Mitochondrial DNA copy number predicts dementia risk with early mobility impairment

Abstract

AbstractBackgroundMobility impairment precedes Alzheimer’s disease (AD) and dementia. Potential mechanisms may involve mitochondrial dysfunction which is a hallmark of aging and links to both mobility impairment and brain health. In this study, we aimed to determine whether mitochondrial DNA copy number (mtDNA‐CN), a blood‐based marker related to mitochondrial function, would predict future dementia with and without the presence of early mobility impairment.MethodIn the UK Biobank, we estimated mtDNA‐CN using fastMitoCalc from complete Whole Genome Sequencing data at study entry. Dementia diagnoses were ascertained from medical records, including AD and non‐AD dementia. Early mobility impairment was defined as having slow walking pace by self‐report at study entry. The absence of mobility impairment was defined as having steady average or brisk walking pace. In participants who were free of dementia at study entry, we examined the association between mtDNA‐CN and future dementia with and without early mobility impairment using cox proportional hazard models, adjusted for age, sex, ethnicity, body mass index, apolipoprotein ε4 carrier status, assessment center, and technical covariates related to mtDNA‐CN.ResultAmong 188,706 participants (mean age = 56±8 years, 55% women, 94% White), 13,821 reported slow walking pace at study entry and 2,564 developed dementia (1,085 AD, 1,479 non‐AD dementia) over a mean follow‐up of 12.5 years. After covariate adjustment, each standard deviation higher mtDNA‐CN (i.e. 16) was marginally associated with a lower risk of any dementia (HR = 0.96, 95%CI: 0.91‐1.00, p = 0.063). Among those who reported slow walking pace at study entry, each standard deviation higher mtDNA‐CN was associated with a 12% lower risk of developing any dementia (HR = 0.88, 95%CI: 0.783‐0.991, p = 0.034). There was a trend toward significance for non‐AD dementia (HR = 0.87, 95%CI: 0.754‐1.01, p = 0.065), and not for AD dementia (HR = 0.89, 95% CI: 0.727‐1.09, p = 0.245). Among those without early mobility impairment, mtDNA‐CN was not significantly associated with dementia (HR = 0.97, 95%CI: 0.92‐1.02, p = 0.176).ConclusionIn a large sample of community‐dwelling adults, higher mtDNA‐CN is associated with a lower risk of developing dementia especially accompanied by early mobility impairment. Maintaining mitochondrial function in aging may protect against dementia that is preceded by mobility impairment.