Serotonergic psychedelics as epigenetic modulators: A paradigm shift in Alzheimer's disease therapeutics.

Alzheimer's disease involves amyloid-β accumulation, tau pathology, synaptic dysfunction, and neuroinflammation, driving progressive memory loss and cognitive decline. Epigenetic dysregulation is increasingly recognized as contributing to these processes by altering gene expression. Serotonergic psychedelics, acting as agonists of the serotonin 2A receptor, promote neuroplasticity and induce sustained transcriptional changes in the brain. Preclinical studies suggest these compounds can modulate epigenetic mechanisms, including histone modifications and DNA methylation. This review proposes that targeted engagement of 5-HT2A receptors may help counteract epigenetic abnormalities that contribute to Alzheimer's disease pathogenesis.

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Abstract

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by amyloid-β (Aβ) accumulation, tau pathology, synaptic dysfunction, and neuroinflammation, which collectively drive progressive memory loss, cognitive decline, and behavioral changes. Increasing evidence implicates epigenetic dysregulation as a key contributor to these pathological processes by altering gene expression programs. Serotonergic psychedelics, which primarily act as agonists of the serotonin 2 A receptor (5-HT₂AR), have recently attracted attention for their ability to robustly promote neuroplasticity and induce sustained transcriptional changes in the brain. Preclinical studies indicate that these compounds can modulate epigenetic mechanisms, including histone modifications and DNA methylation (DNAm). This review examines the emerging intersection between psychedelic-induced epigenetic modulation and AD pathology, and proposes that targeted engagement of 5-HT₂Ars may help counteract epigenetic abnormalities that contribute to AD pathogenesis.