Alzheimer’s Disease (AD)
When people say, “You have Alzheimer’s,” you have no idea what Alzheimer’s is. You know it’s not good. You know there’s no light at the end of the tunnel. That’s the only way you can go. But you really don’t know anything about it. And you don’t know what to expect.
Nancy Reagan, speaking to Mike Wallace on 60 Minutes, September 24, 2002
Dementia is not normal. Normal aging does not result in dementia. Dementia is a pathological state—an abnormal situation—a disease state that may, with healthy choices, be avoided.
Dementia is the term for any condition that damages brain tissue in such a way that there is permanent loss of memory along with at least one other cognitive ability, such as the ability to problem solve, organize, and plan; use language normally; identify common objects; or do simple motor tasks like buttoning a shirt or tying a shoe.
Dementia can be caused by head trauma (recently documented in football players but also boxers and individuals with any severe head injury), multiple strokes, infections (HIV, mad cow disease), or chronic metabolic problems that slowly destroy brain tissue (Alzheimer’s disease). The term Alzheimer’s disease refers to the neurodegenerative changes that occur in the brain. The term Alzheimer’s dementia refers to the constellation of symptoms (memory loss and cognitive impairment) that are caused by the disease (damage to the brain). Thus, dementia can have many causes, the most common of which is Alzheimer’s disease. But how common is dementia and what contributes to it?
Prevalence refers to the proportion of people in a society who have a condition at any given point in time. In most regions of the world 5–7 percent of those over sixty years of age have some form of dementia, with higher rates in Latin America (8.5 percent) and lower rates in sub-Saharan Africa (2–4 percent). In 2010 approximately 35.6 million people worldwide had some form of dementia, and numbers are projected to double every twenty years through 2050 (65.7 million in 2030, 115.4 million in 2050).1
In 2014 in the United States, it was estimated that 5.2 million people had Alzheimer’s disease (AD), 5 million of them over the age of sixty-five and 200,000 under the age of sixty-five. One in nine persons over the age of sixty-five (11 percent) have AD, and almost one in three (32 percent) of those over eighty-five years of age have it. The vast majority of people with AD are over the age of seventy-five (82 percent). In America in individuals over the age of eighty-five, Hispanics have the highest rates of AD (62.9 percent), followed by African Americans (58.8 percent), and then whites (30.2 percent). Almost two-thirds of people with AD are women (3.2 million women, 1.8 million men). Of those seventy-one years old and older, 16 percent of women and 11 percent of men have AD.2 One of the primary reasons for this gender difference is that women live longer than men, and as we have seen throughout this book, the longer a person lives the greater their risk for AD. But I want to emphasize again that living a long life does not mean one will get AD; it all depends on many modifiable factors in a person’s life. One of the main goals of this book is to identify those factors so that people can make changes in their lifestyle that will not only increase length of life but also simultaneously reduce their risk of developing dementia.
What Is Alzheimer’s Disease?
Alzheimer’s disease was first described in 1907 by Alois Alzheimer, who identified the syndrome of memory and cognitive problems in a fifty-one-year-old woman whose autopsy revealed, under microscopic examination, lesions in the brain called neurofibrillary tangles and senile plaques. Neurofibrillary tangles are clumps of a specific protein called tau that has had excessive amounts of phosphate attached to it. The binding of phosphate to tau proteins impairs them from being able to do their normal job. Thus, they congregate together in these tangled masses observable in a biopsy.
Senile plaques are accumulations of a different protein, beta-amyloid (b-amyloid), which is thought to be a hallmark feature of and potential contributing factor in AD. As we will describe shortly, the buildup of tau and b-amyloid occurs when neurons die, thus neurofibrillary tangles and senile plaques are seen only in brains that have lost neurons. By the time a person has symptoms of AD their brain has already lost billions of neurons.
When the brain is operating normally it is in a state of flux with the production of new neurons, the elimination of unneeded neurons, and the constant branching and pruning of its axons and dendrites (the communication fibers that link neurons with other neurons and form vast networks for information processing). This means that the brain has designed methods to eliminate and remove unneeded neurons in a controlled and nontoxic manner. This would be similar to how a demolition company collapses a building in a way to avoid damage to nearby structures. But in the aftermath of the collapse there is a lot of waste material left behind that needs to be cleaned up and removed.
When a neuron dies the various proteins, fats, and chemicals left behind need to be cleaned up. The brain has “crews” to do this. The immune system plays a role with some of the materials being “digested” by phagocytes. Other materials left behind such as copper, zinc, and iron can be very oxidizing and create reactive oxygen molecules that are damaging to the brain. The brain has a special protein designed to bind these trace chemicals and remove them. B-amyloid is the protein that binds these chemicals and then, normally, is quickly removed from the brain through the glymphatic system.3
Not only is b-amyloid involved in binding and removing trace chemicals, but it also, in very small amounts, could be necessary as a signaling molecule to trigger new neuronal growth.4 However, if there is too much b-amyloid it can become toxic and contribute to the formation of destructive oxidizing molecules. Three events are required in order for b-amyloid to turn toxic. First, it must experience a structural change in which it folds back on itself and forms insoluble fibrils in a process called fibrillation. B-amyloid is normally a soluble protein, and as long as it remains in a soluble form the brain can excrete it and prevent a buildup. However, if b-amyloid misfolds into what are called cross-sheets, it then becomes insoluble and builds up in the brain, forming amyloid deposits.5 The second event needed to turn b-amyloid toxic is the binding with copper or iron when cells die. And third is the presence of the amino acid methionine.6 In fact, studies have shown that when b-amyloid increases in the brain without the presence of methionine there is a corresponding reduction in oxidizing molecules, which indicates that b-amyloid may be a compensatory mechanism working to reduce oxidizing molecules in the brain.7 But when methionine binds to it, the clumps of b-amyloid begin generating oxidizing molecules that damage surrounding neurons. This would be analogous to sawdust used in a garage to absorb spilled gasoline. By absorbing the gasoline the sawdust reduces the ability of the gas to corrode other materials in the garage, and the two by themselves reduce damage in the garage. But if a third element is added, a spark, then combustion (which is rapid oxidation) occurs, causing increased damage to the materials in the garage.
So what is happening in the brain that contributes to Alzheimer’s disease, and what can we do to reduce the risk or perhaps even prevent it?
There are two types of AD: early onset (before sixty-five, but more often before sixty) and late onset (sixty-five and older). Early-onset AD is genetically linked and known as Early-Onset Familial Alzheimer’s Disease (EOFAD). Three genes have thus far been identified in EOFAD: amyloid precursor protein (APP on chromosome 21), presenilin-1 (PS1 on chromosome 14), and presenilin-2 (PS2 on chromosome 1). Mutations in any of these genes can cause EOFAD. APP mutations are associated with approximately 10–15 percent of EOFAD and PS1 mutations are linked to 30–70 percent of EOFAD cases. PS2 mutations are rare and contribute to fewer than 5 percent of early-onset AD.8 Because EOFAD accounts for fewer than 5 percent of all cases of AD9 and the primary risk factor is inherited, we will not explore this subtype further in this book.
Late-onset AD, which accounts for 95 percent of all AD, is associated with another gene, ApoE, which codes for a protein that transports fatty vitamins and cholesterol into the brain cells. In the human population three different versions of the gene that codes for ApoE have been identified: ApoE2, ApoE3, ApoE4. We have two sets of chromosomes—one received from our mothers and the other from our fathers—so that each person has two copies of ApoE.10
Seven percent of the population has at least one copy of the ApoE2 gene, which increases their risk of atherosclerosis. This is when fatty plaques infiltrate the artery walls and narrow the width of the vessel, thus impeding blood flow and increasing the risk of heart attacks and strokes. Seventy-nine percent of the population has two copies of ApoE3, which is the healthy version and confers no known disease risk. Fourteen percent of people have at least one copy of the ApoE4 version, which has been implicated in the increased risk of AD.
Persons with two copies of ApoE4 have ten to thirty times the risk of developing AD, and up to 65 percent of people with AD have at least one copy of this gene. But one-third of people with AD do not have a copy of this gene, which means that while the ApoE4 gene may increase the risk of developing AD, it is neither necessary nor sufficient on its own to cause the disease. When I first learned this good news I was so excited and relieved because it means that even if someone has the “bad” genes (often evidenced by family members suffering with late-onset AD), they can make choices that will prevent them from developing AD! Having a parent with AD does not mean you are condemned to getting it! There are choices you can make that will protect your brain and prevent AD from developing.
A recent study out of Washington University found that people with the ApoE4 gene were not demented and had less b-amyloid in their brains if they had a history of exercise!11 In this study, just one modifiable factor—exercise—prevented AD from developing in those with the ApoE4 gene. And there are other modifiable factors as well that reduce the risk of developing AD. Genetics accounts for only about one-third of the risk of developing AD. What is the key, then, to developing AD if it isn’t simply genetics? Strong evidence points to inflammation (the increase in oxidative molecules, cytokines, chemokines, and immune cells described previously), which contributes to insulin resistance in the brain and causes a cascade of events, resulting in the death of brain cells and the development of AD. Exercise, along with most of the other modifiable factors, reduces inflammation and insulin resistance, thereby preventing the development of AD.
Insulin and the Brain
In the body, insulin regulates glucose use and directs the body to store energy, primarily in the form of fat. When insulin levels are high the body is sent the signal to make fat and not to break down and burn the fat already stored. Insulin used throughout the body is produced by small clusters of cells called islet cells located within the pancreas.
But the brain makes its own insulin, and in the brain insulin does far more than just control glucose use. Within the brain insulin also regulates the clearance of b-amyloid protein and tau phosphorylation (remember that both of these are hallmark features of AD), blood flow, inhibition of cell death (apoptosis), response to inflammation, removal of fats from the brain, the ability of new synapses to form, and memory formation, and it facilitates neurotransmitter receptor trafficking.12 As you can see, anything that interferes with insulin function in the brain will have wide-ranging negative effects.
There are striking similarities between AD and diabetes mellitus type 2 (T2DM), which is the adult-onset type that results from insulin resistance, not a lack of insulin in the body. In both AD and T2DM there is insulin resistance, inflammation with increased oxidative stress, b-amyloid protein deposits (in the brain in AD and in the pancreas in T2DM), hyperphosphorylated tau protein, and cognitive decline.
Having T2DM increases the risk of AD by 60 percent, and having elevated blood sugar (105–120 mg/dL) not yet severe enough to be diagnosed with T2DM increases the risk of AD by 10–20 percent.13 This is quite alarming as 50 percent of Americans between the ages of forty-five and sixty-four have peripheral insulin resistance with normal blood sugar levels, and 76 percent of people older than sixty-five have peripheral insulin resistance. This means that inflammation is increasing in their bodies, causing insulin receptors to be less responsive to insulin. The body responds by increasing insulin levels to try to compensate, thus for a while glucose levels are normal. Factors that contribute to insulin resistance are anything that increases inflammation but specifically a high-fructose diet, a high-fat diet, chronic inflammation, chronic stress, and a sedentary lifestyle.14
The Destructive Cascade
In order to formulate a possible mechanism of what is going wrong, we need to understand a little more about neurons and their internal structure. Neurons are brain cells that have thousands of connections to other brain cells and communicate with electrical and chemical signals. Extending from the cell bodies of neurons are projections called axons and dendrites. These projections would be analogous to telephone wires that send (axons) and receive (dendrites) signals. It is through these projections that the neurons communicate with each other. Inside the axons and dendrites are microtubules, made of proteins called tubulin, which give them structure and stability and act as highways transporting vital materials around the inside of the cells. The microtubules in axons, but not dendrites, are held together by tau proteins.15
Consider a scaffold and how at each junction in the scaffold are pins that hold the joints together. The scaffold would be analogous to the microtubules, and the pins would be analogous to the tau proteins that hold the microtubules together. What would happen if someone pulled out the pins in the scaffold? It would collapse, and this is what happens when tau proteins get phosphorylated. When phosphate groups attach to tau it can no longer do its job of holding the microtubules together, and therefore the microtubules in axons fall apart. When this happens the axon loses integrity, various ions flow into the cell, and the neuron dies.
Now let’s put this together to identify a potential pathway contributing to AD that fits the evidence. Anything that contributes to increased inflammation such as unhealthy diet (chaps. 5 and 6), toxic substances (chap. 7), sedentary lifestyle (chap. 8), sleep disorders (chap. 9), failure to mentally unwind (chap. 10), and chronic mental distress and unhealthy belief systems (chaps. 11, 12, and 13) will cause an increase in the concentration of inflammatory molecules circulating throughout the body and, thus, within the brain. These inflammatory molecules will cause the following destructive cascade:
Another potential pathway could look like this:
In addition to this cascade, if the b-amyloid that is building up in the brain is exposed to methionine, then those deposits also become oxidizing engines that damage neurons and contribute to further neuronal loss.
Recommendations to Prevent Dementia
The good news is that for the vast majority of people, this destructive cascade is preventable, even in those who have begun to show mild worsening in memory and cognition. When healthy lifestyle changes are implemented, progression to dementia is halted!19
We can break down the specific actions that promote health, slow aging, reduce dementia risk, and keep the brain young to four major keys: physical exercise, mental stimulation, stress management, and nutrition and lifestyle.
Please review chapter 8 for the science behind the benefits of exercise. But as a quick summary, exercise reduces the risk of dementia and slows aging because it decreases oxidative stress throughout the body, triggers the production of multiple proteins that promote brain health and the production of new neurons, increases the release of brain-produced mood elevators, improves insulin sensitivity, and promotes weight loss. There are no negative health effects to regular, nonexcessive exercise.
Recommendations for optimal exercise include:
Mental Stimulation
Regular physical exercise causes the muscles to produce powerful anti-inflammatory cytokines that reduce inflammation. Physical exercise increases blood vessel growth in the brain, which improves oxygenation. Additionally, regular physical exercise causes the brain to produce proteins that stimulate the brain to make new neurons and that increase the growth of neuron-to-neuron connections. Therefore, physical exercise makes new learning easier! And using your brain is critical to maintaining its health. As we exercise the brain, it produces additional factors that not only keep it healthy but also will even create new networks corresponding to new learning. So include regular, mentally stimulating activities such as puzzles, Bible study, learning a new language or a new sport, music or art lessons, or taking a college class. Combining physical and mental stimulation seems particularly helpful, such as learning to waltz or tango or play ping-pong or tennis. Remember, if you don’t use it, you will lose it—so exercise both brain and body regularly!
Stress Management
Stress management does not mean avoiding anything that is stressful but developing strategies for resolving stress and maintaining an internal state of peace and wellness. Failure to manage stress results in increased activation of stress circuits and inflammatory cascades that accelerate aging and increase the risk of dementia. Specific actions for reducing pathological stress include the following.
Forgive others. Forgiving those who have done us wrong calms the stress circuits and reduces inflammatory cascades. Forgiveness means letting go of resentment, bitterness, and grudges; it does not mean extending trust. We wisely trust only those who are trustworthy. Bitterness, resentment, and holding grudges are toxic and activate the brain’s stress pathways. Failure to resolve such feelings results in increased oxidative stress and damage to physical, mental, and relational health. Forgiving those who have offended us does not mean that what they did was okay but relieves us of carrying the toxic emotions of anger and resentment everywhere we go.21
Develop healthy relationships. Relationship conflict activates the brain’s stress circuits, which turns on the immune system, causing increased levels of inflammatory factors. People with chronic relationship problems have higher rates of mental and physical health problems. Healthy relationships require healthy people, and healthy people are in governance of themselves. This means that the mature evaluate the evidence of the health of others and make decisions in governance of self regarding whom we spend time with, how much credence we give their attitudes and desires, and when to extricate ourselves from relationships that have proven to be toxic.
Be a giver. Multiple studies have demonstrated that persons who are involved in any form of regular volunteerism have better physical health and lower blood pressure, take fewer prescription medicines, maintain independence longer in life, and have lower rates of dementia. Loving other people is healthy for the brain.22
Minimize theatrical entertainment. The brain cannot tell the difference between a real threat and a perceived threat. If you watch stressful television programming it will activate the brain’s stress pathways, increasing inflammation throughout the body. Brain research has demonstrated that theatrical entertainment (but not education programming) alters the brain structure, resulting in underdevelopment of the prefrontal cortex (where we plan, organize, self-restrain, attend, have good judgment) and overdevelopment of the limbic system (where we experience fear and irritability). This imbalance increases the risk for attention problems as well as anxiety and mood problems, which increase the risk of dementia.23
Build a relationship with the God of love. Individuals with a healthy spirituality, meditating on a God of love, have reduced anxiety and stress and overall a more meaningful and satisfied life. Research shows healthy spirituality reduces rates of suicide, increases life-satisfaction scores, and generally results in healthier relationships and lifestyle. Healthy spirituality has multiple benefits:
However, there are unhealthy forms of worship with god constructs that incite fear, promote hostility, and foment conflict. All such belief systems are associated with increased anxiety, dread, and worry; relationship conflict; and a general sense of life dissatisfaction, all of which increase inflammation and are unhealthy for the brain.
A University of Michigan study examined the difference in benevolent versus vengeful God constructs in Muslim refugees from Kosovo and Bosnia, 60 percent of whom had post-traumatic stress disorder. Of the refugees, 77 percent practiced “negative” forms of prayer such as praying their enemies “would pay for what they have done.” In other words, 77 percent sought God to act in vengeance on their enemies. Researchers found that Muslims with positive prayers, prayers of forgiveness and seeking for peace and resolution of hostilities, had high levels of optimism, hope, and healthy adjustment. But those who had vengeance and anger-related prayers experienced reduced levels of optimism, hope, and healthy adjustment.24
Nutrition and Lifestyle
You have probably heard the old adage, You are what you eat. There is much truth in this saying. What we eat provides the nutrients and building blocks from which the tissues of our bodies are made. Diets high in sugar and saturated fats increase inflammation and oxidative stress, which accelerate the aging process and the decline in brain function. Conversely, diets high in fruits, nuts, grains, vegetables, cold-water fish, and olive oil provide antioxidants and other vital nutrients, which reduce inflammation and slow the aging process. In general, the more highly processed the food, the less healthy and more damaging to the body and brain. Multiple studies reveal that a Mediterranean diet not only reduces risk of developing AD but also, when combined with other lifestyle factors as described above, prevents decline in those already showing early memory and cognitive impairments and those with the ApoE4 at-risk gene.25
The International Conference on Nutrition and the Brain symposium held in Washington, DC, July 19–20, 2013, developed specific nutritional guidelines to promote brain health and reduce dementia risk. The seven guidelines that emerged are as follows:
LEARNING POINTS
ACTION PLAN: THINGS TO DO