Neuroinflammatory mechanisms and immunomodulatory therapies in Alzheimer's disease

Abstract

Alzheimer's Disease (AD) is a multifactorial neurodegenerative disorder affecting over 55 million individuals worldwide, characterised by Amyloid beta (Aβ) plaques, neurofibrillary tangles, and sustained neuroinflammation. While amyloid- and tau-targeted therapies have dominated therapeutic research, their limited clinical efficacy has intensified focus on neuroinflammation as a central and modifiable disease mechanism. This review synthesises current understanding of neuroinflammatory pathogenesis in AD, with emphasis on Microglial polarisation (M1/M2), Disease-Associated Microglia (DAM), TREM2 signalling, and reactive astrocyte conversion. This paper further evaluates pharmacological strategies targeting these pathways, including cytokine inhibitors (TNF-α and IL-6 blockade), microglial modulators (CSF-1R inhibitors, TREM2 agonistic antibodies), and emerging innate immune targets (cGAS-STING pathway inhibitors, and S-palmitoylation inhibitors). Despite strong preclinical rationale, clinical translation has been impeded by Blood-Brain Barrier (BBB) penetration challenges, intervention timing, peripheral immunosuppression risks, and the biological redundancy of neuroimmune networks. Future therapeutic success will likely require combination approaches, CNS-targeted delivery systems, and biomarker-guided patient stratification to fully exploit the therapeutic potential of neuroinflammation-directed strategies in AD.