Ketone bodies mediate alterations in brain energy metabolism and biomarkers of Alzheimer’s disease

Abstract

Alzheimer’s disease (AD) is the most common form of dementia. AD is a progressive neurodegenerative disorder characterized by cognitive dysfunction, including learning and memory deficits, and behavioral changes. Neuropathology hallmarks of AD such as amyloid beta (Aβ) plaques and neurofibrillary tangles containing the neuron-specific protein tau is associated with changes in fluid biomarkers including Aβ, phosphorylated tau (p-tau)-181, p-tau 231, p-tau 217, glial fibrillary acidic protein (GFAP), and neurofilament light (NFL). Another pathological feature of AD is neural damage and hyperactivation of astrocytes, that can cause increased pro-inflammatory mediators and oxidative stress. In addition, reduced brain glucose metabolism and mitochondrial dysfunction appears up to 15 years before the onset of clinical AD symptoms. As glucose utilization is compromised in the brain of patients with AD, ketone bodies (KBs) may serve as an alternative source of energy. KBs are generated from the β-oxidation of fatty acids, which are enhanced following consumption of ketogenic diets with high fat, moderate protein, and low carbohydrate. KBs have been shown to cross the blood brain barrier to improve brain energy metabolism. This review comprehensively summarizes the current literature on how increasing KBs support brain energy metabolism. In addition, for the first time, this review discusses the effects of ketogenic diet on the putative AD biomarkers such as Aβ, tau (mainly p-tau 181), GFAP, and NFL, and discusses the role of KBs on neuroinflammation, oxidative stress, and mitochondrial metabolism.

Integration of Proteomic and Metabolomic Data Reveals the Lipid Metabolism Disorder in the Liver of Rats Exposed to Simulated Microgravity

“…Ketone bodies serve as crucial energy substrates for the brain, while the liver is the exclusive organ involved in ketone generation. An insufficient supply of ketone bodies has been implicated in neurodegenerative diseases such as Alzheimer’s disease [ 35 ]. At the protein level, we observed decreased contents of Hmgcs and Hmgcl, key enzymes involved in the production of ketone bodies.…”

Re-energising the brain: glucose metabolism, Tau protein and memory in ageing and dementia

“…In addition, when blood glucose level is low, such as during intense exercise, fasting, or diabetes, ketone bodies can be metabolised for energy. Although controversial, "ketogenic diets" have been suggested for multiple neurological disorders and epilepsy, in particular to mimic fasting and reduce neuronal activity and lactate concentrations [24][25][26] .…”

Characterization of β-Hydroxybutyrate as a Cell Autonomous Fuel for Active Excitatory and Inhibitory Neurons

“…The efficacy of the ketogenic diet is relatively high for inherited metabolic disorders with impaired glycolysis ( Klepper et al, 2005 ; Sofou et al, 2017 ), supporting the notion that an underlying metabolic component contributes to the therapeutic impact. Recent broader applications of the ketogenic diet to modulate neuronal activity in neurodegeneration ( Ramezani et al, 2023 ) and psychiatric conditions ( Sethi et al, 2024 ) raise the possibility that metabolism could modulate synaptic activity and/or circuit dynamics even in non-epileptic individuals.…”