Genes contributing to Alzheimer's disease

Abstract

We propose that Alzheimer's disease (AD) is a single disease with a common metabolic APP-βA4-amyloid pathway. The multiple genetic and other factors already identified to induce this pathway are reviewed. The molecular genetics of AD has been successfully studied within the last years, and we now can account for the genetic and molecular alterations underlying the majority of familial AD cases inherited with an autosomal dominant pattern of complete penetrance. AD in these pedigrees can be caused by missense mutations within the recently identified PS1 (S182) gene on chromosome 14 (AD3 locus) and the PS2 (STM2/E5-1) gene on chromosome 1, in addition to previously described point mutations of the βA4-amyloid protein precursor (APP) gene on chromosome 21 (AD1 locus). The majority of AD cases, however, appears to be sporadic or 'familial' in terms of an increased family-associated AD-probability. Genetic risk factors contributing to AD in these cases have also been identified. On chromosome 19, allelic segregation of the APOE gene with both late onset 'familial' (AD2) and sporadic AD has been demonstrated, with the APOE ∈4 allele conferring a relatively higher risk of developing AD at an earlier age. Several other risk factors have also been proposed, including the α1-antichymotrypsin allele A (ACT-A), the 5-repeat allele of the VLDL-receptor (VLDL-R) gene, the A2 allele of the HLA-A locus, and possibly yet unknown mitochondrial mutations. All these findings are discussed against the background of what is known about APP metabolism leading to βA4 amyloid formation, a process that is also modified by APP expression level, alternative splicing of APP exon 15, extracellular signalling and intracellular sorting.