One of the central aims in Alzheimer's disease (AD) research is the 
identification of clinically relevant drug targets. A plethora of potential 
molecular targets work very well in preclinical model systems both in vitro and 
in vivo in AD mouse models. However, the lack of translation into clinical 
settings in the AD field is a challenging endeavor. Although it is long known 
that N-terminally truncated and pyroglutamate-modified Abeta (AβpE3) peptides 
are abundantly present in the brain of AD patients, form stable and soluble 
low-molecular weight oligomers, and induce neurodegeneration in AD mouse models, 
their potential as drug target has not been generally accepted in the past. This 
situation has dramatically changed with the report that passive immunization 
with donanemab, an AβpE3-specific antibody, cleared aymloid plaques and 
stabilized cognitive deficits in a group of patients with mild AD in a phase II 
trial. This review summarizes the current knowledge on the molecular mechanisms 
of generation of AβpE, its biochemical properties, and the intervention points 
as a drug target in AD.