Genetically Regulated Telomere Length Relates to Brain Amyloidosis.

Background: It is well‐established that telomeres shrink over the course of aging and that this process is genetically regulated. Work from our group and others has highlighted the complex interplay between measured leukocyte telomere length and Alzheimer's Disease (AD) biomarkers over the course of AD. We expand on this work to explore whether a polygenic score predicting telomere length relates to PET measures of brain amyloidosis in the preclinical stages of disease. Method: A Polygenic Risk Score (PRS) of telomere length was built from a published GWAS on telomere length from UK Biobank (N = 472,174). We leveraged genetic data from non‐Hispanic White participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI; N = 1,414) and the Anti‐Amyloid Treatment in Asymptomatic Alzheimer's study (A4; N = 3,002). The relation of the score to measured telomere length was validated using leukocyte telomere length data from ADNI. A linear regression model was used to evaluate whether the PRS relates to a PET measure of brain amyloidosis in a harmonized dataset including ADNI and A4, with a total sample size of 3,940 after restricting to individuals with both genetic data and amyloid measurements. Covariates included age, sex, and diagnostic status. Result: As expected, telomere PRS related to measured telomeres in ADNI when covarying for age, sex, and baseline diagnosis (Figure 1, p = 0.045). Interestingly, we also observed a counter intuitive association between genetically predicted telomere length and amyloidosis whereby longer predicted telomere length was associated with higher amyloid burden (Figure 2, β = 1305, p = 0.006). Conclusion: A PRS for telomere length modestly relates to measured telomere length in older adults and relates to higher amyloid burden. Previous work from our group has highlighted the interaction between measured telomere length and amyloid status such that the association is counter intuitive among those who are biomarker positive. The present results highlight the exciting possibility that telomere length may relate directly to AD biomarkers and open the opportunity for future work further probing the complex interplay between telomere length and AD biomarkers leveraging this powerful genetic tool. [ABSTRACT FROM AUTHOR]