Study Identifies Major Lipid Changes in Alzheimer’s Disease

Researchers at UT Health San Antonio, in collaboration with the University of California at Irvine, have identified key disruptions in brain lipids that contribute to the development and progression of Alzheimer’s disease. The findings were published Oct. 15, 2025, in Nature Communications and provide new evidence that lipid metabolism plays a critical role in how the disease advances.

Researchers Examine Lipid Regulation in Alzheimer’s

The study, co-led by Juan Pablo Palavicini, PhD, and Xianlin Han, PhD, analyzed how brain lipids change in Alzheimer’s conditions. The team reported that lipid imbalances influence the buildup of amyloid proteins, and that several genes linked to lipid metabolism are associated with Alzheimer’s risk.

Using a mouse model of Alzheimer’s, scientists tested two methods to remove microglia, the brain’s immune cells. One method used a drug to eliminate microglia, while the other relied on genetically modified mice that lacked microglia. These approaches helped distinguish lipid changes caused by microglia from those driven by other cell types.

Amyloid Buildup Alters Lipid Patterns

Researchers compared findings from the mouse model with post-mortem human brain samples. They found that amyloid accumulation significantly altered lipid patterns throughout the brain. Two affected lipid groups were lysophospholipids (LPC and LPE) and bis(monoacylglycero)phosphate (BMP).

A form of BMP containing arachidonic acid, known as AA-BMP, accumulated near amyloid plaques. Long-term removal of microglia prevented AA-BMP buildup, indicating that microglia drive this lipid change. The study also found that LPC and LPE levels were influenced mainly by astrocytes and neurons.

Progranulin and Microglia Play Key Roles

The protein progranulin emerged as a regulator of lipid balance. Progranulin levels increased under Alzheimer’s conditions and closely paralleled AA-BMP accumulation. Removing microglia lowered progranulin and AA-BMP levels near plaques, suggesting a specific regulatory role for microglial progranulin.

Researchers reported that microglia also help maintain myelin-related lipids under amyloid stress. Genetic removal of microglia reduced these protective lipids, showing that microglia support neuronal stability.

Implications for Future Alzheimer’s Therapies

The findings show that microglia, astrocytes, and neurons each influence different parts of the brain’s lipid network. By identifying which cells regulate which lipid pathways, the study offers potential direction for therapies aimed at restoring lipid balance and slowing Alzheimer’s progression.