DNA Methylation Signature of a Lifestyle-based Resilience Index for Cognitive Health

Abstract

Cognitive resilience (CR) contributes to the variability in risk for developing and progressing in Alzheimer's disease (AD) among individuals. Beyond genetics, recent studies highlight the critical role of lifestyle factors in enhancing CR and delaying cognitive decline. DNA methylation (DNAm), an epigenetic mechanism influenced by both genetic and environmental factors, including CR-related lifestyle factors, offers a promising pathway for understanding the biology of CR. We studied DNAm changes associated with the Resilience Index (RI), a composite measure of lifestyle factors, using blood samples from the Healthy Brain Initiative (HBI) cohort. After corrections for multiple comparisons, our analysis identified 19 CpGs and 24 differentially methylated regions significantly associated with the RI, adjusting for covariates age, sex, APOE ε4, and immune cell composition. The RI-associated methylation changes are significantly enriched in pathways related to lipid metabolism, synaptic plasticity, and neuroinflammation, and highlight the connection between cardiovascular health and cognitive function. By identifying RI-associated DNAm, our study provided an alternative approach to discovering future targets and treatment strategies for AD, complementary to the traditional approach of identifying disease-associated variants directly. Furthermore, we developed a Methylation-based Resilience Score (MRS) that successfully predicted future cognitive decline in an external dataset from the Alzheimer's Disease Neuroimaging Initiative (ADNI), even after accounting for age, sex, APOE ε4, years of education, baseline diagnosis, and baseline MMSE score. Our findings are particularly relevant for a better understanding of epigenetic architecture underlying cognitive resilience. Importantly, the significant association between baseline MRS and future cognitive decline demonstrated that DNAm could be a predictive marker for AD, laying the foundation for future studies on personalized AD prevention.

Keywords: Alzheimer’s disease; DNA methylation; cognitive resilience; lifestyle factors.

Figure 1

Manhattan plot of significant DNA methylation (DNAm) differences associated with the Resilience Index (RI). The X-axis indicates chromosome number. The Y-axis shows −log₁₀(P-value) of the association between DNAm M-values and RI, adjusting for covariates (age, sex, diagnosis, cell type compositions, APOE ε4 allele count). The genes with promoter regions associated with the top 10 most significant CpGs are highlighted.

Figure 2

Kaplan-Meier curve for Alzheimer’s disease progression (CN to MCI/AD, or MCI to AD) among subjects with the highest and lowest tertiles of baseline MRS score in the ADNI cohort. While survival probability decreases in both groups, the high resilience group consistently shows a higher survival probability, suggesting a protective effect of higher resilience against AD progression. Abbreviations CN, cognitively normal; MCI, mild cognitive impairment; AD, Alzheimer’s disease; MRS, Methylation-based Resilience Score