Early Versus Late Onset | Diagnosis of Alzheimer's Disease | Affected Chromosomes | Protective Factors Against Alzheimer’s Disease | Behavioral Changes in Alzheimer’s Disease | Stages of Alzheimer’s Disease | Vaccine for Alzheimer’s Disease | Neuropsychological Testing | Genotyping | AD Research

 

Alzheimer's Disease:

Alzheimer’s Disease is a progressive form of dementia.  Gradually, the individual experiences changes in baseline functioning that occurs over months and years. There are changes within the brain that lead to both memory loss and behavioral change.  The areas of the brain controlling the memory loss and behavioral changes are usually global, meaning they do not affect a single area of the brain but that there is neuronal damage in several areas of the brain.  Generally, Alzheimer’s disease begins in the medial temporal regions and progresses forward affecting frontal lobe functions involving judgment, social conduct, and behavioral inhibition.

AD and the Brain:

  • AD spreads through the brain. The cerebral cortex begins to shrink as more and more neurons stop working and die.
  • Mild AD signs can include memory loss, confusion, trouble handling money, poor judgment, mood changes, and increased anxiety.
  • Moderate AD signs can include increased memory loss and confusion, problems recognizing people, difficulty with language and thoughts, restlessness, agitation, wandering, and repetitive statements.

Alzheimer’s disease (AD) was named after its discoverer Alois Alzheimer (1864–1915) who first described the pathology of the disease in 1906. AD is the most common form of progressive dementia affecting people today and accounts for 50 to 60 percent of all dementias (Smith and Kiloh 1981). It is suspected that both genetic and environmental factors contribute to the disease. To date, we know of two types of Alzheimer’s disease.

  1. The first type is familial AD. It is genetically based and is inherited through genes from our parents.
  2. The second type is sporadic. In this type, there is no known genetic component. Environmental factors are suspected to play a key role in sporadic Alzheimer’s disease.

Most cases of Alzheimer’s disease carry a strong genetic component. The risk within the general population of developing Alzheimer’s disease is about 1% but moves up to 4% for first degree relatives of those who have been diagnosed with the disease (Campbell 1989). Of all diagnosed cases of Alzheimer’s disease, about 80% are estimated to be genetically based (Plassman and Breitner 1996). Environmental factors are believed to contribute to both familial and sporadic types of AD.

Early Versus Late Onset:

Alzheimer’s disease is further broken down into early and late onset types. In early onset, the disease occurs before the age of sixty-five. This type is rare, usually progresses faster, and accounts for about 10 percent of Alzheimer’s disease cases. In the late onset type, the disease occurs after the age of sixty-five (National Institute of Aging, National Institutes of Health 1999). This type is much more common and makes up the remainder of cases.

Prevalence:

Alzheimer’s disease is the fourth leading cause of death in the U.S. and is believed to occur in 1 to 2 percent of the general population. It is estimated to occur in about 10 percent of individuals over the age of sixty-five and to affect about four million Americans (Brookmeyer et al. 1998). We know of a genetic component to the disease as first degree relatives of people with confirmed Alzheimer’s disease stand a slightly greater risk of developing the disease than does the general population. To date there is no treatment for this disease.

There are 360,000 new Alzheimer’s cases each year (Brookmeyer et al. 1998). The current prevalence rate doubles every five years after the age of sixty. This equals 1 percent for sixty to sixty-four-year-olds, 2 percent for sixty-five- to sixty-nine-year-olds, 4 percent for seventy- to seventy-four-year-olds, 8 percent for seventy-five- to seventy-nine-year-olds, and 16 percent for eighty- to eighty-five-year-olds (Campbell 1989). In short, the prevalence doubles roughly every five years beyond the age of sixty-five (Hebert et al. 1995). The prevalence increases up to 35 to 40 percent for those over the age of eighty-five. The overall prevalence is about 10 percent after the age of sixty-five (Cummings et al. 1998). These odds are not all that bad, as you probably have an equal or greater chance of being involved in a fatal or debilitating auto accident.

Diagnosis of Alzheimer’s Disease:

Alzheimer’s disease can only be diagnosed with certainty upon autopsy or by a biopsy of the brain. This is done by the detection of the two hallmark structures within the brain. These are called amyloid plaques and neurofibrillary tangles. At more sophisticated medical centers, the disease can be diagnosed with up to a 90 percent certainty prior to death (Gearing et al. 1995). Unfortunately this diagnosis is often given out erroneously and made prematurely upon the first onset of minor short-term memory deficits. This creates an unimaginable burden for the patient and their families. If you have been told that you have AD and question the accuracy of the diagnosis, we recommend that you get a second opinion. For a definite diagnosis there must be both structural changes within the brain and behavioral symptoms present before death. Identifiable pathologic changes include: neuronal plaques, neurofibrillary tangles, amyloid angiopathy, loss of synapses and neurons, granuovacuolar degeneration of the hippocampus, and neuronal loss (Cummings et al. 1998).

Neurons:

  1. The brain has billions of neurons, each with an axon and many dendrites.
  2. To stay healthy, neurons must communicate with each other, carry out metabolism, and repair themselves.
  3. AD disrupts all three of these essential jobs.

The formation of amyloid plaques and neurofibrillary tangles are thought to contribute to the degradation of the neurons (nerve cells) in the brain and the subsequent symptoms of Alzheimer's disease.

Neurons have an internal support structure partly made up of microtubules. A protein called tau helps stabilize microtubules. In AD, tau changes, causing microtubules to collapse, and tau proteins clump together to form neurofibrillary tangles.


Current Treatments:

Currently there is no cure or reversible treatment for the disease, however medications are available that may delay the onset of more severe symptoms.  The class of drugs used to treat mild to moderate Alzheimer’s disease is known as cholinesterase inhibitors.  The first of these medications came out in 1993 and is known as Tacrine or Cognex.  This medication remains available although it is no longer actively marketed.  Side-effects from the medication seem to counter its limited benefit.  Donepezil or Aricept was introduced in 1997 for the treatment of mild to moderate Alzheimer’s Disease.  This medication is taken once daily and it takes approximately 6-8 weeks to be effective.  Petersen 1995 showed that Aricept tends to be effective only for the first year of treatment. Razadyne (galantamine) is another medication used in treating mild to moderate AD.  More recently Exelon (rivastigmne) became available.  In addition to breaking down acetylcholine in the brain it also breaks down butyrylcholine.  Side-effects of cholinesterase inhibitors include nausea and diarrhea.  These drugs are not always tolerated well by patients and do have limited benefits.  The dosage is gradually titrated to the maximum effective dose.

More recently, Namenda (memantine) was approved by the FDA for treatment of moderate to severe Alzheimer’s Disease.  Unlike cholinesterase inhibitors, this drug acts on the brain chemical, glutamate. Excess glutamate may lead to the death of brain cells.  This N-theyhl D-aspartate (NMDA) antagonist is believed to delay the onset of later stages of Alzheimer’s Disease, allowing the individual to maintain activities of daily living such as the ability to use the bathroom independently, dressing, etc…Since this medication acts differently than the cholinesterase inhibitors, Namenda can be used in conjunction with the cholinesterase inhibitors.

Plaques are protein deposits of beta-amyloid (toxic substance) that form on the outside of the individual neurons. Tangles are abnormalities within the cell structure where cell fibers become tangled and cease to function. Tangles consist of a protein called “tau.” Tau is involved in the structural integrity of nerve cells. In Alzheimer’s disease, the tau proteins break down, which creates malformations in the structural framework of the neuron. It is unknown whether AD is caused by these abnormalities or whether the cellular abnormalities are a byproduct of the disease process. As both progress, malfunction in key structures within the brain occur. The National Institute on Aging and the Reagan Institute of the Alzheimer’s Association have worked jointly to establish new criteria for the diagnosis of Alzheimer’s disease. The new criteria have placed emphasis on the appearance of both neurofibrillary tangles and neuronal plaques in the neurocortex (Cummings et al. 1998). It should be noted that neuronal plaques are more specific to Alzheimer’s disease, whereas neurofibrillary tangles are also associated with other progressive central nervous system (CNS) diseases. Neuronal plaques are also found in normal aging but to a much lesser degree.

Inflammation within the brain is believed to be a key characteristic of the disease that leads to cognitive decline. Cholinergic neurons or neurons responsible for processing acetyleholine, are believed to be especially vulnerable to damage from inflammation

Affected Chromosomes:

Research has linked Alzheimer’s disease to multiple chromosomes including: 1, 6, 12, 14, 19, and 21. Chromosome 21 is also associated with Down’s syndrome and Down’s syndrome patients almost always develop symptoms similar to Alzheimer’s disease. It is speculated that the amyloid precursor protein gene on chromosome 21 accounts for a few cases of familial Alzheimer’s disease. Familial cases, which often have an early onset, have been linked to abnormalities on chromosomes 1, 14, and 21. Abnormalities on chromosomes 1 and 14 make up the large majority of familial cases of Alzheimer’s disease (Sherrington et al. 1995). Susceptibility genes in themselves do not cause the disease. Rather, it is believed to be a combination of multiple factors that influence the age of onset and increase the chances of developing the disease. Amongst suspected genes related to the sporadic form of the disease, the influence of apolipoprotein E (ApoE) on chromosome 19 has been identified (Strittmatter et al. 1993).

Protective Factors Against Alzheimer’s Disease:

Research has demonstrated that there are several protective factors that seem to prevent or delay the onset of AD. These include: higher intelligence, larger head size, lack of past head injuries, male gender, ApoE-2 genotype verses ApoE-4 genotype, higher educational level, history of use of nonsteroidal anti-inflammatory medications, and use of estrogen replacement therapy in postmenopausal women (Cummings et al. 1998).

Snowdon and colleagues (1996) have demonstrated an example of the protective factor of intelligence and education in delaying or preventing the disease. The group of researchers has been following a group of nuns for several years. They provide yearly examinations and the nuns have agreed to donate their brains for study upon death. Snowdon and his associates found a correlation in the “Nun Studies” between the nuns’ complexity of writing styles in early adulthood and the later onset of AD. Nuns who had more complex writing styles were less likely to develop the disease.

Destructive Aspects of Alzheimer’s Disease:

The average range from onset to death in this progressive disease is five years, with a range of one to ten years. Alzheimer’s disease accounts for about 100,000 deaths per year in the United States with 360,000 new cases diagnosed per year (Brookmeyer et al. 1998). Alzheimer’s disease affects three main processes within the brain.

  1. The first process involves the repair of damaged cells. When most nerve cells within the brain die, they are not replaced. Therefore they must have the capacity to repair and restructure themselves if they are to last throughout our lifetime. Alzheimer’s disease is, at least in part, related to the breakdown of this normal repair process. Recent studies (Xu et al. 1999) have supported the theory that AD may result in part from inappropriate activation of apoptosis (programmed death of cells) and its relation to tumor suppressor proteins.
  2. Another process known to break down in Alzheimer’s disease is the normal communication between nerve cells. This process is dependent upon the integrity of the nerve cell and its interconnections to other nerve cells. It is also dependent upon the availability of neurotransmitters.
  3. The final process involves metabolism or the feeding of the nerve cell. Alzheimer’s disease greatly interferes with the neuron’s ability to receive adequate energy and nutrients. Because the cells lose their ability to obtain nutrition, they eventually starve to death.

Behavioral Changes in Alzheimer’s Disease:

Although the progression of the disease has unique features for each individual, certain patterns can usually be identified. The disruption of degenerative processes eventually leads to cell death that usually begins in the memory-encoding portion of the brain known as the hippocampus. This leads to an initial impairment in recent memory marked by rapid forgetting. This is often marked by patterns of denial of forgetting by the patient. Initial changes also involve naming and word fluency (Murdoch et al. 1987). Often we see the patient use circumlocution (substituting other words for words that are lost to memory impairment) with minimal awareness given to the word-finding difficulties. The ability to form cohesive sentences, procedural memory, and general comprehension usually remain intact early in the disease (Hier et al. 1985). Cueing and other memory strategies usually remain ineffective, and afflicted individuals usually do poorly on both free recall and recognition tasks when tested. As the disease progresses upward into the cerebral hemispheres, disruptions in expressive language, personality, and judgment begin to occur. Patients lose their ability to distinguish between left and right, and there are profound disturbances in visuospatial abilities (Eslinger et al. 1985). In the final stages the brain deteriorates to the point that the afflicted individual becomes completely helpless and reliant on others for their day-to-day functioning. These represent the 4 “A’s” of Alzheimer’s disease: amnesia, aphasia, apraxia, and agnosia. There is also a high prevalence of depression in Alzheimer’s patients.

Oxidative Stress:

Damage through oxidative stress is a current topic of research and is considered a nongenetic factor. Through aging we receive damage to nerve cells through the buildup of free radicals. Free radicals are a normal byproduct of the oxidative process within brain cells but can also modify the structure of proteins or molecules within nerve cell structure. Free radicals have been linked to both AD and cancer (National Institute of Aging, National Institutes of Health 1999).

Stages of Alzheimer’s Disease:

Alzheimer’s disease usually progresses through three distinct phases. Early in the disease process the patient often has limited awareness of his or her deficits. One of the first notable deficits is difficulty with short-term memory. Patients become more forgetful, have difficulty recalling words they wish to use in a conversation (anomia), and begin losing things. Disorientation quickly sets in, and they begin to get lost in familiar places and lose track of time. Apraxia is another cardinal sign of the disease process and involves the person forgetting how to use a familiar tool or an appliance. Personality changes begin to be noticed and personal hygiene begins to be neglected. The middle stage of Alzheimer’s disease is marked by an increased severity of the above symptoms. Those afflicted may begin to experience more pronounced expressive and receptive language difficulties. They may forget when they ate their last meal and become more noticeably disoriented to time. Often they have difficulty identifying people they have known for years and become increasingly more withdrawn. Inappropriate behaviors become more prevalent. Frustration leads to greater episodes of agitation, especially in the evening (referred to as sun downing). Eating and sleep disturbances become more frequent. In the final stages of the disease, both short-term and long-term memory are severely impaired. Illusions, delusions, and hallucinations begin to be prevalent. There ceases to be recognition of others and communication becomes almost impossible. Bladder and bowel control are greatly impaired and constant assistance is needed for daily functioning. The patient becomes increasingly more frail and more susceptible to infections and diseases.

Mild to Moderate AD:

  1. AD spreads through the brain. The cerebral cortex begins to shrink as more and more neurons stop working and die.
  2. Mild AD signs can include memory loss, confusion, trouble handling money, poor judgment, mood changes, and increased anxiety.
  3. Moderate AD signs can include increased memory loss and confusion, problems recognizing people, difficulty with language and thoughts, restlessness, agitation, wandering, and repetitive statements.


Sever AD:

  • In severe AD, extreme shrinkage occurs in the brain. Patients are completely dependent on others for care.
  • Symptoms can include weight loss, seizures, skin infections, groaning, moaning, or grunting, increased sleeping, loss of bladder and bowel control.
  • Death usually occurs from aspiration pneumonia or other infections. Caregivers can turn to a hospice for help and palliative care.

Current Treatments:

According to the Alzheimer’s Association, the current annual cost for treatment of Alzheimer’s disease in the United States is in excess of 60 billion dollars (Cummings 1998). Research is producing new progressive treatments including: a variety of cholinesterase inhibitors, antioxidants such as vitamin E, estrogen, non-steroidal inflammatory drugs, psychotropic agents, free radical inhibitors, transmitter replacement therapies, nerve growth factors, and prevention of amyloid formations through drugs (Cummings 1998). Although treatment options are limited, goals of current treatments are to improve cognition and behavioral symptoms, slow the progression of the disease, and to delay or prevent the onset of the disease (Farlow and Evans 1998).

Current treatments are mostly palliative in nature and seek to delay the progression of the disease. Future interventions will focus on drugs designed to attack the underlying mechanisms associated with the disease ( and Evans 1998). As an example of this, Soto and associates (1998) demonstrated that injection of a small peptide similar to beta-amyloid actually reduced the size of beta-amyloid deposits in rats. This has strong implications for future treatment strategies for multiple neurodegenerative diseases.

Vaccine for Alzheimer’s Disease:

Drug Name
Drug Type and Treatment
Manufacture's Recommended Dosage

Namenda® (memantine):
Blocks the toxic effects associated with excess glutamate and regulates glutamate activation.

N-methyl D-aspartate (NMDA) antagonist prescribed to treat symptoms of moderate to severe AD

5 mg, once a day, available in tablet form
Increase to 10 mg/day (5 mg twice a day), 15 mg/day (5 mg and 10 mg as separate doses), and 20 mg/day (10 mg twice a day) at minimum of one week intervals if well tolerated.

Razadyne® (formerly known as Reminyl®) (galantamine):
Prevents the breakdown of acetylcholine and stimulates nicotinic receptors to release more acetylcholine in the brain.

Cholinesterase inhibitor prescribed to treat symptoms of mild to moderate AD

4mg, twice a day (8mg/day, available in tablet or capsule form
Increase by 8mg/day after 4 weeks to 8mg, twice a day (16mg/day)if well tolerated. After another 4 weeks, increase to 12mg, twice a day (24mg/day) if well tolerated.

Exelon® (rivastigmine):
Prevents the breakdown of acetylcholine and butyrylcholine (a brain chemical similar to acetylcholine) in the brain.
Cholinesterase inhibitor prescribed to treat symptoms of mild to moderate AD 1.5mg, twice a day (3mg/day, available in capsule and liquid form Increase by 3mg/day every 2 weeks to 6mg, twice a day (12mg/day) if well tolerated.

Aricept® (donepezil):
Prevents the breakdown of acetylcholine in the brain.

Cholinesterase inhibitor prescribed to treat symptoms of mild to moderate AD 5mg, once a day, available in tablet form Increase after 4-6 weeks to 10mg, once a day if well tolerated.

Cognex® (tacrine):
Prevents the breakdown of acetylcholine in the brain.
Note: Cognex is still available but no longer actively marketed by the manufacturer.

Cholinesterase inhibitor prescribed to treat symptoms of mild to moderate AD

10mg, four times a day (40mg/day), in capsule form
Increase by 40mg/day every 4 weeks to 40mg, four times a day (160mg/day), if liver enzyme functions remain normal and if well tolerated.

How We Can Predict the Presence of Alzheimer’s Disease?

The proper diagnosis of Alzheimer’s disease usually involves several visits to your physician. He or she may also want you to get additional testing that will assist in the diagnosis. Often a baseline has to be established, and exams such as neuropsychological testing or imaging need to be repeated so that a measure of deterioration can be obtained. New advances in the early diagnosis of possible or probable AD allows patients and their families to better prepare for the future and allows for some autonomy on the part of the patient in the decision-making process. Alzheimer’s disease may be present for many years before symptoms become noticeable. Studies with neuroimaging have shown that structural changes within the brain are often present many years before symptoms of dementia set in (Cummings et al. 1998). Although no diagnosis is definitive in itself, an MRI can set one’s mind at ease if no significant structural abnormalities are found

Neuropsychological Testing:

Neuropsychological testing is an inferential process that compares cognitive behavioral domains of function against established norms (Lezak 1995). It can help to rule out the presence of Alzheimer’s disease. Although there are some atypical presentations of the disease, we can usually differentiate on behavioral tests between Alzheimer’s disease, other dementias, and normal aging.

Genetic Risk Factors:

What is a genetic risk factor? Within the nucleus of most cells within your body is the genetic code that makes you who you are. This genetic code is known as DNA. Chromosomes make up the DNA in the form of two parallel strands (double helix) of twenty-three pairs. You inherit one side of the helix from each parent. Portions of the genetic code arranged in specific sequence patterns make up genes. Genes produce various proteins based on their individual sequence patterns. These proteins determine your physical characteristics and dictate the physical functioning of your body. Sometimes malformed proteins are created that can lead to disease or a predisposition to a disease. These changes or malformations in the gene’s codes are called mutations. We all have numerous polymorphisms (genetic mutations) that do not directly result in disease. When one of these mutations increases an individual’s chance of developing a disease, it is referred to as a risk factor.

Genotyping:

Currently there are no reliable tests that will predict who will develop Alzheimer’s disease (Roses 1995). Genotype testing can help to predict the chances of the current or future onset of the disease. We know that those who have a family history of the disease and present with one or two copies of the apolipoprotein epsilon 4 (ApoE-4) genotype on chromosome 19 stand a better chance of developing the late onset form of the disease. Strittmatter and associates at Duke University (1993) showed that the ApoE allele accounted for up to 50 percent of genetic causes of the late onset form of AD. Hyman et al. (1996) estimates that 60 to 75 percent of sporadic cases carry the ApoE 4 gene. It is speculated that this is due to excessive beta-amyloid buildup. Other studies have confirmed these findings. Holzman and associates (1999) demonstrated in mice that the ApoE protein influenced plaque formation. Buttini et al. (1999) also showed that ApoE 3 proteins protected mice from injury to brain cells where ApoE 4 proteins did not. We also know that those with an ApoE 2 genotype are better protected against the disease or tend to develop the disease much later. Currently it is believed that the ApoE3 variation has a neutral effect in the onset of AD. This is the most common variation of ApoE.

Keep in mind that possessing an ApoE 4 genotype does not mean that you will develop the disease. We know of many people with this genotype who never develop Alzheimer’s disease and those without the genotype who do. Neuroscientists believe that the ApoE protein helps to coordinate the processing of cholesterol throughout the body. The discovery of the relation of the ApoE 2, 3, or 4 pairs has helped us to gain greater understanding in the variations in age of onset of the disease. ApoE testing can also aid in diagnostic certainty in cases of atypical presentation involving visuospatial abnormalities or circumscribed language disturbances (Welsh-Bohmer et al. 1997).

Tau Protein:

The level of Tau Protein in Spinal Fluid can also be measured and predict the presence of Alzheimer’s disease.

AD Research: the Search for Causes:

Genetic Studies:

The two main types of AD are early-onset and late-onset:

  1. Early-onset AD is rare, usually affecting people aged 30 to 60 and usually running in families. Researchers have identified mutations in three genes that cause early-onset AD.
  2. Late-onset AD is more common. It usually affects people over age 65. Researchers have identified a gene that produces a protein called apolipoprotein E (ApoE). Scientists believe this protein is involved in the formation of beta-amyloid plaques.

Studies at the Cellular and Molecular Level:

  1. Oxidative damage from free radical  molecules can injure neurons.
  2. Homocysteine, an amino acid, is a risk factor for heart disease. A study shows that an elevated level of homocysteine is associated with increased risk of AD.
  3. Scientists are also looking at inflammation in certain regions of the brain and strokes as risk factors for AD.

Researchers also are looking at other treatments, including:

  1. cholesterol-lowering drugs called statins
  2. anti-oxidants (vitamins) and folic acid
  3. anti-inflammatory drugs
  4. substances that prevent formation of beta-amyloid plaques
  5. nerve growth factor to keep neurons healthy

Preventative Measures:

Preliminary studies suggest that there are some measures that may be beneficial in reducing or delaying the onset of Alzheimer’s Disease.  It is important to stress that these are only suggestions and there is no unequivocal clinical evidence that these steps are beneficial. 

  1. Nonsteroidal anti-inflammatory drugs (NSAIDs) – may delay or prolong onset, however serious side-effects
  2. Vitamin E has received much press regarding the antioxidant effect, however recent research does not show significant benefits in staving off cognitive decline.
  3. Estrogen has both anti-inflammatory and antioxidant properties and it is speculated that estrogen may even stimulate the growth of neurons that release acetycholine.  Mixed results and serious side-effects.
  4. Statins which reduce cholesterol levels may also reduce the risk of Alzheimer’s Disease.  Research continues to study this relationship.
  5. Exercising your brain is an important component in maintaining cognitive abilities.  Exercises that challenge our attention are particularly helpful.

National Support for Caregivers:

Alzheimer’s Association:

Local chapters provide referrals to area resources and services, and sponsor the Safe Return Program, support groups, and educational programs:

1-800-272-3900
www.alz.org

Eldercare Locator:

Nationwide service of the Federal Government helps caregivers locate local support and resources:

1-800-677-1116
www.eldercare.gov


 

 

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