Autosomal dominant dementia with widespread neurofibrillary tangles.

Several familial dementing conditions with atypical features have been characterized, but only rarely is the neuropathology dominated solely by neurofibrillary lesions. We present a Midwestern American pedigree spanning four generations in which 15 individuals were affected by early-onset dementia with long disease duration, with an autosomal dominant inheritance pattern, and with tau-rich neurofibrillary pathology found in the brain post mortem. The average age at presentation was 55 years with gradual onset and progression of memory loss and personality change. After 30 years' disease duration, the proband's neuropathologic examination demonstrated abundant intraneuronal neurofibrillary tangles (NFTs) involving the hippocampus, pallidum, subthalamic nucleus, substantia nigra, pons, and medulla. Only sparse neocortical tangles were present and amyloid plaques were absent. The tangles were recognized by antibodies specific for phosphorylation-independent (Tau-2, T46, 133, and Alz-50) and phosphorylation-dependent epitopes (AT8, T3P, PHF-1, 12E8, AT6, AT18, AT30) in tau proteins. Electron microscopy of NFTs in the dentate gyrus and midbrain demonstrated paired helical filaments. Although the clinical phenotype resembles Alzheimer's disease, and the neuropathologic phenotype resembles progressive supranuclear palsy, an alternative consideration is that this familial disorder may be a new or distinct disease entity.

Genetic association studies between dementia of the Alzheimer's type and three receptors for apolipoprotein E in a Caucasian population.

The epsilon 4 allele of the apolipoprotein E gene (ApoE) is associated with an increased risk for sporadic and some familial forms of Alzheimer's disease (AD) but the precise mechanism of pathogenesis is unknown. ApoE is a ligand for at least three receptors in the central nervous system, low density lipoprotein receptor (LDL-R), very low density lipoprotein receptor VLDL-R and low density lipoprotein-like receptor (LRP). We have tested for association between these receptors and dementia of the Alzheimer's type (DAT) in a clinically based sample of Caucasian cases and age-matched controls. In contrast to findings in a Japanese cohort we detected no association between DAT and a polymorphism in the VLDL-R gene. No association was detected with the LDL-R gene. We observed a possible association between the 87 allele of a polymorphism within the LRP gene and DAT which remained significant after correction for multiple testing. When the effects of known risk factors for AD such as ApoE epsilon 4 were applied, the effect of LRP no longer reached conventional levels of statistical significance. Nevertheless, LRP is a plausible candidate gene and we may be observing a minor risk factor that will require further examination in other large independent samples to assess whether it truly modifies susceptibility to DAT.

E280A PS-1 mutation causes Alzheimer's disease but age of onset is not modified by ApoE alleles.

A single base substitution of a glutamic acid to an alanine codon 280 was found in the presenilin-1 (PS-1) gene on chromosome 14 in affected individuals in each of seven Colombian early-onset Alzheimer's disease (AD) kindreds. The mutation segregated with disease in kindreds tested. In the largest kindred (C2), the maximum two-point lod score between the mutation and AD was Z = 8.14 at theta = 0. The presence of a single mutation and the common geographic origin, with all families from the state of Antioquia, suggest a founder effect in this population. This finding is supported by the observation of a rare haplotype inherited with AD in all kindreds. These kindreds form the largest collection of AD cases with the same PS-1 mutation and the same educational, environmental, and ethnic background in which to study the phenotypic effect of putative risk factors, such as the epsilon4 allele of apolipoprotein E (ApoE) or head trauma. Of the few AD cases having a history of head trauma, the age of onset was not lowered. No effect of ApoE genotype on the age of onset was detected. Previous investigations of the effect of ApoE genotype on the age of onset were confounded by small patient numbers, familial clustering of ApoE genotypes, and combining data from unrelated families with different mutations.

Genetic association between intronic polymorphism in presenilin-1 gene and late-onset Alzheimer's disease. Alzheimer's Disease Collaborative Group.

BACKGROUND: Mutations in the presenilin-1 (PS-1) gene are associated with early-onset Alzheimer's disease. 40-50% of the risk for late-onset disease has been attributed to alleles at the apolipoprotein E (ApoE) locus. We have looked for an association between PS-1 and late- onset disease. METHODS: We collected blood samples from 208 white cases of dementia of the Alzheimer type and from 185 age-matched controls (mean ages 76.9 and 76.2 years, respectively; 58% female in each series). Clinical diagnostic accuracy for Alzheimer's disease in our patients is 96%. We also studied 29 African-American patients with dementia of the Alzheimer type and 50 age-matched controls (cases vs controls, 77.2 vs 72.0 years; 72 vs 77% female). We used PCR to test for an association between Alzheimer's disease and a polymorphism within the intron 3' to exon 8 of the PS-1 gene. The ApoE genotype of most of the cases and controls was known from previous investigations. FINDINGS: Homozygosity of the 1 allele in the PS-1 gene was associated with a doubling of the risk for late-onset Alzheimer's disease compared with the [12]/[22] genotype (odds ratio 1.97, 95% Cl 1.29-3.00). The proportion of Alzheimer's disease cases in the white population that could be attributed to homozygosity at this locus, as estimated by the attributable fraction, was 0.22. This compares with 0.35 for a single copy of ApoE4 and 0.15 for two copies. The smaller African-American series showed similar distribution of PS-1 genotype between cases and controls. INTERPRETATION: In our white series of cases, PS-1 accounted for about half as much of the risk for late-onset Alzheimer's disease as did ApoE4.

Complete analysis of the presenilin 1 gene in early onset Alzheimer's disease.

The presenilin 1 gene has recently been identified as the locus on chromosome 14 which is responsible for a large proportion of early onset, autosomal dominantly inherited Alzheimer's disease (AD). We have elucidated the intron/exon structure of the gene and designed intronic primers to enable direct sequencing of the entire coding region (10 exons) of the presenilin gene in a large number of families. This strategy has enabled us to find a further two novel mutations in the gene. We discuss the distribution of mutations and the proportions of autosomal dominant AD with a mean age of onset below 60 years caused by mutations in this gene.

The role of presenilin 1 in the genetics of Alzheimer's disease.

Approximately 75% of AD patients have an onset of the disease after the age of 60 years, and 60% of AD patients have no family history of the disease. Some cases of EOAD are clearly inherited in an autosomal-dominant manner. The beta APP gene on chromosome 21, the PS-1 gene on chromosome 14, and the PS-2 gene on chromosome 1 have all been characterized as genes in which mutations lead to familial EOAD. For LOAD, the work on ApoE indicates that the epsilon 4 allele is a risk factor for developing AD. However, 35-50% of all AD patients do not have an epsilon 4 allele. Other loci contributing to LOAD remain to be mapped and characterized. As in other complex disorders, these additional loci may involve genetic interactions with the known AD loci. Identification of all susceptibility loci for AD is a major goal in resolving the pathogenesis of AD.

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 Alzheimer's 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.

No association found between Alzheimer's disease and a mitochondrial tRNA glutamine gene variant.

We have screened a large sample of patients with sporadic late-onset dementia of the Alzheimer type (DAT) and age-matched controls for a mitochondrial tRNA(Gln) variant previously reported to be associated with increased risk of developing Alzheimer's disease (AD). The frequency of an Ava II site gain was determined by restriction analysis of a PCR-amplified mitochondrial DNA product. One of 155 DAT cases and four of 105 age-matched controls carried the variant. Both the affected and control frequencies are statistically different from those previously reported. The mitochondrial lineage of those individuals harboring the variant was determined by sequencing a short region of the hypervariable mitochondrial D-loop. The affected individual and three of the four controls carrying the Ava II variant belong to the same mitochondrial lineage previously reported to be associated with AD.

Foodborne giardiasis in a corporate office setting.

Giardiasis is the most commonly reported intestinal protozoal infection worldwide, but its relatively long incubation period and often insidious onset make detection of common-source outbreaks difficult. Few well-documented foodborne outbreaks of giardiasis have been reported. In November 1990, such an outbreak among insurance company employees resulted in 18 laboratory-confirmed and 9 suspected cases of giardiasis. A case-control study of 26 ill and 162 well employees implicated raw sliced vegetables served in the employee cafeteria and prepared by a food handler infected with Giardia lamblia as the probable vehicle (odds ratio, 5.1; 95% confidence interval, 1.4-22.7). This outbreak illustrates the potential for transmission of Giardia organisms to occur in commercial establishments through a frequently served food item.