Genetic Analysis of Presenilin Genes in Early Onset Alzheimer's Disease

In 1995 the teams of Peter St George-Hyslop and G. Schellenberg identified 2 genes, the presenilin genes PS-1 and PS-2, that are causative for familial early-onset Alzheimer disease (AD) with onset ages ranging from as early as 30 years to midlife. The biological function of the PS proteins is not known yet. However, there is already biochemical evidence that when the PS proteins are mutated, amyloid deposition in the brain is accelerated leading to dementia at earlier age. To date 35 mutations have been identified in PS-1 in 60 early-onset AD families and 2 in PS-2 world wide. From the known mutations we can learn that the same PS-I mutation leads to similar onset ages in different families. Within PS-I families onset age is rather sharp i.e. dose to the mean onset age in the family, while in PS-2 families onset age is highly variable suggesting that other genetic and/or environmental factors may play a role in the expression of the disease in these families. These other factors have not been identified yet. So far PS mutations have only been found in familial AD cases. Also, no mutations have been found yet in late-onset AD cases (disease onset> 65 years). However, most mutation analyses have been restricted to AD families that were included in segregation studies aiming at identifying AD genes. Also, not many mutation reports are yet available on sporadic and late- onset AD cases. There are however, indications that sequence variations in the PS-1 gene, may predispose to late-onset AD and possibly early-onset AD, although the latter needs further investigations. To obtain better information on the contribution of PS mutations/polymorphisms to early-onset AD in general, we propose to use a unique sample of early-onset AD cases and families sampled in an epidemiological study performed in The Netherlands. This study aimed at sampling all AD patients with clinical diagnosis of AD before the age of 65 years in metropolitan Rotterdam and 4 northern provinces of The Netherlands. A total of 198 patients were identified, of these 102 patients are included in this project. Because the AD cases were obtained in an epidemiological study, they are representative for early-onset in general. The sample contains both sporadic cases (no other patients in the family) and familial cases. Among the familial cases, 11 cases belonged to families with autosomal dominant AD. Ten of the families were sampled and used in segregation studies to test whether they segregated one of the known AD genes on chromosomes 14, 19 or 21. Only 1 family was positive for the chromosome 14 gene. Mutation/polymorphism analysis of the PS genes in the Dutch epidemiological sample will allow us to estimate the exact contribution of PS mutations to and the role of PS polymorphisms in autosomal dominant, familial and sporadic early-onset AD in general. This knowledge is important when DNA diagnosis of early-onset AD is considered. Also, the identification of new mutations will help delineating the biological most relevant parts of the PS proteins which will enhance our understanding of the biology of these proteins in relation to their normal and abnormal functioning. This knowledge in tum is important in the development of appropriate cellular and animal models for AD based on mutated PS genes.