{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T15:10:29Z","timestamp":1773760229381,"version":"3.50.1"},"posted":{"date-parts":[[2025,7,17]]},"group-title":"Genetic and Genomic Medicine","reference-count":49,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,7,17]],"date-time":"2025-07-17T00:00:00Z","timestamp":1752710400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,3,14]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background and Objectives<\/jats:title>\n                  <jats:p>Biological age, reflecting the cumulative molecular and cellular damage such as telomere attrition, epigenetic alterations and mitochondrial dysfunction, may better capture ageLrelated decline and Alzheimer\u2019s disease (AD) risk than chronological age. Most studies have focused on one measure of biological age and not investigated joint or interactive contributions to AD pathogenesis.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    We estimated bloodLderived telomere length (TL) via qPCR, epigenetic age (DNAm age) using the CausAge clock, and mitochondrial DNA copy number (mtDNAcn) from whole genome sequencing in 640 participants from the Alzheimer\u2019s Disease Neuroimaging Initiative (ADNI; Age: 74.91\u00b17.56, Female: 44.8%, Cognitively Unimpaired: 34.3%, Mild Cognitive Impairment: 52%, AD: 12.9%). Linear mixedLeffects models examined the associations and interactions of these markers with cognitive decline for memory, executive function, language ability, visuospatial ability, and global cognition, while linear regression tested associations with cross-sectional AD biomarkers (CSF A\u03b2\n                    <jats:sub>42<\/jats:sub>\n                    , totalLtau, pTau\n                    <jats:sub>181<\/jats:sub>\n                    , and meta-ROI for cortical thickness and gray matter volume). Models adjusted for baseline age, sex, clinical dementia rating scale,\n                    <jats:italic>APOE<\/jats:italic>\n                    , blood cell composition, and outcomeLspecific covariates (education and intracranial volume).\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    Individually, TL and DNAm age, were not associated with cognition, CSF biomarkers, or neuroimaging outcomes, while higher mtDNAcn was associated with lower CSF tau and pTau\n                    <jats:sub>181<\/jats:sub>\n                    . Interaction models revealed that mtDNAcn modified the effects of both TL and DNAm age: at higher mtDNAcn, shorter TL predicted poorer global cognition (\u03b2 = 0.033 \u00b1 0.014, p = 0.020) and older DNAm age predicted poorer language performance (\u03b2 = \u20130.059 \u00b1 0.028, p = 0.038). A significant three-way interaction showed that the combination of higher mtDNAcn, longer TL, and older DNAm age was associated with lower grey-matter volume.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Discussion<\/jats:title>\n                  <jats:p>These findings suggest that increased mtDNAcn may act as a compensatory response to accelerated epigenetic aging and telomere attrition. Our results underscore the importance of evaluating the interplay among multiple biological aging markers when investigating AD pathogenesis.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Glossary<\/jats:title>\n                  <jats:p>mtDNAcn: mitochondrial DNA copy number; TL: telomere length; AD: Alzheimer\u2019s disease; CDR-SB: Clinical dementia rating sum of boxes; CSF: cerebrospinal fluid<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.07.16.25331683","type":"posted-content","created":{"date-parts":[[2025,7,17]],"date-time":"2025-07-17T23:35:13Z","timestamp":1752795313000},"source":"Crossref","is-referenced-by-count":0,"title":["Integrative effects of Telomere Length, Epigenetic Age, and Mitochondrial DNA abundance in Alzheimer\u2019s Disease"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1921-9470","authenticated-orcid":false,"given":"Shea J","family":"Andrews","sequence":"first","affiliation":[{"name":"Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, 505 Parnassus Ave, San Francisco, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rakshya U","family":"Sharma","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, 505 Parnassus Ave, San Francisco, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brendan A","family":"Mitchell","sequence":"additional","affiliation":[{"name":"Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA, USA"},{"name":"UCSF-UC Berkeley Joint PhD Program in Bioengineering, Berkeley, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tong","family":"Tong","sequence":"additional","affiliation":[{"name":"Bioinformatics Program, Boston University, Boston, MA, USA"},{"name":"Department of Medicine (Biomedical Genetics), Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luke W.","family":"Bonham","sequence":"additional","affiliation":[{"name":"Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA, USA"},{"name":"Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alan E","family":"Renton","sequence":"additional","affiliation":[{"name":"Ronald M. Loeb Center for Alzheimer\u2019s Disease, Dept of Genetics and Genomic Sciences, Nash Family Dept of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8237-1857","authenticated-orcid":false,"given":"Xiaoling","family":"Zhang","sequence":"additional","affiliation":[{"name":"Bioinformatics Program, Boston University, Boston, MA, USA"},{"name":"Department of Medicine (Biomedical Genetics), Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA"},{"name":"Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marina","family":"Sirota","sequence":"additional","affiliation":[{"name":"Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA, USA"},{"name":"Department of Pediatrics, University of California, San Francisco, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Duygu","family":"Tosun","sequence":"additional","affiliation":[{"name":"Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kristine","family":"Yaffe","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, 505 Parnassus Ave, San Francisco, CA, USA"},{"name":"Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA"},{"name":"Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"name":"the Alzheimer\u2019s Disease Neuroimaging Initiative","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2026031705500547000_2025.07.16.25331683v2.1","doi-asserted-by":"publisher","DOI":"10.1038\/S41591-024-03340-9"},{"key":"2026031705500547000_2025.07.16.25331683v2.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2023.08.003"},{"key":"2026031705500547000_2025.07.16.25331683v2.3","doi-asserted-by":"publisher","DOI":"10.1016\/J.CELL.2022.11.001"},{"key":"2026031705500547000_2025.07.16.25331683v2.4","first-page":"231","article-title":"Causality-enriched epigenetic age uncouples damage and adaptation. Nat","volume":"4","year":"2024","journal-title":"Aging"},{"key":"2026031705500547000_2025.07.16.25331683v2.5","doi-asserted-by":"crossref","unstructured":"Sugden, K. et al. Association of Pace of Aging Measured by Blood-Based DNA Methylation With Age-Related Cognitive Impairment and Dementia. Neurology 99, (2022).","DOI":"10.1212\/WNL.0000000000200898"},{"key":"2026031705500547000_2025.07.16.25331683v2.6","doi-asserted-by":"crossref","first-page":"1807","DOI":"10.1007\/s11357-022-00558-8","article-title":"Comprehensive analysis of epigenetic clocks reveals associations between disproportionate biological ageing and hippocampal volume","volume":"44","year":"2022","journal-title":"GeroScience"},{"key":"2026031705500547000_2025.07.16.25331683v2.7","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2024.01.008"},{"key":"2026031705500547000_2025.07.16.25331683v2.8","doi-asserted-by":"crossref","unstructured":"Grodstein, F. et al. The association of epigenetic clocks in brain tissue with brain pathologies and common aging phenotypes. Neurobiol. Dis. 157, 105428 (2021).","DOI":"10.1016\/j.nbd.2021.105428"},{"key":"2026031705500547000_2025.07.16.25331683v2.9","doi-asserted-by":"publisher","DOI":"10.1038\/nm1006-1133"},{"key":"2026031705500547000_2025.07.16.25331683v2.10","doi-asserted-by":"publisher","DOI":"10.1093\/gerona\/glw053"},{"key":"2026031705500547000_2025.07.16.25331683v2.11","doi-asserted-by":"crossref","first-page":"e13808","DOI":"10.1111\/acel.13808","article-title":"Mid-life leukocyte telomere length and dementia risk: An observational and mendelian randomization study of 435,046 UK Biobank participants","volume":"22","year":"2023","journal-title":"Aging Cell"},{"key":"2026031705500547000_2025.07.16.25331683v2.12","doi-asserted-by":"crossref","unstructured":"Hackenhaar, F. S. et al. Short leukocyte telomeres predict 25-year Alzheimer\u2019s disease incidence in non-APOE \u03b54-carriers. Alzheimers Res. Ther. 13, 130 (2021).","DOI":"10.1186\/s13195-021-00871-y"},{"key":"2026031705500547000_2025.07.16.25331683v2.13","doi-asserted-by":"crossref","first-page":"4251","DOI":"10.1016\/j.csbj.2022.08.006","article-title":"Genetically predicted telomere length and its relationship with neurodegenerative diseases and life expectancy","volume":"20","year":"2022","journal-title":"Comput. Struct. Biotechnol. J"},{"key":"2026031705500547000_2025.07.16.25331683v2.14","doi-asserted-by":"crossref","first-page":"e065088","DOI":"10.1002\/alz.065088","article-title":"Mitochondrial genome abundance is associated with Alzheimer\u2019s disease neuropathological burden and cognitive function","volume":"18","year":"2022","journal-title":"Alzheimers Dement"},{"key":"2026031705500547000_2025.07.16.25331683v2.15","doi-asserted-by":"publisher","DOI":"10.1016\/j.mito.2020.06.004"},{"key":"2026031705500547000_2025.07.16.25331683v2.16","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1002\/alz.12614","article-title":"Association of plasma biomarkers, p-tau181, glial fibrillary acidic protein, and neurofilament light, with intermediate and long-term clinical Alzheimer\u2019s disease risk: Results from a prospective cohort followed over 17 years","volume":"19","year":"2023","journal-title":"Alzheimers Dement"},{"key":"2026031705500547000_2025.07.16.25331683v2.17","unstructured":"Zhang, Y. et al. Association of Mitochondrial DNA Copy Number With Brain MRI Markers and Cognitive Function: A Meta-analysis of Community-Based Cohorts. Neurology 100, (2023)."},{"key":"2026031705500547000_2025.07.16.25331683v2.18","doi-asserted-by":"crossref","unstructured":"Klein, H.-U. et al. Characterization of mitochondrial DNA quantity and quality in the human aged and Alzheimer\u2019s disease brain. Mol. Neurodegener. 16, 75 (2021).","DOI":"10.1186\/s13024-021-00495-8"},{"key":"2026031705500547000_2025.07.16.25331683v2.19","doi-asserted-by":"publisher","DOI":"10.1046\/j.1474-9728.2002.00004.x"},{"key":"2026031705500547000_2025.07.16.25331683v2.20","doi-asserted-by":"publisher","DOI":"10.1038\/nature09787"},{"key":"2026031705500547000_2025.07.16.25331683v2.21","doi-asserted-by":"crossref","first-page":"1627","DOI":"10.18632\/aging.203897","article-title":"The telomere-mitochondrial axis of aging in newborns","volume":"14","year":"2022","journal-title":"Aging"},{"key":"2026031705500547000_2025.07.16.25331683v2.22","doi-asserted-by":"crossref","unstructured":"Morin, A. L. , Win, P. W. , Lin, A. Z. & Castellani, C. A . Mitochondrial genomic integrity and the nuclear epigenome in health and disease. Front. Endocrinol. 13, 1059085 (2022).","DOI":"10.3389\/fendo.2022.1059085"},{"key":"2026031705500547000_2025.07.16.25331683v2.23","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2017.02.004"},{"key":"2026031705500547000_2025.07.16.25331683v2.24","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibs.2022.03.008"},{"key":"2026031705500547000_2025.07.16.25331683v2.25","doi-asserted-by":"publisher","DOI":"10.1093\/ije\/dyw041"},{"key":"2026031705500547000_2025.07.16.25331683v2.26","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1093\/gerona\/gly184","article-title":"Epigenetic Clock and Relative Telomere Length Represent Largely Different Aspects of Aging in the Berlin Aging Study II (BASE-II)","volume":"74","year":"2019","journal-title":"J. Gerontol. Ser. A"},{"key":"2026031705500547000_2025.07.16.25331683v2.27","doi-asserted-by":"crossref","unstructured":"Carlund, O. et al. DNA methylation variations and epigenetic aging in telomere biology disorders. Sci. Rep. 13, 7955 (2023).","DOI":"10.1038\/s41598-023-34922-1"},{"key":"2026031705500547000_2025.07.16.25331683v2.28","doi-asserted-by":"crossref","first-page":"e14321","DOI":"10.1002\/alz.14321","article-title":"Overview of Alzheimer\u2019s Disease Neuroimaging Initiative and future clinical trials","volume":"21","year":"2025","journal-title":"Alzheimers Dement"},{"key":"2026031705500547000_2025.07.16.25331683v2.29","doi-asserted-by":"crossref","unstructured":"Vasanthakumar, A. et al. Harnessing peripheral DNA methylation differences in the Alzheimer\u2019s Disease Neuroimaging Initiative (ADNI) to reveal novel biomarkers of disease. Clin. Epigenetics 12, 84 (2020).","DOI":"10.1186\/s13148-020-00864-y"},{"key":"2026031705500547000_2025.07.16.25331683v2.30","doi-asserted-by":"crossref","first-page":"33","DOI":"10.3233\/JAD-190010","article-title":"Telomere Shortening in the Alzheimer\u2019s Disease Neuroimaging Initiative Cohort","volume":"71","year":"2019","journal-title":"J. Alzheimer\u2019s Dis"},{"key":"2026031705500547000_2025.07.16.25331683v2.31","doi-asserted-by":"crossref","unstructured":"Weiner, M. W. et al. The Alzheimer\u2019s Disease Neuroimaging Initiative: Progress report and future plans. Alzheimers Dement. 6, 202 (2010).","DOI":"10.1016\/j.jalz.2010.04.002"},{"key":"2026031705500547000_2025.07.16.25331683v2.32","doi-asserted-by":"publisher","DOI":"10.1002\/ana.21610"},{"key":"2026031705500547000_2025.07.16.25331683v2.33","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1016\/j.nicl.2016.05.017","article-title":"A large-scale comparison of cortical thickness and volume methods for measuring Alzheimer\u2019s disease severity","volume":"11","year":"2016","journal-title":"NeuroImage Clin"},{"key":"2026031705500547000_2025.07.16.25331683v2.34","doi-asserted-by":"publisher","DOI":"10.1037\/neu0000835"},{"key":"2026031705500547000_2025.07.16.25331683v2.35","doi-asserted-by":"crossref","unstructured":"Timsina, J. et al. Harmonization of CSF and imaging biomarkers in Alzheimer\u2019s disease: Need and practical applications for genetics studies and preclinical classification. Neurobiol. Dis. 190, 106373 (2024).","DOI":"10.1016\/j.nbd.2023.106373"},{"key":"2026031705500547000_2025.07.16.25331683v2.36","doi-asserted-by":"publisher","DOI":"10.1002\/alz.70237"},{"key":"2026031705500547000_2025.07.16.25331683v2.37","doi-asserted-by":"crossref","unstructured":"Ying, K. et al. Biolearn, an open-source library for biomarkers of aging. bioRxiv (2023) doi:10.1101\/2023.12.02.569722.","DOI":"10.1101\/2023.12.02.569722"},{"key":"2026031705500547000_2025.07.16.25331683v2.38","doi-asserted-by":"crossref","unstructured":"Tong, T. et al. Blood-derived mitochondrial DNA copy number is associated with Alzheimer disease, Alzheimer-related biomarkers and serum metabolites. Alzheimers Res. Ther. 16, 234 (2024).","DOI":"10.1186\/s13195-024-01601-w"},{"key":"2026031705500547000_2025.07.16.25331683v2.39","doi-asserted-by":"crossref","unstructured":"O\u2019Bryant, S. E . Staging Dementia Using Clinical Dementia Rating Scale Sum of Boxes Scores: A Texas Alzheimer\u2019s Research Consortium Study. Arch. Neurol. 65, 1091 (2008).","DOI":"10.1001\/archneur.65.8.1091"},{"key":"2026031705500547000_2025.07.16.25331683v2.40","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1016\/j.trci.2019.11.003","article-title":"Telomere length associations with cognition depend on Alzheimer\u2019s disease biomarkers","volume":"5","year":"2019","journal-title":"Alzheimers Dement. Transl. Res. Clin. Interv"},{"key":"2026031705500547000_2025.07.16.25331683v2.41","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2022.03.015"},{"key":"2026031705500547000_2025.07.16.25331683v2.42","doi-asserted-by":"crossref","first-page":"2099","DOI":"10.1007\/s11357-024-01376-w","article-title":"Complementary value of molecular, phenotypic, and functional aging biomarkers in dementia prediction","volume":"47","year":"2024","journal-title":"GeroScience"},{"key":"2026031705500547000_2025.07.16.25331683v2.43","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2021.09.022"},{"key":"2026031705500547000_2025.07.16.25331683v2.44","doi-asserted-by":"crossref","first-page":"287","DOI":"10.3233\/ADR-200205","article-title":"Attempt to Predict A\/T\/N-Based Alzheimer\u2019s Disease Cerebrospinal Fluid Biomarkers Using a Peripheral Blood DNA Methylation Clock","volume":"4","year":"2020","journal-title":"J. Alzheimers Dis. Rep"},{"key":"2026031705500547000_2025.07.16.25331683v2.45","doi-asserted-by":"crossref","unstructured":"Bonham, L. W. et al. DNA methylation age from peripheral blood predicts progression to Alzheimer\u2019s disease, white matter disease burden, and cortical atrophy. Npj Dement. 1, 7 (2025).","DOI":"10.1038\/s44400-025-00007-1"},{"key":"2026031705500547000_2025.07.16.25331683v2.46","doi-asserted-by":"crossref","unstructured":"Br\u00fcser, C. , Keller-Findeisen, J. & Jakobs, S . The TFAM-to-mtDNA ratio defines inner-cellular nucleoid populations with distinct activity levels. Cell Rep. 37, 110000 (2021).","DOI":"10.1016\/j.celrep.2021.110000"},{"key":"2026031705500547000_2025.07.16.25331683v2.47","doi-asserted-by":"crossref","unstructured":"Weidling, I. W. & Swerdlow, R. H . Mitochondria in Alzheimer\u2019s disease and their potential role in Alzheimer\u2019s proteostasis. Exp. Neurol. 330, 113321 (2020).","DOI":"10.1016\/j.expneurol.2020.113321"},{"key":"2026031705500547000_2025.07.16.25331683v2.48","doi-asserted-by":"crossref","unstructured":"Demanelis, K. et al. Determinants of telomere length across human tissues. Science 369, eaaz6876 (2020).","DOI":"10.1101\/793406"},{"key":"2026031705500547000_2025.07.16.25331683v2.49","doi-asserted-by":"crossref","unstructured":"Grodstein, F. et al. Characteristics of Epigenetic Clocks Across Blood and Brain Tissue in Older Women and Men. Front. Neurosci. 14, 555307 (2021).","DOI":"10.3389\/fnins.2020.555307"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.07.16.25331683","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T12:50:35Z","timestamp":1773751835000},"score":1,"resource":{"primary":{"URL":"http:\/\/medrxiv.org\/lookup\/doi\/10.1101\/2025.07.16.25331683"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,17]]},"references-count":49,"URL":"https:\/\/doi.org\/10.1101\/2025.07.16.25331683","relation":{},"subject":[],"published":{"date-parts":[[2025,7,17]]},"subtype":"preprint"}}