What are the safety thresholds for ketone-induced disruption of astrocytic glucose metabolism in human brain?

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Description

While metabolic steal syndrome was identified as a concern, human-relevant safety data for ketone-mediated astrocyte dysfunction is lacking. This knowledge gap is critical for clinical translation of any ketogenic neuroprotective strategy.

Source: Debate session sess_SDA-2026-04-03-gap-debate-20260403-222618-2709aad9 (Analysis: SDA-2026-04-03-gap-debate-20260403-222618-2709aad9)

Resolution criteria

Resolution requires: (1) hyperpolarized [1-13C]pyruvate MRS or 13C-glucose PET imaging in human brain measuring astrocytic glucose metabolism before and after ketone administration (n>=20, >3 ketone dose levels); (2) cognitive testing battery in the same subjects establishing threshold ketone blood level (>=3 mM) where astrocytic dysfunction (impaired lactate export, reduced glucose utilization) begins; (3) comparison of ketone effects in AD patients vs age-matched controls establishing disease-specific vulnerability thresholds. Rodent data alone cannot establish human-relevant safety thresholds due to species differences in astrocyte metabolism and BBB ketone transport.

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