This suggests the following: (i) the signaling dichotomy between TNFR1 and TNFR2 also exists in disease; (ii) unopposed neuron-specific TNFR1 signaling at later stages of disease, when TNFR2 has been selectively down-regulated, increases the severity of AD pathogenesis; and (iii) TNFR2 exerts protective action that may be required to counteract TNFR1 signaling, emphasizing the need for strategies that more selectively modulate TNFα signaling in specific cell types and at different stages of disease. The gene discussed is TNFRSF1B; the disease is Alzheimer disease.