The Growing Science Behind a Fasting Treatment for Alzheimer’s

Early studies suggest fasting improves the symptoms of Alzheimer’s disease and slows cognitive decline in mice.

By Amber JorgensonJun 20, 2019 12:41 AM

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(Credit: SewCream/Shutterstock)

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When it comes to medical diagnoses, Alzheimer’s is a grim one. Those who develop the disease, which causes ever-worsening memory and behavioral problems, don’t have many treatment options. There are a handful of drugs that can ease symptoms, but none of them slow down the disease’s progression or offer a cure. But one approach, outside the realm of drugs and medications, is quickly showing some strong potential for treatment — fasting.

Typically touted as a weight loss method, fasting has been shown in animal studies to help improve the symptoms of Alzheimer’s disease and slow cognitive decline in mice. Research on the link between diet and brain health is now moving to humans, with some researchers hoping that fasting could one day be used to treat and prevent a debilitating disease.

Diet and Alzheimer’s

Alzheimer’s disease is quite common among older adults: an estimated 5.8 million Americans live with it today. The disease manifests itself as memory loss, changes in behavior and problems thinking. These changes are mirrored internally by the degradation of parts of the brain responsible for memory. In Alzheimer’s patients, scientists have long known that harmful collections of proteins between nerve cells, called plaques, as well as proteins inside nerve cells, called tangles, start to accumulate. These plaques and tangles wreak havoc on the brain, killing cells and disrupting normal brain functions as they spread. What exactly causes these plaques and tangles to develop, and why people with them get Alzheimer’s disease, is still up in the air.

Read more: A New Treatment for Alzheimer’s? It Starts with Lifestyle

But Mark Mattson, a recently-retired professor of neuroscience at John Hopkins University, thinks it has something to do with our modern eating habits —  particularly, the timing of our meals.

Mattson has spent decades researching calorie intake and Alzheimer’s disease. In several studies of mice genetically altered to display symptoms of Alzheimer’s he’s found that those fed intermittent fasting diets — where you cycle through short periods of eating and longer periods of fasting — fared better than those who ate whenever they wanted. They had better cognitive function, lived longer and, most importantly, had less plaque build up in their brains.

Fast History

Mattson thinks that the positive effects seen in mice —  whose brains are similar to humans — could be rooted in evolution. Before the rise in agriculture, when people were still hunting for food, they often went long periods without eating. Over time, evolution favored those who could survive without their beloved breakfasts (and lunches and dinners).

We now know that we use the glucose we get from foods, particularly carbohydrates, to fuel our bodies. We use this fuel, called glycogen, for about 12 hours after we eat. When it runs out, our bodies switch to an alternate energy source — ketone bodies.

Produced by the liver during periods of fasting and low carbohydrate intake, ketones also fuel our organs, including the brain. In the brain, much of this energy goes to our neurons. But while both glycogen and ketones fuel our neurons, higher ketone production has been linked to improved thinking, learning and memory. Some scientists theorize that ketones provide neurons with more energy than glycogen does, and with this extra energy, the neurons can better ward off cell death and brain degradation in the long term.

But with early breakfasts and late-night snacking, the standard American diet prevents us from making that metabolic switch from glycogen to ketones. According to Mattson, we could be starving our brains of the fuel they need to live a long, healthy life.

To see if this theory holds true, Mattson is now wrapping up a study in people at high risk for Alzheimer’s — those between the ages of 55 and 70 and who are obese and insulin resistant. The participants were put on a 5:2 fasting diet, where they eat five days out of the week and fast for two. Their cognitive performance and brain activity were tested both before and after implementing the diet. By triggering that metabolic switch, Mattson will be able to note any improvements in brain health and cognitive function. And while the results have yet to be released, Mattson says that his preliminary work indicates clear benefits for those on the intermittent fasting diet.

Valter Longo, a professor of biological sciences at the University of Southern California, has also spent decades studying the link between aging and fasting. And like Mattson, he’s seen slower cognitive decline and increased longevity in mice on fasting diets. Longo similarly thinks that the metabolic switch from glucose to ketone bodies plays a major role in brain health and longevity, and is currently undertaking tests in humans.

Longo recently kicked off a study of 120 patients who have been diagnosed with either Alzheimer’s disease or mild cognitive impairment. He’s using a variation of a fasting diet that’s less drastic, though it mimics the essential effects.

The method was designed with elderly patients in mind, who might not be strong enough to do prolonged fasts every day. Instead, patients do five days of fasting each month while consuming small amounts of healthy fats each day. By eating fats and no carbohydrates during that time, their bodies will keep using ketones instead of glucose as fuel.

It’s an attempt to split the difference: participants will still be able to get nutrients from food while reaping the potential brain-saving benefits of fasting.

Not So Fast

While Longo and Mattson’s studies could start backing up theories about Alzeimer’s and fasting with evidence, we’re still a long way from drawing any official conclusions. With other factors like exercise, sleep, stress and diabetes also being linked to the disease, untangling the mystery of Alzheimer’s is far from over.

For now, and until we know more about the disease, Longo says that limiting calorie intake to about 12 hours a day could be a good way to help brain health. So for now, you might want to think twice about that nighttime snack. Your brain might thank you later.

by Helen Senderovich

Intermittent Fasting: Changing the tides of dementia

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Like the depths of our oceans, the human mind has been charted only at its surface, leaving vast amounts of knowledge yet to be discovered. Among the issues yet to be explored is the effect of intermittent fasting (IF) as a possible intervention for dementia.

IF is defined as an eating pattern in which individuals switch between fasting and normal food intake on a regular schedule. Although the exact mechanism that drives IF outcomes has been a source of contention in the medical community, it has been shown to be an effective intervention against obesity, non-alcoholic fatty liver disease and chronic diseases such as diabetes and cancer. But what about dementia? Can IF play a role in the preservation of the human mind? Let’s dive in.

Due to the sheer magnitude of our oceans, we often take for granted the possible negative impacts of what we introduce into them. Similarly, the harsh reality of human overconsumption has not yet revealed its effect on the human mind. Or has it?

A recent study found that global cognition, verbal memory, language and executive functions improved in correlation with a decrease in body mass index (BMI). The pronounced correlation between the results and the age of patients also suggests improved outcomes with early intervention. Astonishingly, the study goes on to describe the correlation between specific categories of nutrients and their cognitive impact. It found that a decrease in carbohydrate intake was associated with improvement in verbal memory, executive function and subjective complaints. On the other hand, a decrease in fat intake was associated with improvements in verbal memory.

Alzheimer’s disease (AD) remains the leading cause of dementia among the elderly. Although not fully understood, IF has shown to have a possible neuroprotective effect leading to an increase in the neurogenesis levels in the hippocampus. This may provide protection against acute brain injuries such as stroke and neurodegenerative diseases. A study of 1,993 subjects of 60 years old and above revealed that Caloric Restriction (CR) can slow cognitive decline. In contrast, subjects with higher blood sugar and hyperlipidemia were found to be at higher risk for cognitive decline.

As we explore the ecosystem beneath the surface of the mind, we can witness the responses when consumption variables change. For example, gastric bypass surgery is a common procedure aimed at reducing a patient’s caloric intake. However, Roue-En-Y Gastric Bypass surgery leads to an improvement of cognitive functions and a significant reduction in the expression of amyloid beta precursor protein mRNA and protein in mononuclear cells, which has a role in preventing AD. There was a significant reduction in the expression of two other proteins involved in the formation and deposition of β-amyloid.

On a cellular level, the human body engages in a process called autophagy, meaning self (auto) eating (phagy). This cellular function breaks down and recycles cells that are damaged or mutated to provide nutrients to those that are not. Why is this important? The hallmark of AD is the buildup of β-amyloid that damages neuronal cells. CR and IF may have a role in inducing autophagy in protein-laden cells, clearing that buildup and leading to cognitive improvement. IF may provide a mode of cellular maintenance as well as cellular protection.

Brain-Derived Neurotrophic Factor (BDNF), a molecule involved in changes related to learning and memory, has been associated with 10-year risks for incident dementia in a large population-based sample. However, BDNF levels increase with physical activity and reduced caloric intake, leading to a potential therapeutic effect in decreasing dementia risk.

Thus, IF has been shown to have an effective role in the management and prevention of dementia. It improves cognitive functions and no adverse effects have been linked to it in reviewed studies.

It’s commonly said that what we most want to find is in the place we least want to look. Although the idea of exploring the bottom of the ocean induces a sense of anxiety and fear, it may provide the very answers we need to better understand our species. Similarly, future research in the area of CR and IF and their effects on dementia will surely bear these same fruits.

The author would like to acknowledge Keisa Mokenela, BSc.MD candidate at St. James School of Medicine, for his contributions to this post.

J Lipid Atheroscler. 2019 May; 8(1): 1–7.

Published online 2019 Apr 5. doi: 10.12997/jla.2019.8.1.1

PMCID: PMC7379085

PMID: 32821694

Intermittent Fasting: a Promising Approach for Preventing Vascular Dementia

Gwangho Yoon1,2 and Juhyun Song

corresponding author1

Author information Article notes Copyright and License information Disclaimer

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Abstract

Vascular dementia is the most common neuropsychiatric syndrome and is characterized by synaptic dysfunction, neuroinflammation, and cognitive dysfunction. Vascular dementia is associated with various environmental, genetic, and lifestyle risk factors. Recent research has focused on the association between vascular dementia and dietary patterns, suggesting that dietary regulation leads to better control of energy metabolism, improvements in brain insulin resistance, and the suppression of neuroinflammation. Intermittent fasting is a calorie-restriction method known to be more effective in promoting fat loss and regulating the impairment of glucose metabolism as compared with other dietary restriction regimens. Herein, the authors review the effects of intermittent fasting with regard to vascular dementia based on recent evidence and propose that intermittent fasting could be a therapeutic approach for ameliorating vascular dementia pathology and preventing its onset.

Keywords: Intermittent fasting, Vascular dementia, Cognitive function

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INTRODUCTION

Dementia is a highly prevalent chronic neuropsychiatric syndrome globally and is accompanied by memory deficit and cognitive dysfunction, which ultimately result in disability or limitations in the activities of daily living.1 The population with dementia is rapidly increasing compared to those having other diseases and, based on a clinical report, the number of individuals with dementia is projected to reach approximately 66 million by 2030.2 Dementia can be commonly classified into 2 types: Alzheimer's disease (AD) and vascular dementia (VaD).3 AD is characterized by an onset with a progressive course with memory loss and visuospatial functions that leads to global cognitive impairment,4 whereas VaD is markedly characterized by vascular changes and its onset is described as being a less gradual progression compared to AD, which involves a step-by-step cognitive decline.5 The neuropathologic features of these diseases include neuronal loss, atrophy of the frontal and temporal lobes, severe memory loss, and language impairments.6 AD is degenerative and incurable, while VaD is reversible or temporary. AD patients mainly have difficulty recalling recent events or new information and have more severe troubles with memory loss and communication than do individuals with VaD. VaD occurs as a result of a lack of adequate oxygen transfer to the brain and ultimately leads to neuronal cell death. One study demonstrated that VaD patients are more impaired than AD patients in the areas of attention and visual construction tasks.7 Also, several studies have suggested that memory function and temporal lobe function are mainly impaired in AD, whereas frontal lobe function impairment is predominant in VaD.8 AD accounts for more than 60% of cases of dementia in older individuals and is characterized by the deposition of extracellular amyloid-β (Aβ) plaques and intracellular neurofibrillary tangles of hyperphosphorylated tau proteins, representing the most frequent type of dementia worldwide.9 The excessive accumulation of senile plagues composed of Aβ peptide and the hyperphosphorylation of tau proteins trigger neuroinflammation, blood–brain barrier (BBB) dysfunction, and cognitive decline.10 VaD is accompanied by cognitive impairment, is the second most prevalent type of dementia, and is attributable to cerebrovascular pathology.11 Cognitive impairment in VaD is directly correlated with the suppression of cerebral blood pressure (BP) and cardiovascular complications,12 leading to an increase of BBB permeability from neurotoxic substances and the increase of amyloid deposition.13 The impairment of cerebrovascular function triggers excessive Aβ deposition and the early opening of the BBB.14

According to previous studies, dementia is also related to metabolic diseases such as hypertension and type 2 diabetes15 as a result of various risk factors related to cognitive decline. With respect to the relationship between dietary pattern(s) and the onset of dementia, many studies to date have investigated therapeutic approaches for preventing dementia using dietary regulation to support diet's positive role in mitigating memory decline in patients with dementia.16 Calorie restriction achieved by altering dietary patterns results in weight loss and ultimately improves metabolic and cognitive function by regulating lipid metabolism and improving glucose metabolism, inflammation, and insulin resistance.17 Previous studies have reported that caloric restriction has demonstrated neuroprotective effects on neuroinflammation and cognitive function.18 In particular, intermittent fasting as a method of dietary caloric restriction has been shown to more effective in reducing weight and fat mass versus continuous calorie restriction.19

Intermittent fasting is not a type of diet but instead is a pattern of eating. Its success more so relies on when one eats rather than what one eats. There are several different methods of intermittent fasting: for example, well-known methods include the Leangains protocol, which involves eating for eight hours and fasting for 16 hours between feedings; the eat-stop-eat protocol, which involves fasting for 24 hours, once a week; and the 5:2 diet, which involves consuming only 500 calories on 2 nonconsecutive days of the week and then normally eating on the other 5 days.20 Intermittent fasting has been highlighted as a promising method of calorie restriction, in that modulation of the circadian cycle can more effectively regulate the function of the hypothalamus, which controls appetite, energy metabolism, and the inflammatory response.21 In addition, intermittent fasting has demonstrated neuroprotective effects, a reduction of neuroinflammation, and an improvement in redox status and promotes an increase in the production of neurotrophic factors, leading to increased neurogenesis and improvement in mitochondrial function.22 Furthermore, intermittent fasting improves cognitive dysfunction and the dysregulation of energy metabolism and dyslipidemia in patients with AD.23 Another study reported that intermittent fasting protected against brain damage by restoring aquaporin-4 polarity in AD,24 while a recent investigation indicated that intermittent fasting leads to increases in ketone body levels in the blood and continuously supports neuroprotective effects by regulating the activity of β-hydroxybutyrate in AD.25 Herein, we review recent evidence regarding the effects of intermittent fasting on dementia and discuss the therapeutic potential of intermittent fasting to prevent the onset of dementia and attenuate neuropathology.

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THE EFFECTS OF INTERMITTENT FASTING IN DEMENTIA

1. Intermittent fasting: focus on neuroinflammation

A previous study demonstrated that caloric restriction reduces the production of reactive oxygen species and promotes antioxidant responses such as nuclear factor-erythroid 2 signaling.26 Additionally, calorie restriction reduces DNA damage by attenuating telomere erosion through regulating nuclear factor kappa B in inflammatory signaling and the production of proinflammatory mediator C-reactive proteins.27 In particular, intermittent fasting reduces the levels of proinflammatory cytokines including interleukin (IL)-1β and IL-18 in the brain.27 One study reported that intermittent fasting decreases the production of IL-1α, IL-1β, and tumor necrosis factor-α under lipopolysaccharide-induced inflammatory conditions and increases the production of brain-derived neurotrophic factor in the hippocampus.28 Furthermore, intermittent fasting has been reported to improve cognitive decline by downregulating inflammatory responses.29 Intermittent fasting controls inflammatory pathways and contributes to hippocampal neuronal function, relating to memory,30 and inhibits neuronal cell apoptosis by controlling autophagic flux.31

2. Intermittent fasting: focus on neurotransmitters and synaptic plasticity

Neurotransmitters, including glutamate, are involved in synaptic plasticity and contribute to neuronal circuitry.32 Fasting may activate cAMP responsive element binding signaling in hippocampal and entorhinal cortical neurons involved in synaptic function and memory formation.33 In particular, intermittent fasting boosts hippocampal plasticity and mitochondrial function via calcium signaling.34 Intermittent fasting also contributes to neuronal synaptic plasticity by controlling the secretion of neurotransmitters including serotonin, noradrenaline, and dopamine.35 Intermittent fasting additionally improves the impairment of synaptic plasticity in hippocampal neurons36 and enhances autonomic synaptic plasticity,37 subsequently rescuing cognitive impairment.38

3. Intermittent fasting: focus on vascular function

Cerebrovascular dysfunction is commonly exhibited in patients with dementia.39 It leads to neuroinflammation and oxidative stress in the brain and causes neuronal damage; provokes BBB breakdown; and triggers amyloid plaque production by boosting the amyloid precursor protein (APP) cleavage enzyme, beta-secretase, and tau protein phosphorylation.40 A recent study demonstrated that arterial stiffness (or high-pulse wave velocity) could promote the increase of amyloid beta deposition and exacerbate cognitive decline.41 Additionally, neurovascular coupling is impaired in AD, and abnormal blood flow leads to an imbalance between neural activity and glucose metabolism in the brain.42 Calorie restriction has been reported to decrease the risk for atherosclerosis and reduce BP and triglyceride levels in blood vessels.43 Previous research has demonstrated that intermittent fasting improves endothelial dysfunction and attenuates the risk for cardiovascular diseases.44 Intermittent fasting has been found to improve endothelial vasorelaxation and stabilize high BP.45 A few studies have reported dramatic decreases in BP values after intermittent fasting46 as well as improvement in vascular function.47

4. Intermittent fasting: focus on insulin resistance and neurogenesis

Intermittent fasting leads to a decrease in insulin-like growth factor 1 expression and a consequent reduction in glucose levels.30 Additionally, intermittent fasting enhances insulin sensitivity in neurons and ameliorates dysfunction in glucose metabolism.48 Neurogenesis describes the process where new neurons are generated to replace injured neurons in the subventricular and subgranular zones of the hippocampus.49 In dementia, the process of neurogenesis is impaired and, consequently, cognitive impairment occurs.49 In AD, the excessive accumulation of APP triggers a decrease in neurogenesis in both the dentate gyrus and subventricular zone.50 Intermittent fasting enhances hippocampal neurogenesis51 and reduces brain damage by generating new neurons in response to oxidative stress.52

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CONCLUSIONS

We reviewed the effects of intermittent fasting on dementia based on previous significant findings. We focused on the therapeutic potential of intermittent fasting in view of known risk factors for dementia, including neuroinflammation, synaptic dysfunction, vascular dysfunction, insulin resistance, and neurogenesis (Fig. 1). A previous study has reported that chronic intermittent fasting improves cognitive dysfunction.53 Another recent study demonstrated that intermittent fasting inhibits hippocampal neuronal damage against oxidative stress and, ultimately, suppresses memory deficits.54 A separate investigation suggested that intermittent fasting ameliorates memory deficits by controlling inflammatory responses.55 However, although there is much evidence available to support the positive effect of intermittent fasting on cognitive decline in dementia, the mechanisms involved in the fasting process and occurrence of memory deficit remains unclear. We reviewed related mechanisms regarding the therapeutic potential of intermittent fasting in dementia. We suggest that the application of intermittent fasting may be an effective dietary therapy for preventing the onset and/or suppressing the development of dementia.

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Fig. 1

The positive effects of intermittent fasting in dementia. Pathologies in dementia including neuroinflammation, the abnormal secretion of neurotransmitters, synaptic dysfunction, cerebrovascular inflammation, brain insulin resistance, and impaired neurogenesis were improved by intermittent fasting.

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Footnotes

Funding: This study was supported by funded by grants (2016R1D1A1B03930394 to Juhyun Song) of the Basic Science Research Program through the National Research Foundation of Korea (NRF).

Conflict of Interest: The authors have no conflicts of interest to declare.

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