Role of monomeric amyloid-β in cognitive performance in Alzheimer's disease: Insights from clinical trials with secretase inhibitors and monoclonal antibodies

According to the β-amyloid (Aβ) hypothesis of Alzheimer's disease (AD), brain Aβ accumulation is the primary cascade event leading to cognitive deficit and dementia. Numerous anti-Aβ drugs either inhibiting production or aggregation of Aβ or stimulating its clearance have failed to show clinical benefit in large scale AD trials, with β- and γ-secretase inhibitors consistently worsening cognitive and clinical decline. In June 2021, the FDA approved aducanumab, an anti-Aβ monoclonal antibody for early AD based on its ability to reduce brain amyloid plaques, while two other amyloid-clearing antibodies (lecanemab and donanemab) have recently produced encouraging cognitive and clinical results. We reviewed AD trials using PubMed, meeting abstracts and ClinicalTrials.gov and evaluated the effects of such drugs on cerebrospinal fluid (CSF) Aβ levels, correlating them with cognitive effects. We found that β-secretase and γ-secretase inhibitors produce detrimental cognitive effects by significantly reducing CSF Aβ levels. We speculate that monoclonal antibodies targeting Aβ protofibrils, fibrils or plaques may improve cognitive performance in early AD by increasing soluble Aβ levels through Aβ aggregate disassembly and/or stabilization of existing Aβ monomers.These findings suggest that the real culprit in AD may be decreased levels of soluble monomeric Aβ due to sequestration into brain Aβ aggregates and plaques.