Past, present, and future of serotonin-targeting therapeutics for Alzheimer’s disease: Perspectives from DNA methylation

With population aging, Alzheimer’s disease (AD) is becoming increasingly prevalent, causing great health and economic burdens worldwide. Despite decades of research, there are still no effective disease-modifying treatments for AD, highlighting the urgent need for more in-depth understanding of the disease-causing mechanisms. The brain serotonin (5-HT) neurotransmission system undergoes structural and functional changes in aging and AD, which contributes to cognitive decline and comorbid mood disturbances. This review discusses the critical involvement of the brain 5-HT system in aging and AD. Existing findings on the changes in projection fiber innervation and receptor/transporter expression in AD are reviewed. Preclinical and clinical progress on the development of 5-HT-modulating drugs for AD and the obstacles faced by these development efforts are discussed. Epigenetic control of the brain 5-HT system and the potential of modulating 5-HT transmission via DNA methylation are also examined.