Charlotte Forsell

A mutation in Alzheimer's disease destroying a splice acceptor site in the presenilin-1 gene

A series of mutations has been reported in the presenilin-1 (PS-1) gene which cause early onset Alzheimers disease (AD). The mutations reported to date have encoded missense mutations which alter residues conserved between PS-1 and the presenilin-2 (PS-2) gene. We have recently determined the intron/exon structure of the PS-1 gene and this information has been used to identify a mutation in the splice acceptor site for exon 9 in a family with early onset AD. Amplification of cDNA from lymphoblasts of affected individuals revealed that the effect of the mutation was to cause splicing out of exon 9, however it does not change the open reading frame of the mRNA. The importance of this observation is discussed.

Mapping of a disease locus for familial rapidly progressive frontotemporal dementia to chromosome 17q12-21

Familial frontotemporal dementia (FTD) is a complex disorder with lack of distinctive histopathological markers found in other types of dementia. Most of the linkage reports from FTD families map the disease loci to chromosome 17q21-22. However, FTD is genetically heterogeneous, as linkage also has been reported to chromosome 3. In the present study, we investigated the genetics of a Swedish family with an early-onset type of rapidly progressive FTD, associated with muscular rigidity and akinetic movements. Neuropathological features such as severe frontal lobe degeneration, spongy changes, and gliosis were present in affected family members. We here report probable linkage to chromosome 17q12-21 with a maximum two-point lod score of 2.76 at theta = 0 for marker D17S806, and a peak multipoint lod score of 2.86 for the same marker. Linkage to chromosome 3 was excluded, as two-point lod scores of -2.79, and -2.27 at theta = 0.01 for markers D3S1603 and D3S1552, respectively, were obtained. Sequencing of the translated exons of a strong candidate gene in the linked region of chromosome 17, the tau gene, failed to identify any mutations segregating with the disease.

Clinic-Based Cases with Frontotemporal Dementia Show Increased Cerebrospinal Fluid Tau and High Apolipoprotein E ε4 Frequency, but No Tau Gene Mutations

Frontotemporal dementia (FTD) belongs to a group of neurodegenerative disorders known as tauopathies, characterized by intracellular aggregation of hyperphosphorylated tau protein in the brain. Some tauopathies, like Alzheimers disease (AD), consistently show increased levels of tau protein in cerebrospinal fluid (CSF). However, similar studies in FTD populations have shown variable results, although mutations in the tau gene are identified as causes of disease in certain FTD families. In the present study, a Swedish clinic-based FTD population was investigated with respect to CSF tau levels, apolipoprotein E (APOE) genotype distribution and occurrence of mutations in the tau gene. CSF tau levels were significantly increased among FTD patients (534 +/- 235 pg tau/ml, P < 0.001) (n = 47) compared to controls (316 +/- 137 pg tau/ml) (n = 51). Furthermore, a strong increase in the APOE epsilon4 allele frequency was found in the FTD population, as 52% were epsilon4 carriers, compared to 21% of the controls. However, no mutations in the tau gene were identified. These findings support the present notion of a common pathogenic pathway in the disease processes for several tauopathies, with both APOE epsilon4 and CSF tau being a pathological link between the different disorders. Furthermore, we conclude that mutations in the tau gene are a rare cause of FTD. .

Tau gene polymorphisms and apolipoprotein E ε4 may interact to increase risk for Alzheimer’s disease

Abstract In an effort to analyze the genetic role of tau in Alzheimers disease (AD), 17 polymorphisms were identified. Eleven of these polymorphisms were in complete linkage disequilibrium and segregated as two haplotypes, A and B. The A and B haplotypes were investigated in 269 AD cases and 238 controls from two different sources, a clinic-based group (mean age of onset 65±9 years), and a population-based group (mean age of onset 80±5 years). A synergistic effect between the common tau genotype AA and apolipoprotein E (APOE e4) was found in the clinic-based AD group. Our study suggests that the common tau genotype AA may interact with APOE e4 in increasing the risk of AD in a subgroup of the AD population.

Investigations of a CA repeat in the oestrogen receptor beta gene in patients with Alzheimer's disease.

Several studies have shown that oestrogen treatment after menopause decreases the risk for Alzheimers disease (AD). It is also known that oestrogen stimulates the outgrowth of nerve cells and that apolipoprotein E (Apo E) synthesis and amyloid precursor protein (APP) metabolism are regulated by oestrogen. Recently a new oestrogen receptor was identified, oestrogen receptor β (ERβ), located at chromosome 14q22-24. Several genes close to this chromosomal region have been implicated in AD, but the results are conflicting. Our hypothesis was that variations in the ERβ gene could be the underlying cause to the positive findings in these genes and we have therefore investigated a CA repeat1 in intron 5 of the ERβ gene. Three hundred and thirty-six AD cases and 110 healthy age-matched controls were included in this study. Fourteen different alleles were found with frequencies between 0.1 and 37%. There was no significant difference between AD cases and controls when all alleles were compared. However, allele 5 was seen in 13.6% of the controls but only in 8.0% of AD cases (P=0.014; odds ratio (OR)=0.55). No AD patient homozygous for this allele was seen but three controls were homozygous. In conclusion, our findings suggest the ERβ allele 5 to be a protective factor. However, this has to be confirmed in a larger population.

Diagnosis of acute intermittent porphyria in northern Sweden: an evaluation of mutation analysis and biochemical methods

Abstract. Objective. To validate the use of a recently observed guanine to adenine mutation in exon 10 in the porphobilinogen deaminase (PBGD) gene as a diagnostic marker of acute intermittent porphyria (AIP). To evaluate the efficiency of the traditional biochemical diagnostic methods.

Diminished [3H]inositol(1,4,5)P3 but not [3H]inositol(1,3,4,5)P4 binding in Alzheimer's disease brain

Levels of the calcium mobilising receptors for the phosphoinositide hydrolysis derived second messengers, inositol(1,4,5)trisphosphate [Ins(1,4,5)P3] and inositol(1,3,4,5) tetrakis-phosphate [Ins(1,3,4,5)P4] were compared in the cerebellum, superior temporal and superior frontal cortex of a series of Alzheimers disease and matched control cases. Membrane [3H]Ins(1,4,5)P3 radioligand binding experiments performed under steady state conditions revealed that the number of Ins(1,4,5)P3 recognition sites was significantly decreased in all three brain regions of the Alzheimers disease cases, compared to controls. In contrast, [3H]Ins(1,3,4,5)P4 binding levels, as assessed in competition analyses, were not significantly different between the groups in any brain region. Moreover, the Hill coefficients for inhibition of [3H]Ins(1,3,4,5)P4 binding by non-radioactive Ins(1,3,4,5)P4 were less than unity in both the control and Alzheimers disease brains, suggesting that the heterogeneity of these binding sites are also maintained in the disease. It is concluded that disruptions of the phosphoinositide hydrolysis pathway in Alzheimers disease brain are associated with a selective loss of calcium mobilising Ins(1,4,5)P3, but not Ins(1,3,4,5)P4 receptor sites. These alterations may contribute to an altered calcium homeostasis in Alzheimers disease, as well as providing one reason for the lack of success of cholinergic replacement therapies aimed at enhancing muscarinic receptor-mediated phosphatidylinositol hydrolysis.

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.

A novel pathogenic mutation (Leu262Phe) found in the presenilin 1 gene in early-onset Alzheimer's disease

Several mutations causing early-onset familial Alzheimers disease (AD) have been detected in the presenilin 1 (PS-1) gene. Pathogenic mutations have also been described in an homologous gene, presenilin 2 (PS-2). In order to screen for mutations in these genes, cDNA samples from early-onset AD cases were analysed, using single strand conformation polymorphism (SSCP) and direct cDNA sequencing. Two missense mutations in the PS-1 gene were detected, a previously unidentified amino acid substitution Leu262Phe and an earlier reported amino acid substitution Glu318Gly. No disease-related mutations were found in the PS-2 gene.

Amyloid precursor protein mutation at codon 713 (Ala → Val) does not cause schizophrenia: non-pathogenic variant found at codon 705 (silent)

In some families with early-onset Alzheimers disease (AD) pathogenic mutations have been found in exons 16 and 17 of the amyloid precursor protein (APP) gene. One case of schizophrenia has been described with a mutation at codon 713. We have developed a single strand conformation polymorphism (SSCP) method that detects mutations in these exons and investigated 98 AD cases and 56 elderly healthy controls. An earlier reported mutation at codon 713 in a healthy control and a previously undescribed polymorphism at codon 705 in a sporadic case of AD were found. These mutations are probably not related to disease pathogenesis.