For many years, scientists believed that fat inside the brain did not play an important role in diseases like Alzheimer’s.
Most research focused on the well‑known signs of the disease: sticky clumps of a misfolded protein called amyloid beta and twisted strands of another protein called tau.
These markers have been studied for decades, yet Alzheimer’s disease still has no cure, and treatments have had limited success. Now, new research from Purdue University is challenging long‑held ideas and offering a fresh way of understanding how the disease develops.
The study, published in the journal Immunity, shows that too much fat inside the brain’s immune cells—called microglia—may weaken their ability to protect the brain. Microglia normally act like small cleaners. They remove harmful waste, including amyloid beta and damaged cell parts.
But when these cells collect excess fat, they can no longer work well. This discovery may open the door to new treatments that focus on improving the health of microglia rather than only targeting plaques or tangles.
The research was led by Professor Gaurav Chopra at Purdue University. His team has spent years studying how fat behaves inside different brain cells. In earlier work, they found that astrocytes—another type of support cell in the brain—release a fatty acid that can damage neurons.
Another study with scientists at the University of Pennsylvania showed that as people age, problems in mitochondria—the energy centers inside cells—are linked to fat buildup in glial cells. These findings suggest that fat may play a bigger role in neurodegenerative diseases than previously believed.
Professor Chopra believes scientists must move beyond the idea that only plaques and tangles matter. He argues that the immune system inside the brain must be restored if treatments are going to work long‑term.
According to him, the buildup of fat prevents microglia from doing their job of protecting the brain. If researchers can find ways to reduce this fat or stop it from forming, microglia may regain their ability to clear harmful materials and keep the brain in balance.
To explore this idea, the team looked closely at microglia found near amyloid beta plaques in human brain samples. They discovered that microglia sitting close to the plaques had about twice as many fat droplets as microglia farther away.
These overloaded microglia also cleared far less amyloid beta—about 40% less—compared to healthy microglia. This shows that the presence of amyloid beta directly encourages fat buildup that weakens microglia.
Using advanced techniques, the researchers found that microglia near plaques produce too many free fatty acids. Under normal conditions, microglia use these fatty acids for energy.
But in Alzheimer’s disease, microglia convert far too many of these fatty acids into a stored form of fat called triacylglycerol. As this stored fat builds up, the cells become bloated and stop working properly. This process gets worse with age and disease progression.
The scientists traced this fat‑storage problem to an enzyme called DGAT2. This enzyme carries out the final step of turning fatty acids into stored fat. Surprisingly, the DGAT2 gene was not more active in diseased brains; instead, the DGAT2 protein was not being broken down as it should be.
Because of this, the enzyme builds up inside microglia and pushes them to make more and more fat.
To test whether lowering DGAT2 levels could help, the team tried two approaches: blocking DGAT2’s activity and helping the cell degrade the enzyme. The most successful results came from promoting DGAT2 degradation.
When DGAT2 levels were reduced, microglia regained their ability to clear amyloid beta, and signs of neuronal health improved in animal models. This suggests that targeting fat metabolism—not just protein plaques—could be a promising new direction for Alzheimer’s treatments.
The researchers say this discovery brings a new understanding of Alzheimer’s disease. Fat deposits in microglia and astrocytes should no longer be seen as harmless by‑products. Instead, they may be important drivers of brain inflammation and degeneration.
Chopra and his team propose a new “lipid model of neurodegeneration,” where the type and amount of fat inside brain cells can help determine how the disease develops.
In reviewing the study, it is clear that these findings deepen our understanding of Alzheimer’s disease. While amyloid beta and tau remain important pieces of the puzzle, this research suggests that fat buildup in immune cells may play a major role in weakening the brain’s natural defenses.
By focusing on how microglia process fat, scientists may be able to design treatments that repair the brain’s immune system rather than only attacking plaques.
More research is needed to fully understand why DGAT2 builds up and how best to target it, but this work opens an exciting new path toward therapies that may slow or even prevent disease progression.
If you care about Alzheimer’s, please read studies about the likely cause of Alzheimer’s disease, and new non-drug treatment that could help prevent Alzheimer’s.
For more health information, please see recent studies about diet that may help prevent Alzheimer’s, and results showing some dementia cases could be prevented by changing these 12 things.
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