Telomeric alterations in the default mode network during the progression of Alzheimer’s disease: Selective vulnerability of the precuneus

Aims Although telomere length (TL) and telomere maintenance proteins (shelterins) are markers of cellular senescence and peripheral blood biomarkers of Alzheimer's disease (AD), little information is available on telomeric alterations during the prodromal stage (MCI) of AD. We investigated TL in the default mode network (DMN), which underlies episodic memory deficits in AD, as well as shelterin protein and mRNA levels in the precuneus (PreC). Methods Telomere length was evaluated in DMN hubs and visual cortex using quantitative PCR (qPCR). In the PreC, western blotting and NanoString nCounter expression analyses evaluated shelterin protein and mRNA levels, respectively, in cases with an antemortem clinical diagnosis of no cognitive impairment (NCI), MCI and AD. Results TL was significantly reduced in the PreC in MCI and AD compared to NCI, but stable in frontal, inferior temporal, posterior cingulate and visual cortex. PreC TL correlated significantly with performance on cognitive tests. NCI cases with high vs low Braak scores displayed significantly shorter TL in posterior cingulate and frontal cortex, which correlated significantly with neuritic and diffuse amyloid‐β plaque counts. Shelterin protein levels (TIN2, TRF1, TRF2 and POT1) declined in MCI and AD compared to NCI. The PreC displayed stable expression of shelterins TERF1, TERF2, POT1, RAP1 and TPP1, while TINF2 mRNA significantly increased in AD compared to NCI. Conclusions These findings indicate a selective vulnerability to telomere attrition within different nodes of the DMN in prodromal AD and in aged NCI individuals with high Braak scores highlighting a putative role in the pathogenesis of AD. Telomere length was assessed in four hubs of the default mode network (DMN) in individuals with no cognitive impairment (NCI), mild cognitive impairment (MCI) and Alzheimer's disease (AD).Telomere length was selectively reduced in the precuneus (PreC), a cortical hub region of the DMN, in MCI and AD. Levels of telomere maintenance proteins, termed shelterins and shelterin mRNA levels were assessed in the PreC and shelterin protein levels paralleled telomere attrition. ** indicates p < 0.001