The COMT rs4680 polymorphism is associated with rate of cognitive decline in older adults with type 2 diabetes: Biomarkers (non‐neuroimaging) / Longitudinal change over time. (7th December 2020) - Manzali, Sigalit
Abstract: Background: The single nucleotide polymorphism (SNP) rs4680 (Val158Met) in the Catechol‐O‐Methyltransferase ( COMT ) gene affects dopamine level and has been consistently associated with cognitive functioning; the A allele, encoding Methionine, is linked to better cognition (and higher cortical dopamine levels) and lower risk of dementia than the G allele, encoding Valine. Type 2 diabetes (T2D) older adults have greater cognitive decline and higher dementia risk than non‐T2D persons but the role of COMT in this association has not been examined. Method: Using data from the Israel Diabetes and Cognitive Decline (IDCD; N=964) study, we examined associations of COMT rs4680 with cognitive decline over a 48‐month period. Approximately every 18 months, participants completed a comprehensive neuropsychological battery of 15 tests transformed into z‐scores and summarized into four cognitive domains: episodic memory, attention/working memory, executive functions and language/semantic categorization. The average of the z‐scores of the four domains defined global cognition. Mixed regression models examined the associations of rs4680 with cognitive decline adjusting for age, sex, education and Jewish origin (Ashkenazi or Sephardi). Result: Participants were on average 71.6 (SD 4.6) years old; 42% women; 13.2 (3.5) years of education. Compared to carriers of rs4680 GG genotype (N=249, 25.8%), carriers of the A allele (AA genotype [N = 216, 22.4% ]+ AG genotype [N = 499, 51.8% ]) had faster rates of decline in global cognition (estimate= ‐0.004; p=0.03), executive functions (estimate= ‐ 0.009 ; p= 0.01) and episodic memory (estimate= ‐0.007 ; p=0.04), but not in attention/working memory nor language. For language, there was a main effect with significantly and consistent better function among the GG genotype carriers over time (estimate= ‐0.50; p=0.001). Additionally adjusting for numerous cardiovascular and T2D‐related risk factors and T2D medications did not alter the results. Conclusion: Our finding suggests that among T2D elderly, COMT SNP rs4680 affects cognitive decline over time. In contrast to the anticipated direction, A allele carriers had poorer cognitive outcomes. There is evidence indicating that the GG genotype protects against onset of T2D and hyperglycemia; our results suggest a more global protective effect of this genotype against T2D and its complications, including cognitive impairment.