In this cross-sectional survey of cognitive function in rural elderly Chinese, we found that decreasing selenium levels measured in nail samples are associated with lower cognitive scores when controlling for age, gender, education, body mass index, and APOE
status. The effect of the lowest selenium quintile compared with the highest quintile on the CSID score is equivalent to an increase of 10 years in age in this cohort. The amounts of variance explained by selenium level in the CERAD Word List Learning Test and Recall Test scores were lower than for the other scores, because the total variance explained by these models was lower than for those of the other test scores. The explained percentages are similar to reports of other factors associated with cognitive function in the elderly (37
), and there are currently no similar data on selenium with which we can compare our results. The stability of this rural population and the high correlations among different selenium measurements suggest that our results reflect the effect of lifelong selenium exposure on cognitive function.
In two cross-sectional studies that reported on the relation between serum selenium levels of antioxidants and cognitive scores, selenium’s effect did not reach statistical significance after adjustment for other risk factors (8
). However, it is known that the serum selenium level reflects short-term dietary intake and is also heavily influenced by supplemental selenium use. The Third National Health and Nutrition Examination Survey, for example, showed that subjects in the lowest selenium quintile also had the lowest education, lowest income, highest proportion of non-White race, and lowest percentage taking supplement. The relation between antioxidant supplements including selenium and cognitive test performance was examined in the Monongahela Valley Independent Elders Survey (12
), and no significant differences in cognitive test performance between antioxidant users and nonusers were found after adjustment for other covariates. However, the survey did not examine selenium intake or biomarkers for selenium. A longitudinal follow-up of the Etude du Vieillissement Arteriel cohort reported a significant protective plasma selenium level on cognitive decline (9
). In addition, the Duke Epidemiology Study of the Elderly reported a significant association between antioxidant use and less cognitive decline (11
In our population, selenium had a consistent, dose-response relation with cognitive performance, such that higher selenium levels were associated with better cognition. The largest effects were seen for the CSID, which is a multifactorial cognitive screening test, and the IU Token Test, which measures working memory (an executive function) and language comprehension. New learning measures, such as the CERAD Word List Learning Test task and the IU Story Recall Test, were also clearly related to selenium levels. The one test that did not appear to have a relation with selenium levels was the Animal Fluency Test. This test is unique in the battery in tapping a nonmemory, executive ability. It may be that selenium exerts its effects primarily through working and secondary memory mechanisms. Alternatively, it may be that the rural lifestyle produces such a wide and regular exposure to farm animals that the task features of the Animal Fluency Test are altered in subtle ways that cause it to be less of an ‘‘executive function’’ measure. However, the fact that the mean scores from this sample are very much in keeping with those reported for other elderly samples in both rural (26
) and urban settings (42
) argues against this explanation.
Selenium is recognized as an important dietary micronutrient in humans and is hypothesized to impact the aging process. The selenium content in foods varies greatly depending on the selenium content of the soil where plants are grown, while up to 10-fold differences in selenium contents can be found in the same food item (43
). Dietary selenium is found to be highly bioavailable (44
), and its elimination in humans was shown to be in three phases, with the last phase lasting as long as 200 days (45
). Detailed information on selenium absorption, metabolism, and excretion can be found elsewhere (46
). Many studies have examined selenium contents in toenails and found that selenium levels in toenails are highly reproducible in a 1-year period (48
), and toenails are generally regarded as useful biomarkers for long-term exposure (52
). There are also studies demonstrating excellent correlation in the selenium measured between toenail and fingernail samples (r
= 0.919), and both toenail and fingernail samples showed identical correlations with selenium levels measured in blood samples (53
In animal studies, selenium deficiency has been shown to increase protein oxidation in mice and to shorten the lifespan in transgenic Drosophila
). Selenium’s effect on aging has also been investigated in terms of DNA damage (56
). In many previous studies, selenium exposures were measured from either supplement use or blood samples, both reflecting relatively short-term intake and possibly being confounded by supplement ingestion. It is known that the early life environment and its effect in childhood and adolescence are linked to many adult chronic diseases, such as heart disease, stroke, hypertension, diabetes mellitus, and chronic obstructive lung disease (57
). Environmental factors can affect brain maturation in childhood and adolescence and may have an impact on later-life cognitive decline. The areas of the brain that take the longest to mature during childhood are the same areas of the brain that show the earliest signs of Alzheimer’s disease (58
). In addition, animal studies on rats demonstrated that the brain has a unique feature in that it stores selenium (59
). Therefore, after the animal is placed on a low selenium diet, the activity of glutathione peroxidase in the brain does not decrease as fast as observed in the liver (60
). This suggests that long-term exposure to selenium may be needed to impact brain function later in life. The brain’s unique selenium metabolism may also make it more difficult to show the effect of short-term selenium exposure on brain function than on other organs. Because the majority of our participants were lifelong residents of the same towns and villages, selenium measures in the participants reflect lifelong exposure, enhancing our power for detecting a selenium effect.
Selenium levels in various cohorts differ by the geographic locations of the study population (61
). Although US cancer studies report mean nail selenium levels of 0.8 μg/g in control subjects, European cohorts include many control groups with nail selenium levels around 0.5 μg/g, overlapping with the selenium range in our cohort. It is worth noting that the selenium levels reported in cohorts from developed countries may also be influenced by dietary supplements and, hence, may not be reflective of lifelong exposure.
The effect of APOE
in Alzheimer’s disease and cognitive function has been of particular interest in Asian populations, because the frequency of ε4 is lower in these populations than in most but not all European and North American populations. The ε4 allele frequency in our cohort is 8.8 percent, higher than the 6.4 percent allele frequency reported in Singapore (62
), 7.4 percent in Hong Kong (63
), and 4.9 percent in Taiwan (64
), but lower than the 11.0 percent in the Shanghai cohort (65
). Significantly lower cognitive performance in ε4 carriers was found in the CSID and the IU Token Test scores in our cohort. Various studies have examined the ε4 effect on neuropsychological tests measuring different domains. Although the ε4 allele has been reported to be associated with memory-dominated functions, the association with tests concentrating on language, visuospatial, for example, has been inconsistent, providing evidence that ε4 may impact different brain regions and brain functions (66
In our cohort, a lower body mass index was associated with lower cognitive scores. Although body mass index has been associated with a variety of common medical disorders and mortality, the relation between body mass index and cognitive function or the risk of Alzheimer’s disease has been inconsistent, with some studies suggesting that low body mass index increases the risk of Alzheimer’s disease and poor cognitive function (68
), while others suggest the opposite (70
). The differences may be due to the variation in time lapse between body mass index measurements and outcome measures in various studies, since the onset of dementia may affect body mass index (71
). The differences in body mass index results may also be attributed to differences in cohort composition in body mass index, assuming that an optimal body mass index range exists. Hence, cohorts with most participants below this optimal point would be more likely to identify low body mass index as a risk factor, while cohorts with a body mass index range above the optimal would find high body mass index to be a risk factor.
Our study has a number of strengths. Selenium levels were measured in nail samples, dietary intakes, and blood samples, increasing measurement validity. Our study design ensures an extensive range of selenium exposure in the cohort. In addition, the majority of our study participants were lifelong residents of the same towns where they were interviewed, and the participants were known not to take vitamin supplements; hence, the ascertained selenium levels can be inferred as lifelong exposure to selenium without the influence of supplements.
Because lower selenium was previously reported to be associated with increased risk of coronary heart disease and cancer, there was the possibility that selenium’s effect on cognitive function could be impacted by participants suffering coronary heart disease or cancer. However, in our study, the association between selenium levels and cognitive scores remained unchanged after excluding subjects with heart attack, stroke, and cancer, indicating that selenium’s effects on coronary heart disease and cancer are an unlikely explanation for our findings.
Our result showing higher numbers of participants with diabetes, hypertension, stroke, and heart attack with the increase of selenium levels was surprising given previous reports on selenium’s protective effects on coronary heart disease. One potential explanation could be that selenium’s effects on coronary heart disease and cancer in relation to mortality have left fewer participants living with these diseases. This possibility merits further examination in our planned follow-up of this cohort.
This study also has important limitations. The reported association was found in a cross-sectional examination of selenium levels and cognitive function. Although the stability of this population makes a reciprocal effect of low cognitive function on selenium levels unlikely, longitudinal evaluation of the cohort will help to establish whether selenium levels affect the rate of cognitive decline associated with aging.