Zinc Therapy in Early Alzheimer's Disease: Safety and Potential Therapeutic Efficacy

Abstract

Zinc therapy is normally utilized for treatment of Wilson disease (WD), an inherited condition that is characterized by increased levels of non-ceruloplasmin bound ('free') copper in serum and urine. A subset of patients with Alzheimer's disease (AD) or its prodromal form, known as Mild Cognitive Impairment (MCI), fail to maintain a normal copper metabolic balance and exhibit higher than normal values of non-ceruloplasmin copper. Zinc's action mechanism involves the induction of intestinal cell metallothionein, which blocks copper absorption from the intestinal tract, thus restoring physiological levels of non-ceruloplasmin copper in the body. On this basis, it is employed in WD. Zinc therapy has shown potential beneficial effects in preliminary AD clinical trials, even though the studies have missed their primary endpoints, since they have study design and other important weaknesses. Nevertheless, in the studied AD patients, zinc effectively decreased non-ceruloplasmin copper levels and showed potential for improved cognitive performances with no major side effects. This review discusses zinc therapy safety and the potential therapeutic effects that might be expected on a subset of individuals showing both cognitive complaints and signs of copper imbalance.

Keywords: Alzheimer’s disease; Wilson disease safety; copper; efficacy; mild cognitive impairment; zinc therapy.

Figure 1

General zinc absorption and metabolism. Intestine: zinc is absorbed in the small intestine and is responsive to dietary intake. ZnT and Zip transporters have opposite role within the cell: Zip transporters in increasing cytoplasmic zinc concentrations while ZnT in decreasing it, in particular ZnT1 is located in small intestine and regulates zinc release from the enterocyte to general circulation. Zn²⁺ is tightly bound to α2-macroglobulin (α2m) and loosely to albumin (Alb) and other proteins, peptides and amino acids (AA) which serve as primary sources of zinc accessible to all cells. Liver: The liver plays a central role in zinc metabolism as well. Corticosteroids, estrogens and inflammation decrease plasma zinc, associated to an increase of zinc in the liver. Hepatitis, liver dysfunction, or liver diseases with fulminant, but also chronic or subacute hepatic failure are associated with low levels of zinc. Reduced levels of zinc are found in alcoholic hepatitis patients, while they are less decreased in nonalcoholic liver disease. Brain: zinc is necessary for brain development and physiology. The Zn²⁺ ions could be transported into neurons by the transmembrane ZiP proteins. Once inside the accumulation and trafficking of Zn²⁺ are directed by members of ZnT family. ZnT1, 3, and 6 are abundant in the brain and central nervous system (CNS). The homeostasis of Zn²⁺ in the brain is also regulated by the MT3 protein. Zinc is sequestered into presynaptic vesicles by ZnT3, which is coupled with vesicular glutamate transporter (not shown); zinc is then released into synaptic cleft together with glutamate (not shown).