APOE and Alzheimer disease: These studies, together with others demonstrating that (1) TNF-α polymorphisms that elevate TNF-α production may increase AD risk, particularly in patients carrying one or more apolipoprotein E ε4 alleles [46-49], and that (2) genetic ablation of TNF-α receptor 1 (TNFR1) in APP23 AD mice [50] or a selective lowering of soluble TNF-α brain levels in 3xTg-AD mice [25] reduces AD progression, support the concept of TNF-α inhibition strategies for treatment of AD [10,51,52].