Small-Molecule NANT Therapeutics Targeting the Brain–Immune Axis in Alzheimer’s Disease: Mechanisms, Clinical Progress, and Translational Challenges

Alzheimer’s disease (AD) is now widely accepted as a complex disorder involving multiple interconnected pathological processes. Increasing evidence suggest that neuroinflammation and immune system dysregulation actively contribute to neurodegeneration, extending beyond the traditional view that the disease is driven solely by amyloid-β (Aβ) and tau pathology. With the advent of studies showing anti-amyloid antibodies to have only modest effects with significant toxicity, there has been a growing interest in investigating non-amyloid non-tau (NANT) treatment approaches. This review provided a general review of small molecules for neuroinflammation-based NANT therapies in AD. We reviewed several agents that affect the brain/immune axis, namely, kinase inhibitors (nelflamaimod and masitinib), NLRP3 inflammasome inhibitors (MCC950, selnoflast, and dapansutrile), TREM2 activators (VG-3927), gingipain inhibitors, PPARγ activators, KCa3.1 inhibitors, and repurposed drugs such as ambroxol and cromolyn. Some common drawbacks were identified for the drugs that failed to provide their anticipated effects. It was found that they all suffered from late-stage treatment, patient heterogeneity, inadequate central nervous system penetration, and poorly designed preclinical studies. Additional translational challenges included sex-specific differences in neuroimmune responses, APOE ε4-associated immune dysfunction, and the need for biomarker-guided patient selection. Although immune-targeted therapies remain strongly supported by biological evidence in AD, meaningful clinical progress will likely require earlier intervention strategies guided by biomarkers and therapies capable of targeting multiple disease pathways simultaneously.