New study finds link between brain cholesterol and Alzheimer's risk

Key takeaways

• Cholesterol regulation and neuronal vulnerability: The study found that neurons in the locus coeruleus (LC)—a brain region highly vulnerable to Alzheimer’s—are extremely dependent on cholesterol, both producing and absorbing it intensely. This makes them more susceptible to damage from amyloid proteins. 
• Brain region comparison: By comparing two neurochemically and anatomically similar brain regions with different susceptibilities to Alzheimer’s, researchers identified cholesterol metabolism as a key factor in regional vulnerability. This comparison helped isolate cholesterol regulation as a potential underlying mechanism for early Alzheimer’s risk.
• Implications for Alzheimer’s treatment and prevention: Understanding the role of cholesterol in LC neuron degeneration opens new avenues for early intervention and treatment strategies. 

A new study conducted by researchers at the University of California San Francisco looked at some of the neurological processes that may increase the risk of Alzheimer’s disease. 

The researchers explained that the buildup of two proteins – amyloid-beta and tau – typically signal the onset of Alzheimer’s. The more tau builds up in the brain, the more neuron loss patients experience. 

In this study, the team took a closer look at which neurons are at the greatest risk of deterioration in the earliest stages of Alzheimer’s. Ultimately, they learned that the brain’s ability to regulate cholesterol could play a key role in Alzheimer’s risk. 

“The study highlights how cholesterol regulation not only explains differences between people’s vulnerability to Alzheimer’s, but also differences in vulnerability between brain regions at early disease stages,” senior author Dr. Lea Grinberg said in a news release.  

The study

For the study, the researchers analyzed data from deceased patients who were enrolled in two brain banks – the Neurodegenerative Disease Brain Bank at UCSF and the Biobank for Aging Studies at the University of São Paulo. 

The researchers analyzed brain tissue from two different parts of the brain: 

• The locus coeruleus (LC) – a section of the brain that is very susceptible to Alzheimer’s and produces noradrenaline 

• The substantia nigra (SN) – a part of the brain that’s resistant to Alzheimer’s and produces dopamine 

“These two regions are remarkably similar despite their markedly different vulnerabilities to Alzheimer’s Disease,” study first author Alexander Ehrenberg, Ph.D. said. 

“Both are anatomically and neurochemically similar, and both are also similarly vulnerable to other neurodegenerative diseases like Parkinson’s. Given this, we reasoned that the differences between the brain regions at the beginning of the study would offer clues into the baseline selective vulnerability of the LC to Alzheimer’s disease.”

How does cholesterol play a role? 

The researchers explained that the biggest difference between the two parts of the brain they studied were in cholesterol regulation. 

“The LC neurons exhibit signatures suggesting that they are super cholesterol-hungry – these neurons are doing both their best to produce their own cholesterol and take in as much as possible,” Ehrenberg said. “The SN, on the other hand, doesn’t have the same level of demands.”

The researchers explained that because the LC neurons are producing and absorbing cholesterol so intensely, they’re more susceptible to damage from the amyloid protein. This means that they’re more likely to degenerate as Alzheimer’s progresses. 

However, because the SN neurons can better regulate cholesterol, they’re less susceptible to Alzheimer’s-related proteins and aren’t likely to deteriorate in the same way. 

“A deeper understanding of the causal factors underlying LC degeneration – and the development of strategies to mitigate its vulnerability – could have a profound impact on the treatment of Alzheimer’s disease,” Gringberg said. 

“LC dysregulation impairs critical functions such as sleep regulation and neuroinflammatory control, both of which are recognized as key risk factors that can accelerate Alzheimer’s progression.”