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

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'.

Recent work in our lab, and replicated in others, has demonstrated that young healthy adults carrying the genotype APOE e4 (e4+) outperform their peers who have non-e4 alleles of this gene (non-e4) on a range of cognitive measures. This is surprising, as the e4+ allele in clinically healthy older adults is associated with age-related memory deficits. We reported also that young e4+ show bigger cognitive benefits from procholinergic nicotinic stimulation. We have evidence, then, that the e4+ variant of the ApoE gene and nicotinic stimulation both improve performance on cognitive tasks, and we argue that they do so by recruiting frontal and parietal neural systems that together optimise cognitive benefits. In the current proposal we will establish the relationship between frontal and parietal systems in the combined effects on cognition of genotype and nicotinic stimulation. We will extend functional measures of neural activation with highly sensitive measures of micro-brain structures (diffusion tensor imaging, magnetization transfer imaging). Finally, we will ascertain whether the cognitive advantages and procholinergic effects observed for young adult e4+ carriers are sustained in mid-age volunteers. This age group has not been systematically studied, but are arguably the best target group for prophylactic interventions, since subtle deficits in cognition are reported by the fifth decade. The work is relevant to the development of new ways to prevent or remediate impairments in cognitive abilities that emerge across the natural lifespan. It will tell us when the interventions 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'.