Other genes for Alzheimers disease

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Several large surveys of patients with familial AD have indicated that the APP, APOE, PS1 and PS2 genes account for only about half of the genetic risk factors for AD. It is therefore likely that there are several additional AD-susceptibility genes. Some of these loci will be associated with additional rare, but highly penetrant defects similar to those seen with mutations in PS1 and APP. Other genes may result in incompletely penetrant autosomal-dominant traits like those associated with PS2. However, it is likely that a significant proportion of the remaining genes will be genes with low-effect sizes similar to APOE, and in which the ultimate phenotype is likely to be influenced by the presence or absence of other genetic and environmental risk factors.

There have been multiple strategies deployed to try to map these additional AD-susceptibility genes. Genetic linkage studies and family-based association analyses have been employed on datasets with pedigrees multiply affected with AD, and have led to the suggestion that there may be additional susceptibility loci in: (1) the pericentro-meric region of chromosome 12 (Alzheimer Type 5) (Pericak-Vance et al., 1997; Rogaeva et al., 1998); and (2) the long arm and pericentromeric region of chromosome 10q (Alzheimer Type 6) (Bertram et al., 2000; Ertekin-Taner et al., 2000; Myers et al., 2000). However, to date, the exact genes in these regions that cause susceptibility to AD have not been identified. Weaker evidence, in single studies have also implicated chromosome 20p (Olson et al., 2002); 15q22 (Scott et al., 2003); and 9p (Pericak-Vance et al., 2000). The glutathione S-transferase omega-1 (GSTO1) gene on distal chromosome 10q has also been implicated as a gene modulating age-of-onset in both AD and Parkinson's disease (Li etal., 2003), but this has not yet been replicated in other datasets.

A second strategy to identify AD genes has been to use cohorts of sporadic AD cases and age/sex matched controls in a case:control association design. This has led to a long list of potential candidate genes, most of which have not been robustly replicated. A partial list of candidate genes provisionally identified as putative AD susceptibility loci includes homozygosity for the AA allele of an intronic polymorphism in a1-chymotrypsin, A5 repeat allele of an intronic insertion-deletion polymorphism in the very low density lipoprotein receptor, neutral coding sequence and intronic polymorphisms in low density lipoprotein receptor related protein, homozygosity for intronic polymorphisms in presenilin 1 or presenilin 2, K-variant of butyrylcholinesterase, homozygosity for the Val/Val variant of the Val443Ile polymorphism in bleomycin hydroxylase; IL4 etc. However, most of these candidate genes have not received the same widespread confirmation as did APOE e4 when tested in independent but comparable datasets. Interestingly, a number of obvious candidate genes involved in APP processing, including BACE (b-secretase involved in Ab generation) and neprilysin and insulin degrading enzyme (involved in Ab degradation) have been screened, but as of this writing have not been widely found to have genetic variants associated with increased risk for AD.

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