Comparative Analysis of Aducanumab, Zagotenemab and Pioglitazone as Targeted Treatment Strategies for Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is the leading cause of dementia that has remained a major medical, sociocultural and economical challenge globally. Previously developed treatments like anticholinesterase inhibitors (AChEIs) and N-methyl-D-aspartate receptor (NMDAR) antagonists only provide short-term symptomatic improvement and do not prevent progression. Repeated setbacks and failures over the past 25 years in AD clinical trials have hindered efforts to develop effective AD treatments. Fortunately, Aducanumab, a specific anti-amyloid β antibody, has shown promising clinical results and was recently approved by the Food and Drug Administration (FDA) through an accelerated approval pathway. This has raised hopes for AD patients; however post-approval trials are necessary to estimate the true scope of its clinical benefits. We have reviewed several AD clinical studies and summarized the experience to date with Aducanumab and two other potential AD drugs including Zagotenemab (an anti-tau antibody) and Pioglitazone (nuclear Peroxisome-Proliferator Activated Receptor γ (PPARγ) agonist). These have shown mixed results so far and the next few years will be critical to elucidate and interpret their broad long-term protective effects. A concerted effort is required to understand and strengthen the translation of pre-clinical findings from these drugs to routine clinical practice.

Keywords: Aducanumab; Alzheimer’s disease; Pioglitazone; Zagotenemab.

Figure 1.

Alzheimer pathogenesis and the main targets of disease-modifying agents. Aβ is produced from APP via the proteolytic functions of β- and γ-secretase, which aggregates and form amyloid plaques; aberrant phosphorylation and conformational change of Tau decreases its affinity to bind microtubules and triggers aggregation in a concentration dependent manner promoting NFT formation. These processes ultimately lead to AD pathogenesis including neuronal damage, astrocyte activation, microglia dysfunction and mitochondrial damage. Aducanumab has a higher affinity for Aβ aggregates than monomers, Zagotenemab binds to a toxic conformation of Tau protein, and Pioglitazone affects the β- secretase activity by reducing its gene expression. PHF, paired helical filaments; NFT, intracellular neurofibrillary tangles; AICD, amyloid precursor protein intracellular domain; BACE, β- secretase; sAPPβ, soluble amyloid precursor protein- β.