Recent advances in the therapeutic development for Alzheimer’s disease

Abstract

Alzheimer’s disease (AD) is the most common neurodegenerative disorder that mainly affects elderly people. AD is a progressive disease beginning with mild learning and memory impairment and gradually evolving to severe dementia, which is accompanied by impairments in complex attention, language function, behavior, and social ability. Two primary neuropathological hallmarks in the brain of AD patients have been recognized and studied extensively, including the accumulation of extracellular plaques primarily comprising aggregated amyloid-β (Aβ) and intracellular neurofibrillary tangles (NFTs) constituted of hyperphosphorylated Tau protein. As the population aging intensifies, the incidence of AD increases accordingly. Thus, there is an urgent need to develop effective therapies to prevent or slow down the progression of AD. Although many drugs have been designed to target AD pathology, only a few have entered the clinical trials, mainly monoclonal antibodies targeting Aβ. The goal of many anti-Aβ antibodies is to lower the levels of parenchymal Aβ as well as Aβ deposition in the AD brain. The amyloid cascade hypothesis suggests that Aβ accumulation triggers disease pathogenesis, so therapies that lower parenchymal Aβ might be expected to slow AD progression. Recently, the U.S. Food and Drug Administration (FDA) has approved Lecanemab and Donanemab, both are anti-Aβ monoclonal antibodies that target and remove Aβ from the brain, for the treatment of AD. Among AD patients with the early symptom, Lecanemab and Donanemab could effectively reduce Aβ deposition and are proven to be clinically meaningful benefits based on clinical rating scales such as CDR-SB and iADRS. These findings support that Aβ indeed is an effective therapeutic target.Besides having serious adverse events, such as microhemorrhage, superficial siderosis (ARIA-H), and amyloid-related imaging abnormalities (ARIA) with edema or effusions (ARIA-E),these antibody-based regimes appear to be effective only for AD patients in the early stages. In addition to Aβ, therapies targeting other molecules have also been developed, including monoclonal antibodies targeting N-Tau (N-terminal Tau) and P-Tau (phosphorylated Tau). The stage of tau pathology has well correlation with the progression of cognitive impairment. Thus, many antibodies are designed to lower the level of parenchymal tau aggregation or to inhibit abnormal hyperphosphorylation of tau. Unfortunately, N-tau-directed monoclonal antibodies have failed in phase II clinical trials, and the antibodies targeting P-tau are still in phase II clinical trials. Owing to apolipoprotein E (APOE) especially APOE4 being the strongest genetic risk gene in LOAD (late-onset AD), many therapies are designed to modulate the expression or function of APOE. Despite numerous preclinical studies in animal models have investigated APOE-directed therapies that may eventually translate clinically, so far, no therapies targeting APOE have completed phase II clinical trials. Multiple studies suggest that chronic using of anti-inflammation drugs may lower the incidence of AD, but many anti-inflammation drug treatments failed in clinical trials. Up to now, only Trem2 activating and CD33 blocking monoclonal antibody have entered phase I trials. Due to the diversity and complexity of AD pathology, further research efforts are definitely needed to discover more safe and effective therapeutic drugs.