Journal Article

Association of peripheral blood DNA methylation level with Alzheimer’s disease progression

Davis, Justin W., Nho, Kwangsik, Saykin, Andrew J., Li, Qingqin S., Vasanthakumar, Aparna, Idler, Kenneth B., Waring, Jeffrey F.

2021

نظرة عامة

Background 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. Results 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 digit and mPACC trailsB ) 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 mPACC digit , 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 trailsB , mPACC digit , 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. Conclusion 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.

• الناشر: BioMed Central,BioMed Central Ltd,Springer Nature B.V
• موضوع: Advertising executives / Aged / Aged, 80 and over / Alzheimer Disease - blood / Alzheimer Disease - diagnosis / Alzheimer Disease - genetics / Alzheimer's disease / Asymptomatic / Biomarkers / Biomarkers - analysis / Biomarkers - blood / Biomedical and Life Sciences / Biomedicine / Clinical trials / Cognitive ability / Cognitive Dysfunction - genetics / Cohort Studies / CpG islands / Cytosine / Dementia disorders / Deoxyribonucleic acid / Development and progression / Diagnosis / Diagnostic imaging / Disease Progression / DNA / DNA methylation / DNA Methylation - genetics / DNA Methylation - physiology / DNA probes / Epigenetic inheritance / Epigenetics / FDA approval / Female / Gene Function / Genetic research / Genetic testing / Guanine / Human Genetics / Humans / Machine learning / Male / Medical colleges / Medical imaging / Medical prognosis / Methylation / Neurodegenerative diseases / Neuroimaging / Patients / Peripheral blood / Phosphates / Pyrimidines