Evaluation of neprilysin sequence variation in relation to CSF ß-Amyloid levels and Alzheimer disease risk.

Neprilysin (NEP) is a principal peptidase involved in the degradation of ß-amyloid (Aß), and as such its encoding gene (MME) has been the target of numerous genetic association studies on Alzheimer disease. Here, in order to attempt replication of previous findings we have investigated several single nucleotide polymorphisms (SNPs) that have been claimed to be associated with AD. A key feature of the present study is the complementary investigation of both AD risk and quantitative measures of AD severity, including cerebrospinal (CSF) fluid levels of AP1-42. In contrast to the effects of APOE, none of these measures are detectably influenced by genetic polymorphism in the MME region. We thus, fail to find support for previous results suggesting that MME impacts AD.

Towards compendia of negative genetic association studies: an example for Alzheimer disease.

Most genetic sequence variants that contribute to variability in complex human traits will have small effects that are not readily detectable with population samples typically used in genetic association studies. A potentially valuable tool in the gene discovery process is meta-analysis of the accumulated published data, but in order to be valid these require a sample of studies representative of the true genetic effect and thus hypothetically should include some positive and an abundance of negative reports. A survey of the literature on association studies for Alzheimer disease (AD) from January 2004-April 2005, identified 138 studies, 86 of which reported positive findings other than for apolipoprotein E (APOE), strongly indicative of publication bias. We report here an analysis of 62 genetic markers, tested for association with AD risk as well as for possible effects upon quantitative indices of AD severity (mini-mental state examination scores, age-at-onset, and cerebrospinal fluid (CSF) beta-amyloid (Abeta) and CSF tau proteins). Within this set, only modest signals were present that, with the exception of APOE are easily lost when corrections for multiple hypotheses are applied. In isolation, results are thus broadly negative. Genes studied encompass both novel candidates as well as several recently claimed to be associated with AD (e.g. urokinase plasminogen activator (PLAU) and acetyl-coenzyme A acetyltransferase 1 (ACAT1)). By reporting these data we hope to encourage the publication of gene compendia to guide further studies and aid future meta-analyses aimed at resolving the involvement of genes in complex human traits.

Sequence variants of IDE are associated with the extent of beta-amyloid deposition in the Alzheimer's disease brain.

Insulin degrading enzyme, encoded by IDE, plays a primary role in the degradation of amyloid beta-protein (A beta), the deposition of which in senile plaques is one of the defining hallmarks of Alzheimer's disease (AD). We recently identified haplotypes in a broad linkage disequilibrium (LD) block encompassing IDE that associate with several AD-related quantitative traits. Here, by examining 32 polymorphic markers extending across IDE and testing quantitative measures of plaque density and cognitive function in three independent Swedish AD samples, we have refined the probable position of pathogenic sequences to a 3' region of IDE, with local maximum effects in the proximity of marker rs1887922. To replicate these findings, a subset of variants were examined against measures of brain A beta load in an independent English AD sample, whereby maximum effects were again observed for rs1887922. For both Swedish and English autopsy materials, variation at rs1887922 explained approximately 10% of the total variance in the respective histopathology traits. However, across all clinical materials studied to date, this variant site does not appear to associate directly with disease, suggesting that IDE may affect AD severity rather than risk. Results indicate that alleles of IDE contribute to variability in A beta deposition in the AD brain and suggest that this relationship may have relevance for the degree of cognitive dysfunction in AD patients.

Sequence variation in the proximity of IDE may impact age at onset of both Parkinson disease and Alzheimer disease.

We recently reported that a linkage disequilibrium (LD) block on chromosome 10q encompassing the gene encoding insulin-degrading enzyme ( IDE) harbors sequence variants that associate with Alzheimer disease (AD). Evidence also indicated effects upon a number of quantitative indices of AD severity, including age-at-onset (AAO). Since linkage of this immediate region to AAO has been shown in both AD and Parkinson disease (PD), we have explored the possibility that polymorphism within this LD block might also influence PD. Utilizing single nucleotide polymorphisms that delineate common haplotypes from this region, we observed significant evidence of association with AAO in an Australian PD case-control sample. Analyses were complemented with AAO data from two independent Swedish AD case samples, for which previously reported findings were replicated. Results were consistent between AD and PD, suggesting the presence of equivalent detrimental and protective alleles. These data highlight a genomic region in the proximity of IDE that may contribute to AD and PD in a similar manner.

Genetic variation in CTNNA3 encoding alpha-3 catenin and Alzheimer's disease.

Linkage studies have implicated a broad region on chromosome 10q in Alzheimer's disease (AD). A recent genetic association study has provided evidence that polymorphism in the gene encoding alpha-3 catenin (CTNNA3, referred to previously as VR22 and also known as alpha-T catenin) may underlie linkage signals. Here, to investigate this finding, markers that previously exhibited maximum evidence of association have been tested in Swedish and Scottish AD case-control samples. Across models of disease risk and in relation to multiple quantitative indices of AD pathology (CSF A beta 42 and tau levels, age-at-onset, MMSE scores, and measures of senile plaque density) no evidence was found supporting a role for these particular variants in AD. More detailed studies of regional linkage disequilibrium structure around CTNNA3 will likely be required to determine whether sequence variation in this region impacts AD.