GENES CONTRIBUTING TO ALZHEIMERS-DISEASE

We propose that Alzheimer's disease (AD) is a single disease with a co mmon metabolic APP-beta A4-amyloid pathway. The multiple genetic and o ther factors already identified to induce this pathway are reviewed, T he molecular genetics of AD has been successfully studied within the l ast years, and we now can account for the genetic and molecular altera tions underlying the majority of familial AD cases inherited with an a utosomal dominant pattern of complete penetrance. AD in these pedigree s can be caused by missense mutations within the recently identified P SI (S182) gene on chromosome 14 (AD3 locus) and the PS2 (STM2/E5-1) ge ne on chromosome 1, in addition to previously described point mutation s of the beta A4-amyloid protein precursor (APP) gene on chromosome 21 (ADI locus), The majority of AD cases, however, appears to be sporadi c or 'familial' in terms of an increased family-associated AD-probabil ity. Genetic risk factors contributing to AD in these cases have also been identified, On chromosome 19, allelic segregation of the APOE gen e with both late onset 'familial' (AD2) and sporadic AD has been demon strated, with the APOE epsilon 4 allele conferring a relatively higher risk of developing AD at an earlier age. Several other risk factors h ave also been proposed, including the alpha(1)-antichymotrypsin allele A (ACT-A), the 5-repeat allele of the VLDL-receptor (VLDL-R) gene, th e 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 beta A4 amyloid formati on, a process that is also modified by APP expression level, alternati ve splicing of APP exon 15, extracellular signalling and intracellular sorting.