Alzheimer’s disease DNA methylation index (AD-DMI) and its association with late-life cognitive function

Abstract Alzheimer’s disease (AD) is driven by genetic and epigenetic factors. A knowledge gap remains in applying DNA methylation (DNAm) to capture AD-specific signatures. We developed the AD DNA Methylation Index (AD-DMI), a brain-derived risk index constructed from 100 CpG sites identified by elastic-net logistic regression of methylation data from postmortem dorsolateral prefrontal cortex tissue. AD-DMI was evaluated in 722 older adults, including individuals with normal cognition (NC), mild cognitive impairment (MCI), and AD. AD-relevant associations were tested using generalized linear models (GLMs), logistic regression, and path analyses, with applicable covariate adjustments. Higher AD-DMI scores were associated with lower global cognitive function, greater global AD neuropathologic burden, and increased odds of subjective memory complaints. AD-DMI predicted clinical diagnosis across the continuum, independent of cognition and pathology. Compared to the Cortical clock, AD-DMI showed stronger and more specific associations with both cognitive and pathological outcomes. Genes mapped to AD-DMI CpGs overlapped with eight genetic loci identified in AD genome-wide association studies, including RELN , LRP1B , and PDE9A . AD-DMI was significantly associated with increased methylation at CpGs in APOE , HOXA3 , and ANK1 . AD-DMI provides a biologically grounded framework for linking disease-relevant methylation changes with cognitive and pathological outcomes in AD.