Uncertainties in Anti-Amyloid monoclonal antibody therapy for Alzheimer’s disease: the challenges ahead

Alzheimer's disease (AD), the leading cause of dementia, poses a significant burden on patients, caregivers, and healthcare systems worldwide. After two decades of extensive efforts, we are still without significantly effective disease-modifying drugs for AD. Although brain amyloid-β (Aβ) accumulation may predict cognitive decline, several drug candidates, including anti-Aβ monoclonal antibodies, have been developed and tested to reduce Aβ plaque burden effective, but without significant clinical success. The following review presents and discusses anti-Aβ monoclonal antibody therapeutics used to treat AD. The article considers both current approaches and alternatives. This article is multiple database searches (MEDLINE, EMBASE, Scopus, Ovid and Google Scholar) on all the available literature up to 1 February 2025. Randomized clinical trials (RCTs) of anti-Aβ drugs in AD have not fully validated the Aβ cascade hypothesis. Nevertheless, eight anti-Aβ monoclonal antibodies have, thus far, made it to Phase III RCTs. Moving forward, the use of the Apolipoprotein E genotype and tau protein as alternative biomarkers can assist clinicians in providing patients with even more individualized and efficacious anti-Aβ monoclonal antibodies dosing regimens and reduce the risk of serious amyloid-related imaging abnormalities.