Abstract The Apolipoprotein-E ( APOE ) ε4 gene allele, the highest known genetic risk factor for Alzheimer’s disease, has paradoxically been well preserved in the human population. One possible explanation offered by evolutionary biology for survival of deleterious genes is antagonistic pleiotropy. This theory proposes that such genetic variants might confer an advantage, even earlier in life when humans are also reproductively fit. The results of some small-cohort studies have raised the possibility of such a pleiotropic effect for the ε4 allele in short-term memory (STM) but the findings have been inconsistent. Here, we tested STM performance in a large cohort of individuals ( N = 1277); nine hundred and fifty-nine of which included carrier and non-carriers of the APOE ε4 gene, those at highest risk of developing Alzheimer’s disease. We first confirm that this task is sensitive to subtle deterioration in memory performance across ageing. Importantly, individuals carrying the APOE ε4 gene actually exhibited a significant memory advantage across all ages, specifically for brief retention periods but crucially not for longer durations. Together, these findings present the strongest evidence to date for a gene having an antagonistic pleiotropy effect on human cognitive function across a wide age range, and hence provide an explanation for the survival of the APOE ε4 allele in the gene pool.
Abstract Reinforcement learning (RL) is widely regarded as divisible into two distinct computational strategies. Model-free learning is a simple RL process in which a value is associated with actions, whereas model-based learning relies on the formation of internal models of the environment to maximise reward. Recently, theoretical and animal work has suggested that such models might be used to train model-free behaviour, reducing the burden of costly forward planning. Here we devised a way to probe this possibility in human behaviour. We adapted a two-stage decision task and found evidence that model-based processes at the time of learning can alter model-free valuation in healthy individuals. We asked people to rate subjective value of an irrelevant feature that was seen at the time a model-based decision would have been made. These irrelevant feature value ratings were updated by rewards, but in a way that accounted for whether the selected action retrospectively ought to have been taken. This model-based influence on model-free value ratings was best accounted for by a reward prediction error that was calculated relative to the decision path that would most likely have led to the reward. This effect occurred independently of attention and was not present when participants were not explicitly told about the structure of the environment. These findings suggest that current conceptions of model-based and model-free learning require updating in favour of a more integrated approach. Our task provides an empirical handle for further study of the dialogue between these two learning systems in the future.
Ventromedial prefrontal cortex (vmPFC) is vital for decision-making. Functional neuroimaging links vmPFC to processing rewards and effort, while parallel work suggests vmPFC involvement in prosocial behaviour. However, the necessity of vmPFC for these functions is unknown. Patients with rare focal vmPFC lesions (n = 25), patients with lesions elsewhere (n = 15) and healthy controls (n = 40) chose between rest and exerting effort to earn rewards for themselves or another person. vmPFC damage decreased prosociality across behavioural and computational measures. vmPFC patients earned less, discounted rewards by effort more, and exerted less force when another person benefited, compared to both control groups. Voxel-based lesion mapping revealed dissociations between vmPFC subregions. While medial damage led to antisocial behaviour, lateral damage increased prosocial behaviour relative to patients with damage elsewhere. vmPFC patients also showed reduced effort sensitivity overall, but reward sensitivity was limited to specific subregions. These results reveal multiple causal contributions of vmPFC to prosocial behaviour, effort and reward.
Abstract From a gym workout, to deciding whether to persevere at work, many activities require us to persist in deciding that rewards are ‘worth the effort’ even as we become fatigued. However, studies examining effort-based decisions typically assume that the willingness to work is static. Here, we use computational modelling on two effort-based tasks, one behavioural and one during fMRI. We show that two hidden states of fatigue fluctuate on a moment-to-moment basis on different timescales but both reduce the willingness to exert effort for reward. The value of one state increases after effort but is ‘recoverable’ by rests, whereas a second ‘unrecoverable’ state gradually increases with work. The BOLD response in separate medial and lateral frontal sub-regions covaried with these states when making effort-based decisions, while a distinct fronto-striatal system integrated fatigue with value. These results provide a computational framework for understanding the brain mechanisms of persistence and momentary fatigue.
Working memory (WM) and reinforcement learning (RL) both influence decision-making, but how they interact to affect behaviour remains unclear. We assessed whether RL is influenced by the format of visual stimuli held in WM, either feature-based or unified, object-based representations. In a pre-registered paradigm, participants learned stimulus-action combinations that provided reward through 80% probabilistic feedback. In parallel, participants retained the RL stimulus in WM and were asked to recall this stimulus after each RL choice. Crucially, the format of representation probed in WM was manipulated, with blocks encouraging either separate features or bound objects to be remembered. Incentivising a feature-based WM representation facilitated feature-based learning, shown by an improved choice strategy. This reveals a role of WM in providing sustained internal representations that are harnessed by RL, providing a framework by which these two cognitive processes cooperate.
Abstract Healthy cognitive ageing is a societal and public health priority. Cerebrovascular risk factors increase the likelihood of dementia in older people but their impact on cognitive ageing in younger, healthy brains is less clear. The UK Biobank provides cognition and brain imaging measures in the largest population cohort studied to date. Here we show that cognitive abilities of healthy individuals (N = 22,059) in this sample are detrimentally affected by cerebrovascular risk factors. Structural equation modelling revealed that cerebrovascular risk is associated with reduced cerebral grey matter and white matter integrity within a fronto-parietal brain network underlying executive function. Notably, higher systolic blood pressure was associated with worse executive cognitive function in mid-life (44–69 years), but not in late-life (>70 years). During mid-life this association did not occur in the systolic range of 110–140 mmHg. These findings suggest cerebrovascular risk factors impact on brain structure and cognitive function in healthy people.
The effects of apolipoprotein E ( APOE ) and Klotho genes, both implicated in aging, on human cognition as a function of sex and age are yet to be definitively established. Here, we showed in the largest cohort studied to date ( N = 320,861) that APOE homozygous ε4 carriers had a greater decline in cognition with aging compared to ε3 carriers (ε3/ε4 and ε3/ε3) as well as smaller hippocampi and amygdala ( N = 29,510). Critically, sex and age differentially affected the decline in cognition. Younger (40 to 50 y) female homozygous ε4 carriers showed a cognitive advantage over female ε3 carriers, but this advantage was not present in males. By contrast, Klotho-VS heterozygosity did not affect cognition or brain volume, regardless of APOE genotype, sex, or age. These cognitive trajectories with aging demonstrate clear sex-dependent antagonistic pleiotropy effects of APOE ε4, but no effects of Klotho genotype on cognition and brain volume.
Abstract Apathy and impulsivity are debilitating conditions associated with many neuropsychiatric conditions, and expressed to variable degrees in healthy people. While some theories suggest that they lie at different ends of a continuum, others suggest their possible co-existence. Surprisingly little is known, however, about their empirical association in the general population. Here, gathering data from six large studies ( $$n = 3755$$ n=3755 ), we investigated the relationship between measures of apathy and impulsivity in young adults. The questionnaires included commonly used self-assessment tools—Apathy Evaluation Scale, Barratt Impulsiveness Scale (BIS-11) and UPPS-P Scale—as well as a more recent addition, the Apathy Motivation Index (AMI). Remarkably, across datasets and assessment tools, global measures of apathy and impulsivity correlated positively. However, analysis of sub-scale scores revealed a more complex relationship. Although most dimensions correlated positively with one another, there were two important exceptions revealed using the AMI scale. Social apathy was mostly negatively correlated with impulsive behaviour, and emotional apathy was orthogonal to all other sub-domains. These results suggest that at a global level, apathy and impulsivity do not exist at distinct ends of a continuum. Instead, paradoxically, they most often co-exist in young adults. Processes underlying social and emotional apathy, however, appear to be different and dissociable from behavioural apathy and impulsivity.
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