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Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease


Alzheimer disease (AD) is a major cause of age-related dementia. We do not fully understand AD aetiology and pathogenesis, but oxidative damage is a key component. The brain mostly uses glucose for energy, but in AD and amnestic mild cognitive impairment glucose metabolism is dramatically decreased, probably owing, at least in part, to oxidative damage to enzymes involved in glycolysis, the tricarboxylic acid cycle and ATP biosynthesis. Consequently, ATP-requiring processes for cognitive function are impaired, and synaptic dysfunction and neuronal death result, with ensuing thinning of key brain areas. We summarize current research on the interplay and sequence of these processes and suggest potential pharmacological interventions to retard AD progression.

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Fig. 1: Schematic diagrams of the biochemistry of glucose catabolism and ATP synthesis and their oxidative dysfunction in AD and aMCI brains.
Fig. 2: Schematic representation of biochemical events associated with insulin binding to its receptor, leading to activation of mTORC1 with subsequent inhibition of autophagy and development of insulin resistance.
Fig. 3: Schematic drawings of the three components of the proteostasis network in brain cells.


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This work was supported in part by grants from the US National Institutes of Health (1R01 AG060056-01; D.A.B.) and the National Medical Research Council and Tan Chin Tuan Centennial Foundation, Singapore (B.H.). The authors thank X. Ren for assistance with Figures 1–3 and the three reviewers for their very helpful suggestions.

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Nature Reviews Neuroscience thanks R. Martins, and the other anonymous reviewers, for their contribution to the peer review of this work.

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Both authors contributed equally to all aspects of the manuscript.

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Correspondence to Barry Halliwell.

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Higher executive functioning

Cognitive processes that include planning, reasoning and problem solving that in humans largely involve the prefrontal cortex, with connections to other brain areas.

Reactive oxygen species

(ROS). Oxygen-containing species that contain unpaired electrons (which makes them free radicals) or from which free radicals are easily derived.

Reactive nitrogen species

(RNS). Nitrogen-containing species that are free radicals or moieties from which free radicals are easily derived.

Redox proteomics

A method for identification of oxidatively modified proteins that most often involves protein separation and digestion, mass spectrometric utilization to sequence the amino acids of the resulting peptides and protein identification and informatics.


One of the components of the proteostasis network; involves formation of a double membrane (autophagosome) that surrounds the aggregated, damaged protein or organelle and transport of the autophagosome to and fusion with a lysosome, exposing the contents of the autophagosome to proteolysis and degradation.


Sometimes called protein quality control, proteostasis is a term encompassing three different cellular processes (the ubiquitin–proteasome system, autophagy and the endoplasmic-reticulum-resident unfolded-protein response) used to degrade aggregated, damaged proteins or sometimes cellular organelles.

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Butterfield, D.A., Halliwell, B. Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease. Nat Rev Neurosci 20, 148–160 (2019).

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