Lead Exposure, Homocysteine, DNA Methylation and Late-Onset Alzheimer's Disease.

Abstract

The causes of sporadic neurodegenerative disease in aging adults likely involve a complex interplay of genetics, epigenetics, and a lifetime of environmental exposures. The current dissertation uses two molecular epidemiology studies to investigate biomarkers of environmental exposures and neurodegenerative outcomes. A major challenge of chronic disease environmental etiology research is the long latency between environmental exposures and the onset of disease. The Veteran’s Affairs Normative Aging Study is an epidemiologic cohort designed to prospectively measure exposures and monitor early or subclinical disease. Repeated levels of recent exposure to lead were measured in blood and cumulative exposure to lead was measured by bone K-shell X-ray fluorescence. Homocysteine (Hcy), a risk factor for cardiovascular and neurodegenerative diseases when elevated, was measured concurrently with blood lead. Using repeated measures mixed effects models, this research demonstrated that an interquartile range higher blood Pb level (3 ug/dl) was associated with an 8.1% higher Hcy, compared to the percent change in Hcy with a 5-year increase in age (3.1%). We also demonstrated that the effect of Pb on Hcy was reduced in individuals with diets rich in vitamins B6, B12 and folate. This research suggests that interventions to reduce blood Pb and increase dietary B-vitamin intake would reduce circulating Hcy levels, potentially lowering risk for cardiovascular and neurodegenerative disease. The second study investigated the potential contribution of epigenetics, through DNA methylation, to gene expression changes in late-onset Alzheimer’s disease. In two separate thesis papers, the DNA methylomes and transcriptomes of frontal cortex tissues from deceased patients with Alzheimer’s disease were mapped and compared to neuropathologically normal controls using genome-wide approaches and bioinformatic analyses. In a proof-of-concept study, the top disease ranked DNA methylation site was validated for altered gene expression and protein levels. A novel biomarker and potential mechanism for LOAD pathogenicity with environmental implications was proposed. This interdisciplinary thesis implemented laboratory biomarker studies, population exposure assessment and molecular epidemiology to approach the multi-faceted origins of neurological disease in aging populations.