Abstract: The invention provides a novel mutation identified in amyloid precursor protein, which leads to a very aggressive form of Alzheimer's disease. The mutation involves the 43rd codon of amyloid &bgr; peptide (A&bgr;) corresponding to the putative &ggr;42-secretase cleavage site. The novel mutation alters both A&bgr;40 and A&bgr;42 secretion elevating the A&bgr;42/A&bgr;40 ratio by 10-fold in vitro. Furthermore, the main amyloid plaque pathology in brains of these patients is of the diffuse ‘pre-amyloid’ type composed primarily of N-truncated A&bgr;42. Dense-cored plaques although not absent, were significantly reduced. Also, usual sites in brain where A&bgr;40 is predominantly deposited, for instance, in vessels such as cerebral amyloid angiopathy or senile plaque cores, were composed entirely of A&bgr;42 form.