Ketone Body Therapeutic Strategy for Neurodegeneration
Overview
This therapeutic approach exploits exogenous ketone body supplementation (beta-hydroxybutyrate [BHB], medium-chain triglycerides [MCTs]) as an alternative cerebral energy substrate to counteract the glucose hypometabolism characteristic of Alzheimer's disease, Parkinson's disease, FTD, and aging[@su2020]. By providing an alternative fuel source that bypasses defective glucose metabolism, ketone bodies can restore neuronal energy, reduce oxidative stress, and attenuate neuroinflammation.
Rationale
Energy Substrate Shift
Glucose hypometabolism is universal in neurodegeneration: AD brains show 20-45% reduced glucose utilization decades before symptoms[@su2020]
Mitochondrial dysfunction is a core feature across AD/Parkinson's/FTD, limiting ATP production from glucose
Ketone bodies bypass glycolysis: BHB enters mitochondria directly via monocarboxylate transporters, generating ATP independently of complex I and II
Neuronal survival requires ATP: Even modest ATP restoration can preserve synaptic function and prevent apoptosis
Neuroprotective Mechanisms
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Ketone Body Therapeutic Strategy for Neurodegeneration
Overview
This therapeutic approach exploits exogenous ketone body supplementation (beta-hydroxybutyrate [BHB], medium-chain triglycerides [MCTs]) as an alternative cerebral energy substrate to counteract the glucose hypometabolism characteristic of Alzheimer's disease, Parkinson's disease, FTD, and aging[@su2020]. By providing an alternative fuel source that bypasses defective glucose metabolism, ketone bodies can restore neuronal energy, reduce oxidative stress, and attenuate neuroinflammation.
Rationale
Energy Substrate Shift
Glucose hypometabolism is universal in neurodegeneration: AD brains show 20-45% reduced glucose utilization decades before symptoms[@su2020]
Mitochondrial dysfunction is a core feature across AD/Parkinson's/FTD, limiting ATP production from glucose
Ketone bodies bypass glycolysis: BHB enters mitochondria directly via monocarboxylate transporters, generating ATP independently of complex I and II
Neuronal survival requires ATP: Even modest ATP restoration can preserve synaptic function and prevent apoptosis
Neuroprotective Mechanisms
Improved mitochondrial efficiency: BHB metabolism generates more ATP per oxygen than glucose (2.5x more efficient)
Reduced oxidative stress: Ketone oxidation produces fewer reactive oxygen species than glucose metabolism
Anti-inflammatory effects: BHB inhibits NLRP3 inflammasome via inhibition of TXNIP