Sirtuins in Alzheimer’s Disease: SIRT2-Related GenoPhenotypes and Implications for PharmacoEpiGenetics

Sirtuins(SIRT1-7) are NAD+-dependent protein deacetylases/ ADP ribosyltransferaseswith important roles in chromatin silencing, cell cycle regulation, cellular differentiation, cellular stress response, metabolism and aging. Sirtuinsare components of the epigenetic machinery, which is disturbed in Alzheimer’s disease (AD), contributing to AD pathogenesis. There is an association between the SIRT2-C/T genotype (rs10410544) (50.92%) and AD susceptibility in the APOEe4-negative population ( SIRT2-C/C, 34.72%; SIRT2-T/T 14.36%). The integration of SIRT2and APOE variants in bigenic clusters yields 18 haplotypes. The 5 most frequent bigenic genotypes in AD are 33CT (27.81%), 33CC (21.36%), 34CT (15.29%), 34CC (9.76%) and 33TT (7.18%). There is an accumulation of APOE-3/4 and APOE-4/4 carriers in SIRT2-T/T > SIRT2-C/T > SIRT2-C/C carriers, and also of SIRT2-T/T and SIRT2-C/ T carriersin patients who harbor the APOE-4/4 genotype. SIRT2variants influence biochemical, hematological, metabolic and cardiovascular phenotypes, and modestly affect the pharmacoepigenetic outcome in AD. SIRT2-C/ T carriersare the best responders, SIRT2-T/ T carriersshow an intermediate pattern, and SIRT2-C/C carriers are the worst respondersto a multifactorial treatment. In APOE- SIRT2bigenic clusters, 33CC carriers respondbetter than 33TT and 34CT carriers, whereas 24CC and 44CC carriers behave as the worst responders. CYP2D6 extensive metabolizers(EM) are the best responders, poor metabolizers(PM) are the worst responders, and ultra-rapid metabolizers (UM) tend to be better respondersthat intermediate metabolizers(IM). In association with CYP2D6genophenotypes, SIRT2-C/T-EMs are the best responders. Some Sirtuinmodulators might be potential candidates for AD treatment.