BACKGROUND Previous studies have demonstrated an association between DNA methylation-based measures of accelerated ageing and age-related health outcomes and mortality. As a disease closely associated with advancing age, we hypothesized that DNA methylation-based measures of accelerated ageing might be associated with risk for dementia. This study therefore aimed to examine the association between four recognised measures of age acceleration and subsequent dementia. METHODS Study subjects (n = 488) were members of the Lothian Birth Cohort 1921. Dementia case ascertainment used data from death certificates, electronic hospital records, and clinical reviews. Venous blood samples were taken at baseline, at age 79 years. DNA methylation and measures of epigenetic age were calculated in accordance with Horvath's epigenetic clock tutorial, using the online calculator (https://dnamage.genetics.ucla.edu/). From these values, four measures of accelerated ageing were calculated: extrinsic epigenetic age acceleration (EEAA), intrinsic epigenetic age acceleration (IEAA), AgeAccelPheno and AgeAccelGrim. Competing risk regression models - with death as a competing risk - were performed to examine the association between each measure of accelerated ageing and incident dementia. APOE ɛ4 status, sex, age, smoking status, history of cardiovascular disease, cerebrovascular disease, hypertension, and diabetes were included as covariates. RESULTS None of the multivariate models revealed a positive association between increased epigenetic age acceleration and dementia risk. Across all included models, never-smoking increased risk for dementia (HR 1.69 [1.06, 2.71], p = 0.03), and having no APOE ɛ4 alleles reduced risk for dementia (HR 0.44 [0.29, 0.67], p < 0.001). CONCLUSIONS The present study did not demonstrate any consistent association between DNA methylation-based measures of accelerated ageing and dementia in subjects aged over 79 years. Further, larger studies - including separate analyses of dementia subtypes - are required to further investigate the potential association between DNA methylation-based measures of accelerated ageing and dementia.

中文翻译：

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基于 DNA 甲基化的加速生物衰老和老年人痴呆风险的测量：对 1921 年洛锡安出生队列的一项研究。


背景 先前的研究已经证明基于 DNA 甲基化的加速衰老指标与年龄相关的健康结果和死亡率之间存在关联。作为一种与年龄增长密切相关的疾病，我们假设基于 DNA 甲基化的加速衰老措施可能与痴呆风险相关。因此，本研究旨在探讨四种公认的年龄加速指标与随后的痴呆症之间的关联。方法 研究对象 (n = 488) 是 1921 年洛锡安出生队列的成员。痴呆病例确定使用来自死亡证明、电子医院记录和临床回顾的数据。静脉血样本是在 79 岁时采集的。 DNA 甲基化和表观遗传年龄的测量是根据 Horvath 的表观遗传时钟教程，使用在线计算器 (https://dnamage. Genetics.ucla.edu/) 计算的。根据这些值，计算出四种加速衰老的指标：外在表观遗传年龄加速（EEAA）、内在表观遗传年龄加速（IEAA）、AgeAccelPheno 和 AgeAccelGrim。采用竞争风险回归模型（以死亡作为竞争风险）来检查加速衰老的每项指标与痴呆症之间的关联。 APOE ɛ4 状态、性别、年龄、吸烟状况、心血管疾病史、脑血管疾病、高血压和糖尿病作为协变量。结果没有一个多变量模型显示表观遗传年龄加速与痴呆风险之间存在正相关。在所有纳入的模型中，从不吸烟会增加痴呆风险（HR 1.69 [1.06, 2.71]，p = 0.03），并且没有 APOE ɛ4 等位基因会降低痴呆风险（HR 0.44 [0.29, 0.67]，p < 0.001）。 结论 本研究并未证明基于 DNA 甲基化的加速衰老测量与 79 岁以上受试者痴呆之间存在任何一致的关联。此外，还需要进行更大规模的研究，包括对痴呆亚型的单独分析，以进一步调查基于 DNA 甲基化的加速衰老指标与痴呆之间的潜在关联。