DOPAMINE RECEPTOR GENETIC VARIATION AND MOTIVATIONAL DISTURBANCE IN ALZHEIMER's DISEASE

Abstract

Background: Behavioral syndromes are reported to occur in over 80% of patients with AD. Motivational disturbance (MD) varyingly characterized by loss of interest, fatigue, motor retardation, affective blunting, anhedonia, and social withdrawal occurs as frequently as aggression or psychosis and is as important a source of caregiver distress. Although the pathophysiology of MD in AD is not known, there are several reasons to suspect an underlying hypodopaminergic state. Among these are uncontrolled studies indicating benefit of the dopaminergic agent methylphenidate in the treatment of MD. Method: The authors examined whether MD was associated with genetic variation in the dopamine-1 (DRD1), DRD2, DRD3, and DRD4 receptors in patients diagnosed with probable AD. Severity of MD was rated using the CERAD Behavioral rating scale for dementia (items 10,11,12, and 33) at the time of initial presentation to the Alzheimer's Disease Research Center of the University of Pittsburgh. A total of 193 patients were available for analysis. Results: There was no association of MD with age, race, or gender. Severity of MD was correlated with increased measures of depression (Ham-D) and impaired cognition (MATTIS). MD was significantly more severe in subjects with a psychotic or depressed syndrome but not in subjects with aggression. After controlling for the effects of cognitive impairment, psychosis, and depression, MD was significantly more severe in individuals with long alleles of the DRD4 exon III repeat sequence. No association with DRD1, DRD2, or DRD3 were seen. Conclusion: The authors found increased severity of MD in AD subjects with DRD4 long alleles. These results must be considered preliminary pending independent replication. DRD4 may represent a site of action for dopaminergic treatment of MD in AD subjects. P43