A number of hypotheses regarding how anti-A antibodies alter amyloid deposition have been postulated, yet there is no consensus as to how A immunotherapy works. We have examined the in vivo binding properties, pharmacokinetics, brain penetrance, and alterations in A levels after a single peripheral dose of anti-A antibodies to both wild-type (WT) and young non-A depositing APP and BRI-A42 mice. The rapid rise in plasma A observed after antibody (Ab) administration is attributable to prolongation of the half-life of A bound to the Ab. Only a miniscule fraction of Ab enters the brain, and despite dramatic increases in plasma A, we find no evidence that total brain A levels are significantly altered. Surprisingly, cerebral spinal fluid A levels transiently rise, and when Ab:A complex is directly injected into the lateral ventricles of mice, it is rapidly cleared from the brain into the plasma where it remains stable. When viewed in context of daily turnover of A, these data provide a framework to evaluate proposed mechanisms of A attenuation mediated by peripheral administration of an anti-A monoclonal antibody (mAb) effective in passive immunization paradigm. Such quantitative data suggest that the mAbs are either indirectly enhancing clearance of A or targeting a low abundance aggregation intermediate.--Levites, Y., Smithson, L. A., Price, R. W., Dakin. R. S., Yuan, B., Sierks, M. R., Kim, J., McGowan, E., Reed, D. K., Rosenberry, T. L., Das, P., Golde, T. E. Insights into the mechanisms of action of anti-A antibodies in Alzheimer’s disease mouse models.