Schizophrenia and frontotemporal dementia: distinct diseases with converging circuit dysfunctions

Schizophrenia (SCZ) and frontotemporal dementia (FTD) are characterized by widespread neuroanatomical, neurophysiological, and cognitive abnormalities and a progressive course leading to disability. Despite being two distinct clinical entities, SCZ and FTD present overlapping clinical features and neurobiological underpinnings, as highlighted by growing evidence. Both disorders are characterized by cognitive impairment, behavioral alterations, and substantial phenotypic heterogeneity. Parallel pathophysiological alterations include dopaminergic and glutamatergic dysfunction, particularly involving NMDA receptors, excitatory/inhibitory imbalance in the prefrontal cortex, and neuroimmune alterations. Additionally, dysregulation of the kynurenine pathway, driven by chronic inflammation, further contributes to cognitive decline in both conditions. Although SCZ is not conventionally classified as neurodegenerative, subtle neurodegenerative mechanisms may contribute to cognitive decline, complicating differential diagnosis with FTD. This narrative review explores biological systems and molecular pathways affected across both conditions, highlighting the potential for identifying transdiagnostic biomarkers and therapeutic targets. Recognizing the partial overlap in pathophysiology and symptomatology between SCZ and FTD may enhance diagnostic accuracy in atypical or early-stage presentations and support the development of mechanism-based transdiagnostic interventions targeting cognitive and behavioral domains. An integrated perspective on psychiatric and neurodegenerative disorders may inform both clinical practice and translational research.