In the VALE study, we extended our previous findings to show that elevated blood lead levels were associated with a higher ALS risk for a new and larger population and after taking bone turnover into account. ALAD genotype did not seem to modify the lead-ALS association.
Association of lead exposure with ALS is a long-standing hypothesis (1
), although many previous studies used indirect measures of lead exposure. In a previous study, we showed that measured blood and bone lead levels were both associated with a higher risk of ALS; the association was particularly marked for blood lead (odds ratio = 1.9 for each 1-μg/dL increment) (1
). Recently, a similar association between blood lead and ALS was also shown in a Northern California population (13
). Findings from our previous and present studies are similar both qualitatively and quantitatively. In the previous study, the possible contribution of bone demineralization was taken into account by controlling for physical activity. The present study extended these findings by measuring bone turnover directly.
Although blood lead is often considered an indicator of current lead exposure, it may also reflect bone lead levels. In older individuals with no obvious sources of external exposure, bone lead is the largest source of blood lead (14
), suggesting that the latter may serve as an indirect indicator of cumulative lifetime exposure. Alternatively, increased blood lead level may be a consequence of the disease process among ALS patients: decreased physical activity could increase bone turnover, leading to increased release of lead from bone. VALE addressed the latter possibility directly by taking measured bone turnover into account and showed that adjustment for or stratification by bone turnover biomarkers did not substantively alter our results. Interestingly, we found hints of a stronger lead-ALS association among individuals with lower bone resorption or higher bone formation, that is, individuals likely to have less release of lead from bone to blood. These findings suggest that reverse causality does not fully account for the association between blood lead and ALS.
Despite the strong lead-ALS association observed, both cases and controls had low levels of blood lead. However, a small difference in blood lead levels may be biologically significant given the low absolute lead level observed in the controls. Furthermore, a small difference in current blood lead may reflect large differences in past environmental lead exposure or a long period of increased bone lead release after cessation of environmental lead exposure (14
). It is possible that a long-term increase in release of lead from bone to blood, slightly elevating blood lead level, might result in greater exposure to neural target tissues. The mechanisms relating lead neurotoxicity to ALS are still unclear. However, several mechanisms proposed to play a role in ALS pathogenesis, including oxidative stress, excitotoxicity, and mitochondrial dysfunction (24
), are also involved in lead neurotoxicity (25
Veterans may be exposed to lead from firing practice (28
) and other military-related sources, so the observed lead-ALS association may partly explain the higher risk of ALS noted for military service personnel compared with the general population (29
). However, lead exposure can result from many different sources, including residential history, nonmilitary occupational history, and hobbies, and more research is necessary to determine which of these sources (if any) best explains the observed increased lead levels in the VALE cases.
The K59N polymorphic variant of the ALAD
gene may affect an individual's blood and bone lead levels and thus influence susceptibility to lead exposure (33
). In VALE, lead levels did not differ substantially by genotype in either cases or controls; however, this result is not surprising given that an effect of ALAD
genotype on blood lead is primarily observed at much higher blood lead levels (33
). We found a significant lead-ALS association among ALAD1-1
homozygotes but not ALAD2
carriers, but we did not find a significant interaction between ALAD
genotype and blood lead, consistent with our previous finding (11
). In our previous study, we observed an association of ALAD
genotype with ALS, independent of lead level—a finding we did not replicate in VALE (11
). Reasons for this difference between the 2 studies are not apparent, although the present study had a larger sample size.
VALE has several strengths, including its sample size and the available information on both bone turnover and ALAD genotype. In addition, we utilized a highly sensitive assay for lead measurement, which enabled us to detect small differences in blood lead levels in a population with a low absolute level of blood lead.
Limitations should also be appreciated. First, about 22% of the cases were diagnosed more than 2 years before sample collection, and they may represent a selected group of cases with better survival and with blood lead or bone turnover levels different from those of other ALS cases. However, the interval between diagnosis and sample collection did not substantially affect lead levels, nor did excluding individuals diagnosed more than 2 years before sample collection alter the results. Second, the exposure data were collected cross-sectionally, and thus we cannot entirely rule out reverse causality. However, the fact that the lead-ALS relation persisted after adjustment for or stratification by a biomarker of bone resorption suggests that disease-related lead mobilization from bone, the most likely reason to suspect reverse causality, does not fully explain the association. Third, we did not evaluate other genes that may modify the relation between lead exposure and neurologic outcomes, for example, the hemochromatosis gene, HFE
). Finally, residual confounding from other factors could not be completely ruled out. For example, socioeconomic status might be associated with both blood lead level and the risk of ALS. We did not detect a significant association between blood lead levels and years of education, however, a commonly used proxy of socioeconomic status, among either the cases (data available for 100 cases, P
= 0.33) or controls (data available for all controls, P
In summary, we found that elevated blood lead level was associated with higher odds of ALS among US veterans, regardless of bone turnover or ALAD genotype. More studies are needed to support a causal relation between blood lead and ALS risk. Although it would be difficult to collect blood lead data prospectively, before ALS symptom onset, some insight might be achieved by linking ALS to conditions involving abnormal bone resorption.