Abstract
Original language | English |
---|---|
Article number | e12142 |
Journal | Alzheimer's and Dementia: Diagnosis, Assessment and Disease Monitoring |
Volume | 13 |
Issue number | 1 |
DOIs | |
Publication status | Published - 2021 |
Keywords
- Alzheimer’s disease
- Apolipoprotein E genotype
- Dementia
- Polygenic risk score
- Risk factors in epidemiology
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In: Alzheimer's and Dementia: Diagnosis, Assessment and Disease Monitoring, Vol. 13, No. 1, e12142, 2021.
Research output: Contribution to journal › Article › Academic › peer-review
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 - http://www.scopus.com/inward/record.url?scp=85108255801&partnerID=8YFLogxK
U2 - https://doi.org/10.1002/dad2.12142
DO - https://doi.org/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 -