Disease-modifying Therapies Targeting Neuroinflammation in Alzheimer's Disease: Evaluation of Ongoing Clinical Trials

Disease-modifying Therapies Targeting Neuroinflammation in Alzheimer's Disease: Evaluation of Ongoing Clinical Trials

Alvin Sherman Library

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and behavioral changes. While traditionally associated with amyloid-β plaques and tau tangles, growing evidence implicates neuroinflammation as a key driver of disease progression. Microglial, astrocytic, and mast cell activation, along with elevated pro-inflammatory mediators, contribute to synaptic dysfunction and neuronal loss. Targeting these pathways offers promising therapeutic avenues beyond amyloid and tau-centric strategies. This study evaluates the emerging disease-modifying therapies in clinical trials that target neuroinflammation in AD, focusing on mechanisms, trial phases, and emerging clinical findings. The clinical trial website was accessed to find drug therapies under evaluation for AD. Therapies were categorized by mechanism of action and stage of development. Multiple mechanistic approaches are under investigation. Cytokine modulators such as low-dose interleukin-2 enhance regulatory T-cell activity and suppress pro-inflammatory signaling, currently in Phase 2 trials. TNG-α inhibitors like XPro1595 reduce soluble TNF levels to protect synapses (Phase 2). Microglial regulators, including TREM2 agonists, CSF1R inhibitors, and LRRK2 inhibitors, aim to rebalance microglial activation (Phases 1-2). Mast cell/microglial inhibitors such as masitinib have shown preliminary cognitive benefit and are advancing toward Phase 3. These represent just a few examples; additional strategies under investigation include potassium channel blockers, immunomodulators, senolytics, fibrin-targeting therapies, metabolic/mitochondrial modulators, and GLP-1 receptor agonists. While most candidates remain in early to mid-phase evaluation, the upcoming Phase 2 and 3 data will be critical in determining whether targeting immune pathways can complement amyloid and tau-directed therapies and achieve true disease modification.