risk factors and prevention of alzheimer's disease

Risk Factors and Prevention of Alzheimer’s Disease 1

Risk Factors and Prevention of Alzheimer’s disease

Melissa Hoffman

University of Illinois at Chicago

KN 396


Alzheimer’s disease (AD) is a neurodegenerative disease that causes memory loss

and cognitive decline gradually over time. What happens to the brain of a person with AD is the

protein beta-amyloid causes sticky plaques to block or damage the brain or the protein tau

collapses into tangles, causing the transport system to fall out of line. These two occurrences

result in neurons working less efficiently than they should. Neurons are the basic working unit in

the brain and transmit information to allow your brain to work properly. The plaques and tangles

eventually cause the neurons to die and the brain to literally shrink because of it. This, in turn,

affects the functioning in the brain and the decline of cognitive ability present in AD (National

Institute on Aging).

It is estimated that over 5 million Americans are currently suffering from

Alzheimer’s disease. With this number expected to increase significantly in the next few years,

what may be most conducive is to understand the risk factors, or characteristics that increase the

likelihood of developing AD (Pope, Shue, & Beck, 2003). Unlike many of the other most deadly

diseases in our country, AD has no cure. There are a few medications that may slow down the

progression of the disease, but in no way treat it. That being said, being proactive with this

disease may be more beneficial, in hopes of preventing or at least delaying the onset of AD.

Some examples of risk factors associated with AD are genetics, cognitive inactivity, diseases like

diabetes, and accidents such as head injury. The present paper will investigate these risk factors

and more, recognizing whether they are modifiable or non-modifiable, how we can promote a

lifestyle towards prevention, and new research and the outlook for AD.

Non-Modifiable Risk Factors


Non-modifiable risk factors are those that you cannot change or control. Risk factors

that are non-modifiable may be a little more difficult to deal with because there is no lifestyle

factor or cause. Something that one cannot control cannot be improved, so non-modifiable risk

factors are not up to the individual to prevent.

Age

When picturing Alzheimer’s disease, it is generally thought of as a disease occurring

in the elderly population. People over the age of 65 are most likely to develop AD, which at that

age is called late-onset Alzheimer’s disease (LOAD). However, it can occur earlier in life, before

the age of 65 and is then characterized as early-onset Alzheimer’s disease (EOAD). While it does

occur, EOAD cases are more rare and account for about 1-6% of diagnosed AD cases (Alonso

Vilatela, López-López, & Yescas-Gómez, 2012). Cognitive decline is not a “normal” sign of

aging, as some think. Alzheimer’s, dementia, and other neurodegenerative diseases are not a

natural part of getting old by any means. However, just like bones or muscles aging, our brain

ages as well. Changes occur that slow down brain activity after the age of 65, making increased

age a non-modifiable risk factor for AD (Pope et al., 2003).

Unfortunately, we cannot prevent people from getting older. What is being done is

research on how to slow down or reverse signs of aging and age-related diseases. Factors such as

growth hormone, length of telomeres, and free radical production are all being considered as we

attempt to discover how we can improve old age, healthspan, and longevity in our population.

Genetics


Within the two sub-types of AD just explained, there are many proteins and

mutations that can enhance an individual’s likelihood of developing the disease. Most of the

genetic links are more understood or obvious in the EOAD sub-type. LOAD seems to occur

more randomly, at least on a genetic level. The three most common or well-understood genetic

factors for EOAD are the APP gene, PSEN1, and PSEN2. The one link known between genetics

and LOAD is the APOE gene (Alonso Vilatela et al., 2012).

APP Gene

The APP gene, or the beta-amyloid precursor protein, is associated with the

developing beta-amyloid that creates plaques in the brain of AD patients. There are over thirty

mutations of the APP gene that are mostly associated with EOAD (Alonso Vilatela et al., 2012).

PSEN1

Presenilin1, or PSEN1 is the most common cause of EOAD. Many EOAD cases are

autosomal dominant, meaning if you inherit the abnormal gene from one parent, you can get the

disease. These cases are also called eFAD, or early-onset familial Alzheimer’s disease. Nancy

Bartolotti, a researcher in the Anatomy and Cell Biology department at University of Illinois at

Chicago, explained how much research is currently being done on the presenilin1 gene. It plays

such a large role in eFAD because the child of a parent with the mutated gene has a 50% chance

of receiving that same mutation. If the mutation is then passed down, the person will almost

always develop eFAD (personal communication, February 19, 2015). Presenilin1, therefore,

accounts for 18-50% of these autosomal dominant cases and usually develops the most severe

forms in the youngest people (Alonso Vilatela et al., 2012).

PSEN2


Presenilin2, or PSEN2 is another gene that is a less common cause of EOAD. Not as

many correlations have been established between PSEN2 and AD as PSEN1. In addition, the

cases that are established are generally not as severe and occur around the age 45-88 (Alonso

Vilatela et al., 2012).

APOE

Although LOAD is not as understood at the genetic level, apolipoprotein A (APOE)

gene is a genetic factor in LOAD. APOE is present in about 50% of LOAD patients and joins

with amyloid in these individuals, especially those with the Ɛ4 allele. (Alonso Vilatela et al.,

2012). The APOE gene has also been found to be linked to other conditions such as

cardiovascular disease.

Currently, the only option for genetic factors affecting Alzheimer’s disease is early

detection. Nancy Bartolotti also explained how PSEN1 is more commonly tested for now. Since

AD is generally diagnosed after the onset of symptoms, individuals with possible eFAD

occurring in their family members can get a genetic screening to see if they carry the mutation

(personal communication, February 19, 2015). Although options remain the same for individuals

who get genetic screenings, early detection allows for beginning treatment early or may give

people more time to plan and prepare. In addition, some who discover they carry a mutated gene

for AD will choose to not have children because they fear passing the disease on to them.

Modifiable Risk Factors

Modifiable risk factors are those we are able to control. For example, smoking is a

risk factor for lung cancer because it increases your likelihood of developing cancer. It is


important to keep in mind that a risk factor does not directly cause a disease, but having that

characteristic or exposure can increase your chances (Pope et al., 2003).

Head Injury

Since Alzheimer’s disease is a disease of brain degeneration, it has been suggested

that sustaining injuries to the head may play a role in the development of the disease. This is a

factor that has not been investigated as much as others because of the level of difficulty in

determining the extent of injury. Many believe that loss of consciousness may be the biggest

indicator of severe head trauma. A review of case studies in 2003 used loss of consciousness

from head injury prior to the onset of AD as inclusion criteria. What was found was that males

had a larger odds ratio of AD to non-AD after head injury. The difference in sex is believed to be

the possible protective effects of female hormones like estrogen. However, in both sexes, there

does seem to be a link between head trauma and AD (Fleminger, Oliver, Lovestone, Rabe-

Hesketh, & Giora, 2003). It is also thought that repeated head injury will increase chances of

developing AD, instead of just a single case. What is believed to happen when you receive

repeated blows to the head is that amyloid begins building up in the brain. Therefore, the more

times you sustain head injury, the worse this build-up will become (Pope et al., 2003).

Preventing head injuries is becoming extremely important in worksites and sporting

environments. What is important to understand is that an increased likelihood of developing AD

will probably not occur simply from bumping your head once (Fleminger et al., 2003).

However, for individuals such as profession football players or construction workers, wearing

protective headgear can make an enormous difference later in life. Regulations help to promote


safety and protect these individuals from sustaining injury, but protection can also be promoted

in situations such as wearing helmets during activities like biking and snowboarding.

Other Disease/Disorders

With the human body being linked in very intricate ways, there is no surprise that

having one disease may increase the chances of an individual developing another disease.

Although Alzheimer’s is in the brain, diseases that affect the heart and other parts of the body

can have a significant impact on brain health. Vascular disease, metabolic disease, and mood

disorders have been found to be risk factors for developing AD.

Vascular Disease

Vascular diseases are, essentially, diseases having to do with the circulatory system

and blood vessels. A 2005 study of vascular risk and AD found that the two had a strong

correlation, with the risk of AD increasing as the number of vascular risks increases. Two of the

major vascular risks in this study were hypertension, or high blood pressure, and heart disease.

Hypertension may actually cause lesions in the brain that could affect degeneration. Heart

disease often creates blockages in blood vessels that are thought to play a role in AD (Luchsinger

et al., 2005).

Although the direct link may not be known, Susan Frick, a social worker from Rush

Alzheimer’s Disease Center, explained how heart health is so important for brain health, and vice

versa. She said that the two clearly have a strong correlation and that she will often find herself

recommending the same diet and lifestyle changes to heart disease and AD patients (personal

communication, February, 24th, 2015).

Metabolic Disease


The possible effect of diabetes on AD risk is becoming more notorious among

researchers today than it was before. The hippocampus in our brain is responsible for memory. It

is thought that because insulin receptors are located in the hippocampus, this can have a negative

impact on memory by damaging that area. In addition, many researchers believe that

hyperinsulinemia can increase tau tangles in the brain (Luchsinger et al., 2005).Although the

exact mechanisms are not understood, Nancy Bartolotti explained how people in her field are

beginning to call AD “type 3 diabetes” because of the strong link between the two (personal

communication, February 19th, 2015).

What may be beneficial in relation to vascular and metabolic disease is doctors

explaining this connection to AD to patients when they are treated for the diseases. Taking

medication to lower blood pressure or control diabetes is becoming increasingly common in our

country. However, people may not be aware of what else this lifestyle is doing to their body.

Instead of being content with taking medication to control their disease, they can work to change

lifestyle habits that will improve their outlook for that specific condition and others linked to it,

such as AD.

Depression

A symptom that many people experience with the onset of Alzheimer’s disease is

depression. While memory problems may not be very prominent yet in early stage patients, there

is usually a mood shift that will occur. However, there is reason to believe that depression earlier

in life can also increase chances of developing AD later on. A systematic review of studies

conducted in 2006 found that, overall, there was a significant positive relationship between a

history of depression and the risk of developing AD (Ownby, Crocco, Acevedo, John, &

Loewenstein, 2006). Depression was previously seen as just a prodrome to AD. A prodrome is


an early symptom that may indicate the beginning of a disease. However, this study indicated

that not only is depression a prodrome, but also a risk factor (Ownby et al., 2006).

Treating mental illness is just as important as treating physical illnesse. Susan Frick

explained how many AD patients she sees who have a “glass half empty” outlook will not do as

well as far as their progression. She believes that having a positive outlook earlier in life and

after onset will help increase quality of life, even if AD is developed (personal communication,

February 24th, 2015). While treating depression is important for individuals early in life, this may

not eliminate depression as a risk factor for AD. Although more research needs to be done on the

subject, many think that the link between depression and AD is actually the APOE gene. The

APOE gene is thought to also lead to the development of depression. Therefore, if the gene is

present in a person, treating depression will not make a difference. The APOE gene will still be a

part of their genetic makeup (Ownby et al., 2006).

Physical Activity

The current recommendations for exercise state that adults should get 150 minutes of

moderate aerobic exercise every week, with 2 days of strengthening exercises as well. Children

should be active for an hour every day. These recommendations are accompanied by health

benefits and a decreased risk of diseases like diabetes, hypertension, depression, and stroke. As

the prevalence of Alzheimer’s increases, more studies are being conducted on the possible

benefits of physical activity for AD. A systematic review of 24 studies was done in 2008, where

20 of the studies determined that physical activity has a preventative effect on cognitive decline

(Rolland, van Kan, & Vellas, 2008). Nancy Bartolotti explained the research that is done with

rats in the Anatomy and Cell Biology Department’s lab regarding this idea. In one experiment,


mouse models of AD that have amyloid precursor proteins were used, which mimic the human

disease after a period of time. Some of the AD mice and non-AD mice were put on running

wheels in cages, while others had no wheels. The AD mice that had wheels in their cages

showed a slightly higher functioning level than the mice without wheels, once they began to

develop symptoms (personal communication, February 19th, 2015). Other research done with

rodents after death suggests that physical activity decreases the amount of beta amyloid proteins

in the brain. There is also evidence that being physically active helps maintain cognitive reserve,

allowing the brain to regenerate new connections and neurons (Rolland et al., 2008).

Encouraging people to get the recommended amount of exercise early in life can

benefit the brain later on. Including Alzheimer’s disease when talking about benefits of physical

activity might make individuals realize to what degree these factors can affect the brain.

Although physical activity cannot reverse the effects of AD, even a small amount of physical

activity in AD patients can slow down their rate of decline as well. In many cases, AD patients

who are elderly and are in nursing homes or institutions are confined to chairs, beds, and

wheelchairs. Simply having more opportunities to walk around can improve the outlook for them

(Rolland et al., 2008).

Cognitive Activity

With the rise in creation of games like Lumosity and other aids for Alzheimer’s

prevention, many individuals are choosing to engage in more cognitively stimulating brain

games to help “keep their brain young”. Although there is little evidence of success on these

recently developed brain games, longitudinal studies have been done, such as one by Wilson et

al., on activities such as reading, attending fine arts events, and playing board games (Wilson,


Scherr, Schneider, Tang, & Bennett, 2007). In this study, a large group of elderly individuals

who did not have any memory impairment were compared. The individuals rated their cognitive

activity levels from the previously stated activities. Over the years, the researchers took note of

which participants did or did end up developing AD. Although there was no evidence of the

more cognitively inactive participants having more amyloid or tau in the brain after autopsy, it

was seen that lower past and current cognitive activity was seen in the individuals who did

develop AD (Wilson et al., 2007). This is similar to the idea of cognitive reserve. The high

cognitive activity is not preventing the physiological effects of AD, but it is enhancing certain

areas of the brain. For example, gray matter in the Broca’s area is increased in people who are

musical (Wilson et al., 2007).

What can be taken away from studies like this is that, just as with physical activity,

even small amounts of cognitive stimulation can help. Reading a book or playing checkers can

be helpful to keep an individual’s brain healthy. With the increase in technology, it is important

for parents to have children become interested in activities other than television and video

games. By simply enjoying fun board games or going to see plays, an individual has an

opportunity to prepare their brain to protect them at a higher degree later on in life.

Homocysteine Level

Homocysteine is an amino acid found in the blood. When measuring the amount of

homocysteine in an individual’s blood, total plasma homocysteine levels are taken. While high

levels of homocysteine (hyperhomocysteinemia) have been found to be associated with

cardiovascular disease and pregnancy loss, it is now believed that the high levels are also a risk

for AD (Ravaglia et al., 2005). What is limiting is that hyperhomocysteinemia does not have a


definitive level that is deemed being a high amount. Above 15 micromoles per liter is usually

considered a high level of homocysteine. A study that used that amount to determine

hyperhomocysteinemia looked at 937 individuals and found that the risk of dementia and AD

actually doubled when an individual had a high level of homocysteine, even after adjusting for

other risks (Ravaglia et al., 2005). Having hyperhomocysteinemia evidently causes brain damage

and increases amyloid generation and toxicity (Ravaglia et al., 2005).

Many individuals with poor kidney function run the risk of developing

hyperhomocystenemia. Although that aspect is not as preventable, there are certain vitamin

deficiencies that can lead to hyperhomocysteinemia. Poor vitamin B status can lead to

hyperhomocysteinemia, with a very significant link seen with folate. Monitoring and making

sure individuals continue to consume an adequate amount of folate can help prevent

hyperhomocysteinemia. Eating foods like varieties of beans and greens, such as broccoli and

spinach can help increase folate intake (Ravaglia et al., 2005). Similarly, Susan Frick said high

doses of other vitamins, such as E, D, and C have also shown to be beneficial for the brain

(personal communication, February 24th, 2015).

Diet

Aspects of one’s diet other than vitamin intake can also affect brain health. High

levels of cholesterol and saturated fat have been linked to the development of other conditions

such as cardiovascular disease and diabetes. Now, they are also considered a risk to AD. Susan

Frick explained how they tell patients at Rush Alzheimer’s Disease Center that any food

considered “good heart food” is now also considered “good brain food” (personal

communication, February 24th, 2015). A study in male rats was conducted in 2008 to see how


saturated fat and cholesterol affects cognitive function. One group was given soybean oil in their

diet, which is low in saturated fat. The other group was given cholesterol and hydrogenated

coconut oil, which is high in saturated fat. After completing a maze, it was seen that the mice

with a low saturated fat diet did significantly better as far as cognitive ability during the maze

(Granholm et al., 2008).

It was previously believed that saturated fat and cholesterol affected the brain by

increasing the amyloid production. However, in the study previously mentioned, upon

completing autopsies of the mice brains, there was no difference between the development of

amyloid in each group (Granholm et al., 2008). So, although it is not known exactly how having

a diet low in saturated fat and cholesterol directly aids cognitive function, promoting healthy

diets can still help reduce risk of AD and many other diseases.

Education and Occupation

It was previously believed that individuals who were more educated showed a lower

risk of developing Alzheimer’s disease because they are able to do better on neurological exams

to test for AD. However, it is now believed that education and occupational attainment have an

effect at a more complex level. A study done on 593 individuals found that both low education

and low occupational attainment were associated with a higher relative risk of developing AD.

For those who were categorized as low in both aspects, the risk was even higher (Stern et al.,

1994). The results in the study were consistent with the theory of a good education and career

providing a reserve to help an individual cope longer before AD is clinically diagnosed (Stern et

al., 1994).


Staying in school has proved to be beneficial for the overall health of a person. Being

more educated about health and wellness has a significant impact, even if just the little

information that is learned in high school. A higher education also helps individuals to get good

jobs, which provides money and resources. It is evident why these aspects can help a person’s

overall health and why it can also help sustain a healthy brain. Both Nancy and Susan agreed

with this information, Nancy explaining how cognitive reserve is definitely improved in

individuals with a good job and high education (personal communication, February 19th, 2015).

Susan correlated this risk with her idea of “purpose and worth” affecting our brains. She further

explained that many AD patients tend to have led “less purposeful” lives, whether it was their

job or other aspects. Feeling as though you have a purpose in life helps prevent AD (personal

communication, February 24th, 2015). If children are inspired, at a young age, to continue their

education and aim for a successful occupation, we can promote good overall health and,

specifically, brain health.

Social Networks

While it is recommended that Alzheimer’s patients remain socially active after

diagnosis, there is also research indicating that being socially active earlier in life can reduce the

risk of developing AD. A study done in 2006 with Rush Memory and Aging project participants

indicated that individuals with a smaller social network had a greater decline in cognitive

function (Bennett, Schneider, Tang, Arnold, & Wilson, 2006). Susan Frick mentioned that

people who get out of the house to go to social events or have lots of friends and people to talk to

will have a better outlook than individuals who are introverts (personal communication, February

24th, 2015). The Rush study measured social networks by asking how many children, friends, or


other family members the individual saw at least once per month. Not only did the results show a

greater decline in cognitive function in individuals with smaller networks, but it also indicated a

higher presence of tangles in the brains of these individuals when an autopsy was performed

(Bennett et al., 2006).

Having people to talk to and do things with is evidently an important aspect in

keeping the brain and cognition healthy. As with all of the previous recommendations, studies

and experts do not suggest that individuals need to have an exceedingly large social network.

The Rush study indicated that the average social network size was 7 individuals (Bennett et al.,

2006). Therefore, those having a network lower than that might be at a higher risk of developing

AD. Keeping a good-sized group of people to reach out to, communicate with, and spend time

with is a fun and easy way to keep the brain healthy.

Research

Without the development and implementation of the studies previously discussed,

along with many more around the world, working towards prevention of Alzheimer’s disease

would be impossible. There are 29 federally funded Alzheimer’s centers in the United States that

work to find links and solutions for the fight to end AD (Susan Frick, personal communication,

February 24th, 2015). The Rush Alzheimer’s Disease Center receives money to conduct

longitudinal studies on various risk factor possibilities as well as clinical trials to test treatment

options. Since there are not many treatment options currently, many clinical trials are aimed at

trying to find a drug that could possible suppress plaque and tangle formation in the brain (Susan

Frick, personal communication, February 24th, 2015).


Similarly, research labs, such as the Orly Lazarov Lab at University of Illinois at

Chicago, are attempting to come up with more possibilities for treatment through stem cell

research. Although stem cell treatment is currently used mostly for bone marrow and blood

transfusions, lab members at the Orly Lazarov lab are gaining a better understanding of the

biology of stems cell, in hopes of applying new findings to help the aging and diseased brain

(Nancy Bartolotti, personal communication, February 19th, 2015).

Other, less conventional, methods of treatment are becoming popular for AD as well.

Susan Frick also started a program called Without Warning, which is a support group for

individuals with EOAD. The group is mostly a place where patients can connect and share

thoughts and ideas with people who are in a similar situation as them. However, music therapy

sessions are also done at the meetings. Susan said that although some patients may not even be

able to form a sentence, they can often remember lyrics to a song (personal communication,

February 24th, 2015). Music therapy has been found to help people have periods of clarity, as

well as lift their spirits.

Outlook

Although researchers and doctors have made numerous strides for the treatment and

prevention of Alzheimer’s disease, there are still many aspects that remain unknown. The

outlook for AD is expected to become worse before it gets better, with prevalence rates predicted

to increase four times what the current rates are (Pope et al., 2003). The public health impact of

Alzheimer’s is even more troublesome, with annual costs averaging between $80 and $100

billion. That number is also believed to see an increase in the years to come (Pope et al., 2003).

Unlike many types of cancer, AD doesn’t receive the same amount of public attention or the


same level of fundraising and advocating efforts. Groups such as the Alzheimer’s Association

are attempting to increase awareness and gain more support for ending AD.

People who dedicate their lives to Alzheimer’s disease research, like Nancy

Bartolotti and Susan Frick, are hopeful for solutions, yet know that it will be a long journey.

Nancy admitted that she does not think a cure for AD is possible anywhere in the near future.

However, she expressed her concern with the quality of care improving even if a cure is not

found. She explained how many AD patients are treated as though they are not a person

anymore. Simply because their brain is degenerating, some individuals see them as an empty

shell with no feelings (personal communication, February 19th, 2015). Knowing that these people

still feel, think, and matter is essential to the quality care that many caretakers and staff do

practice.

Seeing as the journey towards ending Alzheimer’s disease may be a lengthy one,

promoting a lifestyle aimed towards prevention is key in our current situation. There are

numerous doctors, researchers, social workers, and therapists who dedicate their lives to the fight

to end AD, yet everyone can play a role in some way. Keeping in mind that each person has

control over their own body and how they treat it, living a lifestyle that practices good nutrition,

cognitive and physical exercise, and social involvement can make a significant difference in

brain health. Having a PhD or knowing the science behind brain degeneration is not essential to

have an impact on Alzheimer’s disease prevention. Practicing and promoting ways to reduce the

risk factors previously stated can make an impact on the community.


References

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risk factors and prevention of alzheimer's disease

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