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Review
. 2021 Jun 29;11(7):960.
doi: 10.3390/biom11070960.

Copper Imbalance in Alzheimer's Disease: Meta-Analysis of Serum, Plasma, and Brain Specimens, and Replication Study Evaluating ATP7B Gene Variants

Rosanna Squitti  1 , Mariacarla Ventriglia  2 , Ilaria Simonelli  2 , Cristian Bonvicini  1 , Alfredo Costa  3   4 , Giulia Perini  3   4 , Giuliano Binetti  5 , Luisa Benussi  1 , Roberta Ghidoni  1 , Giacomo Koch  6   7 , Barbara Borroni  8 , Alberto Albanese  9 , Stefano L Sensi  10   11   12 , Mauro Rongioletti  13
Affiliations
Review

Copper Imbalance in Alzheimer's Disease: Meta-Analysis of Serum, Plasma, and Brain Specimens, and Replication Study Evaluating ATP7B Gene Variants

Rosanna Squitti et al. Biomolecules. .

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.

Keywords: ATP7B; Alzheimer’s dementia; Alzheimer’s disease; Cu; Wilson’s disease; brain; ceruloplasmin; meta-analysis; serum.

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Conflict of interest statement

R.S. is Chief Scientific Officer and has some shares in IGEA Pharma N.V. The other authors declare no commercial or noncommercial conflicts of interest relating to this work.

Figures

Figure 1
Figure 1
Flow diagram employed from the screening and selection of the analyzed Cu studies Table 1.
Figure 2
Figure 2
Standardized mean difference (SMD) computed from the studies on Cu brain levels (μg/g) in AD patients and HC subjects. SMDs between patients and controls are represented by squares, whose sizes are proportional to the sample size of the relative study. The whiskers represent the 95% confidence interval (CI). The diamond represents the pooled estimate based on the random-effects model, with the center representing the point estimate and the width indicating the associated 95% CI.
Figure 3
Figure 3
Standardized mean difference (SMD) computed from the studies on Cu serum/plasma levels (μmol/L) in AD patients and HC subjects. SMDs between patients and controls are represented by squares, whose sizes are proportional to the sample size of the relative study. The whiskers represent the 95% confidence interval (CI). The diamond represents the pooled estimate based on the random-effects model, with the center representing the point estimate and the width indicating the associated 95% CI. In panel (A) is the study-wise analysis; in panel (B) is the group-wise analysis. Abbreviations: PY, publication year; N, number; SD, standard deviation; HC, healthy controls.
Figure 4
Figure 4
Standardized mean difference (SMD) computed from the studies on Non-Cp Cu(µmol/L) in AD patients and HC subjects. SMDs between AD subjects and controls are represented by squares, whose sizes are proportional to the sample size of the relative study. The whiskers represent the 95% confidence interval (CI). The diamond represents the pooled estimate based on the random-effects model, with the center representing the point estimate and the width indicating the associated 95% CI. Abbreviations: PY, publication year; N, number; SD, standard deviation; HC, healthy controls.
Figure 5
Figure 5
Standardized mean difference (SMD) computed from the studies on Non-Cp Cu(µmol/L) in AD patients and HC subjects when considering studies with a Cu:Cp ratio lower than 6 and higher than 8. SMDs between AD subjects and controls are represented by squares, whose sizes are proportional to the sample size of the relative study. The whiskers represent the 95% confidence interval (CI). The diamond represents the pooled estimate based on the random-effects model, with the center representing the point estimate and the width indicating the associated 95% CI. Abbreviations: PY, publication year; N, number; SD, standard deviation; HC, healthy controls.
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