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.
Highlights
Zinc has been utilized for some time in the treatment of Wilson disease (WD), an autosomal rare disease of copper imbalance, which mainly harms brain and liver, caused by mutations in the ATP7B gene
Besides the most popular Alzheimer’s disease (AD) hypothesis, the Amyloid Hypothesis [5], questioned in the latest years [8], the Metal Hypothesis [9] postulates that the interaction between iron, copper, zinc, and AD-related proteins (encompassing the amyloid precursor protein (APP)/Aβ system and tau proteins) are important drivers of AD pathology [8,10]
This negative balance is caused by the blockade of both the absorption of dietary copper and of the reabsorption of copper secreted in saliva, gastric juice and intestinal secretions
Summary
Zinc has been utilized for some time in the treatment of Wilson disease (WD), an autosomal rare disease of copper imbalance, which mainly harms brain and liver, caused by mutations in the ATP7B gene. Familial AD (fAD) is rare, but it has an early onset and a known causative mutation in amyloid precursor protein (APP), presenilin (PSEN) 1 or PSEN2 genes, inherited as an autosomal dominant trait. Mutations in these genes affect the normal processing of APP and increase the brain levels of amyloid-beta 1-42 (Aβ) believed to be the main factor in the pathological basis of the disorder [3]. A subset of patients with AD and its prodromal form, known as Mild Cognitive Impairment (MCI), fail to maintain a normal copper balance and distribution in the body. We discuss the applicability of a zinc-based approach to restore copper balance in a subset of MCI patients exhibiting non-ceruloplasmin bound copper values higher than normal (0.1–1.6 μmol/L [4]), by using zinc treatment in WD as a template
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