**5. Conclusions**

Despite significant reductions in the abundance of the Aβ transporters ABCB1 and ABCG2 in the brains of APP/PS1-21 mice, the brain distribution of the dual ABCB1/ABCG2 substrates [11C]tariquidar and [11C]erlotinib was unaltered relative to wild-type mice. This may be related to the high transport capacities of ABCB1 and ABCG2 and is in line and extends previous studies, which failed to detect differences in the brain distribution of diverse ABCB1 substrates between different AD mouse models and wild-type mice. While caution is warranted in extrapolating our results to the human BBB, our findings suggest that while disease-induced alterations in the abundance of ABCB1 and ABCG2 may be sufficient to decrease the brain clearance of Aβ peptides, they may not be sufficient to cause large changes in the brain distribution of clinically used ABCB1/ABCG2 substrate drugs.

**Author Contributions:** Conceptualization, T.W. and O.L.; methodology, T.W., S.M., M.K., M.B., T.P. and T.F.; PET investigation, T.F., M.S., V.Z., S.M. and J.S.; data analysis, V.Z. and T.W.; writing—original draft preparation, T.W. and O.L.; writing—review and editing, V.Z., T.F., T.P. and J.P.; visualization, V.Z. and T.W.; supervision, T.W. and O.L.; project administration, T.W.; funding acquisition, T.W., J.P. and O.L. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research was funded by the Lower Austria Corporation for Research and Education (NFB) [grant number LS14-008, to T.W.], the Austrian Science Fund (FWF) [grant number I 1609-B24, to O. L.] and the Deutsche Forschungsgemeinschaft (DFG) [grant number DFG PA930/9, to J.P.]. The work of J.P. was also supported by the following grants: Deutsche Forschungsgemeinschaft/Germany (DFG PA930/12); Ministerium für Wirtschaft und Wissenschaft Sachsen-Anhalt/Germany (ZS/2016/05/78617); Leibniz Gemeinschaft/Germany (SAW-2015-IPB-2); Latvian Council of Science/Latvia (lzp-2018/1-0275); Nasjonalforeningen (16154), HelseSØ/Norway (2016062, 2019054, 2019055); Barnekreftforeningen (19008); Norges forskningsrådet/Norway (251290, 260786 (*PROP-AD*), 295910). *PROP-AD* is an EU Joint Programme-Neurodegenerative Disease Research (JPND) project and has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement #643417 (JPco-fuND).

**Acknowledgments:** The authors wish to thank Mathilde Löbsch for help in conducting the PET experiments and Alina Zwickl, Jaqueline Koller, Marlies Nemeth and Monika Kühteubl (University of Applied Sciences, Wiener Neustadt, Austria) for support with immunohistochemistry. Open Access Funding by the Austrian Science Fund (FWF).

**Conflicts of Interest:** The authors declare no conflict of interest.
