R Rademakers

Tau negative frontal lobe dementia at 17q21: significant finemapping of the candidate region to a 4.8 cM interval.

We report the results of a genome-wide search in a four-generation pedigree with autosomal dominant early-onset dementia (mean onset age: 64.9 years, range 53–79 years). In this family we previously excluded the known Alzheimers disease genes based on linkage analysis and mutation screening of the amyloid precursor protein gene (exons 16 and 17) and the presenilin 1 and 2 genes. In addition we excluded mutations in the prion protein gene and exons 9–13 of the microtubule associated protein tau (MAPT) gene. We obtained conclusive linkage with chromosome 17q21 markers with a maximum multi-point LOD score of 5.51 at D17S951 and identified a candidate region of 4.8 cM between D17S1787 and D17S958 containing MAPT. Recent clinical and neuropathological follow-up of the family showed that the phenotype most closely resembled frontotemporal dementia (FTD) characterized by dense ubiquitin-positive neuronal inclusions that were tau negative. Extensive mutation analysis of MAPT identified 38 sequence variations in exons, introns, untranslated regions and the 5′ regulatory sequence, however none was comprised within the disease haplotype. Although our findings do not entirely exclude a mutation in a yet unanalyzed region of MAPT, the apparent absence of MAPT mutations combined with the lack of tau pathology is highly suggestive for another defective gene at 17q21 responsible for FTD in this family.

Association of cyclin-dependent kinase 5 and neuronal activators p35 and p39 complex in early-onset Alzheimer's disease

Malfunctioning of cyclin-dependent kinase 5 (CDK5) through aberrant proteolytic cleavage of its neuronal activators p35 and p39 is involved in neurodegeneration in Alzheimers disease (AD) and other neurodegenerative brain diseases. By extensive genetic analysis of the genes encoding CDK5 (CDK5), p35 (CDK5R1) and p39 (CDK5R2), we excluded causal mutations in 70 familial early-onset AD patients. We performed an association study with five informative SNPs in CDK5 in two independent samples of early-onset AD patients and matched control individuals from The Netherlands and northern Sweden. Association was observed with g.149800G>C in intron 5 of CDK5, and a two times increased risk was observed in both patient samples for carriers of the C-allele. Our data are indicative for a role of the CDK5 molecular complex in the genetic etiology of early-onset AD, and suggest that a yet unknown functional variant in CDK5 or in a nearby gene might lead to increased susceptibility for early-onset AD.

Variable expression of presenilin 1 is not a major determinant of risk for late-onset Alzheimer's Disease

Abstract We have previously reported a significant association between early-onset Alzheimers disease (EOAD) and an allele in the promoter of presenilin 1 (PSEN1) significantly decreasing PSEN1 expression in vitro. For late-onset Alzheimers disease (LOAD), numerous studies have reported inconsistent associations with a PSEN1 intronic polymorphism. We therefore hypothesized that linkage disequilibrium between the intronic PSEN1 polymorphism and the functional promoter polymorphism might explain the conflicting reports in LOAD. We analysed both variations in 356 LOAD patients and 230 controls in a population-based case-control study. In addition, we re-analysed all published literature on the PSEN1 intronic polymorphism in a meta-analysis. No significant association was found with the PSEN1 intronic or promoter polymorphism in our case-control sample. In the meta-analysis no major differences between patients and controls were found for the PSEN1 intronic variation. Together, our results do not support a major role for variable expression of PSEN1 in LOAD.

Absence of pathogenic mutations in presenilin homologue 2 in a conclusively 17-linked tau-negative dementia family.

Frontotemporal dementia (FTD) is the second mostcommon neurodegenerative dementia after Alzheimer’s disease (AD), with a frequency of 12%–20% among patients with an onset of dementia below 65 years. Causal mutations leading to FTD were identified in the microtubule-associated protein tau (MAPT) gene located at 17q21. In several autosomal dominant tau-negative FTD families, however, mutations in MAPT could not be identified, despite conclusive linkage to 17q21 [1, 2, 3]. We hypothesized that this subtype of FTD could result from mutations in the gene encoding presenilin (PS) homologue 2 (PSH2), located 50 kb upstream of MAPT. PSH2 is one of five members of a novel family of proteins showing membrane topology and putative catalytic domains similar to PS [4]. Because mutations in presenilins 1 and 2 are responsible for early onset AD [5] (http://molgen-www.uia.ac.be/ADMutations), mutations in PSHs might also lead to neurodegeneration. Previously, mutation analysis of PSH2 in probands of four taunegative FTD families failed to identify PSH2 mutations [4], but these families were not informative for linkage to 17q21. We described a four-generation family, 1083, ascertained in a population-based study in the Netherlands [6], which presented with a clinical phenotype similar to FTD and a mean onset age of 64.9 years (range 53–79 years) [2]. Autopsy demonstrated severe frontal atrophy and complete lack of tau neuropathology in the presence of ubiquitin-positive tau-negative inclusions. A genomewide scan identified conclusive linkage (multipoint LOD score=5.51) in a candidate region of 4.8 cM at 17q21 comprising MAPT. Extensive mutation analysis of MAPT coding and regulatory sequences failed to identify disease-related mutations [2]. In this study, we performed mutation analysis of PSH2 by direct sequencing of three overlapping PCR amplicons of genomic DNA between positions g.6 and g.2195 in XM_091623.4, corresponding to the only coding exon of PSH2, and including 67 bp upstream and 68 bp downstream regulatory sequences. In total we identified 5 novel (Table 1) and 10 known single nucleotide polymorphisms (SNPs) (see electronic supplementary Fig. 1). Segregation analysis in the family indicated that only 1 novel SNP g.1698G>A was contained in the disease haplotype leading to a silent mutation at codon S542. We used a pyrosequencing assay to analyze 89 Dutch control individuals and identified 2 controls that were homozygous and 20 heterozygous for the A allele, resulting in a minor allele frequency of 13.5%. Segregation analysis also illustrated that 4 of the 5 novel SNPs were in linkage disequilibrium with the extended MAPT haplotypes H1/ H2, defined by polymorphic alleles in MAPT exons 1, 2, 3, 9, 11, and 13 [7] (see electronic supplementary Fig. 1). R. Rademakers · M. Van den Broeck · C. van Duijn · C. Van Broeckhoven · M. Cruts Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology, University of Antwerp, Antwerpen, Belgium

Chromosome 17-linked frontotemporal dementia with ubiquitin-positive, tau-negative inclusions

Familial forms of frontotemporal dementia (FTD) are in 10–43% of patients, caused by mutations in the gene encoding the microtubule associated protein tau (MAPT) located at chromosome 17q21. Neuropathologically, these patients are characterized by tau-positive depositions in brain. However, autosomal dominant forms of FTD without MAPT mutations have been reported, suggesting other tauopathy-related genetic defects. One such form is FTD linked to 17q21, with tau-negative but ubiquitine-positive neuronal inclusions or FTD-U. We previously reduced the candidate chromosomal region to 4.8 cM in a Dutch FTD-U family, 1083. A mutation in MAPT was excluded by genomic sequencing. More recently, we identified three Belgian FTD families of which two, DR2 and DR8, showed linkage to the 17q21 region. Both families shared a common haplotype in an 8.04 cM region, indicating that they are genetically related to a common founder. In the third family, DR7, we obtained an autopsy confirmation of the characteristic ubiquitin-positive, tau-negative neuronal inclusions. Currently, there are 11 FTD families linked to 17q21 that do not segregate a MAPT mutation, of which five are conclusively linked (LOD score > 3). Together the data suggest that FTD-U could represent an important subtype of FTD, and that identification of the underlying gene defect might significantly contribute to our understanding of the pathomechanism leading to neurodegeneration in this dementia subtype.