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

Abstract

Background/Aim: The aim of this study was to elucidate the relationship between Alzheimer's disease (AD) and the serotonin transporter gene (SLC6A4). Methods: AD subjects (n = 43) and controls (n = 47) were recruited and evaluated. In leukocytes, we evaluated two polymorphisms in SLC6A4, the serotonin transporter length polymorphic region (5-HTT-LPR) and rs25531, as well as methylation rates of the SLC6A4 promoter region and the SLC6A4 mRNA expression level. We also performed a meta-analysis to examine the relationship between the frequency of the L allele and the risk of AD. Results: The distributions of 5-HTT-LPR and rs25531 polymorphisms in AD subjects were not different from those of controls. Although the methylation rates in AD subjects were not significantly different from those of controls, the expression level in AD subjects was significantly higher than in controls. Additionally, the expression level in AD subjects was significantly correlated with apathy. Meta-analysis revealed that the L/L genotype significantly reduced the risk of AD, but only in the Caucasian population. Conclusion: Higher SLC6A4 mRNA expression in leukocytes in AD was associated with apathy regardless of SLC6A4 genotypes and methylation rates of the promoter region. The L/L genotype may reduce the risk of AD in the Caucasian population.

Identifying Blood Transcriptome Biomarkers of Alzheimer’s Disease Using Transgenic Mice

“…Our list of previously published blood transcriptome biomarkers of AD is shown in Table 4 [7][8][9][10][11][12][13][14][15]. The Trem1 mRNA levels tended to increase with age only in the control mouse blood.…”

“…In addition to the presence of amyloid plaques in the brain parenchyma and intraneuronal neurofibrillary tangles, emerging evidence suggests the existence of additional AD pathophysiological pathways, such as innate immune responses, neuroinflammation, and vascular and cell membrane dysregulation [3][4][5]. Our previous studies suggest that the detection of transcriptome biomarkers related to cell stress and inflammation in the peripheral blood has significant potential as a minimally invasive and inexpensive diagnostic tool for the diagnosis and early detection of developing AD [6][7][8][9][10][11][12][13][14][15]. Although DNA methylation and RNA expression changes in blood might have utility as biomarkers of cognitive dysfunction and brain aging [16,17], the major limitation of blood biomarkers of AD is the lack of a direct correlation with biomarkers in brain tissues.…”

MEF2C mRNA expression and cognitive function in Japanese patients with Alzheimer's disease

“…In addition, epigenetic changes, including DNA methylation, which is involved in neuropsychiatric conditions, may influence MEF2C mRNA expression in AD . Therefore, investigation of MEF2C in peripheral leukocytes from AD patients may help elucidate AD pathogenesis, and MEF2C may become a convenient clinical biomarker . However, the relations between MEF2C expression levels and methylation rates in leukocytes have not been examined.…”

“…18 Therefore, investigation of MEF2C in peripheral leukocytes from AD patients may help elucidate AD pathogenesis, and MEF2C may become a convenient clinical biomarker. [19][20][21][22] However, the relations between MEF2C expression levels and methylation rates in leukocytes have not been examined.…”

DNA methylation changes at SNCA intron 1 in patients with dementia with Lewy bodies

“…The exact mechanisms causing neuropathology in DBL remain unclear; moreover, only a few biomarkers in peripheral blood are available for differential diagnosis of DLB . Epigenetic changes, including DNA methylation, are involved in neuropsychiatric conditions . The synuclein alpha ( SNCA ) gene has two CpG islands.…”