Neuroinflammation is a hallmark of Alzheimer’s disease (AD), with microglia playing a central role in AD pathogenesis. While many immunological parameters are associated with AD, the mechanisms that control AD-associated inflammation remain elusive. The anti-inflammatory properties of free fatty acid receptor 4 (Ffar4) make it an intriguing target for diseases that result from chronic inflammation, such as AD. Ffar4 is a G- protein coupled receptor (GPCR) for medium and long-chain fatty acids (FAs), including w3-polyunsaturated fatty acids (w3-PUFAs). In many tissues, Ffar4 attenuates inflammation, reduces oxidative stress, and prevents apoptosis. Ffar4 is expressed in a variety of tissues, most notably in macrophages and brain. In multiple tissues Ffar4 is upregulated in response to injury or stress and loss of Ffar4 exacerbates pathological responses, while activation of Ffar4 is protective. In humans, we recently discovered that the Ffar4 inactivating polymorphism, R270H, was associated with an increased risk of AD and memory loss. These data form the premise of our hypothesis that, Ffar4 in microglia attenuates inflammation, while the absence of Ffar4 results in a higher propensity for neuroinflammation and AD. To test this hypothesis, we propose two aims. 1.) To determine the role of Ffar4 in AD we will test if loss of Ffar4 exacerbates progression of AD in APP-SAA knock- in (KI) mice. 2.) We will determine the neuroinflammatory effect of loss of Ffar4 by examining cytokine production and microglia phenotypes in APP-SAA KI mice. This work will identify how loss of Ffar4 function contributes to disease and potentially identify a target to improve disease outcome. By targeting Ffar4 it might be possible to redirect the immune response, resulting in improved cognitive function.