Association of Polymorphisms in Genes Involved in Serotonergic Signaling with the Risk of Developing Alzheimer’s Disease
Ladan Saeb, Seyedehleila Abtahi, Raheleh Masoudi, Ali JavadpourIntroduction/Aim:
Serotonin (5-hydroxytryptamine, 5-HT) is a monoamine neurotransmitter involved in mood, learning, and memory regulation. Disruptions in serotonin signaling have been linked to neurodegenerative disorders such as Alzheimer’s Disease (AD). This case-control study aimed to examine whether specific polymorphisms in serotonergic genes are associated with AD risk in an Iranian population.
Materials and Methods:
This research employed a case–control observational design to investigate potential associations between serotonin-related gene polymorphisms and the risk of Alzheimer’s disease. Blood samples were collected from 68 patients diagnosed with AD and 69 healthy controls from southwest Iran. DNA was extracted, and genotyping for the 5-HT6 receptor gene C267T polymorphism, the 5-HT1A receptor promoter C(-1019)G polymorphism, and the 5- HTTLPR polymorphism in the serotonin transporter gene was performed using PCR with specific primers. Statistical analyses assessed associations between genotypes and AD risk.
Results:
Statistical analysis showed significant associations between allele and genotype frequencies of these polymorphisms and AD. The T allele of the 5-HT6, C267T polymorphism increased the risk of Alzheimer's disease by 2.3 times (OR = 2.382, p= 0.017). In addition, a positive association was observed between individuals carrying the T allele and an increased risk of developing AD (OR = 2.202, p = 0.049). C allele of C(-1019)G was also associated with increased risk of AD (OR =1.72, p = 0.029). Individuals with the CG genotype (OR = 2.402, p= 0.024) or those carrying the C allele (OR = 2.500, p= 0.015) were more in risk of developing AD. Lastly, while no significant statistical association was found between 5-HTTLPR polymorphism and AD, adjustment for literacy suggested the SL genotype as a potential risk factor (OR = 4.163, p= 0.035).
Discussion:
Our findings indicate that variations in serotonin-related genes may contribute to Alzheimer’s Disease (AD) susceptibility, although their effects appear population-dependent. The 5-HT6 T and 5-HT1A C alleles were associated with a higher risk of AD, while the HTTLPR short allele showed significance only after adjusting for literacy, suggesting that education may influence genetic vulnerability.
Conclusion:
These results reinforce the multifactorial nature of AD, emphasizing the interaction between genetic and environmental factors. Larger, population-based studies are needed to validate these associations and clarify the mechanisms linking serotonergic signaling to AD pathogenesis.