Neuroscience, Janssen Research and Development, LLC, 1125 Trenton-Harbourton Road, Titusville, NJ, 08560, USA.
Genomics Research Center, AbbVie, North Chicago, IL, USA.
Clin Epigenetics. 2021 Oct 15;13(1):191. doi: 10.1186/s13148-021-01179-2.
Identifying biomarkers associated with Alzheimer's disease (AD) progression may enable patient enrichment and improve clinical trial designs. Epigenome-wide association studies have revealed correlations between DNA methylation at cytosine-phosphate-guanine (CpG) sites and AD pathology and diagnosis. Here, we report relationships between peripheral blood DNA methylation profiles measured using Infinium® MethylationEPIC BeadChip and AD progression in participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort.
The rate of cognitive decline from initial DNA sampling visit to subsequent visits was estimated by the slopes of the modified Preclinical Alzheimer Cognitive Composite (mPACC; mPACC and mPACC) and Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) plots using robust linear regression in cognitively normal (CN) participants and patients with mild cognitive impairment (MCI), respectively. In addition, diagnosis conversion status was assessed using a dichotomized endpoint. Two CpG sites were significantly associated with the slope of mPACC in CN participants (P < 5.79 × 10 [Bonferroni correction threshold]); cg00386386 was associated with the slope of mPACC, and cg09422696 annotated to RP11-661A12.5 was associated with the slope of CDR-SB. No significant CpG sites associated with diagnosis conversion status were identified. Genes involved in cognition and learning were enriched. A total of 19, 13, and 5 differentially methylated regions (DMRs) associated with the slopes of mPACC, mPACC, and CDR-SB, respectively, were identified by both comb-p and DMRcate algorithms; these included DMRs annotated to HOXA4. Furthermore, 5 and 19 DMRs were associated with conversion status in CN and MCI participants, respectively. The most significant DMR was annotated to the AD-associated gene PM20D1 (chr1: 205,818,956 to 205,820,014 [13 probes], Sidak-corrected P = 7.74 × 10), which was associated with both the slope of CDR-SB and the MCI conversion status.
Candidate CpG sites and regions in peripheral blood were identified as associated with the rate of cognitive decline in participants in the ADNI cohort. While we did not identify a single CpG site with sufficient clinical utility to be used by itself due to the observed effect size, a biosignature composed of DNA methylation changes may have utility as a prognostic biomarker for AD progression.
识别与阿尔茨海默病（AD）进展相关的生物标志物，可能有助于患者选择，并改善临床试验设计。全基因组范围内的表观遗传学关联研究已经揭示了胞嘧啶-磷酸-鸟嘌呤（CpG）位点的 DNA 甲基化与 AD 病理和诊断之间的相关性。在此，我们报告了阿尔茨海默病神经影像学倡议（ADNI）队列参与者外周血 DNA 甲基化谱与 AD 进展之间的关系，该谱是使用 Infinium® MethylationEPIC BeadChip 进行测量的。
使用稳健线性回归，在认知正常（CN）参与者和轻度认知障碍（MCI）患者中，分别根据改良的临床前期阿尔茨海默认知综合评分（mPACC；mPACC 和 mPACC）和临床痴呆评定量表总和评分（CDR-SB）图中初始 DNA 采样访视到后续访视的斜率来估计认知下降的速度。此外，使用二分类终点评估诊断转换状态。在 CN 参与者中，有两个 CpG 位点与 mPACC 斜率显著相关（P<5.79×10[Bonferroni 校正阈值]）；cg00386386 与 mPACC 斜率相关，cg09422696 注释到 RP11-661A12.5 与 CDR-SB 斜率相关。未发现与诊断转换状态相关的显著 CpG 位点。涉及认知和学习的基因被富集。通过 comb-p 和 DMRcate 算法，分别鉴定了与 mPACC、mPACC 和 CDR-SB 斜率相关的 19、13 和 5 个差异甲基化区域（DMR）；这些 DMR 注释到 HOXA4。此外，CN 和 MCI 参与者的转换状态分别与 5 和 19 个 DMR 相关。最显著的 DMR 注释到 AD 相关基因 PM20D1（chr1：205818956 至 205820014[13 个探针]，Sidak 校正 P=7.74×10），该基因与 CDR-SB 斜率和 MCI 转换状态均相关。
在 ADNI 队列参与者中，确定了外周血中与认知下降速度相关的候选 CpG 位点和区域。由于观察到的效应大小，虽然我们没有发现一个具有足够临床实用性的单个 CpG 位点可以单独使用，但由 DNA 甲基化变化组成的生物标志物可能可用作 AD 进展的预后生物标志物。
