Artificial intelligence and leukocyte epigenomics: Evaluation and prediction of late-onset Alzheimer's disease

PLoS One. 2021 Mar 31;16(3):e0248375. doi: 10.1371/journal.pone.0248375. eCollection 2021.


We evaluated the utility of leucocyte epigenomic-biomarkers for Alzheimer's Disease (AD) detection and elucidates its molecular pathogeneses. Genome-wide DNA methylation analysis was performed using the Infinium MethylationEPIC BeadChip array in 24 late-onset AD (LOAD) and 24 cognitively healthy subjects. Data were analyzed using six Artificial Intelligence (AI) methodologies including Deep Learning (DL) followed by Ingenuity Pathway Analysis (IPA) was used for AD prediction. We identified 152 significantly (FDR p<0.05) differentially methylated intragenic CpGs in 171 distinct genes in AD patients compared to controls. All AI platforms accurately predicted AD with AUCs ≥0.93 using 283,143 intragenic and 244,246 intergenic/extragenic CpGs. DL had an AUC = 0.99 using intragenic CpGs, with both sensitivity and specificity being 97%. High AD prediction was also achieved using intergenic/extragenic CpG sites (DL significance value being AUC = 0.99 with 97% sensitivity and specificity). Epigenetically altered genes included CR1L & CTSV (abnormal morphology of cerebral cortex), S1PR1 (CNS inflammation), and LTB4R (inflammatory response). These genes have been previously linked with AD and dementia. The differentially methylated genes CTSV & PRMT5 (ventricular hypertrophy and dilation) are linked to cardiovascular disease and of interest given the known association between impaired cerebral blood flow, cardiovascular disease, and AD. We report a novel, minimally invasive approach using peripheral blood leucocyte epigenomics, and AI analysis to detect AD and elucidate its pathogenesis.

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / blood*
  • Alzheimer Disease / genetics*
  • Biomarkers / blood
  • Case-Control Studies
  • CpG Islands / genetics
  • DNA Methylation / genetics
  • Deep Learning*
  • Epigenesis, Genetic*
  • Epigenomics / methods*
  • Female
  • Genome-Wide Association Study
  • Humans
  • Late Onset Disorders / genetics*
  • Leukocytes / metabolism*
  • Male
  • Prognosis
  • Sensitivity and Specificity
  • Signal Transduction / genetics


  • Biomarkers

Grants and funding

The funder provided support in the form of salaries for authors [BA), but did not have any additional role in the study design, data collection, and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.