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Brain amyloid is part of the definition of Alzheimer’s disease (AD) and increasingly used in clinical trial screening. ApoE genotype is associated with presence of brain Amyloid. Biomarkers of neurodegeneration reflect disease progression and can yield theoretical power advantages in mild cognitive impairment (MCI) trials. Whether and how these different markers can be combined, and the implications for trial design, remain open questions.
We propose different strategies for patient selection in trial design: A): Screen out amyloid negative (AM-) subjects. B): Screen out subjects with no neurodegeneration. Then further screen out AM- subjects. C): Screen out subjects with no ApoE risk factor. Then further screen out subjects with no neurodegeneration. Strategy A) is the implementation of the Amyloid hypothesis into trial design. Strategy B) follows the hypothesis that amyloid positive (AM+) MCI subjects with neurodegeneration are closer to clinical onset of AD and can have operational advantages over A). Strategy C) hypothesizes that MCI subjects at genetic risk and with neurodegeneration are closer to clinical onset of AD. We hypothesize that Strategy C) is similar with Strategy A) with lower costs. All strategies were assessed on 152 ADNI I and 112 ADNI II subjects with an amyloid marker and clinical follow-up over 24 months. AM+ was defined using established criteria. Neurodegeneration was defined as hippocampal volume below the 15th percentile of healthy subjects. All subjects carrying at least one ε4 allele were defined as being at genetic risk of AD. Trial cost, the number of subjects needed to screen (NNS) and effect size were calculated for both studies and three clinical endpoints, MMSE, CDR-SB and ADAS-Cog 13.
All three enrichment strategies increased effect size and reduced trial cost in both ADNI studies (Figure 1). Strategy C) resulted in a trial population with 96% AM+ subjects.
Additional or alternative biomarkers can have operational advantages over using amyloid markers alone for patient selection: Strategy B) helps further reduces costs and screens out slowly progressing AM+ subjects; Strategy C) screens out most AM- subjects without actually measuring amyloid marker.