Researchers Identify Key Lipid Pathways That Influence Alzheimer’s Progression

Changes in lipids in the brain play a significant role in Alzheimer disease (AD) development and progression, according to findings published in Nature Communications. The discovery builds on existing knowledge of the causal factors underlying AD.¹

“The brain is a unique organ,” Juan Pablo Palavicini, PhD, assistant professor in the Department of Cellular and Integrative Physiology at UT San Antonio’s Long School of Medicine and co-lead of the study, said in a news release. “Unlike most other organs, which are rich in protein, more than half of the brain’s dry weight is made up of different kinds of lipids, including cholesterol, phospholipids and sphingolipids. In [AD], we see massive disruption of these lipids, yet most studies focus only on genes and proteins.”²

AD is a neurodegenerative disorder in which progressive brain changes lead to the loss of neurons and, ultimately, declines in memory, language, and overall cognitive abilities. It remains the most prevalent form of dementia in adults, and global cases are projected to rise to 82 million by 2050.³

Excessive accumulation of fragment beta-amyloid and tau proteins is a well-established causal mechanism for AD, which is the focus of most research. However, emerging evidence reveals the significant role of lipids in AD development and progression, signifying a potential opportunity for new treatment options.³

“We wanted to understand which cells are driving these lipid changes,” Palavicini said. “Some lipids go up, some go down, but which cell types are responsible? By removing microglia, we could see which changes depend on them and which do not.”²

The study, conducted by researchers from UT Health San Antonio, pointed toward microglia—the brain’s resident immune cells—as key players in how lipids are managed during AD. The researchers found that microglia selectively regulate specific lipid changes that closely track with disease pathology in both AD mouse models and human postmortem tissue.^1,2

Through lipidomic profiling and histological analysis, investigators identified a notable buildup of arachidonic acid–containing bis(monoacylglycero)phosphate (BMP) surrounding amyloid plaques. This accumulation was dependent on microglial activity and influenced by GRN, a gene associated with AD risk.

Notably, not all lipid changes followed this pattern. The study found that lysophosphatidylcholine and lysophosphatidylethanolamine increased regardless of microglial involvement, instead aligning with astrocyte activation and markers of oxidative stress.^1,2

“In the Alzheimer’s brain, rather than lowering BMP, it may be important to maintain or support its levels,” Palavicini remarked. “Progranulin helps maintain this lipid and protect neurons. Therapies that boost progranulin could potentially restore balance and support brain health.”²

These findings draw a clear connection between dysregulated lipid metabolism in AD and the specific brain cell populations that shape these changes. By distinguishing the lipid pathways governed by microglia from those driven by astrocytes, the research highlights microglial lipid homeostasis as a promising therapeutic target for slowing or altering the course of AD.

REFERENCES

1. Xu Z, Kiani Shabestari S, Barannikov S, et al. Microglia-specific regulation of lipid metabolism in Alzheimer’s disease revealed by microglial depletion in 5xFAD Mice. Nat Commun. October 15, 2025. Doi:10.1038/s41467-025-64161-z

2. Targeting brain immune cells could restore Alzheimer’s-related lipid imbalance, UT Health San Antonio research shows. News Release. November 20, 2025. Accessed December 1, 2025. https://www.eurekalert.org/news-releases/1106953

3. Gerlach A. Alzheimer disease prevalence reaches record high, surpassing 7.2 million cases. Pharmacy Times. May 2, 2025. Accessed December 1, 2025. https://www.pharmacytimes.com/view/alzheimer-disease-prevalence-reaches-record-high-surpassing-7-2-million-cases