Dopamine receptor genetic variation, psychosis, and aggression in Alzheimer disease

Objective: To examine if selected polymorphisms in the dopamine receptor genes DRD1, DRD2, DRD3, and DRD4 are associated with the presence of psychosis or aggressive behavior in patients with Alzheimer disease (AD). Design: A cohort of patients with AD were longitudinally evaluated for behavioral symptoms and classified with regard to the presence of psychotic symptoms and physical aggression. Setting: Alzheimer's Disease Research Center. Patients: Two hundred seventy-five elderly outpatients diagnosed as having probable AD. Results: Among white patients, psychosis and aggression were both significantly more frequent in DRD1 B2/B2 homozygotes (P<.02), while psychosis was significantly more frequent in DRD3 1/1 or 2/2 homozygotes (P<.05). The joint risk for psychosis due to the DRD1 and DRD3 polymorphisms exceeded the risks due to either locus alone, suggesting an interaction. Neither the DRD2 S311C polymorphism nor the presence of long alleles for the DRD4 exon III repeat sequence was associated with psychosis or aggression. Conclusions: Genetic variation in DRD1 and DRD3 genes may act to modify the course of AD, predisposing to the development of psychotic or aggressive symptoms. Confirmation in other samples of patients with AD is required.