Alzheimer’s disease (AD) is the most common cause of dementia. It is characterized by b-amyloid plaques, neurofibrillary tangles and the degeneration of selected populations of vulnerable brain neurons. A well-established risk factor for the development of AD is the e4 allele of the gene encoding apolipoprotein E (APOE), which is central to the maintenance of brain cholesterol homeostasis. Because depletion of brain cholesterol levels reduces the generation of b-amyloid peptides (Ab) and because cholesterol-lowering drugs may reduce the risk of dementia we hypothesized that additional cholesterol-related genes may contribute to the genetic risk of AD. By combining information derived from case-control association studies, neuropathological examinations, cerebrospinal fluid studies, and differential expression experiments we observed that the genes encoding cholesterol 24-hydroxylase (CYP46), cholesterol 25-hydroxylase (CH25H), ATP-binding cassette transporter A1 (ABCA1), and Acyl-coenzyme A: cholesterol acyltransferase (SOAT1) are associated with AD and AD-related traits. In addition, application of methods enabling the study of multiple genetic interactions suggested that these genes may form a distinct genetic cluster with significant impact on the risk for the development of AD. Hypothesis-driven, large-scale association studies examining large numbers of genetic polymorphisms and gene-gene interactions will help identify genetic clusters contributing to the risk of AD.
Back to Clinical genetics in dementia
Back to Symposia
Back to The IPA European Regional Meeting (1-4 April 2003) of IPA