The familial mutations associated with early AD onset localized within the TM or JM region were shown to be capable of altering APP recognition and cleavage by secretases and/or affecting oligomerization and toxicity of mature Aβ species at the expense of global or local conformational rearrangements and intermolecular interactions of varying degree of specificity [58,60,64,65,66,67,68]. This evidence concerns the gene APP and Alzheimer disease.