In particular, we propose that loss of function mutations upstream of NF-κB such as ADAM17, SHARPIN, HOIL, or OTULIN affect NF-κB-activity in Alzheimer’s disease (AD) patients, in turn driving anatomical defects such as shrinkage of entorhinal cortex and the limbic system in early AD. The gene discussed is OTULIN; the disease is early-onset autosomal dominant Alzheimer disease.