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Invited Address: Can We Detect Alzheimer's Disease a Decade before Dementia (and why would we want to)?
Reisa Sperling
The pathophysiological process of Alzheimer's disease (AD) is thought to begin years, if not decades, prior to the onset of clinical dementia. Converging data from PET amyloid imaging, cerebrospinal fluid studies and large autopsy series suggest that approximately one-third of clinically normal older individuals harbor a substantial burden of cerebral amyloid-β. Our multi-modality imaging studies, using PET amyloid imaging and functional MRI, have demonstrated that amyloid deposition in key nodes of the default network is associated with aberrant default network fMRI activity during the encoding of new memories, as well as disrupted default network connectivity at rest. Furthermore, we have found evidence of early cortical thinning in amyloid-laden regions in cognitively intact normal older individuals. A small number of studies have also reported an association between higher amyloid burden and lower memory performance even among the range of clinically normal elders. These findings provide support for the hypothesis that amyloid pathology is linked to synaptic dysfunction in the networks supporting memory processes, detectable prior to the emergence of significant cognitive impairment. Longitudinal studies are ongoing to determine if these amyloid positive older individuals are indeed in the preclinical stages of AD, and are at increased risk for the development of AD dementia. We are also planning secondary prevention clinical trials in amyloid-positive older populations, including the "A4" trial—Anti-Amyloid Treatment in Asymptomatic AD—to determine if decreasing amyloid burden prior to cognitive symptoms will impact markers of neurodegeneration and prevent the emergence or at least slow the progression of cognitive decline.
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