Alzheimer’s disease (AD) is best known for causing memory loss and confusion, but early signs often include non-cognitive symptoms like sleep problems, anxiety, and depression.
These changes can begin decades before memory issues appear.
Scientists have long been trying to understand why certain brain cells are affected early in Alzheimer’s, while others stay healthy.
Now, researchers from UC San Francisco (UCSF) believe that how the brain handles cholesterol might be a key part of the puzzle.
The team studied brain tissue from people who had died with early-stage Alzheimer’s.
They focused on two specific brain regions: the Locus Coeruleus (LC), which is usually affected early in AD, and the Substantia Nigra (SN), which is typically more resistant to the disease.
Interestingly, both brain regions are similar in structure and chemical activity, and both are vulnerable in other diseases like Parkinson’s.
That made the researchers wonder—why is the LC more at risk in Alzheimer’s?
By studying the activity of thousands of genes in these two regions, the scientists found something striking: the LC appears to need more cholesterol than the SN. In fact, the LC cells try to make and absorb as much cholesterol as they can, making them “cholesterol-hungry.”
On the other hand, SN cells don’t have such high cholesterol needs.
This could be a problem because harmful clumps of a protein called amyloid-beta—thought to play a major role in Alzheimer’s—may be entering LC cells through the same pathways used for cholesterol.
The LC cells have more of a receptor called LDLR, which brings cholesterol into the cells. Unfortunately, this may also allow toxic amyloid-beta to slip in. In contrast, SN cells produce a substance that helps break down LDLR, possibly protecting them from damage.
To confirm their findings, the scientists used a special staining technique to look at the proteins in the brain cells. Their results showed clear differences in cholesterol-related proteins between the two brain areas.
The researchers also noticed differences in how these regions handle metals and other important cell processes. Together, these differences may help explain why the LC is more vulnerable to Alzheimer’s than the SN.
This discovery could lead to new treatments for Alzheimer’s. If scientists can figure out how to protect LC cells—possibly by adjusting how they manage cholesterol—they might be able to slow down or even prevent some early symptoms of the disease.
“Understanding why certain brain cells are more at risk can help us target Alzheimer’s earlier and more effectively,” said lead author Dr. Alexander Ehrenberg. “This could be a game-changer in how we treat or prevent the disease in the future.”
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