The Inflammatory Nexus: Unraveling Shared Pathways and Promising Treatments in Alzheimer’s Disease and Schizophrenia

Russo, Aurelio Pio ORCID: https://orcid.org/0009-0003-7672-2798, Pastorello, Ylenia ORCID: https://orcid.org/0009-0004-3833-0184, Dénes, Lóránd ORCID: https://orcid.org/0009-0008-8319-8134, Brînzaniuc, Klara, Krupinski, Jerzy ORCID: https://orcid.org/0000-0002-5136-8898 and Slevin, Mark ORCID: https://orcid.org/0000-0003-3767-4861 (2025) The Inflammatory Nexus: Unraveling Shared Pathways and Promising Treatments in Alzheimer’s Disease and Schizophrenia. International Journal of Molecular Sciences, 26 (13). 6237. ISSN 1422-0067

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Abstract

Alzheimer’s disease (AD) and schizophrenia are traditionally considered distinct clinical entities, yet growing evidence highlights substantial overlap in their molecular and neuroinflammatory pathogenesis. This review explores current insights into the shared and divergent mechanisms underlying these disorders, with emphasis on neuroinflammation, autophagy dysfunction, blood–brain barrier (BBB) disruption, and cognitive impairment. We examine key signaling pathways, particularly spleen tyrosine kinase (SYK), the mechanistic (or mammalian) target of rapamycin (mTOR), and the S100 calcium-binding protein B (S100B)/receptor for advanced glycation end-products (RAGE) axis, that link glial activation, excitatory/inhibitory neurotransmitter imbalances, and impaired proteostasis across both disorders. Specific biomarkers such as S100B, matrix metalloproteinase 9 (MMP9), and soluble RAGE show promise for stratifying disease subtypes and predicting treatment response. Moreover, psychiatric symptoms frequently precede cognitive decline in both AD and schizophrenia, suggesting that mood and behavioral disturbances may serve as early diagnostic indicators. The roles of autophagic failure, cellular senescence, and impaired glymphatic clearance are also explored as contributors to chronic inflammation and neurodegeneration. Current treatments, including cholinesterase inhibitors and antipsychotics, primarily offer symptomatic relief, while emerging therapeutic approaches target upstream molecular drivers, such as mTOR inhibition and RAGE antagonism. Finally, we discuss the future potential of personalized medicine guided by genetic, neuroimaging, and biomarker profiles to optimize diagnosis and treatment strategies in both AD and schizophrenia. A greater understanding of the pathophysiological convergence between these disorders may pave the way for cross-diagnostic interventions and improved clinical outcomes.