Disrupted calcium homeostasis plays a part in neurodegeneration,1 and normalization of calcium levels in persons with hyperparathyroidism improves cognitive function.2 Calcium ions diffuse through the blood-brain barrier, and serum calcium levels are directly related to extracellular calcium levels in the brain.3 Vitamin D regulates calcium homeostasis,4 and several studies have linked vitamin D to cognitive performance.5–9
Two prospective studies have shown that high levels of serum calcium are associated with greater cognitive decline in older adults.10,11 No previous studies have examined the association of serum calcium with cognitive function in young adults, when reverse causality (early undetected cognitive decline resulting in changes to behavior that influence calcium levels) and survivor bias are less likely. If calcium were importantly associated with cognitive function in early life, it might provide a modifiable risk factor for preventing later cognitive decline.
We investigated the association between ionized serum calcium levels and cognitive function among the adults who participated in the third National Health and Nutrition Examination Survey (NHANES III), examining whether any association differed between younger adults (age, 20-59 years) and older adults (60-90 years). A previous publication using NHANES III12 did not replicate the positive associations of vitamin D with cognitive function seen in other studies5–9,13; we therefore also investigated whether this was due to calcium masking the effects of 25-hydroxyvitamin D.
NHANES III, conducted 1988-1994, is a survey of the noninstitutionalized population of the United States.14 The data and documentation are freely available at http://www.cdc.gov/nchs/nhanes/nh3rrm.htm. In people age 20-59 years, cognitive function was assessed with 3 different tests, and the number of participants with each assessment varied. Both serum calcium levels and cognitive function test scores were available for 4314-4471 persons and both 25-hydroxyvitamin D levels and test scores for 4760-4932 persons (approximately 30% of NHANES III participants in this age group). For those age 60-90 years, these figures are 4319 and 4831, respectively (52% and 58% of older participants).
Serum calcium was analyzed with NOVA 7 analyzer (Nova Biomedical, Waltham, MA). pH-normalized calcium levels were derived by adjusting the measured ionized calcium for serum pH. 25-hydroxyvitamin D was analyzed with INCSTAR 25-OH-D I25 radioimmunoassay (Diasorin, Stillwater, MN).
In persons age 20-59 years, cognitive function was assessed by mean reaction time, mean of the 2 best error-corrected latencies in a symbol-digit substitution test, and the summary score from a serial-digit learning test.15,16 For older persons, we used a combination score from both the free immediate and delayed recall. These measurements are described in more detail in the eAppendix (http://links.lww.com/EDE/A430).
The following were considered potential confounding factors due to their associations with calcium/vitamin D and cognitive function: age, sex, race/ethnicity, health status, poverty-income ratio of the household, years of education, outdoor physical activity, smoking, and alcohol use. Details of how these were measured are available on the eAppendix (http://links.lww.com/EDE/A430).
Factors that might have affected the performance in computerized cognitive tests (pretest caffeine consumption, familiarity with computer games, examiner, and test language) were included as possible covariables to improve statistical efficiency. There were considerable missing data for smoking and alcohol. In younger adults, data were available for 52% and 50% of participants for alcohol and smoking, respectively. In older adults, data were available for 29% and 57%, respectively. Therefore, these variables were not included in the main analyses, but separate sensitivity analyses were conducted to examine their effect.
Statistical analyses were conducted with Stata 11.0 (Stata Corp LP, College Station, TX). To correctly account for the sampling procedures (including clustering), the analyses were done with the svy procedure, using the sampling weights from mobile examination centers. More methodological details for this are provided in the eAppendix (http://links.lww.com/EDE/A430). We assessed the distribution of participant characteristics across quartiles of pH-normalized serum calcium and 25-hydroxyvitamin D with linear or logistic regression. Multivariable linear regression was used to examine associations of exposures with cognitive function. Serum calcium and 25-hydroxyvitamin D levels and cognitive scores were z-scored to allow the comparison between different models.
In participants age 20-59 years, the weighted mean (standard error) serum pH-normalized calcium was 1.24 (0.00) mmol/L (range, 0.89 to 1.95 mmol/L). Mean 25-hydroxyvitamin D level was 75.3 (1.06) nmol/L (range, 9 to 243 nmol/L). Among the older participants, mean calcium and 25-hydroxyvitamin D levels were 1.23 (0.00) mmol/L (range, 0.81 to 1.84 mmol/L) and 69.0 (0.67) nmol/L (range, 9 to 400 nmol/L), respectively. The correlation coefficient for pH-normalized calcium and 25-hydroxyvitamin D was 0.02 (95% confidence interval [CI] = −0.01 to 0.04) in the younger adults and 0.05 (0.02 to 0.07) in the older adults.
The age- and sex-adjusted characteristics across quartiles of pH-normalized calcium are shown in Tables 1 and 2. The description of these results is provided in the eAppendix (http://links.lww.com/EDE/A430). Equivalent age- and sex-adjusted characteristics across 25-hydroxyvitamin D quartiles are shown in eTables 1 and 2 (http://links.lww.com/EDE/A430).
Table 3 shows the multivariable associations of pH-normalized calcium levels and 25-hydroxyvitamin D with the cognitive test scores in both age groups. Neither pH-normalized serum calcium nor 25-hydroxyvitamin D was associated with any of the cognitive scores in either age group after adjusting for age, race/ethnicity, and sex (Model 1). Further adjustments for other possible confounders did not alter the results (Model 2). With additional mutual adjustment of associations of calcium and 25-hydroxyvitamin D for each other, the null associations remained unchanged (Model 3). The results were also unchanged when we restricted the analysis to participants with data on smoking and alcohol use, and adjustment for these did not alter the null associations (eTable 3, http://links.lww.com/EDE/A430).
We know of no previous studies that have examined the association of serum calcium with cognitive function in young adults and compare these results to similar associations in older adults. Our results in older adults are consistent with 2 previous cross-sectional analyses in this age group,9,10 but not consistent with prospective associations relating calcium to cognitive decline.10,11,17 Thus, our null cross-sectional findings do not necessarily rule out an association of serum calcium with cognitive decline in older age. Results may also differ among studies because of differences in the ways in which cognitive function is assessed, and in the potential confounding factors that are taken into account. Our results do suggest that between-person variation in serum calcium levels (or 25-hydroxyvitamin D levels) is not associated with cognitive function in early adulthood. In addition, we showed that the previous null association between 25-hydroxyvitamin D levels and cognitive function in the same population12 was not masked by serum calcium levels.
The main strengths of this study are its sample size, the comparison of associations in younger and older adults, and adjustment for a wide range of potential confounders. The study population is representative of the US adult population (82% response of younger adults and 79% response of older adults who were invited to take part). Serum ionized calcium was measured instead of the total or albumin-adjusted serum calcium. The validity of total or albumin-adjusted calcium as a surrogate for the biologically-active ionized calcium has been questioned.17,18
The main weakness is that the study is cross-sectional, and we therefore cannot rule out an overall null effect due to the combination of a true prospective inverse association with calcium and a reverse positive association (ie, adults with higher cognitive function engaging in more sedentary activities and consuming diets that result in higher levels of serum calcium). Because calcium and, 25-hydroxyvitamin D, together with cognitive function, were available for only 29%-32% of younger adults and 52%-58% of older adults in NHANES III, it is possible that selection bias has affected our results. However, for this selection to have resulted in the null associations we observe, in the presence of true inverse associations with calcium and positive associations with 25-hydroxyvitamin D, we would have to assume that participants with lower calcium or higher 25-hydroxyvitamin D and who were also of higher cognitive ability (or those with higher calcium or lower 25-hydroxyvitamin D, with higher cognitive ability) were more likely to not be included. Although we cannot rule this out, we think it is unlikely. Because only the noninstitutionalized population is sampled for NHANES, it has been suggested that the lack of association of vitamin D with cognition in a previous publication using these data12 might be due to cognitive homogeneity.8 The same criticism could be made of our results with respect to calcium. However, only a minority of the population are institutionalized because of poor cognition, particularly at younger ages, and we found no evidence that associations differed between younger and older adults. In both age groups, there was a wide range of cognitive scores, and because most people are not institutionalized these data are relevant most adults in the United States. NHANES III only has single measurements of calcium and 25-hydroxyvitamin D, which may be inadequate to reflect long-term status.11 However, serum calcium levels are normally maintained at relatively narrow limits within individuals19; other studies, including those finding associations with bone phenotypes,20–22 have used single measurements.
In summary, although some recent data suggest that even moderate hypercalcemia may be related to impaired cognitive performance, our results do not concur with those studies. These data highlight the need for much larger prospective studies on this question.
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