The Molecular Basis of Disease:

Alzheimers

Alzheimers disease is an irreversible, progressive brain disease that slowly destroys memory and thinking skills, and eventually even the ability to carry out the simplest tasks.1
-National Institute on Aging-

Because the trend of Alzheimers disease increases dramatically with age, combined with the trend toward extended lifespan in our population, the number of individuals affected with the disease will rise significantly over the next several decades. -Boston University School of Medicine-

Submitted by Lance Michael Raeper

Introduction:

Discovery: In 1901, a neuropathologist by the name of Alois Alzheimer, who worked in a state asylum in Germany, received a 51 year old female patient, Auguste Deter. This patient was said to be suffering from Language deficits, auditory hallucinations, delusions, paranoia, and agressive behaviour. Dr. Alzheimers first conversation with Auguste, according to his medical dossier: Sitting in bed, expression distraught. He asks her what her name is. Auguste. Last name? Auguste. What is your husbands name? I think its Auguste. Are you married? To Auguste. He shows her various objects: a pencil, a pen, a key, a cigar. She is able to identify them, but shortly afterwards when Alzheimer asks her to name the objects without showing them to her, she has forgotten everything. Auguste would ultimately spend five years in the clinic before passing. Auguste D passed away in 1906, and her brain was immediately sent to Alzheimer, then in Munich, for examination. According to Dr. Draaisma of the University of Groningen, Alzheimer was an institutional physician who did his rounds with great dedication, but believed that his greatest service to his patients was rendered after their brains became available for microscopic examination. Alzheimer performed an autopsy on her brain, using a silver staining technique that allowed him to visualize the presence of neurons. The doctor noted dense deposits surrounding the nerve cells (neuritic plaques). Inside the nerve cells he observed twisted bands of fibres (neurofilrillary tangles). He concluded that these leisions might be the cause of the soon to be called Alzheimers disease. In November that year, Alzheimer presented Augustes case at a psychiatry meeting, and published this talk in 1907.

These plaques and tangles, when found today, are the definitive indication of the degenerative neurological disorder, Alzheimers disease.

The tangles block the transmission of information(electric signals) between neurons through synapses. A synapse is a structure that enables a neuron to pass an electrical signal to another cell. Tangles are composed of a protein known as tau, form within the neurons themselves, and are considered intracellular leisons. Additionally, nutrients and other essential supplies are prevented from moving through the nerve cells, which eventually die. The tangles also cause surrounding cells to die. The plaques come about from an aggregation of the protein Ab, amyloid beta, outside the cell membrane. Ab is a naturally occuring neuronal substance, and only becomes a problem when the body ceases to metabolize and remove the excess amount around the neurons. Ab is chemically "sticky" and gradually builds up into plaques. This aggregation prevents the transmission of electrical signals between neurons. Thus AD is not a disease of the neurons, but of the commuication between neurons.

Progression: AD first attacks the area of the brain that enables us to hold memoriesthe hippocampus. This is the portion of the brain that

translates our new thoughts and truns them into long-term memories. Since this is attacked first, short-term memory failure is the first noticable symptom. Eventually, the formation of new memories becomes extremely difficult. The plaques and tangles spread through the cortex in a predictable pattern: First to the hippocampus, then to the frontal lobe, which helps in carrying out purposeful behavior and complex reasoning (top left picture below). This loss of processing skills makes reasoning with people who have Alzheimer's virtually impossible. People with AD are not being stubborn; their brains just aren't healthy enough to carry out the complex processes that logic demands. This is the stage at which most people are diagnosed with AD.

The next areas that are affected are the temporal lobe, and the parietal lobe(top right picture above) . The temporal lobe plays a key role in memory, language and high-level sensory processing, like understanding speech. Early on, the AD affected individal will be incapable of recalling words, and eventually the recal of nouns will be severely affected. In later stages, some patients experience auditory and visual hallucinations, which can be monitored in this portion of the brain. The parietal lobe helps us orient our bodies in space, and to decipher where and what things

are. When this area of the brain is affected, victims become lost and disoriented, even in familiar settings. In the last stages of the disease, the rest of the brain is affected the occipital lobe, and the amygdala(bottom picture above). The occipital lobe is primarily responsible for visual interpretation, and is not usually completely damaged. However, some visual association areas are affected. It becomes difficult to recognise subtle visual cues, such as peoples faces. The Amygdala has been shown to be the emptional center of the brain. It is where emptional imprints and reactions are formed. Once Alzheimer's disrupts the brain's emotional center, a person may display surprising behaviors such as apathy, paranoia, emotional outbursts and inappropriate sexual advances. Unprovoked hostility and anxiousness might appear completely out-of-theblue. In the advanced stages of AD, most of the cortex is severely damaged. The brain shrinks dramaticallydown to 1/3rd its original weightdue to the widespread death of cells. A person with advanced AD loses his ability to communicate, to recognize friends and family, to create new memories, and to care for himself. In the past, people suffering from AD were said to be entering their second childhood. Newborn babies spread their toes upward when you touch the toes of their feetthe Babinski reflex. After about six months, that reflex disappears and babies spread their toes downwards when touched, in the direction of the stimulus. In the very last stages of Alzheimers, the Babnski reflex returns, together with other reflexes characteristic of newborn babies, such as sucking and grasping. Even today, the most common causes of death among AD sufferers are the same as that which killed Auguste D: bedsores and pneumonia. Like Auguste, the patient will curl up into the foetal position and die. There are two types of AD, which each reflect the age at which the disease develops. Early-onset AD is a rare form of AD, affecting only about 5 percent of all people who have AD. It develops in people ages 30 to 60. Most cases of Alzheimers are of the late-onset form, developing after age 60.

It is interesting to note that the average life expectancy person in 1900 was approximately 47 years. Most people develop symptoms of AD do so after the age of 60. AD discovered in an age where no more than five people hundred reached the age of 65.

of a that was in a

Certainly Alzheimers must have been much less prevalent in these times. In this period Syphilis was the more common cause of dementia (which is a symptom of AD), because of the lack of antibiotics. In its later stages Syphilis can affect the central nervous system and lead to dementia. The one important thing that Dr. Alzheimer missed was that AD is strongly linked to the age of the patient. The older a person is, the greater is the chance of AD occuring.

Causes of Alzheimers Diseasse: Scientists generally agree that there is unlikely to be a single clear "cause" of Alzheimer's. It is more likely the result of a combination of inter-related factors, including genetic factors, which are passed along family lines of inheritance, and environmental influences, which range from previous head trauma (when the victim is a carrier of a specific gene) to educational level to one's experiences early in life. Genetics:

Among individuals from families with early onset AD (before age 60) there is a cumulative life-time risk of developing the disease of 53%. Over the past 20 years, data have accumulated to suggest that genetic factors may play a role in some, if not all, cases of AD, according to Adult Neuropsychology (1992).

More recently, it has been estimated that genetic mutations account for under 5% of all cases. Scientifically these cases are important, even though they only account for 5 percent, because of what they tell us about what goes wrong in the brain to cause alzheimers.

The first major genetic risk factor discovered was ApolipoproteinE (ApoE). We have two copies of the gene that codes for this protein, one from our father, the other from our mother. These two genes, together, determine this protein. As with variations in say eye color, there are variations in the protein. These variations are labelled e2, e3, and e4. We can have either zero, one, or two of copies of this gene, and the more we have, the greater our risk of AD. Another gene, called clusterin, helps to protect the brain from exessive inflammation caused by infections and other illnesses. The gene is involved in removing clumps of the rogue amyloid plaques. Defects in the gene hamper its ability to do these jobs and increase the risk of AD. A gene called Picalm is crucial for maintaining the health of neurological connections between brain cells. Mutations in the Picalm gene are thought to disrupt the ability of brain neurons to talk to each other and form memories. A new gene called CR1 is also linked to Alzheimer's disease. The CR1 gene is involved in protecting the brain by clearing out amyloid plaques that can build up in Alzheimer's patients brains. Environmental causes:

Low education: There is a negative correlation between education and the incidence of ADmany studies have shown that the risk of Alzheimers disease goes down, as the educational attainment of a person goes up. Schooling, in most cases, involves use of our various cognitive abilities. Neurological connections within our brains are strengthened with repeated usage. It follows that, generally, the longer we have been formally educated, the more robust will be our neurological circuitry (connections between cells), and the better able our brains will be to protect against the effects of AD.

Education does not only affect the brain, but affects health in general; educated people tend to have health insurance, earm more money, visit their doctors more regularly and they live in better neighborhoods to name a few factors. They are more likely to do all the things that keep you healthier in general. Their chances of contracting most diseases is lower.

Aside from schooling, it has also been abundantly shown that other mentally stimulating activities are another factor that reduce the incidence of AD. This can involve playing games, reading, socializing, etc.

There appears to be a strong connection between the risk factors of cardiovascular conditions and those of AD. When an individual is physically healthy as a result of exercise and dietary habits, the risk for AD and stroke both go down. By exactly how much they go down is not easily predictable, as the level varies from person to person. What we can be sure about though, is that being healthy has been positively correlated with reduced AD incidence.

The specific risk factors associated with stroke and AD are: Smoking, diabetes, a sedentary/lazy lifestyle, high blood pressure, high fat diet and being overweight.

Conclusion: Alzheimers disease, as is obvious from my essay, has yet to be completely understood. What we have discovered about it is that AD is caused by a number of interrelated environmental and genetic factors. For example, as a result of improved health (for various reasons such as germ theory, anti-biotics, sanitation, more food, etc.), a significant demographic trend is that people are living longer. As people get older we have observed that they become more succeptible to AD. Because of the mix of causes we cannot say that it is solely inherited, or simply a result of laziness (atrophy of the brain). I thus conclude that AD is a result of both environmental as well as genetic factors.

Discovery of Alzheimers: Douwe Draaisma, Disturbances of the Mind, Cambridge University Press , 2006, pp.199-228. http://www.ahaf.org/alzheimers/about/understanding/history.html http://genome.wellcome.ac.uk/doc_WTD020951.html http://www.nia.nih.gov/Alzheimers/Publications/adfact.htm Progression: http://www.alz.org/brain/12.asp http://www.pbs.org/theforgetting/symptoms/#brain http://www.nia.nih.gov/alzheimers/publications/geneticsfs.htm Causes of AD: Mark B. Moss, Marilyn S. Albert and Thomas L. Kemper, Clinical Syndromes in Adult Neuropsychology: The Practitioners Handbook, Elsevier Science Publishers, 1992, pp.305-334 Michael Baraitser, The Genetics of Neurological Disorders, Oxford Medical Publications, 1990, pp.85-88 Video: Dr. Bruce Reed, Coming of Age Lecture Series, Alzheimers Disease Research Center, UC davis. http://www.youtube.com/watch?v=FRFRuTUAfro http://www.guardian.co.uk/science/2009/sep/06/alzheimersdisease-genes-research

http://www.alzinfo.org/alzheimers-research-causes.asp