Genetic Factors in Early- and Late-Onset Alzheimer’s Disease

Summary

In recent years, considerable progress has been made in unravelling the genetic etiology of Alzheimer’s disease (AD). Three genes have been identified that are involved in the autosomal dominant forms of early-onset AD: the β-amyloid precursor protein gene (APP) and two homologous genes, presenilin 1 (PS-1) and presenilin 2 (PS-2). Mutations in each of these genes have been found to be rare. Screening a population-based sample of patients with early-onset AD (< 65 years) revealed APP mutations in 0.5% of the patients, PS-1 mutations in 6% and PS-2 mutations in 1%. Although the risk of AD for carriers of mutations in these genes is extremely high, the relative contribution of these genes to the occurrence of disease in the general population is lower than 1%. On the population level, the apolipoprotein E (APOE) gene is a more important genetic determinant for early-onset AD as well as for the predominant, late-onset form (90–95% of the patients). The APOE4 allele may explain up to 17% of AD in the general population. A key issue to resolve from a public health point of view will be the interaction of this gene with drugs and other genetic and non-genetic risk factors. Large scale, long-term follow-up studies, ongoing at present, may clarify this issue. Another issue to be resolved in AD research will be the identification of other, yet unknown genes involved in the etiology of AD.