Cumulative effect of COMT and 5-HTTLPR polymorphisms and their interaction with disease severity and comorbidities on the risk of psychosis in Alzheimer disease

Objective: The objective of this study was to investigate the cumulative effect of the genes likely involved in Alzheimer disease (AD)-related psychosis and their interaction with disease stage and environmental factors. Methods: Two hundred thirty-four patients with AD underwent clinical and neuropsychologic examination, behavioral and psychiatric disturbances evaluation, and were subsequently divided into two subgroups according to the presence (AD-P) or the absence (AD-nP) of psychotic symptoms. Cathecol-O- methyltransferase (COMT), serotonin gene-linked promoter region (5-HTTLPR), and Apolipoprotein E ( ApoE) genotypes were performed. Results: COMT*H (H/H or H/liter; odds ratio [OR]: 2.4; 95% confidence interval [CI]: 1.13 - 5.11) and 5-HTTLPR*S (S/S or S/liter, OR: 2.14; 95% CI: 1.13 - 4.07) were associated with AD-P. A gene dose effect was observed; in fact, carriers of both polymorphisms showed a fivefold risk for psychosis compared with patients bearing no polymorphisms. An interaction between these two genetic variations with disease stage and ischemic cardiomyopathy was found, the latter influencing AD-P risk only if "at-risk" genetic polymorphisms were present. The combined trend effect of COMT*H plus 5-HTTLPR*S and advance disease stage on AD-P risk was approximately 200% greater than that predicted by assuming additive effects, whereas the one obtained by COMT*H plus 5-HTTLPR*S and ischemic cardiomyopathy was 50% greater. ApoE genotype did not influence AD-P risk. Conclusions: These findings claim for a synergic effect of COMT*H and 5-HTTLPR*S polymorphisms on the risk of psychosis in AD and for their interaction with disease stage and ischemic cardiomyopathy. This study suggests that considering both the genetic background and the environmental correlates might provide new insight for understanding psychosis mechanisms related to AD.