Slower and more variable simple reaction times are associated with elevated rates of all-cause [1], [2], [3], [4] and cardiovascular disease (CVD) [2], [3], [5] mortality risk. Simple reaction time is thought to be a more basic index of neuropsychological functioning than choice reaction time. Choice reaction time involves choosing one of several response options, which is more cognitively complex. Reaction time variability represents variability across multiple trials within each participant's performance during a testing session. Such variability is also thought to be an important index of neuropsychological functioning [6]. Reliability of reaction time as a measure is increased by averaging scores over numerous trials.

As a measure of processing speed, reaction time is moderately inversely correlated with higher-level cognitive ability as assessed by psychometric tests: people with higher cognitive ability tend to have shorter, less variable reaction times [7]. Lower cognitive ability measured in childhood [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], early adulthood [20], [21], [22], [23], [24], [25], and old age [4], [5], [26] is also associated with greater risk of all-cause [4], [13], [18], [23], [25], [26], [27], [28] and cardiovascular disease [5], [24], [27], [29] mortality. In a meta-analysis comprising 16 studies of over one million participants, a 1 standard deviation increase in cognitive ability in childhood was associated with 24% lower risk of mortality [28]. Reaction time and cognitive ability may both predict mortality risk because they both measure important aspects of neuropsychological functioning or reflect the integrity of one or more bodily systems. However, reaction time is also seen to explain the IQ-mortality association [2] suggesting that it may mediate the association between more complex cognitive processes and mortality.

In most studies of mortality risk factors, cognition has been ascertained using standard, psychometric tests of intelligence which some commentators claim are not equally valid for adults from different cultural backgrounds. Compared to psychometric tests of intelligence, [30], [31] simple reaction time can be regarded as a ‘culture-reduced’ measure of cognitive ability. It also relatively quick to measure at low cost [32]. In studies to date, slower and more variable simple reaction times have been associated with all-cause and CVD mortality risk [1], [2], [3], [33].

Our aim was to examine the relation between slower and more variable simple reaction times, with cause-specific mortality, in a representative sample of the US civilian community-dwelling population.

In preliminary analyses (not shown), we found no evidence that the reaction time-mortality associations differed by sex or ethnic minority status (p-values for interactions all >.05). We thus pooled data for men and women.

The baseline characteristics of the study population in relation to later vital status are shown in Table 1. A total of 378 (7.4%) participants died during 14.6 years of follow-up (104 cardiovascular deaths; 84 cancer deaths). Adjusted for age, participants who died were more likely to be male, have lower socio-economic position, were physically inactive, and smoked cigarettes and drank alcohol more heavily (Table 1).

In Table 2 we depict baseline characteristics of study members according to reaction time. Taken together, shorter reaction time was associated with more favourable levels of some baseline characteristics (e.g. occupational grade and poverty/income ratio) but not others (e.g. smoking and alcohol drinking). Slower participants tended to have more variable reaction time scores, as indicated by the strong positive correlation between both measures (r = 0.64, p<0.001).

Results from the Cox Regression analyses for the associations between reaction time and mortality are shown in Table 3. After adjusting for age, sex and ethnic minority status, being 1 SD slower on reaction time was associated with a 25% increase in all-cause mortality risk (HR = 1.25, 95% CI 1.12, 1.39). A significant association was observed for CVD mortality (HR = 1.36, 95% CI 1.17, 1.58) but not cancer mortality for which there was no significant relation with reaction time (HR = 0.85, 95% CI 0.54, 1.34). In fully adjusted models which also adjusted for educational attainment, occupational grade, poverty/income ratio, health behaviors and CVD risk factors, the association was attenuated but remained statistically significant for all-cause mortality (HR = 1.15, 95% CI 1.02,1.29; 37% attenuation), and CVD mortality (HR = 1.22, 95% CI 1.15,1.29; 36% attenuation).

Having 1 SD more variable reaction time was also associated with all-cause mortality, increasing risk by 36% (HR = 1.36, 95% CI 1.19, 1.55), adjusting for age, sex and ethnic minority status. The association was somewhat stronger for CVD mortality (HR = 1.50, 95% CI 1.33, 1.70). Again, there was no significant relationship between this component of reaction time and cancer mortality (HR = 0.99, 95% CI 0.72, 1.34). In fully adjusted models, the association was attenuated but remained significant for all-cause (HR = 1.25, 95% CI 1.09, 1.44; 27% attenuation) and CVD (HR = 1.35, 95% CI 1.16, 1.58; 25% attenuation) mortality. Associations were only slightly attenuated in additional models for reaction time variability in which simple reaction time was controlled for, allowing for the fact that participants with slower reaction times tended to have more variable reaction times (Table S2). This suggests that the association between reaction time variability and mortality is not simply accounted for by the tendency of those with more variable to have slower reaction times. Reaction time mean was not significantly associated with mortality after adjustment for variability (Table S2) suggesting that reaction time variability was driving the association.

The effect sizes were generally similar when analyses were performed on a nested sample of participants with complete data (Table S1), adjusting for age, sex and ethnic minority status. One exception was all-cause mortality and reaction time mean, which was markedly stronger among complete case data (HR = 1.68, 95% CI 1.28, 2.20). The general pattern of results and conclusions drawn were largely unaffected. Repeating results after excluding participants who died within five years of cognitive assessment weakened the associations (HR for reaction time mean = 1.14, 95% CI 1.03, 1.26; HR for reaction time variability = 1.19, 95% CI 1.19, 1.07, 1.31), but had little influence the overall pattern of findings, mitigating concerns about reverse causation. Results were similar across age groups (Table 4).

In a representative sample of adults, slower and more variable performance on a simple reaction time task was associated with increased rates of both all-cause and cardiovascular disease mortality over a follow-up period of approximately 15 years. The association between reaction time variability and mortality remained after adjustment for reaction time mean, and was therefore not accounted for by the tendency for people with more variable reaction times to have slower responses. No association was observed for cancer mortality, although fewer deaths were available for this outcome. Socio-economic status, health behaviors and established CVD risk factors partly but not fully explained these associations.

The strengths of the study include the range of covariates considered, some of which occur between reaction time and survival. For this reason, we calculated their contribution to the attenuation of the association separately to avoid over-adjustment. No variables attenuated the associations fully, suggesting that the association between simple reaction time and mortality is independent of socio-demographic, socio-economic, health behaviors and CVD risk factors. The pattern of results was similar to those found in the Health and Lifestyle Survey (HALS) [4], [5], the Twenty-07 Study [2], and also to the Baltimore Longitudinal Study of Aging [1]. For example, in the Twenty-07 study, reaction time mean and variability both predicted mortality, consistent with our findings [2]. These studies also considered choice reaction time. Simple reaction time scores were averaged over 50 trials and thus the reliability of scores in this study are greater than those of the other studies which averaged over 20 trials.

To our knowledge, this is the first study to estimate the association between simple reaction time (mean and variability) and mortality in a representative sample of the US community-dwelling population. Our study replicates findings in the UK population [2], [3]. The associations we found for simple reaction time converge with those found in other studies. Data were not available on choice reaction time, but it is likely that simple reaction time mean and variability are less susceptible to confounding than choice reaction time. Choice reaction time involves choosing between stimuli and responding with several response options. This involves more complex cognitive processes and decision-making than simple reaction time. Study limitations include the lack of statistical power available to consider other specific causes of death, particularly cancer. Since cancer is not a single disease entity, site-specific cancers may have different associations with reaction time [42]. Analysis of site-specific cancer risk was not possible given the relatively small number of cancer deaths. Reaction time was only measured once at baseline, and so we were not able to adjust for changes in the exposure over follow-up or consider time-varying confounders. Reaction time scores are stable in the short [32] to medium term [43], but show age-related decline [44]. Although we proposed several variables as possible mediators and evaluated by how much they attenuated associations between reaction time and mortality, mediation is not straightforwardly assessed in cross-sectional data [45] and so longitudinal repeated measures of these covariates would be informative. Another limitation is that age-related cognitive decline may have occurred prior to baseline, particularly for older adults in the sample [46]. In descriptive analyses, the often weak and inconsistent relation between reaction time and covariates is likely to account for why these variables explained relatively little of the association with mortality. There may be further explanatory variables or effect modifiers that were not included in our models [43]. However, the fact that results were very similar when re-run on participants with complete data provides support for the view that results were not influenced by missing data patterns. The two exceptions in complete case analysis, a stronger association between reaction time mean in relation to all-cause mortality and between reaction time variability in relation to cancer mortality, could have been biased by non-ignorable missing data patterns. The fact that the sample were relatively young is both a strength and a limitation – reaction time could be measured before the onset of disease and death, but relatively few deaths occurred over follow-up because the sample were young. Finally, there are likely several confounding factors that were not considered in our analysis. Residual confounding could have introduced bias.

Mechanisms underlying the association between slower and more variable reaction times and mortality risk are not known. One hypothesis concerns ‘system integrity’, which suggests that since bodily systems deteriorate with age, slower and more variable reaction times reflect a central nervous system that is deteriorating in parallel with other bodily systems [2], [47]. Given the correlated heterogeneity in the aging of these systems, slower and more variable reaction times in adulthood might indicate poor physiological functioning across several bodily systems, any of which might increase risk of death in turn [48]. Simple reaction time, being less proximal to cognitive abilities than choice reaction time, might be an indicator of system integrity. It is likely however, to be one of several possible markers, and depends on whether simple reaction time actually measures functioning in one, or several systems. This question can be addressed if researchers consider if, how and why reaction time reflects functioning in other systems both cross-sectionally and longitudinally.

Our results demonstrate that slower and more variable reaction times are predictors of mortality risk in a representative population sample. Priorities for future research should include identifying the mechanisms underlying these associations. Since reaction time can be measured at low cost relatively quickly [32], it should be measured routinely in epidemiological studies.