Objectives: Recent large-scale meta-analysis of genome-wide association studies (GWAS) from multiple cohorts, demonstrated the association of the single nucleotide polymorphism (SNP) rs17518584, with processing speed (measured by the Digit Symbol Substitution Test (DSST) or the Letter Digit Substitution Test (LDST)), at GWAS significance level. This SNP is located within the cell adhesion molecule 2 (CADM2) gene. We aimed to validate this finding in our sample of 944 cognitively normal Jewish elderly individuals with type 2 diabetes (T2D), a population which is at risk for cognitive decline and dementia.Methods: Using linear regression, we studied the association of rs17518584 with DSST performance, adjusting for demographic, T2D-related characteristics and cardiovascular factors. In secondary analyses, associations with performance in four cognitive domains (episodic memory, language/semantic categorisation, attention/working memory and executive function) and overall cognition were examined.Results: Controlling for sex, age at cognitive assessment, years of education and ancestry, we found a significant association of rs17518584 with DSST performance (P = 0.013), consistent with the originally reported effect direction. Results remained significant even when the additional covariates (T2D-related and cardiovascular factors) were included in the analysis (P = 0.034). Moreover, this SNP was significantly associated with performance in the cognitive domains of language/semantic categorisation and executive function, as well as overall cognition.Conclusions: Taken together, irrespective of T2D-related characteristics and cardiovascular factors, our findings provide independent support for the association of CADM2 SNP rs17518584 with processing speed (and demonstrate association with additional cognitive phenotypes), among cognitively normal elderly individuals with T2D.
Keywords: CADM2; Digit Symbol Substitution Test; processing speed; cognition; type 2 diabetes.