Blood mitochondrial DNA biomarkers of midlife cognitive decline and adverse brain imaging changes – A longitudinal investigation in the CARDIA population-based cohort study.

A. SPECIFIC AIMS Alzheimer’s Disease (AD) accounts for 60–80% of all dementia cases. By 2050, the number of people with AD will increase from 5.4 million to between 11-16 million in the U.S. alone. By 2030, dementia will cost $2 trillion worldwide. Despite these alarming numbers, there are no widely scalable tools or biomarkers to identify pre-symptomatic disease, which may begin 15-20 years before patients develop clinically diagnosable disease5 and might be the only stage of the disease’s trajectory where we could intervene.3,4 As brain imaging is expensive and cerebrospinal fluid (CSF) biomarkers are invasive, there is a need for blood-based biomarkers to identify pre-symptomatic disease. To do so, the key is to prospectively study how cognitive decline and brain imaging changes in pre-symptomatic stages relate to changes in the blood decades before AD is diagnosed. Many blood-based blood biomarkers have been characterized, including genomic and epigenomic biomarkers. However, the role of mitochondrial molecular aging, i.e., the changes of the mitochondrial DNA (mtDNA), as indicators of pre-symptomatic of AD remains largely unknown. Due to the paucity of mtDNA repair, mtDNA mutations accumulate over time and are therefore prime biomarkers of age-related processes. Indeed, mitochondria are a primary target of oxidative damage and inflammation—two major AD-related pathways—and damaged mitochondria, in turn, are the primary source of age-related systemic oxidation.5,6 Each cell has thousands mitochondria, each carrying 2-10 copies of mtDNA. The mtDNA molecules contain either normal or mutated DNA in a mixture known as heteroplasmy. Blood mtDNA mutations are more frequent in AD patients than healthy controls suggesting the possible mechanistic role of mtDNA mutations in AD.8-10 However, no study has longitudinally investigated mtDNA heteroplasmic mutations in healthy individuals and their prospective associations with midlife cognitive decline and structural brain changes. In the NHLBI-funded Coronary Artery Risk Development in Young Adults (CARDIA) study, we propose to longitudinally study mtDNA heteroplasmic mutations and their associations with structural brain changes and cognitive decline through midlife. CARDIA is a multicenter, community-based, biracial prospective cohort that recruited 5,116 young adults and has now nearly 40 years of follow up with repeated measures of risk factors, circulating inflammatory, oxidative stress, metabolic and lipid biomarkers, cognitive function, and brain imaging. Blood samples collected over time will allow for longitudinal measurements of mtDNA heteroplasmic mutations and to determine whether mtDNA changes anticipate and then track along midlife greater cognitive decline and brain structural changes associated with pre-symptomatic AD patterns. In addition, through the NHLBI’s TOPMed program, longitudinal genomic and epigenomic data will be available for all CARDIA participants, which we will use—together with mtDNA data and clinical blood-based inflammatory, oxidative stress, lipid metabolic biomarkers—to create a novel multifactorial prediction model for AD. Our specific aims are to: Aim 1. Determine whether the levels and longitudinal changes of mtDNA heteroplasmic mutations are associated with greater midlife cognitive decline. Hypothesis 1. Middle-aged healthy individuals with higher blood mtDNA mutation loads and/or specific mtDNA mutation profiles will show greater cognitive declines. Aim 2. Determine whether the levels and longitudinal changes of mtDNA heteroplasmic