Charisis Sokratis, Mourtzi Niki, Scott Matthew R, Ntanasi Eva, Mamalaki Eirini, Hatzimanolis Alexandros, Ramirez Alfredo, Lambert Jean-Charles, Yannakoulia Mary, Kosmidis Mary, Dardiotis Efthimios, Hadjigeorgiou Georgios, Sakka Paraskevi, Satizabal Claudia L, Beiser Alexa, Yang Qiong, Georgakis Marios Κ, Seshadri Sudha, Scarmeas Nikolaos
Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, UT Health San Antonio, San Antonio, TX, USA.
1st Department of Neurology, Aiginition Hospital, National and Kapodistrian University of Athens Medical School, Athens, Greece.
J Prev Alzheimers Dis. 2025 Jan;12(1):100018. doi: 10.1016/j.tjpad.2024.100018. Epub 2025 Jan 1.
Aging is accompanied by immune dysregulation, which has been implicated in Alzheimer's disease (AD) pathogenesis. Individuals who are genetically predisposed to elevated levels of proinflammatory mediators might be at increased risk for AD.
To investigate whether genetic propensity for higher circulating levels of interleukin 6 (IL-6) is associated with AD risk.
We analyzed data from the Hellenic Longitudinal Investigation of Aging and Diet (HELIAD). Mean follow-up was 2.9 (SD, 0.8) years. Baseline assessment was from 11/2009 to 11/2016, and cognitive follow-up from 01/2013 to 07/2019. Associations of interest were also examined in the UK Biobank (UKB) for replication purposes (mean follow-up was 12.9 (SD, 2.4) years; baseline assessment was from 12/2006 to 10/2010).
Population-based study.
The HELIAD sample included 622 participants ≥65 years of age without baseline dementia or amnestic mild cognitive impairment (aMCI-the prodromal stage of AD). The UKB sample included 142,637 participants ≥60 years of age without prevalent dementia.
Genetic predisposition to elevated circulating levels of IL-6 was estimated using a polygenic risk score (PRS), calculated based on the summary statistics of a current GWAS meta-analysis.
AD and MCI diagnoses were based on standard clinical criteria [HELIAD], or hospital records and death registry data [UKB]. Associations with AD or aMCI incidence [HELIAD] and AD incidence [UKB] were examined with Cox regression models.
In HELIAD, mean age was 73.4 (SD, 5.0) years; 363 (58%) women. An increase in IL-6 PRS by 1 standard deviation unit (SDU) was associated with up to a 43% increase in the risk for incident AD/aMCI (HR 1.43 [95%CI, 1.14 - 1.80]). In UKBB, mean age was 64.2 (SD, 2.8) years; 73,707 (52%) women. A 1 SDU increase in IL-6 PRS was associated with up to an 8% increase in the risk for incident AD (HR, 1.08 [95%CI, 1.04 - 1.12]).
Genetic predisposition to higher circulating levels of IL-6 was associated with an increased risk for AD, supporting the role of IL-6-related pathways in AD pathogenesis, and suggesting that genetic predisposition to proinflammatory states might trigger or accelerate AD-related neuropathology.
衰老伴随着免疫失调，这与阿尔茨海默病（AD）的发病机制有关。具有促炎介质水平升高遗传倾向的个体患AD的风险可能会增加。
研究循环白细胞介素6（IL-6）水平升高的遗传倾向是否与AD风险相关。
我们分析了希腊衰老与饮食纵向调查（HELIAD）的数据。平均随访时间为2.9（标准差，0.8）年。基线评估时间为2009年11月至2016年11月，认知随访时间为2013年1月至2019年7月。为了进行重复验证，我们还在英国生物银行（UKB）中检验了相关关联（平均随访时间为12.9（标准差，2.4）年；基线评估时间为2006年12月至2010年10月）。
基于人群的研究。
HELIAD样本包括622名年龄≥65岁、无基线痴呆或遗忘性轻度认知障碍（aMCI，AD的前驱阶段）的参与者。UKB样本包括142,637名年龄≥60岁、无现患痴呆的参与者。
使用基于当前全基因组关联研究（GWAS）荟萃分析的汇总统计数据计算的多基因风险评分（PRS）来估计循环IL-6水平升高的遗传倾向。
AD和MCI诊断基于标准临床标准[HELIAD]，或医院记录和死亡登记数据[UKB]。使用Cox回归模型检验与AD或aMCI发病率[HELIAD]以及AD发病率[UKB]的关联。
在HELIAD中，平均年龄为73.4（标准差，5.0）岁；363名（58%）为女性。IL-6 PRS增加1个标准差单位（SDU）与新发AD/aMCI风险增加高达43%相关（风险比1.43[95%置信区间，1.14 - 1.80]）。在UKB中，平均年龄为64.2（标准差，2.8）岁；73,707名（52%）为女性。IL-6 PRS增加1个SDU与新发AD风险增加高达8%相关（风险比，1.08[95%置信区间，1.04 - 1.12]）。
循环IL-6水平升高的遗传倾向与AD风险增加相关，支持IL-6相关通路在AD发病机制中的作用，并表明促炎状态的遗传倾向可能触发或加速AD相关神经病理学进程。
