Association of the Serotonin Transporter and Receptor Gene Polymorphisms in Neuropsychiatric Symptoms in Alzheimer Disease

Abstract

Serotonin has been associated with various neuropsychiatric symptoms in Alzheimer disease (AD), such as agitation/aggression, depression, or psychosis.¹ These noncognitive symptoms, and in particular agitation, constitute a major source of distress for the patient's caregiver and increase the likelihood of nursing home placement.^2,3 Recent genetic studies in AD showed associations between several polymorphisms of the serotonin neurotransmitter genes and some neuropsychiatric symptoms. A 102T/C polymorphism in the 5-HT2A receptor (5-HT2AR) gene was associated with visual and auditory hallucinations⁴ or psychosis⁵ in patients with AD. The Cys23Ser polymorphism in the 5-HT2C receptor (5-HT2CR) gene was significantly associated with visual hallucinations and hyperphagia in another sample of patients with AD.⁴ A 44–base pair (bp) insertion (the long form or l form) of the 5-HTT promoter region (5-HTTPR) was reported to be associated with psychosis and aggression.^6,7 A variable number tandem repeat (VNTR) polymorphism in intron 2 of the 5-HTT gene was also associated with susceptibility to unipolar or bipolar depression,⁸ but this association was not found in patients with AD with depression.⁹ The purpose of this brief study was to examine whether variations in serotonin genes were related to neuropsychiatric symptoms in a sample of patients with AD. Based on the literature, we addressed the following questions: (1) Are 5-HT2AR and 5-HT2CR polymorphisms associated with psychosis (delusions, hallucinations)? (2) Are these polymorphisms related to agitation/aggression? and (3) Are 5-HTTPR and 5-HTTVNTR polymorphisms associated with anxiety, depression, or agitation/aggression in patients with AD?