Serotonin transporter and saitohin genes in risk of Alzheimer's disease and frontotemporal lobar dementia: Preliminary findings

Clinical Neurosciences Department, San Raffaele Turro Hospital, Vita-Salute San Raffaele University, via Stamira D'Ancona 20, Milan, Italy.
Neurological Sciences (Impact Factor: 1.45). 12/2010; 31(6):741-9. DOI: 10.1007/s10072-010-0400-8
Source: PubMed

ABSTRACT 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.

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Available from: Cristina Lorenzi, Nov 27, 2014
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    • "Significant associations (P < 0.05) are shown in bold. the 5HTTLPR S-allele to associate as risk factor with AD [Li et al., 1997; Oliveira et al., 1998; Lorenzi et al., 2010]. These conflicting results might arise from a possible protective effect of L-allele carriers in regard to survival and longevity. "
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    ABSTRACT: Alzheimer's disease (AD) and depression (DE) are common psychiatric disorders strongly intertwined with one another. Nevertheless, etiology and early diagnosis of the disorders are still elusive. Several genetic variations have been suggested to associate with AD and DE, particularly in genes involved in the serotonergic system such as the serotonin transporter (SERT/SLC6A4), responsible for the removal from the synaptic cleft, and the monoamine-oxidase-A (MAOA), responsible for the presynaptic degradation of serotonin. Here, we attempt to characterize this pleiotropic effect for the triallelic SERT gene-linked polymorphic region (5HTTLPR) and for the MAOA-uVNTR, in participants in the Vienna-Transdanube-Aging (VITA)-study. The VITA-study is a community-based longitudinal study following a birth cohort (75 years old at baseline examination, n = 606) from Vienna for a period of 90 months with a regular follow-up interval of 30 months. Our main finding, confirming previous reports, is that the 5HTTLPR S-allele is a risk allele for DE (OR = 1.55 CI 95% 1.03-2.32) and its carriers had a steeper increase in SGDS sum score. No association to AD was found. MAOA-uVNTR did not associate with either AD or DE. However, in AD MAOA-uVNTR S-allele carriers a steeper increase of HAMD and STAI1 sum scores (P < 0.05) was observed. Although the VITA-study cohort is rather small with low power to detect gene alterations, the uniqueness of this very thoroughly investigated and homogenous cohort strengthens the results through exceptional data collection. Still, reinvestigation in a larger cohort similar to this, as well as a meta-analysis, is important to confirm these results. © 2014 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 03/2014; 165(2). DOI:10.1002/ajmg.b.32220 · 3.42 Impact Factor
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    • "The promoter region of the SLC6A4 gene bears a functional polymorphism, named serotonin-transported linked-polymorphic region (5-HTTLPR), consisting of a 43-bp insertion or deletion (ind/del) leading to a hypofunctional short (S) or to a normal long (L) variant [11, 12]. This polymorphism has been investigated in association with AD risk (Table 1) [13–19], and a meta-analysis of the available data shows no significant effect [20]. A different SLC6A4 promoter polymorphism, rs25531 (A→G), is able to modulate 5-HTTLPR transcriptional efficiency, as the presence of the rs25531 G-variant in an L-allele carrier reduces the normal transcriptional rate to a level comparable to the S-allele [21]. "
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    ABSTRACT: 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 the SLC6A4 promoter functional variant rs25531 (A → G). By comparing the genotypic and allelic frequencies in an Italian population of 235 AD and 207 controls, we found an association between 5-HTTLPR and AD (odds ratio for the L-allele versus the S-allele: 0.74, associated P value = .03), while no difference was found for the rs25531. A meta-analysis of studies in Italy assessing 5-HTTLPR and AD risk gave an estimation of odds ratio for the L-allele versus the S-allele of 0.85 (associated P value = .08). Overall, our findings are not supportive of a large genetic effect of the explored polymorphisms on AD risk.
    International Journal of Alzheimer's Disease 06/2011; 2011:312341. DOI:10.4061/2011/312341
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    ABSTRACT: Saitohin (STH) is an intronless gene nested within the human tau gene, which contains a single nucleotide polymorphism (A/G), suggested to be involved in the physiopathology and clinical course of several neurodegenerative and neuropsychiatric diseases. Recently, an association between this polymorphism and frontal hypoperfusion and clinical prognosis in frontotemporal dementia was reported. The present study sought to evaluate the possible role of the STH polymorphism as a concurring factor of cognitive decline in schizophrenia, a disease sharing both early psychotic manifestations, a core deficit of executive functions and hypofrontality with frontotemporal lobe dementia. 220 clinically stabilized patients with schizophrenia were assessed with the Wisconsin Card Sorting Test (WCST) for evaluation of executive functions and compared for STH allele frequency with 48 patients affected by frontotemporal dementia and 47 healthy subjects. There was no significant difference in allelic distribution between the healthy controls and all other groups, while we observed a significantly greater frequency of G allele among both patients with frontotemporal dementia (p = 0.037) and schizophrenia patients with poor performances of WCST (p = 0.044), compared to schizophrenia patients with best WCST performances. Among the patients with schizophrenia, stratified for age and gender, the STH polymorphism resulted in a significant predictor of WCST performance (p = 0.007). These results suggest a possible contribution of STH gene products on the heterogeneity of core frontal executive functions deterioration, probably through complex interactions with mechanism involved in neurodevelopment and neurodegeneration.
    Neurological Sciences 12/2011; 33(5):1051-6. DOI:10.1007/s10072-011-0893-9 · 1.45 Impact Factor
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