Genetic associations between cathepsin D exon 2 C→T polymorphism and Alzheimer’s disease, and pathological correlations with genotype

• Published in: Journal of neurology, neurosurgery and psychiatry neurosurgery and psychiatry, 2006-04, Vol.77 (4), p.515-517
• Main Authors: Davidson, Y, Gibbons, L, Pritchard, A, Hardicre, J, Wren, J, Tian, J, Shi, J, Stopford, C, Julien, C, Thompson, J, Payton, A, Thaker, U, Hayes, A J, Iwatsubo, T, Pickering-Brown, S M, Pendleton, N, Horan, M A, Burns, A, Purandare, N, Lendon, C L, Neary, D, Snowden, J S, Mann, D M A
• Format: Article
• Language: English
• Subjects: Aged; Alleles; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer's disease; amyloid beta; Amyloid beta-Peptides - genetics; Amyloid beta-Peptides - metabolism; Amyloid beta-Protein Precursor - genetics; Amyloid beta-Protein Precursor - metabolism; amyloid β precursor protein; amyloid β protein; apolipoprotein E gene; Apolipoprotein E4; Apolipoproteins E - genetics; Apolipoproteins E - metabolism; APP; Biological and medical sciences; CAA; cathepsin D; Cathepsin D - genetics; cathepsin D gene; cerebral amyloid angiopathy; cerebral function unit; CFU; CTSD; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; early onset AD; EOAD; Exons; Female; Gene Expression; Gene Frequency; Genotype; Genotype & phenotype; genotype/phenotype correlation; Haplotypes; Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy; Humans; late onset AD; LOAD; Male; Medical sciences; Middle Aged; Nervous system (semeiology, syndromes); Neurology; OAP; old age psychiatry; Pathology; Plaque, Amyloid - metabolism; Plaque, Amyloid - pathology; Point Mutation; Polymerase Chain Reaction; Polymorphism, Genetic; Prospective Studies; Proteins; Risk Factors; Sensitivity and Specificity; Short Report; single nucleotide polymorphism; SNP
• ISSN: 0022-3050; 1468-330X
• DOI: 10.1136/jnnp.2005.063917

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 β protein (Aβ), as plaque Aβ40 and Aβ42(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 Aβ40 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 Aβ40, especially in those individuals who were homozygous for the APOE e4 allele. Possession of the CTSD T allele had no effect on plaque Aβ42(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 Aβ deposited as senile plaques in the brain in the form of Aβ40.