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Association of the Serotonin Transporter and Receptor Gene Polymorphisms in Neuropsychiatric Symptoms in Alzheimer Disease
Frédéric Assal, MD;
Maricela Alarcón, PhD;
Esther C. Solomon, BS;
Donna Masterman, MD;
Daniel H. Geschwind, MD, PhD;
Jeffrey L. Cummings, MD
Arch Neurol. 2004;61:1249-1253.
Background Serotonin has been linked to neuropsychiatric symptoms in Alzheimer disease, mainly agitation/aggression, depression, and psychosis. Neuropsychiatric symptoms have been associated with polymorphisms of the promoter region (5-HTTPR ) and intron 2 of the serotonin transporter gene (5-HTTVNTR) or the 5-HT2A and 5-HT2C receptor genes in some but not all studies.
Objective To examine the association of the serotonin promoter, transporter, and receptor genes with neuropyschiatric symptoms in patients with Alzheimer disease.
Methods The sample included 96 patients with Alzheimer disease from the outpatient clinic of the University of California Los Angeles Alzheimer’s Disease Research Center, Los Angeles. The Neuropsychiatric Inventory was used to measure neuropsychiatric symptoms, and blood samples were available for genetic analysis. Based on the literature, we hypothesized that the 5-HT2A and 5-HT2C receptor polymorphisms would be associated with agitation/aggression and psychosis and the 5-HTTPR or 5-HTTVNTR polymorphisms, with agitation/aggression or depression and anxiety. One-way analyses of variance were performed with age, ethnicity, sex, or education as covariates.
Results The 102T genotype of the 5-HT2A receptor was significantly associated with delusions (P = .045) and agitation/aggression (P = .002). We did not replicate previous associations of the 5-HT2C receptor polymorphism with psychosis or of the 5-HTTPR polymorphism with agitation/aggression, psychosis, or depression. We did not find any associations with the 5-HTTVNTR polymorphism and agitation/aggression, depression, or anxiety.
Conclusions The 5-HT2A receptor polymorphism may contribute to the expression of psychosis and agitation/aggression in patients with Alzheimer disease. Absence of other positive associations may be due to the relatively small sample size and/or potentially small effect size of the polymorphisms and requires further study.
Author Affiliations: Departments of Neurology (Drs Assal, Alarcón, Masterman, Geschwind, and Cummings) and Psychiatry and Biobehavioral Sciences (Dr Cummings), the Center for Neurobehavioral Genetics Program (Drs Alarcón, Solomon, and Geschwind) and the Kagan Treatment Program (Drs Masterman and Cummings), The David Geffen School of Medicine at UCLA, Los Angeles, Calif; and the Department of Neurology, Hôpitaux Universitaires de Genève, Geneva, Switzerland (Dr Assal).
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