Vanderlip Casey R, Stark Craig E L
Department of Neurobiology and Behavior, University of California Irvine.
bioRxiv. 2024 Dec 24:2024.12.23.630203. doi: 10.1101/2024.12.23.630203.
Apolipoprotein E4 (APOE4) is the strongest genetic risk factor for sporadic Alzheimer's disease (AD). Individuals with one copy of APOE4 exhibit greater amyloid-beta (Aβ) deposition compared to noncarriers, an effect that is even more pronounced in APOE4 homozygotes. Interestingly, APOE4 carriers not only show more AD pathology but also experience more rapid cognitive decline, particularly in episodic memory. The underlying mechanisms driving this domain-specific vulnerability, however, remain unclear. In this study, we examined whether the accelerated decline in episodic memory among APOE4 carriers is due to increased Aβ deposition or heightened susceptibility to Aβ-related effects. Using data from the Alzheimer's Disease Research Initiative, we modeled amyloid duration, the estimated number of years an individual has been amyloid-positive, and its impact on cognitive trajectories. Our findings reveal that APOE4 is associated with more rapid episodic memory decline as a function of amyloid duration. This decline was dose-dependent, with APOE4 homozygotes declining more rapidly than heterozygotes, and it was consistently observed across multiple episodic memory tasks and measures. Importantly, this pattern was not observed in other cognitive domains, such as processing speed, executive function, visuospatial skills, language, or crystallized intelligence. These results suggest that cognitive trajectories in AD differ by APOE genotype, with APOE4 conferring increased vulnerability to hippocampal dysfunction early in the disease course. Future research should investigate whether these cognitive differences stem from distinct pathological cascades in APOE4 carriers.
载脂蛋白E4（APOE4）是散发性阿尔茨海默病（AD）最强的遗传风险因素。与非携带者相比，携带一份APOE4的个体表现出更多的β淀粉样蛋白（Aβ）沉积，这种效应在APOE4纯合子中更为明显。有趣的是，APOE4携带者不仅表现出更多的AD病理学特征，而且认知衰退更快，尤其是在情景记忆方面。然而，导致这种特定领域易损性的潜在机制仍不清楚。在本研究中，我们研究了APOE4携带者情景记忆加速衰退是由于Aβ沉积增加还是对Aβ相关效应的易感性增加。利用阿尔茨海默病研究倡议的数据，我们建立了淀粉样蛋白持续时间的模型，即个体淀粉样蛋白呈阳性的估计年数，及其对认知轨迹的影响。我们的研究结果表明，APOE4与情景记忆随淀粉样蛋白持续时间的更快衰退有关。这种衰退是剂量依赖性的，APOE4纯合子比杂合子衰退更快，并且在多个情景记忆任务和测量中一致观察到。重要的是，在其他认知领域，如处理速度、执行功能、视觉空间技能、语言或晶体智力中未观察到这种模式。这些结果表明，AD中的认知轨迹因APOE基因型而异，APOE4在疾病早期使海马功能障碍的易感性增加。未来的研究应该调查这些认知差异是否源于APOE4携带者不同的病理级联反应。
