AbstractBackgroundTelomere stability may be a potential biomarker for Alzheimer’s disease progression. Indeed, previous studies have observed significant associations with telomere length and risk for Alzheimer’s disease (AD) in both carriers and non‐carriers of APOE4. In contrast, (cognitively healthy) centenarians—an extreme control group in the spectrum of brain health—have been observed to harbour longer telomere lengths relative to younger age groups. In this study, we investigated telomere stability in the whole‐blood compartment of AD patients, centenarians, and centenarian children through single‐molecule long‐read sequencing.MethodLong‐read HiFi sequencing of the whole‐blood compartment was performed in AD patients (n = 59, mean age = 68.5), centenarians (n = 84, mean age = 101.6), and centenarian children (n = 10, mean age = 71.0), using the Pacific Bioscience Sequel II instrument. For each sample, we identified reads with telomeric content based on alignments to the CHM13 reference genome. Per‐read telomere lengths were calculated via a high‐density clustering approach of the TTAGGG repeat sequence, keeping only reads that have a higher likelihood of harbouring complete telomeric content. The sub‐telomeric portion of each read was then used to assign chromosomal origin based on sequence similarity all chromosomes in CHM13. Whole‐blood and chromosome‐specific telomere lengths were then compared across the three sample‐groups.ResultCentenarian children were observed to harbour the longest telomeres with a median length of 6.88 kbp, and 95% C.I. of 6.78‐7.00 kbp. This was followed by AD patients with median length of 5.82 kbp, 95% CI 5.78‐5.85 kb; and centenarians with a median length of 5.52 kbp, and 95% C.I. of 5.50‐5.55 kbp. Telomere lengths across all groups were significantly different (p < 0.001). A similar pattern was observed across each individual chromosome, with the exception of chromosome X which harboured smaller telomere lengths in AD patients and centenarians.Centenarians harboured significantly smaller telomere lengths than their children (p < 0.001), with the exception of two centenarians that did not have significant differences.ConclusionDespite being aged‐match, AD patients harbour shorter telomere lengths than centenarian children, and only slightly longer telomere lengths than centenarians.