RESEARCH ARTICLE Telomere Longitudinal Shortening as a Biomarker for Dementia Status of Adults With Down Syndrome Edmund C. Jenkins, 1 * Lingling Ye, 1 Sharon J. Krinsky-McHale, 1 Warren B. Zigman, 1 Nicole Schupf, 1,2 and Wayne P. Silverman 3 1 New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York 2 Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University, New York, New York 3 The Kennedy Krieger Institute and The Johns Hopkins University School of Medicine, Baltimore, Maryland Manuscript Received: 30 March 2015; Manuscript Accepted: 28 September 2015 Previous studies have suggested that Alzheimer’s disease (AD) causes an accelerated shortening of telomeres, the ends of chromosomes consisting of highly conserved TTAGGG repeats that, because of unidirectional 5 0 –3 0 DNA synthesis, lose end point material with each cell division. Our own previous work suggested that telomere length of T-lymphocytes might be a remarkably accurate biomarker for “mild cognitive im- pairment” in adults with Down syndrome (MCI-DS), a popu- lation at dramatically high risk for AD. To verify that the progression of cognitive and functional losses due to AD produced this observed telomere shortening, we have now examined sequential changes in telomere length in five indi- viduals with Down syndrome (3F, 2M) as they transitioned from preclinical AD to MCI-DS (N ¼ 4) or dementia (N ¼ 1). As in our previous studies, we used PNA (peptide nucleic acid) probes for telomeres and the chromosome 2 centromere (as an “internal standard” expected to be unaffected by aging or dementia status), with samples from the same individuals now collected prior to and following development of MCI-DS or dementia. Consistent shortening of telomere length was observed over time. Further comparisons with our previous cross-sectional findings indicated that telomere lengths prior to clinical decline were similar to those of other adults with Down syndrome (DS) who have not experienced clinical decline while telomere lengths following transition to MCI-DS or dementia in the current study were comparable to those of other adults with DS who have developed MCI-DS or dementia. Taken together, findings indicate that telomere length has significant promise as a biomarker of clinical progression of AD for adults with DS, and further longitudinal studies of a larger sample of individuals with DS are clearly warranted to validate these findings and determine if and how factors affecting AD risk also influence these measures of telomere length. Ó 2015 Wiley Periodicals, Inc. Key words: Down syndrome; mild cognitive impairment (MCI); dementia status; biomarker; telomere longitudinal shortening; FISH with PNA (peptide nucleic acid) probes; telomere length in light intensity units; telomere length in microns INTRODUCTION Trisomy 21 [Down syndrome (DS)] is the most prevalent chro- mosomal cause of intellectual disability (ID), with an incidence rate of approximately one in every 690–730 newborns [Presson et al., 2013]. It is caused by the presence of a third copy of chromosome 21, either the whole chromosome 21 (approximately 97% of cases), as a partial trisomy, or as mosaicism. In previous generations, survival of newborns with DS into middle age was unusual [Presson et al., 2013; Zigman, 2013]. However, survival has increased dramatically since the 1950s, and the population of “older” adults with DS has expanded rapidly as life expectancy has increased to Conflicts of interest: This paper has no conflicts of interest relating to money or contents of the article. Grant sponsor: NYS OPWDD Institute for Basic Research in Develop- mental Disabilities; Grant sponsor: Alzheimer’s Association; Grant numbers: IIRG-07-60558, IIRG-96-077; Grant sponsor: NIH; Grant numbers: P01-HD35897, R01-HD37425, R01-AG-14673, P30- HD024061. Ã Correspondence to: Edmund Jenkins, New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY 10314. E-mail: edjenkins.jenkins85@gmail.com Article first published online in Wiley Online Library (wileyonlinelibrary.com): 00 Month 2015 DOI 10.1002/ajmg.b.32389 How to Cite this Article: Jenkins EC, Ye L, Krinsky-McHale SJ, Zigman WB, Schupf N, Silverman WP. 2015. Telomere Longitudinal Shortening as a Biomarker for Dementia Status of Adults With Down Syndrome. Am J Med Genet Part B 9999:1–6. Ó 2015 Wiley Periodicals, Inc. 1 Neuropsychiatric Genetics