Mitochondrial DNA copy number is associated with cognitive function, cognitive decline, and dementia: a longitudinal study in UK Biobank.

Mitochondria are the principal generators of ATP, playing a crucial role in brain health. Mitochondrial DNA copy number (mtDNA-CN) is a proxy for mitochondrial function and has been linked to cognitive function and impairment. However, existing studies are often limited by cross-sectional designs, small sample sizes, or a focus on dementia patients. Using data from 239,070 UK Biobank participants of European ancestry, we examined the longitudinal relationship between mtDNA-CN in blood and cognitive function, as well as its association with cognitive decline, including incident dementia, over a 16-year follow-up. Additionally, we leveraged publicly available genome-wide association study (GWAS) summary statistics to assess the genetic relationship between mtDNA-CN and cognitive function. We found that a higher mtDNA-CN was positively associated with a greater level of cognitive function. Moreover, a higher baseline mtDNA-CN was protective against cognitive decline and all-cause dementia over the 16-year follow-up. However, the effects of mtDNA-CN observed at population-level differed from those observed in individuals experiencing cognitive decline, suggesting heterogeneous influences of mtDNA-CN. Genetic analyses revealed a moderate degree of shared genetic architecture between mtDNA-CN and cognitive function, with overlapping genes involved in pathways associated with known mitochondrial diseases. However, no casual effect of mtDNA-CN was observed on cognitive function. Our findings support mtDNA-CN as a potential biomarker for cognitive health and cognitive ageing. The observed heterogeneity suggests that mtDNA-CN may influence cognition through distinct pathways in normal and cognitively declining individuals. Further research is needed to establish the underlying mechanisms.