How a Key Alzheimer’s Risk Gene May Damage the Brain Decades Early
Researchers have long known that the APOE4 variant of the APOE gene is one of the strongest genetic risk factors for late-onset Alzheimer’s disease. Now, a study in mice offers a possible explanation for how it begins damaging the brain long before memory problems show up.
The team found that APOE4 increased production of a protein called Nell2 in the brain. Higher Nell2 levels appeared to shrink neurons and cause unusual hyperactivity in memory-related circuits. Crucially, this early overactivity turned out to be a predictor of poorer memory performance later in life.
The most encouraging finding: when researchers reduced Nell2 in adult mice, the abnormal changes were reversed. This suggests that targeting Nell2—or the pathways it influences—could potentially open a window for intervention before Alzheimer’s progresses to symptomatic stages.
While the work was done in mice and will need to be validated in humans, it highlights a specific molecular mechanism that links a well-known genetic risk factor to early, measurable changes in brain structure and function. Understanding that chain of events may eventually help clinicians intervene years earlier than is currently possible.