Jenny Rusted and colleagues are working on gene-environment interplay in cognitive ageing
Rising to the Challenge: Understanding causes and consequences of neural overactivation in young adult APOE-4 carriers
Research focus
As people age, they tend to find that their minds are not as ‘sharp’ as when they were younger. However, some people will experience more change than others. It has been discovered that a particular gene called APOE influences the way cognitive abilities change with age. Specifically, individuals with the e4 variant of the gene seem to experience greater decline in cognitive skills than those without – and this is evident even in healthy individuals (notable as the e4 variant is also linked to risk of dementia and mild cognitive impairment).
In our recent work, funded by the BBSRC, we have shown that the effects of this gene are actually present at a relatively young age. Our work and that of others has reported that in their twenties, e4 carriers can show better performance on certain cognitive tests, and this is linked to greater brain activity in specific parts of the brain. By the fifth decade, however, a different pattern emerges. Cognitive performance is about the same, but the brain activity patterns of e4 carriers look more like what you’d see in someone considerably older. Healthy aging is linked to greater brain activity, as the brain tries to work around the changes that are happening as a natural part of the aging process. It seems that e4 carriers show this ‘compensation’ pattern earlier in life: this can produce better performance in some tasks in youth, but at middle age and beyond, e4 carriers cannot compensate further to counteract normal aging. This means that they are more susceptible to cognitive decline in later life.
As e4s get older, they show a distinctive pattern of brain activity. Here we compared brain activation patterns in young adults and mid-aged individuals. We found that mid-aged e4 carriers show decreased activation in certain regions of the brain, but increased activation in others. Increased activity was seen in frontal parts of the brain, possibly as a compensatory response for decreased activity elsewhere. This pattern is similar to that usually observed in much older people. Therefore it seems that e4 carriers are ageing quicker in neural terms.
Study Design
So as to better understand the effects of APOE in young adults, we recruited 30 e4 carriers and 30 non-e4 carriers aged 18-28. These volunteers visited the lab on 3 occasions. The first 2 sessions were in the MRI scanner, and consisted of some tasks of attention and memory (participants lie in the scanner and make responses using a button box in their lap), and some structural scanning (taking detailed pictures of their brain structure).
The structural measures acquired were:
- NODDI (a new diffusion MRI technique for measuring the microstructure of connecting fibres in the brain, see movie below, right)
- qMT (measures myelination: myelin is a fatty sheath that surrounds these connecting fibres)
- High-resolution T1 (provides detailed images of both the white and grey matter of the brain, these can then be analysed to see whether APOE causes differences in volume, see movie below, left)
The 3rd session involved other tasks and cortisol measures (saliva samples) were collected throughout the session. Volunteers completed a series of challenging cognitive tasks in quick succession (including arithmetic, attention, memory) as well as various questionnaires. Cortisol is a hormone that is released under conditions of stress. Cortisol is a hormone that is released under conditions of stress. In the long-term cortisol has negative consequences and the aim was to see if e4 carriers have a different cortisol response to a cognitive stress test.
Results
Data analysis is well underway. Results confirm that young adult e4 carriers overactivate specific brain regions across a variety of tasks, although this does not necessarily lead to improved performance. For example, on a memory task where participants are shown a list of words followed by a surprise memory test, we have found that e4 carriers show greater activity in a part of the brain called the hippocampus (see images below). This overactivity at a young age could be a reason why e4 carriers are at greater risk of cognitive decline in later life.
Young adult e4 carriers (e4+) show greater activity in the hippocampus to remembered words (R), while non-e4 carriers (e4-) do not.
The aim of the current project is to explore why e4 carriers show greater activity in young adulthood. We will find out if it’s limited to particular aspects of cognition, whether it’s related to the amount of effort people put in to doing a task, and whether the overactivity is present all the time or can be ‘switched off’ under certain circumstances. This will tell us what the overactivity in e4 carriers means in terms of performance, and how it could be modified. Longer-term, this will inform strategies that aim to correct the overactivity, and help e4 carriers to stay cognitively healthy as they age. We’ll also be looking at differences in brain connectivity patterns and brain structure that might relate to the overactivity.
Below are examples of structural movies that may reveal important differences in e4 carriers.
The movie on the left depicts how the brain is organised structurally, while the movie on the right shows how connections between brain areas (fiber tracts) are laid out.
The current project is again funded by the BBSRC, and our overarching aim is to define the cognitive profile associated with the e4 genotype and also the conditions under which it can best be supported in older adulthood.
Key researchers
Prof Jenny Rusted, Professor in Experimental Psychology, School of Psychology, University of Sussex
Relevant weblinks:
Homepage for Jenny Rusted
Website for Jenny Rusted's Lab Group
http://www.bsms.ac.uk/research/cisc/research
Dr Simon Evans, Post Doctoral Researcher, School of Psychology, University of Sussex
Relevant weblinks:
http://www.sussex.ac.uk/profiles/277290
http://www.bsms.ac.uk/research/cisc/research
Dr Sarah King, Lecturer in Behavioural Neuroscience, University of Sussex
Relevant weblinks:
http://www.sussex.ac.uk/psychology/people/peoplelists/person/9946
Dr Nick Dowell, Lecturer in Imaging Physics, Brighton and Sussex Medical School
Special interest: Quantitative MRI of the brain.
Relevant weblinks:
http://www.sussex.ac.uk/Users/bsms1623/participate/index.html
http://www.bsms.ac.uk/research/cisc/research
Prof Paul Tofts, Emeritus Professor, Brighton and Sussex Medical School
Special interest: Quantitative MRI of the brain: measuring changes caused by disease.
Relevant weblinks:
http://www.paul-tofts-phd.org.uk
http://www.qmri.org
Dr Naji Tabet, Senior Lecturer in Old Age Psychiatry, Brighton and Sussex Medical School
Relevant weblinks:
http://www.bsms.ac.uk/research/our-researchers/naji-tabet/
Posters and presentations
ARUK 2016:
“Young adult APOE-e4 carriers show different patterns of neural activity during a subsequent memory task"
Evans SL, Dowell NG, Tabet N, King SL, Hutton S, Rusted JM
SINDEM 2015:
“APOE e4 effects on regional brain volume and correlations with memory and attentional performance"
Evans SL, Dowell NG, Tabet N, King SL, Rusted JM
ISMRM 2013:
“Evidence for structural differences in normal appearing brain tissue of those carrying different alleles of APOE”
Dowell NG, Evans SL, Ruest T, Tofts PS, King SL, Tabet N, Rusted JM
BNA festival of Neuroscience 2013:
“Defining the cognitive and neural signatures of the APOE E4 allele in middle age”
Evans SL, Dowell NG, King SL, Tabet N, Tofts PS, Rusted JM
British Association for Psychopharmacology 2012:
“Nicotine enhances prospective memory performance in APOE E4 carriers: an fMRI study”
Evans SL, Gray M, Dowell NG, King SL, Tabet N, Tofts PS, Rusted JM
Society for Neuroscience 2011:
"Neural signatures of the APOE e4 genetic predisposition to Alzheimer's Disease in healthy young adults”
King SL, Ruest T, Broulidakis J, Dowell NG, Rusted JM
Public engagement activities
Brighton Science Fair 2015: We ran a stall at the Bright Sparks event designed to educate and entertain children aged 7-14 (and their parents). Activities included build a brain hat/DNA, eyetracker demo (watch your pupil size change in real time as you do a cognitive task) and a competition using one of the vigilance tasks we use in the brain scanner.
Café Scientifique 21st Jan 2015: Dr. Naji Tabet presented an overview of our work on APOE and led a Q&A session at Café Scientifique in Brighton.
Relevant publications
Evans, S, Dowell, N G, Tabet, N, Tofts, P S, King, S L, Rusted, J M (2014) Cognitive and neural signatures of the APOE E4 allele in mid-aged adults. Neurobiology of Aging, 35 (7). pp.1615-23.
Evans, S, Dowell, N G, Tabet, N, Tofts, P S, King, S L, Gray, M and Rusted, J M (2013) Nicotine effects on attentional reorienting in mid-age adults, and interactions with apolipoprotein E status. Journal of Psychopharmacology, 27 (11). pp. 1007-1014. ISSN 0269-8811
Dowell, Nicholas G, Ruest, Torsten, Evans, Simon L, King, Sarah L, Tabet, Naji, Tofts, Paul S and Rusted, Jennifer M (2013) MRI of carriers of the apolipoprotein E e4 allele-evidence for structural differences in normal-appearing brain tissue in e4+ relative to e4- young adults. NMR in Biomedicine, 26 (6). pp. 674-682. ISSN 0952-3480
Rusted, J M, Evans, S L, King, S L, Dowell, N G, Tabet, N and Tofts, P S (2013) APOE e4 polymorphism in young adults is associated with improved attention and indexed by distinct neural signatures. NeuroImage, 65 (1). pp. 364-373. ISSN 1053-8119
Evans, Simon, Gray, Marcus A, Dowell, Nicholas, Tabet, Naji, Tofts, Paul S, King, Sarah and Rusted, Jennifer M (2013) APOE E4 carriers show prospective memory enhancement under nicotine, and evidence for specialisation within medial BA10. Neuropsychopharmacology, 38 (4). pp.655-63
Marchant, Natalie L, King, Sarah L, Tabet, Naji and Rusted, Jennifer M (2010) Positive effects of cholinergic stimulation favor young APOE epsilon4 carriers. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 35 (5). pp. 1090-6. ISSN 1740-634X