Behnosh F. Björk

Association study of two genetic variants in mitochondrial transcription factor A (TFAM) in Alzheimer's and Parkinson's disease

Mitochondrial (mt) dysfunction has been implicated in Alzheimers (AD) and Parkinsons disease (PD). Mitochondrial transcription factor A (TFAM) is needed for mtDNA maintenance, regulating mtDNA copy number and is absolutely required for transcriptional initiation at mtDNA promoters. Two genetic variants in TFAM have been reported to be associated with AD in a Caucasian case-control material collected from Germany, Switzerland and Italy. One of these variants was reported to show a tendency for association with AD in a pooled Scottish and Swedish case-control material and the other variant was reported to be associated with AD in a recent meta-analysis. We investigated these two genetic variants, rs1937 and rs2306604, in an AD and a PD case-control material, both from Sweden and found significant genotypic as well as allelic association to marker rs2306604 in the AD case-control material (P=0.05 and P=0.03, respectively), where the A-allele appears to increase risk for developing AD. No association was observed for marker rs1937. We did not find any association in the PD case-control material for either of the two markers. The distribution of the two-locus haplotype frequencies (based on rs1937 and rs2306604) did not differ significantly between affected individuals and controls in the two sample sets. However, the global P-value for haplotypic association testing indicated borderline association in the AD sample set. Our data suggests that the rs2306604 A-allele could be a moderate risk factor for AD, which is supported by the recent meta-analysis.

Genome scan on Swedish Alzheimer's disease families

Alzheimers disease (AD) is an age-related disease, which affects approximately 40% of the population at an age above 90 years. The heritability is estimated to be greater than 60% and there are rare autosomal dominant forms indicating a significant genetic influence on the disease process. Despite the successes in the early 1990s when four genes were identified, which directly cause the disease (APP, PSEN1 and PSEN2) or greatly increase the risk of disease development (APOE), it has proved exceedingly difficult to identify additional genes involved in the pathogenesis. However, several linkage and association studies have repeatedly supported the presence of susceptibility genes on chromosomes (chrms) 9, 10 and 12. The study populations have, however, mostly been of great genetic heterogeneity, and this may have contributed to the meagre successes in identifying the disease associated genetic variants. In this study, we have performed a genome wide linkage study on 71 AD families from the relatively genetically homogeneous Swedish population where it is also possible to study the genetic ancestry in public databases. We have performed nonparametric linkage analyses in the total family material as well as stratified the families with respect to the presence or absence of APOE ɛ4. Our results suggest that the families included in this study are tightly linked to the APOE region, but do not show evidence of linkage to the previously reported linkages on chrms 9, 10 and 12. Instead, we observed the next highest LOD score on chromosome 5q35 in the total material. Further, the data suggest that the major fraction of families linked to this region is APOE ɛ4 positive.

Genetic and biochemical studies of SNPs of the mitochondrial Aβ-degrading protease, hPreP

Several studies suggest mitochondrial dysfunction as a possible mechanism underlying the development of Alzheimer disease (AD). There is data showing that amyloid-beta (A beta) peptide is present in AD brain mitochondria. The human presequence protease (hPreP) was recently shown to be the major mitochondrial A beta-degrading enzyme. We investigated if there is an increased susceptibility to AD, which can be attributed to genetic variation in the hPreP gene PITRM1 and if the proteolytic efficiency of recombinant hPreP variants is affected. When a total of 673 AD cases and 649 controls were genotyped for 18 single nucleotide polymorphisms (SNPs), no genetic association between any of the SNPs and the risk for AD was found. In contrast, functional analysis of four non-synonymous SNPs in hPreP revealed a decreased activity compared to wild type hPreP. Using A beta, the presequence of ATP synthase F(1)beta subunit and a fluorescent peptide as substrates, the lowest activity was observed for the hPreP(A525D) variant, corresponding to rs1224893, which displayed only 20-30% of wild type activity. Furthermore, the activity of all variants was restored by the addition of Mg(2+), suggesting an important role for this metal during proteolysis. In conclusion, our data suggest that genetic variation in the hPreP gene PITRM1 may potentially contribute to mitochondrial dysfunctions.

Progranulin mutation causes frontotemporal dementia in the Swedish Karolinska family

Frontotemporal dementia (FTD) is a neurodegenerative disease characterized by cognitive impairment, language dysfunction, and/or changes in personality. Recently it has been shown that progranulin (GRN) mutations can cause FTD as well as other neurodegenerative phenotypes.

P1-312: Successful replication of association between late-onset Alzheimer’s disease and the Insulin degrading enzyme (IDE)

The common apolipoprotein E (APOE) e4 allele is strongly associated with risk of dementia and age at onset, but studies are inconclusive as to whether the e4 allele affects rate of progression or survival in demented patients. Furthermore, previous observations suggest a contribution of two APOE promoter polymorphisms (-491 A/T and -219 G/T) in dementia, but the influence of these two polymorphisms on survival in demented patients have not been evaluated yet.

AbstractPoster presentation: Sunday posterP1-333: Genetic association to the novel CLAC gene in familial and clinic based Alzheimer’s disease cases

Background: One of the main pathological hallmarks of Alzheimer’s disease (AD) is the senile plaques mainly consistent of insoluble deposits of the amyloid peptide (A ). A number of other components have been identified to co-localize with senile plaques in the brains of AD patients. Recently, the novel collagenous Alzheimer amyloid plaque component (CLAC) was described. It shows a specific binding to A , implicating involvement of CLAC in A fibrillization, proteolysis protection and A -mediated cytotoxicity. The gene encoding CLAC is located on chromosome band 4q24-25, in a region where we have observed increased allele sharing in Swedish AD pedigrees. Objective(s): To investigate the potential role of CLAC as a susceptibility gene for AD. Methods: Association studies in two AD populations were performed: one containing familial AD (FAD) cases, the other made up of cases from the Memory Clinic at Karolinska University Hospital. A third, population based sample set is under investigation. Results: We observed significant association in FAD cases to four single nucleotide polymorphisms (SNPs) that are in linkage disequilibrium. Furthermore, the clinic based sample confirmed the association in two of the SNPs. Conclusions: Our results add genetic evidence to the previous experimental evidence for CLAC’s involvement in AD pathogenesis possibly by affecting the interaction between and CLAC.