The goal of this study was to further define the role of TNF alpha in neuroinflammation, neuronal dysfunction and cognitive impairment. This was determined by testing the efficacy of a TNF alpha synthesis lowering agent 3,6′-dithiothalidomide on neuroinflammation-induced cognitive impairment exhibited in the 3x Tg AD mouse model, mice challenged with Aβ1–42 peptide, and LPS-challenged rats. 6′-Dithiothaliodmide treatment lowered TNF-α, nitrite (an indicator of oxidative damage) and secreted amyloid precursor protein (sAPP) levels. In mice centrally challenged with Aβ1–42 peptide, prior systemic 3,6′-dithiothalidomide suppressed Aβ-induced memory dysfunction, microglial activation and neuronal degeneration. Chronic 3,6′-dithiothalidomide administration to an elderly symptomatic cohort of 3xTg-AD mice reduced multiple hallmark features of AD, including phosphorylated tau protein, APP, Aβ peptide and Aβ-plaque number along with deficits in memory function to levels present in younger adult cognitively unimpaired 3xTg-AD mice. Levels of the synaptic proteins, SNAP25 and synaptophysin, were found to be elevated in older symptomatic drug-treated 3xTg-AD mice compared to vehicle-treated ones, indicative of a preservation of synaptic function during drug treatment. The data suggest a strong beneficial effect of 3,6′-dithiothalidomide in the setting of neuroinflammation and AD, supporting a role for neuroinflammation and TNF-α in disease progression and their targeting as a means of clinical management.