Loss‐of‐function presenilin mutations in Alzheimer disease

Presenilin mutations are the main cause of familial Alzheimer disease. From a genetic point of view, these mutations seem to result in a gain of toxic function; however, biochemically, they result in a partial loss of function in the γ‐secretase complex, which affects several downstream signalling pathways. Consequently, the current genetic terminology is misleading. In fact, the available data indicate that several clinical presenilin mutations also lead to a decrease in amyloid precursor protein‐derived amyloid β‐peptide generation, further implying that presenilin mutations are indeed loss‐of‐function mutations. The loss of function of presenilin causes incomplete digestion of the amyloid β‐peptide and might contribute to an increased vulnerability of the brain, thereby explaining the early onset of the inherited form of Alzheimer disease. In this review, I evaluate the implications of this model for the amyloid‐cascade hypothesis and for the efficacy of presenilin/γ‐secretase as a drug target.