TY - JOUR
T1 - An updated Alzheimer hypothesis
T2 - Complement C3 and risk of Alzheimer's disease-A cohort study of 95,442 individuals
AU - Rasmussen, Katrine Laura
AU - Nordestgaard, Børge Grønne
AU - Frikke-Schmidt, Ruth
AU - Nielsen, Sune Fallgaard
N1 - Copyright © 2018 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.
PY - 2018/12
Y1 - 2018/12
N2 - INTRODUCTION: We tested the hypothesis that low plasma complement C3 is observationally and genetically associated with high risk of Alzheimer's disease (AD).METHODS: We studied 95,442 individuals enrolled in the Copenhagen General Population Study. In genetic analyses, we further included 8367 individuals from the Copenhagen City Heart Study. In the two studies, 1189 and 35 developed AD during median 8 years follow-up.RESULTS: The multifactorially adjusted hazard ratio for risk of AD for a one standard deviation lower levels of complement C3 was 1.11 (95% confidence interval: 1.04-1.19) in all individuals and 1.66 (1.33-2.07) in APOE ε44 carriers. In Mendelian randomization, the corresponding genetic estimates were 1.66 (1.05-2.63) overall and 1.99 (0.52-7.65) in APOE ε44 carriers.DISCUSSION: Low baseline levels of complement C3 were associated with high risk of AD. The risk was amplified in APOE ε44 highly susceptible individuals, and these findings were substantiated by a Mendelian randomization approach, potentially implying causality. Based on these findings, we present and thoroughly discuss an updated Alzheimer hypothesis incorporating low complement C3 levels.
AB - INTRODUCTION: We tested the hypothesis that low plasma complement C3 is observationally and genetically associated with high risk of Alzheimer's disease (AD).METHODS: We studied 95,442 individuals enrolled in the Copenhagen General Population Study. In genetic analyses, we further included 8367 individuals from the Copenhagen City Heart Study. In the two studies, 1189 and 35 developed AD during median 8 years follow-up.RESULTS: The multifactorially adjusted hazard ratio for risk of AD for a one standard deviation lower levels of complement C3 was 1.11 (95% confidence interval: 1.04-1.19) in all individuals and 1.66 (1.33-2.07) in APOE ε44 carriers. In Mendelian randomization, the corresponding genetic estimates were 1.66 (1.05-2.63) overall and 1.99 (0.52-7.65) in APOE ε44 carriers.DISCUSSION: Low baseline levels of complement C3 were associated with high risk of AD. The risk was amplified in APOE ε44 highly susceptible individuals, and these findings were substantiated by a Mendelian randomization approach, potentially implying causality. Based on these findings, we present and thoroughly discuss an updated Alzheimer hypothesis incorporating low complement C3 levels.
U2 - 10.1016/j.jalz.2018.07.223
DO - 10.1016/j.jalz.2018.07.223
M3 - Journal article
C2 - 30243924
SN - 1552-5260
VL - 14
SP - 1589
EP - 1601
JO - Alzheimer's & Dementia
JF - Alzheimer's & Dementia
IS - 12
ER -