"Flipping a Switch" on APOE Reverses Alzheimer's Risk

University of Kentucky researchers have developed a new experimental model that could point the way toward more effective Alzheimer’s disease treatments by targeting one of the brain’s most important genes for risk and resilience.

The study, published in Nature Neuroscience, focuses on apolipoprotein E (APOE), a gene long known to play a major role in Alzheimer’s disease. The team created a first-of-its-kind mouse model that allows scientists to “flip a switch,” changing the high-risk version of the gene (APOE4) to the protective form (APOE2) in adult animals.

People who inherit APOE4 have up to a 15 times greater risk of developing Alzheimer’s, while those with APOE2 tend to have lower risk and better cognitive outcomes. In the new study, when researchers activated the gene switch in brain cells called astrocytes, the mice showed striking benefits: fewer Alzheimer’s-related brain changes such as amyloid plaque buildup and inflammation, and stronger performance on memory tests.

“This model allows us to test what happens when we go from risk to resilience. Remarkably, even switching the gene later in life improved multiple aspects of Alzheimer’s pathology at once,” said Lesley Golden, lead author. Golden trained with co-author Lance Johnson in the UK College of Medicine Department of Physiology through support from the UK Sanders-Brown Center on Aging.

The findings demonstrate how precise gene editing of APOE could potentially recalibrate many biological pathways involved in the disease. The results also suggest that astrocytes — star-shaped support cells that help maintain brain health — play a central role in how APOE influences Alzheimer’s risk.

Although the work was done in mice, researchers say it provides a critical foundation for future human studies exploring gene-based strategies to prevent or slow Alzheimer’s.

“By understanding and manipulating APOE, we may one day be able to transform the biology of Alzheimer’s rather than just treating its symptoms,” Johnson said. 

Reference: Golden LR, Siano DS, Stephens IO, et al. APOE4 to APOE2 allelic switching in mice improves Alzheimer’s disease-related metabolic signatures, neuropathology and cognition. Nat Neurosci. 2025. doi: 10.1038/s41593-025-02094-y

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