VA San Diego Healthcare System, 3350 La Jolla Village Dr., San Diego, 92161, USA; SDSU/UC San Diego Joint Doctoral Program in Clinical Psychology, 6363 Alvarado Court, Suite 103, San Diego, CA, 92120, USA.
Department of Psychiatry, UC San Diego, 9500 Gilman Dr., La Jolla, CA, 92093, USA; SDSU/UC San Diego Joint Doctoral Program in Clinical Psychology, 6363 Alvarado Court, Suite 103, San Diego, CA, 92120, USA.
Neuroimage. 2019 Nov 15;202:116162. doi: 10.1016/j.neuroimage.2019.116162. Epub 2019 Sep 4.
The ε4 allele of the apolipoprotein E (APOE) gene increases risk for cognitive decline in normal and pathologic aging. However, precisely how APOE ε4 exerts its negative impact on cognition is poorly understood. The present study aimed to determine whether APOE genotype (ε4+ vs. ε4-) modifies the interaction of medial temporal lobe (MTL) resting cerebral blood flow (CBF) and brain structure (cortical thickness [CT], volume [Vo]) on verbal memory performance.
Multiple linear regression models were employed to investigate relationships between APOE genotype, arterial spin labeling MRI-measured CBF and FreeSurfer-based CT and Vo in four MTL regions of interest (left and right entorhinal cortex and hippocampus), and verbal memory performance among a sample of 117 cognitively normal older adults (41 ε4+, 76 ε4-) between the ages of 64 and 89 (mean age = 73).
Results indicated that APOE genotype modified the interaction of CBF and CT on memory in the left entorhinal cortex, such that the relationship between entorhinal CBF and memory was negative (lower CBF was associated with better memory) in non-carriers with higher entorhinal CT, positive (higher CBF was associated with better memory) in non-carriers with lower entorhinal CT, and negative (higher CBF was associated with worse memory) in ε4 carriers with lower entorhinal CT.
Findings suggest that older adult APOE ε4 carriers may experience vascular dysregulation and concomitant morphological alterations in the MTL that interact to negatively affect memory even in the absence overt clinical symptoms, providing potential insight into the mechanistic link between APOE ε4 and detriments in cognition. Moreover, findings suggest a distinct multimodal neural signature in ε4 carriers (higher CBF and lower CT in the entorhinal cortex) that could aid in the identification of candidates for future clinical trials aimed at preventing or slowing cognitive decline. Differential findings with respect to ε4 carriers and non-carriers are discussed in the context of neurovascular compensation.
载脂蛋白 E（APOE）基因的 ε4 等位基因增加了正常和病理性衰老认知能力下降的风险。然而，APOE ε4 如何对认知产生负面影响仍知之甚少。本研究旨在确定 APOE 基因型（ε4+与 ε4-）是否会改变内侧颞叶（MTL）静息脑血流（CBF）与脑结构（皮质厚度[CT]，体积[Vo]）对言语记忆表现的相互作用。
采用多元线性回归模型，研究了认知正常的老年个体（年龄 64 至 89 岁，平均年龄 73 岁，41 名 ε4+，76 名 ε4-）中 APOE 基因型、动脉自旋标记 MRI 测量的 CBF 与基于 FreeSurfer 的 CT 和 Vo 之间的关系，以及这四个 MTL 感兴趣区（左、右内嗅皮层和海马体）的言语记忆表现。
结果表明，APOE 基因型改变了左内嗅皮层 CBF 和 CT 对记忆的相互作用，在内嗅皮层 CBF 与记忆之间的关系中，非携带者的关系为负相关（较低的 CBF 与较好的记忆相关），较高的内嗅 CT；非携带者为正相关（较高的 CBF 与更好的记忆相关），较低的内嗅 CT；ε4 携带者为负相关（较高的 CBF 与较差的记忆相关），较低的内嗅 CT。
研究结果表明，老年 APOE ε4 携带者可能会出现血管调节异常和内侧颞叶形态改变，这些改变相互作用，即使在没有明显临床症状的情况下，也会对记忆产生负面影响，为 APOE ε4 与认知能力下降之间的机制联系提供了潜在的见解。此外，研究结果还表明，ε4 携带者存在一种独特的多模态神经特征（内嗅皮层的 CBF 较高，CT 较低），这可能有助于识别未来旨在预防或减缓认知能力下降的临床试验的候选者。在神经血管代偿的背景下，讨论了与 ε4 携带者和非携带者的差异发现。
