Identification of brain metabolomic profiles associated with dementia

PROJECT SUMMARY/ ABSTRACT Identifying mechanistic pathways underlying Alzheimer's Disease/Alzheimer's Disease-Related Dementias (AD/ADRD) is critical to discovering new targets to test for preventive and therapeutic interventions. Metabolic dysregulation, both systemic (e.g., diabetes) and cerebral (e.g., dysfunctional lipid/insulin signaling), is associated with higher dementia risk and AD-related neuropathology. Growing evidence from genetic and molecular research, and initial studies of metabolomic profiling in postmortem brain tissue, collectively indicate that metabolic mechanisms may underlie AD/ADRD. However, the specific brain metabolic pathways involved in AD/ADRD are not well-understood; and critical research gaps remain. First, existing metabolomic studies in brain tissue – the target organ of dementia – have modest sample sizes and limited replication. Second, deeper interrogation is needed for brain biochemicals that appear related to brain function (e.g., complex lipids and fatty acids, lipid mediators of inflammation, gut microbiome-related neurochemicals, glucose/bioenergetic metabolites). Finally, the plausible causal role of brain metabolic regulation in dementia is yet to be explored. The overarching goal of this proposal is to comprehensively examine brain metabolites associated with cognitive decline. Specifically, we will use clinical, neuropathologic, and genomic data, as well as postmortem brain tissue from 1,200 deceased individuals from two community-based aging cohorts – the Religious Orders Study (ROS) and Rush Memory and Aging Project (MAP). For the proposed research, we will leverage existing brain metabolomic data in ROSMAP, and strategically generate new data by extending the sample size as well as metabolites profiled -- allowing us to examine a total of ~1,800 metabolites across three platforms. In Aim 1, we will use agnostic discovery to identify and then independently replicate metabolites and metabolomic coregulatory networks associated with cognitive decline; and we will integrate genetic data using Mendelian randomization analyses to infer plausible causality. In addition, as a novel approach to discovery, in Aim 2, we will anchor discovery to a metabolic risk factor for dementia. Specifically, diet is integral to metabolism, and healthy dietary patterns are associated with slower cognitive decline and lower dementia risk; thus, we will identify brain metabolomic profiles associated with healthy dietary pattern in MAP, and then test these profiles in relation to cognitive decline in ROS. We have successfully utilized such approaches in our prior work. Finally, in the exploratory Aim 3, we will identify metabolomic profiles associated with cognitive resilience (the ability to maintain cognition despite the presence of neuropathology). IMPACT: Led by an Early- Stage Investigator and supported by an interdisciplinary team of experienced researchers, this proposal is poised to discover novel brain metabolic pathways associated with cognitive health, and provide new evidence that may inform novel interventions. In addition, we will generate extensive brain metabolomics data to share with the scientific community, yielding a significant and sustained impact on the field.