A Groundbreaking Study on Alzheimer’s Disease

Millions of people around the world carry the APOE4 gene variant, which is the strongest known genetic risk factor for Alzheimer’s disease. New research suggests that this gene variant may begin altering brain activity years before memory problems become noticeable. Scientists at the Gladstone Institutes have mapped out a molecular sequence that could help explain these early effects and have found a possible way to reverse some of the changes.

The study, published in Nature Aging, used mouse models to examine the effects of APOE4 on brain cells. The researchers found that APOE4 increases the production of a protein called Nell2, which causes neurons to become smaller and more active. Mice with the greatest brain hyperactivity when they were young later developed the most severe memory problems.

However, when the researchers reduced Nell2 production in adult mice carrying APOE4, the neurons returned to their normal size and firing behavior. This finding raises the possibility that future drugs targeting Nell2 could help people with APOE4 who face an elevated risk of Alzheimer’s disease.

The researchers also found that the extent of hyperactivity in young mice predicted how poorly they performed on spatial learning and memory tests later in life. Notably, those same hippocampal regions have also been found to be hyperactive in people carrying APOE4.

‘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.’

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.’

The researchers also found that Nell2 levels were elevated in the brains of Alzheimer’s patients, with higher amounts associated with poorer cognitive function. What’s exciting about Nell2 is that the researchers were able to reverse the disease manifestations in adult mice by lowering its level. This tells us that the damage is not irreversible, and that there may be a window for intervention even after disease processes have been triggered.