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Blood DNA methylation signature of cognitive reserve moderates the association between CSF tau pathology and memory in prodromal Alzheimer's disease.
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Lukacsovich David, Young Juan I, Gomez Lissette, Kunkle Brian W, Mao Zhixin, Zhang Wei, Chen X Steven, O'Shea Deirdre M, Rundek Tatjana, Martin Eden R, Wang Lily, Alzheimer's Disease Neuroimaging Initiative
Аннотация
INTRODUCTION: Cognitive reserve (CR) reflects variability in cognitive adaptability that modifies the impact of Alzheimer's disease (AD) pathology on cognition. However, blood-based biomarkers of CR have not been established in prodromal AD. We operationalized CR as memory reserve, defined by the attenuation of the cerebrospinal fluid (CSF) phosphorylated tau threonine 181 (pTau181)-memory association and aimed to identify blood DNA methylation (DNAm) loci involved in memory reserve.
METHODS: We studied 92 amyloid-positive participants with mild cognitive impairment (MCI) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) with blood DNAm, CSF pTau181, and memory (PHC_MEM) measured at the same visit. Memory was residualized after adjustment for age, sex, APOE 𝜀4 allele count, and estimated immune cell-type proportions. For each CpG, linear models tested DNAm, pTau181, and DNAm×pTau181 interaction; inflation was corrected using the bacon method. In addition, we also identified differentially methylated regions (DMRs). Moreover, we constructed a methylation reserve score (MRS) from loci identified in this cohort at baseline and tested its associations with longitudinal memory using linear mixed-effects models in 88 participants with follow-up information.
RESULTS: After removing low-variability CpGs, we identified six CpGs with suggestive DNAm×pTau181 interaction (p value < 1 × 10-5, none passed a 5% false discovery rate) and 11 DMRs passing multiple-comparisons correction. The suggestive CpGs and significant DMRs mapped to genes implicating synaptic function, vascular/blood-brain barrier integrity, and immune regulation, with minimal marginal associations with pTau181 or memory, consistent with a moderation model rather than mediation. In this cohort, higher baseline MRS was associated with attenuation of the pTau181-memory association and with slower subsequent memory decline, independent of age, sex, education, APOE ε4, and baseline pTau181.
DISCUSSION: Blood DNAm that moderates the pTau181-memory association may reflect epigenetic correlates of memory reserve (i.e., differential susceptibility to tau-related memory impairment), rather than reflecting variations in pTau181 levels. These DNAm patterns can be summarized as a MRS that, in this cohort, was associated with longitudinal memory trajectories in MCI. Further validation in independent cohorts is warranted.
METHODS: We studied 92 amyloid-positive participants with mild cognitive impairment (MCI) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) with blood DNAm, CSF pTau181, and memory (PHC_MEM) measured at the same visit. Memory was residualized after adjustment for age, sex, APOE 𝜀4 allele count, and estimated immune cell-type proportions. For each CpG, linear models tested DNAm, pTau181, and DNAm×pTau181 interaction; inflation was corrected using the bacon method. In addition, we also identified differentially methylated regions (DMRs). Moreover, we constructed a methylation reserve score (MRS) from loci identified in this cohort at baseline and tested its associations with longitudinal memory using linear mixed-effects models in 88 participants with follow-up information.
RESULTS: After removing low-variability CpGs, we identified six CpGs with suggestive DNAm×pTau181 interaction (p value < 1 × 10-5, none passed a 5% false discovery rate) and 11 DMRs passing multiple-comparisons correction. The suggestive CpGs and significant DMRs mapped to genes implicating synaptic function, vascular/blood-brain barrier integrity, and immune regulation, with minimal marginal associations with pTau181 or memory, consistent with a moderation model rather than mediation. In this cohort, higher baseline MRS was associated with attenuation of the pTau181-memory association and with slower subsequent memory decline, independent of age, sex, education, APOE ε4, and baseline pTau181.
DISCUSSION: Blood DNAm that moderates the pTau181-memory association may reflect epigenetic correlates of memory reserve (i.e., differential susceptibility to tau-related memory impairment), rather than reflecting variations in pTau181 levels. These DNAm patterns can be summarized as a MRS that, in this cohort, was associated with longitudinal memory trajectories in MCI. Further validation in independent cohorts is warranted.