Several lines of evidence indicate that the etiology of late-onset Alzheimer’s disease (LOAD) is complex, with
significant contributions from both genes and environmental factors. Recent research suggests the importance of epigenetic
mechanisms in defining the relationship between environmental exposures and LOAD. In epidemiologic studies of
adults, cumulative lifetime lead (Pb) exposure has been associated with accelerated declines in cognition. In addition, research
in animal models suggests a causal association between Pb exposure during early life, epigenetics, and LOAD.
There are multiple challenges to human epidemiologic research evaluating the relationship between epigenetics, LOAD,
and Pb exposure. Epidemiologic studies are not well-suited to accommodate the long latency period between exposures
during early life and onset of Alzheimer’s disease. There is also a lack of validated circulating epigenetics biomarkers and
retrospective biomarkers of Pb exposure. Members of our research group have shown bone Pb is an accurate measurement
of historical Pb exposure in adults, offering an avenue for future epidemiologic studies. However, this would not address
the risk of LOAD attributable to early-life Pb exposures. Future studies that use a cohort design to measure both Pb exposure
and validated epigenetic biomarkers of LOAD will be useful to clarify this important relationship.