Neuropathologic-Epidemiological Study of Metallomics and Alzheimer's Disease

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PROJECT SUMMARY The project Neuropathologic-Epidemiological Study of Metallomics and Alzheimer's Disease (RF1AG054057) demonstrated for the first time that pro-oxidant iron directly measured in human brain is strongly associated with cognitive decline in older persons with AD pathology. In this proposed continuation, we propose to further these studies to resolve mechanisms underlying brain iron elevation, susceptibility to iron-mediated damage, and resultant decline. Underpinning our hypothesis is the recently discovered programmed death pathway, ferroptosis, which causes destruction of synaptic and cellular membranes by iron dependent peroxidation of certain lipids. Strong preliminary data supports these aims. In this competive renewal, we propose to test the hypotheses that (1) dietary fat and brain lipids contribute to the elevation of brain iron; and (2) iron interacts with brain lipids to promote lipid peroxidation, resulting in toxic brain injury (via ferroptosis), neuronal loss, and ultimately accelerated cognitive and motor decline in aging. We propose to use novel methodologies, incorporating (oxidized) lipidomics using advanced methodologies (i.e. targeted and oxidized lipidomics and immune-assisted, tandem Laser Ablation MALDI/ICP-MS) to map iron and lipid-mediated neurodegeneration in cognitive and motor brain regions. We will expand dietary studies, and leverage a rich resource of clinical and pathologic data available from Rush Memory and Aging Project. Overall, we propose to collect new data on brain lipids, increase data on iron and dietary fats to goal of 850 brains. In Aim 1, we will test the hypotheses that dietary fat intake is associated with brain lipid composition and iron content; that brain lipid composition is associated with brain iron content; and use advanced technology to map and test their relationship across the layered cortex. In Aim 2, we propose to detect oxidized lipids and test the hypotheses that lipid peroxidation is associated with brain iron, Alzheimer’s pathology, and cognitive decline. We also will investigate whether lipid peroxides mediate cognitive decline associated with iron in AD. In Aim 3 we will determine brain iron and (oxidized) lipid content in brain motor regions and test the hypothesis that regional brain iron is associated with lipid composition and with motor function and decline and motor pathology (Lewy body, vascular, AD, etc.) in older persons. In each aim, we will investigate how relationships differ by APOE ε4, Alzheimer’s pathologic diagnosis and sex. Overall, these studies have the potential to uncover new mechanisms by which iron, lipids (diet and brain), and APOE ε4 increase cognitive and motor decline in aging and AD. These studies have the potential to reveal new and targetable biologic pathways.