The rate of clinical progression and brain atrophy is greater with increasing severity of Alzheimer's disease: Results from the volumetric MRI substudies of two phase III trials with bapineuzumab

Rate of clinical progression is greater in moderate compared to mild AD. In several small datasets with long periods of observation, brain atrophy (as indexed by brain boundary shift integral, BBSI) has been observed to accelerate over time, in parallel with clinical progression. These observations suggest that rate of change in BBSI is a biomarker of the rate of disease progression. The recently completed bapineuzumab Phase 3 studies comprise the largest set of observations to date of longitudinal brain atrophy in relation to disease severity. Two randomized, double blind, placebo-controlled studies of intravenous bapineuzumab in subjects with mild to moderate AD, Studies 301 (for ApoE4 non-carriers) and 302 (for Apo E4 carriers), included 559 and 590 subjects, respectively, in the pertinent analysis population. Of these, 60% and 51%, respectively, had mild AD at baseline, defined as score on the Mini-Mental Status Exam (MMSE) >21. BBSI was converted to annual rate (mL/year) for these analyses. The primary clinical outcomes were change from baseline in the Alzheimer disease assessment scale - cognitive (ADAS-Cog 11) and the disability assessment in dementia (DAD), assessed at baseline and Weeks 13, 26, 39, 52, 65, and 78. A mixed model repeated measures analysis was used to assess differences between the mild and moderate subjects with respect to each outcome in each treatment group in both studies. BBSI was significantly greater for subjects with moderate AD (least squares [LS] mean ranging from 19.3 to22.6 mL/year) compared with mild AD (LS mean ranging from 14.4 to18.6 mL/year), in all treatment groups for both studies. The magnitude of the differences between the moderate and mild subjects was comparable for both ApoE4 carriers and noncarriers. These observations from 2 large randomized clinical trials are consistent with a gradually accelerating trajectory of brain atrophy that occurs with progression of disease, in keeping with the changes seen for the clinical measures in these studies, and further supports BBSI as a disease progression biomarker. In addition, the data suggest that baseline clinical severity predicts future rate of brain atrophy.