Unraveling the Immune Puzzle: Role of Immunomodulation in Alzheimer's Disease.

Alzheimer's disease (AD) is a complex neurodegenerative disorder with growing evidence highlighting the dual role of immunomodulation in its pathogenesis and potential therapeutic strategies. Disturbance in the immune system increases the inflammatory cytokines that cause tau hyperphosphorylation and neuroinflammation. Also, immune checkpoint inhibition further increases the amyloid-beta deposition. Therefore, this review examines the intricate interplay between the immune system and AD, focusing on how immunomodulatory mechanisms influence key pathological hallmarks, including amyloid-beta aggregation, tau hyperphosphorylation, neuroinflammation, and cholinergic dysfunction. We analyse critical signaling pathways involved in immune regulation, such as Toll-like receptor (TLR), Janus kinase/signal transducer and activator of transcription (JAK/STAT), phosphoinositide 3-kinase/Akt (PI3K/Akt), Wnt/β-catenin, tumor necrosis factor (TNF), and triggering receptor expressed on myeloid cells (TREM), along with immune checkpoints like programmed cell death protein 1 (PD-1). Preclinical studies of immunomodulatory agents, including salidroside, festidinol, astragalin, sulforaphane, BM-MSC, simvastatin, Ab-T1, hTREM2, and XENP345, demonstrate promising effects. Additionally, clinical investigations of drugs such as simufilam, AL002, TB006, VGL101, DNL919, XPro1595, astragalus, and IBC-Ab002 underscore the therapeutic potential of targeting immune pathways in AD. This review emphasizes how neuroinflammation, microglial activation, and peripheral immune responses contribute to disease progression. By exploring immunomodulatory mechanisms, the article sheds light on potential therapeutic targets that could help mitigate AD pathology which may pave the way for novel interventions preventing neurodegeneration in AD.