Chapter 20 - Molecular Imaging in Alzheimer Clinical Trials

Abstract

The rising prevalence of Alzheimer’s disease (AD) makes the discovery of a treatment that could arrest disease progression a social and economic imperative. The tissue damage and accumulation of pathophysiological features of AD occur over decades, as demonstrated in longitudinal studies, cross-sectional analyses of postmortem brain, and subjects with dominantly inherited forms of AD. This points to a long incubation period for AD and suggests an opportunity for intervention prior to cognitive and functional decline. Advances in molecular imaging with positron emission tomography (PET) targeting signature elements of AD—neuronal dysfunction and the accumulation of pathognomonic beta-amyloid and tau protein aggregates—promise earlier detection of disease processes in vivo. Amyloid PET is now being used to define clinical trial participants at risk for AD, while FDG PET can be used for detection of neurodegeneration in advance of cognitive decline. Autopsy studies support the claim that amyloid PET can detect fibrillar amyloid in brain, although challenges to reliable quantitative measurement in longitudinal studies have emerged, especially in multisite trials. Back-translation of molecular PET imaging to rodent models of AD pathology has been achieved and could allow for mechanistic studies of how the PET signal evolves, and allow selection and identification of exposure ranges of candidate treatments and in considerably less time and with less expense than are required for clinical trials. Recent efforts to develop ligands targeting hyperphosphorylated tau aggregates indicate the potential for identifying molecular imaging biomarkers that can provide additional information on the risk and progression of AD.