Recent research advancements, lead to a crucial change in AD pathogenic model, overcoming the preceding hypotheses based on (i) key role of the EBD (“outside-in” theory); (ii) immunoglobulin E (IgE)- response (type 1 hypersensitivity), or (iii) principal role of the abnormal systemic immune activation (“inside-out” theory) (9–11). This evidence concerns the gene IGHE and Alzheimer disease.