Molecular genetics of Alzheimer's disease: an update

Alzheimer's disease (AD) is a complex disorder of the central nervous system (CNS). Molecular genetic research has provided a wealth of information regarding the genetic etiology of this devastating disease. Identification and functional characterization of autosomal dominant mutations in the amyloid precursor protein gene (APP) and the presenilin genes 1 and 2 (PSEN1 and PSEN2) have contributed substantially to our understanding of the biological mechanisms leading towards CNS neurodegeneration in AD. Nonetheless, a large part of the genetic etiology remains unresolved, especially that of more common, sporadic forms of AD. While substantial efforts were invested in the identification of genetic risk factors underlying sporadic AD, using carefully designed genetic association studies in large patient-control groups, the only firmly established risk factor remains the epsilon4 allele of the apolipoprotein E gene (APOE). Nevertheless, one can expect that with the current availability of high-throughput genotyping platforms and dense maps of single-nucleotide polymorphisms (SNPs), large-scale genetic studies will eventually generate additional knowledge about the genetic risk profile for AD. This review provides an overview of the current understanding in the field of AD genetics, covering both the rare monogenic forms as well as recent developments in the search for novel AD susceptibility genes.