In search of pathogenic amyloid β-peptide in familial Alzheimer's disease

Early-onset familial Alzheimer's disease (FAD) is pathologically and clinically similar to the more common late-onset sporadic form of the disease. The study of rare genetic mutations that cause FAD should provide insight into the pathogenesis of sporadic Alzheimer's disease. FAD mutations have only been found in the substrate (amyloid precursor protein, APP) and protease (gamma-secretase) that produces the amyloid-beta peptide (A beta). The secreted, aggregation-prone 42-residue A beta peptide (A beta 42) has long been considered the pathogenic entity in Alzheimer's disease. However, recent understanding of the complexity of the processing of APP by gamma-secretase and the effects of FAD mutations on this processing suggest other forms of A beta as potentially pathogenic.