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Alzheimer’s is a sub-form of dementia. It is a serious neurodegenerative disease characterized by memory loss, language problems, disorientation, mood swings, loss of motivation, neglect of basic life activities (such as eating, bathing) and behavioral problems. Physical functions are gradually lost and in the more severe disease state the patient can no longer lead an independent life. They would be placed in a hospice, where essential functions such as toileting and feeding would have to be performed by caregivers. The life expectancy of Alzheimer’s patients is seriously reduced (Zanetti et al. 2009). Prevalence is increasing rapidly due to the aging of the population, from 2.9 million cases in 1980 (Brookmeyer et al. 2012) to 7.2 million cases by 2025 (Alzheimer’s Association, nd). About 5% of 65-74 year olds have Alzheimer’s disease, while that percentage rises to 35% among those over 85 (Us against Alzheimer’s, nd).
There are several risk factors for Alzheimer’s disease. These include genetic risk factors (having a certain allele of apolipoprotein E), head injury, clinical depression, high blood pressure, lack of physical and mental exercise, or poor diet. At the molecular level, the brain is increasingly affected by the accumulation of malformed protein deposits in the cerebral cortex. These are called amyloid plaques (beta-amyloid proteins) and neurofibrillary tangles (tau protein). These two proteins become misfolded and increasingly interfere with normal cell function, resulting in the degeneration of neuron and synaptic connections in the brain.
In the Alzheimer’s brain, the amyloid precursor protein is processed through an amyloidogenic pathway by enzymes called beta-secretase and gamma-secretase, which produce abnormal beta-amyloid peptides. They form small toxic aggregates called oligomers, which accumulate into larger, insoluble deposits called plaques, which build up between neurons. Abnormal chemical changes (hyperphosphorylation) cause tau proteins to detach from microtubules. These tau proteins then misfold and stick together, creating twisted wires called neurofibrillary tangles in neurons. This causes synaptic failure and ultimately cell death. Living a good and rich human life is highly dependent on a functioning brain that cannot simply be replaced like the pacemaker in a heart or leg prosthesis for amputees or physically injured patients.
Once diagnosed, there are no known treatments for Alzheimer’s. Pharmaceutical treatments often involve targeting protein pathways to slow the rate of neurodegeneration. These include acetylcholinesterase inhibitors or memantine. Researchers have also experimented with gingko extract, a plant native to Asia, to treat Alzheimer’s. Psychosocial therapies include listening to music, exercising, pursuing recreation, reminiscing about past events to aid memory, playing a recording of voices of close family members, and cognitive retraining of forgotten activities. The psychosocial therapies provide temporary improvement, but it has not been shown that they can stop neurodegeneration.
Thus, another therapeutic option to consider is the dietary approach. Mainstream nutritionists like to point to their favorite American Mediterranean/DASH diet, consisting of whole grains, legumes, nuts, seeds, fish, eggs, fruits, vegetables, and wine “in moderation” as protection against Alzheimer’s. One wonders if that advice would work because of the lower consumption of ultra-processed foods. But even these studies admit that the regular diet only has epidemiological data showing the potential for lower cardiovascular risk, rather than randomized control trials (RCT). The authors accuse other diets, such as paleo and keto diets, of lacking rigorous testing, but their favorite Med/DASH diets also lack these studies (Dominguez and Barbagallo 2018).
Mental disorders such as schizophrenia or depression can be controlled through a ketogenic diet (Palmer 2022; Language 2024). The hypothesized mechanism is that diets high in processed carbohydrates and sugars cause chronic inflammation, oxidative stress and insulin resistance. These can disrupt normal brain function. On a ketogenic diet, on the other hand, the body switches from glucose to ketones as its primary fuel source. Ketones provide efficient and consistent fuel for brain cells. The diet lowers blood glucose and insulin levels, restoring more normal metabolic functions in the brain. Inflammation and oxidative stress are reduced. Neurotransmitter systems such as dopamine and serotonin become more stable.
The reduction in glucose use could also have therapeutic effects for Alzheimer’s patients. A high glycemic index diet is associated with higher amyloid burden and more cognitive impairment.Taylor et al. 2017; Hersant and Grossberg 2022). Ketones are believed to reduce the formation of amyloid plaques (Bezem et al. 2019) and inflammation in the neurons. Neuronal inflammation is related to the activation of the COX-2 pathway and a lack of PPARγ (peroxisome proliferator-activated receptor (PPAR)γ) activation. The former is suppressed and the latter is stimulated by ketones (Jeong et al. 2011). Alzheimer’s patients have deficiencies in GLUT1 receptors, which means their brains are unable to efficiently transport glucose across the blood-brain barrier.Oliveira et al. 2024). Neurons then starve and die. Beta-amyloid can increase AMPA currents, the fast electrical signals generated in neurons when neurotransmitter glutamate binds to AMPA receptors on the postsynaptic membrane. This results in higher glutamate activity, neurotoxicity and memory loss. Alzheimer’s is linked to hyperphosphorylated tau protein, and the keto diet increases the excretion of phosphorus in the urine, depriving fuel for misshapen tau proteins (Oliveira et al. 2024).
Small pilot studies in 12 Alzheimer’s patients showed improvements in cognitive scores after 3 months on the keto diet. Generalization is difficult due to the small sample size and low compliance among the more severe cases of AD (Taylor et al. 2018). Another study consisted of 26 patients, whose cognitive abilities and quality of life indicators improved with 3 months of keto therapy (Philips et al. 2021). In another study of 20 Alzheimer’s patients, the modified Mediterranean ketogenic diet was associated with an increase in cerebrospinal fluid Aβ42 and a decrease in tau, both of which are indicators of less severe Alzheimer’s.Neth et al. 2020). A three-month study in 20 patients taking MCT (medium-chain triglycerides) oil reported cognitive improvements in memory and processing speed tests (Ota et al. 2019).
A case report of a mild Alzheimer’s patient who combined the keto diet with exercise also showed cognitive benefits (Morrill and Gibas 2019). Mouse studies show that laboratory mice’s cognitive and motor skills improved and beta-amyloid and tau production decreased with a keto diet (Lilamand et al. 2020). In addition to diet and exercise, intellectually challenging activities will also be helpful in delaying the onset of Alzheimer’s. Intellectual activity increases cognitive reserves and maintains brain functions longer, but as soon as symptoms appear, the pathology is already quite advanced and the disease develops faster.Stern 2002; Hyun et al. 2019).
The supposed link between a carbohydrate diet and Alzheimer’s led neuroscientist Suzanne de la Monte to call Alzheimer’s “Type 3 diabetes”. Due to insulin resistance, the cells can no longer store glucose as fat, despite the excessive production of insulin. Also, insulin receptors in the brain cells can become resistant, contributing to unfavorable protein accumulation and cognitive decline. What makes the Type 3 diabetes hypothesis so compelling is that diabetic and insulin-resistant patients are at much higher risk for cognitive disorders, including Alzheimer’s and dementia.Nguyen et al. 2020). The critics of the Type 3 diabetes thesis counter that correlation is not causation. In an interview, De la Monte spoke positively about a ketogenic diet as a prescription for Alzheimer’s patients, but also stated that patient compliance and doctors’ nutritional education are low.
Ketogenic diets are almost impossible to maintain, but this is the kind of thing where as a geriatrician you could feel free to say, ‘Let’s try this,'” de la Monte said. ‘But you can only do something about it if doctors know enough about nutrition and lifestyle to be able to give that advice. The amount of nutritional information we get in medical school is quite limited, one lesson if you are lucky.
St. Clair Health, December 16, 2023
The problem with the clinical trials of the keto diet and Alzheimer’s is the lack of large, long-term, randomized control trials, despite positive reported clinical results (Hersant and Grossberg 2022; Lilamand et al. 2020). The large RCTs require more funding, which comes from neither government nor industry. Both institutions favor the more expensive clinical trials in pharmaceutical drug development, where it is not clear whether a cure for Alzheimer’s can be found or is desirable, as a drug would reduce future profits. These institutions therefore say that it is better not to invest in research into the effectiveness of a cheap diet approach. Patients looking to alleviate their cognitive impairment and researchers looking to find a cure for it should consider the ketogenic diet as a viable therapeutic approach.
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