Discordance in treatment effects on clinical and imaging outcomes in recently published amyloid removing trials

Abstract Background Longitudinal changes in volumetric MRI (vMRI) are correlated with longitudinal changes in cognition and function in subjects with Alzheimer’s disease (AD). In clinical trials, vMRI has been used as an exploratory outcome measure with the assumption that an effective treatment would slow down brain atrophy, in addition to slowing down cognitive decline. We have recently shown that in clinical AD trials published up to November 2020, treatment effects on clinical outcomes were associated with treatment effects on vMRI measures 1 . Here, we assess these relationships in three more recently published trials (Donanemab 2 , Lecanemab 3 , Lanabecestat 4,5 ), and compared it to our previous findings. Method Treatment effects were computed as the percent slowing in change from baseline in the active group relative to the control group for clinical (ADAS‐Cog, MMSE, CDR‐SB) and imaging (whole brain volume [WBV], ventricular volume [VV], hippocampal volume [HV]) outcomes. We assessed the concordance in directionality and magnitude of treatment effects between variables. Result In trials published up to November 2020, treatment effects on ADAS‐Cog and CDR‐SB were directionally concordant and significantly associated with treatment effects on WBV and VV. The trials with Donanemab and Lecanemab, amyloid‐removing antibodies, showed a clear discordance between treatment effects on all three cognitive scales and global brain atrophy (WBV and VV), with decreased cognitive decline being accompanied by an increase in atrophy (illustrated for ADAS‐Cog and WBV in Figure 1 ). In contrast, results from the trials with Lanabecestat, a BACE inhibitor, were more consistent with the historical relationship. Conclusion Both Donanemab and Lecanemab, two monoclonal antibodies with amyloid‐removal properties, showed a discrepancy in treatment effects on cognition and brain atrophy. Possibly, the atrophy reflects acute reductions in brain volume related to the removal of amyloid from the brain (“pseudo‐atrophy”). Further regional analyses and follow‐up imaging studies may help elucidate the mechanism and temporal evolution. References : 1. Ten Kate M et al., submitted 2. Mintun MA et al. N Engl J Med 2021;384:1691: 3. Swanson CJ et al. Alzheimers Res Ther 2021;13:80. 4. Zimmer JA et al. Alzheimers Dement 2021;7:e12123: 5. Wessels AM et al. JAMA Neurol 2020; 77(2):199