STM heavyweight: identifying tau protein as a key driver of Alzheimer's disease

In a study published in Science Translational Medicine, scientists from the center for memory and aging at the University of California, San Francisco (UCSF) have conducted a new study that shows that brain imaging of pathological tau protein tangles can reliably predict the location of brain atrophy in patients with Alzheimer's disease in the next year or earlier In contrast, amyloid plaques, which have been the focus of disease research and drug development for decades, have been found to have little effect The results of this study make researchers more and more aware that tau causes brain degeneration in Alzheimer's disease more directly than amyloid protein, and also show the potential of their recently developed pet (positron emission tomography) brain imaging technology in accelerating clinical trials of Alzheimer's disease and improving personalized care of patients Professor Gil D Rabinovici, a neuroscientist at the UCSF and Lawrence Berkeley National Laboratory, who is the study's co-author, said: "the match between the spread of tau and the changes in the brain the next year is really striking Tau's PET imaging not only predicts how much shrinkage we're going to see, but also where it's going to happen These predictions are much more powerful than anything we have done with other imaging tools, and further prove that tau is a major driver of the disease " With the failure of other therapies, tau "stands out" for a long time Researchers in the field of Alzheimer's disease have been arguing about the relative importance of amyloid plaques and tau protein tangles These two misfolded protein clusters were found in autopsy studies of patients' brains, both of which were first discovered by Alois Alzheimer in the early 20th century For decades, the amyloid camp has dominated, leading to a number of high-profile attempts to target drugs with amyloid to slow down Alzheimer's disease, but the results are either disappointing or mixed Many researchers are now beginning to reexamine tau protein and see if it is an important biological driver of Alzheimer's disease Amyloid protein is widely accumulated in the brain, sometimes even in people without any symptoms On the contrary, tau happens to be concentrated in the areas with the most severe brain atrophy and in the areas that help explain the differences in symptoms of patients, such as areas related to language and memory "No one doubts the role of amyloid in Alzheimer's disease, but more and more discoveries about tau are beginning to change people's view of the actual factors that lead to disease," said Renaud La joie, a postdoctoral researcher at the molecular neuroimaging laboratory who co authored the study However, only from the dead brain tissue, it is difficult to prove that tau protein tangles can lead to brain degeneration One of our main goals is to develop noninvasive brain imaging tools that can see if the location of tau in the early stages of the disease indicates subsequent brain degeneration " New technology for tracking the accumulation of tau although there were early concerns that tau might not be measured in the living brain, scientists have recently developed an injectable molecule called flortucipir (currently under FDA review), which combines with the misfolded tau in the brain and sends a mild radioactive signal, which can be obtained through PET scanning Rabinovici and William jagust, M.D., of the University of California, Berkeley, were among the first teams to use PET imaging of tau to study the distribution of tau protein tangles in normal aging brains Their new study is the first to test whether tau levels in Alzheimer's patients can predict future brain degeneration La joie recruited 32 patients with early Alzheimer's through the UCSF memory and Aging Center, all of whom received PET scans using two different tracers to measure the levels of amyloid and tau proteins in their brains Both at the start of the study and at a follow-up visit one to two years later, participants also underwent MRI scans to measure the structural integrity of their brains The researchers found that at the start of the study, the overall level of tau protein in participants' brains predicted how much degradation would occur at their follow-up (after an average of 15 months) In addition, tau's local accumulation model predicted subsequent shrinkage at the same site with an accuracy of more than 40% In contrast, baseline amyloid PET scans correctly predicted only 3% of future brain degeneration La joie said: "the accumulation of tau protein indicates the occurrence of degeneration, which supports our hypothesis that tau protein is a key driver of neurodegeneration in Alzheimer's disease." It is worth noting that PET scans showed that the overall level of tau protein in the brain of younger participants was higher than that of older participants, and that the link between baseline tau protein and subsequent brain atrophy was stronger This suggests that other factors, perhaps other abnormal proteins or vascular damage, may play a greater role in late-onset Alzheimer's, the researchers said Predicting atrophy as a "valuable precision medical tool" has increased the hope of the research team UCSF memory and aging center and other institutions are currently studying drugs targeting tau, which may provide clinical benefits for patients by blocking the key drivers of neurodegeneration in this disease At the same time, researchers say that using tau's pet to predict future brain degeneration can enable more personalized dementia care and accelerate ongoing clinical trials "When people hear the diagnosis of Alzheimer's, the first thing they want to know is what the future will be for them or their loved ones," Rabinovici said Whether this is a long-term decline in memory or a rapid decline to dementia, how long patients can live independently, whether they will lose the ability to speak or move around, these are questions that we cannot answer at present, unless in the most general terms But now, for the first time, this tool allows us to give patients and their families expectations of the disease by revealing the biological process behind the disease " Rabinovici said that tau's pet may be an extremely valuable precision medical tool in future clinical trials Its ability to track the accumulation of tau in patients sensitively will enable clinical researchers to find treatments to slow down or even prevent specific brain atrophy patterns for each patient "