A study published in Neuron by researchers at the University of Alabama at Birmingham, Rush University Medical Center, and SUNY Upstate Medical Center provides new insight into how tau tangles spread between brain regions in Alzheimer's disease, according to an April 8 announcement. The research offers evidence that targeting the spread of tau could help slow or prevent the progression of Alzheimer's.
Alzheimer's disease is a progressive disorder that impairs memory and thinking skills, eventually interfering with daily life. It is marked by two proteins: amyloid-beta plaques outside cells and tau inside neurons. As tau becomes abnormal, it forms neurofibrillary tangles that move through key areas of the brain, causing cell death and cognitive decline.
The study involved analysis of postmortem brain samples and data from 128 participants in the ROSMAP project—a long-term study involving older Catholic clergy who underwent annual evaluations before donating their brains for research. Researchers examined samples from both the lower temporal lobe (important for memory recall) and upper frontal lobe (involved in complex thought), finding that tau typically accumulates first in the temporal lobe before spreading to other regions.
Researchers used genetic methods like Mendelian randomization along with functional MRI data to track how individual differences in brain wiring affect tau spread. "We used a genetic approach called Mendelian Causality to make the conclusion that the seeds that were generated in the temporal cortex caused the neurofibrillary tangle pathology in the neocortex. The Mendelian causality that we used is a statistical algorithm that utilizes the genomic DNA that we had from each participant, and that allowed us to make this conclusion," said Herskowitz.
The findings suggest tau seeds travel primarily along each person's unique neural pathways, moving from synapse to synapse as they form new tangles. This helps explain why some people experience faster or more widespread cognitive decline than others. "This is a major advancement in Alzheimer's research for both therapy development and understanding how the disease works," said Herskowitz.
The results reinforce potential therapies targeting extracellular tau—such as antibodies—to stop its movement between regions. "Tau antibodies would stop tau from spreading from one brain region to the next. If you stop that spreading, it would delay or prevent Alzheimer's disease dementia," said Herskowitz.
