Epigenetic Clocks in Neurodegeneration — Causal Drivers or Passive Markers

SUMMARY

# Epigenetic Clocks in Neurodegeneration — Causal Drivers or Passive Markers ## Background and Rationale Epigenetic clocks represent sophisticated molecular chronometers that quantify biological aging through DNA methylation patterns at hundreds of carefully selected CpG dinucleotides across the genome. These algorithms, pioneered by Steve Horvath and subsequently refined by numerous research groups, can predict chronological age with remarkable precision (median absolute error ~3-4 years) and m

METHODOLOGY NOTES

**Phase 1: Cohort Recruitment and Clinical Assessment (Months 1-6)** • Recruit n=300 participants across 4 groups: healthy controls (n=75), mild cognitive impairment (MCI, n=75), Alzheimer's disease (AD, n=75), and Parkinson's disease (PD, n=75) • Age-match groups (65±10 years) with balanced sex distribution (50% female) • Conduct comprehensive neuropsychological testing using MMSE, MoCA, CDR, and UPDRS scales • Collect detailed medical history, medication use, and lifestyle factors • Obtain blood samples (10mL EDTA tubes) for DNA extraction and methylation analysis • Perform structural MRI and optional CSF collection for biomarker validation **Phase 2: DNA Methylation Profiling (Months 4-8)** • Extract genomic DNA using QIAamp DNA Blood Mini Kit with minimum yield of 500ng • Perform bisulfite conversion using EZ DNA Methylation Kit (Zymo Research) • Conduct genome-wide methylation analysis using Illumina EPIC BeadChip (850K CpG sites) • Calculate established epigenetic age using Ho