Alzheimer’s disease (AD) is the leading cause of dementia, and affects about 5 million Americans at present. It is projected to afflict 16 million Americans by 2050 and cost the economy $1.1 trillion. The prevalence of AD is much greater in veterans than in the general population because of a constellation of risk factors including age, traumatic brain injury, depression, and PTSD all of which are more prevalent in the veterans. While there is no effective treatment for AD at present, several studies in animal models have shown beneficial effects of docosahexaenoic acid (DHA) which is uniquely concentrated in the brain, and is known to be essential for its function. However, clinical trials using the currently available DHA supplements (fish oil, krill oil, algal oil, ethyl esters etc) to improve cognitive function in patients have been disappointing. We postulate that this failure is due to the inability of these supplements to enrich brain DHA at the recommended safe doses, because they are all absorbed in the form of triacylglycerol (TAG) rather than in the phospholipid form required by the transporter at the blood brain barrier (BBB). We have recently demonstrated that dietary DHA in the form of lysophosphatidylcholine (LPC), which is absorbed in the phospholipid form, not only enriches brain DHA at low doses, but also improves cognition and spatial memory in normal mice. The current proposal will explore the potential of LPC and other lysophospholipids (LPL) in enriching brain DHA and in the prevention of AD in a mouse model of the disease. In Aim 1, we will test the hypothesis that dietary DHA-lysophospholipids (LPL) are superior to either TAG-DHA (as in fish oil) or natural phospholipid DHA (as in krill oil) in enriching the brain DHA and improving cognitive function in normal mice. In addition, the effect of the polar head group of the LPL (choline, ethanolamine, or serine), as well as the effect of eicosapentaenoic acid (EPA) will be determined, to identify the most efficient LPL for improving the brain function. In Aim 2, we will test the hypothesis that treatment with a low dose of LPL-DHA (identified in Aim 1) will prevent or delay the development of AD in a double transgenic mouse model of AD. Three-month-old APPswe/PS1ΔE9 mice will be treated with either LPL-DHA or TAG-DHA at a daily dose of 40 mg DHA/kg for 9 months, and the effects on cognitive behavior, memory, and neuropathology will be determined. It is anticipated that LPL-DHA, but not TAG-DHA would alleviate the pathological symptoms of AD at these low doses. In Aim 3, we will determine the mechanisms underlying the beneficial effects of LPL-DHA, compared to the currently available supplements of DHA, in enriching brain DHA and in improving brain function. The hypotheses to be tested include: a) that the metabolic advantage of LPL-DHA is due its ability to cross both the intestinal barrier and blood brain barrier, b) that LPL-DHA is more anti-inflammatory than free DHA, c) th...