Can Ketogenic Diet Improve Alzheimer's Disease? Association With Anxiety, Depression, and Glutamate System

Abstract

Background: Alzheimer's disease is the most common neurodegenerative disorder in our society, mainly characterized by loss of cognitive function. However, other symptoms such as anxiety and depression have been described in patients. The process is mediated by alterations in the synaptic and extrasynaptic activity of the neurotransmitter glutamate, which are linked to a hypometabolism of glucose as the main source of brain energy. In that respect, Ketogenic diet (KD) has been proposed as a non-pharmacological treatment serving as an alternative energy source to the neurons increasing the fat percentage and reducing the carbohydrates percentage, showing promising results to improve the cognitive symptoms associated with different neurodegenerative disorders, including AD. However, the association of this type of diet with emotional symptoms and the modulation of glutamate neurotransmission systems after this dietary reduction of carbohydrates are unknown. Objective: The aim of this short review is to provide update studies and discuss about the relationship between KD, anxiety, depression, and glutamate activity in AD patients. Discussion: The main results suggest that the KD is an alternative energy source for neurons in AD with positive consequences for the brain at different levels such as epigenetic, metabolic and signaling, and that the substitution of carbohydrates for fats is also associated with emotional symptoms and glutamate activity in AD.

Keywords: Alzheimer's disease; anxiety; depression; glutamate; ketogenic diets.

Figure 1

Interaction of glutamate activity on alterations in anxiety and depression levels characteristic of the disease. (A) Pathogenic mechanisms based on the activity of the excitatory neurotransmitter glutamate both at synaptic and extrasynaptic levels, which could explain the elevated perception of anxiety and depression described in Alzheimer's disease (AD). At the synaptic level, in the animal model of the disease 3xTgAD mice the activation of mGluR2/3 receptors due to excess glutamate (red dots), has been linked to the formation of β-amyloid peptides with 42 residues long (Aβ42), while at the extrasynaptic level, it has been linked to high glutamate levels, which can increase the activation of its NMDA receptors (eNMDAR), producing an increase in inflammation. Both processes have been linked to the presence of anxiety and depression. (B) Proposed mechanisms of action of a ketogenic diet (KD) in the improvement of perception of anxiety and depression in patients with AD. (1) The production of ketone bodies derived from the intake of KDs act as glutamate inhibitors in the NMDA extrasynaptic receptor (eNMDAR), decreasing the extrasynaptic activity of glutamate (red dots) and, as a consequence, the inflammation. (2) They are also capable of blocking the toxicity derived from the formation of amyloid plaques, whose production is partly due to the activation of the mGluR2/3 glutamate receptors. (3) Moreover, they could improve the activity of glutamate at a synaptic level because of a greater ATP contribution (with regard to glucose metabolism), which would have a positive impact on the cognitive and emotional capacity. (4) Finally, the neuroprotector effect of ketone bodies (as a result of the improvement in the electron chain functioning) could lessen the levels of oxidative stress and inflammation. All these processes achieve a decrease in the perception of anxiety and depression, characteristic of this pathology.