Will Neuroimaging help us understand Alzheimer's disease?

Background: The amyloid hypothesis of AD is the leading theory of the cause and pathogenesis of the disease. Yet this hypothesis remains contentious partly because associations between beta-amyloid deposition and cognition are weak. While major insights have been gained from pathological and molecular approaches, it is only in vivo studies that provide the ability to relate biomarkers of pathology to cognition in close temporal proximity, and to evaluate the dynamics of longitudinal change and compensation. Imaging of beta amyloid and glucose metabolism with PET, hippocampal volume with MRI, and brain activation with functional MRI offer ways of analyzing both pathology and the brain's response to this pathology. Methods: These studies support an evolving model whereby brain beta-amyloid deposition is an early and critical step in the initiation of a chain of events that involve neurofibrillary pathology and synaptic dysfunction that ultimately lead to dementia. Most interestingly, it appears that while beta-amyloid may play an inciting role, regional vulnerability to this downstream pathology may be more important in defining the nature and severity of cognitive impairment than the deposition of beta-amyloid itself. Results: Imaging studies have been crucial in supporting this model since they have demonstrated that biomarkers of downstream pathology - specifically hippocampal volume and glucose metabolism - are better correlated with cognition than are beta-amyloid measures. While there is evidence of regional vulnerability in terms of where beta-amyloid is deposited in the brain, there is also evidence of regional vulnerability in the brain's response to beta-amyloid since regions with similar beta-amyloid load are differentially affected. This regional vulnerability is expressed in abnormalities of specific structures and networks, but these are not identical in all affected individuals. In fact, response to beta-amyloid appears to be an important factor in the inter-individual vulnerability as individuals with similar beta-amyloid loads show differential cognitive impairment that is also reflected by downstream markers. Conclusions: This model also has important clinical implications, since biomarkers that reflect the severity and extent of this downstream pathology are likely to be important in the prediction of who will develop cognitive decline.