Telomere longitudinal shortening as a biomarker for dementia status of adults with Down syndrome

Abstract

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'-3' 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 impairment" in adults with Down syndrome (MCI-DS), a population 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 individuals with Down syndrome (3F, 2M) as they transitioned from preclinical AD to MCI-DS (N = 4) or dementia (N = 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.

Brain-predicted age in Down syndrome is associated with beta amyloid deposition and cognitive decline

“…Previously, shortened lymphocyte telomere length has been reported in people with DS (Jenkins et al., 2006, Vaziri et al., 1993) and shorter telomeres have been associated with cognitive decline and dementia status in DS (Jenkins et al., 2010, Jenkins et al., 2016). Indices of age-associated oxidative stress have also been reported as elevated in DS (Jovanovic et al., 1998).…”

Aspectos nutricionais associados ao envelhecimento de indivíduos com síndrome de Down: uma revisão integrativa

“…Contudo, em estudo publicado por Gruszecka et al (2015), o tamanho também foi maior em pacientes com síndrome de Down do que no grupo controle (sem SD). Já Jenkins et al (2016) observou encurtamentos de telômeros consistentes em indivíduos com SD.…”

“…Uma das hipóteses para o envelhecimento é a redução no tamanho dos telô-meros (JENKINS et al, 2016). Contudo, no estudo de Gruszecka et al (2015) não foi possível demonstrar diferenças significativas entre os grupos com e sem SD.…”

A Review of Biomarkers for Alzheimer’s Disease in Down Syndrome

“…Compared with healthy controls, people with DS have been reported to have higher levels of ProNGF, MMP-1, MMP-3, MMP-9, TNF-a, IL-6, IL-10, and S -adenosylhomocysteine (SAH), a lower SAM/SAH ( S -adenosylmethionine/ S -adenosylhomocysteine) ratio and CpG methylation percentage, and lower levels of amyloid precursor-like protein 1 (APLP1) peptides (APL1β25, APL1β27, and APL1β28) and CSF Orexin-A [ 63 , 73 , 76 ]. A lower serum 3-methoxy-4-hydroxyphenylglycol (MHPG) level and shortening of the telomere length predicts the conversion of AD into DS [ 77 , 78 ]. With the combination of amyloid and inflammatory markers, these biomarkers may be strong predictors of cognitive deterioration [ 76 ].…”