fMRI: use in early Alzheimer's disease and in clinical trials

The pathophysiological process of Alzheimer's disease (AD) begins years, even decades, prior to the time a clinical diagnosis can be established. This long asymptomatic or minimally symptomatic phase of AD provides a potential period for early therapeutic interventions to slow and perhaps ultimately prevent the progression to clinical dementia. Functional MRI (fMRI) provides an in vivo means to investigate alterations in brain function related to the earliest symptoms of AD, possibly before development of significant irreversible structural damage. fMRI during tasks probing episodic memory, which is the cognitive function most characteristically impaired in early AD, are of particular interest. In this paper, we review the current knowledge of the pathophysiological fMRI correlates of AD and of at-risk states for AD, such as presence of mild cognitive impairment or the apolipoprotein E epsilon 64 allele. We will summarize previous studies demonstrating changes in task-related fMRI activity, primarily focusing on memory tasks, as well as studies investigating resting-state fMRI findings in clinical AD patients and at-risk subjects compared with healthy elderly individuals. We will also discuss the potential use of fMRI in clinical trials of AD therapeutic agents, as well as the limitations of this promising imaging technique.