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Delta-aminolevulinic acid dehydratase polymorphism and the relation between low level lead exposure and the Mini-Mental Status Examination in older men: the Normative Aging Study
  1. J Weuve1,
  2. K T Kelsey1,2,
  3. J Schwartz1,8,
  4. D Bellinger3,4,
  5. R O Wright1,8,9,
  6. P Rajan1,
  7. A Spiro III5,6,
  8. D Sparrow5,6,7,
  9. A Aro1,8,
  10. H Hu1,8
  1. 1Department of Environmental Health, Harvard School of Public Health, Boston, MA, USA
  2. 2Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA, USA
  3. 3Department of Neurology, Children’s Hospital Boston, Boston, MA, USA
  4. 4Department of Neurology, Harvard Medical School, Boston, MA, USA
  5. 5Department of Veterans Affairs, Boston, MA, USA
  6. 6Boston University School of Public Health, Boston, MA, USA
  7. 7Boston University School of Medicine, Boston, MA, USA
  8. 8Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
  9. 9Department of Pediatrics, Children’s Hospital Boston, Boston, MA, USA
  1. Correspondence to:
 Dr J Weuve
 Department of Environmental Health, Harvard School of Public Health, Landmark Center – Third Floor East, 401 Park Drive, Boston, MA 02215, USA; jweuve{at}


Objective: To determine whether a polymorphism the in δ-aminolevulinic acid dehydratase (ALAD) gene modifies the neurotoxicity of lead in older adults.

Methods: The authors studied men participating in the Department of Veterans Affairs’ Normative Aging Study, assessing their recent exposure to lead by measuring blood lead (n = 915) at each triennial clinic visit, and, beginning in 1991, assessing their cumulative exposure by measuring lead levels in tibia (n = 722) and patella (n = 720), using K-shell x ray fluorescence. Starting in 1993 and again at each triennial visit, the authors administered the Mini-Mental State Examination (MMSE) to assess their cognitive functioning. The relation of the lead biomarkers to MMSE score was evaluated and this association was compared among men who carried the variant allele, ALAD-2, versus men without the allele.

Results: Sixteen per cent of men carried the ALAD-2 allele. Median tibia and patella lead levels (first-third quartile) were 19 (13–28) and 27 (18–39) μg/g. Blood lead levels were consistent with non-occupational exposure: only 6% of men had levels ⩾10 μg/dl. In multivariable adjusted analyses, higher levels of blood lead were associated with poorer performance on the MMSE. This association was most pronounced among ALAD-2 carriers, among whom a 3 μg/dl increment in blood lead (the interquartile range) was associated with a 0.26 point lower mean MMSE score (95% CI −0.54 to 0.01), compared with a 0.04 point lower score (95% CI −0.16 to 0.07) among non-carriers. The modest 0.22 point difference in these associations did not attain statistical significance, however (pinteraction = 0.13). The associations between bone lead levels and MMSE score did not vary by ALAD-2 status.

Conclusions: Although not statistically significant, these findings suggest that ALAD genotype may modify blood lead’s adverse association with cognition among older men who had community exposures to lead. However, despite a relatively large sample size and the use of sensitive methods for measuring lead burden, the evidence overall was fairly weak.

  • ALAD, δ-aminolevulinic acid dehydratase
  • GAM, general additive model
  • GAMM, general additive mixed model
  • MMSE, Mini-Mental State Examination
  • NAS, Normative Aging Study
  • lead
  • delta-aminolevulinic acid dehydratase
  • polymorphism
  • genetic
  • cognition
  • aging

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  • Published Online First 6 June 2006

  • Competing interests: none.

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