Considering the large and increasing number of Alzheimer's disease (AD) cases and the devastating course of the disease, there is a great need for developing drugs that target critical pathologic mechanisms in AD. Continuing research has revealed additional insights into the pathogenesis and molecular mechanisms behind AD and has created more hope for disease-modifying therapies, rather than merely symptomatic treatment. Because beta-secretase (BACE1) is one of the two key enzymes in processing the amyloid precursor protein (APP) for A[unreadable] generation, which has been considered a pathological hallmarker for AD. Recent discoveries have shown that BACE1 activity was significantly increased in the brain and CSF affected AD mild cognitive impairment (MCI). Thus, BACE1 inhibitors, as well as potential pilot studies for clinical trials, are crucial for the early detection of AD. Recently, we and others have discovered that blocking TNF signaling reduces amyloid plaques and A[unreadable] production through inhibition of BACE1 in AD transgenic mice. The clinical study has also demonstrated that using the TNF fusion protein antagonist, Enteracept, has been beneficial to one AD case. However, Enteracept is a fusion protein drug which is not penetrable to the brain blood barrier (BBB), and peri-neck injections may carry potential risks for patients. Thus, we decided to test this notion by using the TNF inhibitor Thalidomide. Our novel approach is based on developing TNF1 inhibitor drugs that target BACE1 and, thus, provide the ability to influence specific downstream pathways. As a proof of this concept, we will administer Thalidomide to logically pursue this drug in AD subjects. We propose that Thalidomide may represent a BACE1 inhibitor. PUBLIC HEALTH RELEVANCE: Considering the large and increasing number of Alzheimer's disease (AD) cases and the devastating course of the disease, there is a great need for developing drugs that target critical pathologic mechanisms in AD. Continuing research has revealed additional insights into the pathogenesis and molecular mechanisms behind AD and has created more hope for disease-modifying therapies, rather than merely symptomatic treatment. Beta-secretase (BACE1) is one of the two key enzymes in processing the amyloid precursor protein (APP) for A[unreadable] production, which has long been considered the pathological hallmark of AD. Recent discoveries have shown that BACE1 activity was significantly increased in sporadic AD brain samples. In correlation with these studies, we have discovered an elevation in both BACE1 enzymatic activity level and BACE1 protein level in the CSF from patients with mild cognitive impairment (MCI). Thus, BACE1 inhibitors, as well as potential pilot studies for clinical trials, are crucial for the early detection of AD. Recently, we and others have discovered that blocking TNF signaling reduces amyloid plaques and A[unreadable] production through inhibition of BACE1 in AD transgenic mice. The clinical study has also demonstrated that using the TNF fusion protein antagonist, Enteracept, has been beneficial to one AD case. However, Enteracept is a fusion protein drug which is not penetrable to the brain blood barrier (BBB), and peri-neck injections may carry potential risks for patients. Thus, we decided to test this notion by using the TNF inhibitor Thalidomide. Our novel approach is based on developing TNF1 inhibitor drugs that target BACE1 and, thus, provide the ability to influence specific downstream pathways. As a proof of this concept, we will administer Thalidomide to logically pursue this drug in AD subjects and test our hypothesis that thalidomide decreases CSF BACE1 and Ab and improves CSF neuronal markers for neuron loss in AD subjects. We propose that Thalidomide may represent a BACE1 inhibitor.