Understanding two novel factors related to motor impairment in the development of dementia - UK Biobank project (Alzheimer's disease concept)

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Motor slowing predicts mild cognitive impairment and Alzheimers disease (AD) up to 12 years later. Potential mechanisms for this relationship include brain oxidative stress related to mitochondrial dysfunction and iron deposition, but data that connect these factors with brain health in humans is scarce. We aim to determine whether mitochondrial dysfunction and brain iron deposition predict incident dementia with and without motor dysfunction in the 500,000 participants from the UK Biobank (UKB) prospective cohort. Mitochondrial dysfunction is a hallmark of aging and has been involved in AD pathogenesis. It has been suggested that mitochondrial mass estimated as mitochondrial DNA copy number in blood from whole-genome sequencing data is a proxy measure of mitochondrial mass in the brain. The wealth of UKB data will allow us to assess mitochondrial dysfunction in over 125,000 participants and to correlate these data to incident dementia over up to 14 years of follow-up. Brain iron deposition occurs in AD, but its causal significance is unclear. Our preliminary work in the first 20,000 MRIs has shown that the iron overload hemochromatosis HFE p.C282Y homozygote mutations in men are associated with increased brain iron deposition, a doubling of incident dementia, frailty, and low muscle strength. MRI-based brain iron deposition data will be available in 100,000 UKB participants. We will extend this work using the greatly expanding MRI and diagnostic data. There is a strong rationale to believe that mitochondrial dysfunction and iron deposition may be synergic in causing brain damage. Mitochondrial dysfunction increases the production of Reactive Oxygen Radicals (ROS), including hydrogen peroxide that may react with iron deposits and produce highly toxic hydroxyl free radicals (Fenton reaction). Treatments to prevent iron accumulation are already available and a number of drugs that can improve mitochondrial function are currently tested in clinical trials. Thus, a better understanding of the contribution of mitochondria dysfunction to Alzheimers disease and related dementias could support further research particularly in brain energetics, one of the evolving plans in NIAs Intramural Research Program.