Introduction

Alzheimer’s Disease (AD) effects approximately 24 million people worldwide and that number is set to increase as the population continues to get older. Despite its prevalence, there is no effective treatment routinely practiced for AD. This is mainly due to the lack of understanding regarding the exact biological mechanisms of the disease. The purpose of this article is to explain how a functioning nervous system normally operates, how AD disrupts that normal operation, the current understanding of the pathology of AD, and some lifestyle interventions everyone can use to reduce the risk of developing AD.

The brain  

The brain is made up of billions of cells that communicate with one another to give rise to all the complex emotions and behaviors we display as humans. The “main” cell type in the brain is a specific type of brain cell called the neuron. For all intents and purposes, neurons are similar to every other cell type in the body. They have a nucleus that contains all of your genes located on strands of your DNA. They have ribosomes that help produce proteins. They have mitochondria that produce energy for the cell. And they have the ability to excrete molecules that function as signals to communicate with other cells nearby. It just so happens that the pattern in which these specialized cells communicate produces an array of consequences such as complex behavior, consciousness, a sense of self, language, and emotions. A resting neuron holds a certain electrical charge. To become activated, a positive shift in the electrical charge has to occur and when the voltage reaches a certain threshold, the neuron releases molecules that travel across the space between two neurons until it reaches a second neuron. Once this molecule reaches a second neuron it will bind to a receptor located on the surface or inside of the second neuron and, depending on the type of molecule, change the electrical charge and cause the second neuron to become either activated or inhibited. These cell-to-cell interactions are called synapses. A collection or specific sequence of synapses are what make up circuits in the brain. The communication between these individual cells in these circuits are what ultimately produce the complex thoughts and actions we display as people.

synapse

In the human brain there are approximately 80-100 billion neurons that produce over a trillion synapses. To further complicate the system, the brain contains an equal number, and by some estimates an even greater number, of other cell types called glial cells that serve their own specific functions. Two of the most abundant glial cells are called microglia and astrocytes. Microglia are the brain’s innate immune cells and protect the brain from viruses, traumatic brain injury (like a concussion), or some other harmful stimuli. Microglia can also function to provide support for neurons and their many synapses and help with clean-up of cellular debris produced throughout the day. These cells have two-way communications with neurons and are integral to a healthy functioning brain. Astrocytes can also provide immune and synaptic support but serve a variety of other functions. Given the hundreds of billions of cells in the brain and the trillions of communications between them, it is not hard to comprehend how easy it is for something to go wrong. When communication between cells go wrong you can get dysregulated thoughts and behaviors. Brain malfunction can happen at many stages in life. Most commonly these malfunctions occur during child development and adolescence when the brain is still being “set up” or in later in life as an individual ages and the brain starts to “break down.” Over the years physicians and psychologists have given labels to common symptoms of  brain malfunction. Some of the more well- known labels include depression, anxiety, schizophrenia, autism, bipolar disorder, etc.

Due to the complexity of the brain described above, it is generally difficult to treat brain disorders with great success. However, using simpler models such as animals (typically mice or rats) or cell cultures (cells in a Petri dish) to systematically design experiments to tease apart biological mechanisms of brain function has provided some key insights to how these disorders occur and what we can do to fix them. One common disorder that occurs later in life is Alzheimer’s disease (AD). In the next section I will talk more in depth about AD, specifically, and what is known to go wrong in the AD brain.

Alzheimer’s disease (AD) background

Generally speaking, AD is classified as a chronic neurodegenerative disease that progressively worsens over time. The earliest symptoms typically include short term memory loss but, as the disease progresses, symptoms extend to include disorientation, language problems, mood swings, and overall personality shifts. Ultimately, as the brain continues to deteriorate, this can put patients at a greater risk of developing other deadly health concerns. Though it can vary, the typical life expectancy after diagnosis is 3-9 years. The following paragraphs will attempt to break down the biology of what is happening as AD develops.

When compared to other types of dementias, a characteristic unique to AD is the presence of amyloid plaques and tau tangles in the brain 1. Amyloid plaques are aggregates of the amyloid beta protein that accumulate outside of neurons. Amyloid beta is produced in healthy individuals as well, though the primary function is still unknown. However, in a diseased brain, the “clean-up” of amyloid beta is impaired and these proteins accumulate to form the plaques present in an AD brain. It is thought that these plaques become toxic to the surrounding neurons and induce a programmed cell death called apoptosis.

Another major player in AD pathology are tau proteins. Tau proteins have a specific known function in the healthy individual. While expressed in other cell types, they are mainly expressed in neurons and are essential building blocks of microtubules, which offer structure and support to cells. In a diseased brain, tau proteins become damaged and start pairing with other damaged tau proteins and form “tau tangles.” One prevailing hypothesis is that when these tau tangles form, it destroys the cell’s structure causing the neuron to essentially collapse and eventually die.

Normal_vs_Alzheimers_Brain

In cases of amyloid beta and tau, it is thought that the accumulation of proteins become toxic and over time results in the death of individual neurons. In AD, this type of pathology becomes first noticeable in an area of the brain called the hippocampus. The hippocampus is crucial for the conversion of short-term memory to long-term memory and learning. When one neuron dies, it breaks a link in the circuit. The brain is extremely adaptable and can handle the loss of a few cells at first. However, as more individual cells in the circuit continue to die, memory will start to decline. Eventually this pathology will spread to neighboring parts of the brain causing the array of symptoms described above.

Despite all that is known about the pathology of AD, the underlying cause is still debated. Just because an increase in amyloid plaques and tau tangles are correlated with the progression of AD, it does not mean they are the root cause. In fact, these proteins are not inherently toxic to neurons. If they were, the cell would not produce them. Scientists even hypothesize that tau and/or amyloid beta may be protective, at least initially. The hypothesis is they are produced to compensate for some other unknown insult to cellular health. There is some scientific evidence for this but conclusive data and consensus is lacking within the field of AD research.

AD and brain inflammation

In recent years, it has become clear that brain inflammation, a.k.a. neuroinflammation, is another pathological hallmark of AD 2. In general, neuroinflammation is initiated by microglia (the brain’s immune cells) in response to both the initial cause of cell injury (maybe amyloid beta and tau tangles) as well as the dying cells resulting from that insult. If brain tissue health is not restored, then neuroinflammation can become chronic and erode the surrounding tissue by continuously releasing inflammatory molecules. It is true that in regions of the brain most effected by AD, there is a significant increase in activated microglia, as well as astrocytes, which also have some immune function.

In AD, the hypothesis is that the increased accumulation of amyloid beta plaques and tau tangles stimulates a chronic inflammatory reaction to clean up the debris. Chronically activated microglia releasing inflammatory molecules can kill neighboring neurons. This inflammatory response can actually perpetuate a vicious cycle, causing more amyloid beta buildup, more inflammation, and more cell death. Indeed, animal studies have shown that inhibiting chronic neuroinflammation has a positive outcome on learning and memory in rodents, as well as prevents neuronal death. The inflammatory pathology of AD and other neurodegenerative diseases is a growing field in neuroscience. Current research, including the research I do at Ohio State, is investigating the hypothesis that microglia may not function normally during natural aging and what cellular mechanisms and environmental factors may be driving these changes. It is also becoming increasingly clear that many lifestyle factors, such as diet and exercise, can have major impacts on microglial function and memory as we age.

Preventing AD

If everything up until now sounds bleak, there is some good news. Recent scientific evidence suggests that AD risk can be decreased if the right steps are taken early on. In the past, pharmaceuticals were the most common treatment option for individuals with AD. Billions of dollars have been spent and hundreds of drugs have been developed with little success. The complexity of the brain and underlying mechanisms leading to cell death contributes to the poor success of pharmacologically fighting AD. In recent years, research has begun to investigate the role of lifestyle in developing AD and has identified ways to be proactive in reducing your risk of developing AD and slowing AD progression by implementing lifestyle changes.

Having good overall health is critical to preventing AD. In fact, good overall health is vital for brain health in general. The brain is an organ. It is an organ in the same way the heart is an organ. Or the liver. Or the pancreas. Or the lungs. You get the point. Brain health, or “mental” health, is just health. In the same way you are told to take care of your heart or your lungs or your liver, you should be being told to take care of your brain. The good news is, research suggests the same things that are good for your body are also good for your brain. The basic lifestyle habits we can develop to promote optimal brain health and reduce the risk of AD revolve around sleep, exercise, and diet.

Sleep is crucial for a healthy brain. During sleep, your cells, including neurons, enter a state called autophagy, in which the cell’s waste removal system is activated and begins clearing out excess proteins and damaged cellular components that accumulated throughout the day 3. Removal of these excess cellular components promotes cell survival by conserving energy. This is one of the primary benefits of sleep. Data suggest ~ 8 hours of sleep per night is ideal for the average adult human and is an important lifestyle factor to maintain for optimal brain health and AD prevention. A lack of sleep can result in less cellular clean-up and eventual protein accumulation, including amyloid beta, which can become toxic as described above.

Just like exercise is good for the lungs, heart, and other muscles, it is also good for your brain. Exercise has been shown to increase levels of neuroprotective chemicals, reduce chronic inflammation, and reduce signs of aging. It has also been shown to improve cognitive tasks and memory 3. All of these will lead to a decreased risk for AD.

One of the biggest lifestyle factors for brain health and AD risk is diet 3. Diet has an overwhelming impact on all bodily functions and the brain is no exception. In a few recent clinical trials, dietary changes were a huge component of AD treatment. In general, data suggest that diet should be plant-rich. This means lots of fruits and vegetables. Being vegetarian is not a necessity but dramatically limiting your meat and poultry consumption is important, particularly red meat. While still debated at times, the general consensus is that red meat consumption has been associated with negative health outcomes 4. In particular, saturated fatty acids, which are very high in red meat, has been shown to be pro-inflammatory in both the systemic immune system and the brain. A chronic saturated fat-rich diet leads to chronic immune activity in the brain, increased neuronal stress, and eventual cell death. Diets high in saturated fat (and sugar!) have been shown to lead to neuroinflammation and cognitive decline 5. This cognitive decline can be reversed in animal studies by inhibiting inflammation. In humans, saturated fats and obesity are huge risk factors for AD development. Interestingly, unsaturated fatty acids have been shown to be anti-inflammatory. Thus, consumption of foods high in unsaturated fats, such as fish, nuts, and oils (like olive oil) are encouraged for the maintenance of a healthy brain. Another important aspect of diet is timing of food consumption. There is a large literature suggesting that time-restricted eating has many positive health benefits for the brain. Eating within an 8-10 hour window, and not eating within 3 hours before going to sleep, have shown positive health benefits, including anti-aging effects in the brain and immune system 6.

Menu-and-Meal-Planning-3.png

Another important aspect of diet and overall brain health is your gut microbiota. The gut microbiota is the population of bacteria that live in your gut. In the average human body, there are more bacterial cells than human cells. In fact, the majority of these bacterial species are critical to our health. In the gut, bacterial cells live off of the food we eat and in return they release metabolites that are important for regulating our immune system and communicating with our brain 7. Since our gut bacteria eat what we eat, our diet plays a huge role in the proper functioning of our gut bacteria. Important nutrients for gut bacterial health are complex carbohydrates and fiber. Thus, eating foods high in fiber and whole grains is recommended. Overall, having a healthy, daily mix of fruits, vegetables, grains, fiber, and unsaturated fats (fish, nuts, oils) will result in a healthy immune system, a healthy gut, and optimal brain health. This, along with adequate sleep and regular exercise will greatly reduce the risk of AD. Simple, right?

gut brian

201807-orig-psychobioltic-food-pyramid-949x534

 

Conclusion

For decades everyone has been told to “eat right”, get sleep, and exercise regularly. The only difference is no one realized those rules were also good for your brain. And now, with new insights and understandings of how integrated the brain is with the immune system and rest of the body, scientists are beginning to reveal the mechanisms of how lifestyle effects brain health. While the above lifestyle changes will impact AD risk, it can also be extended to other disorders of the brain. Increased immune activity and diet, sleep, and exercise have been implicated in almost every brain disorder, including mood disorders, schizophrenia, and autism. Due to advances in science and modern medicine, people are living easier and longer than ever before. In the Western world, there has never been more food readily available for easy preparation and consumption than there is right now. As technology improves many aspects of our lives, it promotes a more sedentary lifestyle with limited physical exercise and disrupts our sleep patterns (how often do you lie in bed at night watching TV for hours?). It is helpful to recognize how these issues contribute to impaired brain health and overall health and then implement practices to help mitigate these outcomes. Until brain health or “mental” health is viewed as the same as health, there will always be a stigma surrounding disorders of the brain.

AD is a perfect, yet unfortunate, example of what happens when you slowly start to take away parts of the brain. It completely changes a person. Their moods, their inhibitions, their motivations. You are your brain and it needs to be taken care of, just like the rest of your body. Hopefully this article has not bored you to death and you have reached the end with a better general understanding of how the brain functions normally and what goes wrong in AD. To sum up, the brain functions in circuits of neurons and other cell types communicating with each other. When mechanisms of cell function and protein removal start to break down, neurons die, resulting in impaired brain function and cause dramatic behavioral shifts. These symptoms and pathology can be mitigated by lifestyle interventions such as an anti-inflammatory diet, adequate sleep, and regular exercise.

References:

  1. Ittner, L. M. & Götz, J. Amyloid-β and tau — a toxic pas de deux in Alzheimer’s disease. Nat. Rev. Neurosci. 12, 67–72 (2011).
  2. Rubio-Perez, J. M. & Morillas-Ruiz, J. M. A Review: Inflammatory Process in Alzheimer’s Disease, Role of Cytokines. Sci. World J. 2012, 1–15 (2012).
  3. Pistollato, F. et al. Associations between Sleep, Cortisol Regulation, and Diet: Possible Implications for the Risk of Alzheimer Disease. Adv. Nutr. An Int. Rev. J. 7, 679–689 (2016).
  4. McAfee, A. J. et al. Red meat consumption: An overview of the risks and benefits. Meat Sci. 84, 1–13 (2010).
  5. Miller, A. A. & Spencer, S. J. Obesity and neuroinflammation: A pathway to cognitive impairment. Brain. Behav. Immun. 42, 10–21 (2014).
  6. Mattson, M. P., Longo, V. D. & Harvie, M. Impact of intermittent fasting on health and disease processes. Ageing Res. Rev. 39, 46–58 (2017).
  7. Singh, R. K. et al. Influence of diet on the gut microbiome and implications for human health. J. Transl. Med. 15, (2017).

 

Images obtained from:

https://www.brightfocus.org/alzheimers-disease/infographic/amyloid-plaques-and-neurofibrillary-tangles

https://fitnessgoals.com/anti-inflammation-diet-plan-review-and-weight-loss-results/

The book The Psychobiotic Revolution: Mood, Food, and the New Science of the Gut-Brain Connection. Amazon link: https://www.amazon.com/Psychobiotic-Revolution-Science-Gut-Brain-Connection/dp/142621846X

https://thriveglobal.com/stories/the-gut-brain-connection-2/

https://lifesciences.umaryland.edu/neuroscience/Research-Focus-Groups/Synapses–Circuits/