Patricia Friedrich

No association of TDP-43 with sporadic frontotemporal dementia.

A hyperphosphorylated, ubiquitinated form of TDP-43, known as pathologic TDP-43, was shown to be a central component of ubiquitin-positive, tau-negative and alpha-synuclein-negative inclusions in frontotemporal lobar degeneration (FTLD-U) and amytrophic lateral sclerosis (ALS). To investigate the role of the TDP-43 gene in sporadic forms of frontotemporal dementia (FTD), we genotyped 10 single nucleotide polymorphisms covering the entire TDP-43 genomic region, including the MASP2 gene in 173 patients with sporadic FTD (including 7 patients that were diagnosed with FTD and ALS) and 184 matched controls from Germany. Although we could observe a weak trend towards a potential disease association in a few FTD/ALS patients, no significant association with sporadic FTD could be demonstrated. There is no evidence, that common variants in TDP-43 confer a strong risk to the development of sporadic FTD.

Weak independent association signals between IDE polymorphisms, Alzheimer's disease and cognitive measures

Functional and genetic studies suggest that insulin-degrading enzyme (IDE) may be a strong functional and positional candidate. As there is a lack of consensus in regards to the level and location of IDE association signals we aimed to clarify these discrepancies through genotyping 28 SNPs in a large case-control collective together with quantitative measures of cognitive ability (MMSE). Four SNPs (rs11187007, rs2149632_ide12, rs11187033, rs11187040) were found to be associated with AD (nominal p<0.01). Tests with MMSE scores adjusted for disease duration identified associations, with the most significant result for rs1999763 (nominal p=0.008). Similarly, different reconstructed IDE haplotypes were associated with AD and higher MMSE scores. The association signals are only borderline significant after adjustment for multiple testing, but add further evidence to previous published results on the association between IDE and AD or MMSE. A subgroup analysis indicated more prominent associations with AD in younger, and with MMSE in older patients. There may be two independent effects mediated by IDE variants, risk for AD and modification of disease progression.

Lack of evidence to support the association of polymorphisms within the alpha- and beta-secretase genes (ADAM10/BACE1) with Alzheimer's disease

Cleavage of the amyloid precursor protein (APP) occurs through either an amyloidogenic or a non-amyloidogenic pathway. The first results in the generation of beta-amyloid (Aβ) and is initiated through cleavage by the beta-site amyloid beta A4 precursor protein-cleaving enzyme 1 (BACE1). The second precludes the formation of Aβ through cleavage by alpha-secretase, an enzymes activity demonstrated in a disintegrin metalloproteinase, ADAM10. To assess the contribution of variants in the BACE1 and ADAM10 genes we used a detailed fine mapping approach. Genotyping of 11 single nucleotide polymorphisms covering the complete BACE1 gene, and 27 covering the entire ADAM10 gene, revealed no single-marker or haplotypic association with AD. We conclude that, in this present study, neither ADAM10 nor BACE1 present with any evidence to suggest that they are major candidate genes involved in conferring risk for AD.

No association of chromatin-modifying protein 2B with sporadic frontotemporal dementia

Mutations of the chromatin modifying protein 2B gene (CHMP2B) were identified, in a Danish pedigree, to cause familial frontotemporal dementia (FTD). To explore the possible genetic contribution of common CHMP2B variants in sporadic FTD, we analyzed 14 single nucleotide polymorphisms covering the entire genomic region of CHMP2B. After adjustment for multiple testing single marker and haplotype analysis revealed no significant association with sporadic FTD. Thus, we conclude that CHMP2B can be excluded as a susceptibility gene conferring risk to sporadic forms of FTD.

Genetic analysis of MAPT haplotype diversity in frontotemporal dementia

The H1 haplotype of the tau gene, MAPT, has been linked to the sporadic tauopathies corticobasal degeneration and progressive supranuclear palsy; however, there have been inconsistent findings regarding association with frontotemporal dementia (FTD). We investigated MAPT haplotype diversity, in 171 sporadic FTD and 186 healthy controls individuals, and report no single marker or haplotype association with increased risk or changes in age at onset. These findings do not support an association of MAPT with FTD but do not rule out its association with other tauopathies.

No association of vacuolar protein sorting 26 polymorphisms with Alzheimer's disease.

Using a case-control sample we evaluated a possible involvement of the Vacuolar protein sorting 26 (VPS26) gene in the pathogenesis of AD. VPS26 located at 10q22.1 denotes a retromer subunit functionally involved in the cellular trafficking of Memapsin 2 (BACE). Genotyping of eight single nucleotide polymorphisms covering the complete VPS26 gene and haplotypic analysis revealed no association with AD. Thus, we conclude that VPS26 can be excluded as a major positional and functional candidate gene conferring risk to AD.

No Association of Common VCP Variants With Sporadic Frontotemporal Dementia

Mutations in the gene for valosin containing protein (VCP) cause autosomal dominant inclusion body myopathy associated with Paget disease and frontotemporal dementia (IBMPFD). To investigate the role of this novel gene in sporadic forms of frontotemporal dementia (FTD), we genotyped 27 single nucleotide polymorphisms covering the entire VCP genomic region in 198 patients with sporadic FTD and 184 matched controls from Germany. No significant association could be demonstrated. There is no evidence, that common variants in VCP confer a strong risk to the development of sporadic FTD.

No association of lipase C polymorphisms with Alzheimer's disease

Hepatic lipase, also known as hepatic triglyceride lipase (LIPC), much like the major genetic risk factor for Alzheimers disease (AD), apolipoprotein E (APOE), is associated with altered lipid metabolism. As such this link makes LIPC a potential functional candidate for AD risk. Previously, three single nucleotide polymorphisms (SNPs) have been investigated in AD with a lack of association reported. To rule out a possible contribution of other variants in LIPC, located at 15q21-q23, we used a detailed fine mapping approach in a German case-control sample. Genotyping of 25 single nucleotide polymorphisms covering the complete LIPC gene and haplotypic analysis revealed no association with AD. Thus, we conclude that LIPC can be excluded as a major functional candidate gene conferring risk to AD.

No association of Tachykinin receptor 2 (TACR2) polymorphisms with Alzheimer's disease

The Tachykinin Receptor 2 (TACR2) located at chromosome 10q21.3 belongs to a class of receptors that bind members of the tachykinin neurotransmitter family. The TACR2 binds neurokinin A, also known as substance K, and is expressed in distinct parts of the human brain. Functionally, the TACR2 has been implicated in stress induced hippocampal acetylcholine release and the gene TACR2 is located within a previously identified linkage region for Alzheimers disease (AD) on chromosome 10q21. Together, both facts make the TACR2 a reasonable positional and functional candidate gene for AD. Genotyping of 13 single nucleotide polymorphisms (SNPs) covering the entire gene and haplotypic analysis revealed no association with AD. Thus, we conclude that TACR2 can be excluded as a major susceptibility gene conferring risk to AD.

P3-256: Whole-genome association approaches identify new susceptibility genes of Alzheimer's disease

Matthias Riemenschneider, Patricia Friedrich , Simon M. Laws , Caroline Graff, Alexander Kurz , Sebastian Wurst , Stefan Wagenpfeil, Hans Forstl , Neurochemistry and Neurogenetics Laboratory, Munich, Germany; Karolinska Institut, Stockholm, Sweden; Dept. of Psychiatry & Psychotherapy, Munich, Germany; Institute for Medical Statistics and Epidemiology, Munich, Germany. Contact e-mail: m.riemenschneider@lrz.tu-muenchen.de