Influence and interactions of cathepsin D, HLA-DRB1 and APOE
on cognitive abilities in an older non-demented population
by
Payton A, van den Boogerd E, Davidson Y, Gibbons L,
Ollier W, Rabbitt P, Worthington J, Horan M, Pendleton N.
Centre for Integrated Genomic Medical Research,
Stopford building,
University of Manchester, Oxford Road, Manchester, UK.
tony@fs1.ser.man.ac.uk
Genes Brain Behav. 2006;5 Suppl 1:23-31.

ABSTRACT

Cathepsin D (CTSD), human leukocyte antigen DRB1 (HLA-DRB1) and apolipoprotein E (APOE) have all been associated with cognitive ability in both demented and non-demented individuals. CTSD is a pleiotrophic protein whose functions include the processing of proteins prior to presentation by HLA. Several studies have also reported that a functional exon 2 polymorphism in the CTSD gene interacts with APOEepsilon4 resulting in an increased risk of developing Alzheimer's disease (AD). We have previously reported that the CTSD exon 2 polymorphism regulates fluid intelligence. In this study, we extend this finding to other cognitive domains and investigate interactions with APOE and HLA-DRB1. Using a cohort of 766 non-demented volunteers, we found that the CTSD exon 2 T allele was associated with a decrease in several cognitive domains that comprise processing speed [random letters (RLs) test, P = 0.012; alphabet-coding task (ACT), P = 0.001], spatial recall (SR) (P = 0.016) and an additional test of fluid intelligence (P = 0.010). We also observed that the HLA-DR1 was associated with enhanced cumulative recall ability (P = 0.006), and conversely HLA-DR5 was associated with diminished delayed verbal recall and SR abilities (P = 0.014 and P = 0.003, respectively). When analysed independently, APOEepsilon4 did not influence any cognitive domains. In contrast, CTSD T/APOEepsilon4-positive volunteers scored lower on tests of fluid intelligence (P = 0.015), processing speed (ACT, P = 0.001; RL, P = 0.013) and immediate recall (P = 0.029). Scores were lower for all these tests than when CTSD and APOE were analysed independently. This supports previous findings in AD that have also reported an epistatic interaction. In addition, we found that CTSD T/HLA-DR2-positive volunteers had reduced processing speed (ACT, P = 0.040; RL, P = 0.014) and had significantly lower cumulative and SR abilities (P = 0.003 and P = 0.001, respectively). Biological interaction between these two proteins has previously been shown where HLA-DR2 binds more readily to the myelin basic protein (MBP) compared with other DR antigens, preventing MBP cleavage by CTSD.

NR2B gene
ASPM gene
Microcephalin
SNAP-25 gene
Liberal Eugenics
Cognitive genetics
Human self-domestication
Brain size/human evolution
Selecting potential children
Alzheimer's disease: resources
Transhumanism/Brave New World?
Francis Galton and contemporary eugenics
Gene therapy and performance enhancement
Preimplantation genetics and stem cell therapy
Institute for Germinal Choice ('Genius Sperm Bank')

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