Eric M. Reiman, MD University of Arizona Good Samaritan Medical Center

1. Brain Imaging in Phase 3 Clinical Trialsof Drugs for the Putative Treatmentand Prevention of Alzheimer’s Dementia Eric M. Reiman, MD University of Arizona Good Samaritan Medical Center Arizona Alzheimer’s Disease Core Center Arizona Alzheimer’s Research Center Current Financial Arrangements with Industry: None

2. Brain imaging techniques should provide ancillarymeasures of efficacy in phase 3 clinical trials • MRI and FDG PET are “reasonably likely” to predict a drug’s clinical benefit. • They are “reasonably likely” to determine the extent to which a drug’s benefit is related to disease modification • They offer greater statistical power than traditional outcome measures • Their use in phase 3 trials is needed for the validation of these reasonably likely surrogate markers • Their use is needed to provide a foundation for the efficient discovery of prevention therapies

3. Volumetric MRI and FDG PET are currentlythe imaging modalities of choice for phase 3 clinical trials • MRI measurements of hippocampal, entorhinal cortex, and whole brain volume • PET measurements of posterior cingulate, parietal, temporal, and prefrontal glucose metabolism • Reasonably likely to to predict a drug’s clinical benefit and determine the extent to which it is related to disease modification • Correlated with dementia severity, predict subsequent clinical decline, and predict the histopathological diagnosis of AD • Longitudinal studies indicate that these declines are progressive and offer greater statistical power than traditional outcome measures • Since these declines precede the onset of dementia, they offer extraordinary promise in AD prevention trials

4. Two imaging modalities are better than one: Use BOTH volumetric MRI and FDG PET in phase 3 clinical trials • Complementary measures, converging evidence in support of a drug’s therapeutic effects • Increases the certainty that the effects on both of the imaging outcome measures will predict clinical outcome and reflect disease modification • (Increases the certainty of detecting a possible therapeutic effect, even in the unlikely event that a treatment masks this effect in one of the two imaging modalities) • Provides the best foundation for the validation of these reasonably likely surrogate markers • Provides the best foundation for establishing their relative roles in the efficient discovery of prevention therapies • The additional costs are justified, both imaging techniques are widely available, and the logistical challenges can be readily addressed.

5. Conclusions • Volumetric MRI and FDG PET should provide ancillary measures of efficacy in phase 3 clinical trials • They are “reasonably likely” to predict a drug’s clinical benefit and determine the extent to which it is related to disease modification • They offer greater statistical power than traditional outcome measures • Two imaging modalities are better than one: use both MRI and PET in phase 3 clinical trials • In addition to the discovery of drugs for the treatment of AD, their use in phase 3 clinical trials will have two extremely important long-term benefits: • The validation of these reasonably likely surrogate markers • The development of a way to discover prevention therapies without losing a generation along the way.