APOE-ε4 is best known as a risk factor for Alzheimer's disease (AD). Consequently, there is considerable research interest in understanding whether APOE-ε4 influences cognition in healthy adults. Despite a substantial literature reporting effects of APOE genotype on cognition, findings are inconsistent. In particular, it is challenging to separate whether cognitive deficits in APOE-ε4 carriers reflect the influence of prodromal dementia pathology ("prodromal hypothesis"), or a direct contribution of APOE genotype to individual differences ("phenotype hypothesis"). Variable methodology across studies further complicates the issue. These challenges have limited what can be learnt about the processes underlying cognitive ageing and dementia by studying the influence of APOE genotype on cognition. In this review, we focus on the two compatible neurobiological mechanisms by which APOE genotype may influence cognition in healthy adults (prodromal and phenotype). We summarise the behavioural evidence for the influence of APOE on cognition in non-demented adults and explore key methodological challenges for disentangling the cognitive effects of different neurobiological mechanisms of APOE. Evidence suggests that at least some APOE-ε4 cognitive deficits are due to early AD pathology, whilst sensitive measures of cognition are beginning to reveal subtle cognitive differences between APOE genotypes in mid-adulthood, prior to the onset of the AD prodromal period. We conclude with recommendations for future research to investigate the cognitive consequences of neurobiological processes affected by APOE and maximise the translational potential of this research.

Previous imaging studies of congenital blindness have studied individuals with heterogeneous causes of blindness, which may influence the nature and extent of cross-modal plasticity. Here, we scanned a homogeneous group of blind people with bilateral congenital anophthalmia, a condition in which both eyes fail to develop, and, as a result, the visual pathway is not stimulated by either light or retinal waves. This model of congenital blindness presents an opportunity to investigate the effects of very early visual deafferentation on the functional organization of the brain. In anophthalmic animals, the occipital cortex receives direct subcortical auditory input. We hypothesized that this pattern of subcortical reorganization ought to result in a topographic mapping of auditory frequency information in the occipital cortex of anophthalmic people. Using functional MRI, we examined auditory-evoked activity to pure tones of high, medium, and low frequencies. Activity in the superior temporal cortex was significantly reduced in anophthalmic compared with sighted participants. In the occipital cortex, a region corresponding to the cytoarchitecturalareaV5/MTϩwasactivatedintheanophthalmicparticipantsbutnotinsightedcontrols.Whereaspreviousstudiesintheblind indicate that this cortical area is activated to auditory motion, our data show it is also active for trains of pure tone stimuli and in some anophthalmic participants shows a topographic mapping (tonotopy). Therefore, this region appears to be performing early sensory processing, possibly served by direct subcortical input from the pulvinar to V5/MTϩ.

Positive affect and optimism play an important role in healthy ageing and are associated with improved physical and cognitive health outcomes. This study investigated whether it is possible to boost positive affect and associated positive biases in this age group using cognitive training. The effect of computerised imagery-based cognitive bias modification on positive affect, vividness of positive prospective imagery and interpretation biases in older adults was measured. 77 older adults received 4 weeks (12 sessions) of imagery cognitive bias modification or a control condition. They were assessed at baseline, post-training and at a one-month follow-up. Both groups reported decreased negative affect and trait anxiety, and increased optimism across the three assessments. Imagery cognitive bias modification significantly increased the vividness of positive prospective imagery post-training, compared with the control training. Contrary to our hypothesis, there was no difference between the training groups in negative interpretation bias. This is a useful demonstration that it is possible to successfully engage older adults in computer-based cognitive training and to enhance the vividness of positive imagery about the future in this group. Future studies are needed to assess the longer-term consequences of such training and the impact on affect and wellbeing in more vulnerable groups.

The ability to form positive mental images may be an important aspect of mental health and well-being. We have previously demonstrated that the vividness of positive prospective imagery is increased in healthy older adults following positive imagery cognitive training. The rostral anterior cingulate cortex (rACC) is involved in the simulation of future affective episodes. Here, we investigate the effect of positive imagery training on rACC activity during the imagination of novel, ambiguous scenarios vs closely matched control training. Seventy-five participants received 4 weeks of positive imagery or control training. Participants underwent a functional magnetic resonance imaging scan, during which they completed an Ambiguous Sentences Task, which required them to form mental images in response to cues describing ambiguous social events. rACC activity was positively correlated with the pleasantness ratings of images formed. Positive imagery training increased rACC and bilateral hippocampal activity compared with the control training. Here, we demonstrate that rACC activity during positive imagery can be changed by the cognitive training. This is consistent with other evidence that this training enhances the vividness of positive imagery, and suggests the training may be acting to increase the intensity and affective quality of imagery simulating the future.

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IntroductionDespite major advances in the field of neuroscience over the last three decades, the quality of assessments available to patients with memory problems in later life has barely changed. At the same time, a large proportion of dementia biomarker research is conducted in selected research samples that often poorly reflect the demographics of the population of patients who present to memory clinics. The Oxford Brain Health Clinic (BHC) is a newly developed clinical assessment service with embedded research in which all patients are offered high quality clinical and research assessments, including MRI, as standard.Methods and analysisHere we describe the BHC protocol, including aligning our MRI scans with those collected in the UK Biobank. We evaluate rates of research consent for the first 108 patients (data collection ongoing) and the ability of typical Psychiatry-led NHS memory-clinic patients to tolerate both clinical and research assessments.Ethics and disseminationOur ethics and consenting process enables patients to choose the level of research participation that suits them. This generates high rates of consent, enabling us to populate a research database with high quality data that will be disseminated through a national platform (the Dementias Platform UK data portal).ARTICLE SUMMARYThe Oxford Brain Health Clinic embeds high-quality assessments into routine clinical care for typical patients with memory problems.The BHC MRI protocol is aligned with the UK Biobank providing a unique opportunity to link the power of big-data and individual patients at the clinical interface.The BHC ethics and consenting process, designed in partnership with an active PPI advisory group, enables patients to choose the level of research participation that suits them.The BHC research database and associated information governance will facilitate research use of real-world clinical information where consent is given.The Oxford BHC pilot required that patients were not contraindicated for MRI. Future work to expand the model will remove this constraint.

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Working memory (WM) is essential for normal cognitive function, but shows marked decline in aging. The importance of selective attention in guiding WM performance is increasingly recognized. Studies so far are inconclusive about the ability to use selective attention during WM in aging. To investigate the neural mechanisms supporting selective attention in WM in aging, we tested a large group of older adults using functional magnetic resonance imaging whilst they performed a category-based (faces/houses) selective-WM task. Older adults were able to use attention to encode targets and suppress distractors to reach high levels of task performance. A subsequent, surprise recognition-memory task showed strong consequences of selective attention. Attended items in the relevant category were recognized significantly better than items in the ignored category. Neural measures also showed reliable markers of selective attention during WM. Purported control regions including the dorsolateral and inferior prefrontal and anterior cingulate cortex were reliably recruited for attention to both categories. Activation levels in category-sensitive visual cortex showed reliable modulation according to attentional demands, and positively correlated with subsequent memory measures of attention and WM span. Psychophysiological interaction analyses showed that activity in category-sensitive areas were coupled with non-sensory cortex known to be involved in cognitive control and memory processing, including regions in the prefrontal cortex and hippocampus. In summary, we found that older adults were able to recruit a network of brain regions involved in top-down attention during selective WM, and individual differences in attentional control corresponded to the degree of attention-related modulation in the brain.