Genetics of Alzheimer's disease

• Mutations in any one of three genes can cause autosomal dominant, early-onset Alzheimer's disease: these genes are the amyloid precursor protein (APP) gene on chromosome 21, the presenilin-1 (PS-1) gene on chromosome 14 and the presenilin-2 (PS-2) gene on chromosome 1. • Pathogenic mutations at all these loci cause mismetabolism of APP such that more of the peptide Aβ42 is produced. • This peptide is deposited in the plaques in the brains of Alzheimer's patients. These facts have led to the dominant hypothesis for the disease process: the 'amyloid cascade hypothesis', which proposes that overproduction or failure to clear the peptide Aβ42 is always central to the disease. • Genetic variability at the apoliprotein E locus is a major determinant of late onset Alzheimer's disease. • The mechanism by which apoliprotein E is involved in the pathogenesis of Alzheimer's disease is not yet known. • There are likely to be other genetic factors which impinge on Alzheimer's disease.