Abstract Alzheimer’s disease (AD) is a progressive neurodegenerative disorder, and previous studies have shown its association with accelerated aging. In this study, we hypothesized that single nucleotide polymorphisms (SNPs) that contributed to aging acceleration are also associated with the progression from mild cognitive impairment (MCI) to AD. By applying genetic correlation analysis and single-locus survival analysis, we investigated the associations between intrinsic- and extrinsic-epigenetic-age-acceleration (IEAA and EEAA) related SNPs and the progression time from MCI to AD dementia using the data of 767 MCI participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) study and 1 373 MCI patients from the National Alzheimer’s Coordinating Center (NACC) study. Genetic correlations were found between IEAA/EEAA and AD (positive for IEAA-AD and negative for EEAA-AD). We revealed that 70 IEAA and 81 EEAA SNPs had associations with the progression time from MCI to AD with Bayesian false-discovery probability ≤ 0.8 in the ADNI study, with 22 IEAA SNPs and 16 EEAA SNPs being replicated in the NACC study (p < .05). Polygenic risk score (PRS) analysis showed that EEAA PRS but not IEAA PRS was associated with AD progression and the trend of decreasing fusiform gyrus volume in 2 data sets. Risk models incorporating both EAA PRSs did not show any significant improvement in predictive accuracy. Our results revealed multiple genetic variants with pleiotropic effects on both EAA and AD, which suggested shared genetic architecture between epigenetic age acceleration and AD progression.

中文翻译：

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表观遗传衰老加速与阿尔茨海默病轻度认知障碍进展之间的遗传关联

摘要阿尔茨海默病 (AD) 是一种进行性神经退行性疾病，之前的研究已表明其与加速衰老有关。在这项研究中，我们假设导致衰老加速的单核苷酸多态性 (SNP) 也与从轻度认知障碍 (MCI) 到 AD 的进展有关。通过应用遗传相关分析和单基因座生存分析，我们使用 767 名 MCI 参与者的数据研究了内在和外在表观遗传年龄加速（IEAA 和 EEAA）相关 SNP 与从 MCI 到 AD 痴呆的进展时间之间的关联来自阿尔茨海默病神经影像倡议 (ADNI) 研究的 1,373 名 MCI 患者来自国家阿尔茨海默病协调中心 (NACC) 研究。在 IEAA/EEAA 和 AD 之间发现了遗传相关性（IEAA-AD 呈阳性，EEAA-AD 呈阴性）。我们发现，在 ADNI 研究中，70 个 IEAA 和 81 个 EEAA SNP 与从 MCI 到 AD 的进展时间存在关联，贝叶斯错误发现概率 ≤ 0.8，其中 22 个 IEAA SNP 和 16 个 EEAA SNP 在 NACC 研究中得到了重复（p < 1）。 .05）。多基因风险评分 (PRS) 分析显示，在 2 个数据集中，EEAA PRS 而不是 IEAA PRS 与 AD 进展和梭状回体积减少趋势相关。纳入两种 EAA PRS 的风险模型并未显示预测准确性有任何显着改善。我们的结果揭示了对 EAA 和 AD 具有多效性作用的多种遗传变异，这表明表观遗传年龄加速和 AD 进展之间存在共享的遗传结构。