Potential for Ketotherapies as Amyloid-Regulating Treatment in Individuals at Risk for Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative condition characterized by clinical decline in memory and other cognitive functions. A classic AD neuropathological hallmark includes the accumulation of amyloid-β (Aβ) plaques, which may precede onset of clinical symptoms by over a decade. Efforts to prevent or treat AD frequently emphasize decreasing Aβ through various mechanisms, but such approaches have yet to establish compelling interventions. It is still not understood exactly why Aβ accumulates in AD, but it is hypothesized that Aβ and other downstream pathological events are a result of impaired bioenergetics, which can also manifest prior to cognitive decline. Evidence suggests that individuals with AD and at high risk for AD have functional brain ketone metabolism and ketotherapies (KTs), dietary approaches that produce ketone bodies for energy metabolism, may affect AD pathology by targeting impaired brain bioenergetics. Cognitively normal individuals with elevated brain Aβ, deemed "preclinical AD," and older adults with peripheral metabolic impairments are ideal candidates to test whether KTs modulate AD biology as they have impaired mitochondrial function, perturbed brain glucose metabolism, and elevated risk for rapid Aβ accumulation and symptomatic AD. Here, we discuss the link between brain bioenergetics and Aβ, as well as the potential for KTs to influence AD risk and progression.

Keywords: Alzheimer’s disease; amyloid; exogenous ketones; ketogenic diet; ketotherapy; medium chain triglyceride (MCT); mitochondria.

FIGURE 1

Simplified schematic illustrating putative pleiotropic effects of ketotherapies as modulators of amyloid-β. Ketotherapies (KTs) potentially modulate amyloid-β (Aβ) through various direct and indirect mechanisms targeting poor mitochondrial bioenergetics, increased ROS, and increased inflammation. KTs, especially the ketogenic diet (KD), reduce systemic insulin and potentially improve peripheral metabolic status which may improve systemic inflammation and reduce Aβ. The ketone body, β-hydroxybutyrate (BHB), serves as an energy substrate for mitochondrial metabolism, upregulates the astrocyte-neuron lactate shuttle, activates hydrocarboxylic acid receptor 2 (HCA2) to regulate inflammation, and may directly scavenge reactive oxygen species (ROS). Through bioenergetic effects in the mitochondria, KTs stimulate genesis of new mitochondria, increase uncoupling of the electron transport chain (ETC) to increase ATP production, generate less ROS than glucose metabolism, and reduce mitochondrial import of amyloid precursor protein (APP) and Aβ. KTs also activate nuclear factor-E2 related factor 2 (Nrf2) to upregulate synthesis of ROS-scavenging antioxidants and AMP-activated protein kinase (AMPK) to regulate transcription of pro-inflammatory cytokines. This figure created with BioRender (https://biorender.com).