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SHORT REPORT |
T polymorphism and Alzheimer’s disease, and pathological correlations with genotype
1 Clinical Neuroscience Research Group, University of Manchester, Greater Manchester Neurosciences Centre, Hope Hospital, Stott Lane, Salford, UK
2 Department of Molecular Psychiatry, University of Birmingham, Vincent Drive, Birmingham, UK
3 Department of Old Age Psychiatry, University of Manchester, Wythenshawe Hospital, Southmoor Road, Manchester, UK
4 Centre for Integrated Genomic Medical Research, University of Manchester, Oxford Road, Manchester, UK
5 Department of Neuropathology and Neuroscience, University of Tokyo, Bunkyo-ku, Tokyo, Japan
6 Division of Neuroscience, Mayo Clinic, Jacksonville, FL, USA
Correspondence to:
Correspondence to:
Professor D M A Mann
Clinical Neuroscience Research Group, University of Manchester, Greater Manchester Neurosciences Centre, Hope Hospital, Stott Lane, Salford M6 8HD, Manchester, UK; david.mann{at}manchester.ac.uk
ABSTRACT
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 (224AlaVal) 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 ß protein (Aß), as plaque Aß40 and Aß42(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 Aß40 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 Aß40, especially in those individuals who were homozygous for the APOE e4 allele. Possession of the CTSD T allele had no effect on plaque Aß42(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 Aß deposited as senile plaques in the brain in the form of Aß40.
Abbreviations: Aß, amyloid beta; AD, Alzheimer’s disease; APP, amyloid ß precursor protein; CAA, cerebral amyloid angiopathy; CFU, cerebral function unit; CTSD, cathepsin D; EOAD, early onset AD; LOAD, late onset AD; OAP, old age psychiatry; SNP, single nucleotide polymorphism
Keywords: Alzheimer’s disease; cathepsin D gene; apolipoprotein E gene; amyloid ß protein; genotype/phenotype correlation
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