阿尔茨海默病风险基因可在症状出现前数年导致脑细胞萎缩

Gladstone研究所的研究团队发现，阿尔茨海默病主要风险基因APOE4通过增加Nell2蛋白的产生，引发神经元萎缩和脑活动异常亢进，这些早期变化可预测后期的记忆衰退1。APOE4是已知最强的遗传风险因素，约四分之一的人口携带该基因1。

研究人员在小鼠模型中发现，年轻阶段的脑活动亢进程度能够预示其后期记忆问题的严重程度1。更为重要的是，使用CRISPRi技术降低成年APOE4小鼠的Nell2水平后，神经元恢复到正常大小和功能，表明这些异常变化具有可逆性1。这是首项直接研究APOE4在不同年龄对神经元功能影响的工作1，为开发新的干预治疗策略提供了希望。该研究已发表在《Nature Aging》期刊2026年第6卷第4期1。

Researchers at Gladstone Institute have identified a mechanism by which APOE4, the strongest known genetic risk factor for Alzheimer's disease, damages neurons years before cognitive decline emerges 1. The team discovered that APOE4 increases production of the Nell2 protein, which causes neurons to shrink and exhibit excessive brain activity 1. This early pathological change in young mice proved predictive of subsequent memory problems later in life 1.

The study, published in Nature Aging in 2026, represents the first direct investigation of how APOE4 affects neuronal function across different ages 1. Approximately one-quarter of the population carries the APOE4 variant 1. In experiments using CRISPRi technology, researchers demonstrated that reducing Nell2 levels in adult mice carrying APOE4 reversed the abnormal neuronal shrinkage and restored normal brain function 1. These findings suggest that Nell2 could serve as a therapeutic target for developing interventions to prevent or delay Alzheimer's disease progression in APOE4 carriers 1.