Urinary metal levels, cognitive test performance, and dementia in the multi-ethnic study of atherosclerosis

Authors: DOMINGO-RELLOSO, ARCE - Columbia University - New York; MCGRAW, KATLYN - Columbia University - New York; HECKBERT, SUSAN - University Of Washington; LUCHSINGER, JOSE - Columbia University Medical Center; SCHILLING, KATHRIN - Columbia University - New York; GLABONJAT, RONALD - Columbia University - New York; MARTINEZ-MORATA, IRENE - Columbia University - New York; MAYER, MELANIE - Columbia University - New York; LIU, YONGMEI - Duke University; WOOD, ALEXIS - Children'S Nutrition Research Center (CNRC); GOLDSMITH, JEFF - Columbia University - New York; HAYDEN, KATHLEEN - Wake Forest School Of Medicine; HABES, MOHAMAD - University Of Texas Health Science Center; NASRALLAH, ILYA - University Of Pennsylvania; BRYAN, NICK - University Of Pennsylvania; RASHID, TANWEER - University Of Texas At San Antonio; POST, WENDY - Johns Hopkins University School Of Medicine; ROTTER, JEROME - Harbor-Ucla Medical Center; PALTA, PRIYA - University Of North Carolina; VALERI, LINDA - Columbia University - New York; HUGHES, TIMOTHY - Wake Forest School Of Medicine; NAVAS-ACIEN, ANA - Columbia University - New York

Submitted to: JAMA Network Open
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/9/2024
Publication Date: 12/2/2024
Citation: Domingo-Relloso, A., Mcgraw, K.E., Heckbert, S.R., Luchsinger, J.A., Schilling, K., Glabonjat, R.A., Martinez-Morata, I., Mayer, M., Liu, Y., Wood, A.C., Goldsmith, J., Hayden, K.M., Habes, M., Nasrallah, I.M., Bryan, N., Rashid, T., Post, W.S., Rotter, J.I., Palta, P., Valeri, L., Hughes, T.M., Navas-Acien, A. 2024. Urinary metal levels, cognitive test performance, and dementia in the multi-ethnic study of atherosclerosis. JAMA Network Open. 7(12). Article e2448286. https://doi.org/10.1001/jamanetworkopen.2024.48286.
DOI: https://doi.org/10.1001/jamanetworkopen.2024.48286

Interpretive Summary: Heavy metals occur naturally in the environment, and can penetrate into the food we eat. This study looked at the relationship between metal excreted in urine and cognitive performance, particularly focusing on how these effects differ based on genetic factors (specifically the APOE4 gene). Researchers found that higher levels of certain metals were linked to worse cognitive performance, particularly in people with the APOE4 gene, suggesting that these metals could accelerate cognitive decline. Notably, metals like copper and cobalt showed strong associations with cognitive impairment and dementia risk. The study also highlighted a potential threshold effect, indicating that low levels of metals might not be harmful, but higher levels could be detrimental. Overall, understanding metal exposure's impact on brain health could inform future prevention strategies for dementia.

Technical Abstract: Metals are established neurotoxicants, but evidence of their association with cognitive performance at low chronic exposure levels is limited. The objective of this study was to investigate the association of urinary metal levels, individually and as a mixture, with cognitive tests and dementia diagnosis, including effect modification by apolipoprotein epsilon4 allele (APOE4). The multicenter prospective cohort Multi-Ethnic Study of Atherosclerosis (MESA) was started from July 2000 to August 2002, with follow-up through 2018. A total of 6303 MESA participants were included. Data analysis was performed from October 12, 2023, to June 13, 2024. Urine samples were collected at baseline (2000-2002), and arsenic, cadmium, cobalt, copper, lead, manganese, tungsten, uranium, and zinc levels were measured in 2020-2022. Digit Symbol Coding (DSC) (n=3819) (possible score range, 0-133), Cognitive Abilities Screening Instrument (CASI) (n=3918) (possible score range, 0-100), and Digit Span (DS) (n = 4176) (possible score range, 0-30) cognitive tests were administered in 2010-2012; higher scores of each test indicate increasing levels of positive response. A total of 6303 participants were followed up for dementia diagnosis through 2018. The median age at baseline was 60 (IQR, 53-70) years, and 3303 participants (52.4%) were female. The median cognitive scores were 51 (IQR, 38-64) for DSC, 90 (IQR, 84-95) for CASI, and 15 (IQR, 12-18) for DS. There were 559 cases of dementia through the follow-up period. Inverse associations with DSC were identified: mean differences in z scores per IQR increase in metal levels were -0.03 (95% CI, -0.07 to 0.00) for arsenic, -0.05 (95% CI, -0.09 to -0.004) for cobalt, -0.05 (95% CI, -0.07 to -0.02) for copper, -0.04 (95% CI, -0.08 to -0.001) for uranium, and -0.03 (95% CI, -0.06 to -0.01) for zinc. Among 1058 APOE4 carriers, manganese was also inversely associated with DSC. The joint mean difference of DSC comparing percentile 95th with the 25th of the 9-metal mixture was -0.30 (95% CI, -0.47 to -0.14) for APOE4 carriers and -0.10 (95% CI, -0.19 to -0.01) for noncarriers. Arsenic, cadmium, cobalt, copper, tungsten, uranium, and zinc were individually associated with dementia, with hazard ratios per IQR of metal ranging from 1.15 (95% CI, 1.03-1.29) for tungsten to 1.46 (95% CI, 1.06-2.02) for uranium. The joint hazard ratio of dementia comparing percentiles 95th with the 25th of the 9-metal mixture was 1.71 (95% CI, 1.24-3.89), with no significant difference by APOE4 status. In this study, participants with higher concentrations of metals in their urine, compared with those with lower concentrations, had worse performance on cognitive tests and greater likelihood of developing dementia. The findings of this multicenter multiethnic cohort study might inform screening and potential interventions for prevention of dementia based on individuals' metal exposure levels and genetic profiles.