7. PROJECT SUMMARY The 'Western diet' characterized by high fat feeding (HFF) is a risk factor for Alzheimer's disease (AD). However, individuals who carry the AD risk gene APOE ε4 (E4) respond differently to high fat feeding (HFF) in terms of several metabolic and cognitive responses. We present evidence that arterial spin labeling (ASL) MRI is an effective non-invasive method to evaluate acute changes in total and regional cerebral blood flow (∆CBF). We will propose a clinical study in older adults involving ingestion of a high fat drink to test the prediction that E4 carriers will show higher CBF in response to HFF compared to fasting, whereas E4 non-carriers will show lower CBF. We will further examine regional differences in ∆CBF with emphasis on brain regions known to be involved in AD pathogenesis, and we will conduct cognitive testing on all participants to explore relationships between CBF and fluid measures of cognition. With this proposal we will also investigate whether peripheral metabolic measures of glucose tolerance and body composition predict ∆CBF, and whether E4 status influences those predictions. This intervention will be done in parallel with lipidomic and metabolomic analyses of cerebrospinal fluid from an ongoing study of older adults after ingestion of a high fat meal with similar lipid content to the high fat drink. With these studies we hope to gain a more in-depth understanding of how HFF exerts influence on brain function and metabolism for E4 carriers and non-carriers, and identify brain regions which are particularly vulnerable to the acute effects of HFF.