Ketogenic Diet and Alzheimer’s disease

Current recommended treatment options for Alzheimer’s disease (AD) are discouraging. Approved medications, such as cholinesterase inhibitors and NMDA receptor antagonists, control symptoms for a short time and do not treat the causes.

How do Alzheimer’s medications work?

Cholinesterase inhibitors such as Donepezil (Aricept), Rivastigmine (Exelon) and Galantamine (Razadyne) work by slowing the degradation of acetylcholine, a neurotransmitter involved in memory and cognition and which may be depleted in Alzheimer’s patients. Common side effects of using the medication are nausea, vomiting and diarrhea.

NMDA receptor antagonists like Memantine (Namenda) work by regulating the activity of glutamate, another neurotransmitter that plays a role in memory and learning. Glutamate overactivity can cause cellular damage, which Memantine tries to prevent. The most common side effects of memantine are dizziness, headaches and mental confusion.

Although these medications can provide temporary relief for some symptoms, such as memory disorders and confusion, they often fail to stop or even slow the progression of the disease. There are also anti-beta amyloid (anti-βA) drugs. Unfortunately, there is evidence that they can even compromise long-term brain health [1]. 

What are the causes of Alzheimer’s?

We do not fully understand the causes of Alzheimer’s disease. However, cerebral glycolytic hypometabolism appears central to the pathophysiology of the disease. This means that the brain becomes, over the years, less capable of capturing and using the glucose present in foods that are sources of carbohydrates (bread, rice, potatoes, biscuits, pasta, candy, fruits…). This metabolic change creates a lack of energy, impairing neuronal function and interrupting communication between brain cells.

Neurons are highly energy dependent and even a slight ATP deficit can significantly affect their ability to function well. Without the use of glucose as fuel, the cells of the nervous system fail to transmit signals, the ability to form new connections – essential for learning and memory – and also their cleaning capacity.

Over time, sustained hypometabolism can lead to loss of neurons and subsequent reduction in brain volume (brain shrinkage), worsening cognitive decline and increasing the severity of symptoms associated with Alzheimer’s disease.

Brain imaging studies have consistently shown a reduction in glucose uptake in certain areas of the Alzheimer’s brain. Numerous peer-reviewed studies have linked this decreased metabolic activity to the cognitive decline and memory loss that characterize Alzheimer’s disease. Thus, limiting carbohydrates in the diet becomes important.

Effects of ketogenic diet on Alzheimer’s

A study published in 2022 examined the effects of a Modified Mediterranean Ketogenic (MMK) diet on body composition and brain biomarkers in older adults at risk for Alzheimer’s disease. Improvements in body composition and body fat distribution were observed and those changes were significantly correlated with positive changes in cerebrospinal fluid biomarkers. Decreases in body fat were related to changes in Aβ biomarkers. Weight loss that maximizes visceral fat loss has a significant impact on brain health [2].

Another potential cause of Alzheimer’s-related changes is mitochondrial dysfunction. If mitochondria do not function well, oxidative stress increases. The term oxidative stress describes the imbalance that occurs in our bodies between harmful molecules called reactive oxygen species (ROS) and our ability to defend ourselves against them. In the brain, oxidative stress, that is, excess free radicals, causes damage to our neurons, proteins and DNA and contributes to the advancement of Alzheimer’s disease [3].

Lipid peroxidation is one of the most common results of oxidative stress. Free radicals begin to attack the cells’ fatty membrane, stealing electrons and affecting the fluidity of the cells, the permeability of the membranes and the function of the proteins linked to them. One common feature of Alzheimer’s is the accumulation of beta-amyloid in the brain. This peptide can induce oxidative stress on its own, creating a vicious cycle of damage. Additionally, proteins and lipids damaged by oxidation are prone to forming aggregates, which can exacerbate the formation of beta-amyloid plaques [3].

The role of oxidative stress is also evident in tau hyperphosphorylation, another hallmark of Alzheimer’s. Under conditions of oxidative stress, there is increased activation of several kinases (enzymes that add phosphate groups to other proteins), which may contribute to the hyperphosphorylation of tau. Hyperphosphorylated tau is more prone to aggregation, leading to the formation of neurofibrillary tangles, another hallmark of AD. Oxidative stress can lead to neuronal death in AD through a process called apoptosis or programmed cell death [4] .

Oxidative stress can be attenuated by the ketogenic diet as mitochondrial dysfunction is attenuated [5]. There is also evidence that exogenous ketone supplementation may provide treatment benefits in AD patients [6]. You can find BeKeto exogenous ketones here.

Source of image: Sharma, & Kim, 2023

Bibliography:

[1] Alves A, Kalinowski P, Ayton S. Accelerated Brain Volume Loss Caused by Anti–β-Amyloid Drugs: A Systematic Review and Meta-analysis. 

Neurology May 2023, 100 (20) e2114-e2124; DOI: 10.1212/WNL.0000000000207156 

[2] Brinkley TE, Leng I, Register TC, Neth BJ, Zetterberg H, Blennow K, Craft S. Changes in Adiposity and Cerebrospinal Fluid Biomarkers Following a Modified Mediterranean Ketogenic Diet in Older Adults at Risk for Alzheimer’s Disease. Front Neurosci. 2022 Jun 2;16:906539. doi: 10.3389/fnins.2022.906539. PMID: 35720727; PMCID: PMC9202553.

[3] Kalani K, Chaturvedi P, Chaturvedi P, Verma, et al. Mitochondrial mechanisms in Alzheimer’s disease: Quest for therapeutics, Drug Discovery Today, 28(5), 2023. 

[4] Sharma C, Kim SR. Oxidative stress: culprit or consequence in Alzheimer’s amyloidopathy. Neural Regen Res. 2023 Sep;18(9):1948-1949. doi: 10.4103/1673-5374.367843. PMID: 36926715; PMCID: PMC10233784.

[5] Greco T, Glenn TC, Hovda DA, Prins ML. Ketogenic diet decreases oxidative stress and improves mitochondrial respiratory complex activity. J Cereb Blood Flow Metab. 2016 Sep;36(9):1603-13. doi: 10.1177/0271678X15610584. Epub 2015 Oct 13. PMID: 26661201; PMCID: PMC5012517.

[6] Hersant H, Grossberg G. The Ketogenic Diet and Alzheimer’s Disease. J Nutr Health Aging. 2022;26(6):606-614. doi: 10.1007/s12603-022-1807-7. PMID: 35718870.