Evaluating genomic signatures of aging in brain tissue as it relates to Alzheimer’s disease
Abstract Telomere length (TL) attrition, epigenetic age acceleration, and mitochondrial DNA copy number (mtDNAcn) decline are established hallmarks of aging. Each has been individually associated with Alzheimer’s dementia, cognitive function, and pathologic Alzheimer’s disease (AD). Epigenetic age a...
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| Format: | Article |
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Nature Portfolio
2023-09-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-023-41400-1 |
| _version_ | 1797453212540731392 |
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| author | Megan T. Lynch Margaret A. Taub Jose M. Farfel Jingyun Yang Peter Abadir Philip L. De Jager Francine Grodstein David A. Bennett Rasika A. Mathias |
| author_facet | Megan T. Lynch Margaret A. Taub Jose M. Farfel Jingyun Yang Peter Abadir Philip L. De Jager Francine Grodstein David A. Bennett Rasika A. Mathias |
| author_sort | Megan T. Lynch |
| collection | DOAJ |
| description | Abstract Telomere length (TL) attrition, epigenetic age acceleration, and mitochondrial DNA copy number (mtDNAcn) decline are established hallmarks of aging. Each has been individually associated with Alzheimer’s dementia, cognitive function, and pathologic Alzheimer’s disease (AD). Epigenetic age and mtDNAcn have been studied in brain tissue directly but prior work on TL in brain is limited to small sample sizes and most studies have examined leukocyte TL. Importantly, TL, epigenetic age clocks, and mtDNAcn have not been studied jointly in brain tissue from an AD cohort. We examined dorsolateral prefrontal cortex (DLPFC) tissue from N = 367 participants of the Religious Orders Study (ROS) or the Rush Memory and Aging Project (MAP). TL and mtDNAcn were estimated from whole genome sequencing (WGS) data and cortical clock age was computed on 347 CpG sites. We examined dementia, MCI, and level of and change in cognition, pathologic AD, and three quantitative AD traits, as well as measures of other neurodegenerative diseases and cerebrovascular diseases (CVD). We previously showed that mtDNAcn from DLPFC brain tissue was associated with clinical and pathologic features of AD. Here, we show that those associations are independent of TL. We found TL to be associated with β-amyloid levels (beta = − 0.15, p = 0.023), hippocampal sclerosis (OR = 0.56, p = 0.0015) and cerebral atherosclerosis (OR = 1.44, p = 0.0007). We found strong associations between mtDNAcn and clinical measures of AD. The strongest associations with pathologic measures of AD were with cortical clock and there were associations of mtDNAcn with global AD pathology and tau tangles. Of the other pathologic traits, mtDNAcn was associated with hippocampal sclerosis, macroscopic infarctions and CAA and cortical clock was associated with Lewy bodies. Multi-modal age acceleration, accelerated aging on both mtDNAcn and cortical clock, had greater effect size than a single measure alone. These findings highlight for the first time that age acceleration determined on multiple genomic measures, mtDNAcn and cortical clock may have a larger effect on AD/AD related disorders (ADRD) pathogenesis than single measures. |
| first_indexed | 2024-03-09T15:19:32Z |
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| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-03-09T15:19:32Z |
| publishDate | 2023-09-01 |
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| spelling | doaj.art-6ff218eea22048358a72390dd75c2eed2023-11-26T12:54:10ZengNature PortfolioScientific Reports2045-23222023-09-0113111110.1038/s41598-023-41400-1Evaluating genomic signatures of aging in brain tissue as it relates to Alzheimer’s diseaseMegan T. Lynch0Margaret A. Taub1Jose M. Farfel2Jingyun Yang3Peter Abadir4Philip L. De Jager5Francine Grodstein6David A. Bennett7Rasika A. Mathias8Department of Medicine, School of Medicine, Johns Hopkins UniversityDepartment of Biostatistics, Johns Hopkins Bloomberg School of Public HealthRush Alzheimer’s Disease Center, Rush University Medical CenterRush Alzheimer’s Disease Center, Rush University Medical CenterDepartment of Medicine, School of Medicine, Johns Hopkins UniversityCenter for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Irving Medical CenterRush Alzheimer’s Disease Center, Rush University Medical CenterRush Alzheimer’s Disease Center, Rush University Medical CenterDepartment of Medicine, School of Medicine, Johns Hopkins UniversityAbstract Telomere length (TL) attrition, epigenetic age acceleration, and mitochondrial DNA copy number (mtDNAcn) decline are established hallmarks of aging. Each has been individually associated with Alzheimer’s dementia, cognitive function, and pathologic Alzheimer’s disease (AD). Epigenetic age and mtDNAcn have been studied in brain tissue directly but prior work on TL in brain is limited to small sample sizes and most studies have examined leukocyte TL. Importantly, TL, epigenetic age clocks, and mtDNAcn have not been studied jointly in brain tissue from an AD cohort. We examined dorsolateral prefrontal cortex (DLPFC) tissue from N = 367 participants of the Religious Orders Study (ROS) or the Rush Memory and Aging Project (MAP). TL and mtDNAcn were estimated from whole genome sequencing (WGS) data and cortical clock age was computed on 347 CpG sites. We examined dementia, MCI, and level of and change in cognition, pathologic AD, and three quantitative AD traits, as well as measures of other neurodegenerative diseases and cerebrovascular diseases (CVD). We previously showed that mtDNAcn from DLPFC brain tissue was associated with clinical and pathologic features of AD. Here, we show that those associations are independent of TL. We found TL to be associated with β-amyloid levels (beta = − 0.15, p = 0.023), hippocampal sclerosis (OR = 0.56, p = 0.0015) and cerebral atherosclerosis (OR = 1.44, p = 0.0007). We found strong associations between mtDNAcn and clinical measures of AD. The strongest associations with pathologic measures of AD were with cortical clock and there were associations of mtDNAcn with global AD pathology and tau tangles. Of the other pathologic traits, mtDNAcn was associated with hippocampal sclerosis, macroscopic infarctions and CAA and cortical clock was associated with Lewy bodies. Multi-modal age acceleration, accelerated aging on both mtDNAcn and cortical clock, had greater effect size than a single measure alone. These findings highlight for the first time that age acceleration determined on multiple genomic measures, mtDNAcn and cortical clock may have a larger effect on AD/AD related disorders (ADRD) pathogenesis than single measures.https://doi.org/10.1038/s41598-023-41400-1 |
| spellingShingle | Megan T. Lynch Margaret A. Taub Jose M. Farfel Jingyun Yang Peter Abadir Philip L. De Jager Francine Grodstein David A. Bennett Rasika A. Mathias Evaluating genomic signatures of aging in brain tissue as it relates to Alzheimer’s disease Scientific Reports |
| title | Evaluating genomic signatures of aging in brain tissue as it relates to Alzheimer’s disease |
| title_full | Evaluating genomic signatures of aging in brain tissue as it relates to Alzheimer’s disease |
| title_fullStr | Evaluating genomic signatures of aging in brain tissue as it relates to Alzheimer’s disease |
| title_full_unstemmed | Evaluating genomic signatures of aging in brain tissue as it relates to Alzheimer’s disease |
| title_short | Evaluating genomic signatures of aging in brain tissue as it relates to Alzheimer’s disease |
| title_sort | evaluating genomic signatures of aging in brain tissue as it relates to alzheimer s disease |
| url | https://doi.org/10.1038/s41598-023-41400-1 |
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