Energetic crisis, mitochondrial vulnerability and disruption of lactate shuttle in Alzheimer’s disease

05/08/2026

AI Summary

Mitochondrial dysfunction reduces electron transport chain activity and ATP production, preceding neurodegeneration and structural cognitive decline in Alzheimer’s disease.
Early brain glucose hypometabolism and disruption of the astrocyte to neuron lactate shuttle cause lactate deprivation and primary bioenergetic failure.
Metabolic uncoupling triggers neuroinflammation, impairs hippocampal neurogenesis and cognitive function; restoring ANLS is proposed as a therapeutic strategy.

AI Summary

Early glucose hypometabolism and lactate deprivation or interference with their utilization represent a primary bioenergetic failure driving mitochondrial dysfunction and neuroinflammation prior to the clinical manifestation of AD.

This chapter discusses the evidence for the energetic crisis in AD, focusing on the disruption of the astrocyte-neuron lactate shuttle (ANLS), hypometabolism of glucose, and mitochondrial vulnerability, as interconnected pathogenic mechanisms.

We emphasise cerebral bioenergetic metabolic failure as a central driver of cognitive decline, arising from irreversible reactive gliosis and neuroblastosis mechanisms and highlight various therapeutic options, including restoration of ANLS to mitigate the pathogenesis and memory loss in AD.

Basic summary

Int Rev Neurobiol. 2026;188:67-89. doi: 10.1016/bs.irn.2026.05.012. Epub 2026 May 28.

ABSTRACT

Alzheimer’s disease (AD) has traditionally been characterized by amyloid-beta (Aβ) plaques and neurofibrillary tangles. Emerging evidence reveals that metabolic dysfunction represents a key pathological feature central to disease progression. Mitochondrial dysfunction in AD leads to impaired electron transport chain activity and reduced level of adenosine triphosphate (ATP) synthesis, preceding neurodegeneration and structural abnormalities in cognitive centres of the brain. Early glucose hypometabolism and lactate deprivation or interference with their utilization represent a primary bioenergetic failure driving mitochondrial dysfunction and neuroinflammation prior to the clinical manifestation of AD. While the brain relies on lactate as a prominent energy substrate, astrocytic metabolic defects lead to impaired neuronal energy homeostasis, thereby promoting neurodegeneration. In turn, this metabolic uncoupling could also be associated with defects in regenerative mechanisms by impairing adult neurogenesis in the hippocampus due to energy deprivation, accounting for memory deficits. This chapter discusses the evidence for the energetic crisis in AD, focusing on the disruption of the astrocyte-neuron lactate shuttle (ANLS), hypometabolism of glucose, and mitochondrial vulnerability, as interconnected pathogenic mechanisms. We emphasise cerebral bioenergetic metabolic failure as a central driver of cognitive decline, arising from irreversible reactive gliosis and neuroblastosis mechanisms and highlight various therapeutic options, including restoration of ANLS to mitigate the pathogenesis and memory loss in AD.

PMID:42552048 | DOI:10.1016/bs.irn.2026.05.012

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