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
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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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    • " , anterior cingulate cortex and amygdala in healthy subjects ( Gallinat et al . , 2008 ) . bvFTD is associated with degeneration of these and other paralimbic structures , as well as seroto - nergic neuron loss . However , studies of 5 - HTTLPR - s association with FTD risk have been inconsistent ( Albani et al . , 2008 ; Borroni et al . , 2010 ; Lorenzi et al . , 2010 ) . Given that it reduces circulating serotonin levels and is associated with volume loss in frontal and limbic brain regions , 5 - HTTLPR - s could be a risk factor for bvFTD , at least in the sense that it might exac - erbate symptoms or progression . Conversely , since 5 - HTTLPR - s is asso - ciated with heightened emotional reactiv"
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    ABSTRACT: The serotonin transporter length polymorphism (5-HTTLPR) short allele (5-HTTLPR-s) has been associated with differential susceptibility for anxiety and depression in multiple psychiatric disorders. 5-HTTLPR-s modifies the serotonergic systems that support emotion and behavioral regulation by reducing gene expression, which slows the reuptake of serotonin, and is associated with distinct morphological and functional effects. Serotonergic systems are also shown to be dysfunctional in behavioral variant frontotemporal dementia (bvFTD), a disease characterized by marked socioemotional dysfunction. However, studies of 5-HTTLPR-s effects in bvFTD have been inconsistent. Our objective was to investigate the patterns of gray matter volume by 5-HTTLPR-s genotype in both healthy older controls and bvFTD patients. We performed voxel-based morphometry of 179 cognitively normal older adults and 24 bvFTD cases to determine brain changes associated with dose (0/1/2) of 5-HTTLPR-s allele. 5-HTTLPR-s frequency did not differ between controls and bvFTD. We found a significant interaction effect whereby carrying more 5-HTTLPR-s alleles in bvFTD was associated with smaller volume in left inferior frontal gyrus (T = 4.86, PFWE = 0.03) and larger volume in right temporal lobe (T = 5.01, PFWE = 0.01). These results suggest that the 5-HTTLPR-s allele differentially influences brain morphology in bvFTD. We propose that patients with bvFTD and 5-HTTLPR-s have altered volumes in regions that support socioemotional behavior, which may be a developmental or disease-related compensation for altered serotonergic activity.
    Clinical neuroimaging 08/2015; 9:283-290. DOI:10.1016/j.nicl.2015.07.017 · 2.53 Impact Factor
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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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