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<p>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 <i>RELN</i>, <i>LRP1B</i>, and <i>PDE9A</i>. AD-DMI was significantly associated with increased methylation at CpGs in <i>APOE</i>, <i>HOXA3</i>, and <i>ANK1</i>. AD-DMI provides a biologically grounded framework for linking disease-relevant methylation changes with cognitive and pathological outcomes in AD.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月29日

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  • Nwanyieze Ngozi Jiakponnah,
  • Ifechukwude J. Biose,
  • Tracy Fischer,
  • Katie Cherry,
  • James Cronin,
  • S.Michal Jazwinski,
  • Sangkyu Kim

摘要

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.