Researchers combined animal models, human brain tissue, and molecular analysis to uncover a connection between Alzheimer’s disease, cell function issues, and cholesterol in the brain.
A research team from the Keck School of Medicine at USC has identified the mechanisms of a cellular pathway that drives inflammation and aging, particularly in individuals with the APOE4 genetic risk for Alzheimer’s disease. Their study also reveals a method for restoring cells to a healthy state, offering a potential new avenue for treatment. This discovery, the result of a decade-long investigation into the ATP-binding cassette transporter A1 (ABCA1) protein, was recently published in the journal Molecular Neurodegeneration.
Previous research has shown that low levels of HDL cholesterol—often called “good” cholesterol—in the brain increase the risk of Alzheimer’s disease. This risk is linked to dysfunction in ABCA1, a protein responsible for producing HDL when functioning correctly.
But fixing those problems requires understanding the exact biological mechanisms at play—and those details have long eluded researchers, who faced an apparent paradox. In brains affected by Alzheimer’s disease, ABCA1 molecules increased, but their activity decreased.
“This presented a conundrum. There is less HDL in the brain, but the protein that makes it is increased. The obvious question is: Is that protein working as it’s supposed to? We went deep inside cells to figure out what’s happening,” 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.
Uncovering the Cellular Mechanism
Led by Shaowei Wang, MD, a research associate at the Keck School of Medicine, and funded in part by the National Institutes of Health, the scientists used a range of methods to pinpoint the processes unfolding inside brain cells. They found that in the brains of people affected by Alzheimer’s disease or who carried the APOE4 gene putting them at higher risk for the disease, ABCA1 increased, but became trapped in a part of the cell that typically clears waste. That change was linked to a rise in a modified form of cholesterol known as oxysterol. Lowering oxysterol, in both animal models and human stem cells, freed the trapped ABCA1 and restored the pathway to its healthy state.
Lowering oxysterol could be a new way to prevent or treat Alzheimer’s disease in its earliest stages, Yassine said. Past clinical trials that aimed to boost HDL by increasing ABCA1 failed—and this study finally explains why. Without releasing trapped ABCA1, the pathway cannot function as it should.
“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,” Yassine said.
Resetting the ABCA1 pathway
The researchers began by analyzing the ABCA1 pathway, both in mouse models of Alzheimer’s disease and postmortem samples of human brain tissue. They observed ABCA1 getting trapped inside lysosomes, cellular structures responsible for breaking down and clearing waste.
To find out why, they ran a series of discovery experiments, including proteomics and lipidomics, which take a deep dive into proteins and lipids, to look for changes in other molecules that might help explain problems with ABCA1. With support from researchers at USC’s Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, they also measured levels of many forms of cholesterol. Those analyses revealed that an oxidized form of cholesterol, known as oxysterol, was building up inside the cell.
The researchers deduced that elevated oxysterol levels caused ABCA1 to become trapped inside lysosomes. That prevented ABCA1 from producing healthy HDL cholesterol. It also triggered inflammation and cellular senescence, a state common in aging and Alzheimer’s disease in which cells stop replicating.
Those findings suggested that lowering oxysterol levels could help return the ABCA1 pathway to its normal state. In mice, researchers used a drug called cyclodextrin to lower oxysterol, which freed trapped ABCA1 and reduced cellular senescence and neuroinflammation. They repeated a similar study in brain cells grown from human stem cells, again finding that cyclodextrin lowered oxysterol levels and reduced inflammation.
A new treatment target
The study provides a potential explanation for early changes in Alzheimer’s disease that could precede the hallmark buildup of amyloid plaques and tau tangles, the researchers said.
“This fits well with what we know so far about Alzheimer’s disease,” Yassine said. “If we stop and ask why amyloid and tau are accumulating, it’s plausible that is happening because a critical waste recycling system is not working.”
Drugs that lower oxysterols in people at risk for Alzheimer’s disease or in its earliest stages might help prevent the disease from advancing, he said.
Wang, Yassine, and their colleagues are also exploring the role of a cellular enzyme known as cytosolic phospholipase A2 (CPLA2). Similar to the ABCA1 pathway, problems with CPLA2 also lead to oxidation that later triggers inflammation in the brain. Inhibiting CPLA2 might offer another way to prevent or treat Alzheimer’s disease.
“Understanding what drives these oxidation processes may be the next frontier for Alzheimer’s researchers,” Yassine said.
Reference: “Cellular senescence induced by cholesterol accumulation is mediated by lysosomal ABCA1 in APOE4 and AD” by Shaowei Wang, Boyang Li, Jie Li, Zhiheng Cai, Cristelle Hugo, Yi Sun, Lu Qian, Julia TCW, Helena C. Chui, Dante Dikeman, Isaac Asante, Stan G. Louie, David A. Bennett, Zoe Arvanitakis, Alan T. Remaley, Bilal E. Kerman and Hussein N. Yassine, 4 February 2025, Molecular Neurodegeneration.
DOI: 10.1186/s13024-025-00802-7
This work was supported by the National Institute on Aging [RF1AG076124, R01AG055770, R01AG067063, R01AG054434, R21AG056518, P30AG066530, R01AG082362, K01AG062683, P30AG10161, P30AG72975 and R01AG15819]; the Alzheimer’s Drug Discovery Foundation [GC-201711-2014197] and donations from the Vranos and Tiny Foundations and Ms. Lynne Nauss.
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1 Comment
As a senior lay American male with family histories of very, very mild food allergy reactions and dementia, since first diagnosed with a high serum level of uric acid (UA) in early 1981, allergies to common foods and food additives in late 1981 and with high cholesterol in 1992, I’ve been postulating since that uric acid erodes cholesterol from the myelin sheaths of brain and nerve cells, somehow resulting in dementia and/or any number of other neurological/neuromuscular disorders.
In 2000 I learned of the true toxicity of added MSG (FDA approved for expanded use in 1980) and made that connection to dementia. Much more recently I learned and share that my kind of allergies cause very mild inflammation and that inflammation of any kind can stimulate the release of xanthine oxidase (XO) which breaks down into UA and free radicals (ROS). The article suggests to me I was right all along and what the researchers need to do next is to verify the allergy-inflammation-MSG-XO-UA-ROS connection and how that relates to accumulated HDL (e.g., mitochondria switched from glycolysis to glycogenesis?).