Genetic variation in caspase-1 as predictor of accelerated progression from mild cognitive impairment to Alzheimer’s disease

Abstract

There has been a lot of interest in the detection of predictors of conversion from mild cognitive impairment (MCI) to Alzheimer’s disease (AD) using neuroimaging methods, CSF biomarkers and cognitive tests [2]. Despite the many genetic studies of AD, there has been little research directed toward determining the influence of genetic variation on progression from MCI to AD [1, 4]. Variation in the caspase-1 (CASP1) gene has been evaluated in both cognitive function in elderly individuals with normal cognition [5] and in predisposition to AD [6], but no previous study has specifically explored the association between genetic variation in CASP1 and progression from MCI to AD. As a primary goal in this study, we investigate APOE e4 allele and CASP1 (rs580253) polymorphisms in order to predict MCI individuals likely to convert to AD in a relatively short follow-up period. Between 2007 and 2009, we examined 84 consecutive patients who attended the Department of Neurology of University Hospital ‘‘Marques de Valdecilla’’ (Santander, Spain) and that fulfilled the Petersen criteria for amnestic MCI [3]. Patients with MCI were longitudinally assessed at 6-month intervals (mean duration of follow-up 26.5 months; SD 8.1; range 7–37 months). According to their Clinical Dementia Rating (CDR) scores during the follow-up period, 50 MCI patients whose global CDR score changed from CDR = 0.5 to CDR = 1 were diagnosed as MCI-converters to AD (70% women; mean age 76.3 years; SD 5.7; range 60–85 years), and two additional MCI patients converted to dementia with Lewy bodies and vascular dementia, respectively; 32 MCI whose global CDR score remained stable were classified as MCI-nonconverters to AD (63% women; mean age 74.8 years; SD 7.0; range 60–86 years). Except one MCI-converter to AD patient with a minimal follow-up period of 7 months, the rest of our patients were followed up for at least 1 year to avoid the risk to label as MCI-non-converter to AD subjects who will develop dementia over time. We selected the CASP1 gene (rs580253) polymorphism that had been previously related to cognitive function [5]. Blood samples were taken after written informed consent had been obtained from the subjects or their representatives. The study was approved by the ethical committee of the University Hospital ‘‘Marques de Valdecilla’’. Kaplan–Meier curves and Cox regression model (including APOE status, age and gender) were used to assess whether timeto-conversion was associated with CASP1 (rs580253) polymorphism. Kaplan–Meier survival analysis (Fig. 1), shows the effect of APOE e4 allele and CASP1 (rs580253) T allele on the time-to-conversion to AD in patients with MCI. Survival function estimates did not differ significantly between APOE e4 allele carriers and non-carriers. Conversely, the mean time of conversion from MCI to AD was 25.2 months (SD 9.1) in people with CASP1 (rs580253) T allele (CT and TT genotypes) versus 31.7 months (SD 7.4) in CASP1 (rs580253) T allele non-carriers (CC genotype); thus, CASP1 (rs580253) T allele accelerated the progression from MCI to AD by an average of 6.5 months (P = 0.009). The risk factors of conversion from MCI to AD were analyzed simultaneously with a multivariate Cox A. Pozueta J. L. Vazquez-Higuera P. Sanchez-Juan E. Rodriguez-Rodriguez C. Sanchez-Quintana I. Mateo J. Berciano O. Combarros (&) Neurology Service and CIBERNED, University Hospital ‘‘Marques de Valdecilla’’ (University of Cantabria), 39008 Santander, Spain e-mail: combarro@unican.es