Telomere Shortening in the Alzheimer’s Disease Neuroimaging Initiative Cohort

Article type: Research Article

Authors: Nudelman, Kelly N.H.^{a; b; c; *} | Lin, Jue^d | Lane, Kathleen A.^e | Nho, Kwangsik^{c; f} | Kim, Sungeun^{f; g} | Faber, Kelley M.^{a; b} | Risacher, Shannon L.^{c; f} | Foroud, Tatiana M.^{a; b; c} | Gao, Sujuan^e | Davis, Justin W.^h | Weiner, Michael W.ⁱ | Saykin, Andrew J.^{a; c; f; *} | for the Alzheimer’s Disease Neuroimaging Initiative¹

Affiliations: [a] Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA | [b] National Centralized Repository for Alzheimer’s Disease and Related Dementias (NCRAD), Indiana University School of Medicine, Indianapolis, IN, USA | [c] Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA | [d] Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA | [e] Biostatistics, Indiana University School of Medicine, Indianapolis, IN, USA | [f] Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA | [g] Electrical and Computer Engineering, SUNY Oswego, Oswego, NY, USA | [h] Genomics Research Center, AbbVie, North Chicago, IL, USA | [i] Center for Imaging of Neurodegenerative Diseases, Department of Radiology, San Francisco VA Medical Center/University of California San Francisco, San Francisco, CA, USA

Correspondence: [*] Correspondence to: Kelly N.H. Nudelman, IU Neuroscience Center, 355W. 16th St., Ste. 4100, Indianapolis, IN 46202, USA. Tel.: +1 317 963 7511; E-mail: [email protected]. and Andrew J. Saykin, IU Neuroscience Center, 355W. 16th St., Ste. 4100, Indianapolis, IN 46202, USA. Tel.: +1 317 963 7501; E-mail: [email protected].

Note: [1] Data used in the preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (http://adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of 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 at: http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf

Abstract: Background:Although shorter telomeres have been associated with Alzheimer’s disease (AD), it is unclear whether longitudinal change in telomere length is associated with AD progression. Objective:To investigate the association of telomere length change with AD diagnosis and progression. Methods:In 653 individuals from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort, T/S ratio (telomere versus single copy gene), a proxy of telomere length, was measured for up to five visits per participant (N = 1918 samples post-QC) using quantitative PCR (qPCR). T/S ratio was adjusted for batch effects and DNA storage time. A mixed effects model was used to evaluate association of telomere length with AD diagnostic group and interaction of age and diagnosis. Another mixed effects model was used to compare T/S ratio changes pre- to post-conversion to MCI or AD to telomere change in participants with stable diagnoses. Results:Shorter telomeres were associated with older age (Effect Size (ES) = –0.23) and male sex (ES = –0.26). Neither baseline T/S ratio (ES = –0.036) nor T/S ratio change (ES = 0.046) differed significantly between AD diagnostic groups. MCI/AD converters showed greater, but non-significant, telomere shortening compared to non-converters (ES = –0.186). Conclusions:Although AD compared to controls showed small, non-significant effects for baseline T/S ratio and T/S ratio shortening, we did observe a larger, though still non-significant effect for greater telomere shortening in converters compared to non-converters. Although our results do not support telomere shortening as a robust biomarker of AD progression, further investigation in larger samples and for subgroups of participants may be informative.

Keywords: Alzheimer’s disease, longitudinal, progression, shortening, telomere

DOI: 10.3233/JAD-190010

Journal: Journal of Alzheimer's Disease, vol. 71, no. 1, pp. 33-43, 2019