Millions of people carry APOE4, the strongest known genetic risk factor for Alzheimer's disease. New research suggests the gene variant may begin altering brain activity well before memory problems become noticeable. Researchers at Gladstone Institutes have now mapped out a molecular sequence that could help explain these early effects.
Their findings also point to a possible way to reverse some of the changes. In a study using mouse models, published in Nature Aging, the researchers found that APOE4 increases production of a protein called Nell2. Higher Nell2 levels caused neurons to become smaller and unusually active.
Mice with the greatest brain hyperactivity when they were young later developed the most severe memory problems. The team then reduced Nell2 production. Even in adult mice carrying APOE4, neurons returned toward their normal size and firing behavior.
The result raises the possibility that future drugs targeting Nell2 could help people with APOE4 who face an elevated risk of Alzheimer's disease. "To the best of our knowledge, this is the first study that has directly examined what APOE4 does to the function of neurons at different ages," says Misha Zilberter, PhD, principal staff research scientist at Gladstone and a senior author of the study. "We found fundamental changes in brain circuits occurring in young mice that still had normal learning and memory, and importantly, that those changes predicted the development of cognitive deficits at older ages." A Major Genetic Risk Factor for Alzheimer's APOE4 is one of three common forms of the APOE gene, but it has a much stronger connection to Alzheimer's risk than the others.
Roughly one in four people carry APOE4, and the variant is estimated to occur in 60 to 75 percent of people with Alzheimer's. "This study is a big breakthrough for the field of Alzheimer's research," says Yadong Huang, MD, PhD, associate director of the Gladstone Institute of Neurological Disease and a senior author of the study. "It opens the door to a better understanding of how APOE4 alters the function of neurons at a young age to increase risk of cognitive decline, and to the development of therapies that could block the detrimental effects of APOE4 early on." APOE4 Makes Memory Circuits Hyperactive Early Earlier research had already found signs of unusually high brain activity in human APOE4 carriers before middle age.
That early hyperactivity has also been associated with later cognitive decline. What remained unclear was how APOE4 produced these cellular changes and why they might contribute to memory problems later in life. To investigate, the researchers studied recordings of brain activity in young mice and examined individual neurons from their brains.
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