Similar or different: neural signatures behind the cognitive effects of apolipoprotein E e4 polymorphism and cholinergic stimulation in healthy adults

我们实验室最近的工作发现了一个悖论--携带一种与老年记忆障碍相关的基因变体的年轻人似乎比没有携带这种变体的年轻人有更好的记忆力。这是令人惊讶的，因为这种变异与健康的人在大约50年的生命中的记忆缺陷有可靠的联系。此外，我们还证明，作为年轻人，携带者比非携带者对改善记忆性能的化合物--所谓的“认知增强剂”--的反应更好。这项拨款中提出的研究将帮助我们了解该基因变体携带者和非携带者的大脑有何不同，以及当人们从年轻到中年时，它们是如何变化的。我们将对携带该基因变体的中青年成年人的大脑进行成像，并将其与年龄匹配的非携带者的大脑进行比较。特别是，我们将比较在重要的日常记忆任务中使用的大脑区域的活动。这些实验将揭示，拥有变异基因是否会改善大脑中这些区域在典型和具有挑战性的情况下的使用方式。我们将确定为什么变异体的携带者从认知增强剂中获得额外的认知促进。我们认为，基因变体和认知增强剂正在刺激不同的大脑区域，两者结合在一起的附加值为基因变体的携带者带来了额外的好处。最后，我们将确定年轻携带者对认知增强药物的更好反应是否在中年继续保持不变。由于该基因的变异与健康老年人的记忆障碍有关，这一知识将对开发新的方法来预防或补救自然出现的认知能力障碍产生直接影响。这项工作将告诉我们，何时对记忆衰竭进行干预将产生最大的效果，并将直接影响老年人的幸福感和独立生活。这项工作与BBSRC的优先领域“老龄化研究：终身健康和福祉”直接相关。

Recent work in our lab has identified a paradox - younger adults carrying a variant of a gene associated with memory impairment in older life appear to have better memories than their young adult peers who are not carrying this variant. This is surprising, because the variant is reliably associated with memory deficits in otherwise healthy people from about the fifth decade of life. In addition, we have demonstrated that as young adults, the carriers respond better than non-carriers to compounds that improve memory performance - so called 'cognitive enhancers'. The studies proposed in this grant will help us to understand how the brains of carriers and non-carriers of the gene variant differ, and how they change as people move from young to middle adulthood. We will image the brains of younger and mid-aged adults who carry the gene variant and compare them to the brains of age-matched non-carriers. In particular, we will compare the activity in areas of the brain that are used during important everyday memory tasks. The experiments will reveal whether having the variant gene improves the way those areas of the brain are used in typical and in challenging situations. We will establish why carriers of the variant get an extra cognitive boost from cognitive enhancers. We believe that the gene variant and cognitive enhancers are stimulating different brain areas, and that the added value of having the two together produces extra benefits to the carriers of the gene variant. Finally, we will determine whether the better response in young carriers to a cognitive enhancing drug continues undiminished in mid-age. Because the variant of the gene is linked to memory impairments in healthy older adults, this knowledge will have a direct impact on the development of new ways to prevent or remediate impairments in cognitive abilities that naturally emerge across the lifespan. The work will tell us when interventions for memory failure will have the maximum effectiveness, and will impact directly on wellbeing and independent living on older adulthood. The work relates directly to the BBSRC priority area 'Ageing research: lifelong health and wellbeing'.