Serotonin Receptor Gene Polymorphisms Are Associated with Cerebrospinal Fluid, Genetic, and Neuropsychological Biomarkers of Alzheimer’s Disease (original) (raw)
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Depression in Alzheimer's disease: The effect of serotonin receptor gene variation
American Journal of Medical Genetics, 2003
This study investigated possible associations between selected polymorphisms in the serotonin receptor genes, 5-HT2A and 5-HT2C, with the presence of co-morbid depressive illness at baseline in a community based cohort of 158 patients with late onset patients with Alzheimer's disease (AD). An association was found between the presence of major depressive illness at baseline and both the 5-HT2A and 5-HT2C polymorphisms. Specifically, homozygous carriers of the 5-HT2A C102 allele were five times more likely to have major depressive illness than heterozygotes. In addition, homozygous or hemizygous carriers of the 5-HT2C Ser allele were 12 times more likely to have major depressive illness than homozygous or hemizygous carriers of the 5-HT2C Cys allele.
International Journal of Alzheimer's Disease, 2011
Alzheimer’s disease (AD) is a neurodegenerative disorder whose clinical onset is mainly characterized by memory loss. During AD progression, behavioral and psychological symptoms of dementia (BPSD) frequently occur. In this paper we evaluated the association between AD and the short/long (S/L) functional polymorphism of the promoter region of the 5-hydroxytryptamine (5-HT) transporter gene (SLC6A4). The S-allele shows a 2-fold reduced transcriptional rate, causing an imbalance in 5-HT intracellular availability that might in turn trigger behavioral and cognitive alterations. We also genotyped theSLC6A4promoter functional variantrs25531(A→G). By comparing the genotypic and allelic frequencies in an Italian population of 235 AD and 207 controls, we found an association between5-HTTLPRand AD (odds ratio for the L-allele versus the S-allele: 0.74, associatedPvalue = .03), while no difference was found for thers25531. A meta-analysis of studies in Italy assessing5-HTTLPRand AD risk gave ...
2009
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by memory loss and often accompanied during its progression by behavioral and psychological symptoms of dementia (BPSD). We decided to evaluate the association between AD-related behavioral disturbances and the short/long (S/L) polymorphism of the promoter region of the 5-hydroxytryptamine (5-HT) transporter gene (SLC6A4). This functional polymorphism modulates SLC6A4 transcription rate, with the S-allele having a 2-fold reduced efficiency, leading to a diminished availability of 5-HT that might in turn trigger behavioral and cognitive alterations. The SLC6A4 promoter functional single nucleotide polymorphism rs25531 (A→G) was genotyped as well. We collected 235 sporadic AD subjects that were classified as AD with (n = 122) or without (n = 113) behavioral alterations, assessed with the Spontaneous Behavior Interview scale, section Behavioral Problems (SBI-BP). Comparing the genotypic and allelic frequencies of AD without and with BPSD, we did not find a difference for the 5-HTTLPR or the rs25531, even after stratification according to single SBI-BP item. We conclude that 5-HTTLPR and rs25531 are not major genetic modulators of BPSD development in AD.
2005
Schizophrenia is a severe mental illness affecting around 1% of adults with a high degree of morbidity and mortality. Affected individuals are at increased risk for unemployment, handicap, obesity, diabetes mellitus, hearth attack and suicide. Antipsychotic drugs are the best treatment for this disease, but about 20% of patients display drug resistance, or refractoriness, and may receive a special neuroleptic named Clozapine. Despite its superiority from other neuroleptics, only 30e60% of drug-resistant patients are responsive to clozapine. Clozapine's action results from interactions between dopaminergic and serotonergic neurotransmitter systems and since clozapine appears to exert its effect strongly through the serotonergic systems, alterations in serotonin synaptic levels may influence antipsychotic response. The serotonin transporter (5-HTT) is responsible for pre-synaptic re-uptake of serotonin, making this transporter a logical candidate gene for prediction of clozapine response and to increase understanding about mechanisms of refractoriness. Therefore, we investigated the influence of two polymorphisms in the 5-HTT gene (HTTLPR/rs25531 and VNTR Stin2) in clozapine response in a sample of 116 schizophrenic individuals of European descent from South-Brazil. Significant differences between responders and non-responders to clozapine were observed for the HTTLPR/rs25531 polymorphism. Nonresponders to clozapine showed a higher frequency of S 0 -allele (P ¼ 0.01) and also were more likely to be S 0 /S 0 homozygous or S 0 /L 0 heterozygous than those who did respond (P ¼ 0.04). After controlling for confounding variables, logistic regression analyses confirmed this association (OR ¼ 3.15; 95% CI: 1.13e8.80). The observed association suggests that increased availability of extracellular serotonin concentrations at all synapses may reduce clozapine effect.
Serotonin-Related Gene Polymorphisms and Central Nervous System Serotonin Function
Neuropsychopharmacology, 2003
Central nervous system (CNS) serotonergic function affects a wide range of biological and behavioral functions affecting health and disease. Our objective in this study was to determine whether functional polymorphisms of the genes that encode for the serotonin transporter promoter (5HTTLPR) and monoamine oxidase A (MAOA-uVNTR) are associated with CNS serotonin turnoverFindexed by cerebrospinal fluid levels of 5-hydroxyindoleacetic acid (5-HIAA)Fin a community sample of healthy adults. Subjects were 165 community volunteers without current medical or psychiatric illness, stratified with respect to ethnicity, gender, and socioeconomic status who underwent inpatient evaluation in the General Clinical Research Center of a university medical center. A significant ethnicity  genotype interaction (P ¼ 0.008) indicated that, compared to the long/long and long/short genotypes, the 5HTTLPR short/short genotype was associated with higher CSF 5-HIAA levels in African Americans, but with lower levels in Caucasians. A gender  genotype interaction (P ¼ 0.04) indicated that 5HTTLPR short/short genotype was associated with higher 5-HIAA levels in women but with lower levels in men. MAOA-uVNTR 3.5 and 4 repeat alleles were associated with higher 5-HIAA (P ¼ 0.03) levels in men, but were unrelated to 5-HIAA levels in women. These findings suggest that effects of serotonin-related gene polymorphisms on CNS serotonergic function vary as a function of both ethnicity and gender. Further research will be required to determine the mechanism(s) underlying these differential effects. In the meanwhile, both ethnicity and gender should be taken into account in research evaluating effects of these and related polymorphisms on CNS serotonergic function, as well as the broad range of biological and behavioral functions that are regulated by CNS serotonergic function.
Neurobiology of Aging, 2015
In frontotemporal dementia (FTD), nonmodifiable (genetic background) and modifiable (cognitive reserve [CR]) factors might interact in affecting frontotemporal damage. Serotoninergic dysfunction has been suggested as a key factor in FTD pathogenesis. 5-HTTLPR polymorphism on SCLA4 gene modulates the serotoninergic transmission. To evaluate the impact of 5-HTTLPR polymorphism on regional cerebral blood flow (rCBF) and its possible interaction with CR, 76 FTD patients with a 5-HTTLPR genotyping were recruited. All subjects underwent neuropsychological assessment and single-photon emission computed tomography imaging. Reserve index (RI) was computed from educational and occupational attainments, as proxy measure of CR. 5-HTTLPR analysis evidenced 14 S/S, 24 L/L, and 38 S/L carriers. No neuropsychological/behavioral differences were present. At the same disease stage, L/L carriers have a greater bilateral frontal rCBF decrease. Patients with higher RI had greater damage in right frontal and temporal regions. The additive effect of 5-HTTLPR polymorphism and RI was characterized by greater frontal rCBF deficit. 5-HTTLPR and CR act together to counteract brain pathology in FTD. Further studies are warranted to test the serotonin role in monogenic forms of FTD.
Serotonin transporter (5-HTT) gene polymorphism in psychogeriatric patients
Neuroscience Letters, 2000
Several studies have attempted to con®rm an association between a deletion/insertion polymorphism within the promoter region of the serotonin transporter gene (5-HTT) and Alzheimer's disease independent from the apolipoprotein E (APOE) 14 status. We examined this deletion/insertion polymorphism of the serotonin transporter gene in a sample of 222 consecutively recruited gerontopsychiatric patients which was divided into four different diagnostic groups: Alzheimer's disease (N 84), mild cognitive impairment (N 29), subjective cognitive complaints (N 49), depression/other psychiatric disorders (N 56) and 118 healthy, non-demented controls. The aim of this approach was to test whether the investigated polymorphism has a high enough selectivity and speci®city to distinguish between the different gerontopsychiatric disorders or to differentiate genetically AD from other forms of dementia, respectively. We could not detect any signi®cant differences in the allelic distribution of the deletion/insertion polymorphism of the 5-HTT gene between the four patient subgroups and the control group. This ®nding indicates that the serotonin transporter does not appear to be a major susceptibility factor in the pathophysiology of Alzheimer's disease and other psychogeriatric disorders. q
Dementia and Geriatric Cognitive Disorders, 2010
Background: Genotypes of the solute carrier family 6 (neurotransmitter transporter, serotonin) member 4 (SLC6A4) have been variously associated with depression, obsessive-compulsive disorder, memory impairment, and anxiety. Less clear are data regarding their association with severe dementia, in particular with vascular dementia (VaD). Aims: To evaluate the possible involvement of different SLC6A4 genotypes/haplotypes in VaD. Methods: The analysis of the 3 markers rs3813034, rs140701 and rs4795541 spanning the SLC6A4 locus was made in 541 consecutive patients clinically diagnosed as having VaD (n = 372) or no cognitive impairment (n = 169) attending a geriatric ward. A community-dwelling sample of 353 healthy subjects, as a reference for the genetic frequencies in the recruitment area, was also included in the study. All patients and subjects were free from any symptoms of depression, obsessive-compulsive disorder and anxiety. A complete neuroimaging documentation was available for ...
Neurological Sciences, 2010
Serotonergic transmission impairment and abnormal phosphorylation of tau protein have been implicated in the physiopathology of Alzheimer's disease (AD) and frontotemporal lobar dementia (FTLD). Associations between a functional polymorphism (5-HTTLPR), in the promoter region of the serotonin transporter gene, and susceptibility to sporadic AD and FTLD have been reported. A polymorphism (Q7R) in saitohin gene inside the microtubule-associated protein tau gene has also been related to dementia. To determine the possible role of the two polymorphisms in susceptibility to AD and FTLD, we performed a case-control study collecting 218 Italian sporadic dementia patients and 54 controls. We found a significant excess of 5-HTTLPR short alleles and an interaction between 5-HTTLPR and Q7R polymorphisms in demented subjects. Our study confirms the role of 5-HTTLPR as a potential susceptibility factor for sporadic dementia in the Italian population, and suggests a possible interaction between 5-HTTLPR and Q7R polymorphisms in neurodegenerative diseases.
Sertraline for the Treatment of Depression in Alzheimer Disease: Genetic Influences
Journal of Geriatric Psychiatry and Neurology, 2011
Objective. To assess the potential for genetic influences on sertraline treatment efficacy for depression of Alzheimer disease (dAD). Four functional genetic variants were studied: 2 serotonin receptors (HTR2A-T102C and HTR2C-Cys23Ser), the serotonin transporter (5HTT-LPR), and brain-derived neurotrophic factor (BDNF-Val66Met). Treatment response by genotype was measured by (1) the modified Alzheimer's Disease Cooperative Study Clinical Global Impression of Change, (2) the Cornell scale for Depression in Dementia, and (3) remission of depression. Methods. We utilized data from the Depression in Alzheimer's Disease Study 2 (DIADS-2), a 24-week, randomized, multicenter trial showing no significant treatment effect of sertraline on dAD. Proportional odds logistic regression and mixed effects models were used to examine the above mentioned outcome measures. Results. No significant interactions were seen between any of the genetic polymorphisms and the selected outcomes above at 12 or 24 weeks. Discussion. Treatment outcomes in the DIADS-2 trial were not significantly influenced by genetic variation at the loci that were assessed. Future studies should continue to examine the interaction of depression-related genetic variants with antidepressant treatment in Alzheimer disease patients with depression.