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. 2025 Apr 22;17(1):88.
doi: 10.1186/s13195-025-01733-7.

DNA methylation signature of a lifestyle-based resilience index for cognitive health

Wei Zhang  1 , David Lukacsovich  1 , Juan I Young  2   3 , Lissette Gomez  3 , Michael A Schmidt  2   3 , Eden R Martin  2   3 , Brian W Kunkle  2   3 , X Steven Chen  1   4 , Deirdre M O'Shea  5 , James E Galvin  6 , Lily Wang  7   8   9   10
Affiliations

DNA methylation signature of a lifestyle-based resilience index for cognitive health

Wei Zhang et al. Alzheimers Res Ther. .

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; Cognitive resilience; DNA methylation; Lifestyle factors.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: The HBI study was approved by the University of Miami Institution Review Board. The ADNI Study was approved by the Institutional Review Boards of all participating institutions. Written informed consent was obtained from all the participants or their authorized representatives. The study procedures were approved by the institutional review boards of all participating centers ( https://adni.loni.usc.edu/wp-ontent/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf ), and written informed consent was obtained from all participants or their authorized representatives. The study was conducted in accordance with the Declaration of Helsinki and all study participants provided written informed consent for data collection. All work complied with ethical regulations for working with human participants. Ethics approval was obtained from the institutional review boards of each institution involved: Oregon Health and Science University; University of Southern California; University of California—San Diego; University of Michigan; Mayo Clinic, Rochester; Baylor College of Medicine; Columbia University Medical Center; Washington University, St. Louis; University of Alabama at Birmingham; Mount Sinai School of Medicine; Rush University Medical Center; Wien Center; Johns Hopkins University; New York University; Duke University Medical Center; University of Pennsylvania; University of Kentucky; University of Pittsburgh; University of Rochester Medical Center; University of California, Irvine; University of Texas Southwestern Medical School; Emory University; University of Kansas, Medical Center; University of California, Los Angeles; Mayo Clinic, Jacksonville; Indiana University; Yale University School of Medicine; McGill University, Montreal-Jewish General Hospital; Sunnybrook Health Sciences, Ontario; U.B.C. Clinic for AD & Related Disorders; Cognitive Neurology—St. Joseph’s, Ontario; Cleveland Clinic Lou Ruvo Center for Brain Health; Northwestern University; Premiere Research Inst (Palm Beach Neurology); Georgetown University Medical Center; Brigham and Women’s Hospital; Stanford University; Banner Sun Health Research Institute; Boston University; Howard University; Case Western Reserve University; University of California, Davis—Sacramento; Neurological Care of CNY; Parkwood Hospital; University of Wisconsin; University of California, Irvine—BIC; Banner Alzheimer’s Institute; Dent Neurologic Institute; Ohio State University; Albany Medical College; Hartford Hospital, Olin Neuropsychiatry Research Center; Dartmouth-Hitchcock Medical Center; Wake Forest University Health Sciences; Rhode Island Hospital; Butler Hospital; UC San Francisco; Medical University South Carolina; St. Joseph’s Health Care Nathan Kline Institute; University of Iowa College of Medicine; Cornell University and University of South Florida: USF Health Byrd Alzheimer’s Institute. The investigators within the ADNI contributed to the design and implementation of the ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found online ( http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf ). Consent for publication: Not Applicable. Competing interests: The authors declare no competing interests.

Figures

Fig. 1
Fig. 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
Fig. 2
Fig. 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
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