In Alzheimer’s disease, some types of brain cells are affected very early on, while others escape the disease process until much later.

What causes this difference in vulnerability?

Finding the answer to this question could pave the way for new targeted treatment strategies. When a team of scientists sought to solve this mystery, they made some important discoveries that are worth sharing.

As you’ve read in this newsletter before, proteins known as tau form tangles which are toxic to brain cells and lead to their early death.

These tangles spread throughout the brain and are strongly linked to the development of Alzheimer’s disease. However, not everyone with tau tangles will get Alzheimer’s disease. Research has shown that in some people, some brain cells become clogged with tangles and still keep functioning years later.

What’s behind these cells’ remarkable survival and these brains’ ability to avoid Alzheimer’s disease?

Neuroscientist Lea Grinberg at the University of California San Francisco calls this the “million dollar question.”

She likens it to “three people in a storm. One develops pneumonia, the other a cold, and the third, nothing. Same storm, different outcomes.”

RORB: The Key to Selective Vulnerability

Dr. Grinberg’s team began their research into this issue by obtaining brain tissue from ten people who died with different stages of Alzheimer’s. This included some who were never diagnosed with a neurological disorder but whose autopsy samples revealed the very earliest signs of disease.

Next, they used a special technique to find out which genes or proteins are expressed by the tau-damaged neurons.

In the entorhinal cortex, an area involved with memory and one of the first to be affected by Alzheimer’s, they identified a subset of neurons that began to disappear very early on in the disease process.

As the disease progressed and reached the superior frontal gyrus of the brain—which has roles in self-awareness— a similar group of neurons died off.

What did these cells have in common?

The scientists discovered that these cells all expressed a protein called RORB that made them especially prone to a build-up of tau tangles.

A Potentially New Approach to Treating Alzheimer’s

In the next phase of the study, Dr. Grinberg’s team looked at cells from healthy donor brains as well as from brains of people who suffered early and late stage Alzheimer’s. The team confirmed that neurons expressing RORB are the ones that die off in the early stages of the disease. What’s more, they confirmed that these cells accumulate tau tangles before neighboring cells that don’t express RORB.

Although the study, published in the journal Nature Neuroscience last month, established RORB-expressing neurons as highly vulnerable to Alzheimer’s, it will take further research to test whether RORB is the actual cause of this vulnerability and not simply related to the disease process.

However, research team member Rana Eser was hopeful, saying, “These findings support the view that tau buildup is a critical driver of neurodegeneration, but we also know from other data from the Grinberg lab that not every cell that builds up these aggregates is equally susceptible.

“Our discovery of a molecular identifier for these selectively vulnerable cells gives us the opportunity to study in detail exactly why they succumb to tau pathology, and what could be done to make them more resilient.

“This would be a totally new and much more targeted approach to developing therapies to slow or prevent the spread of Alzheimer’s disease.”