基于血液 DNA 甲基化的衰老速度与年龄相关性认知障碍和痴呆的关联。
Association of Pace of Aging Measured by Blood-Based DNA Methylation With Age-Related Cognitive Impairment and Dementia.
机构信息
From the Department of Psychology and Neuroscience (K.S., A.C., M.L.E., K.C., A.R.H., R.M.H., B.S.W., T.E.M.), and Center for Genomic and Computational Biology (K.S., A.C., B.S.W., T.E.M.), Duke University, Durham, NC; Department of Psychiatry and Behavioral Sciences (A.C., T.E.M.), Duke University School of Medicine, Durham, NC; Social, Genetic, and Developmental Psychiatry Centre (A.C, T.E.M.), Institute of Psychiatry, Psychology, and Neuroscience, King's College London, UK. Center for the Study of Aging and Human Development (K.J.B.), Duke University, Durham, NC; Department of Genetics (D.L.C.), University of North Carolina School of Medicine, Chapel Hill; Butler Columbia Aging Center (M.K., D.W.B.), Columbia University, New York, New York; Sticht Center for Healthy Aging and Alzheimer's Prevention (S.K.), Wake Forest School of Medicine, Winston-Salem, NC; UConn Center on Aging (G.A.K.), University of Connecticut, Farmington, Connecticut, USA; College of Medicine and Health (J.S.M.), University of Exeter Medical School, Devon, UK; and Department of Epidemiology (D.W.B.), Columbia University Mailman School of Public Health, New York, New York.
出版信息
Neurology. 2022 Sep 27;99(13):e1402-e1413. doi: 10.1212/WNL.0000000000200898. Epub 2022 Jul 6.
BACKGROUND AND OBJECTIVES
DNA methylation algorithms are increasingly used to estimate biological aging; however, how these proposed measures of whole-organism biological aging relate to aging in the brain is not known. We used data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the Framingham Heart Study (FHS) Offspring Cohort to test the association between blood-based DNA methylation measures of biological aging and cognitive impairment and dementia in older adults.
METHODS
We tested 3 "generations" of DNA methylation age algorithms (first generation: Horvath and Hannum clocks; second generation: PhenoAge and GrimAge; and third generation: DunedinPACE, Dunedin Pace of Aging Calculated from the Epigenome) against the following measures of cognitive impairment in ADNI: clinical diagnosis of dementia and mild cognitive impairment, scores on Alzheimer disease (AD) / Alzheimer disease and related dementias (ADRD) screening tests (Alzheimer's Disease Assessment Scale, Mini-Mental State Examination, and Montreal Cognitive Assessment), and scores on cognitive tests (Rey Auditory Verbal Learning Test, Logical Memory test, and Trail Making Test). In an independent replication in the FHS Offspring Cohort, we further tested the longitudinal association between the DNA methylation algorithms and the risk of developing dementia.
RESULTS
In ADNI ( = 649 individuals), the first-generation (Horvath and Hannum DNA methylation age clocks) and the second-generation (PhenoAge and GrimAge) DNA methylation measures of aging were not consistently associated with measures of cognitive impairment in older adults. By contrast, a third-generation measure of biological aging, DunedinPACE, was associated with clinical diagnosis of Alzheimer disease (beta [95% CI] = 0.28 [0.08-0.47]), poorer scores on Alzheimer disease/ADRD screening tests (beta [Robust SE] = -0.10 [0.04] to 0.08[0.04]), and cognitive tests (beta [Robust SE] = -0.12 [0.04] to 0.10 [0.03]). The association between faster pace of aging, as measured by DunedinPACE, and risk of developing dementia was confirmed in a longitudinal analysis of the FHS Offspring Cohort ( = 2,264 individuals, hazard ratio [95% CI] = 1.27 [1.07-1.49]).
DISCUSSION
Third-generation blood-based DNA methylation measures of aging could prove valuable for measuring differences between individuals in the rate at which they age and in their risk for cognitive decline, and for evaluating interventions to slow aging.
背景与目的
DNA 甲基化算法越来越多地被用于估计生物年龄；然而，这些整体生物老化的测量方法与大脑老化的关系尚不清楚。我们使用来自阿尔茨海默病神经影像学倡议 (ADNI) 和弗雷明汉心脏研究 (FHS) 后代队列的数据，测试了老年人血液中基于 DNA 甲基化的生物老化测量值与认知障碍和痴呆之间的关联。
方法
我们测试了 3 代 DNA 甲基化年龄算法（第一代：Horvath 和 Hannum 时钟；第二代：PhenoAge 和 GrimAge；第三代：DunedinPACE、从表观基因组计算的 Dunedin 衰老速度）与 ADNI 中的以下认知障碍测量值的关系：痴呆和轻度认知障碍的临床诊断、阿尔茨海默病 (AD) /阿尔茨海默病和相关痴呆症 (ADRD) 筛查测试（阿尔茨海默病评估量表、简易精神状态检查和蒙特利尔认知评估）的评分，以及认知测试（Rey 听觉言语学习测试、逻辑记忆测试和连线测试）的评分。在 FHS 后代队列的独立复制中，我们进一步测试了 DNA 甲基化算法与痴呆发病风险之间的纵向关联。
结果
在 ADNI（=649 人）中，第一代（Horvath 和 Hannum DNA 甲基化年龄时钟）和第二代（PhenoAge 和 GrimAge）的衰老 DNA 甲基化测量值与老年人的认知障碍测量值没有一致的相关性。相比之下，第三代生物衰老测量指标 DunedinPACE 与阿尔茨海默病的临床诊断相关（β[95%CI] = 0.28 [0.08-0.47]），与阿尔茨海默病/ADRD 筛查测试的评分较差相关（β[稳健 SE] = -0.10 [0.04] 至 0.08[0.04]），以及认知测试（β[稳健 SE] = -0.12 [0.04] 至 0.10 [0.03]）。在弗雷明汉心脏研究后代队列（=2264 人）的纵向分析中，更快的衰老速度与痴呆发病风险之间的关联得到了证实（风险比[95%CI] = 1.27 [1.07-1.49]）。
讨论
第三代基于血液的衰老 DNA 甲基化测量值可能在衡量个体之间衰老速度的差异以及他们的认知能力下降风险方面具有重要价值，并且可以评估减缓衰老的干预措施。
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