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Copper in Glucose Intolerance, Cognitive Decline, and Alzheimer Disease

Squitti, Rosanna, PhD*; Mendez, Armando, PhD†,‡; Ricordi, Camillo, MD†,§; Siotto, Mariacristina, PhD; Goldberg, Ron, MD

Alzheimer Disease & Associated Disorders: January-March 2019 - Volume 33 - Issue 1 - p 77–85
doi: 10.1097/WAD.0000000000000280
Review Article

Trace metal dyshomeostasis has been linked to loss of cognitive performance. In particular, a disturbance in the regulation of copper (Cu), characterized by an increase in circulating Cu not bound to ceruloplasmin (non-Cp Cu), is thought to play a role in the development of Alzheimer disease (AD) and other neurodegenerative diseases in the aging population. Non-Cp Cu is redox active and its toxicity is thought to result from its ability to accelerate oxidative stress and advanced glycation endproduct (AGE) formation, leading to extracellular matrix damage in tissues including the brain. Cognitive loss is increasingly recognized to be a feature of type 2 diabetes and the increased AGE formation characteristic of diabetes may play a role in the development of this complication. There also is evidence for copper dyshomeostasis in type 2 diabetes, and therefore this could contribute to the cognitive deterioration associated with this disease. Demonstrating that disturbances of copper homeostasis correlate with an increased rate of cognitive decline in type 2 diabetes patients, and that they correlate with an increased rate of conversion from prediabetes to diabetes would bring almost immediate benefits in the clinical community in terms of treatment efficacy, AD prevention, and cost savings.

*Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio-Fatebenefratelli, Brescia, Italy

Department of Medicine, Diabetes Research Institute

Department of Surgery, Cell Transplant Program

§University of Miami Miller School of Medicine, Miami, FL

IRCCS Fondazione Don Carlo Gnocchi, Milan, Italy

R.S. and C.R. are currently receiving a grant from Italian Ministry of Health (project code: CO-2016-02361018) and R.S. from Ricerca Corrente. R.S. 3% has shares in Canox4drug but does not receive monetary compensation and 3% shares in Igea Research Corporation but does not receive monetary compensation. The remaining authors declare that they have nothing to disclose.

Reprints: Rosanna Squitti, PhD, IRCCS Istituto Centro San Giovanni di Dio-Fatebenefratelli, Brescia, Via Pilastroni 4, 25125 Brescia, Italy. (e-mail:

Received June 9, 2018

Accepted September 24, 2018

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