Research
Potential new drug target for Alzheimer’s disease uncovered

A team of researchers has unlocked the details of a cellular pathway that triggers cellular inflammation and ageing and is linked to Alzheimer’s disease, particularly among those who carry the APOE4 genetic risk.
They have also found a way to return cells to a healthy state, revealing a new potential approach to treatment.
The study is the culmination of a decade of research on a protein known as ATP-binding cassette transporter A1 (ABCA1).
Past research found that a shortage of HDL cholesterol (or “good cholesterol) in the brain raises a person’s risk for Alzheimer’s disease. That risk is related to problems with ABCA1, which produces HDL when working properly. 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, a professor of medicine and neurology and director of the Center for Personalized Brain Health at the Keck School of Medicine.
The scientists used a range of methods to pinpoint the processes unfolding inside brain cells and found that in 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 analysing the ABCA1 pathway, both in mouse models of Alzheimer’s disease and post-mortem 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.
News
Low doses of weight loss drugs may slow ageing

Microdoses of weight loss drugs like Ozempic could slow ageing and increase longevity, according to new research in mice.
The study found that exenatide, a drug with similar chemical make-up to Ozempic, produced molecular changes in mice that opposed typical patterns seen with ageing across multiple organs.
Scientists treated mice starting at 11 months of age with small doses of the drug for about 30 weeks, then compared tissue samples from brain, liver, kidney, muscle and fat.
Researchers from the Chinese University of Hong Kong measured levels of RNA and DNA modifications, proteins and metabolism-related molecules to assess how age-related molecular signatures had changed in each tissue.
The treated mice showed metabolic health consistent with younger animals, with their molecular “age-signature” significantly shifted to a younger-looking profile compared with untreated older mice.
Many of the drug’s positive effects appeared to involve brain activity, suggesting the brain acted as a hub influencing the ageing profiles of multiple organs throughout the body.
Exenatide and semaglutide (sold as Ozempic and Wegovy) are GLP-1 receptor agonists. These medicines mimic a naturally occurring hormone in the gut and brain that regulates appetite, helping people feel fuller for longer.
Originally developed for diabetes treatment, these drugs have surged in popularity for weight loss. A new trend has emerged online with some people reportedly taking very small doses for longevity, though health experts warn the anti-ageing effect has not been proven in humans.
“Our work has provided multifaceted evidence for a comprehensive body-wide anti-ageing strategy,” the researchers wrote. “Future longitudinal studies are necessary to explore whether GLP-1R agonism may complement other anti-ageing methods.”
The study examined multiple biological markers of ageing, including epigenetic modifications (changes to DNA that affect gene activity without altering the genetic code), protein levels and metabolic indicators across different tissues.
The findings showed consistent changes across many tissues that opposed typical ageing patterns. However, researchers emphasised several important limitations to their work.
The results were observed only in mice, not humans, meaning whether the drug has any real effect on human ageing remains unknown. The study was conducted on middle-aged mice, so the effects might not be the same in very old animals.
Additionally, while the drug appeared to induce many molecular signs of younger age across tissues, the study did not prove that actual biological ageing was reversed or that the mice lived longer.
GLP-1 receptor agonists work by binding to receptors that respond to the GLP-1 hormone. This binding triggers metabolic processes, including insulin release and appetite suppression, and potentially, as this study suggests, molecular changes linked to younger biological age.
The researchers hope their findings will lead to larger clinical trials and help in developing anti-ageing drugs. However, they stress that longitudinal studies tracking subjects over extended periods are necessary to determine whether these drugs could form part of a comprehensive anti-ageing strategy.
The growing interest in using diabetes and weight-loss drugs for longevity reflects wider trends in anti-ageing research, where scientists increasingly examine how existing medicines might have benefits for healthspan and lifespan.
Experts caution that people should not start taking these medicines for anti-ageing purposes based on animal studies alone, as human trials are needed to establish safety and efficacy for this use.
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