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.