[From neuropathology to biomarker development in Alzheimer research]

Recent advances in our understanding of neurobiology of Alzheimer's disease (AD) demonstrate that AD starts with accumulation of amyloid beta-protein (Abeta) followed by abnormal phosphorylation of tau protein and a massive neuron death in vulnerable brain areas. We have shown that cerebrospinal fluid tau and phosphorylated tau are elevated in subjects with mild cognitive impairment, the earliest detectable clinical stage of dementia and AD, suggesting that the pathogenic cascade of AD may arrive at the stage that finally leads to an accumulation of abnormally phosphorylated tau in the MCI stage. These results may highlight the need to develop another diagnostic tool that reliably monitors and visualize brain beta-amyloid burden in living subjects who are at increased risk of developing AD. We assume that the detection of asymptomatic stage of AD followed by an early intervention may lead to maximum therapeutic benefits. In an attempt to accomplish this goal, we have generated several novel chemicals that specifically bind to Abeta peptide upon entry into mouse brain. The "amyloid imaging" seems closest to ideal biomarker if safely and successfully applied in humans because this non-invasive technique can also monitor treatment outcome following anti-Abeta therapy.