Effect of Ketosis on Cognitive Decline in Patients with MCI and AD

Introduction: This review examines effects of exogenous and endogenous ketones in patients with mild cognitive impairment (MCI) and Alzheimer’s Disease (AD). As medical advances extend the human lifespan, chronic diseases such as AD have become more prevalent. Hypometabolism of glucose in the brain is a key indicator of cognitive decline. Without sufficient uptake of glucose, patients become at risk for AD and its prodromal condition MCI, and development of AD further diminishes regional cerebral metabolism. At the same time, ketone utilization in the brain is preserved and supplements the brain with energy as demonstrated by PET studies. Endogenous ketosis involves limited glucose consumption through a ketogenic diet or fasting, increasing the rate of ketone production in the liver. Exogenous ketosis is the direct administration or consumption of ketones thereby increasing blood ketone levels. The ketones β-hydroxybutyrate and acetoacetate usually serve to supply the brain with energy in the absence of glucose. Thus, inducing ketosis, or elevating ketone blood levels, may preserve brain function, especially in the areas affected by MCI and AD.

Methods: The Pubmed database was used to search for clinical trials prioritizing randomized, controlled trials involving exogenous administration of ketones and endogenous ketosis in patients with MCI or AD. Key search terms included "Ketone bodies and brain and metabolism", "Intermittent fasting and MCI OR AD," "PET and ketone bodies," "Ketogenic diet and MCI OR AD," and "Ketosis and MCI OR AD."

Results: Previous studies have presented promising findings concerning endogenous ketosis precipitated by ketogenic diets. Increasing blood concentrations of ketones through endogenous ketosis is effective in alleviating energy deficits in the brain and has been shown to positively affect cognitive performance. However, further testing and long-term studies are necessary to come to guide routine clinical recommendations. Current studies available that use exogenous ketones such as ketone esters have tested the safety of the formulations and also assessed resultingblood ketone levels. Endogenous ketosis has been more successful in raising blood ketone concentration. Additionally, various risk factors for AD and MCI such as genetics and insulin resistance have been shown to influence the onset and progression of cognitive decline thereby affecting the efficacy of induced ketosis.

Conclusions: The efficacy of ketones in mitigating cognitive decline continues to be a growing area of interest. Future research directions could compare the impact of both exogenous and endogenous ketones, employing a blinded cross-over design that controls for placebo effects and considers the influence of the APOE ε4 allele. Furthermore, studies may consider exploring the efficacy of endogenous ketosis and intermittent fasting, examining how interventions mitigate cognitive decline in patients with AD or MCI. Such comprehensive investigations aim to deepen our understanding of the intricate interplay between ketone metabolism and cognitive function, paving the way for more targeted and effective therapeutic strategies in maintaining neurological health.