Mid-life leukocyte telomere length and dementia risk: a prospective cohort study of 435,046 UK Biobank participants

Abstract Importance Telomere attribution is one of biological aging hallmarks and may be intervened to target multiple aging-related diseases, including Alzheimer’s disease and Alzheimer’s disease related dementias (AD/ADRD). Objective To assess associations of leukocyte telomere length (TL) with AD/ADRD and early markers of AD/ADRD, including cognitive performance and brain magnetic resonance imaging (MRI) phenotypes. Design, Setting, and Participants Data from European-ancestry participants in the UK Biobank (n=435,046) were used to evaluate whether mid-life leukocyte TL is associated with incident AD/ADRD over a mean follow-up of 12.2 years. In a subsample without AD/ADRD and with brain imaging data (n=43,390), we associated TL with brain MRI phenotypes related to AD or vascular dementia pathology. Exposures Relative mean leukocyte TL at baseline was measured in T/S ratio, using a multiplex quantitative polymerase chain reaction technique by comparing the amount of the telomere amplification product (T) to that of a single-copy gene (S). Main Outcomes and Measures AD/ADRD was confirmed by mapping multi-source data to 3-charcter ICD codes (G30; F00; F01; F03; G31), excluding other-cause dementias (F02). Results Longer TL was associated with a lower risk of incident AD/ADRD (adjusted HR [aHR] per SD=0.93, 95% CI 0.90 to 0.96, P =3.37×10 −7 ). Longer TL also was associated with better cognitive performance in specific cognitive domains, larger hippocampus volume (adjusted standardized β [a β ] per SD=0.012, 95% CI 0.003 to 0.021, P =0.012), lower total volume of white matter hyperintensities (a β per SD= -0.015, 95% CI -0.024 to -0.006, P =0.002), and higher fractional anisotropy (FA; a β per SD=0.018, 95% CI 0.009 to 0.027, P =9.44×10 −5 ) and lower mean diffusivity (MD; a β per SD=0.045, 95% CI 0.035 to 0.056, P =1.07×10 −17 ) in the fornix. Conclusions and Relevance Longer TL is a protective factor against AD/ADRD, cognitive impairment, and brain structural lesions toward the development of AD/ADRD. A better understanding of underlying mechanisms may help improve diagnosis and management of AD/ADRD in older adults. Key Points Question Is leukocyte telomere length (TL) associated with Alzheimer’s disease (AD) and AD related dementias (AD/ADRD) and early markers of AD/ADRD, including cognitive performance and brain magnetic resonance imaging phenotypes? Findings Longer TL was associated with a lower risk of incident AD/ADRD, larger hippocampus volume, lower total volume of white matter hyperintensities, higher fractional anisotropy and lower mean diffusivity in the fornix. Meaning Longer TL in midlife may play a protective role against AD/ADRD, and a better understanding of underlying mechanisms may help improve diagnosis and management of AD/ADRD in older adults.