Diet supplementation with
ketone bodies (
acetoacetate and β-hydroxybuturate) or medium-length
fatty acids generating
ketone bodies has consistently been found to cause modest improvement of mental function in Alzheimer's patients. It was suggested that the
therapeutic effect might be more pronounced if treatment was begun at a pre-clinical stage of the disease instead of well after its manifestation. The pre-clinical stage is characterized by decade-long
glucose hypometabolism in brain, but
ketone body metabolism is intact even initially after disease manifestation. One reason for the impaired
glucose metabolism may be early destruction of the noradrenergic brain stem nucleus, locus coeruleus, which stimulates
glucose metabolism, at least in astrocytes. These glial cells are essential in Alzheimer pathogenesis. The β-
amyloid peptide Aβ interferes with their
cholinergic innervation, which impairs synaptic function because of diminished astrocytic
glutamate release. Aβ also reduces
glucose metabolism and causes hyperexcitability.
Ketone bodies are similarly used against
seizures, but the effectively used concentrations are so high that they must interfere with
glucose metabolism and de novo synthesis of
neurotransmitter glutamate, reducing neuronal glutamatergic signaling. The lower
ketone body concentrations used in
Alzheimer's disease may owe their effect to support of energy metabolism, but might also inhibit release of gliotransmitter
glutamate.
Alzheimer's disease is a panglial-neuronal disorder with long-standing brain hypometabolism, aberrations in both neuronal and astrocytic
glucose metabolism,
inflammation, hyperexcitability, and
dementia. Relatively low doses of β-hydroxybutyrate can have an ameliorating effect on cognitive function. This could be because of metabolic supplementation or inhibition of Aβ-induced release of
glutamate as gliotransmitter, which is likely to reduce hyperexcitability and
inflammation. The therapeutic β-hydroxybutyrate doses are too low to reduce neuronally released
glutamate.