Author(s)

Huiyu Shi

Corresponding Author

Huiyu Shi

ABSTRACT

Alzheimer's Disease (AD) is a neurodegenerative disease with complex pathogenesis. Clinically, it is the leading cause of dementia, leading to cognition and memory decline, behavioural changes, and loss of daily functions. Currently, two biological hallmarks have been identified: extracellular deposits of amyloid-beta (Aβ) and intracellular tau-containing neurofibrillary tangles (NFT). Before the approval of aducanumab, all four treatments available targeted the clinical dementia stage, which only brings modest reliefs from symptoms without slowing down the progression of the disease. Since the establishment of the amyloid cascade hypothesis over 30 years ago, Aβ remains the promising target for a potential cure of AD. Numerous Aβ-directed monoclonal antibodies were designed, however, none have shown statistically significant efficacy in a dosage-dependent manner with minimal side effects. Although the approval of aducanumab provided novel treatment to the AD community, inconsistency in result analysis gained significant doubts on its validity, among other issues. With such unsuccessful clinical trial results targeting Aβ, anti-tau therapeutics become the center of treatment development. Multiple mechanisms of action, including GSK-3β and tau aggression inhibitors, microtubule stabilizers, and immunotherapies, have been considered. However, this remains a novel and under-researched field. Only one tau aggression inhibitor has reached phase 3 clinical trials, while four monoclonal antibodies and a vaccine in phase 2 studies. This review aims to briefly explain Aβ and tau as biomarkers of AD and targets of AD treatment development; and to summarise current treatment development up to date with future directions.

KEYWORDS

Alzheimer’s Disease, Amyloid-beta, Tau, Neurofibrillary Tangles