The short variant of the polymorphism within the promoter region of the serotonin transporter gene is a risk factor for late onset Alzheimer's disease

Oliveira, João Ricardo Mendes de; Gallindo, Rodrigo Melo; Maia, L G S; Brito-Marques, Paulo Roberto de; Otto, Paulo Alberto; Passos‐Bueno, Maria Rita; Morais, M.; Zatz, Mayana

doi:10.1038/sj.mp.4000417

Cited by 64 publications

(50 citation statements)

References 29 publications

(30 reference statements)

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“…An increased frequency of the 5-HTTLPR short variant polymorphism and LOAD was recently reported by Li et al (32) and confirmed by us in a Brazilian sample of AD patients (33). Subsequently we demonstrated that the association of the short variant in the APOE e4 allele does not increase the risk for LOAD (34).…”

Section: Introductionsupporting

confidence: 66%

The study of genetic polymorphisms related to serotonin in Alzheimer's disease: a new perspective in a heterogenic disorder

Oliveira

Zatz

1999

Braz J Med Biol Res

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Genetic and environmental factors have been implicated in the development of Alzheimers disease (AD), the most common form of dementia in the elderly. Mutations in 3 genes mapped on chromosomes 21, 14 and 1 are related to the rare early onset forms of AD while the e4 allele of the apolipoprotein E (APOE) gene (on chromosome 19) is the major susceptibility locus for the most common late onset AD (LOAD). Serotonin (5-hydroxytryptamine or 5-HT) is a key neurotransmitter implicated in the control of mood, sleep, appetite and a variety of traits and behaviors. Recently, a polymorphism in the transcriptional control region upstream of the 5-HT transporter (5-HTT) gene has been studied in several psychiatric diseases and personality traits. It has been demonstrated that the short variant(s) of this 5-HTT gene-linked polymorphic region (5-HTTLPR) is associated with a different transcriptional efficiency of the 5-HTT gene promoter resulting in decreased 5-HTT expression and 5-HT uptake in lymphocytes. An increased frequency of this 5-HTTLPR short variant polymorphism in LOAD was recently reported. In addition, another common polymorphic variation in the 5-HT 2A and 5-HT 2C serotonin receptor genes previously analyzed in schizophrenic patients was associated with auditory and visual hallucinations in AD. These observations suggest that the involvement of the serotonin pathway might provide an explanation for some aspects of the affective symptoms commonly observed in AD patients. In summary, research on genetic polymorphisms related to AD and involved in receptors, transporter proteins and the enzymatic machinery of serotonin might enhance our understanding of this devastating neurodegenerative disorder.

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Section: Introductionsupporting

confidence: 66%

The study of genetic polymorphisms related to serotonin in Alzheimer's disease: a new perspective in a heterogenic disorder

Oliveira

Zatz

1999

Braz J Med Biol Res

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“…85 This has led investigators to consider the prevalence of the 5-HTT s allele in AD patients. Studies have been inconclusive, with some observing the s/s genotype to be more prevalent in late-onset AD 86,87 and other larger studies observing no association. 88,89 However, an increasing number of investigations suggest that diminished serotonergic function may contribute to cognitive impairment in both demented and non-demented patients.…”

Section: Serotonin Transporter Polymorphism Memory and Hippocampal Vmentioning

confidence: 99%

Serotonin transporter polymorphism, memory and hippocampal volume in the elderly: association and interaction with cortisol

et al. 2007

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The s allele variant of the serotonin transporter gene (5-HTT) has recently been observed to moderate the relationship of stress to depression and anxiety. To date no study has considered interactive effects of 5-HTT genotype, stress and hypothalamic-pituitary-adrenal (HPA) function on cognition in healthy, older adults, which may reflect developmental, functional or neurodegenerative effects of the serotonin transporter polymorphism. We investigated whether 5-HTT genotype interacts with cumulative life stress and HPA-axis measures of waking and diurnal cortisol slope to impact cognition in 154 non-depressed, older adults. Structural images of hippocampal volume were acquired on a subsample of 56 participants. The 5-HTT s allele was associated with both significantly lower delayed recall and higher waking cortisol levels. Presence of the s allele interacted with higher waking cortisol to negatively impact memory. We also observed a significant interaction of higher waking cortisol and the s allele on lower hippocampal volume. Smaller hippocampi and higher cortisol were associated with lower delayed recall only in s allele carriers. No impact or interactions of cumulative life stress with 5-HTT or cortisol were observed. This is the first investigation to identify an association of the 5-HTT s allele with poorer memory function in older adults. The interactive effects of the s allele and waking cortisol levels on reduced hippocampal volume and lower memory suggest that the negative effect of the serotonin polymorphism on memory is mediated by the HPA axis. Further, given the significant association of the s allele with higher waking cortisol in our investigation, future studies may be needed to evaluate the impact of the serotonin transporter polymorphism on any neuropsychiatric or behavioral outcome which is influenced by HPA axis function in older adults.

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“…95 Similarly, there is no evidence that any of the risk genes found to be associated with AD þ P in casecontrol studies (see above) also contribute to AD risk. Though some, 96,97 but not all, 98 studies have found an association of AD with short alleles of a 44 bp insertion/deletion polymorphism in the 5 0 promoter region of HTT, it was the presence of long alleles that was associated with increased AD þ P risk. 26 In Pathway C, genes contributing major risk for idiopathic psychoses such as schizophrenia would be seen to also contribute to AD þ P risk.…”

Section: Cosegregation Of Ad þ P and Idiopathic Psychosesmentioning

confidence: 99%

Psychotic symptoms in Alzheimer disease: evidence for a distinct phenotype

et al. 2003

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Though efforts to identify the genetic etiology of Alzheimer disease (AD) have made substantial progress, to date only some of the genes contributing to AD risk have been identified. Utilization of more etiologically homogeneous subphenotypes represents one strategy to facilitate the identification of novel risk genes in complex disorders. In this review, we evaluate the hypothesis that psychotic symptoms, such as delusions and hallucinations, define a suitable subphenotype in AD patients for gene-mapping efforts. Psychotic symptoms occur in 40-60% of patients with AD and are associated with more severe cognitive deficits and a more rapidly deteriorating course. The presence of psychotic symptoms in AD confers increased risk of similar symptoms to affected siblings. Candidate gene association analyses and initial linkage analysis have yielded significant results. We discuss possible genetic models of psychotic symptoms in AD, and suggest strategies for further investigation. Identification of such genetic factors may facilitate gene-mapping studies for both AD and idiopathic psychoses. OverviewThe genetic basis of Alzheimer disease (AD) is unknown, although considerable strides have been made using gene-mapping efforts. Success has been most notable for the highly heritable early onset form, which comprises a minority of the entire population of AD cases. 1 While the impact of apolipoprotein E e4 alleles (APOE4) is well established, the genetic architecture of the more common late-onset AD (LOAD) is unclear. Like other genetically complex disorders, such as diabetes mellitus, progressively greater attention has been paid to utilizing defined subgroups of AD (eg late age-of-onset, APOE4 presence, autopsy confirmation) for mapping liability genes. 2,3 We have previously proposed that the presence of psychotic symptoms, delusions and hallucinations, define a subgroup of AD 4 that may be suitable for genetic investigation. 5,6 To our knowledge, however, the available evidence pertaining to whether AD with psychosis (AD þ psychosis (AD þ P)) identifies a phenotype suitable for genetic study has not been the subject of critical review.Stedman's Medical Dictionary defines phenotype as 'the observable characteristics, at the physical, morphologic, or biochemical level, of an individual, as determined by the genotype and environment '. 7 The genes associated with a behavioral phenotype, however, are unknown. The task for the psychiatric geneticist, therefore, is to identify a behavioral phenotype that varies according to alleles at a restricted set of genes. As in all psychiatric nosology, a behavioral phenotype must be readily and reliably identifiable in all patients of interest. If this behavioral phenotype has clinical relevance (eg bipolar illness) it provides a measure of face validity, and adds significance to its use in the search for causative genes. Tsuang et al. 8 enumerated additional criteria for determining that a behavioral phenotype has a substantial genetic basis, including state independence, biolog...

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The short variant of the polymorphism within the promoter region of the serotonin transporter gene is a risk factor for late onset Alzheimer's disease

Cited by 64 publications

References 29 publications

The study of genetic polymorphisms related to serotonin in Alzheimer's disease: a new perspective in a heterogenic disorder

The study of genetic polymorphisms related to serotonin in Alzheimer's disease: a new perspective in a heterogenic disorder

Serotonin transporter polymorphism, memory and hippocampal volume in the elderly: association and interaction with cortisol

Psychotic symptoms in Alzheimer disease: evidence for a distinct phenotype

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