Key Alzheimer's risk gene may shrink and overexcite brain cells years before symptoms appear
Gladstone Institutes researchers found that in mice, the APOE4 gene variant drives overproduction of a protein called Nell2, which shrinks and overactivates neurons long before memory problems emerge — and that lowering Nell2 partly reverses the effect.
About one in four people carry APOE4, the strongest known genetic risk factor for Alzheimer's disease, and it is present in 60 to 75 percent of Alzheimer's patients. A new study from Gladstone Institutes, published in Nature Aging, suggests the variant can begin altering brain function long before memory decline becomes noticeable.
Using mouse models, researchers found that APOE4 boosts production of a protein called Nell2, which causes neurons to shrink and become unusually active. Young mice with the strongest brain hyperactivity later went on to develop the most severe memory problems. This hyperactivity appeared in two regions of the hippocampus, the brain area central to memory, and predicted poor performance on spatial learning and memory tests later in life.
Compared with mice carrying APOE3, a variant linked to lower Alzheimer's risk, APOE4 mice had smaller neurons in the affected brain regions, making them more prone to fire excessively. APOE3 mice eventually developed similar changes, but only in old age — suggesting APOE4 accelerates a process resembling normal aging.
Neurons, not astrocytes, drive the effect
While most APOE4 in a healthy brain is produced by astrocytes, support cells for neurons, the study found the hyperactivity was driven entirely by APOE4 made within neurons themselves. Deleting the gene from astrocytes changed nothing, but deleting it from neurons restored their normal size and function.
Nell2 as a potential treatment target
Using CRISPRi, a technique that reduces gene activity without permanently altering DNA, researchers lowered Nell2 levels in hippocampal neurons of adult APOE4 mice. The neurons then grew larger and less excitable, showing the changes were reversible even after they had already occurred. The researchers say the finding points to Nell2 as a possible target for future drugs aimed at people carrying APOE4 who face elevated Alzheimer's risk.
