Association of serotonin and dopamine gene pathways with behavioral subphenotypes in dementia

Genetic association studies investigating the association between genes of serotonergic and dopaminergic systems and behavioral and psychological symptoms in dementia (BPSD) are contradictory. We have utilized 1008 probable Alzheimer's disease (AD) patients from the UK and used the 12-item Neuropsychiatric Inventory. We applied a multiple indicators-multiple causes (MIMIC) approach to investigate the effect of 11 polymorphisms on the 4 behavioral subphenotypes “psychosis”, “moods”, “agitation”, and “behavioural dyscontrol”. Significant associations were observed between the serotonin transporter gene (SERT) polymorphism STin2 and “psychosis”; the dopamine transporter gene (DAT) 3′ variable number tandem repeats (VNTR) and “agitation”; and the dopamine receptor 4 (DRD4) VNTR and “moods” factors. Direct associations were identified between the dopamine receptor 3 (DRD3) BalI polymorphism and depression; the dopamine receptor 1 (DRD1) and dopamine transporter gene 3′ VNTR polymorphisms and aberrant motor behavior; the DRD4 VNTR and sleep disturbances; and the SERT gene VNTR 5HTTLPR and apathy items. Significant interactions observed between polymorphisms suggested epistatic effects and interactions between polymorphisms and medications highlighted potential treatment response. This multiple indicators multiple causes (MIMIC) model efficiently captured the complexity of the interrelations between genetic variation, behavioral symptoms, and clinical variables.