Abstract
Alzheimer disease (AD) is the most common form of dementia in the elderly. Due to the complexity of AD, it has been difficult to find genetic risk factors predisposing to disease. To date, three genes (APP, PSEN1 and PSEN2) with disease causing genetic variants have been reported for the rare early onset monogenic forms of AD. For the more prevalent, late onset Alzheimer disease (LOAD), the epsilon4 allele of the APOE gene, is the only confirmed genetic risk factor. However, since functional studies on AD cases with known mutations have shed light on the molecular mechanisms of the disease and linkage studies have highlighted additional candidate regions for AD in our genome, it is of great importance to identify additional susceptibility genes for AD.
All studies included in this thesis use single nucleotide variation (SNV) genotyping as a method for identifying new susceptibility genes involved in the sporadic, late onset forms of AD. Studies I and II are replication studies, investigating the role of genetic variants in the genes IDE and TFAM in case-control populations from Sweden. These genes are located in a reported linkage area in chromosome region 10q. Studies III and IV are original association studies on the genes COL25A1 and PITRM1 encoding two recently reported proteins, CLAC and hPreP, respectively. The gene encoding CLAC is located in chromosome region 4q24-25, which is a region associated with increased allele sharing in two linkage studies on Swedish AD families.
These findings, together with results from functional studies on this protein, prompted us to test the role of genetic variants in COL25A1 with respect to risk for AD. The study on PITRM1 was initiated by published results from functional studies on hPreP in post-mortem brain tissue from AD cases. We used a gene-wide association approach to test whether variants in this gene affect the risk for developing AD.
