The discussion of whether amyloid plaque Aβ is a valid drug target to fight 
Alzheimer's disease (AD) has been a matter of scientific dispute for decades. 
This question can only be settled by successful clinical trials and the approval 
of disease-modifying drugs. However, many clinical trials with antibodies 
against different regions of the amyloid Aβ peptide have been discontinued, as 
they did not meet the clinical endpoints required. Recently, passive 
immunization of AD patients with Donanemab, an antibody directed against the 
N-terminus of pyroglutamate Aβ, showed beneficial effects in a phase II trial, 
supporting the concept that N-truncated Aβ is a relevant target for AD therapy. 
There is long-standing evidence that N-truncated Aβ variants are the main 
variants found in amyloid plaques besides full-length Aβ1-42, t, therefore their 
role in triggering AD pathology and as targets for drug development are of 
interest. While the contribution of pyroglutamate Aβ3-42 to AD pathology has 
been well studied in the past, the potential role of Aβ4-42 has been largely 
neglected. The present review will therefore focus on Aβ4-42 as a possible drug 
target based on human and mouse pathology, in vitro and in vivo toxicity, and 
anti-Aβ4-X therapeutic effects in preclinical models.