Old CLD development, mainly corresponding to the moderate/severe forms of new BPD, was associated with increased proinflammatory and profibrotic/angiogenic cytokines, while mild forms of new BPD were characterized only by increases in profibrotic/angiogenic cytokines, suggesting a different balance of two pathogenic mechanisms in different phases of the disease.

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Objectives: Meta-analyses show that nonbound ceruloplasmin copper (Non-Cp-Cu, also known as "free" or labile copper) in serum is higher in patients with Alzheimer disease (AD). It was demonstrated that ATP7B gene associates with AD, and being carriers of some ATP7B variants accounted for a large proportion of serum Non-CpCu levels, suggesting a "copper dysfunction" phenotype of sporadic AD. However, a dedicated genetic study to demonstrate the existence of a copper subtype of AD has not yet been performed. Methods: The study analyzed an independent patient sample, including 345 AD patients. We assessed levels of Non-Cp-Cu, informative genetic variants of ATP7B and APOE4 genotype. Patients were stratified on the basis of a Non-Cp-Cu cut-off (1.9 µm, C4D test). A binary logistic regression analysis -with age, sex and MMSE as covariates -was applied to compare the AD subgroups for ATP7B and APOE4 frequencies. Results: Concentrations of Non-Cp-Cu in the AD population had a bimodal distribution. ATP7B and APOE4 frequencies were different between the two AD groups, with a significant increase of the rs1801243 CC, rs1061472 GG and rs732774 TT genotypes in the AD group with Non-Cp-Cu > 1.9 µm, accounting for a percentage of the disease risk. Interpretation: Diverse genetic frequencies of ATP7B between the two AD groups confirm the existence of a copper subtype of AD, which has a genetic basis, and Non-Cp-Cu appears as reliable marker to identify this form of AD. Copper modifying drugs can be effective to stop or delay cognitive decline in this for AD.