, 2004-0145, 2006-0596, 2008-1111, 2010-0870, 2013-1202, 2013-2300, 2013-2496; Swedish Alzheimer Foundation, Grant/Award Numbers: AF-742881, AF-930582, AF-646061, AF-741361, AF-842471, AF-737641; Swedish Brain Power, Hj{\"a}rnfonden, Sweden, Grant/Award Numbers: FO2016-0214, FO2017-0243, FO2018-0214, FO2019-0163; The Alzheimer{\textquoteright}s Association Zenith Award, Grant/Award Number: ZEN-01-3151; The Alzheimer{\textquoteright}s Association Stephanie B. Overstreet Scholars, Grant/Award Number: IIRG-00-2159; The Alzheimer{\textquoteright}s Association, Grant/Award Numbers: IIRG-03-6168, IIRG-09-131338; The Bank of Sweden Tercentenary Foundation; Stiftelsen S{\"o}derstr{\"o}m-K{\"o}nigska Sjukhemmet; Magnus Bergvalls Stiftelse; Stif-telsen f{\"o}r Gamla Tj{\"a}narinnor; Handlanden Hjalmar Svenssons Forskningsfond; Fredrik och Ingrid Thurings Stiftelse, Grant/Award Number: 2019-00522; UK Medical Research Council, Alzheimer{\textquoteright}s Society and Alzheimer{\textquoteright}s Research UK; Medical Research Council, Grant/Award Number: MR/N026004/1; Wellcome Trust Hardy, Grant/Award Number: 202903/Z/16/Z; Dolby Family Fund, National Institute of Health Research University College London Hospitals Biomedical Research Centre; National Institute for Health Research University College London Hospitals Biomedical Research Centre; European Research Council, Grant/Award Number: 81712; Alzheimer Drug Discovery Foundation (ADDF), USA, Grant/Award Number: 201809-2016862; Alzheimer Drug Discovery Foundation, Grant/Award Number: RDAPB-201809-2016615; European Union Joint Program for Neurodegenerative Disorders, Grant/Award Number: JPND2019-466-236 Publisher Copyright: {\textcopyright} 2021 The Authors. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

year = "2021",

doi = "10.1002/dad2.12142",

language = "English",

volume = "13",

journal = "Alzheimer's and Dementia: Diagnosis, Assessment and Disease Monitoring",

issn = "2352-8729",

publisher = "John Wiley and Sons Inc.",

number = "1",

}

Najar, J, van der Lee, SJ, Joas, E, Wetterberg, H, Hardy, J, Guerreiro, R, Bras, J, Waern, M, Kern, S, Zetterberg, H, Blennow, K, Skoog, I & Zettergren, A 2021, 'Polygenic risk scores for alzheimer’s disease are related to dementia risk in apoe ɛ4 negatives', Alzheimer's and Dementia: Diagnosis, Assessment and Disease Monitoring, vol. 13, no. 1, e12142. https://doi.org/10.1002/dad2.12142

TY - JOUR

T1 - Polygenic risk scores for alzheimer’s disease are related to dementia risk in apoe ɛ4 negatives

AU - Najar, Jenna

AU - van der Lee, Sven J.

AU - Joas, Erik

AU - Wetterberg, Hanna

AU - Hardy, John

AU - Guerreiro, Rita

AU - Bras, Jose

AU - Waern, Margda

AU - Kern, Silke

AU - Zetterberg, Henrik

AU - Blennow, Kaj

AU - Skoog, Ingmar

AU - Zettergren, Anna

N1 - Funding Information: Swedish state under the agreement between the Swedish government and the county councils; the Swedish State Support for Clinical Research, Grant/Award Numbers: ALF 716681, ALFGBG-81392, ALFGBG-715986, ALFGBG-720931, ALFGBG-81392, ALF GBG-771071; the Swedish Research Council, Grant/Award Numbers: 11267, 825-2012-5041, 2013-8717, 2015-02830, 2017-00639, 2017-00915, 2018-02532, 2019-01096, 2019-02075, 2018-02532; Swedish Research Council for Health, Working Life and Welfare, Grant/Award Numbers: 2001-2646, 2001-2835, 2001-2849, 2003-0234, 2004-0150, 2005-0762, 2006-0020, 2008-1229, 2008-1210, 2012-1138, 2004-0145, 2006-0596, 2008-1111, 2010-0870, 2013-1202, 2013-2300, 2013-2496; Swedish Alzheimer Foundation, Grant/Award Numbers: AF-742881, AF-930582, AF-646061, AF-741361, AF-842471, AF-737641; Swedish Brain Power, Hj?rnfonden, Sweden, Grant/Award Numbers: FO2016-0214, FO2017-0243, FO2018-0214, FO2019-0163; The Alzheimer?s Association Zenith Award, Grant/Award Number: ZEN-01-3151; The Alzheimer?s Association Stephanie B. Overstreet Scholars, Grant/Award Number: IIRG-00-2159; The Alzheimer?s Association, Grant/Award Numbers: IIRG-03-6168, IIRG-09-131338; The Bank of Sweden Tercentenary Foundation; Stiftelsen S?derstr?m-K?nigska Sjukhemmet; Magnus Bergvalls Stiftelse; Stiftelsen f?r Gamla Tj?narinnor; Handlanden Hjalmar Svenssons Forskningsfond; Fredrik och Ingrid Thurings Stiftelse, Grant/Award Number: 2019-00522; UK Medical Research Council, Alzheimer?s Society and Alzheimer?s Research UK; Medical Research Council, Grant/Award Number: MR/N026004/1; Wellcome Trust Hardy, Grant/Award Number: 202903/Z/16/Z; Dolby Family Fund, National Institute of Health Research University College London Hospitals Biomedical Research Centre; National Institute for Health Research University College London Hospitals Biomedical Research Centre; European Research Council, Grant/Award Number: 81712; Alzheimer Drug Discovery Foundation (ADDF), USA, Grant/Award Number: 201809-2016862; Alzheimer Drug Discovery Foundation, Grant/Award Number: RDAPB-201809-2016615; European Union Joint Program for Neurodegenerative Disorders, Grant/Award Number: JPND2019-466-236T he authors thank the participants in the Prospective Population Study of Women, and the Gothenburg H70 Birth Cohort Study. The authors also thank the members of the study group for their cooperation in data collection and management; UCL Genomics, London, UK, for performing the genotyping; and the Genomic Aggregation Project in Sweden (GAPS), the Karolinska Institute, Stockholm, for help and advice with the QC and imputation. Further, we thank the International Genomics of Alzheimer?s Project (IGAP) for providing summary results data for these analyses. The investigators within IGAP contributed to the design and implementation of IGAP and/or provided data but did not participate in analysis or writing of this report. IGAP was made possible by the generous participation of the control sub-jects, the patients, and their families. The i?Select chips was funded by the French National Foundation on Alzheimer?s disease and related dis-orders. EADI was supported by the LABEX (laboratory of excellence program investment for the future) DISTALZ grant, Inserm, Institut Pasteur de Lille, Universit? de Lille 2 and the Lille University Hospi-tal. GERAD/PERADES was supported by the Medical Research Council (Grant no 503480), Alzheimer?s Research UK (Grant no 503176), the Wellcome Trust (Grant n? 082604/2/07/Z) and German Federal Ministry of Education and Research (BMBF): Competence Network Dementia (CND) grant no 01GI0102, 01GI0711, 01GI0420. CHARGE was partially supported by the NIH/NIA grant R01 AG033193 and the NIA AG081220 and AGES contract N01?AG?12100, the NHLBI grant R01 HL105756, the Icelandic Heart Association, and the Erasmus Medical Center and Erasmus University. ADGC was supported by the NIH/NIA grants: U01 AG032984, U24 AG021886, U01 AG016976, and the Alzheimer?s Association grant ADGC?10-196728. The study was financed by grants from the Swedish state under the agreement between the Swedish government and the county councils, the Swedish State Support for Clinical Research (the ALF-agreement; ALF 716681, ALFGBG-81392, ALFGBG-715986, ALFGBG-720931, ALFGBG-81392, ALF GBG-771071), the Swedish Research Council (no 11267, 825-2012-5041, 2013-8717, 2015-02830, 2017-00639, 2017-00915, 2018-02532, 2019-01096, 2019-02075, 2018-02532), Swedish Research Council for Health, Working Life and Welfare (no 2001-2646, 2001-2835, 2001-2849, 2003-0234, 2004-0150, 2005-0762, 2006-0020, 2008-1229, 2008-1210, 2012-1138, 2004-0145, 2006-0596, 2008-1111, 2010-0870, 2013-1202, 2013-2300, 2013-2496), the Swedish Alzheimer Foundation (AF-742881, AF-930582, AF-646061, AF-741361, AF-842471, AF-737641), Swedish Brain Power, Hj?rnfonden, Sweden (FO2016-0214, FO2017-0243, FO2018-0214, FO2019-0163), The Alzheimer?s Association Zenith Award (ZEN-01-3151), The Alzheimer?s Association Stephanie B. Overstreet Scholars (IIRG-00-2159), The Alzheimer?s Association (IIRG-03-6168, IIRG-09-131338), The Bank of Sweden Tercentenary Foundation, Stiftelsen S?derstr?m-K?nigska Sjukhem-met, Magnus Bergvalls Stiftelse, Stiftelsen f?r Gamla Tj?narinnor, Handlanden Hjalmar Svenssons Forskningsfond, and Fredrik och Ingrid Thurings Stiftelse (2019-00522). John Hardy is supported by the UK Dementia Research Institute, which receives its funding from DRI Ltd and is funded by the UK Medical Research Council, Alzheimer?s Society and Alzheimer?s Research UK, and Medical Research Council (award number MR/N026004/1), Wellcome Trust Hardy (award number 202903/Z/16/Z), Dolby Family Fund, National Institute of Health Research University College London Hospitals Biomedical Research Centre, and supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. Henrik Zetterberg is a Wallenberg Scholar and is further supported by grants from the European Research Council (81712), the Alzheimer Drug Discovery Foundation (ADDF), USA (201809-2016862), and the UK Dementia Research Institute at UCL. Kaj Blennow is further supported by the Alzheimer Drug Discovery Foundation (ADDF), USA (RDAPB-201809-2016615), and European Union Joint Program for Neurodegenerative Disorders (JPND2019-466-236). The funding organizations had no role in design, conduct of the study, or preparation of the manuscript. Funding Information: The authors thank the participants in the Prospective Population Study of Women, and the Gothenburg H70 Birth Cohort Study. The authors also thank the members of the study group for their cooperation in data collection and management; UCL Genomics, London, UK, for performing the genotyping; and the Genomic Aggregation Project in Sweden (GAPS), the Karolinska Institute, Stockholm, for help and advice with the QC and imputation. Further, we thank the International Genomics of Alzheimer’s Project (IGAP) for providing summary results data for these analyses. The investigators within IGAP contributed to the design and implementation of IGAP and/or provided data but did not participate in analysis or writing of this report. IGAP was made possible by the generous participation of the control subjects, the patients, and their families. The i–Select chips was funded by the French National Foundation on Alzheimer’s disease and related disorders. EADI was supported by the LABEX (laboratory of excellence program investment for the future) DISTALZ grant, Inserm, Institut Pasteur de Lille, Université de Lille 2 and the Lille University Hospital. GERAD/PERADES was supported by the Medical Research Coun- cil (Grant no 503480), Alzheimer’s Research UK (Grant no 503176), the Wellcome Trust (Grant n◦ 082604/2/07/Z) and German Federal Ministry of Education and Research (BMBF): Competence Network Dementia (CND) grant no 01GI0102, 01GI0711, 01GI0420. CHARGE was partially supported by the NIH/NIA grant R01 AG033193 and the NIA AG081220 and AGES contract N01–AG–12100, the NHLBI grant R01 HL105756, the Icelandic Heart Association, and the Erasmus Medical Center and Erasmus University. ADGC was supported by the NIH/NIA grants: U01 AG032984, U24 AG021886, U01 AG016976, and the Alzheimer’s Association grant ADGC–10-196728. The study was financed by grants from the Swedish state under the agreement between the Swedish government and the county councils, the Swedish State Support for Clinical Research (the ALF-agreement; ALF 716681, ALFGBG-81392, ALFGBG-715986, ALFGBG-720931, ALFGBG-81392, ALF GBG-771071), the Swedish Research Council (no 11267, 825-2012-5041, 2013-8717, 2015-02830, 2017-00639, 2017-00915, 2018-02532, 2019-01096, 2019-02075, 2018-02532), Swedish Research Council for Health, Working Life and Welfare (no 2001-2646, 2001-2835, 2001-2849, 2003-0234, 2004-0150, 2005-0762, 2006-0020, 2008-1229, 2008-1210, 2012-1138, 2004-0145, 2006-0596, 2008-1111, 2010-0870, 2013-1202, 2013-2300, 2013-2496), the Swedish Alzheimer Foundation (AF-742881, AF-930582, AF-646061, AF-741361, AF-842471, AF-737641), Swedish Brain Power, Hjärnfonden, Sweden (FO2016-0214, FO2017-0243, FO2018-0214, FO2019-0163), The Alzheimer’s Association Zenith Award (ZEN-01-3151), The Alzheimer’s Association Stephanie B. Overstreet Scholars (IIRG-00-2159), The Alzheimer’s Association (IIRG-03-6168, IIRG-09-131338), The Bank of Sweden Tercentenary Foundation, Stiftelsen Söderström-Königska Sjukhem-met, Magnus Bergvalls Stiftelse, Stiftelsen för Gamla Tjänarinnor, Handlanden Hjalmar Svenssons Forskningsfond, and Fredrik och Ingrid Thurings Stiftelse (2019-00522). John Hardy is supported by the UK Dementia Research Institute, which receives its funding from DRI Ltd and is funded by the UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK, and Medical Research Council (award number MR/N026004/1), Wellcome Trust Hardy (award number 202903/Z/16/Z), Dolby Family Fund, National Institute of Health Research University College London Hospitals Biomedical Research Centre, and supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. Henrik Zetterberg is a Wallenberg Scholar and is further supported by grants from the European Research Council (81712), the Alzheimer Drug Discovery Foundation (ADDF), USA (201809-2016862), and the UK Dementia Research Institute at UCL. Kaj Blennow is further supported by the Alzheimer Drug Discovery Foundation (ADDF), USA (RDAPB-201809-2016615), and European Union Joint Program for Neurodegenerative Disorders (JPND2019-466-236). The funding organizations had no role in design, conduct of the study, or preparation of the manuscript. Funding Information: ALFGBG-720931, ALFGBG-81392, ALF GBG-771071; the Swedish Research Council, Grant/Award Numbers: 11267, 825-2012-5041, 2013-8717, 2015-02830, 2017-00639, 2017-00915, 2018-02532, 2019-01096, 2019-02075, 2018-02532; Swedish Research Council for Health, Working Life and Welfare, Grant/Award Numbers: 2001-2646, 2001-2835, 2001-2849, 2003-0234, 2004-0150, 2005-0762, 2006-0020, 2008-1229, 2008-1210, 2012-1138, 2004-0145, 2006-0596, 2008-1111, 2010-0870, 2013-1202, 2013-2300, 2013-2496; Swedish Alzheimer Foundation, Grant/Award Numbers: AF-742881, AF-930582, AF-646061, AF-741361, AF-842471, AF-737641; Swedish Brain Power, Hjärnfonden, Sweden, Grant/Award Numbers: FO2016-0214, FO2017-0243, FO2018-0214, FO2019-0163; The Alzheimer’s Association Zenith Award, Grant/Award Number: ZEN-01-3151; The Alzheimer’s Association Stephanie B. Overstreet Scholars, Grant/Award Number: IIRG-00-2159; The Alzheimer’s Association, Grant/Award Numbers: IIRG-03-6168, IIRG-09-131338; The Bank of Sweden Tercentenary Foundation; Stiftelsen Söderström-Königska Sjukhemmet; Magnus Bergvalls Stiftelse; Stif-telsen för Gamla Tjänarinnor; Handlanden Hjalmar Svenssons Forskningsfond; Fredrik och Ingrid Thurings Stiftelse, Grant/Award Number: 2019-00522; UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK; Medical Research Council, Grant/Award Number: MR/N026004/1; Wellcome Trust Hardy, Grant/Award Number: 202903/Z/16/Z; Dolby Family Fund, National Institute of Health Research University College London Hospitals Biomedical Research Centre; National Institute for Health Research University College London Hospitals Biomedical Research Centre; European Research Council, Grant/Award Number: 81712; Alzheimer Drug Discovery Foundation (ADDF), USA, Grant/Award Number: 201809-2016862; Alzheimer Drug Discovery Foundation, Grant/Award Number: RDAPB-201809-2016615; European Union Joint Program for Neurodegenerative Disorders, Grant/Award Number: JPND2019-466-236 Publisher Copyright: © 2021 The Authors. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021

Y1 - 2021

N2 - Introduction: Studies examining the effect of polygenic risk scores (PRS) for Alzheimer’s disease (AD) and apolipoprotein E (APOE) genotype on incident dementia in very old individuals are lacking. Methods: A population-based sample of 2052 individuals ages 70 to 111, from Swe-den, was followed in relation to dementia. AD-PRSs including 39, 57, 1333, and 13,942 single nucleotide polymorphisms (SNPs) were used. Results: AD-PRSs (including 39 or 57 SNPs) were associated with dementia (57-SNPs AD-PRS: hazard ratio 1.09, confidence interval 1.01–1.19, P = .03), particularly in APOE ɛ4 non-carriers (57-SNPs AD-PRS: 1.15, 1.05–1.27, P = 4 × 10–3, 39-SNPs AD-PRS: 1.22, 1.10–1.35, P = 2 × 10–4 ). No association was found with the other AD-PRSs. Further, APOE ɛ4 was associated with increased risk of dementia (1.60, 1.35–1.92, P = 1 × 10–7 ). In those aged ≥95 years, the results were similar for the AD-PRSs, while APOE ɛ4 only predicted dementia in the low-risk tertile of AD-PRSs. Discussion: These results provide information to identify individuals at increased risk of dementia.

AB - Introduction: Studies examining the effect of polygenic risk scores (PRS) for Alzheimer’s disease (AD) and apolipoprotein E (APOE) genotype on incident dementia in very old individuals are lacking. Methods: A population-based sample of 2052 individuals ages 70 to 111, from Swe-den, was followed in relation to dementia. AD-PRSs including 39, 57, 1333, and 13,942 single nucleotide polymorphisms (SNPs) were used. Results: AD-PRSs (including 39 or 57 SNPs) were associated with dementia (57-SNPs AD-PRS: hazard ratio 1.09, confidence interval 1.01–1.19, P = .03), particularly in APOE ɛ4 non-carriers (57-SNPs AD-PRS: 1.15, 1.05–1.27, P = 4 × 10–3, 39-SNPs AD-PRS: 1.22, 1.10–1.35, P = 2 × 10–4 ). No association was found with the other AD-PRSs. Further, APOE ɛ4 was associated with increased risk of dementia (1.60, 1.35–1.92, P = 1 × 10–7 ). In those aged ≥95 years, the results were similar for the AD-PRSs, while APOE ɛ4 only predicted dementia in the low-risk tertile of AD-PRSs. Discussion: These results provide information to identify individuals at increased risk of dementia.

KW - Alzheimer’s disease

KW - Apolipoprotein E genotype

KW - Dementia

KW - Polygenic risk score

KW - Risk factors in epidemiology

UR - https://www.scopus.com/pages/publications/85108255801

U2 - 10.1002/dad2.12142

DO - 10.1002/dad2.12142

M3 - Article

C2 - 33532541

SN - 2352-8729

VL - 13

JO - Alzheimer's and Dementia: Diagnosis, Assessment and Disease Monitoring

JF - Alzheimer's and Dementia: Diagnosis, Assessment and Disease Monitoring

IS - 1

M1 - e12142

ER -

Polygenic risk scores for alzheimer’s disease are related to dementia risk in apoe ɛ4 negatives

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