Study links mitochondrial complex IV dysfunction to Alzheimer’s pathology

Researchers assessed CIV function in postmortem temporal-lobe tissue from people with AD and controls, and used mouse and human-based models of AD risk to investigate whether CIV dysfunction contributes to disease-associated changes. The human tissue cohort included 14 cases; the authors report that sex was not included as a statistical covariate because the cohort was small and imbalanced. They also used alternative oxidase (AOX), an experimental approach intended to bypass the defective part of the respiratory chain, to test the effects of restoring mitochondrial respiration in model systems.

The authors report an association between neuronal CIV dysfunction and AD pathological characteristics. In the tested models, CIV deficits were linked to mitochondrial dysfunction and synaptic loss; the study also found evidence of a reciprocal relationship between CIV dysfunction and amyloid pathology, including increased amyloid production associated with amyloidogenic processing of APP. A proteome-wide association analysis using genetic data from large AD cohorts associated lower levels of COX11, a CIV assembly factor, with AD risk.

The results support a potential mechanistic contribution of CIV dysfunction to AD-related neuronal damage, rather than showing that it is only a consequence of amyloid pathology. However, the evidence is based on postmortem tissue, experimental models, and genetic associations; it does not demonstrate that targeting CIV prevents or treats AD in people. The small human tissue cohort and lack of formal blinding in animal allocation are additional limitations reported in the source.