# Presentation: 464553

## Definition of Dementia

-  An acquired complex of intellectual     deterioration which affects at least two  areas of cognitive function.
-  A syndrome, not a diagnosis.
-  In the past, commonly referred to as  senility or “hardening of the arteries”

**Notes:**
Slide 1 - Definition of Dementia
Dementia refers to an acquired persistent loss of intellectual functions due to a brain disorder. This is not a normal part of the aging process, even though the vast majority of persons who experience a dementia are persons age 65 or older. Dementia is really a broad, umbrella term. A medical diagnosis is required to determine the underlying cause or causes of symptoms.  In the past, terms like “senility” and “hardening of the arteries” were commonly used to describe dementia but do not accurately explain the disease processes at work.

## Cognitive Functions

- Memory
- Orientation
- Language
- Judgement

- Perception
- Attention
- Ability to perform  tasks in sequence

**Notes:**
Slide 2 - Cognitive Functions
Dementia typically unfolds gradually over a period of many years but it can begin abruptly. It affects some or all of the following brain functions:
—Memory - The hallmark of dementia is impairment with respect to recent events, what is often referred to as “working memory.” Forgetting appointments, conversations, and the like typically herald the onset of dementia. New learning becomes defective whereas memories from the distant past may be intact.
—Orientation - The inability to know one’s place and time may also be indicative of dementia - for example, getting lost outside one’s home or not knowing the month or year.
—Language - Word finding difficulty is also typically seen among persons with dementia. Comprehension of spoken language may also be impaired. Rules of syntax and grammar may be impaired although speech itself may be intact.
—Judgment - Reasoning skills, especially with respect to abstract tasks, are often impaired resulting in poor judgment.
—Visuospatial skills - Distortions in interpreting one’s environment may also be seen in dementia. Although eyesight itself may be well preserved, the brain’s ability to accurately interpret what one is seeing may be impaired.
—Concentration - The ability to pay attention or concentrate may also be impaired. This may be seen in difficulty with making change or balancing a checkbook.
—Ability to sequence tasks - Performing any task requires the ability to put a series of steps together in the right order. Someone with dementia may forget the steps in preparing a meal or shopping for groceries.

## Dementia = Brain failure

- Two basic types                                                                                                          1) Reversible dementias                                                                                                                                                                                                                                        2) Irreversible dementias
- All dementias are treatable to a degree

**Notes:**
Slide 3 - Dementia = Brain Failure
We are familiar with terms like congestive heart failure, liver failure and kidney failure. When the brain fails to do its work, dementia is the appropriate term. There are dozens of causes for dementia, some that are reversible through proper treatment, some that can be stabilized and others that are irreversible and progressive. 

## Reversible Dementias

- Intoxications
- Infections
- Metabolic disorders
- Major depression

- Brain tumors
- Head injuries
- Normal pressure hydrocephalus

**Notes:**
Slide 4 - Reversible Dementias
There are numerous causes of dementia including reversible conditions and other conditions that may be stabilized. These include:  
—Medications -  Older adults are often on complex medication regimens. Dementia can be related to toxic effects of these medications or drug-food interactions. Moreover, many classes of drugs are known to affect mental status such as psychotropics, anticonvulsants, antibiotics, and antihypertensives.  
—Infections - An infection in one’s blood or central nervous system can cause dementia. Laboratory tests usually reveal such infections causing dementia.
—Metabolic disorders - There are numerous metabolic disturbances associated with dementia. These include vitamin deficiencies, chronic kidney failure, thyroid, liver and pancreatic disorders.
—Depression -  Depression is a psychiatric disorder with the principal symptoms of sadness, difficulty in thinking and concentration, decreased activity, feelings of helplessness and hopelessness, and sometimes suicidal ideation. Many severely depressed people will have some cognitive deficits, like poor concentration and attention, which can mimic a dementia. This condition is sometimes called pseudodementia. These people may not receive treatment for their depression unless it is differentiated from the symptoms of dementia.  Depression is treatable but requires prompt evaluation and treatment. Another challenge is the presence of both dementia and depression. In this situation, the intellectual presentation may be more extreme for the stage of the dementia. A skilled diagnosis by a psychiatrist, neurologist, or geriatrician is important to sort out this complex clinical picture. Depression is treatable, whether alone or in combination with dementia.
—Brain tumor and subdural hematoma - The presence of a brain tumor or traumatic brain injury can result in dementia depending on the location of the mass or injury in the brain. These problems are diagnosed using brain imaging techniques such as a CT scan or MRI.
—Normal pressure hydrocephalus - Normal pressure hydrocephalus (NPH) is a relatively uncommon brain disorder that involves an obstruction in the normal flow of cerebral spinal fluid. This blockage causes a buildup of cerebral spinal fluid in the ventricle (space) in the brain. The clinical symptoms of NPH are urinary incontinence, poor balance and gait, and dementia. NPH is sometimes treatable with a neurosurgical procedure in which a shunt is inserted to divert the cerebral spinal fluid away from the brain.

## Irreversible Dementias

- Alzheimer’s disease
- Multi-infarct or vascular dementia
- Parkinson’s disease
- Lewy Body disease

- Creutzfeldt-Jakob disease
- Pick’s disease
- Huntington’s disease
- AIDS dementia complex
- Progressive aphasia

**Notes:**
Slide 5 - Irreversible Dementias
Most dementias are irreversible in nature. Sometimes two or more types of these dementias may occur together as a “mixed dementia.” There are several dozen causes, but the major types are listed below. 
—Alzheimer’s Disease - More than four million Americans have Alzheimer's disease (AD), the leading cause of dementia in older adults. By the year 2050, it is estimated that 14 million Americans will be afflicted. The characteristics of AD are progressive loss of working memory, disorientation, and confusion. The stages of AD will be noted later as well as possible causes and treatments.AD was first described in 1906 by Dr. Alois Alzheimer, a German neurologist and pathologist. His patient was a female in her early 50s who presented with symptoms of suspiciousness, memory loss, disorientation, and hoarding behaviors, among other symptoms. This condition was progressive and her symptoms worsened over time. After 41⁄2 years she was stuporous and lay in bed in a fetal position until her death due to pneumonia. Alzheimer was the first scientist to describe this set of clinical symptoms and relate them to pathologic changes in the brain. At autopsy, he described brain shrinkage as well as microscopic abnormalities he referred to as neurofibrillary tangles and senile (amyloid) plaques. These clinical and pathologic changes have become the hallmarks of AD.
—Multi-Infarct Dementia - Multi-infarct dementia or vascular dementia is caused by multiple, tiny infarcts or strokes in the brain. A stroke is an injury to a blood vessel (either a clot in the vessel or the tearing of the vessel wall) that results in bleeding into brain tissue. In either case, there is death to the area of brain tissue immediately around the infarct. When the stroke is in an area responsible for learning and memory, then symptoms of memory loss and thinking problems are evident. This form of dementia is not reversible or curable, but if an underlying treatable cause of the strokes can be determined (e.g., hypertension), then treating the cause may decrease the risk of future infarcts. Instead of the gradual decline associated with AD, someone with MID usually has an abrupt, stepwise decline.
Just as the chest pain of angina precedes many heart attacks, about 10 percent of major strokes causing paralysis or weakness are preceded by mini‐strokes, also referred to as transient ischemic attacks or TIAs. These occur when an internal blood clot temporarily blocks an already‐narrowed artery in the brain, causing a brief period of substantially reduced blood flow or "ischemia." TIAs strike suddenly and usually don't last more than a few minutes. They may cause symptoms such as numbness, fainting, dizziness, clumsiness, and/or loss of speech or vision. However, many TIAs go unnoticed, especially if they cause only momentary dizziness or fainting. Even though most people recover from TIAs completely, each episode causes some tissue death in the brain. Those who experience several TIAs may suffer enough cumulative brain damage to develop MID. 
Today, low‐dose aspirin is widely recommended as a stroke preventive for people who have had TIAs, and many physicians also recommend it to treat vascular dementia. In cases where vascular dementia and Alzheimer's co‐exist, low‐dose aspirin can help minimize the risk of additional mini-strokes.
—Parkinson’s Disease - Parkinson’s disease, a progressive neurological disorder that affects about one million Americans, is the result of the loss of dopamine-producing brain cells. The central nervous system needs the neurotransmitter dopamine to control motor activity. The classic symptoms of the disease are resting tremors, rigidity of limbs and joints, mask-like facial expressions, speech and swallowing difficulties, and difficulty initiating movement. Late in the disease, symptoms of dementia occur in 20 to 30 percent of cases. The relationship between Parkinson’s disease and AD is an area of great interest to researchers today.
—Lewy Body Disease - Also known as Dementia with Lewy Bodies, it typically presents with a combination of motor difficulties and dementia, similar to the symptoms of Parkinson’s disease and Alzheimer’s disease. Behavioral disturbances including delusions and hallucinations are often part of the presentation.
—Creutzfeldt-Jakob Disease - This is a rare transmissible brain disease that is rapidly progressive in most cases that also includes motor difficulties and dementia. 
—Pick’s Disease  -  Pick’s disease is a rare brain disorder, which is usually difficult to diagnose at first since it is usually associated with psychiatric conditions. Disturbances in personality, behavior, and orientation may precede and initially be more severe than memory defects. A definitive diagnosis can only be determined at autopsy. The brain shows unusual shrinkage of the frontal cortex, the region involved in reasoning and other higher mental functions as well as unusual protein deposits (Pick bodies). The condition is more common in women than men, and most sufferers develop it between age 40 and 60. It is rare in people over 75 years of age.
—Huntington’s Disease - Huntington’s is a hereditary disease that usually strikes in one’s 20s and 30s. Symptoms include a pronounced movement disorder and dementia. Although the specific genetic defect responsible for this disease has been identified on Chromosome 6, there are no effective treatments at this time.
—AIDS Dementia Complex - HIV infection can also cause dementia, especially in the later stages of AIDS. In rare cases, dementia is seen in the early stages of AIDS.
—Progressive Aphasia - Progressive aphasia is another rare brain disorder, marked by gradual loss of the abilities to speak and write. The person may not express any other symptoms except loss of the ability to speak. At present, the cause for this disorder is not known, and no treatment or cure exists.

## Diagnostic Evaluation of Dementia

- History from patient and relative or friend
- Clinical exam
- Blood work: CBC, Chem profile, Thyroid function tests, Syphilis serology, Vit B12, Folate
- Brain scan, CT or MRI

- If indicated:                             - Psychological   testing    - HIV                                - Brain biopsy                  - SPECT or PET    scan                   - Lumbar puncture            - EEG

**Notes:**
Slide 6 - Diagnostic Evaluation of Dementia
A medical evaluation is always needed to sort out the diagnosis so that (1) concern can be eliminated if it is not warranted; (2) treatable conditions can be identified and addressed appropriately; and (3) nonreversible conditions can be diagnosed early enough to permit the patient and family to plan for contingencies such as long‐term care. Getting an accurate history, conducting a clinical examination including a cognitive screening test, blood tests, and brain imaging are basic elements of a diagnostic evaluation. Sometimes additional tests are ordered for the sake of thoroughness in diagnosing unusual forms of dementia. There is no single test available to diagnose AD such as a blood test, as is the case with diabetes for example. However, when other disorders have been ruled out and typical symptoms of AD have been documented, there is a high probability for obtaining an accurate diagnosis by an experienced physician

## Criteria for Probable Alzheimer’s Disease

- Dementia established     by clinical and neuropsychological examination
- Deficits in at least two areas of cognition
- Progressive worsening of memory and other cognitive functions

- No disturbances of consciousness
- Onset between ages 40 and 90
- Absence of other disorders to account for dementia

**Notes:**
Slide 7 - Criteria for Probable Alzheimer’s Disease
Since there is currently no simple and reliable biological test to diagnose AD, criteria have been established to guide physicians in making the diagnosis. In the vast majority of cases, these criteria are useful in helping physicians differentiate between AD and other forms of irreversible dementia. Any doubts about the accuracy of the diagnosis should be addressed to a medical specialist, most likely a neurologist, in the form of a second opinion.

## Prevalence of Alzheimer’s Disease

- More than 4 million Americans plus their families
- Number doubles every 5 years after age 65
- Estimated cost of $100 billion annually
- Numbers may triple by 2050

**Notes:**
Slide 8 - Prevalence of Alzheimer’s Disease
AD is far and away the most common form of dementia. The prevalence of the disease clearly increases with age, although it can affect middle-aged persons. The economic costs of the disease are estimated to be $100 billion annually. The personal toll on individuals and families is incalculable. In light of increasing longevity and 76 million aging baby boomers, the number of persons with AD is likely to triple over the next 50 years.

## Prevalence of Alzheimer’s Disease by Age

- SOURCE:  Evans, D.A. et al. (1989).* Journal of the American Medical Association*. Vol. 262: 2251-2256.

**Notes:**
Slide 9 - Prevalence of Alzheimer’s Disease by Age (bar graph)
According to a large, community-based study by Evans and his colleagues in East Boston during the 1980s, about 3 percent of persons aged 65-74 have AD, nearly 1 in 5 persons aged 75 to 84 years have the disease, and almost half of those over age 85 years have the disease. The 85+ age group is currently the fastest growing segment of the U.S. population. Taking into account these figures, it is now estimated that there are more than four million Americans with the disease. U.S. Census projections of the aging population clearly show that the number of Americans with AD will grow dramatically in the coming decades unless means of prevention are found.

## Stages of Alzheimer’s disease

*Function*		*Early Stage*
- Memory		Routine loss of recent memory
- Language		Mild aphasia (word finding                                     difficulty)
- Orientation		Seeks familiar and avoids unfamiliar
- Motor			Some difficulty writing and using 				objects
- Mood and behavior	Apathy & depression
- Activities of 		Needs reminders with some ADL’s
- daily living (ADL)

**Notes:**
Slide 10 - The Early Stage of Alzheimer’s Disease
AD is slowly progressive and may last three to 20 years. The rate of progression varies from person to person. The disease tends to advance according to stages of severity. It unfolds in subtle ways, not unlike normal absent-mindedness, except with regularity. Early stage symptoms may be imperceptible until the patient or family notices that a pattern has developed or a stressor such as acute illness make symptoms more apparent. Forgetting appointments, misplacing things, difficulty managing a checkbook, word finding problems, and loss of initiative are typical changes at this stage. Symptoms may be inconsistent, with “good days” and “bad days” making life unpredictable for all concerned. One’s ability to manage self-care tasks is usually not compromised at this point but reminders and supervision are needed with certain activities of daily living (ADLs) such as cooking, shopping, and paying bills.

Early Stage Symptoms
Memory		    Recent memory loss much of the time
Language    		    Mild aphasia
Orientation		    Seeks the familiar and avoids the unfamiliar
Motor		    Some difficulty writing and using objects
Mood and Behavior	    Apathy, depression
Activities of Daily Living (ADLs)	    Needs reminders with some ADLs

## Stages of Alzheimer’s disease

- Memory		Chronic, recent memory loss
- Language		Moderate aphasia
- Orientation		May get lost at times, even inside the 			home
- Motor			Repetitive actions, apraxia
- Mood and behavior	Possible mood and behavioral 				disturbances
- Activities of 		Needs reminders and help with
- daily living (ADL) 	most ADL’s

**Notes:**
Slide 11 - The Middle Stage of Alzheimer’s Disease
As AD progresses to the middle stage, the symptoms are more obvious. Memory loss and disorientation worsen, expressive and receptive language difficulties increase, and independence with activities of daily living is compromised. The patient’s ability to make autonomous health care and financial decisions is questionable and others must assume the role of surrogate decision-makers. At this point, difficulty with self-care tasks usually arises.

Middle Stage Symptoms
Memory		Routine loss of recent memory 
Language		Moderate aphasia
Orientation		May get lost at times, even inside the home
Motor		Repetitive actions, apraxia
Mood and Behavior	Possible mood and behavioral disturbances
ADLs		Needs reminders and help with most ADLs

## Stages of Alzheimer’s disease

- Memory		Mixes up past and present
- Language		Expressive and receptive aphasia
- Orientation		Misidentifies familiar persons and 				places
- Motor			Bradykinesia, at risk for falls
- Mood and behavior	Greater incidence of mood and 				behavioral disturbances
- Activities of 		Needs reminders with all ADL’s
- daily living (ADL)

**Notes:**
Slide 12 - The Late Stage of Alzheimer’s Disease 
Late in AD, all cognitive functions are severely impaired and the person is completely dependent on others for most or all ADLs. Even long-term memory is significantly compromised at this point. Individuals may misidentify familiar people, places and objects. Constant supervision is required for the sake of safety and care. 

Late Stage Symptoms
Memory		Mixes up past and present
Language		Expressive and receptive aphasia
Orientation		Misidentifies familiar persons and places
Motor		Bradykinesia, falls
Mood and Behavior	Greater incidence of mood and behavioral disturbances
ADLs		Needs help with all ADLs

## Stages of Alzheimer’s disease

- Memory		No apparent link to past or present
- Language		Mute or few incoherent words
- Orientation		Oblivious to surroundings
- Motor			Little spontaneous movement, 				dysphagia, myoclonus, seizures
- Mood and behavior	Completely passive
- Activities of 		Requires total care
- daily living (ADL)

**Notes:**
Slide 13 - The Terminal Stage of Alzheimer’s Disease  
In the final stage of AD, there is little or no language, little purposeful movement, and total dependence on others. Death usually results from sepsis or pneumonia at this stage. At any point in the disease, co-existing medical problems can exacerbate symptoms and hasten decline if not properly treated. 

Terminal Stage Symptoms
Memory		No apparent link to past or present
Language		Mute or few incoherent words
Orientation		Mostly oblivious to surroundings
Motor		Little spontaneous movement, dysphagia, 			myoclonus, seizures
Mood and Behavior	Generally passive
ADLs		Needs total care

## Alzheimer’s Disease & Brain Changes 

- Loss of brain cells and mass
- Neurofibrillary tangles
- Neuritic plaques
- Change in blood flow & glucose utilization

**Notes:**
Slide 14 - Alzheimer’s Disease & Brain Changes
Currently, AD cannot be diagnosed with 100 percent certainty until a brain autopsy after the person's death reveals the disease's characteristic anatomical abnormalities. These were first described by Dr. Alzheimer as neurofibrillary tangles and neuritic plaques. These tangles and plaques represent the death of nerve cells or neurons throughout the brain. The brain shrinks in size, losing as much as one-third of its normal weight. 

Tangles consist of a protein called tau that clog up the insides of certain brain cells and their connections. Similar deposits of tangled tau are seen in most people as they age, but in much smaller amounts. Beta-amyloid is the other protein that accumulates abnormally in the brains of persons with AD, forming neuritic plaques. Both beta-amyloid and tau appear to be important pieces in the puzzle of AD. Scientists have also found that AD causes changes in other important brain functions, including nerve cell communication, metabolism, and neuron repair. 

## Neurotransmitters

- Facilitate communication among nerve cells
- Acetylcholine production & other neurotransmitters reduced in Alzheimer’s disease
- Communication between nerve cells disrupted
- Nerve cells die

**Notes:**
Slide 15 – Neurotransmitters
Most people think of the nervous system as the body's electrical wiring. This is correct – but only up to a point. Nerve cells transmit impulses much like wires transmit electricity. But unlike wires, which are continuous filaments, nerve fibers are discontinuous. Nerve cells do not touch one another. They have microscopic gaps between them called synapses. Nerve impulses must jump these gaps to proceed on their way. They do it with the help of special chemicals called neurotransmitters. As a nerve impulse passes through a nerve cell, it activates the release of  neurotransmitters into the cell's synapses, allowing the impulse to jump the gap, and proceed on its way. Once the impulse crosses the synapse, special enzymes eliminate the neurotransmitter, leaving the cell and synapse ready to react to the next impulse. One important neurotransmitter is acetylcholine.

During the late 1970s, researchers discovered that people with AD suffer a loss of acetylcholine from their synapses. This observation fueled theories that Alzheimer's might disrupt the synthesis of acetylcholine, or that the disease triggers overproduction of the enzyme that eliminates it, acetylcholinesterase – generally known as cholinesterase. Scientists speculated that drugs that either increased acetylcholine or inhibited cholinesterase might help treat AD. 

Cholinesterase inhibition has yielded the most promising results so far. The four drugs currently approved for treatment of Alzheimer's disease in the United States – tacrine (Cognex), donepezil (Aricept), rivastigmine (Exelon), and galantamine (Reminyl) – are cholinesterase inhibitors. They do not cure the disease but when they work, they may help prevent some symptoms from worsening for a limited time. 

## Definite Risk Factors for Alzheimer’s Disease

- Increasing age
- Family history; genetics
- Female gender
- Down Syndrome

**Notes:**
Slide 16 - Definite Risk Factors
Circumstances that put one at risk for diseases are referred to as risk factors. A common risk factor for acquiring many diseases involves exposure to environmental toxins. For example, inhaling tobacco smoke is known to increase one's risk of getting lung and heart diseases. Also, high blood pressure, high cholesterol levels, and obesity significantly increase one's chances for heart disease. Identification of these risk factors has led to advances in prevention, treatments, and cures.

Another common risk factor for developing diseases involves heredity. Some genetic disorders may be well known and easily identified through genetic testing, even before birth. For example, someone with Huntington's disease inherits the gene associated with this disease from one parent. In turn, the affected person may put his or her offspring at a 50% chance of inheriting the disease. Other diseases may not have a clear-cut genetic cause and may not be triggered unless combined with environmental factors. Such diseases pose an uncertain risk of inheritance or genetic susceptibility. Clear risk factors for AD include:
—Increasing age - Aging is clearly the main risk factor. The older you grow, the greater your risk, as shown by the above noted graph based on the community-based study on the prevalence of AD.
—Family history - Having a close blood relative who develops Alzheimer's increases one’s personal risk. In a 1996 study, researchers with the MIRAGE project tracked the lifetime Alzheimer's risk of nearly 13,000 people who had a first‐degree relative (mother, father, sister, brother, son, daughter) with the condition. By age 80, people with AD in both parents had a 54 percent risk, 1.5 times the risk of the disease in people with just one affected parent, and 5 times the risk of people with two unaffected parents. Furthermore, if one identical twin develops AD, the other's risk is unusually high – 40 to 50 percent – which argues for a genetic predisposition. Several genes now associated with AD are described below.
—Female gender - Women tend to live longer than men and thus are more likely to develop AD due to longevity alone. Some studies have shown that at all ages, women have a higher risk of AD than men but other studies have contradicted this finding.
—Down syndrome - Over age 40, all persons with Down Syndrome, a genetic disorder, evidence plaques and tangles at autopsy although not all are symptomatic during their lifetime.   

We obviously do not have the luxury of choosing our biological parents, whose genetic makeup may influence our health. For better or worse, we inherit a set of genes from both mother and father that may protect or put us at risk for certain diseases. Advances in understanding the human genetic map may ultimately lead to ways of blocking the action of defective genes and promoting drugs that mimic genes that have protective effects. In the meantime, the search continues for factors in the environment that put us at risk for developing certain diseases so that we can modify our lifestyles. We are just beginning to understand risk factors for AD. If potentially reversible risk factors can be identified, we may discover clues about prevention, treatment, or a cure.

## Genes Linked to Alzheimer’s Disease

**Chromosome   Type      Age of Onset    % of Cases           Gene**
-           21                 Autosomal           45-65	               < 1%                   APP (Amyloid 		             Dominant 				       precursor protein)
- 	   14  	             Autosomal	      28-62                  < 1%                   Presenilin 1
- 		             Dominant
- 	    1	             Autosomal            45-65                  < 1%          	        Presenilin 2
-                                Dominant
-           19	             Risk Factor	      > 60	                > 50%                 ApoE 4
- 	   12	             Risk factor	      > 70		?	        A2M
- Source: Marx, J., (1998, July 24) *Science*, Vol. 281, 509.

**Notes:**
Slide 17 - Genes Linked to Alzheimer’s Disease
The genetic mechanisms of familial Alzheimer's remain largely unexplained, but a few genetic mutations have been identified that greatly increase risk in some families. Research has focused on specific abnormalities of genes on chromosomes 1, 14, and 21. Chromosome 21 contains the gene for amyloid precursor protein (APP), which appears to play a role in the deposition of beta‐amyloid, the substance involved in the amyloid plaques of AD. People with Down syndrome appear to produce extra APP, which in turn leads to abnormal levels of beta‐amyloid. This may explain why people with Down syndrome develop AD. The mutations on chromosomes 1 and 14 cause rare clusters of AD in small numbers of families. The defects on chromosome 14 occur in a gene called presenilin 1 and on chromosome 1 in the gene presenilin 2. They appear to play a major role in the rare hereditary form of AD that is seen among persons under the age of 60.

The gene for apolipoprotein E (APOE) is located on chromosome 19. Several studies show that its natural variations correlate well with risk of AD. The APOE gene comes in three varieties, called alleles e2, e3, and e4. Everyone's APOE gene has two of these three alleles, so there are six possible combinations in any individual's DNA. The e2 allele is associated with decreased risk of AD. The e3 allele is associated with average risk. Having one or two copies of the e4 allele increases a person’s risk of getting AD, but it does not mean AD is certain. Scientists have yet to determine the exact degree of risk of AD for any given person based on APOE status. Scientists have long been aware of the APOE gene and the protein it instructs the body to make, ApoE, because this protein plays a role in the metabolism of cholesterol, a key risk factor for heart disease.  ApoE also binds to amyloid, the protein associated with the amyloid plaques of Alzheimer's. The various alleles of APOE affect amyloid differently. The e4 allele appears to increase deposition of amyloid in the brain. The mechanism remains a mystery, but is the focus of a great deal of research.

Genetic testing for naturally occurring APOE alleles is currently possible. However, testing has little predictive value and is not recommended by the Alzheimer’s Association and several medical societies. Despite the increased risk of having two e4 APOE alleles, many people with these two alleles live into their 80s with no sign of AD. Currently, genetic testing for APOE alleles only suggests increased risk; it does not predict development of the disease. However, if drugs are developed that can prevent AD, then APOE testing would be useful to identify those who would benefit from preventive treatment.

## Possible Risk Factors for AD

- Environmental toxins
- Low formal education & occupational attainment
- Previous head trauma
- Cerebrovascular disease

**Notes:**
Slide 18 - Possible Risk Factors
Possible risk factors are those suspected of being linked somehow to AD, but the linkage has not been proven. Weak or strong associations with AD may be attributed to a complex number of factors still unidentified. In the meantime, possible risk is associated with the following factors:  
—Environmental factors - Hazardous elements in the environment may play a contributing role in AD, but researchers have not yet been able to identify any with certitude. Experts agree that environmental factors may influence a genetic predisposition to AD. Because ingestion of heavy metals such as lead can cause brain damage, there has been a constant search for something in the environment that we eat or breathe that may be a culprit. Studies of identical twins show that genetics play a key role in AD but also show that genetic makeup is not destiny. Identical twins are genetically the same, but AD develops in only about half of identical twin pairs. In addition, when both identical twins develop Alzheimer's, their age at diagnosis often differs by as much as 15 years. For many years, the role of aluminum in AD was studied; however, aluminum is no longer a major consideration in spite of occasional published reports suggesting it may play a role.
—Low education & occupational attainment - Another risk factor with major social implications relates to one's level of education and occupation. Growing evidence suggests that people with low educational and occupational attainment may be at greater risk of developing AD than the rest of the population. Conversely, those with high educational and occupational attainment may be at lower risk for developing AD than the rest of the population. Two possible explanations have been put forth about the role of education and occupation. First, the more educated people perform better on tests of intellectual ability than others and are not easily identified as having symptoms of AD. Second, higher levels of education may increase brain reserve, delaying onset of symptoms for many years. These theories have not yet been proven. Whether education and occupation represent true risk factors or are merely markers for some other disease-related factors will not be known without further research.
—Head trauma - It is well known that professional boxers who suffer repeated blows to the head are at great risk of brain damage resulting in permanent impairment of memory, language, and other cognitive functions. Recent studies have shown that anyone who suffers a severe blow to the head at any time in life is more prone to getting AD than those without such experience. It has also been speculated that even a minor head injury occurring early in life may have dormant yet lasting effects that make one vulnerable to AD late in life. Head trauma may put a person at risk for developing AD, but whether the risk is large or small is not yet fully understood.
—Cerebrovascular disease - A study of Catholic nuns by Dr. David Snowden and colleagues at the University of Kentucky suggests that the presence of tiny strokes or TIAs in combination with the plaques and tangles characteristic of AD significantly increases its clinical manifestations. Further study is needed to clarify the role of vascular disease in the onset of AD.

## Strategies for Medical Treatment ofAlzheimer’s Disease 

- Prevention of disease
- Delay onset
- Slow rate of progression
- Treat primary symptoms (cognitive)
- Treat secondary symptoms (behavioral)

**Notes:**
Slide 19 - Strategies for Medical Treatment
—Prevention - The ideal approach to deal with any disease is to prevent it altogether, for example, with a vaccine. Since the causes of AD are not known at this time, it is difficult to arrive at such a simple solution. However, as understanding of risk factors grows, there may be ways of reducing personal risk for the disease that ultimately prevent the onset of the AD.
—Delay the onset - If the disease cannot be prevented, the next best approach is to delay its symptoms for 5 or 10 years. Since most people with AD are elderly, delaying the disease might result in their death from other common causes. It has been estimated that if AD could be postponed, in effect, for just 5 years, then the incidence could be cut by one-third.
—Slow down progression - After early symptoms of the disease develop, the goal then is to maintain individuals at their highest possible level of functioning. Stopping or slowing down the usual advance of the disease could theoretically enable individuals to remain independent and living in their own homes with minimal supports. Drugs currently approved and in testing phases aim to accomplish this goal but have thus far fallen short of expectations.
—Treat primary symptoms - If none of the above steps can be accomplished, the next best approach is to improve memory and other brain functions impaired by AD. By treating these symptoms, there is a hope of slowing down progression too. Again, current drugs and experimental drugs are directed toward this goal but have thus far fallen short of expectations for dramatic benefits.
—Treat secondary symptoms - If the cognitive symptoms of AD cannot be successfully treated, the next best approach is to treat behavioral symptoms often associated with the disease: insomnia, agitation, hallucinations, delusions, etc.. A variety of behavioral and pharmacologic approaches aim to alleviate these symptoms.

##  Tacrine  (COGNEXTM)

- Approved for treatment of AD in 1993
- Intended for use with mildly & moderately impaired patients
- Limited benefit for a limited duration in a minority of patients
- High risk of adverse effects
- Rarely prescribed today

**Notes:**
Slide 20 - Cognex (tacrine)
Tacrine was the first of only four prescription drugs currently approved for treatment of AD. Although still available, tacrine is hardly ever prescribed today due to its potentially adverse effects. The Food and Drug Administration (FDA) approved tacrine largely because a 30‐week study showed that high doses improve cognition in people with mild to moderate AD, but clinical experience proved disappointing.

Tacrine has significant side effects, but the one that has caused the most concern is the possibility of liver damage. Tacrine can substantially increase levels of a liver enzyme, so doctors prescribing tacrine generally advise blood tests to assess liver function every two weeks. Tacrine has generally fallen out of favor among most physicians as newer treatments have become available, and it is no longer actively marketed by its manufacturer. 

##  Donepezil (ARICEPTTM)

- Approved for treatment of AD in 1996
- Intended for use with mildly & moderately impaired patients
- Improvement or stability in almost half of patients during clinical trials; long-term effects unknown
- Minimal adverse effects, usually at higher dose
- Dosage 5 mg or 10 mg tablet once at night

**Notes:**
Slide 21 - Aricept (donepezil)
The FDA approved the cholinesterase inhibitor Aricept, or donepezil, in 1996. This drug is better targeted than tacrine. It affects only acetylcholine in the brain, preventing its breakdown, while tacrine affects related compounds throughout the body. Donepezil's possible side effects include nausea, vomiting, and diarrhea, but it is considered safer than tacrine. In addition, donepezil is taken only once a day, whereas tacrine must be taken four times a day. Like tacrine, donepezil does not work for everyone who uses it. Clinical trials showed that a majority of persons taking donepezil showed improvement or stability in working memory over a period of several months. Although the long-term effects of the drug are not fully known, it may delay the worsening of some of the disease’s symptoms. Donepezil is manufactured by Eisai, Inc and Pfizer, Inc..

## Rivastigmine (EXELONTM)

- Approved in 2000 for treatment of mild to moderate AD
- Improvement or stability in a majority of patients during clinical trials who had highest dose
- Benefits and minimal adverse effects tied to increasing dosage

**Notes:**
Slide 22 - Exelon (rivastigmine)
Exelon, or rivastigmine, was approved by the FDA in 2000. Like donepezil, rivastigmine inhibits the breakdown of acetylcholine in the brain, which in turn may enhance memory and other brain functions. This particular drug is administered twice daily in pill form with dosages increasing according to one’s tolerance for potential side effects. Studies have shown that both the benefits and side effects of rivastigmine are associated with increasing dosages so careful monitoring is required. Side effects are mainly gastrointestinal in nature. In clinical trials, a majority of persons taking the drug at the maximum dosage showed improvement or stability in recent memory over a period of several months. Like donepezil, the long-term effects of rivastigmine are unknown but it is believed to delay the worsening of symptoms in some cases. Rivastigmine is manufactured by Novartis. 

## Galantamine (REMINYLTM)

- Approved in 2001 for treatment of mild to moderate AD
- Twice daily dosage starting at 4 mg tablets each, increasing to 8 mg at 4 weeks, then to a maximum of 12 mg after 4 more weeks
- Increasing dosage tied to greater benefit and more side effects

**Notes:**
Slide 23 - Reminyl (galantamine)
Reminyl, or galantamine, was approved by the FDA in 2001. It also comes in pill form and is available in 4 mg, 8 mg, and 12 mg tablets. The recommended dose is 16-24 mg daily. It should be taken twice daily with meals, starting with 4 mg twice daily and increasing dosage every 4 weeks if well tolerated. Increasing doses are linked to both increased benefits and increased side effects. Most common side effects are gastrointestinal in nature – nausea, vomiting, and diarrhea. Like any drug, it may interact with other medications. The drug is manufactured by Janssen.

There has not yet been a research study to show which of these “anti-dementia” drugs is superior to the rest. All of them appear to act in the same way, but each one has its own mechanism for acting upon the brain. Some people will react well to Aricept, whereas others will react well to Reminyl or Exelon. Some people choose to stop taking one drug if there appears to be no benefit and instead try another one. However, it should be noted that no improvement is observed in many cases. At best, improvement is mild, and the worsening of symptoms may be slowed a bit.

## Potential Treatments/ Prevention

- Non-steroidal anti-inflammatory drugs  (NSAIDs)
- Antioxident agents
- Estrogen
- Alternative medicine
- Others???

**Notes:**
Slide 24 - Potential Treatments/Prevention
Many other cholinesterase inhibitors are now in various stages of development. Meanwhile, several other approaches are under investigation:
—NSAIDs - Some years ago, researchers noticed that people with severe arthritis have strikingly low rates of AD. Treatment of arthritis involves large doses of medications known as non‐steroidal anti‐inflammatory drugs (NSAIDs). These drugs include such common, over‐the‐counter medications as aspirin, ibuprofen (Motrin, Advil), and naproxen (Aleve), plus many prescription drugs – but not acetaminophen (Tylenol). Meanwhile, researchers have discovered that inflammation of brain tissue may play a key role in the development of neurofibrillary tangles and beta‐amyloid plaques, the anatomical hallmarks of AD. These observations suggest that NSAIDs might treat, prevent, or delay the onset of AD. The main problem with NSAIDs is that they carry a significant risk of adverse effects. Newer drugs for treating arthritis known as COX-2 inhibitors have overcome this obstacle but their benefits in treating or preventing AD have not yet been proven.
—Antioxidents - Daily intake of 2,000 International Units vitamin E showed some slowed progression among a group of 350 persons with AD. Vitamin E is now being tested in a nationwide study to find out if it may actually delay the onset of the disease.
—Estrogen - Growing evidence suggests that estrogen‐replacement therapy for postmenopausal women may protect brain cells from AD. Again, several retrospective studies show that women who have taken estrogen seem to be at a lowered risk for AD than women who have not taken estrogen. A large study known as The Women’s Health Initiative is currently exploring this possibility in depth. Moreover, another study is examining the effects of estrogen among women who already have AD. The “Estrogen and Alzheimer’s Disease” fact sheet available through ADEAR (1-800-438-4380) is a good resource for further information. 
—Alternative medicine - Natural agents and food supplements such as ginkgo biloba have been touted as treatments for AD and related dementias but there is little scientific credence to such claims. Although these remedies have been used in Asian countries for centuries, they are just beginning to be closely scrutinized by Western medicine. The National Center for Complementary and Alternative Medicine (NCCAM) is charged with investigating such substances since they currently fall outside the jurisdiction of the FDA. NCCAM is currently sponsoring a large-scale study to determine the effect of ginkgo in decreasing the incidence of AD and related dementias. This study is due to be completed in 2003. In the meantime, caution must be exercised in using these unproven remedies. The “Ginkgo Biloba” fact sheet available through ADEAR (1-800-438-4380) is a good source of information.

At any given time, there are dozens of anti-dementia drugs in various phases of testing at research centers around the world. For a partial listing of AD drug studies currently in progress in the United States, check out the ADEAR Web site ( under the heading of “Clinical Trials.”

## Directions for Research

- Further identify risk factors & underlying biological causes
- Improve diagnostic tools
- Develop better drugs
- Improve approaches to care
- Reduce caregiver distress

**Notes:**
Slide 25 - Directions for Research
—Further identify risk factors and underlying biological causes - Until the risks factors and many causes of AD are found, means of preventing and treating it will remain difficult.
—Improve diagnostic tools for accurate and early detection - Pinpointing biological markers for AD and finding ways of detecting the disease as early as possible also have enormous implications for diagnosis and treatment.
—Develop better drugs - Better drugs for the treatment of AD include cholinesterase inhibitors as well as novel approaches to treating primary and secondary symptoms,
—Improve approaches to care of individuals with AD - Better approaches include the largely unexplored realm of psychosocial interventions that promote the well-being of persons with the disease.
—Reduce the negative effects of caregiving - Families provide the bulk of care and their role is clearly fraught with risks to their psychological, social, and financial well-being. Research is focusing on ways to reduce the negative outcomes associated with caring for a relative with AD and promoting positive means of coping.

## Care of  Persons with Alzheimer’s disease

- Create a supportive atmosphere
- Structure appropriate activities & routine
- Design “dementia friendly” environments
- Facilitate peer groups (for emotional support & shared activities)

**Notes:**
Slide 26 - Care of Persons with the Disease
In the absence of completely effective medical treatments of AD right now, much attention must be given to psychosocial approaches to caring for affected individuals. The rest of the training program will focus on meeting their needs as well as helping families in their traditional role as caregivers. Major areas of concern for persons with the disease include:
—Creating a supportive atmosphere by understanding how the person with AD perceives his or her world,
—Developing programs of structured activities that promote remaining abilities and minimize the effects of compromised abilities, 
—Designing “dementia friendly” environments that offer cues to simplify surroundings,
—Enabling persons with AD to talk about their challenges together in peer groups and giving them a voice in their own care.

## Help for Family Caregivers

- Offer education, training and consultation
- Promote respite services, e.g., adult day care, companion
- Offer individual and family counseling
- Encourage participation in support groups

**Notes:**
Slide 27 - Help for Families
Relatives of persons with AD are the main providers of their care. The challenges of caregiving over the long course of the disease are most stressful. Working with families will be discussed in more depth later in the training program. Major areas that professionals can help family caregivers include:   
—Providing family caregivers with education and training about the disease and effective approaches to care,
—Promoting the use of respite services such as adult day care and home companions,
—Providing individual and family counseling,
—Encouraging participation in support groups.