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.