TY - JOUR
T1 - Complement dysregulation and Alzheimer's disease in Down syndrome
AU - Veteleanu, Aurora
AU - Pape, Sarah
AU - Davies, Kate
AU - Kodosaki, Eleftheria
AU - Hye, Abdul
AU - Zelek, Wioleta M.
AU - Strydom, Andre
AU - Morgan, B. Paul
N1 - Funding Information:
Thank you to all the participants of the LonDownS study and their families and caregivers. We also thank our NHS network of sites that helped to identify participants. Recruitment support and data collection for the LonDownS study has been provided by Carla Startin, Sarah Hamburg, Rosalyn Hithersay, Fedal Sinai, Marie-Stephanie Cahart, and Deborah Ness (all based at both the department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK, and Division of Psychiatry, University College London, London, UK). Genetic data extraction was supported by Kin Y. Mok (Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK). The authors thank Professor Claire Harris and her team (Newcastle University) for preparation of control samples. This work is supported by the UK Dementia Research Institute, which receives its funding from UK DRI Ltd, funded by the UK Medical Research Council, Alzheimer's Society, and Alzheimer's Research UK. AV is supported by a ARUK studentship. SP is supported by a fellowship from the Alzheimer's Society (AS-CP-18-0020). The LonDownS study is supported by the Medical Research Council, and via Joint Programming Initiative on Neurodegenerative Diseases Research (JPND) and CoEN (grant number: MRC S011277/1, MR/R024901/1, MR/S005145/1). Other funders include Jérôme Lejeune Foundation. The LonDownS Consortium: The LonDownS Consortium principal investigators are Andre Strydom (chief investigator), Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK, and Division of Psychiatry, University College London, London, UK; Elizabeth Fisher, Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK; Dean Nizetic, Blizard Institute, Barts and the London School of Medicine, Queen Mary University of London, London, UK, and Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore; John Hardy, Reta Lila Weston Institute, Institute of Neurology, University College London, London, UK, and UK Dementia Research Institute at UCL, London, UK; Victor Tybulewicz, Francis Crick Institute, London, UK, and Department of Medicine, Imperial College London, London, UK; and Annette Karmiloff-Smith (Birkbeck University of London, London, UK, deceased).
Funding Information:
Thank you to all the participants of the LonDownS study and their families and caregivers. We also thank our NHS network of sites that helped to identify participants. Recruitment support and data collection for the LonDownS study has been provided by Carla Startin, Sarah Hamburg, Rosalyn Hithersay, Fedal Sinai, Marie‐Stephanie Cahart, and Deborah Ness (all based at both the department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK, and Division of Psychiatry, University College London, London, UK). Genetic data extraction was supported by Kin Y. Mok (Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK). The authors thank Professor Claire Harris and her team (Newcastle University) for preparation of control samples. This work is supported by the UK Dementia Research Institute, which receives its funding from UK DRI Ltd, funded by the UK Medical Research Council, Alzheimer's Society, and Alzheimer's Research UK. AV is supported by a ARUK studentship. SP is supported by a fellowship from the Alzheimer's Society (AS‐CP‐18‐0020). The LonDownS study is supported by the Medical Research Council, and via Joint Programming Initiative on Neurodegenerative Diseases Research (JPND) and CoEN (grant number: MRC S011277/1, MR/R024901/1, MR/S005145/1). Other funders include Jérôme Lejeune Foundation. The LonDownS Consortium: The LonDownS Consortium principal investigators are Andre Strydom (chief investigator), Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK, and Division of Psychiatry, University College London, London, UK; Elizabeth Fisher, Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK; Dean Nizetic, Blizard Institute, Barts and the London School of Medicine, Queen Mary University of London, London, UK, and Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore; John Hardy, Reta Lila Weston Institute, Institute of Neurology, University College London, London, UK, and UK Dementia Research Institute at UCL, London, UK; Victor Tybulewicz, Francis Crick Institute, London, UK, and Department of Medicine, Imperial College London, London, UK; and Annette Karmiloff‐Smith (Birkbeck University of London, London, UK, deceased).
Publisher Copyright:
© 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.
PY - 2023/9/23
Y1 - 2023/9/23
N2 - IntroductionDown syndrome (DS) is associated with immune dysregulation and a high risk of early onset Alzheimer's disease (AD). Complement is a key part of innate immunity and driver of pathological inflammation, including neuroinflammation in AD. Complement dysregulation has been reported in DS; however, the pattern of dysregulation and its relationship to AD risk is unclear.MethodsPlasma levels of 14 complement biomarkers were measured in 71 adults with DS and 46 controls to identify DS-associated dysregulation; impact of apolipoprotein E (APOE) ε4 genotype, single nucleotide polymorphisms (SNPs) in CLU and CR1, and dementia on complement biomarkers was assessed.ResultsPlasma levels of complement activation products (TCC, iC3b), proteins (C1q, C3, C9), and regulators (C1 inhibitor, factor H, FHR4, clusterin) were significantly elevated in DS versus controls while FI and sCR1 were significantly lower. In DS with AD (n = 13), C3 and FI were significantly decreased compared to non-AD DS (n = 58). Neither APOE genotype nor CLU SNPs impacted complement levels, while rs6656401 in CR1 significantly impacted plasma sCR1 levels.ConclusionsComplement is dysregulated in DS, likely reflecting the generalized immune dysregulation state; measurement may help identify inflammatory events in individuals with DS. Complement biomarkers differed in DS with and without AD and may aid diagnosis and/or prediction.HighlightsComplement is significantly dysregulated in plasma of people with DS who show changes in levels of multiple complement proteins compared to controls.People with DS and dementia show evidence of additional complement dysregulation with significantly lower levels of C3 and factor I compared to those without dementia.rs6656401 in CR1 was associated with significantly elevated sCR1 plasma levels in DS.
AB - IntroductionDown syndrome (DS) is associated with immune dysregulation and a high risk of early onset Alzheimer's disease (AD). Complement is a key part of innate immunity and driver of pathological inflammation, including neuroinflammation in AD. Complement dysregulation has been reported in DS; however, the pattern of dysregulation and its relationship to AD risk is unclear.MethodsPlasma levels of 14 complement biomarkers were measured in 71 adults with DS and 46 controls to identify DS-associated dysregulation; impact of apolipoprotein E (APOE) ε4 genotype, single nucleotide polymorphisms (SNPs) in CLU and CR1, and dementia on complement biomarkers was assessed.ResultsPlasma levels of complement activation products (TCC, iC3b), proteins (C1q, C3, C9), and regulators (C1 inhibitor, factor H, FHR4, clusterin) were significantly elevated in DS versus controls while FI and sCR1 were significantly lower. In DS with AD (n = 13), C3 and FI were significantly decreased compared to non-AD DS (n = 58). Neither APOE genotype nor CLU SNPs impacted complement levels, while rs6656401 in CR1 significantly impacted plasma sCR1 levels.ConclusionsComplement is dysregulated in DS, likely reflecting the generalized immune dysregulation state; measurement may help identify inflammatory events in individuals with DS. Complement biomarkers differed in DS with and without AD and may aid diagnosis and/or prediction.HighlightsComplement is significantly dysregulated in plasma of people with DS who show changes in levels of multiple complement proteins compared to controls.People with DS and dementia show evidence of additional complement dysregulation with significantly lower levels of C3 and factor I compared to those without dementia.rs6656401 in CR1 was associated with significantly elevated sCR1 plasma levels in DS.
KW - Alzheimer's disease
KW - complement system
KW - dementia
KW - Down syndrome
KW - immune dysregulation
UR - http://www.scopus.com/inward/record.url?scp=85138662895&partnerID=8YFLogxK
U2 - 10.1002/alz.12799
DO - 10.1002/alz.12799
M3 - Article
C2 - 36149090
AN - SCOPUS:85138662895
SN - 1552-5260
VL - 19
SP - 1383
EP - 1392
JO - Alzheimer's and Dementia
JF - Alzheimer's and Dementia
IS - 4
ER -
