Globally, the World Health Organisation (WHO) reports that over 55 million people are currently diagnosed with dementia, while an estimated 280 million people suffer from major depression; where the prevalence of depression is higher among adults aged 60 years and older (World Health Organisation, 2023a, 2023b). There is a complex inter-relationship between major depression and dementia. Specifically, a diagnosis of major depressive disorder (MDD) is associated with a 1.5-fold increased likelihood of a dementia diagnosis (Brzezińska et al., 2020; Cherbuin, Kim, & Anstey, 2015; Diniz, Butters, Albert, Dew, & Reynolds, 2013; Fernández Fernández, Martín, & Antón, 2023; Gracia-García et al., 2015; Liu et al., 2023; Livingston et al., 2020; Ownby, Crocco, Acevedo, John and Loewenstein, 2006a, Ownby, Crocco, Acevedo, John and Loewenstein, 2006b; Yang et al., 2023). It follows that with a rising prevalence of both conditions more people may be at increased risk of developing dementia if their major depression is not effectively managed (Elser et al., 2023). Therefore, the current lack of safe, disease-modifying therapies that prevent, halt or reverse dementia signifies a major unmet medical need (Alves, Kallinowski, & Ayton, 2023; Andrews et al., 2019; van Dyck et al., 2022).

We need to understand common mechanisms underlying risk and resilience in the context of major depression and the development of dementia. Understanding how MDD and neurodegenerative diseases leading to dementia are connected mechanistically may aid identification of those at risk of developing dementia during the preclinical phase to allow for earlier intervention. One mechanism of interest is adult hippocampal neurogenesis (AHN), a phenomenon characterised by the generation of new neurons in the hippocampus, which is suggested to be essential for maintaining and regulating processes associated with learning, memory and mood throughout life. Important modulators of AHN are microglia; macrophages in the central nervous system (CNS), derived from erythromyeloid progenitor cells in the yolk sac that colonise the brain during neurodevelopment (Pérez-Rodríguez, Blanco-Luquin, & Mendioroz, 2021). Pertinently, disturbances in AHN are associated with both clinical depression and neurodegenerative diseases (Arber et al., 2019; Arber et al., 2021; Boldrini et al., 2013; Boldrini et al., 2019; Moreno-Jiménez et al., 2019; Salta et al., 2023; Tartt, Mariani, Hen, Mann, & Boldrini, 2022; Terreros-Roncal et al., 2021; Tobin et al., 2019; Zhou et al., 2022). Shifts towards disease-associated microglial functional states are associated with neurodegeneration and subsequent cognitive decline (Al-Onaizi, Al-Khalifah, Qasem, & Elali, 2020; Appel et al., 2018; Santos, Beckman, & Ferreira, 2016; Xu, He, & Bai, 2016). Therefore, compounds that modulate the neurobiological mechanisms overlapping both conditions may be beneficial for treating depressive symptoms and preserving cognitive function by altering the underlying pathology and subsequent trajectory of neurodegeneration.

Interest in psychedelics, such as psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine), for the treatment of mental health conditions has increased significantly in recent years (Butlen-Ducuing et al., 2023; da Costa, Oesterle, Rummans, Richelson, & Gold, 2022). In various clinical trial designs, psilocybin-assisted psychotherapy has demonstrated rapid amelioration of depressive symptoms, in some patients with MDD and treatment-resistant depression (TRD) (Davis et al., 2021; Goodwin et al., 2023; Raison et al., 2023; von Rotz et al., 2023). In some cases, prolonged antidepressant effects have persisted for up to 12 weeks (Carhart-Harris et al., 2021; Carhart-Harris et al., 2018; Gukasyan et al., 2022). Further studies investigating the benefit of psilocybin specifically in TRD are underway (Rucker et al., 2021).

Emerging evidence suggests that psilocin, the active metabolite of psilocybin, may be a “psychoplastogen”, a term that suggests it mediates its effects via the promotion of neural plasticity (de Vos, Mason, & Kuypers, 2021; Moliner et al., 2023; Olson, 2018; Vargas et al., 2023a; Vargas, Meyer, Avanes, Rus, & Olson, 2021). Psilocin may also have anti-inflammatory activity (Szabo, 2015). Mechanisms associated with AHN and microglial activity produce and regulate the number of newly generated neurons in the hippocampus; the resultant influence on synaptic architecture constitutes a form of neuroplasticity.

This narrative review aims to elucidate the relationship between AHN and microglial activity, identifying them as mechanisms underpinning major depression and the associated increase in dementia incidence. It examines the dynamic interplay between AHN and microglia in regulating neurogenesis and shaping hippocampal synaptic architecture, a key aspect of neuroplasticity. We will consider the potential of psychedelic compounds, namely psilocybin, to promote neuroplasticity, potentially affecting these processes through direct or indirect interactions with hippocampal stem cells and microglia in the dentate gyrus. Since depression is a risk factor for developing dementia, the neuroplastic and immunomodulatory potential of psilocybin to moderate cellular mechanisms associated with AHN and microglia, at the interface of depression and dementia, may influence neurodegenerative pathology and cognitive function, and may be relevant for reducing dementia risk.