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 (DN...
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BMC
2025-04-01
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| Series: | Alzheimer’s Research & Therapy |
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| Online Access: | https://doi.org/10.1186/s13195-025-01733-7 |
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| author | Wei Zhang David Lukacsovich Juan I. Young Lissette Gomez Michael A. Schmidt Eden R. Martin Brian W. Kunkle X. Steven Chen Deirdre M. O’Shea James E. Galvin Lily Wang |
| author_facet | Wei Zhang David Lukacsovich Juan I. Young Lissette Gomez Michael A. Schmidt Eden R. Martin Brian W. Kunkle X. Steven Chen Deirdre M. O’Shea James E. Galvin Lily Wang |
| author_sort | Wei Zhang |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-a0ea64e8751d4e46852992589ab39984 |
| institution | OA Journals |
| issn | 1758-9193 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Alzheimer’s Research & Therapy |
| spelling | doaj-art-a0ea64e8751d4e46852992589ab399842025-08-20T02:30:22ZengBMCAlzheimer’s Research & Therapy1758-91932025-04-0117111710.1186/s13195-025-01733-7DNA methylation signature of a lifestyle-based resilience index for cognitive healthWei Zhang0David Lukacsovich1Juan I. Young2Lissette Gomez3Michael A. Schmidt4Eden R. Martin5Brian W. Kunkle6X. Steven Chen7Deirdre M. O’Shea8James E. Galvin9Lily Wang10Division of Biostatistics, Department of Public Health Sciences, University of Miami, Miller School of MedicineDivision of Biostatistics, Department of Public Health Sciences, University of Miami, Miller School of MedicineDr. John T Macdonald Foundation Department of Human Genetics, University of Miami, Miller School of MedicineJohn P. Hussman Institute for Human Genomics, University of Miami Miller School of MedicineDr. John T Macdonald Foundation Department of Human Genetics, University of Miami, Miller School of MedicineDr. John T Macdonald Foundation Department of Human Genetics, University of Miami, Miller School of MedicineDr. John T Macdonald Foundation Department of Human Genetics, University of Miami, Miller School of MedicineDivision of Biostatistics, Department of Public Health Sciences, University of Miami, Miller School of MedicineComprehensive Center for Brain Health, Department of Neurology, University of Miami Miller School of MedicineComprehensive Center for Brain Health, Department of Neurology, University of Miami Miller School of MedicineDivision of Biostatistics, Department of Public Health Sciences, University of Miami, Miller School of MedicineAbstract 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.https://doi.org/10.1186/s13195-025-01733-7Alzheimer’s diseaseCognitive resilienceDNA methylationLifestyle factors |
| spellingShingle | Wei Zhang David Lukacsovich Juan I. Young Lissette Gomez Michael A. Schmidt Eden R. Martin Brian W. Kunkle X. Steven Chen Deirdre M. O’Shea James E. Galvin Lily Wang DNA methylation signature of a lifestyle-based resilience index for cognitive health Alzheimer’s Research & Therapy Alzheimer’s disease Cognitive resilience DNA methylation Lifestyle factors |
| title | DNA methylation signature of a lifestyle-based resilience index for cognitive health |
| title_full | DNA methylation signature of a lifestyle-based resilience index for cognitive health |
| title_fullStr | DNA methylation signature of a lifestyle-based resilience index for cognitive health |
| title_full_unstemmed | DNA methylation signature of a lifestyle-based resilience index for cognitive health |
| title_short | DNA methylation signature of a lifestyle-based resilience index for cognitive health |
| title_sort | dna methylation signature of a lifestyle based resilience index for cognitive health |
| topic | Alzheimer’s disease Cognitive resilience DNA methylation Lifestyle factors |
| url | https://doi.org/10.1186/s13195-025-01733-7 |
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