S4‐01‐02: Interaction Between Pollutant Exposures And Genetics In Aging Populations At Risk For Cognitive Decline

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/152654/1/alzjjalz2018062860.pd

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

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.PHDEnvironmental Health SciencesUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/96166/1/bakulski_1.pd

P2‐540: Polygenetic Risk For Alzheimer’S Disease And Dementia Status

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/153242/1/alzjjalz2019062948.pd

P3‐558: Exposures Prior To Age 16 Are Associated With Dementia Status In The Health And Retirement Study

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/152762/1/alzjjalz2019063595.pd

Lead Exposure, B Vitamins, and Plasma Homocysteine in Men 55 Years of Age and Older: The VA Normative Aging Study

Background: Lead (Pb) exposure may influence the plasma concentration of homocysteine, a one-carbon metabolite associated with cardiovascular and neurodegenerative diseases. Little is known about the associations between Pb and homocysteine over time, or the potential influence of dietary factors. Objectives: We examined the longitudinal association of recent and cumulative Pb exposure with homocysteine concentrations and the potential modifying effect of dietary nutrients involved in one-carbon metabolism. Methods: In a subcohort of the Veterans Affairs (VA) Normative Aging Study (1,056 men with 2,301 total observations between 1993 and 2011), we used mixed-effects models to estimate differences in repeated measures of total plasma homocysteine across concentrations of Pb in blood and tibia bone, assessing recent and cumulative Pb exposure, respectively. We also assessed effect modification by dietary intake and plasma concentrations of folate, vitamin B6, and vitamin B12. Results: An interquartile range (IQR) increment in blood Pb (3 μg/dL) was associated with a 6.3% higher homocysteine concentration (95% CI: 4.8, 7.8%). An IQR increment in tibia bone Pb (14 μg/g) was associated with a 3.7% higher homocysteine (95% CI: 1.6, 5.6%), which was attenuated to 1.5% (95% CI: –0.5, 3.6%) after adjusting for blood Pb. For comparison, a 5-year increase in time from baseline was associated with a 5.7% increase in homocysteine (95% CI: 4.3, 7.1%). The association between blood Pb and homocysteine was significantly stronger among participants with estimated dietary intakes of vitamin B6 and folate below (vs. above) the study population medians, which were similar to the U.S. recommended dietary allowance intakes. Conclusions: Pb exposure was positively associated with plasma homocysteine concentration. This association was stronger among men with below-median dietary intakes of vitamins B6 and folate. These findings suggest that increasing intake of folate and B6 might reduce Pb-associated increases in homocysteine, a risk factor for cardiovascular disease and neurodegeneration. Citation: Bakulski KM, Park SK, Weisskopf MG, Tucker KL, Sparrow D, Spiro A III, Vokonas PS, Nie LH, Hu H, Weuve J. 2014. Lead exposure, B vitamins, and plasma homocysteine in men 55 years of age and older: the VA Normative Aging Study. Environ Health Perspect 122:1066–1074; http://dx.doi.org/10.1289/ehp.130693

Mendelian Randomization of Dyslipidemia on Cognitive Impairment Among Older Americans

Background: Altered lipid metabolism may be a risk factor for dementia, and blood cholesterol level has a strong genetic component. We tested the hypothesis that dyslipidemia (either low levels of high-density lipoprotein cholesterol (HDL-C) or high total cholesterol) is associated with cognitive status and domains, and assessed causality using genetic predisposition to dyslipidemia as an instrumental variable.Methods: Using data from European and African genetic ancestry participants in the Health and Retirement Study, we selected observations at the first non-missing biomarker assessment (waves 2006–2012). Cognition domains were assessed using episodic memory, mental status, and vocabulary tests. Overall cognitive status was categorized in three levels (normal, cognitive impairment non-dementia, dementia). Based on 2018 clinical guidelines, we compared low HDL-C or high total cholesterol to normal levels. Polygenic scores for dyslipidemia were used as instrumental variables in a Mendelian randomization framework. Multivariable logistic regressions and Wald-type ratio estimators were used to examine associations.Results: Among European ancestry participants (n = 8,781), at risk HDL-C levels were associated with higher odds of cognitive impairment (OR = 1.20, 95% CI: 1.03, 1.40) and worse episodic memory, specifically. Using cumulative genetic risk for HDL-C levels as a valid instrumental variable, a significant causal estimate was observed between at risk low HDL-C levels and higher odds of dementia (OR = 2.15, 95% CI: 1.16, 3.99). No significant associations were observed between total cholesterol levels and cognitive status. No significant associations were observed in the African ancestry sample (n = 2,101).Conclusion: Our study demonstrates low blood HDL-C is a potential causal risk factor for impaired cognition during aging in non-Hispanic whites of European ancestry. Dyslipidemia can be modified by changing diets, health behaviors, and therapeutic strategies, which can improve cognitive aging. Studies on low density lipoprotein cholesterol, the timing of cholesterol effects on cognition, and larger studies in non-European ancestries are needed

Cross-region reduction in 5-hydroxymethylcytosine in Alzheimer's disease brain

Epigenetic processes play a key role in the central nervous system and altered levels of 5-methylcytosine have been associated with a number of neurologic phenotypes, including Alzheimer's disease (AD). Recently, 3 additional cytosine modifications have been identified (5-hydroxymethylcytosine, 5-formylcytosine, and 5-carboxylcytosine), which are thought to be intermediate steps in the demethylation of 5-methylcytosine to unmodified cytosine. Little is known about the frequency of these modifications in the human brain during health or disease. In this study, we used immunofluorescence to confirm the presence of each modification in human brain and investigate their cross-tissue abundance in AD patients and elderly control samples. We identify a significant AD-associated decrease in global 5-hydroxymethylcytosine in entorhinal cortex and cerebellum, and differences in 5-formylcytosine levels between brain regions. Our study further implicates a role for epigenetic alterations in AD. © 2014 Elsevier Inc