The major histopathological features of Alzheimer’s disease (AD), the commonest form of dementia worldwide, are senile plaques and neurofibrillary tangles. AD is due to an abnormal processing of the APP (amyloid precursor protein) by β- and γ-secretases (
Table 2A summarizes the main pathogenic mechanisms). The epsilon 4 allele of the apolipoprotein E (APOE) gene augments the risk of AD by three-fold and decreases age onset [
75]. Patients with two epsilon 4 alleles have a 15-fold increase in AD risk as compared with the APOE epsilon 3 [
76]. The regions of the brain that are particularly involved by atrophy at the beginning of the disease are the entorhinal cortex, the hippocampus and the amygdala.
In addition to the hypothesis of the amyloid cascade
per se, the role of biometals in the pathogenesis of AD is a subject of growing interest. Indeed, free plasma levels of copper increase with ageing [
77]. Metal dyshomeostasis might impact not only on AD onset, but also on its progression [
1]. There is a negative correlation between free copper in blood and cognitive status in AD [
78]. Although the total levels of copper are similar in healthy subjects and in AD, the ratios of plasma/serum copper levels are significantly higher in AD [
79]. Copper not bound to ceruloplasmin, rather than absolute serum copper levels, is a key-concept for the understanding of the pathogenesis of AD [
80]. Both
in vitro and
in vivo studies have shown local and systemic defects in copper metabolism in AD. Very high concentrations of copper have been found in senile plaques [
8]. There is a very appealing relationship between the levels of free copper in serum and the levels of free copper in the more severely affected areas of the brain, arguing strongly in favor of a systemic dyshomeostasy of copper [
81]. The impaired homeostasis of copper is presumed to participate in oxidative stress, promoting free radicals-mediated pathways. The hypermetallation of the Aβ peptide might be at the origin of redox cycles of oxidative stress and H
2O
2 production, Aβ oligomer formation and precipitation [
1]. Whereas Cu
2+ can bind to nitrogen donors or oxygen donors, such as glutamate, Cu
+ preferentially binds to free thiols of cysteine/methionine. This causes a cross-linking between proteins. It should be emphasized that copper-related oxidative stress is also associated with states of copper deficiency, indicating that the fine regulation of copper concentrations within margins is critical. From the genetic standpoint, some loci in the ATP7B gene are associated with an increased risk of developing AD and Parkinson’s disease (PD) [
1]. ATP7B loss-of-function variants in transmembrane domains increase disease risk. Patients with some genetic background might be at greater risk of AD in the case of chronic copper exposure. Interestingly, the possibility of environmental contamination has been raised. Indeed, one recent hypothesis is that the ingestion of inorganic copper in drinking-water (contamination from copper pipe-lines) could increase the risk of AD [
82].
The role of copper in the initiation and propagation of an inflammatory cascade within the aging brain has been suggested [
83]. Copper may independently initiate inflammatory events and could interact with aluminum to increase the levels of APP [
84].
In vitro studies have demonstrated that copper triggers a pro-inflammatory state by modulating the production of molecules, such as IL-1alpha or IL-12 [
85].
Overall, the hypothesis of a genuine copper-related phenotype in AD is now solid. Critical outcomes in terms of prevention and active therapies might emerge for a devastating disorder whose prevalence is now a major public health issue. Clinical trials with metal modulators are in progress, in order to assess the effects of therapies redistributing copper amongst the different compartments [
86]. Chelating agents improve cognitive symptoms in animal models of AD [
87].