SMAD4 and Alzheimer disease: Neurodegeneration is a pathological hallmark of AD with multiple causative mechanisms that involve various response elements including LPS/IL-1 response element (LILRE), TGF-β/Activin/SMAD2/SMAD3/SMAD4 response element (TARE), and p53 response element (p53-RE) Suppression of interleukin-1β (which stimulates LILRE) or p53-RE is expected to reduce apoptotic cell death [32, 33].