Low cognitive ability has been associated with higher risk of cardiovascular morbidity1–10 and premature death.11,12 Low cognitive score in childhood and young adulthood has been linked specifically with hypertension6,7,13 and coronary artery disease.1–5,9,10 Results are conflicting as to whether4,8,10 or not2,3 an association exists with stroke. Although low cognitive childhood score has been associated with unhealthy diet,14 less physical activity,14 and obesity in adults,15–18 most studies have not found an association with type 2 diabetes.13,19 Despite the link between atherosclerosis, metabolic syndrome and venous thromboembolism,20–22 no previous study has examined venous thromboembolism as an outcome. We examined the association between cognitive scores in young adulthood and the risk of type 2 diabetes, hypertension, myocardial infarction, stroke, venous thromboembolism, and death before 55 years of age.
Setting and Study Cohort
The Danish National Health Service provides universal tax-supported health care, guaranteeing unrestricted access to general practitioners and hospitals. Individual-level linkage of all Danish registries is possible using unique personal identifiers.23
We used a conscription research database (described in online supplementary eMethods, http://links.lww.com/EDE/A699) covering the Fifth Military Conscription District in Denmark (700,000 inhabitants)24 to identify all persons from the 1955 birth cohort who appeared before the draft board in Northern Denmark (n = 6,502).25–27
Cognitive Test, Education, and Body Mass Index
From the conscription database, we obtained data on cognitive ability as measured by the Boerge Prien test.25,28 This 78-item group intelligence test has four subscales (letter matrices, verbal analogies, number sequences, and geometric figures), does not involve multiple-choice responses, is timed, and has a single final score (range 0–78).25 The test has remained unchanged since its introduction in 1957 and had by 2009 been taken by approximately 90% of all Danish men aged 18–70 years.25 The conscription database also provided years of education and body mass index (BMI) at time of examination.
We used the Danish National Registry of Patients (eMethods, http://links.lww.com/EDE/A699)29 to identify all first-time diagnoses of type 2 diabetes, hypertension, myocardial infarction, stroke (ischemic stroke, intracerebral hemorrhage, or subarachnoid hemorrhage), or venous thromboembolism (deep venous thromboembolism or pulmonary embolism). To ensure more complete identification of examinees with type 2 diabetes, we also searched the Aarhus University Prescription Database (eMethods, http://links.lww.com/EDE/A699)30 covering the study region for any use of antidiabetic drugs from 1 January 1989 through 2010. We obtained information on all-cause mortality from the Danish Civil Registration System (eMethods, http://links.lww.com/EDE/A699).23 Finally, a combined outcome was defined as the first-time occurrence of any of the individual outcomes.
We characterized the study cohort by categories of cognitive score, education, and BMI. To ensure that the hospital registry (initiated in 1977) would capture all hospitalizations, follow-up started at the examinee’s 22nd birthday (17 examinees died and 8 emigrated before this date and were excluded). Follow-up continued until first occurrence of an outcome, emigration, or 33 years of follow-up (ie, their 55th birthday). Using the Kaplan–Meier estimator,31 we illustrated graphically the cumulative incidence function associating cognitive score with the combined outcome. We used the pseudo-value method32 to calculate 33-year risks and risk differences (treating death as a competing risk in analyses of nonfatal outcomes). We used Cox proportional hazards regression to compute hazard ratios (HRs). Test scores were analyzed in quartiles and as a continuous variable (change per one standard deviation [SD]). For the categorical variable, the proportional hazard assumption was assessed by log–log plots and Schoenfeld’s test and found valid. We assessed the scale of the continuous variable using fractional polynomials and found no evidence of nonlinearity in the log hazard. In secondary analyses, we stratified and adjusted for years of education and BMI. The study was approved by the Danish Data Protection Agency (2011-41-5807).
Compared with men whose cognitive test score was in the highest quartile, men with lower test scores were more obese and attained lower levels of education at time of examination (Table 1). The 33-year risk of the combined outcome was 26% for men in the lowest quartile of cognitive score, corresponding to an almost 10% higher absolute risk than among the highest scoring men (Table 2 and Figure). Compared with very high scores, the HR for the combined outcome was 1.20 (95% confidence interval = 1.02, 1.41) for high, 1.43 (1.22, 1.68) for moderate, and 1.67 (1.43, 1.95) for low scores. In general, estimates of association were not substantially modified by either BMI or years of education. One exception was that obese men with low or moderate scores had a higher risk of the combined outcome than similarly scoring men of normal weight (eTable 1, http://links.lww.com/EDE/A699). Unconditional adjustment for years of education reduced the HRs substantially, whereas additional adjustment for BMI did not.
Consistently increased effect estimates were observed for the separate outcomes (Table 3). Comparing low score with very high score, the HR was 1.76 (1.28, 2.40) for type 2 diabetes, 1.68 (1.30, 2.17) for hypertension, 1.74 (1.13, 2.69) for myocardial infarction, 1.57 (0.99, 2.51) for stroke, 2.97 (1.34, 6.56) for venous thromboembolism, and 1.81 (1.40, 2.35) for premature death. Although reduced, the HRs remained elevated after adjustment for years of education and BMI. The crude HR associated with one SD decrease in cognitive test score was 20% increased for the combined outcome and between 20% and 40% across individual outcomes (eTable 2, http://links.lww.com/EDE/A699).
Low cognitive scoring was associated with increased long-term risk for type 2 diabetes, hypertension, myocardial infarction, stroke, venous thromboembolism, and premature death. Compared with men with very high scores, an additional 10% of men with low scores experienced one of these outcomes before 55 years of age.
Strengths and Limitations
The population-based design and complete follow-up reduced selection biases.23 The items of the four subtests of the Boerge Prien test involve abstract reasoning rather than acquired knowledge, which prevents gradual obsolescence of the test over time.28 The scores are strongly correlated with conventional intelligence test scores such as the Wechsler Adult Intelligence Scale.25 The positive predictive values of registry diagnoses have previously been validated and found to be approximately 90% for diabetes33 and myocardial infarction33,34 and 80% for stroke33,35 and venous thromboembolism.36 Among men diagnosed with hypertension in our cohort, 88% had redeemed a prescription for antihypertensive medication. Any potential underreporting of diabetes and hypertension would provide underestimates of the absolute risks, and thus cannot explain the associations.
Although we cannot exclude potential unmeasured confounding, an advantage of studying mortality rates among young (healthy) adults is that preexisting medical conditions are uncommon, and therefore adjustments for these conditions is largely unnecessary.12 Moreover, most lifestyle factors relating to health behaviors (eg, diet, smoking initiation, excess alcohol consumption, and exercise) and risk factors developing later in life (eg, hypercholesterolemia, hypertension, diabetes, and the metabolic syndrome) lie on the causal pathway and therefore should not be adjusted for (eFigure, http://links.lww.com/EDE/A699).18,31 Although they are complex factors,11 years of education37 and BMI14–16,18 most likely also represent intermediates. To avoid overadjustment, we therefore favored the crude estimates. Childhood socioeconomic status1,11,12 and smoking measured concurrently with cognitive testing12,38 have previously been found not to confound the association with premature mortality. It was, nevertheless, a limitation that we did not have information on socioeconomic and smoking status. Finally, although the results derive from a study that included only young men, previous reports suggest the associations are likely also to hold for young women.11
Comparison with Other Studies
No previous study has assessed the combined risks of all major cardiometabolic outcomes associated with premorbid cognitive score. Our results are in line with previous studies reporting on subsets of our outcomes. Low cognitive score has frequently11,12 but not always39 been associated with premature mortality. Supporting the magnitude of our mortality estimates, a recent meta-analysis with 17 to 69 years of follow-up concluded that one SD decrease in cognitive test score was associated with 24% increased mortality.11 Previous studies also support our results for hypertension,6,7,13 myocardial infarction,1–5,9,10 and stroke.4,8,10 Another Danish study examining test scores (although among children) by quartiles and SD decrease found that the adjusted HR for the lowest quartile was 2.58 (1.51, 4.41) for coronary artery disease and 1.29 (0.75, 2.25) for stroke compared with the highest quartile.3 The HR associated with one SD decrease was 1.39 (1.19, 1.64) for coronary artery disease and 1.11 (0.90, 1.37) for stroke.3 In contrast to most previous studies,13,19 our results support the finding by Olsson et al40 showing an association with type 2 diabetes. The established association between low childhood cognitive scores and obesity in adults supports this finding.15–18 Finally, our study is the first to link low cognitive score with long-term risks of venous thromboembolism and combined cardiometabolic outcomes.
In conclusion, a low cognitive score in young adulthood was a strong predictor for type 2 diabetes, cardiovascular morbidity, and death before 55 years of age.
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