Copper imbalance in Alzheimer's disease: Convergence of the chemistry and the clinic

Kasper P. Kepp, Rosanna Squitti

Research output: Contribution to journalReview articlepeer-review


In this perspective we list the many clinical, histopathological, genetic and chemical observations relating copper to Alzheimer's disease (AD). We summarize how the coordination chemistry of the APP/Aβ system is centrally involved in neuronal copper transport at the synapses, and that genetic variations in the gene coding for the copper transporter ATP7B cause a subset of AD, which we call CuAD. Importantly, the distinction between loss of function and gain of toxic function breaks down in CuAD, because copper dyshomeostasis features both aspects directly. We argue that CuAD can be described by a single control variable, a critical, location-dependent copper dissociation constant, Kd c. Loss of functional copper from protein-bound pools reduces energy production and oxidative stress control and is characterized by a reduced pool of divalent Cu(II) with Kd < Kd c. Gain of redox-toxic function is described by more copper with Kd > Kd c. In the blood, the critical threshold is estimated to be Kd c ∼10−12 M whereas at synapses it is argued to be Kd c ∼10−9 M. The synaptic threshold is close to the values of Kd for Cu(II)-binding to Aβ, prion protein, APP, and α-synuclein, implied in copper buffering at the synapses during glutamatergic transmission. The empirical support for and biochemical and pathological consequences of CuAD are discussed in detail.

Original languageEnglish
Pages (from-to)168-187
Number of pages20
JournalCoordination Chemistry Reviews
Publication statusPublished - Oct 15 2019


  • Alzheimer's disease
  • ATP7B
  • Copper
  • K, ceruloplasmin
  • β-Amyloid

ASJC Scopus subject areas

  • Physical and Theoretical Chemistry
  • Inorganic Chemistry
  • Materials Chemistry


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