Copper is an essential micronutrient for brain health and dyshomeostasis of copper could have a pathophysiological role in Alzheimer’s disease (AD), however, there are limited data from community-based samples. In this study, we investigate the association of brain copper (assessed using ICP-MS in four regions -inferior temporal, mid-frontal, anterior cingulate, and cerebellum) and dietary copper with cognitive decline and AD pathology burden (a quantitative summary of neurofibrillary tangles, diffuse and neuritic plaques in multiple brain regions) at autopsy examination among deceased participants (N = 657; age of death: 90.2(±6.2)years, 70% women, 25% APOE-ɛ4 carriers) in the Rush Memory and Aging Project. During annual visits, these participants completed cognitive assessments using a 19-test battery and dietary assessments (using a food frequency questionnaire). Regression, linear mixed-effects, and logistic models adjusted for age at death, sex, education, and APOE-ε4 status were used. Higher composite brain copper levels were associated with slower cognitive decline (β(SE) = 0.028(0.01), p = 0.001) and less global AD pathology (β(SE) = −0.069(0.02), p = 0.0004). Participants in the middle and highest tertile of dietary copper had slower cognitive decline (T2vs.T1: β = 0.038, p = 0.0008; T3vs.T1: β = 0.028, p = 0.01) than those in the lowest tertile. Dietary copper intake was not associated with brain copper levels or AD pathology. Associations of higher brain copper levels with slower cognitive decline and with less AD pathology support a role for copper dyshomeostasis in AD pathogenesis and suggest that lower brain copper may exacerbate or indicate disease severity. Dietary and brain copper are unrelated but dietary copper is associated with slower cognitive decline via an unknown mechanism.
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We thank the participants and the staff of Rush Memory and Aging Project and the Rush Alzheimer’s Disease Center. We also thank the biostatisticians Yamin Wang and Woojeong Bang who worked on this project.
This study was supported by grants from the National Institute of Health (R01AG054057 (JAS, AIB), R01AG017917 (DAB), and the National Health and Medical Research Council of Australia (SA, AIB). None of the funding sources have any role in data analysis, interpretation, and manuscript preparation.
AIB Holds equity: Alterity Biotechnology Ltd, Cogstate Ltd, Mesoblast Ltd, Collaborative Medicinal Development LLC. Paid consultant: Collaborative Medicinal Development Pty Ltd. Julie A Schneider and other authors report no competing interests.
The authors dedicate this manuscript to Dr. Martha Clare Morris, who passed away during its drafting.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Agarwal, P., Ayton, S., Agrawal, S. et al. Brain copper may protect from cognitive decline and Alzheimer’s disease pathology: a community-based study. Mol Psychiatry (2022). https://doi.org/10.1038/s41380-022-01802-5