Alzheimer's Disease is a major cause of morbidity and mortality in aging populations and incurs a heavy toll on health services. It affects 5% of the population over 65 years and 15% over 85 years. The pathogenic pathways are not established but it is clear that the disease is etiologically heterogeneous. Using traditional reverse genetic approaches we have isolated missense mutations in the amyloid precursor protein (APP) gene which cause the illness in some early onset families. In this project we will apply reverse genetics and direct screening to separate those families (from extensive sources in the UK and US) which have APP mutations. New mutations in APP will be characterized by direct sequencing. The families which do not have APP mutations will be subject to a genome search. With the use of large pedigrees and concurrent simulation studies we will circumvent the problem of heterogeneity to genetically isolate (an) additional (locus) loci. By dissecting the genetics of Alzheimers disease in this way we will further delineate the pathogenic pathways which cause not only the pure genetic cases but the more common cases of mixed aetiology.