Abstract
BackgroundIdentifying 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.ResultsThe 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; mPACCdigit and mPACCtrailsB) 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 × 10−8 [Bonferroni correction threshold]); cg00386386 was associated with the slope of mPACCdigit, 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 mPACCtrailsB, mPACCdigit, 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 × 10−24), which was associated with both the slope of CDR-SB and the MCI conversion status.ConclusionCandidate 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.
Highlights
Identifying biomarkers associated with Alzheimer’s disease (AD) progression may enable patient enrichment and improve clinical trial designs
Methylated positions in peripheral blood Two Cytosine-phosphate-guanine (CpG) sites were associated with the rate of cognitive decline in cognitively normal (CN) participants and patients with mild cognitive impairment (MCI) at a level surpassing Bonferroni correction threshold of P = 5.79 × 10–8 (Table 1)
No CpG probe was significantly associated with disease conversion status (Additional file 1: Figs. 1C, E, 2C, and E) passing Bonferroni correction threshold
Summary
Identifying biomarkers associated with Alzheimer’s disease (AD) progression may enable patient enrichment and improve clinical trial designs. Most (99.6%) clinical trials of Alzheimer’s disease (AD) that were registered at ClinicalTrials.gov during 2002 to 2012 failed, likely because of inadequate understanding of disease pathways and drug targets and. Li et al Clin Epigenet (2021) 13:191 difficulty in identifying patients at early stages of the disease [1]. As of January 5, 2021, 126 investigative agents were in clinical trials for AD; most of them targeting the biological processes underlying AD to modify the disease [6]. A new drug that reduces beta-amyloid (Aβ) plaques and may delay disease progression in patients with AD recently received an accelerated FDA approval [7]
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