Compelling evidence suggests that pyroglutamate-modified Aβ (pGlu3-Aβ; AβN3pG) 
peptides play a pivotal role in the development and progression of Alzheimer's 
disease (AD). Approaches targeting pGlu3-Aβ by glutaminyl cyclase (QC) 
inhibition (Varoglutamstat) or monoclonal antibodies (Donanemab) are currently 
in clinical development. Here, we aimed at an assessment of combination therapy 
of Varoglutamstat (PQ912) and a pGlu3-Aβ-specific antibody (m6) in transgenic 
mice. Whereas the single treatments at subtherapeutic doses show moderate 
(16-41%) but statistically insignificant reduction of Aβ42 and pGlu-Aβ42 in mice 
brain, the combination of both treatments resulted in significant reductions of 
Aβ by 45-65%. Evaluation of these data using the Bliss independence model 
revealed a combination index of ≈1, which is indicative for an additive effect 
of the compounds. The data are interpreted in terms of different pathways, in 
which the two drugs act. While PQ912 prevents the formation of pGlu3-Aβ in 
different compartments, the antibody is able to clear existing pGlu3-Aβ 
deposits. The results suggest that combination of the small molecule 
Varoglutamstat and a pE3Aβ-directed monoclonal antibody may allow a reduction of 
the individual compound doses while maintaining the therapeutic effect.