Non-Ceruloplasmin Copper Distincts Subtypes in Alzheimer’s Disease: a Genetic Study of ATP7B Frequency

Rosanna Squitti, Mariacarla Ventriglia, Massimo Gennarelli, Nicola A. Colabufo, Imane Ghafir El Idrissi, Serena Bucossi, Stefania Mariani, Mauro Rongioletti, Orazio Zanetti, Chiara Congiu, Paolo M. Rossini, Cristian Bonvicini

Research output: Contribution to journalArticlepeer-review


Meta-analyses show that serum copper non-bound-to-ceruloplasmin (non-Cp-Cu) is higher in patients with Alzheimer’s disease (AD). ATP7B gene variants associate with AD, modulating the size of non-Cp-Cu pool. However, a dedicated genetic study comparing AD patients after stratification for a copper biomarker to demonstrate the existence of a copper subtype of AD has not yet been carried out. An independent patient sample of 287 AD patients was assessed for non-Cp-Cu serum concentrations, rs1801243, rs1061472, and rs732774 ATP7B genetic variants and the APOE4 genotype. Patients were stratified into two groups based on a non-Cp-Cu cutoff (1.9 μM). Single-locus and haplotype-group analyses were performed to define their frequencies in dependence of the non-Cp-Cu group. The two AD subgroups did not differ regarding age, sex, MMSE score, or APOE4 frequency allele, while they did differ regarding non-Cp-Cu concentrations in serum, allele, genotype, and haplotype frequencies of rs1061472 A > G and rs732774 C > T after multiple testing corrections. AD patients with a GG genotype had a 1.76-fold higher risk of having a non-Cp-Cu higher than 1.9 μmol/L (p = 0.029), and those with a TT genotype for rs732774 C > T of 1.8-fold (p = 0.018). After 100,000 permutations for multiple testing corrections, the haplotype containing the AC alleles appeared more frequently in AD patients with normal non-Cp-Cu [43 vs. 33 %; Pm = 0.03], while the haplotype containing the GT risk alleles appeared more frequently in the higher non-Cp-Cu AD (66 vs. 55 %; Pm = 0.01). Genetic heterogeneity sustains a copper AD metabolic subtype; non-Cp-Cu is a marker of this copper AD.

Original languageEnglish
Pages (from-to)1-11
Number of pages11
JournalMolecular Neurobiology
Publication statusE-pub ahead of print - Jan 12 2016


  • Alzheimer’s disease
  • ATP7B
  • Ceruloplasmin
  • Copper
  • Free copper
  • Non-ceruloplasmin-copper

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience


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