Immune modulation to treat Alzheimer's disease

Abstract

Immune mechanisms play a fundamental role in Alzheimer's disease (AD) pathogenesis, suggesting that approaches which target immune cells and immunologically relevant molecules can offer therapeutic opportunities beyond the recently approved amyloid beta monoclonal therapies. In this review, we provide an overview of immunomodulatory therapeutics in development, including their preclinical evidence and clinical trial results. Along with detailing immune processes involved in AD pathogenesis and highlighting how these mechanisms can be therapeutically targeted to modify disease progression, we summarize knowledge gained from previous trials of immune-based interventions, and provide a series of recommendations for the development of future immunomodulatory therapeutics to treat AD.

Fig. 1

Proposed mechanisms of action for immunomodulatory therapeutics in Alzheimer’s disease (AD) clinical trials. Clinical stage immunomodulatory therapeutics currently being examined for AD target receptors on immune cells (e.g., peripheral myeloid cells, microglia) and immune mediators in circulation (e.g., sTNF). Drug names are listed in red. Below each drug name is the proposed mechanism of action. The immune pathways and processes affected by each drug are described in the adjacent box. Abbreviations: ACV, acyclovir; ADAM12, ADAM metallopeptidase domain 12; ADAM17, ADAM metallopeptidase domain 17; CSF1R, colony stimulating factor 1 receptor; DAP12, transmembrane immune signaling adaptor TYROBP; ERK, extracellular signal-regulated kinase; FIMP, chromosome 16 open reading frame 92; IKK, inhibitor of NF-kB kinase; IL-34, interleukin 34; IRF7, interferon regulatory factor 7; ITRAM, immunoreceptor tyrosine-based activation motif; MAPK, mitogen-activated protein kinase; MS4A, membrane spanning 4-domains; MyD88, myeloid differentiation primary response 88; NF-kB, nuclear factor kappa-light-chain enhancer of activated B cells; PKC, protein kinase C; sTNF, soluble tumor necrosis factor; STAT1, signal transducer and activator of transcription 1; STAT2, Signal transducer and activator of transcription 2; sTREM2, soluble triggering receptor expressed on myeloid cells 2; SYK, spleen associated tyrosine kinase; TLR9, Toll-like receptor 9; TNFR1, tumor necrosis factor receptor 1; TREM2, triggering receptor expressed on myeloid cells 2

Fig. 2

Research roadmap. Future studies to advance immunomodulatory AD therapeutics are depicted, including the continued development of next-generation therapies, the application of individualized treatment approaches, the investigation of novel therapeutic strategies, and the employment of multi-modal interventions that target a combination of immunologically relevant disease mechanisms