Current Neuropharmacology · 3 authors, 2 centres
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This review summarizes evidence that energy crisis (glucose hypometabolism) is an early feature of Alzheimer's disease (AD), potentially preceding amyloid and tau pathology. It links energy deficits to impaired autophagy and the induction of ferroptosis, a form of iron-dependent cell death, suggesting these pathways may drive AD progression. The authors propose that targeting energy metabolism, autophagy, and ferroptosis could offer new therapeutic strategies for AD.
**Background:** Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and memory loss. While the amyloid-beta (Aβ) cascade and tau hyperphosphorylation are central hypotheses, recent evidence highlights that glucose hypometabolism (energy crisis) is an invariant pathological feature that precedes clinical symptoms by decades. This review explores the interplay between energy crisis, autophagy, and ferroptosis in AD, aiming to identify potential therapeutic targets.
**Methods:** The authors conducted a narrative review of the literature, synthesizing findings from clinical studies, animal models, and cellular experiments. They focused on energy metabolism in the brain, including glucose transport, insulin signaling, mitochondrial function, and lactate shuttling. They also examined the roles of autophagy (macroautophagy, chaperone-mediated autophagy, mitophagy) and ferroptosis in AD pathology. Key techniques discussed include FDG-PET, fMRI, MRS, and histopathological analyses.
**Key Results:** The review reports that glucose hypometabolism in AD is evident in the parietotemporal, posterior cingulate, and frontal cortices, as measured by FDG-PET. For example, Pezzoli et al. found decreased glucose metabolism mainly in the temporal lobe, and Ossenkoppele et al. observed reduced FDG uptake in frontal, parietal, and lateral temporal lobes over 2.0–4.0 years. GLUT1 and GLUT3 expression are decreased in AD brains, while MCT levels increase, suggesting a shift toward lactate utilization. Insulin resistance is prominent, with reduced IRS1/2 and IR levels in AD brains. Mitochondrial dysfunction is marked by decreased ATP production, reduced oxidative phosphorylation, and increased oxidative damage (e.g., 8-OHdG). Autophagy is impaired: autophagosome-related genes are misexpressed in MCI and AD, and PS1 mutations cause autophagic deficiency. Mitophagy is damaged, with reduced PINK1 and Parkin expression. Ferroptosis is implicated by iron accumulation in neurons and SPs, and GPX4 knockout in mice leads to neurodegeneration and cognitive impairment, reversed by vitamin E or liproxstatin-1. The review also notes that lactate levels are elevated in CSF of AD patients and positively associated with reduced glucose consumption in the left mPFC, OFC, and PHG.
**Clinical Implications:** The review suggests that energy crisis may be an etiologic factor in AD, occurring earlier than Aβ deposition and tau phosphorylation. Therapeutic strategies discussed include energy-replacement therapy (e.g., medium-chain triglycerides, ketogenic diet), improvement of glucose metabolism (e.g., liraglutide, metformin), and intranasal insulin. For instance, ketogenic drink treatment in MCI patients increased brain ketone metabolism by about 230% and enhanced cognitive ability. Intranasal insulin in clinical trials showed mixed results: Kellar et al. found reduced white matter hyperintensity volume and preserved cognition, while another RCT found no cognitive or functional benefits. The authors emphasize that targeting autophagy and ferroptosis may be promising, but caution that the relationship between energy crisis and ferroptosis in AD requires further investigation.