An Overview of the Genetics of Alzheimer's Disease

Over the past decade, a variety of different methods have been applied to identify genes associated with susceptibility to Alzheimer’s disease. Initial studies focussed on pedigrees with apparent autosomal dominant transmission. These studies identified missense mutations and/or duplications in these families in the amyloid precursor protein gene, presenilin 1 and presenilin 2. Molecular biological analysis of the effects of mutations in these genes revealed that they cause misprocessing of APP and either the overproduction of all forms of amyloid beta peptide (Abeta peptide), or the production of more amyloidogenic species of Abeta, including Abeta42. These latter species are more prone to aggregate and form into neurotoxic higher-order oligomers. More recently, the application of case-control methods using either a candidate gene approach or hypothesis-free genome-wide association methods have led to the identification of several other genes, including APOE, SORL1, PICALM, BIN1, CLU, CD2AP, CD33, EPHA1, ABCA7, CR1 and MS4A. Some of these genes are likely to be involved in the vesicular trafficking of APP and the production of Abeta peptide (this is particularly the case for SORL1, and possibly PICALM). Other members of these genes likely modulate the innate immune response to protein aggregates (this is likely to be the case for CR1 and probably CLU). The implications of these new genetic findings will be discussed.