The Shortening of Leukocyte Telomere Length Contributes to Alzheimer’s Disease: Further Evidence from Late-Onset Familial and Sporadic Cases

SIMPLE SUMMARY: Alzheimer’s disease (AD) is one of the most common forms of dementia in the aging population. The shortening of telomeres, which are complex structures at the ends of chromosomes, is considered one of the hallmarks of aging and has been implicated in several neurodegenerative diseases, especially AD, where the results are conflicting. Thus, to help clarify the association of telomere length with AD risk, leukocyte telomere length (LTL), measured as T/S ratio (telomere vs single-copy gene) was assessed in a cohort of 534 subjects, comprising sporadic and familial cases of late-onset AD (LOAD) and cognitively healthy controls. Compared with controls, LOAD cases showed significantly shorter telomeres. The association with disease risk was independent of confounders such as age, sex, Mini-Mental State Examination (MMSE), and Apolipoprotein E ε4 (APOE-ε4) status. Our findings support telomere shortening as a potential biomarker of LOAD risk. ABSTRACT: Telomeres are structures at the ends of eukaryotic chromosomes that help maintain genomic stability. During aging, telomere length gradually shortens, producing short telomeres, which are markers of premature cellular senescence. This may contribute to age-related diseases, including Alzheimer’s disease (AD), and based on this, several studies have hypothesized that telomere shortening may characterize AD. Current research, however, has been inconclusive regarding the direction of the association between leukocyte telomere length (LTL) and disease risk. We assessed the association between LTL and AD in a retrospective case–control study of a sample of 255 unrelated patients with late-onset AD (LOAD), including 120 sporadic cases and 135 with positive family history for LOAD, and a group of 279 cognitively healthy unrelated controls, who were all from Calabria, a southern Italian region. Following regression analysis, telomeres were found significantly shorter in LOAD cases than in controls (48% and 41% decrease for sporadic and familial cases, respectively; p < 0.001 for both). Interestingly, LTL was associated with disease risk independently of the presence of conventional risk factors (e.g., age, sex, MMSE scores, and the presence of the APOE-ε4 allele). Altogether, our findings lend support to the notion that LTL shortening may be an indicator of the pathogenesis of LOAD.