Published on: Nov 17, 2025
Researchers at the University of Kentucky have developed a groundbreaking experimental model that could pave the way for more effective Alzheimer’s disease treatments by targeting one of the brain’s most influential risk-related genes.
The study, recently published in Nature Neuroscience, centers on apolipoprotein E (APOE) — a gene strongly associated with Alzheimer’s disease. The research team engineered the first mouse model that can flip a switch, converting the high-risk APOE4 gene variant to the protective APOE2 form in adult animals.
Individuals carrying APOE4 have up to a 15-fold higher risk of developing Alzheimer’s, while APOE2 is linked to reduced risk and better cognitive performance. In the new study, switching the gene specifically in astrocytes — brain support cells critical for maintaining neural health — led to remarkable results. The treated mice showed fewer Alzheimer’s-related changes such as amyloid plaque accumulation and inflammation, along with improved memory function.
This model enables us to examine what happens when we transition from genetic risk to resilience. Surprisingly, even switching the gene later in life improved multiple Alzheimer’s-related outcomes simultaneously, said lead author Lesley Golden, who trained under co-author Lance Johnson in the UK College of Medicine’s Department of Physiology with support from the Sanders-Brown Center on Aging.
The study highlights that targeted gene editing of APOE could modulate several biological pathways involved in Alzheimer’s, underscoring the key role of astrocytes in how APOE affects disease vulnerability.
Although the research was conducted in mice, the findings provide a strong foundation for future human studies exploring gene-based strategies to prevent or slow Alzheimer’s disease.
“By understanding and modifying APOE, we may eventually be able to alter the biology of Alzheimer’s rather than just manage the symptoms,” said Johnson.
This large collaborative effort involved 22 researchers across the Sanders-Brown Center on Aging, multiple departments within the UK College of Medicine, the Saha Cardiovascular Research Center, the University of North Carolina at Chapel Hill, and TransViragen Inc.
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