Abstract
Evidence indicates that patients with Alzheimer’s dementia (AD) show signs of copper (Cu) dyshomeostasis. This study aimed at evaluating the potential of Cu dysregulation as an AD susceptibility factor. We performed a meta-analysis of 56 studies investigating Cu biomarkers in brain specimens (pooled total of 182 AD and 166 healthy controls, HC) and in serum/plasma (pooled total of 2929 AD and 3547 HC). We also completed a replication study of serum Cu biomarkers in 97 AD patients and 70 HC screened for rs732774 and rs1061472 ATP7B, the gene encoding for the Cu transporter ATPase7B. Our meta-analysis showed decreased Cu in AD brain specimens, increased Cu and nonbound ceruloplasmin (Non-Cp) Cu in serum/plasma samples, and unchanged ceruloplasmin. Serum/plasma Cu excess was associated with a three to fourfold increase in the risk of having AD. Our replication study confirmed meta-analysis results and showed that carriers of the ATP7B AG haplotype were significantly more frequent in the AD group. Overall, our study shows that AD patients fail to maintain a Cu metabolic balance and reveals the presence of a percentage of AD patients carrying ATP7B AG haplotype and presenting Non-Cp Cu excess, which suggest that a subset of AD subjects is prone to Cu imbalance. This AD subtype can be the target of precision medicine-based strategies tackling Cu dysregulation.
Highlights
Alzheimer’s dementia (AD) is a multifactorial condition for which a new diseasemodifying therapy, aducanumab, has been recently approved by FDA, even though postapproval studies have been requested to demonstrate its clinical efficacy [1,2,3]
We entered in PubMed the keywords “Alzheimer’s disease”, “Alzheimer’s dementia”, “ceruloplasmin ratio (Cu)”, “serum”, “plasma”, “brain”, “metals”, and their combinations and selected studies published from January 1984 to July 2020
We excluded from the original 69 one study that did not report standard deviations (SD) [38], one that reported a geometrical mean [39], and two that did not report the absolute value of Cu levels [10,40]
Summary
Alzheimer’s dementia (AD) is a multifactorial condition for which a new diseasemodifying therapy, aducanumab, has been recently approved by FDA, even though postapproval studies have been requested to demonstrate its clinical efficacy [1,2,3]. PAR for dietary factors and metal imbalance has been impeded since data regarding population prevalence of abnormal values were missing in the literature. This initial gap contributed to hampering the full exploration of the hypothesis that metals might be modifiable risk factors for AD. A novel metal hypothesis [8] and several meta-analysis studies (reviewed in [9]) had triggered a new interest in the pathogenic interaction between metals, mainly iron (Fe), copper (Cu), and zinc (Zn), and a set of AD-related proteins
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