In this large study of healthy “young old” women, cumulative community-level exposure to lead, measured by concentration of lead in tibia bone, was associated with significantly worse overall performance on cognitive function tests. Specifically, the average decrement in cognitive test scores we observed for each SD increase in tibia lead corresponded to the decrement in scores we observed for each 3-year increase in age among women in our study.
Levels of two other lead biomarkers—patella lead and blood lead—were also associated with worse cognitive function, but these associations were not significant. This pattern of association suggests that lead exposures in the distant past may be more important than relatively recent exposures in influencing cognitive function in these women, because tibia lead levels measure cumulative exposures over the past decades, in contrast to the more recent exposures measured by patella and blood lead levels (Hu et al. 2007
). Although tibia lead assessments cannot distinguish between chronic low-dose exposures and high exposures during a critical period in the past (Shih et al. 2007
), chronic low-dose exposures likely prevailed among the women in this study, who probably incurred most of their exposures to lead from gasoline emissions and consumer products beginning in childhood and lasting at least through the 1980s, when these products were phased out in the United States.
The only large-scale study to report on lead’s association with cognition among older women occurred in the Study of Osteoporotic Fractures. Investigators cross-sectionally examined urban- and rural-dwelling women and found that higher blood lead levels predicted worse performance on several cognitive tests (Muldoon et al. 1996
), although this association was present only among the rural-dwelling women. The reason for these restricted findings is unclear. One possibility, which is indirectly supported by our data, is that the measure of lead exposure—blood lead level—did not adequately capture the range of relevant exposures experienced by these U.S.-based women.
Numerous studies of adults with occupational exposures to lead have found adverse associations between current blood lead level and cognitive outcomes. Nonetheless, many of these studies also have found that measures of cumulative dose (e.g., serial blood lead measurements) generally are more strongly associated than current blood lead with adverse cognitive outcomes (Shih et al. 2007
). These cohorts are characterized by high past and current exposures, with mean current blood lead levels often exceeding 25 μg/dL. In contrast, patterns of exposure among community- exposed adults in the United States reflect high past exposures followed by low current exposures, making current blood lead level a potentially less sensitive measure than cumulative exposure measures for evaluating the relation between lead exposure and cognitive aging in this population. This notion is supported by findings from studies of two community-based cohorts that suggest apparent effects of cumulative but not current low-level lead exposure on poor cognition and cognitive decline. In > 400 men (mean age, 67 years) participating in the Normative Aging Study, bone lead levels were associated with significantly steeper decline over a 3.5-year interval on the MMSE (Weisskopf et al. 2004
) and three visuospatial tests (Weisskopf et al. 2007
). Blood lead levels were cross-sectionally associated with performance only on a vocabulary test (Weisskopf et al. 2007
) and the MMSE (Weuve et al. 2006
). Similarly divergent findings for bone and blood lead initially emerged from a study of 994 older adults participating in the Baltimore Memory Study, in which tibia lead levels—but not blood lead levels—were associated with worse performance on all seven cognitive domains tested; however, these associations were substantially attenuated and no longer significant upon further adjustment for education, race/ethnicity and wealth (Shih et al. 2006
), closer to the analytical framework of our study. A third study of 533 young adults (mean age, 24 years) found significant associations between living next to a lead smelter during childhood and performance on several cognitive tests (Stokes et al. 1998
More generally, although lead levels in the environment have fallen dramatically in the past two decades, many older adults have endured protracted exposures to lead in the preceding decades and have accumulated lead in their skeletons. Together with previous findings, our results have important implications for the cognitive functioning of this growing population of older adults. In the United States, the population of persons ≥ 65 years of age is projected to double between 2000 and 2030 (He et al. 2005
), leading to a rapid rise in the number of individuals afflicted with age-related dementia. This phenomenon will likely be echoed throughout the globe (Ferri et al. 2005
). One model has forecasted that a broadly applied intervention, such as a regulatory intervention that delays the onset of AD by 2 years, could reduce the number of prevalent cases in the United States by about 2 million over a 40-year interval (Brookmeyer et al. 1998
). Thus, even if lead has a subtle effect in accelerating cognitive aging, given the pervasiveness of lead exposure in the United States and globally, widespread reductions in this exposure could have a substantial impact on the burden of cognitive impairment in the population.
Chronic, low-dose exposure to lead may adversely affect cognitive functioning in older age through several actions. Chiefly, lead can damage and eventually kill neurons through its oxidative toxicity, whereby lead both induces oxidative stress (Acharya and Acharya 1997
; Adonaylo and Oteiza 1999b
) and impedes responses to oxidative stress (Adonaylo and Oteiza 1999a
; Ercal et al. 1996
) in the brain. Oxidative stress, in turn, appears to be integral to the pathogenesis of cognitive decline and dementia (Andersen 2004
; Markesbery and Lovell 2007
). Lead also accumulates in neural mitochondria, where it eventually generates the abnormal release of calcium and induces apoptotic cell death (Anderson et al. 1996
; Fox et al. 1997
; He et al. 2000
; Silbergeld 1992
). Chronic exposure to lead is followed by astrogliosis in the hippocampus, indicating neuronal injury or death in a region that is critical for learning and memory function (Selvin-Testa et al. 1994
). Acutely, lead also appears to interfere with calcium-dependent enzymes (Toscano and Guilarte 2005
) as well as cholinergic, glutaminergic, and dopaminergic neuro-transmitter systems—all integral components of cognition (Cory-Slechta 1995
Several limitations of our study warrant consideration. It is unlikely that our study findings directly reflect the acute cognitive effects of lead because current exposure levels, indicated by blood lead levels, were distributed over a very limited range. However, as a result of these limited current exposures, our study provides further evidence that past and cumulative exposures—apart from current exposures—may have chronic cognitive effects.
Previous studies have identified inverse associations between cumulative lead exposure and visuo spatial ability (Barth et al. 2002
; Schwartz et al. 2000
; Shih et al. 2006
; Stewart et al. 1999
; Weisskopf et al. 2007
), but we were not able to explore this association in our study due to practical limitations in administering the cognitive battery by telephone. However, telephone testing has important advantages and enabled us to maximize recruitment into the cognitive study.
In addition, the GEE analysis was useful for summarizing our results and effectively optimized the precision of our effect estimates. Use of these models is contingent on reasonably homogeneous associations between lead and cognitive function for all cognitive tests included; however, the puzzling association of higher patella lead with better performance on the letter fluency test violated this assumption. This appears to be a unique finding, likely due to chance. Alternatively, this finding may hint that lead-induced cognitive impairments in older age overlap with those of AD. In AD, deficits in semantic fluency (e.g., category fluency) are common, whereas deficits in phonemic fluency (e.g., letter fluency) are not (Henry et al. 2004
; Rascovsky et al. 2007
). However, this explanation requires confirmation from future research.
Our single assessments of cognitive function do not directly capture change in cognitive function, nor do they evaluate dementia status. The women in our study were in their 50s and 60s at the time of their lead assessments, and were 5 years older, on average, when cognitive testing occurred. At these ages, dementia is still relatively rare (Rocca et al. 1998
), but subtle decrements in cognition may be considered a preclinical stage of the condition, preceding it by many years (Elias et al. 2000
; Kawas et al. 2003
; Morris et al. 2001
). Nonetheless, the direct evaluation of lead exposure in relation to cognitive change is of great interest, and repeated cognitive assessments will be conducted.
It is possible that our results were influenced by selection processes, although the direction of the ensuing bias, if any, is not altogether clear. About half of the participants were women from a case–control study of hypertension. Because lead exposure appears to be related to hypertension (Navas-Acien et al. 2007
), it is possible that we overestimated lead’s adverse cognitive effects if cognition, too, was related to participation. Nonetheless, for our cognitive study, the cases from the hypertension study represented only 14% of participants. Conversely, the women in our study were healthy at enrollment, free of chronic diseases (except hypertension alone for cases); they also had low exposures to lead. Thus, again assuming that cognition was related to participation, then the overrepresentation of women who had both excellent cognition and low exposures to lead might have led us to underestimate lead’s adverse cognitive effects.
Finally, as in any observational study, our results could be confounded by unmeasured or mismeasured factors. The NHS cohort is fairly well-characterized, however, and is more homogeneous in terms of occupational and socioeconomic factors than most community-based cohorts. In addition, our results were robust to adjustment for numerous potential confounders, including education and husband’s education, indicators of socioeconomic status. It remains possible that the lead exposure during adulthood that we measured directly via tibia lead is a proxy for lead exposures and its consequences endured during childhood and, therefore, that the association between tibia lead and cognition mis specifies the importance of adult exposures. Although our data are insufficient to satisfactorily confirm or refute this possibility, we examined our findings in the presence and absence of adjustment for educational attainment—a blunt indicator of the consequences of childhood lead exposure—and the findings were unchanged.
In summary, in this study of 587 “young old” women who had community-level exposures to lead, higher levels of tibia lead (a measure of cumulative dose) were significantly associated with worse overall performance on a series of cognitive tests. In contrast, associations between a measure of recent lead exposure and cognition were weaker and not significant. This pattern of results suggests that, even in the absence of substantial current exposures to lead, chronic, low-level historical exposures to lead may have adverse consequences for the cognitive aging of women and thus merit further research.