B--amyloid deposition is central to the pathology ofboth Alzheimer's disease (AD) and some forms of cerebral congophilicangiopathy (CA)'. In AD, B--amyloid deposition is found predominantly in the characteristic neuritic plaques and also in cerebral vessels. In CA, deposition is almost solely in cerebral vessels, with deposition in the brain parenchyma associated only (apparently) with vessel rupture. In AD, the massive brain parenchymal deposition is associated with a neuritic response and there is intraneuronal pathology, particularly neurofibrillary tangles (which consist of abnormally phosphorylated tau, conjugated with other proteins). The neuronal circuitry damage caused by this process is responsible for the characteristic dementia in AD. In CA, there is little or no neuritic response and thus dementia is not a prominent feature (but see below). Until recently, the pathogenesis of these disorders was unclear. But, a recent series of molecular genetic investigations, including three papers appearing in Nature Genetid--4, have shown that mutations in the gene encoding B--amyloid (the B--amyloid precursor protein (APP) gene) on chromosome 21 are one cause of these disorders (and possibly others). However, the genotype/phenotype relationship for these diseases is not always clear: most cases of AD are not caused by mutations in APP (ref. 5). APP has several isoforms generated by alternative splicing of a 19 exon gene (exons 1--13, 13a, 14--18) 6• The predominant transcripts are APP695 (exons 1--6, 9--18, not 13a), APP751 (exons 1--7, 9--18, not 13a) andAPP770 (exons 1--18, not 13a). All of these encode multidomain proteins with a single membrane-spanning region'. They differ in that APP751 and APP770 contain exon 7, which encodes a serine protease inhibitor domain8· IO. APP695 is the pre--dominant form in neuronal tissue. APP751, the predominant variant elsewhere. B--amyloid is derived from that part of the protein encoded by parts of exons 16 and 17 (ref. 6). The B--amyloid section of the molecule is nature genetics volume I july 1992 partly embedded within the membrane and partly extending into the extracellular space'(see Fig.). B--amyloid itself cannot be generated by alternative splicing and seems to be an abnormal proteolytic codon 687 (lysine) of APP (APP770 transcript): this cleavage is in the middle of the B--amyloid section of the molecule (codons 672-714) and precludes amyloidogenesis15• 16• The second, the endosomal/lysosomal pathway, cleaves outside the B--amyloid fraction of the molecule leaving the B--amyloid containing stub within the membrane17• 18• AD/CA? The precise position of this cleavage is not known but a likely site is at Lys 670.