Genetic determinism of Alzheimer's disease

The genetic determinism of alzheimer's disease (AD) is heterogeneous. Autosomal dominant forms of the disease involve the amyloid precursor protein (APP) gene located on chromosome 21, the presenilin-1 gene on chromosome 14 and the presenilin-2 gene on chromosome 1. Altogether these genes account for less than 20% of early-onset AD cases (onset before 60). APP mutations cause AD by altering the APP processing in a way that is amyloidergic. How mutations of presenilin-1 and -2 act to promote AD neuropathology is currently unknown. Besides these major genes, the apolipoprotein E (APOE) gene, located on chromosome 19, is also implicated in the diathesis of the disease. A strong association has been described between AD and the APOE epsilon 4 allele. This allele is a risk factor for AD whatever the sex and the age. Cases bearing the epsilon 4 allele have more deposition of amyloid beta peptide in brain than those who do not. APOE epsilon 4 isoform could act as a molecular chaperone conforming soluble beta peptide into an insoluble amyloid form.