Search

Genetic variations represent major risk factors for Alzheimer's disease (AD). While familial early onset AD is associated with mutations in the amyloid precursor protein and presenilin genes, only the e4 allele of the apolipoprotein E (APOE) gene has so far been established as a genetic risk factor for late onset familial and sporadic AD. It has been suggested that the C-->T (224Ala-->Val) transition within exon 2 of the cathepsin D gene (CTSD) might represent a risk factor for late onset AD. The objective of this study was to investigate whether possession of the CTSD exon 2 T allele increases the risk of developing AD, and to determine whether this modulates the amyloid pathology of the disease in conjunction with, or independent of, the APOE e4 allele. Blood samples were obtained from 412 patients with possible or probable AD and brain tissues from a further 148 patients with AD confirmed by postmortem examination. CTSD and APOE genotyping were performed by PCR on DNA extracted from blood, or from frontal cortex or cerebellum in the postmortem cases. Pathological measures of amyloid beta protein (Abeta), as plaque Abeta40 and Abeta42(3) load and degree of cerebral amyloid angiopathy were made by image analysis or semiquantitative rating, respectively. CTSD genotype frequencies in AD were not significantly different from those in control subjects, nor did these differ between cases of early or late onset AD or between younger and older controls. There was no gene interaction between the CTSD T and APOE e4 alleles. The amount of plaque Abeta40 was greater in patients carrying the CTSD T allele than in non-carriers, and in patients bearing APOE e4 allele compared with non-carriers. Possession of both these alleles acted synergistically to increase levels of plaque Abeta40, especially in those individuals who were homozygous for the APOE e4 allele. Possession of the CTSD T allele had no effect on plaque Abeta42(3) load or degree of CAA. Possession of the CTSD T allele does not increase the risk of developing AD per se, but has a modulating effect on the pathogenesis of the disorder by increasing, in concert with the APOE e4 allele, the amount of Abeta deposited as senile plaques in the brain in the form of Abeta40.

Objective: To determine whether polymorphic variations in the apolipoprotein E gene (APOE) are associated with increased risk of frontotemporal lobar degeneration (FTLD) when mutation in tau gene is absent., Methods: The APOE gene was genotyped by polymerase chain reaction from DNA routinely extracted from blood or brain tissues. The APOE epsilon4 allele frequency in 198 patients with FTLD not associated with mutations in tau gene was compared with that of a control group of 756 normal individuals drawn from the same geographical region. Analyses were done according to clinical subtype or sex., Results: The APOE epsilon4 allele frequency (19.4%) was increased (p = 0.01) in FTLD v the whole control group (14.1%), while the APOE epsilon2 allele frequency in FTLD (6.5%) was slightly lower than in controls (8.0%) (NS). The APOE epsilon4 allele frequency in men with FTLD (22.3%) was greater (p = 0.002) than in male controls (12.3%); the frequency in women (16.3%) was similar to that in female controls (14.8%) (NS). The APOE epsilon2 allele frequency in men with FTLD was 4.9% while in male controls it was 9.5% (p = 0.06), but there was no difference in women (7.5% v 7.9%, NS). Neither the APOE epsilon2 nor APOE epsilon4 allele frequency varied significantly between any of the clinical subtypes., Conclusions: In FTLD not associated with mutations in tau gene, possession of APOE epsilon4 allele in men roughly doubles the chances of developing disease, whereas this has no impact upon disease risk in women.

Background: Frontotemporal dementia (FTD) and Alzheimer's disease are clinically distinct disorders, yet neuropsychological studies have had variable success in distinguishing them. A possible reason is that studies typically rely on overall accuracy scores, which may obscure differences in reasons for failure., Objectives: To explore the hypothesis that analysis of qualitative performance characteristics and error types, in addition to overall numerical scores, would enhance the neuropsychological distinction between FTD and Alzheimer's disease., Methods: 38 patients with FTD and 73 with Alzheimer's disease underwent assessment of language, visuospatial abilities, memory, and executive function, using a neuropsychological screening instrument and standard neuropsychological tests. In each of these cognitive domains, performance characteristics and error types were documented, in addition to numerical scores on tests., Results: Whereas comparison of neuropsychological test scores revealed some group differences, these did not occur consistently across tests within cognitive domains. However, analysis of performance characteristics and error types revealed qualitative differences between the two groups. In particular, FTD patients displayed features associated with frontal lobe dysfunction, such as concrete thought, perseveration, confabulation, and poor organisation, which disrupted performance across the range of neuropsychological tests., Conclusions: Numerical scores on neuropsychological tests alone are of limited value in differentiating FTD and Alzheimer's disease, but performance characteristics and error types enhance the distinction between the two disorders. FTD is associated with a profound behavioural syndrome that affects performance on cognitive assessment, obscuring group differences. Qualitative information should be included in neuropsychological research and clinical assessments.