(300 WORDS MAX) There is strong evidence that the immune system protects the brain and affects the progression of Alzheimer disease (AD). Amyloid-beta 1-42 (ABETA) vaccine therapies based on adaptive immunity are under study but are complicated by inflammation. Although the innate immunity is crucial in AD for clearance of ABETA, it has been difficult to evaluate and drugs enhancing innate immunity have not been developed for clinical use. This study has two objectives. The first is to investigate the prognostic value of the transcription in peripheral blood mononuclear cells of AD patients of the gene MGAT3. This test is easy to perform and preliminary results suggest that patients have different prognosis based on MGAT3 transcription: Those patients strongly transcribing the gene after stimulation with ABETA ("Type I") and those strongly transcribing after stimulation with a curcumin drug ("Type II") have slower progression of AD dementia compared to those patients not transcribing this gene after any stimulation ("Type 0"). The second objective is to develop new synthetic curcuminoids and cannabinoids for inhibition of inflammation and enhancement of clearance of ABETA. We have already shown the ability of curcuminoids to inhibit inflammation and enhance clearance of ABETA in vitro, but there are obstacles to clinical use: pharmacological issues, such as absorption, metabolism and distribution; and potency issues, such as upregulation of the immune function related to complex signaling pathways of inflammation in AD. We have expertise in synthesis of curcuminoids and cannabinoids, which contain at least one Michael acceptor moiety within the molecule and thus are more reactive with the vitamin D receptor. We are also interested in an alternative approach to block the inflammation using omega-3 fatty acids and their endogenous products called resolvins. Our project will create a new prognostic biomarker for AD and new small molecular therapeutics for AD.