Scientists have known for a while that Alzheimer’s disease affects some areas of the brain more than others. One key player in this damage is a protein called tau.
Normally, tau helps support healthy brain cells. But in Alzheimer’s disease, it changes shape, forms tangles inside brain cells, and spreads across the brain. These clumps of tau hurt brain function and lead to cell death.
Some brain areas, like the entorhinal cortex and hippocampus, are affected early in the disease. Others, like the primary sensory areas, stay healthy much longer. Researchers have been trying to understand why some parts of the brain are more vulnerable while others are more resistant.
Now, scientists at UC San Francisco (UCSF) may have found some answers. In a new study published on July 9 in the journal Brain, they combined brain scans, genetic data, and computer modeling to get a clearer picture. Their work shows that different sets of genes may either increase the risk or protect certain brain regions from tau buildup.
The team used a new computer model called the extended Network Diffusion Model (eNDM) to track how tau spreads in the brain. They looked at brain scans from 196 people at various stages of Alzheimer’s. This model predicted where tau would likely go next, based on how brain regions are connected in healthy people.
They then compared the model’s predictions to what they actually saw in the scans. Any differences—called “residual tau”—showed that something else, like genes, might be affecting tau buildup.
To explore this, they used brain gene expression maps from the Allen Human Brain Atlas. This helped them check if certain Alzheimer’s-related genes were linked to either the predicted or the unexpected tau buildup. In doing so, they discovered that some genes work along with the brain’s wiring system, while others operate independently of it.
The researchers grouped the genes into four types based on how they affected tau buildup. Some genes helped tau spread along brain connections. Others caused tau to build up even in areas not connected by the brain’s wiring. Some genes helped protect areas that are normally vulnerable to tau, and some protected areas not usually affected by tau.
Genes linked to vulnerability were often involved in stress, metabolism, or cell death. In contrast, protective genes helped manage the immune system and clean up harmful proteins like amyloid-beta—another key problem in Alzheimer’s.
This research builds on a previous UCSF study in mice. That study, published in May, showed that tau doesn’t spread randomly. Instead, it follows specific brain pathways and prefers to travel in a particular direction using active transport, not just by drifting through brain tissue.
By combining brain maps and genetic information, the UCSF team is creating a clearer picture of how Alzheimer’s disease spreads and which genes might be involved. This could help scientists find better ways to stop the disease in the future.
“By blending biology and brain maps, we now have a smarter way to study Alzheimer’s and find new treatments,” said study leader Dr. Ashish Raj.
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The study is published in Brain.
