IGHE and Alzheimer disease: Although all these immunologic features are well established in AD, the pathogenic model has profoundly changed in the last two decades, overcoming previous hypotheses based on the immune response mediated by immunoglobulin E (IgE) (type 1 hypersensitivity), the primary role of the epidermal barrier impairment (“outside-in” theory), and the primary role of the aberrant immune activation (“inside-out” theory).