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

Sirtuins (SIRT1-7) are NAD⁺-dependent protein deacetylases/ADP ribosyltransferases with important roles in chromatin silencing, cell cycle regulation, cellular differentiation, cellular stress response, metabolism and aging. Sirtuins are components of the epigenetic machinery, which is disturbed in Alzheimer's disease (AD), contributing to AD pathogenesis. There is an association between the <i>SIRT2-C/T</i> genotype (rs10410544) (50.92%) and AD susceptibility in the <i>APOEε4</i>-negative population (<i>SIRT2-C/C</i>, 34.72%; <i>SIRT2-T/T</i> 14.36%). The integration of <i>SIRT2</i> and <i>APOE</i> variants in bigenic clusters yields 18 haplotypes. The 5 most frequent bigenic genotypes in AD are <i>33CT</i> (27.81%), <i>33CC</i> (21.36%), <i>34CT</i> (15.29%), <i>34CC</i> (9.76%) and <i>33TT</i> (7.18%). There is an accumulation of <i>APOE-3/4</i> and <i>APOE-4/4</i> carriers in <i>SIRT2-T/T</i> > <i>SIRT2-C/T</i> > <i>SIRT2-C/C</i> carriers, and also of <i>SIRT2-T/T</i> and <i>SIRT2-C/T</i> carriers in patients who harbor the <i>APOE-4/4</i> genotype. <i>SIRT2</i> variants influence biochemical, hematological, metabolic and cardiovascular phenotypes, and modestly affect the pharmacoepigenetic outcome in AD. <i>SIRT2-C/T</i> carriers are the best responders, <i>SIRT2-T/T</i> carriers show an intermediate pattern, and <i>SIRT2-C/C</i> carriers are the worst responders to a multifactorial treatment. In <i>APOE-SIRT2</i> bigenic clusters, <i>33CC</i> carriers respond better than <i>33TT</i> and <i>34CT</i> carriers, whereas <i>24CC</i> and <i>44CC</i> 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 responders that intermediate metabolizers (IM). In association with <i>CYP2D6</i> genophenotypes, <i>SIRT2-C/T</i>-EMs are the best responders. Some Sirtuin modulators might be potential candidates for AD treatment.