Brain lipids and AD

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Project Summary Alzheimer’s dementia (AD) affects over 35 million people worldwide, and this number is expected to triple by 2050. As early as a century ago, Alois Alzheimer noted three significant neuropathological features in the brain of AD patients: senile plaques, neurofibrillary tangles, and lipid granule accumulation. While senile plaques and neurofibrillary tangles are now widely accepted as hallmarks of AD pathology, and thus have been extensively studied, the role of lipid accumulation in AD pathogenesis has been less studied. Lipidomics is a new omics technique that can identify and accurately quantify hundreds to thousands of lipids in biospecimens in large- scale population studies. Using this technology, many lipid species have been reported to be associated with cognitive phenotypes and AD neuropathologies (e.g., amyloid-beta, tau tangles). However, several key knowledge gaps exist in this field. First, previous studies have largely focused on blood, but the brain lipidomic profile is likely different from that of blood. To date, little is known about the global lipid composition and individual lipid species that trigger neuropathologies in human AD brains. Second, of the few existing lipidomic studies in human AD brains, sample size was mostly small and results were inconsistent. Importantly, the coverage of brain lipidome (i.e., collection of all lipid species in brain) in previous studies was low, and thus many disease-related lipids have not been investigated. To date, a full spectrum of brain lipidome in relation to AD pathology is lacking, especially in large-scale epidemiological studies. Finally, the potential causal role of lipid regulation in brain aging and AD neuropathology remains largely unknown and unexplored. To address these important questions, we leverage the large-collection of postmortem brain tissue samples, the deep clinical and neuropathological phenotypes, and the rich brain omics data (e.g., genomics, epigenomics, and transcriptomics) in two community-based longitudinal cohorts of aging and dementia – the Religious Orders Study and Rush Memory and Aging Project (ROSMAP). Specifically, we will conduct the first comprehensive lipidomic profiling in 1,450 frozen dorsolateral prefrontal cortex (DLPFC) using the Metabolon’s Complex Lipid Panel (CLP), a mass spectrometry based platform that can identify and accurately quantify the absolute concentrations of up to 1,100 individual lipid species and 14 lipid classes in large-scale epidemiological studies. Our goals here are to 1) generate the first comprehensive reference map of brain lipidome in relation to Alzheimer’s dementia-phenotypes (Aim 1); 2) identify individual brain lipid species associated with AD neuropathologies and cognitive phenotypes (Aims 1 and 2); and 3) elucidate the potential causal role of altered brain lipid regulation in AD pathology (Aim 3). Such results will shed light on the mechanisms through which lipid accumulation in the aging brain affects AD pathology, and provide evidence for targeting lipid metabolism in developing novel therapeutics for AD prevention and treatment.