ABSTRACT & COMMENTARY
Copper and AD New Information
By Richard S. Isaacson, MD
Associate Professor of Neurology (Education), Weill Cornell Medical College
Dr. Isaacson reports he is a retained consultant and on the speakers bureau for Novartis, and is a retained consultant for and receives grant/research support from Accera.
Patients with mild cognitive impairment with elevated free serum copper levels may have a higher rate of conversion to Alzheimer’s disease compared to those with normal free serum copper levels.
Squitti R, et al. Value of serum nonceruloplasmin copper for prediction of mild cognitive impairment conversion to Alzheimer disease. Ann Neurol 2014;75:574-580.
While there are many uncertainties as to the exact cause of Alzheimer’s disease (AD), recent research has started to clarify the relationship between a variety of metals, or more specifically the heavy metals, and development of AD.1 While heavy metals are found naturally in the environment and several are essential for optimal health, high concentrations have been associated with a variety of diseases. Aside from being contained in dietary sources, heavy metals may also enter the body through air inhalation or handling manually. In the landscape of AD, controversy has surrounded the potential influence of several essential heavy metals, including copper, zinc, and iron, as well as the nonessential metal aluminum. Further, the potential clinical efficacy of chelating agents to remove these metals has also been controversial, and evidence is insufficient to warrant its use.
A new longitudinal study helps to clarify this controversy by demonstrating that higher levels of nonbound ceruloplasmin (non-Cp) copper, also called "free copper," in the earliest stages of mild cognitive impairment (MCI) could account for a faster rate of progression to dementia due to AD. This study follows meta-analyses demonstrating that free copper levels are higher in AD patients. This study by Squitti and colleagues included 42 MCI converters and 99 stable MCI patients. Levels of copper, ceruloplasmin, and non-Cp copper, as well as a host of other biomarkers (iron, transferrin, ferritin, APOE genotype, MMSE scores) and potential risk factors (age, sex, hypercholesterolemia, blood pressure) were assessed. Of these, the only significant predictor of conversion from MCI to AD was non-Cp copper (P = 0.022). Of note, conversion rates were independent of APOE4 genotype. Based on these findings, the authors suggested healthy lifestyle choices and potential dietary modification to mitigate this risk.
While the body needs copper, there is the potential that high amounts from either food or the environment over a long period of time could lead to increased beta-amyloid deposition or decreased clearance in the brain, as well as inflammation. Additionally, copper metabolic dysfunction (as evidenced by increased serum-free copper levels) is a condition exhibited only by a subset of AD patients (about 60% of AD patients and 50% of MCI). This "copper phenotype" is recognizable early in the disease course, and defining this group further may provide more targeted interventions while also preventing ineffective and even potentially dangerous adverse events derived from chelating agents (e.g., D-penicillamine) or the use of zinc therapy in AD patients not exhibiting this phenotype.
Preliminary evidence supports the idea that changes toward a safer diet in patients with copper dysfunction should carefully follow the RDA for copper. In this regard, copper enters the body mainly through dietary intake (food ~75%, drinking water ~25%). RDA for copper is 0.9 mg/day, whereas the tolerable upper intake level has been set at 10 mg/day.2 Scientific and medical consensus will only be reached after further research proves that reducing copper absorption can change the clinical history of cognitive decline. Some of the foods that may have the highest amounts of copper include canned clams, liver, and oysters. Other surprising high sources of copper include mushrooms and sesame seeds.
The body of evidence toward dietary interventions in AD is growing, and progress continues to be made in determining modifiable and non-modifiable risk factors involved in the development of AD, as well as pharmacogenomics and nutrigenomic considerations for AD management.3 While further studies are warranted regarding the association of non-Cp copper with cognitive dysfunction and AD, minimizing chronic high exposure and/or copper reduction strategies may be one of the myriad of potentially useful strategies in the multi-modal AD risk-reducing armamentarium.
1. Bush AI, Tanzi RE. Therapeutics for Alzheimer’s disease based on the metal hypothesis. Neurotherapeutics 2008;5:421-432.
2. Food and Nutrition Board. Institute of Medicine of the National Academies. Dietary Reference Intakes (DRIs): Recommended Dietary Allowances and Adequate Intakes. 2001.
3. Oboudiyat C, et al. Alzheimer’s disease. Semin Neurol 2013;33:313-329.