Accounting for the relationship between low education and dementia: A twin study

Abstract

We evaluated whether the association between low education and greater risk of dementia is explained by genetic influences, using three different types of analyses. The HARMONY study (Swedish for “health” (Hälsa), “genes” (ARv), “environment” (Miljö), “and” (Och), and “new” (NY)) includes members of the Swedish Twin Registry who were aged 65 and older and alive in 1998, and who were screened and clinically assessed for dementia. There were 394 cases with dementia and 7786 unrelated controls. Analyses included co-twin control, tests for association between education and a measured genotype, and bivariate twin modeling. Low education was a significant risk factor for dementia both in case-control analyses (odds ratio = 1.77, 95% confidence interval 1.38 to 2.28) and co-twin control analyses with monozygotic twin pairs (odds ratio = 3.17, 95% confidence interval 1.26 to 7.93). Apolipoprotein E genotype was not associated with education and did not account for the relationship between education and dementia. Bivariate twin modeling showed that the association between education and dementia was not mediated by genetic influences in common between education and dementia. The association was mediated by shared environmental influences that were related to both dementia and to education. Low education is confirmed as a risk factor for dementia. Findings from three different analytic approaches showed that genetic influences did not explain this association.

Introduction

Dementia, defined as age-related progressive impairment of memory, language, visual processing, problem solving skills, and eventually ability to function independently, is a major public health problem, affecting up to 40% of adults aged 85 and older [1], [2]. Especially among the oldest old, the majority of dementia is accounted for by Alzheimer's disease, with the next most frequent type being vascular, although increasingly these subtypes are being viewed as less distinctive [3]. It is generally claimed that half of the explanation for Alzheimer's disease is genetic and half is environmental, while identification of specific gene variants and specific environmental exposures that account for risk of dementia remains incomplete [4], [5].

Low educational achievement is one of the few variables consistently reported to be related to higher risk of dementia, beyond age and family history [6], [7], [8], [9], [10], [11], [12], [13], [14]. Only a small number of studies have failed to confirm this association [15], [16], [17]. Summaries of the literature suggest that the strongest relationships between education and dementia occur in geographical locales where education is more likely based on intellectual potential, whereas weaker relationships characterize places where education is more likely made available based on position in society [18], [19]. Further, it has been shown that the association observed between education and dementia cannot simply be explained as an artifact of differential case detection of dementia in individuals with less education [13].

Mechanisms to explain the association between dementia and education remain uncertain. The predominant interpretation, often referred to as “use it or lose it,” is that education indexes level of mental activity and that mental stimulation strengthens connectivity in the brain, e.g., increasing synaptic density [20]. This line of theorizing is supported by studies that have found associations between greater engagement in mentally stimulating leisure activities and lower risk of Alzheimer's disease [21], [22], [23], and has led to recommendations that individuals might reduce their risk of dementia through increasing their level of cognitive activity—for instance, by learning a foreign language or working crossword puzzles [24], [25].

An alternative possibility is that differences in education reflect genetic influences associated with individual differences in intelligence [26]. It is well established that individual differences in IQ scores in part reflect genetic differences [27], [28]. In turn, children who score higher on intelligence tests are likely to progress further in school. Furthermore, Scottish data have shown that those who became demented had lower IQ test performance at age 11 compared to those who did not become demented [29].

We addressed these two contrasting explanations using a study of dementia in a population-based twin sample. We took three approaches to testing the extent to which the relationship between low education and risk of dementia was explained by genetic influences.

• We evaluated low education as a risk factor for dementia using both an unrelated comparison group and monozygotic co-twin controls [30]. Analysis of unrelated controls is essentially a classic case-control study, comparing twins diagnosed as demented with other twins not related to the index probands. The co-twin control design, on the other hand, compares the demented twin to their non-demented monozygotic co-twin as control. The co-twin control design controls for potential confounding from genetic factors, as the cases and controls are genetically the same.

• We tested the role of Apolipoprotein E є4, the best established measured genetic risk factor for dementia [4], in explaining the association between education and dementia.

• We employed bivariate twin modeling to test whether genetic influences in common between education and dementia explain the correlation between dementia and education.