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

Abstract

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.

Neurobiology of Delusions in Alzheimer’s Disease

“…There is mixed evidence for the serotonin 2A (5HT-2A) receptor single nucleotide polymorphism 102 T/C. Association studies have identified the T allele as the risk allele for AD+D [42]. The T allele also has been associated with a higher prevalence of delusions and treatment resistance to second-generation antipsychotics [43].…”

Association Study and Meta-Analysis of Polymorphisms, Methylation Profiles, and Peripheral mRNA Expression of the Serotonin Transporter Gene in Patients with Alzheimer's Disease

“…Quaranta et al [19] demonstrated that the risk of psychosis is increased in individuals with the 5-HTT-LPR L allele, and Sukonick et al [15] and Sweet et al [16] reported that the L allele is significantly associated with aggression in AD. Conversely, other studies did not find significant associations between 5-HTT-LPR polymorphisms and neuropsychiatric symptoms in AD [21,22,23,24,25,26,27,28] (online suppl. table 1).…”

“…Several studies showed that 5-HTT-LPR genotypes are associated with neuropsychiatric symptoms in AD [15,16,17,18,19,20], whereas other studies did not replicate associations of 5-HTT-LPR polymorphisms with neuropsychiatric symptoms [21,22,23,24,25,26,27,28]. Although previous studies consistently demonstrated that SLC6A4 mRNA levels in leukocytes are significantly higher in patients with MDD compared to healthy controls [29,30], the mRNA expression level in leukocytes from AD patients has not been examined yet.…”

Evaluation of the 5-<i>HTTLPR</i> and 5-<i>HTTVNTR</i> Polymorphisms in the Serotonin Transporter Gene in Women with Postpartum Depression

“…Our results showed no an association between the 5-HTTVNTR polymorphisms and PPD in white women. Additionally, Alaerts et al [40] did not find an association between the 5-HTTVNTR polymorphisms and bipolar disorder, and Assal et al [41] found no relationship between the 5-HTTVNTR polymorphisms and agitation/ aggression, depression, or anxiety. However, in a previous study, the increased frequency of the 5-HTTVNTR*12 allele was observed in subjects with bipolar disorder but not in subjects diagnosed with major depression [19].…”