Genome scan on Swedish Alzheimer's disease families.

Alzheimer's 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 varepsilon4. 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 varepsilon4 positive.

Increased frequency of a new polymorphism in the cell division cycle 2 (cdc2) gene in patients with Alzheimer's disease and frontotemporal dementia.

Recent studies show linkage between Alzheimer's disease (AD) and two loci on chromosome 10. The cell division cycle 2 (cdc2) gene is located close to one of the chromosome 10 markers, and is a candidate gene for AD since it is involved in the pathogenesis of AD. We sequenced coding exons and flanking intronic sequences and the promoter region on the cdc2 gene and found three new single nucleotide polymorphisms (SNPs). We analyzed 272 Caucasian AD cases, 160 controls and 70 cases with frontotemporal dementia (FTD) for these SNPs. Homozygosity for one of the SNPs (Ex6+7I/D) was more frequent in both AD and FTD cases than in controls. In the combined tauopathy (AD and FTD) group the odds ratio (OR) was 1.77 (95% CI 1.19-2.63) for the Ex6+7II genotype. Our findings suggest that the Ex6+7I allele is associated with tauopathies, both AD and FTD.

APOE genotypes and disease severity in multiple sclerosis.

Apolipoprotein E (opoE) is involved in the transport of lipids necessary for membrane repair and is encoded by a gene on chromosome 19q13, a region positive for linkage in two multiple sclerosis (MS) genome-wide screens. The APOE epsilon4 allele confers susceptibility to both familial and sporadic Alzheimer's disease (AD). Carriage of epsilon4 is associated with defective dendritic remodeling in AD, and with unfavorable clinical outcome in head trauma and cerebrovascular disease. According to the results of previous studies, APOE epsilon4 does not increase the risk of developing MS, but it may influence disease progression and ultimate disability. From a total cohort of over 900 MS patients, we compared APOE epsilon2-4 genotypes in, roughly, the cohort's least disabled and most disabled septiles. 'Benign MS' (n=124) was defined as an Expanded Disability Status Scale (EDSS) score of 3.0 or less, despite at least 10 years of disease duration, and 'severe MS' (n=140) as the attainment of an EDSS score of 6.0 within 8 years of disease onset. We found no significant differences in genotype or phenotype frequencies between the benign-MS and severe-MS septiles; however, the risk conferred by epsilon4 rose progressively upon comparison of carriage rates in more narrowly defined anti-podal quantiles.

Increased risk for frontotemporal dementia through interaction between tau polymorphisms and apolipoprotein E epsilon4.

The tau gene has an important role in frontotemporal dementia (FTD) as pathogenic mutations have been found in hereditary forms of the disease. Furthermore, a certain extended tau haplotype has been shown to increase the risk for progressive supranuclear palsy, corticobasal degeneration, Parkinson's disease and, in interaction with the apolipoprotein E (apoE) epsilon4 allele, Alzheimer's disease. By microsatellite analysis we investigated an intronic tau polymorphism, in linkage disequilibrium with the extended tau haplotype, in FTD patients (n = 36) and healthy controls (n = 39). No association between any of the tau alleles/genotypes and FTD was seen, but certain tau alleles and apoE epsilon4 interactively increased the risk of FTD (p = 0.006). We thus propose that this extended tau haplotype in combination with apoE epsilon4 is a genetic risk factor for FTD.

No detected mutations in the genes for the amyloid precursor protein and presenilins 1 and 2 in a swiss early-onset Alzheimer's disease family with a dominant mode of inheritance.

Mutations have been found in more than a hundred early-onset families with Alzheimer's disease (AD) in the genes for the amyloid precursor protein, presenilin 1 and presenilin 2. The object of our investigation was to identify if these mutations or novel ones were operating in a Swiss early-onset AD family (mean age of onset: 53.3 years) with 7 members available, all neuropathologically confirmed. No known or new mutations were detected. Thus, our data support the existence of a yet unknown mutation, or other genes, contributing to familial early-onset AD. CopyrightCopyright 1999S.KargerAG,Basel

Decreased plasma insulin-like growth factor-I level in familial Alzheimer's disease patients carrying the Swedish APP 670/671 mutation.

The plasma insulin-like growth factor I (IGF-I) level was determined in family members carrying the Swedish amyloid precursor protein (APP) 670/671 mutation with or without Alzheimer's disease (AD) and in age-matched controls from the same family. Plasma growth hormone (GH) and prolactin (PRL) levels were also determined. Measurement of the plasma IGF-I level by radioimmunoassay revealed a significant reduction only in the family members with AD compared to age-matched controls. However, there was no significant difference in the levels of GH and PRL between the mutation carriers with or without AD and their respective age-matched controls. These findings indicate that the mechanism(s) regulating GH and PRL were preserved and those regulating IGF-I levels might be affected in AD patients with the Swedish APP 670/671 mutation. CopyrightCopyright 1999S.KargerAG, Basel

A DLST genotype associated with reduced risk for Alzheimer's disease.

Recent studies suggest that variants of the DLST gene alter the risk of AD. DLST encodes the core subunit of the mitochondrial alpha-ketoglutarate dehydrogenase complex, which is deficient in AD. The authors report that in 247 US white subjects, homozygosity for DLST A19,117, T19,183 was associated with a reduced risk of AD (odds ratio [OR] = 0.35, p = 0.018). The reduced risk was marked in subjects who did not carry the apolipoprotein (APOE)-4 allele (OR = 0.16, p = 0.014). Further study of DLST in AD appears warranted.

Modulation by DLST of the genetic risk of Alzheimer's disease in a very elderly population.

The mitochondrial alpha-ketoglutarate dehydrogenase complex (KGDHC) is deficient in Alzheimer's disease (AD). The DLST gene encodes the core, dihydrolipoyl succinyltransferase (DLST) component of KGDHC, and recent reports indicate an association between polymorphisms of DLST and AD in both white and Japanese patients. We therefore examined the relationship between AD and the DLST and apolipoprotein E (APOE) genes in elderly (89 +/- 7 years) AD patients, in whom the epsilon4 allele of APOE (APOE4) is a weak risk factor for AD. Polymorphisms of DLST (A19,117G and T19,183C), shown to be of interest in previous studies, were analyzed by restriction fragment length polymorphism analysis after polymerase chain reaction amplification. In a series of 429 white subjects from two Jewish nursing homes, an association of APOE4 with AD was found only in patients homozygous for the G,C allele of DLST. Similar relationships occurred in the "very elderly" (> or =85 years, n = 302) subgroup of this series, and also in an autopsy series (n = 225) that included white subjects from the Jewish nursing homes as well as other white subjects. These findings suggest a relationship between APOE4 and a DLST locus in the pathogenesis of AD in very elderly subjects.

Tau gene polymorphisms and apolipoprotein E epsilon4 may interact to increase risk for Alzheimer's disease.

In an effort to analyze the genetic role of tau in Alzheimer's 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 epsilon4) was found in the clinic-based AD group. Our study suggests that the common tau genotype AA may interact with APOE epsilon4 in increasing the risk of AD in a subgroup of the AD population.

The Glu318Gly mutation of the presenilin-1 gene does not necessarily cause Alzheimer's disease.

In early-onset familial Alzheimer's disease (AD) pathogenic mutations have been found in the amyloid precursor protein (APP) gene and in the presenilin (PS)-1 and PS-2 genes. We screened for mutations in these genes in 20 patients with familial AD from the Finnish population. In addition, we sampled 41 sporadic AD patients and 59 controls to test for mutations identified in our familial AD cases. We detected an A-to-G transition in the PS-1 gene, resulting in a glutamic acid (Glu)-to-glycine (Gly) substitution at codon 318 in 2 familial and 2 sporadic AD patients. The Glu318Gly mutation has previously been reported to cause AD. We also found the Glu318Gly mutation in 4 healthy aged controls (range, 74-87 years). We thus conclude that the mutation is most likely a rare polymorphism not related to AD.

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

Several mutations causing early-onset familial Alzheimer's 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.

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.

Allelic association but only weak evidence for linkage to the apolipoprotein E locus in late-onset Swedish Alzheimer families.

An association between the epsilon 4 allele of the apolipoprotein E gene (APOE) and late-onset Alzheimer's disease (AD) was recently demonstrated. In order to confirm the association and to gauge the ability of standard genetic linkage methods to identify susceptibility genes, we investigated 15 Swedish late-onset Ad families. We found an association of familial AD to the APOE epsilon 4 allele (P = 0.01) but no indication of linkage to the APOE region using 2-point linkage analysis, and only weak evidence using the affected pedigree-member (APM) method. Our results confirm an APOE epsilon 4 association with late-onset familial AD and indicate that susceptibility genes can easily be missed when using standard lod score and APM genetic linkage analysis.

Microsatellite D21S210 (GT-12) allele frequencies in sporadic Alzheimer's disease.

Four disease-causing mutations have so far been described in the amyloid precursor protein gene on chromosome 21 in familial early-onset Alzheimer's disease. Linkage analysis with a fourteen-allele microsatellite at D21S210 named GT-12 has proven useful in the elucidation of amyloid precursor protein gene involvement in Alzheimer's disease families, as it is closely linked to the gene. Most cases of Alzheimer's disease are thought to be sporadic and not familial. However, evidence from earlier studies suggests an important genetic contribution also in sporadic cases, where gene-environment interaction may contribute to the disease. We have determined frequencies of the GT-12 alleles in 78 Swedish and 49 British sporadic Alzheimer's disease cases and 104 healthy elderly control subjects, to investigate if the disease associates with a particular genotype in GT-12. However, no differences in allele frequencies were observed between any of the groups.

Apolipoprotein epsilon 4 allele in Swedish twins and siblings with Alzheimer disease.

Allelic frequencies of apolipoprotein epsilon 4 were compared in 13 dizygotic twin pairs and 13 sibling pairs in which at least one member has Alzheimer disease (AD). Among discordant pairs of twins and siblings, frequencies were significantly greater in affected than intact partners. There was no significant difference in allelic frequencies between twins with a positive family history and twins with a negative family history. The epsilon 4 allele was more common in the sibling sample selected for family aggregation of AD than the twin sample. Several lines of evidence indicate that while the epsilon 4 allele appears to be one risk factor for AD, other etiological factors must be considered as well.

Lack of association between apolipoprotein E allele epsilon 4 and sporadic Alzheimer's disease.

Apolipoprotein E (apoE) is a protein involved in the transport of lipids and a component of Alzheimer's disease (AD) plaques. There are three common alleles of the apoE gene, designated epsilon 2, epsilon 3 and epsilon 4. An association between familial and sporadic AD and the epsilon 4 allele was recently reported. We have investigated Swedish Alzheimer patients and controls. The epsilon 4 allele frequency in familial and sporadic cases and in controls was 47, 22 and 18%, respectively. There was no significant difference between sporadic AD and controls but in familial cases the increased epsilon 4 allele frequency previously reported was confirmed.

Amyloid precursor protein mutation causes Alzheimer's disease in a Swedish family.

Since the report of a double mutation at codons 670 and 671 of the amyloid precursor protein (APP) gene identified in two Swedish families with clinically diagnosed Alzheimer's disease (AD), a carrier with dementia has died. Neuropathology confirmed the clinical diagnosis of AD. Genealogical investigations have confirmed that the two families are related to common founders. Two-point linkage analysis of the mutation versus the disease in the revised pedigree now gives a lod score of 7.62.

Genetic carrier detection in Norwegian families with acute intermittent porphyria.

Early detection of carriers of acute intermittent porphyria (AIP) is of great value as an assistance for correct diagnosis and prevention of attacks. In order to complement traditional biochemical methods, restriction fragment length polymorphism (RFLP) studies as well as analysis for a previously identified point mutation were included in a study of three Norwegian AIP families. Several asymptomatic carriers could be identified, and the study thus demonstrates the usefulness of the combination of biochemical and genetic analysis.