PROJECT SUMMARY We hypothesize manipulating brain energy metabolism through a ketogenic diet (KD) will benefit Alzheimer's disease (AD) patients. To test this hypothesis, we designed the “Therapeutics Diet in Alzheimer's Disease (TDAD)” trial, a single blind, randomized, controlled study of a KD in AD participants. The TDAD will evenly randomize 80 AD participants to a three-month KD or a Therapeutic Lifestyles Changes (TLC) diet intervention. Aim 1 focuses on the clinical hypothesis and its primary endpoint analysis compares the mean change in KD participant pre and post-diet ADASCog11 scores to the mean change in the TLC diet participant pre and post-diet ADASCog11 scores. Secondary Aim 1 clinical outcomes include pre and post-intervention changes in Clinical Dementia Rating (CDR) scale sum of the boxes (SOB), mini-mental state exam (MMSE), logical memory test (LMT), and Stroop test scores. Aim 2 determines how a KD affects human physiology, and includes a biomarker-based assessment of depth of ketosis, mitochondrial function, insulin and insulin signaling, lipid homeostasis, and inflammation. We will further co-analyze the Aim 1 and Aim 2 data to identify relationships between physiologic parameters and cognitive performance. In Aim 1, comparing the magnitude of change in cognitive test and functional assessment scores between the two groups will determine whether a high fat, low carbohydrate, ketone body-inducing KD truly and uniquely benefits AD symptoms. The Aim 2 assessments will provide mechanistic insight into KDs, immediate target engagement feedback, and over the long term help guide the development of future metabolism-based AD interventions.