Amyloid precursor protein gene mutations responsible for early-onset autosomal dominant Alzheimer's disease.

According to the "amyloid cascade hypothesis", the accumulation of A beta peptides in the brain is a primary event in the pathogenesis of Alzheimer's disease (AD). Other pathological features (neurofibrillary tangles, neuronal damage and cell death) are regarded as secondary. One of the strong pieces of evidence supporting this hypothesis was the identification of over 20 pathogenic mutations within the APP gene responsible for familial EOAD. The APP mutations are located close to the sites recognised by the alpha-, beta- and gamma-secretases. The mutations affect the APP processing, causing overproduction of A beta42 peptide. The imbalance between A beta production and A beta clearance releases a cascade of subsequent cellular processes leading to AD. In this paper, all APP mutations have been summarised and their molecular effects on the APP metabolism have been discussed.