Novel Therapeutic Approaches for Alzheimer's Disease: An Updated Review

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disease and accounts for most cases of dementia. The prevalence of AD has increased in the current rapidly aging society and contributes to a heavy burden on families and society. Despite the profound impact of AD, current treatments are unable to achieve satisfactory therapeutic effects or stop the progression of the disease. Finding novel treatments for AD has become urgent. In this paper, we reviewed novel therapeutic approaches in five categories: anti-amyloid therapy, anti-tau therapy, anti-neuroinflammatory therapy, neuroprotective agents including N-methyl-D-aspartate (NMDA) receptor modulators, and brain stimulation. The trend of therapeutic development is shifting from a single pathological target to a more complex mechanism, such as the neuroinflammatory and neurodegenerative processes. While drug repositioning may accelerate pharmacological development, non-pharmacological interventions, especially repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), also have the potential for clinical application. In the future, it is possible for physicians to choose appropriate interventions individually on the basis of precision medicine.

Keywords: Alzheimer’s disease; NMDA; amyloid; brain stimulation; neuroinflammation; neuroprotection; precision medicine; rTMS; tDCS; tau.

Figure 1

Signaling pathways of microglia modulators and astrocyte modulators. (A) Signaling pathways in microglia; (B) signaling pathways in astrocytes. Created with BioRender.com. * TREM2—triggering the receptor expressed on myeloid cells 2, TLR—Toll-like receptor, CSF1R—colony-stimulating factor-1 receptor, JAK—Janus kinase, STAT3—signal transducer and activator of transcription 3, NFAT—nuclear factor of activated T cells, NFκB—nuclear factor-kB, NLRP3—nod-like receptor family pyrin domain containing 3, MAPK—mitogen-activated protein kinase, P2Y1R—P2Y1 purinoreceptor.

Figure 2

NMDAR signaling pathway. Created with BioRender.com. NMDAR—N-methyl-D-aspartate receptor, DAAO—D-amino acid oxidase. The sharo arrow means activation of the chemical reaction. The blunt head arrow means inhibition of the chemical reaction.

Figure 3

The diagram of the brain stimulation devices. (A) Deep-brain stimulation (DBS); (B) invasive vagus nerve stimulation (iVNS); (C) non-invasive vagus nerve stimulation (nVNS); (D) repetitive transcranial magnetic stimulation (rTMS); (E) transcranial direct current stimulation (tDCS); (F) transcranial alternating current stimulation (tACS). Created with BioRender.com. The sharp arrow means the direction of energy flow.