Mitochondrial Energetics, Circuits and Cognitive Decline in the Aging Human Brain

PROJECT SUMMARY The brain-wide networks that enable cognitive functions rely on the availability of large amounts of energy. Most of the brain’s energy is generated by mitochondria, unique organelles with their own DNA (mtDNA) that populate the cytoplasm of all cell types. Recent studies suggest that mitochondrial energetics are a rate-limiting step in healthy neural function, and mitochondrial dysfunction contributes to Alzheimer’s disease (AD) and other forms of dementia and psychopathology. Two lines of work from our group has contributed support to this hypothesis. First, we have examined the ROSMAP cohort, a large-scale study with longitudinal (up to 20 years) neuroimaging, cognitive, and clinical measures prior to death, with comprehensive assessments of postmortem brain pathology. Our multi-omic data in >500 postmortem ROSMAP samples of dorsolateral prefrontal cortex has identified gene expression, protein abundance, and mtDNA copy number differences in AD, which indirectly suggest alterations in mitochondrial function. Second, we have access to a unique cohort of individuals with rare genetically-inherited primary mtDNA disorders (MITO), which allow us to examine more directly the influence of mitochondrial dysfunction on the brain. Our MITO cohort exhibits signs of cognitive deficits across multiple cognitive domains implicating prefrontal brain areas. Therefore, in this project, we have assembled a transdisciplinary team capable of integrating sensitive measures of cognitive reserve, tissue mitochondrial function, and multivariate neuroimaging-based pattern recognition and network models. In Aim 1, we deploy our mitochondrial phenotyping platform optimized for brain tissue to characterize mitochondrial dysfunction across eight brain regions (6 grey matter, 2 white matter tracks) in n=500 individuals from ROSMAP. We will use this dataset to develop well-powered statistical models testing mitochondrial function, separately for each region or as a global aggregate across 8 regions, as a predictor of cognitive outcomes, including cognitive reserve – preserved cognition function despite abundant pathology. In Aim 2, we leverage functional and structural neuroimaging data collected prior to death in the same individuals to build neuroimaging-based predictive models of i) regional and global mitochondrial dysfunction and ii) cognitive reserve. In Aim 3, to examine structural and functional brain alterations associated with specific, highly penetrant primary mitochondrial defects, we conduct neuroimaging and neuropsychological studies in our rare MITO cohort with mtDNA defects without the confounding effect of advanced age or dementia. These analyses will allow us to identify common brain features linked to mitochondrial dysfunction across both ROSMAP and MITO cohorts. Combined, our direct measurements of mitochondrial function across multiple brain regions provides a unique opportunity to examine the energetic basis of normal and abnormal connectivity in the human brain, and opens opportunities for future translational studies in living subjects at risk of AD.