Blostein Freida, Bakulski Kelly M, Fu Mingzhou, Wang Herong, Zawistowski Matthew, Ware Erin B
Department of Epidemiology, School of Public Health, University of Michigan.
Department of Medical Informatics, University of California, Los Angeles.
medRxiv. 2024 Sep 22:2024.09.19.24314012. doi: 10.1101/2024.09.19.24314012.
DNA methylation clocks have emerged as promising biomarkers for cognitive impairment and dementia. Longitudinal studies exploring the link between DNA methylation clocks and cognitive decline have been constrained by limited sample sizes and a lack of diversity.
Our study aimed to investigate the longitudinal associations between DNA methylation clocks and incident cognitive impairment using a larger sample size encompassing a US nationally representative sample from the Health and Retirement Study.
We measured DNA methylation age acceleration in 2016 by comparing the residuals of DNA methylation clocks, including GrimAge, against chronological age. Cognitive decline was determined by the change in Langa-Weir cognition status from 2016 to 2018. Using multivariable logistic regression, we evaluated the link between DNA methylation age acceleration and cognitive decline, adjusting for cell-type proportions, demographic, and health factors. We also conducted an inverse probability weighting analysis to address potential selection bias from varying loss-to-follow-up rates.
The analytic sample (N=2,713) at baseline had an average of 68 years old, and during the two years of follow-up, 12% experienced cognitive decline. Participants who experienced cognitive decline during follow-up had higher baseline GrimAge (mean = 1.2 years) acceleration compared to those who maintained normal cognitive function (mean = -0.8 years, p < 0.001). A one-year increase in GrimAge acceleration was associated with 1.05 times higher adjusted and survey-weighted odds of cognitive decline during follow-up (95% CI: 1.01-1.10). This association was consistent after accounting for loss-to-follow-up (OR = 1.07, 95% CI: 1.04-1.11).
Our study offers insights into DNA methylation age acceleration associated with cognitive decline, suggesting avenues for improved prevention, diagnosis, and treatment.
DNA甲基化时钟已成为认知障碍和痴呆症颇具前景的生物标志物。探索DNA甲基化时钟与认知衰退之间联系的纵向研究受到样本量有限和缺乏多样性的限制。
我们的研究旨在使用来自健康与退休研究的美国全国代表性样本这一更大的样本量，调查DNA甲基化时钟与新发认知障碍之间的纵向关联。
我们在2016年通过比较包括GrimAge在内的DNA甲基化时钟的残差与实际年龄，测量了DNA甲基化年龄加速情况。认知衰退由2016年至2018年兰加-韦尔认知状态的变化来确定。我们使用多变量逻辑回归评估DNA甲基化年龄加速与认知衰退之间的联系，并对细胞类型比例、人口统计学和健康因素进行了调整。我们还进行了逆概率加权分析，以解决因随访失访率不同而产生的潜在选择偏倚。
基线时的分析样本（N = 2713）平均年龄为68岁，在两年的随访期间，12%的人经历了认知衰退。与保持正常认知功能的参与者（平均 = -0.8岁，p < 0.001）相比，随访期间经历认知衰退的参与者基线GrimAge（平均 = 1.2岁）加速更高。GrimAge加速每增加一年，随访期间认知衰退的校正和调查加权几率就高出1.05倍（95%置信区间：1.01 - 1.10）。在考虑随访失访情况后，这种关联仍然一致（OR = 1.07，95%置信区间：1.04 - 1.11）。
我们的研究为与认知衰退相关的DNA甲基化年龄加速提供了见解，为改进预防、诊断和治疗方法指明了方向。
