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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Atwood CS, Moir RD, Huang X, Scarpa RC, Bacarra NM, Romano DM, et al. Dramatic aggregation of Alzheimer abeta by Cu(II) is induced by conditions representing physiological acidosis. J Biol Chem. 1998;273:12817–26.
Atwood CS, Scarpa RC, Huang X, Moir RD, Jones WD, Fairlie DP, et al. Characterization of copper interactions with alzheimer amyloid beta peptides: identification of an attomolar-affinity copper binding site on amyloid beta1-42. J Neurochem. 2000;75:1219–33.
Miller LM, Wang Q, Telivala TP, Smith RJ, Lanzirotti A, Miklossy J. Synchrotron-based infrared and X-ray imaging shows focalized accumulation of Cu and Zn co-localized with beta-amyloid deposits in Alzheimer’s disease. J Struct Biol. 2006;155:30–7.
Squitti R, Faller P, Hureau C, Granzotto A, White AR, Kepp KP. Copper Imbalance in Alzheimer’s Disease and Its Link with the Amyloid Hypothesis: Towards a Combined Clinical, Chemical, and Genetic Etiology. J Alzheimer’s Dis: JAD. 2021;83:23–41.
Li DD, Zhang W, Wang ZY, Zhao P. Serum Copper, Zinc, and Iron Levels in Patients with Alzheimer’s Disease: A Meta-Analysis of Case-Control Studies. Front Aging Neurosci. 2017;9:300.
Phinney AL, Drisaldi B, Schmidt SD, Lugowski S, Coronado V, Liang Y, et al. In vivo reduction of amyloid-beta by a mutant copper transporter. Proc Natl Acad Sci. 2003;100:14193–8.
Sasaguri H, Nilsson P, Hashimoto S, Nagata K, Saito T, De Strooper B, et al. APP mouse models for Alzheimer’s disease preclinical studies. Embo j. 2017;36:2473–87.
Itoh S, Ozumi K, Kim HW, Nakagawa O, McKinney RD, Folz RJ, et al. Novel mechanism for regulation of extracellular SOD transcription and activity by copper: role of antioxidant-1. Free Radic Biol Med. 2009;46:95–104.
Sensi SL, Granzotto A, Siotto M, Squitti R. Copper and Zinc Dysregulation in Alzheimer’s Disease. Trends Pharm Sci. 2018;39:1049–63.
Waggoner DJ, Bartnikas TB, Gitlin JD. The role of copper in neurodegenerative disease. Neurobiol Dis. 1999;6:221–30.
Morris MC, Evans DA, Tangney CC, Bienias JL, Schneider JA, Wilson RS, et al. Dietary copper and high saturated and trans fat intakes associated with cognitive decline. Arch Neurol. 2006;63:1085–8.
Wang X, Li X, Xing Y, Wang W, Li S, Zhang D, et al. Threshold Effects of Total Copper Intake on Cognitive Function in US Older Adults and the Moderating Effect of Fat and Saturated Fatty Acid Intake. J Acad Nutr Diet. 2021;121:2429–42.
Bennett DA, Buchman AS, Boyle PA, Barnes LL, Wilson RS, Schneider JA. Religious Orders Study and Rush Memory and Aging Project. J Alzheimer’s Dis: JAD. 2018;64:S161–S189.
Morris MC. Validity and Reproducibility of a Food Frequency Questionnaire by Cognition in an Older Biracial Sample. Am J Epidemiol. 2003;158:1213–7.
Wilson RS, Boyle PA, Yu L, Barnes LL, Sytsma J, Buchman AS, et al. Temporal course and pathologic basis of unawareness of memory loss in dementia. Neurology 2015;85:984–91.
Bennett DA, Schneider JA, Arvanitakis Z, Kelly JF, Aggarwal NT, Shah RC, et al. Neuropathology of older persons without cognitive impairment from two community-based studies. Neurology. 2006;66:1837–44.
Boyle PA, Yu L, Leurgans SE, Wilson RS, Brookmeyer R, Schneider JA, et al. Attributable risk of Alzheimer’s dementia attributed to age-related neuropathologies. Ann Neurol. 2019;85:114–24.
Bennett DA, Schneider JA, Wilson RS, Bienias JL, Arnold SE. Neurofibrillary tangles mediate the association of amyloid load with clinical Alzheimer disease and level of cognitive function. Arch Neurol. 2004;61:378–84.
Mirra SS, Heyman A, McKeel D, Sumi SM, Crain BJ, Brownlee LM, et al. The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer’s disease. Neurology 1991;41:479–86.
Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathologica. 1991;82:239–59.
Consensus recommendations for the postmortem diagnosis of Alzheimer’s disease. The National Institute on Aging, and Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer’s Disease. Neurobiol Aging. 1997;18:S1–2.
Yu L, Lutz MW, Wilson RS, Burns DK, Roses AD, Saunders AM, et al. TOMM40'523 variant and cognitive decline in older persons with APOE epsilon3/3 genotype. Neurology 2017;88:661–8.
Bennett DA, Schneider JA, Aggarwal NT, Arvanitakis Z, Shah RC, Kelly JF, et al. Decision rules guiding the clinical diagnosis of Alzheimer’s disease in two community-based cohort studies compared to standard practice in a clinic-based cohort study. Neuroepidemiology 2006;27:169–76.
Wilson RS, Barnes LL, Krueger KR, Hoganson G, Bienias JL, Bennett DA. Early and late life cognitive activity and cognitive systems in old age. J Int Neuropsychol Soc. 2005;11:400–7.
Buchman AS, Boyle PA, Wilson RS, Bienias JL, Bennett DA. Physical activity and motor decline in older persons. Muscle Nerve. 2007;35:354–62.
Agarwal P, Wang Y, Buchman AS, Holland TM, Bennett DA, Morris MC. Dietary antioxidants associated with slower progression of parkinsonian signs in older adults. Nutritional Neurosci. 2020;25:550–557. https://doi.org/10.1080/1028415X.2020.1769411.
Willett WC Implication of Total Energy Intake fo Epidemiological Analyses, vol. Third Edition 2013, 260-286pp.
Magaki S, Raghavan R, Mueller C, Oberg KC, Vinters HV, Kirsch WMIron. copper, and iron regulatory protein 2 in Alzheimer’s disease and related dementias. Neurosci Lett. 2007;418:72–6.
Rembach A, Hare DJ, Lind M, Fowler CJ, Cherny RA, McLean C, et al. Decreased copper in Alzheimer’s disease brain is predominantly in the soluble extractable fraction. Int J Alzheimers Dis. 2013;2013:623241–623241.
Schrag M, Mueller C, Oyoyo U, Smith MA, Kirsch WM. Iron, zinc and copper in the Alzheimer’s disease brain: a quantitative meta-analysis. Some insight on the influence of citation bias on scientific opinion. Prog Neurobiol. 2011;94:296–306.
Gerber H, Wu F, Dimitrov M, Garcia Osuna GM, Fraering PC. Zinc and Copper Differentially Modulate Amyloid Precursor Protein Processing by γ-Secretase and Amyloid-β Peptide Production. J Biol Chem. 2017;292:3751–67.
Acevedo KM, Hung YH, Dalziel AH, Li Q-X, Laughton K, Wikhe K, et al. Copper promotes the trafficking of the amyloid precursor protein. J Biol Chem. 2011;286:8252–62.
Cater MA, McInnes KT, Li QX, Volitakis I, La Fontaine S, Mercer JF, et al. Intracellular copper deficiency increases amyloid-beta secretion by diverse mechanisms. Biochem J. 2008;412:141–52.
Adlard PA, Cherny RA, Finkelstein DI, Gautier E, Robb E, Cortes M, et al. Rapid restoration of cognition in Alzheimer’s transgenic mice with 8-hydroxy quinoline analogs is associated with decreased interstitial Abeta. Neuron 2008;59:43–55.
Adlard PA, Bica L, White AR, Nurjono M, Filiz G, Crouch PJ, et al. Metal ionophore treatment restores dendritic spine density and synaptic protein levels in a mouse model of Alzheimer’s disease. PloS One. 2011;6:e17669.
Bayer TA, Schäfer S, Simons A, Kemmling A, Kamer T, Tepest R, et al. Dietary Cu stabilizes brain superoxide dismutase 1 activity and reduces amyloid Abeta production in APP23 transgenic mice. Proc Natl Acad Sci. 2003;100:14187–92.
Lannfelt L, Blennow K, Zetterberg H, Batsman S, Ames D, Harrison J, et al. Safety, efficacy, and biomarker findings of PBT2 in targeting Abeta as a modifying therapy for Alzheimer’s disease: a phase IIa, double-blind, randomised, placebo-controlled trial. Lancet Neurol. 2008;7:779–86.
Diouf I, Bush AI, Ayton S. Cerebrospinal fluid ceruloplasmin levels predict cognitive decline and brain atrophy in people with underlying β-amyloid pathology. Neurobiol Dis. 2020;139:104810.
Giacoppo S, Galuppo M, Calabrò RS, D’Aleo G, Marra A, Sessa E, et al. Heavy metals and neurodegenerative diseases: an observational study. Biol Trace Elem Res. 2014;161:151–60.
Kessler H, Pajonk FG, Bach D, Schneider-Axmann T, Falkai P, Herrmann W, et al. Effect of copper intake on CSF parameters in patients with mild Alzheimer’s disease: a pilot phase 2 clinical trial. J Neural Transm (Vienna). 2008;115:1651–9.
Yaffe K, Clemons TE, McBee WL, Lindblad AS. Impact of antioxidants, zinc, and copper on cognition in the elderly: a randomized, controlled trial. Neurology 2004;63:1705–7.
Lamtai M, Zghari O, Ouakki S, Marmouzi I, Mesfioui A, El Hessni A, et al. Chronic copper exposure leads to hippocampus oxidative stress and impaired learning and memory in male and female rats. Toxicol Res. 2020;36:359–66.
Yu H, Jiang X, Lin X, Zhang Z, Wu D, Zhou L, et al. Hippocampal Subcellular Organelle Proteomic Alteration of Copper-Treated Mice. Toxicological Sci: Off J Soc Toxicol. 2018;164:250–63.
Yu J, Luo X, Xu H, Ma Q, Yuan J, Li X, et al. Identification of the key molecules involved in chronic copper exposure-aggravated memory impairment in transgenic mice of Alzheimer’s disease using proteomic analysis. J Alzheimer’s Dis: JAD. 2015;44:455–69.
Lin X, Wei G, Huang Z, Qu Z, Huang X, Xu H, et al. Mitochondrial proteomic alterations caused by long-term low-dose copper exposure in mouse cortex. Toxicol Lett. 2016;263:16–25.
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 27, 4307–4313 (2022). https://doi.org/10.1038/s41380-022-01802-5