Researchers have uncovered a connection between brain cell function, cholesterol, and Alzheimer’s disease—a discovery that restores a key Alzheimer’s pathway.
A team from the Keck School of Medicine at the University of Southern California (USC) discovered that a protein essential for brain health becomes trapped when cholesterol levels are unbalanced. This disruption may cause inflammation, and premature aging of brain cells, and eventually lead to Alzheimer’s disease.
The findings, published in the journal Molecular Neurodegeneration, offer insight into early changes that occur before the disease’s hallmark plaques and tangles appear.
“This provides new drug targets outside of lowering amyloid or tau, and we need new targets that deal with core issues happening much earlier in the progression of the disease,” said the study’s corresponding author, Hussein Yassine, MD, a professor of medicine and neurology and director of the Center for Personalized Brain Health at the Keck School of Medicine.
Restoring key Alzheimer’s pathway
The researchers focused on ABCA1, a protein that aids in producing high-density lipoprotein (HDL) cholesterol, often referred to as “good” cholesterol. In healthy brains, HDL supports cell communication and waste removal.
The study revealed that in Alzheimer’s patients or those with a genetic risk for the disease, ABCA1 increases in number but malfunctions by becoming trapped in lysosomes, the part of a cell responsible for clearing waste.
A connection between Alzheimer’s and cholesterol? 🧪
Researcher Hussein Yassine, MD, @usccpbh, discovered a link between #Alzheimer’s disease and issues with cell function and cholesterol in the brain, potentially opening new pathways for treatment. https://t.co/oVw9txWrbO pic.twitter.com/T77DwUhhyM
— Keck School of Medicine of USC (@KECKSchool_USC) February 11, 2025
To understand the cause, the scientists analyzed brain tissue from deceased Alzheimer’s patients and conducted experiments on lab-grown human brain cells and mice with the disease. They identified a harmful buildup of oxysterol, an oxidized form of cholesterol, which interfered with ABCA1’s normal function.
When oxysterol levels rise, ABCA1 becomes impaired. Without ABCA1 functioning correctly, the brain struggles to produce HDL cholesterol, leading to inflammation and premature cell aging.
Testing Cyclodextrin as a potential treatment
The team then tested cyclodextrin, a drug known for its cholesterol-lowering properties. In both mouse models and human brain cells, cyclodextrin reduced oxysterol levels. As a result, ABCA1 was released from the lysosomes, allowing cholesterol production to resume. Inflammation decreased, and the brain cells showed signs of healthier function.
The discovery may explain why earlier clinical trials, which aimed to increase ABCA1 levels, failed to slow Alzheimer’s progression. Boosting ABCA1 without addressing the trapped protein does not work. Now researchers understand why.
The findings highlight a potential new path for Alzheimer’s treatments by targeting cholesterol oxidation. Researchers are also investigating the role of another enzyme, CPLA2, which may trigger similar oxidative damage in the brain.
“Understanding what drives these oxidation processes may be the next frontier for Alzheimer’s researchers,” Yassine said.
If further studies confirm the findings, lowering oxysterol in high-risk individuals may one day help slow or even prevent Alzheimer’s disease.