What Is Alzheimer’s Disease? 

Alzheimer’s disease is a type of dementia caused by the degeneration of cells in the brain that leads to severe cognitive decline and impairment of daily activities.^1,2 Its hallmark includes the accumulation of a type of protein called amyloid peptides.³ These amyloid peptides tend to build up in the brain as insoluble plaques and lead to neurodegeneration and memory loss. Recent theory of Alzheimer’s disease development says that these plaques are neurotoxic at the neuronal synapse, where neurons connect and communicate. One of the ways of measuring this synaptic function is through long-term potentiation (LTP), a process by which synaptic learning is refined through weakening and strengthening of synaptic connections. Studies have shown that LTP is reduced in animal models with Alzheimer’s disease and overexpressed amyloid peptides.

What Did the New Study Find?

A recent study published on February 16^th, 2024 by Lucente et al. on Communications Biology by Nature Portfolio found that the ketogenic diet significantly improved LTP in mouse models with Alzheimer’s disease when compared to normal diet, suggesting that these findings may be translated to humans.³ The ketogenic diet is a diet consisting of very low amounts of carbohydrate and high amounts of fat,^4,5 with promising new studies showing that it may have benefits on mental health as well as metabolic health.^6,7

The study tested a 7-month intervention with ketogenic diet on genetically modified mice called “APP/PS1”, a mouse model of Alzheimer’s disease with significantly elevated amyloid peptide production.³ Although no changes in body weight, lean mass, fat mass, and percent body fat were observed with ketogenic diet, mice fed with the ketogenic diet showed significant differences from mice fed with the control diet. For instance, LTP measured in the hippocampus (ie, an area of the brain with its primary function in memory) of mice fed with the ketogenic diet were comparable to wild-type mice, whereas hippocampal LTP of mice fed with the control diet showed significant deficits when compared to wild-type mice. In addition, the ketogenic diet showed to activate enzymes involved in synaptic function.

How Can the Ketogenic Diet Improve Brain Function?

The study found that the ketogenic diet’s potential role in improving LTP was not by lowering levels of amyloid peptides in the brain.³ Instead, researchers hypothesize that the ketogenic diet’s effect on raising levels of b-hydroxybutyrate (BHB) was key. BHB is a compound made by the liver from fatty acids during ketosis, a process by which the body breaks down and uses fat as a primary source of energy.^8–10 Its levels rise when consuming ketogenic diets and can cross the blood-brain barrier to provide energy for the neurons when glucose availability is low.³ BHB levels in ketogenic diet-fed mice were significantly elevated during both fed and fasting state. Additionally, when brain slices were bath-incubated in BHB, LTP was found to be significantly increased, showcasing its potential role in improving synaptic function.

Does This Apply to Humans?

Deterioration in LTP-like activity is one of the earliest signs of Alzheimer’s disease progression in humans, similar to what is observed in APP/PS1 mouse model.³ Researchers of the new study believe that the results may be translated to improving mild cognitive impairment in humans with interventions using the ketogenic diet or BHB supplements. However, current research on human studies is very limited,¹¹ and thus the results of this study should be interpreted with critical optimism. Emerging evidence suggests that the ketogenic diet and BHB supplementation may show improvements in Alzheimer’s disease in humans. However, it should be noted that the current studies are often uncontrolled and small, only investigating the short-term effects of ketosis on cognition. Long-term, large, and randomized controlled trials studying the effects of ketogenic diet on mild cognitive impairment and Alzheimer’s disease are called for.