Grant: Canada Postdoctoral Research Award (CPRA) program

Dementia, a leading cause of disability, affects more than 55 million people worldwide, including over 770,000 Canadians as of 2025. Each day, approximately 685 Canadians are diagnosed with dementia, 65% of whom are Alzheimer's disease (AD) cases, placing a severe burden on health care systems and caregivers. Notably, about 45% of individuals with AD also experience depression, which doubles dementia risk, accelerates cognitive decline, and worsens daily functioning. Despite more than 200 clinical trials, therapies targeting amyloid plaques and tau tangles have failed, while recently approved antibody treatments provide only modest and uncertain benefits. These limitations underscore the urgent need for strategies that move beyond plaques and tangles to explain why some individuals remain resilient despite high disease burden, while others decline rapidly. The proposed project, NeuroPsilo, will test whether psilocybin, a compound found in mushrooms, can enhance brain repair and connectivity. Once converted in the body to psilocin, it activates serotonin 5-HT2A receptors, which are known to drive structural plasticity. This project will focus on two processes disrupted early in AD with depression: the generation of new neurons in the hippocampus (critical for memory and mood) and the trafficking of synaptic proteins essential for effective neuronal communication. To address this, we will use patient-derived stem cells differentiated into hippocampal neurons and a validated human hippocampal progenitor assay exposed to serum from AD patients. These complementary models capture both genetic and systemic factors driving disease. By determining whether psilocybin can promote neurogenesis and restore synaptic integration, this project aims to lay the groundwork for a new therapeutic strategy that improves both cognition and mood in people living with AD.