PSEN1 and Alzheimer disease: A more direct causal link between Aβ production and disease development is established for familial AD (FAD), where causative mutations in APP, PSEN1, and PSEN2 lead to early onset of AD (mean age of ~ 45 years) and the enhanced production of a 42-residue-long Aβ peptide (Aβ42) that is a major component of extracellular amyloid plaques in patient brains [12] and rapidly aggregates in cell-free assays and AD models [13].