Brain Advance Access originally published online on February 26, 2008
Brain 2008 131(4):1069-1077; doi:10.1093/brain/awn023
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Genetic variation in the interleukin-1β-converting enzyme associates with cognitive function. The PROSPER study
1Department of Gerontology and Geriatrics, 2Department of Molecular Epidemiology, Leiden University Medical Centre, Leiden, The Netherlands, 3Department of Vascular Biochemistry, University of Glasgow, Glasgow, Scotland, 4Department of Pharmacology and Therapeutics, Cork University Hospital, Cork, Ireland, 5Department of Neurology, Leiden University Medical Centre, Leiden, The Netherlands, 6Robertson Centre for Biostatistics, University of Glasgow, 7Clinical Trials Unit, North Glasgow Division, Greater Glasgow Health Board, 8Division of Cardiovascular and Medical Sciences, 9Department of Geriatric Medicine, University of Glasgow, Glasgow, Scotland and 10Department of Cardiology, Leiden University Medical Centre, Leiden, The Netherlands
Correspondence to: Stella Trompet MSc, Department of Gerontology and Geriatrics, C-2-R, Leiden University Medical Center, PO Box 9600, 2300 RC, Leiden, The Netherlands E-mail: s.trompet{at}lumc.nl
Inflammation is thought to play an important role in the development of cognitive decline and dementia in old age. The interleukin-1 signalling pathway may play a prominent role in this process. The gene encoding for interleukin-1β-converting enzyme (ICE) is likely to influence IL-1β levels. Inhibition of ICE decreases the age-related increase in IL-1β levels and may therefore improve memory function. We assessed whether genetic variation in the ICE gene associates with cognitive function in an elderly population. All 5804 participants of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) were genotyped for the 10643GC, 9323GA, 8996AG and 5352GA polymorphisms in the ICE gene. Cross-sectional associations between the polymorphisms and cognitive function were assessed with linear regression. Longitudinal associations between polymorphisms, haplotypes and cognitive function were assessed with linear mixed models. All associations were adjusted for sex, age, education, country, treatment with pravastatin and version of test where appropriate. Subjects carrying the variants 10643C and 5352A allele had significantly lower IL-1β production levels (P < 0.01). Furthermore, we demonstrated that homozygous carriers of the 10643C and the 5352A allele performed better on all executive function tests at baseline and during follow-up compared to homozygous carriers of the wild-type allele (all P < 0.02). The haplotype with two variants present (10643C and 5352A) was associated with better executive function (all P < 0.02) compared to the reference haplotype without variants. For memory function the same trend was observed, although not significant. Genetic variation in the ICE gene is associated with better performance on cognitive function and lower IL-1β production levels. This suggests that low levels of IL-1β are protective for memory and learning deficits. Inhibition of ICE may therefore be an important therapeutic target for maintaining cognitive function in old age.
Key Words: interleukin-1beta converting enzyme; cognitive function; elderly; inflammation
Abbreviations: ICE, interleukin-1β-converting enzyme; MMSE, Mini-Mental State Examination; LDT, Letter–Digit Coding Test; PLT, Picture Learning test; LD, linkage disequilibrium
Received May 10, 2007. Revised January 14, 2008. Accepted January 27, 2008.