Information package from HELP (Health Education Library for People)
Om Chambers, 5th floor,
Kemps Corner,
Mumbai - 400 036
India
Tel: 91-22-368 3334
Web-site: www.healthlibrary.com
email: malpani@vsnl.com

18th March, 2002

Information compiled by Vaishali Tripathi,
Librarian, HELP
For any clarifications email: vaishali_tripathi@hotmail.com

Table of Contents

1) What You need to Know about Alzheimer’s Disease………...3

2) Diagnosis……………………………………………………………..24

3) Treatment……………………………………………………………..26

4) Leading researchers………………………………………………..29

5) Recent Advances……………………………………………………30

6) Useful online resources……………………………………………31

7) Support Groups……………………………………………………..32

8) Mailing List & Newsgroups………………………………………..33

Alzheimer's disease destroys brain cells. It causes a decline in mental function that affects:

• memory
• thinking
• language
• behavior.

The disease can occur in people in their 40s and 50s, but it most often affects those 65 and older. About 1 in every 10 people over age 65 is diagnosed with Alzheimer's disease. For every 10 years of life after age 65, the numbers double (2 out of 10 over age 75, 4 out of 10 after 85, and so on).

Dementia, a general decline in mental ability, is the most common reason people are placed in nursing facilities. Alzheimer's disease, the most common cause of dementia, affects more than 4 million people in this country.

How does it occur?

Studies show that changes in the chemistry and structures of the brain occur in people with Alzheimer's disease. These changes hinder the ability to process, store, and retrieve information. No one knows why these changes happen.

Between 5% and 10% of people with Alzheimer's disease have a family history of the illness and show signs of the disease earlier in life, before age 65. In a small number of these families, genes have been found that cause some of these so-called familial forms of the disease.

What are the symptoms?

The symptoms of Alzheimer's disease vary from person to person and change as the illness gets worse.

The first symptom is being forgetful. Almost all people begin to have some memory problems as they get older. For a person in the early stages of Alzheimer's disease, however, these problems are more obvious than in others of the same age. Forgetting people's names or the location of familiar items is common. The attention span becomes shorter. The person has a harder time concentrating. But at this stage of the disease, being forgetful still has little impact on lifestyle or work.

Over time the memory loss becomes more severe. Co-workers and friends notice the memory loss and that the person has problems dealing with written matter. He or she may misplace or lose important objects. As the disease gets worse the person can forget even major recent events and personal history. He or she cannot handle money. In general, recent memory is affected more than is long-term memory.

In later stages of Alzheimer's disease the person becomes disoriented and confused. The person can no longer recall major facts about him- or herself and others. Objects and people that once were familiar become unfamiliar. Changes in emotions and personality may occur. The person may have false beliefs (delusions) or see or hear things that aren't there (hallucinations). He or she may be anxious and often restless and active at night.

Someone with Alzheimer's disease may not see the need for care and may resist help. At first, he or she can go to the bathroom and eat without help. But in time, brain function declines and the ability to talk, move, or do any self-care is lost.

How is it diagnosed?

A definite diagnosis of Alzheimer's disease can be made only by examining brain tissue after death. However, probable Alzheimer's disease can be diagnosed with a careful medical history and physical exam.

While there is no one test to diagnose Alzheimer's disease, memory testing can be helpful. Blood work and brain scans can help show if there is a treatable cause of the decline in brain function. It is especially important to rule out major depression, a treatable condition that can cause symptoms similar to Alzheimer's disease.

How is it treated?

There is no cure. The goal of treatment is to preserve mental and physical function as much and as long as possible. The best approach seems to include control of other illnesses, a healthy diet, regular exercise, and suitable activities.

Medicine is sometimes helpful. Some doctors believe medicines such as donepezil (Aricept) and rivastigmine (Exelon) can be used early in Alzheimer's disease to slow memory loss. These drugs are costly and have side effects. Vitamin E and other medicines continue to be studied to see whether they might be helpful. None of the medicines can cure or reverse Alzheimer's disease. More often other medicines may be used to help treat anxiety, depression, or difficult behaviors.

Many people who have Alzheimer's disease are depressed, especially in the earlier stages. Most do not show sadness as much as a loss of pleasure and joy in life. When depression occurs in late stages of Alzheimer's disease, the person may be hostile or agitated and may often refuse food and drink. Depression makes brain function much worse than it otherwise would be. Treatment for depression is available and works well.

Community resources are very important. The following services may be coordinated through the doctor's office, the local county health department, or visiting nurses association:

Social workers identify and organize help, including possible financial aid.

What can be done to help prevent Alzheimer's disease?

It is difficult to prevent Alzheimer's disease until its causes are better understood. People with a family history of Alzheimer's disease should see their doctor regularly. Early diagnosis will allow them to take advantage of new treatments as they become available.

• Home health care agencies provide the services of nurses, medical social workers, and therapists. They also provide home health aides for personal care.
• Out-of-home services include adult day care centers; mental health services, including support groups for patients and family caregivers; transportation; and nursing homes.

How long will the effects last?

The brain function of a person who has Alzheimer's disease continues to get worse until he or she dies.

What can be done to help take care of a person with this disease?

While still possible, the person with Alzheimer's disease should be involved in making decisions about the care he or she will get. The fear of being abandoned and embarrassment over the loss of independence are key issues for a person with Alzheimer's disease. He or she needs to be reassured sincerely and often.

Friends and family, as well as the person with Alzheimer's disease, should join support groups as soon as possible after the disease is diagnosed. A balance must be maintained between the needs of the person with Alzheimer's disease and those of family caregivers. The caregivers will become emotionally and physically worn out if they have no help or respite.

While the person with Alzheimer's disease is still able to make legal decisions, he or she should sign a power of attorney for medical and financial matters. If desired, a living will should be made out as well. Ask the doctor for more information about these documents

What can be done to help prevent Alzheimer's disease?

It is difficult to prevent Alzheimer's disease until its causes are better understood. People with a family history of Alzheimer's disease should see their doctor regularly. Early diagnosis will allow them to take advantage of new treatments as they become available.

Caregiver Issues with Alzheimer's Disease

What is Alzheimer's Disease (AD)?

What is Alzheimer's Disease (AD)? Alzheimer's Disease (AD) is an incurable brain disease that slowly gets worse over time. It causes the most common form of dementia, a gradual loss of mental functions such as thinking, remembering, and reasoning. People with AD have symptoms ranging from mild anxiety and memory loss to agitation, violence, and being unable to talk. In the very early stages, some people with AD try to hide their problem. Others, and all who are severely affected, are unaware of their problem. These behaviors can pose a risk of physical harm to the person with Alzheimer's disease and to others. People with AD may not like to be around other people. Other people may shun those with AD because of their strange behavior. People with AD often have sleep problems. They may sleep more during the day and less during the night. This is very hard for caregivers because it often results in caregiver exhaustion from stress and lack of sleep. What should I do as a caregiver for someone with AD? Caring for someone with AD calls for extra patience and understanding. Try to simplify the routine and surroundings. Minimize the situations that cause the most stress and unusual behaviors. Although safety is important, encourage independence of the person as much as possible. Some ideas are: Reduce stress by keeping routines and the environment as much the same as possible. Do only those things for the person that he or she can no longer do. The person with AD may be able to do part of a task. Let the person do whatever he or she is able to do successfully. Do not tease or argue with the person. Do not let the person get overly tired. Try to limit the number of new people that are around at any one time. New people increase stress for some of those with AD. Watch for situations that may cause unwanted behavior. For example, crowds and noise may increase anxiety. Give choices, but limit the number of choices to two. Too many choices can be difficult for someone with AD to handle. Choices can sometimes help to channel behavior. If your care receiver resists cleaning up, you may ask, "Do you want to wipe your chin or shall I?" instead of asking, "Can I wipe your chin?" Celebrate what the person can do well; don't focus on what he or she can't do. Don't remind the person of what he or she used to do. Don't try to get the person to act like he or she used to act. Make time for fun and togetherness in the present time, even if the person forgets quickly. When the person with AD can't keep from behaving badly or is having trouble with self-control, divert the person to something else. For example, say, "Let's do this now, over here," rather than trying to tell the person why he or she shouldn't do something. Listen to what the person with AD is saying. Try to understand the feeling behind the person's words. Don't argue with the content of the person's thought. Agree with the feeling. For example, don't tell the person that his or her mother isont-size: 7.0pt"> Try to understand the person's past experiences and habits. Make current routines as much like the past as possible. How should I respond to a problem behavior? Remember that the behavior is a symptom of the disease and not directed toward you or others. Who is the behavior is affecting? Is the behavior really a problem or not? For example, a person talking constantly to an imaginary person without bothering other people does not have a problem behavior. However, a person arguing with another resident or a family member and using foul language does have a problem behavior. Change the way you respond, rather than trying to change the person's behavior. The person with AD is not aware that his or her behavior is inappropriate. The way you respond can have a calming effect or make the situation worse. Do not argue or explain what is happening. Divert the person's attention and offer reassurance. Change any routines that may have started the behavior. Schedule events to be at the best time of the day for the person. Provide frequent breaks from stressful activities, provide snacks, or return to a nonstressful familiar activity. Make changes in the surroundings if possible to prevent the behavior from happening. For example, a person who wanders may need several types of locks installed on doors or a bolt put up high where one ordinarily wouldn't be. For a person who rummages through drawers, provide a specific place (like a drawer, dresser, or closet) for items that he or she can rummage through. When at the doctor, don't expect or encourage a medicine for every health or behavior problem. Expect and encourage your doctor to minimize medications. Especially avoid medicines such as antihistimines, some antispasmodics, some antidepressants, certain pills for incontinence of urine, and others. Also, try to minimize tranquilizers and sleeping pills, especially long-term use. Generally, the problem behaviors caused by AD cannot be magically handled with medication. Medication can make the problems worse. In some situations, however, it may be necessary and beneficial to use medication. What help is available in my community? Ask your doctor about agencies in the community that provide assistance for caregivers. The local Department of Social Services, along with home health care agencies, provide sources of information for caregivers. You also can get help through community agencies such as Retired Senior Volunteers Program (R.S.V.P.), or senior centers. A variety of services may be available such as: homemakers home health aides companions licensed nurses social workers therapists respite care adult day care centers transportation services grocery shopping services chore services support groups. Many churches offer respite programs or other elder care assistance. Many others would do so if asked. Occasionally, other older adults can be organized to "bank" volunteer hours and then draw on those hours someday when they need the help. Churches and civic organizations in your area may be willing to start and coordinate these programs if requested. Respite care programs provide a break to families who care for people with AD at home. Services can vary from a few hours to several weeks. Brief stays in nursing homes can also be arranged. Adult day care programs offer care during daytime hours. This provides respite for the caregiver and different surroundings for the person with AD. Many communities offer assisted living or personal board and care homes with secured units for persons with AD. These facilities provide homelike, nonstress environments for small numbers of persons with AD. Consult your local Area Agency on Aging or the Alzheimer's Association for information.

Alzheimer's Disease (AD) is an incurable brain disease that slowly gets worse over time. It causes the most common form of dementia, a gradual loss of mental functions such as thinking, remembering, and reasoning.

People with AD have symptoms ranging from mild anxiety and memory loss to agitation, violence, and being unable to talk. In the very early stages, some people with AD try to hide their problem. Others, and all who are severely affected, are unaware of their problem. These behaviors can pose a risk of physical harm to the person with Alzheimer's disease and to others. People with AD may not like to be around other people. Other people may shun those with AD because of their strange behavior.

People with AD often have sleep problems. They may sleep more during the day and less during the night. This is very hard for caregivers because it often results in caregiver exhaustion from stress and lack of sleep.

What should I do as a caregiver for someone with AD?

Caring for someone with AD calls for extra patience and understanding. Try to simplify the routine and surroundings. Minimize the situations that cause the most stress and unusual behaviors. Although safety is important, encourage independence of the person as much as possible. Some ideas are:

• Reduce stress by keeping routines and the environment as much the same as possible.
• Do only those things for the person that he or she can no longer do. The person with AD may be able to do part of a task. Let the person do whatever he or she is able to do successfully.
• Do not tease or argue with the person.
• Do not let the person get overly tired.
• Try to limit the number of new people that are around at any one time. New people increase stress for some of those with AD.
• Watch for situations that may cause unwanted behavior. For example, crowds and noise may increase anxiety.
• Give choices, but limit the number of choices to two. Too many choices can be difficult for someone with AD to handle. Choices can sometimes help to channel behavior. If your care receiver resists cleaning up, you may ask, "Do you want to wipe your chin or shall I?" instead of asking, "Can I wipe your chin?"
• Celebrate what the person can do well; don't focus on what he or she can't do. Don't remind the person of what he or she used to do. Don't try to get the person to act like he or she used to act. Make time for fun and togetherness in the present time, even if the person forgets quickly.
• When the person with AD can't keep from behaving badly or is having trouble with self-control, divert the person to something else. For example, say, "Let's do this now, over here," rather than trying to tell the person why he or she shouldn't do something.
• Listen to what the person with AD is saying. Try to understand the feeling behind the person's words. Don't argue with the content of the person's thought. Agree with the feeling. For example, don't tell the person that his or her mother isont-size: 7.0pt"> Try to understand the person's past experiences and habits. Make current routines as much like the past as possible.

How should I respond to a problem behavior?

Remember that the behavior is a symptom of the disease and not directed toward you or others.

Who is the behavior is affecting? Is the behavior really a problem or not? For example, a person talking constantly to an imaginary person without bothering other people does not have a problem behavior. However, a person arguing with another resident or a family member and using foul language does have a problem behavior.

Change the way you respond, rather than trying to change the person's behavior. The person with AD is not aware that his or her behavior is inappropriate. The way you respond can have a calming effect or make the situation worse. Do not argue or explain what is happening. Divert the person's attention and offer reassurance.

Change any routines that may have started the behavior. Schedule events to be at the best time of the day for the person. Provide frequent breaks from stressful activities, provide snacks, or return to a nonstressful familiar activity.

Make changes in the surroundings if possible to prevent the behavior from happening. For example, a person who wanders may need several types of locks installed on doors or a bolt put up high where one ordinarily wouldn't be. For a person who rummages through drawers, provide a specific place (like a drawer, dresser, or closet) for items that he or she can rummage through.

When at the doctor, don't expect or encourage a medicine for every health or behavior problem. Expect and encourage your doctor to minimize medications. Especially avoid medicines such as antihistimines, some antispasmodics, some antidepressants, certain pills for incontinence of urine, and others. Also, try to minimize tranquilizers and sleeping pills, especially long-term use. Generally, the problem behaviors caused by AD cannot be magically handled with medication. Medication can make the problems worse. In some situations, however, it may be necessary and beneficial to use medication.

What help is available in my community?

Ask your doctor about agencies in the community that provide assistance for caregivers. The local Department of Social Services, along with home health care agencies, provide sources of information for caregivers. You also can get help through community agencies such as Retired Senior Volunteers Program (R.S.V.P.), or senior centers. A variety of services may be available such as:

• homemakers
• home health aides
• companions
• licensed nurses
• social workers
• therapists
• respite care
• adult day care centers
• transportation services
• grocery shopping services
• chore services
• support groups.

Many churches offer respite programs or other elder care assistance. Many others would do so if asked. Occasionally, other older adults can be organized to "bank" volunteer hours and then draw on those hours someday when they need the help. Churches and civic organizations in your area may be willing to start and coordinate these programs if requested.

Respite care programs provide a break to families who care for people with AD at home. Services can vary from a few hours to several weeks. Brief stays in nursing homes can also be arranged. Adult day care programs offer care during daytime hours. This provides respite for the caregiver and different surroundings for the person with AD. Many communities offer assisted living or personal board and care homes with secured units for persons with AD. These facilities provide homelike, nonstress environments for small numbers of persons with AD. Consult your local Area Agency on Aging or the Alzheimer's Association for information.

What can I do to take care of myself?

Caring for a person with AD doesn't have to be a lonely experience, although it's common to feel that no one else understands what you are going through. Family support groups offer the chance to share feelings with others who are in similar situations. A support group is made up of caregivers, family members, and friends of those with AD or other dementia. Your local AD organization can help you join or start a support group in your community.

As a caregiver, you need help and support as behavior and care needs change in the person with AD. It's easy to feel alone because of the demands made upon you for care and attention. Support groups can help by giving you a chance to meet others who have similar experiences. Meetings provide information but are also social events for you. The Alzheimer's Association supports these groups by providing information and referrals.

Topics discussed in support groups usually focus on feelings about caregiving, ideas to help you, and open discussions about a variety of issues pertaining to AD. Caregivers feel more in control of their lives when they understand more about the disease and learn from others in the group. The shared experiences and the encouragement given and received are important functions of a support group. Explore your community's available resources, such as adult day care or respite care. Remember, it is as important to care for yourself as it is to care for the person with AD.

Source: www.mdconsult.com

Diet

Fats and Oils. Some population studies have reported an association between low-fat diets and a lower incidence in Alzheimer's. For example, in China and Nigeria, where fat intake is low, the risk of developing Alzheimer's is 1% at age of 65 compared to 5% in the US. Conversely, a study in the Netherlands reported an association between dementia and diets high in total fat, saturated fat, and cholesterol. A high-fat diet in people who carry the ApoE4 gene may confer a particularly high risk. In one 2000 study of Americans between the ages of 40 and 50, those who carried the ApoE4 gene and whose diet consisted of 40% fat calories had 29 times the risk for Alzheimer's compared to non-ApoE4 carriers on the same high-fat diet. Some dietary tips concerning fat intake are as follows:

• Saturated fats (found in animal products) and trans-fatty acids (found in fast foods and commercial baked goods) should be avoided.
• Some fats, however, such as omega-3 fatty acids, which are found in fish such as salmon, halibut, swordfish, and tuna, are essential for the development of the nervous system. These fatty acids also may help protect against mental decline in old age.
• The recommended dietary goal is to limit total fat intake to 30% or fewer calories from fat.
• Antioxidant-Rich Supplements and Foods. Much research on Alzheimer's disease has indicated that oxidation (release of damaging unstable particles) may play an important role in the disease process. Some reports have suggested, then, that dietary antioxidants, such as vitamins C and E, selenium and other food chemicals, may be protective against mental decline.
• Vitamin E and vitamin C are important antioxidants, but studies have not provided any evidence that they can prevent Alzheimer's. In one study, a combination of these supplements was associated with a lower risk for dementia in older people (although not of Alzheimer's itself).
• According to several studies, eating plenty of darkly colored fruits and vegetables may slow brain aging. Of interest was a 1999 study on animals, in which extracts taken from blueberries and strawberries actually reversed age-related decline in brain function. Blueberries were the most effective. Dark-colored fruits and vegetables are recommended in any case for good health.
• Some studies on wine have reported a lower risk but they have not been consistent. One suggested that wine may have some protective properties for noncarriers of ApoE4 but actually increase the risk for carriers of the gene.
• Soy has estrogen-like properties and might be protective. Of some concern, however, was a study reporting greater decline in mental function among older people who had a high intake of soy. Some experts suggest that the plant estrogens in soy may interfere with natural protective estrogens in the brain. This was one small study, however, and more are needed to confirm these results.)
• Calorie Restriction. Caloric intake itself may play a role in brain health. In one study on animals, restricting calories below normal (but above starvation levels) helped prevent age-related nerve degeneration. It should be pointed out, however, that in patients with existing Alzheimer's, weight loss is a strong indicator of mental decline. Educational Levels and Alzheimer'sA number of studies have reported a higher risk for Alzheimer's disease in people with less education and a lower risk for dementia and Alzheimer's in those who remain mentally active. Concluding that education helps protect against Alzheimer's, however is under debate.

Source: Knowledge Base of www.healthwise.org/hworg

Medical Details

New approaches to diagnose and treat Alzheimer's disease
A glimpse of the future

Douglas Galasko, MD
Clinics in Geriatric Medicine
Volume 17 • Number 2 • May 2001

From the Department of Neurosciences, University of California, San Diego, California

The endeavor to develop effective treatment of Alzheimer's disease (AD) has gained momentum in the past few years. There is now a solid enough foundation of basic science and clinical knowledge about AD to select rational targets and approaches. As some of these advances begin to cross over into the clinical arena, new ways of screening for dementia and diagnosing and tracking the progression of AD are evolving. As reviewed elsewhere in this issue, current symptomatic treatment of AD by augmenting cholinergic function stemmed from the findings that there was a pronounced deficit of markers of acetylcholine in the brain in AD, and that this neurotransmitter played an important role in attention and memory. Emerging and future treatment is based on a richer understanding of biochemical and pathologic processes in AD, and data from clinical and epidemiologic studies. A key challenge is to try to slow progression or delay the onset of AD by interfering with important steps in biochemical pathways in the brain in AD. Meeting this challenge takes us into uncharted territories, because there is no existing paradigm to slow or reverse any of the major neurodegenerative disorders of adults. The challenge of developing promising new forms of treatment is linked to the clinical problems of deciding how and when to intervene to accomplish these treatment goals, and how to measure outcomes of treatment. This article reviews some of the opportunities that have emerged from research advances, and predicts which areas are likely to mature to a stage of testing of treatment in clinical trials.

Identifying Targets for Treatment

The defining lesions in the brain in AD are the extracellular deposition of amyloid in the form of plaques, and neurofibrillary degeneration within neurons, forming tangles. Decreased density of synaptic contacts between neurons also is widespread. Consequences of this pathology are dysfunction and eventual loss of neurons and synapses, and weakening of many neurotransmitter pathways. Replacement or augmentation of specific neurotransmitters is likely to provide temporary benefit, but does not effectively counter the ongoing widespread degeneration as dementia progresses. More fundamental treatment approaches are necessary to interfere with mechanisms that lead to progressive damage to neurons.

Neurodegeneration in AD is thought to be the product of a cascade of events, in which initiating or upstream factors trigger a succession of downstream factors or pathways, culminating in irreversible damage to neurons. In AD, the beta-amyloid protein (Abeta) may act as an initiating or proximal factor, by aggregating, forming fibrils, or being deposited in plaques in an insoluble amyloid conformation. Damage to neurons may result from several mechanisms, such as inflammation, oxidative damage, or overactive excitatory neurotransmission, which may be considered as downstream or propagating factors. It may be most valuable to cast the net as widely as possible in developing treatment strategies, and consider upstream and downstream steps in the cascade as worthwhile targets. It is possible that efforts to treat propagating mechanisms may only be partially successful if the initiating factors remain unchallenged. If initiating factors in AD can be clearly identified, then targeting treatment toward them may be the most robust approach. To achieve the full benefits of treatment, a multipronged approach, combining treatment of upstream and downstream factors, may ultimately be needed.

The Amyloid Hypothesis of Alzheimer's Disease

Many clues incriminate Abeta as an important marker and possible initiating factor in AD. Abeta is a protein of 38 to 43 amino acids, and is derived from the larger amyloid precursor protein (APP) by a series of proteolytic cleavage events. Amyloid deposition in the brain in senile and neuritic plaques is a pathologic hallmark of AD, regardless of age of onset or whether the AD is caused by autosomal dominant inheritance or is sporadic. Genetic evidence strongly implicates Abeta. In familial AD with onset before age 55 and an autosomal dominant pattern of inheritance, three causative genes (Table 1) have been identified: APP on chromosome 21, presenilin 1 on chromosome 14, and presenilin 2 on chromosome 1.

Gene	Mutations	Age at Onset
APP	At least eight different sites of pathogenic mutations, in or near the Abeta region	40-60
	All lead to AA substitutions
	Some are associated with amyloid
	Trisomy 21 (Down syndrome) includes an extra copy of the APP gene
PS-1	Over 40 sites of mutations	25-60
	Most lead to AA substitutions
	Two exon deletion and two truncation mutations have been reported
PS-2	Two sites of mutations	45-65
	AA substitutions
apo E	e4 allele increases risk of late-onset AD	>60
APP = amyloid precursor protein; PS = presenilin; APO = apolipoprotein; AA = amino acid.

Remarkably, pathogenic mutations in all of these genes influence the formation of Abeta, in cellular and animal models, in fibroblasts grown from skin biopsies of patients, and as measured in plasma from patients with familial AD. The changes in Abeta production lead to increases in the relative or absolute amounts of longer forms of Abeta that have an increased propensity to aggregate into polymers, seed plaques, or produce neuronal damage. Mutations have been identified in at least eight locations in the APP gene, resulting in single (or in one case double) amino-acid substitutions. Every mutation in APP that is linked to AD is located within or flanks the Abeta peptide sequence that is embedded in APP. In Down syndrome, there is trisomy of chromosome 21, with an extra copy of DNA that includes the APP gene. Patients with Down syndrome have increased levels of Abeta and invariably develop plaques and tangles in their brains, with clinical dementia in many cases. Importantly, the pathologic changes exhibited by the brain in familial forms of AD and Down syndrome seem identical to those seen in late-onset sporadic AD.

Genes are being sought that modify the risk of apparently sporadic later-onset AD. The first of these susceptibility genes to be identified codes for apolipoprotein E (apo E), a lipoprotein with roles in cholesterol transport in the brain. There are three main variants, or allelic polymorphisms of apo E, called e2, e3, and e4. The e4 allele is over-represented in AD compared with elderly nondemented individuals and seems to promote AD by lowering the age at onset relative to the e3 or e2 alleles. Although the mechanism whereby apo E e4 promotes AD is unclear, one possibility is that apo E binds to Abeta and may influence its clearance. Apo E e2, e3, and e4 bind to differing degrees to Abeta, and may influence the extent of deposition of amyloid in the brain and the extent of neuritic plaque formation, which further strengthens the case for Abeta in AD.

The amyloid hypothesis contends that increased levels of Abeta are a key upstream factor in the pathogenesis of AD and lead to neurodegeneration. Many of the specific details of this pathway are controversial. For example, it is thought that Abeta needs to aggregate to initiate a pathway that results in cellular toxicity. The nature of the aggregates that are the culprits is not well understood. There is evidence that soluble Abeta is not toxic at physiologic concentrations, whereas oligomers (loose clumps of several Abeta molecules), small fibrils, or larger filaments may be toxic to neurons in model systems. There is evidence for many structural forms of Abeta in the brain in AD, and it is possible that some polymeric forms of Abeta may be inert. Another area of debate is whether intracellular or extracellular aggregates of Abeta are the villains. If Abeta first aggregates intracellularly, then decreasing the biosynthesis (or production) of this molecule may be essential. If extracellular Abeta is the critical component, then decreasing production, increasing elimination (also referred to as clearance), or decreasing aggregation could be effective forms of intervention. There are further possible scenarios involving extracellular Abeta. Correlations between diffuse or amorphous deposits of Abeta and measures of clinical dementia are relatively weak, whereas the presence of neuritic plaques, which are surrounded by degeneration processes of neurons, correlates more strongly. It is possible that maturation of plaques is required before they result in damage by neuritic degeneration. This maturation process may involve interactions with other molecules.

Tools to Probe the Amyloid Hypothesis: Mice and Enzymes

An important spin-off of identifying genes responsible for early onset AD has been the development of transgenic animal models that mimic the pathology of AD. Inserting the genes for mutant APP or mutant PS-1 into mice provides a model of how these genes affect aspects of AD pathology. Overexpression of mutant human APP turned out to be a critical step in modeling amyloid deposition. Mice that overexpress mutations in human APP have increased levels of Abeta in their brains and develop amyloid deposition into plaques as they age. These plaques are widespread but prominently affect the hippocampus followed by the neocortex. Mice that express mutant human PS have increased levels of Abeta in the brains without developing plaques. By crossing APP and PS transgenic mice, the resulting double mutants develop plaques over an accelerated time course. Although these mice are useful models of amyloid deposition, they have some limitations. They do not develop tangles, and have usually failed to show neuron loss (although some lines of mice may develop mild neuron loss). Measures of synaptic density may be decreased in APP transgenic mice even in the absence of Abeta deposition in plaques, which again raises questions about which form or pool of Abeta may be important in AD. Nonetheless, transgenic mice are excellent tools to evaluate whether treatment approaches can alter levels of Abeta and its deposition in the brain. Some strains of these transgenic mice show deficits in learning, allowing the effects of treatment on improving or preventing these deficits to be tested.

To determine whether interventions influence amyloid formation in AD, two further pieces of information are critical: (1) defining how Abeta is cut from APP within neurons, and (2) developing sensitive methods to measure the resulting forms of Abeta and cleaved APP. The cleavage of Abeta from APP is turning out to be a complicated sequence of events

Abeta is cut from APP at its first amino acid (Abeta1, or the amino- or N-terminal) by an enzyme called beta-secretase, that has recently been identified and named beta amyloid cleaving enzyme. This cut occurs intracellularly while APP is in the Golgi network. Biochemical sequencing of Abeta from amyloid deposits in AD and in cellular model systems showed that there were several different forms of Abeta that varied in length. Most of the Abeta peptide in cellular systems ends at amino acid 40, termed Abeta40. A minor fraction of Abeta is slightly longer, resulting from a cut at different sites within APP when Abeta is cleaved out, and most of this longer form ends at amino acid 42, termed Abeta42. These varying forms of Abeta that differ at the distal, or carboxy end (C-terminus), are produced by the action of another enzyme, called gamma-secretase. The gamma-secretase cleavage also occurs within cells in an endoplasmic reticulum compartment. gamma-Secretase has not yet been completely identified and characterized, and there may be multiple enzymes with this activity. Interestingly, much recent evidence points to PS as being either a gamma-secretase itself or part of a group of proteins that is complexed together to accomplish this cleavage. PS contains two aspartate amino acids aligned in positions where they could form key sites of a protease that cuts other proteins in or close to a cellular membrane. In cultured cells from transgenic mice in which PS-1 has been inactivated (knocked out), levels of secreted Abeta are markedly reduced, and if both PS1 and PS2 are knocked out, Abeta release from cells is undetectable. Mutations that remove the two key aspartate amino acids in PS-1 markedly decrease Abeta secretion. Other experiments have suggested that presenilins may not be the final molecular scissors that cuts Abeta, but may control the trafficking of APP fragments to the gamma-secretase. Very recently, a protein that binds to PS has been identified and named nicastrin. This protein seems to interact with PS to enable the processing of APP fragments that result from cleavage by beta-secretase into Abeta. It seems likely that PS, nicastrin, and possibly additional proteins form a complex with gamma-secretase activity that carries out the intramembranous cleavage of APP.

Secretase Inhibitors

By developing compounds that inhibit the beta or gamma-secretases, it may be possible to decrease Abeta production within cells, which would allow the amyloid hypothesis to be tested. Several important assumptions are critical to using secretase inhibitors to treat AD. First, the inhibitors must be able to penetrate into the central nervous system and selectively inhibit beta- or gamma-secretase without affecting other proteases. In addition to crossing from blood into the brain, the inhibitors need to penetrate deep into cells to reach the location of the secretases, which may require much effort in drug design. Second, it is not known whether these secretases have important functions beyond cutting Abeta from APP; blocking other important cellular pathways could have unintended adverse effects. Protease inhibitors that act against secretases could also inhibit other proteases and lead to unanticipated side effects. To date, several compounds with activity against gamma-secretase have been developed, some of which are undergoing preliminary testing in humans. Purification of the secretases or secretase complex so that they can be worked with in isolation has proved difficult, but is an important step to allow the development of highly tailored enzyme inhibitors.

Yet another protease, called alpha-secretase, cuts APP at the cell surface in the middle of the Abeta sequence (see Fig. 1). This alpha-cleavage precludes the formation of full-length Abeta. An alternative strategy to decrease the production of Abeta may be to increase alpha-secretase activity. There may be several different enzymes capable of accomplishing alpha-secretase cleavage, which may occur at the surface of cells and within cellular membranes of the trans-

Golgi network. Within the trans-Golgi, the extent of alpha-secretase activity seems to be under regulatory control, and a pool of APP may compete for alpha- and beta-secretase cleavage. The strongest candidate for the regulated alpha-secretase is tumor necrosis factor-alpha converting enzyme. It may be possible to develop medications that shift the balance to favor APP cleavage by the alpha-rather than the beta-secretase, with the net effect of decreasing Abeta production. In model systems, some acetylcholinesterase inhibitors enhance beta-secretase activity, and it is possible that these medications have indirect neuroprotective effects on AD.

To identify secretases and study how Abeta is produced and may be modulated, sensitive measurement techniques have been developed. It is possible to quantify Abeta, and specifically to measure the concentration of the different forms of Abeta. Assays are capable of detecting low levels of Abeta40 or Abeta42 specifically. Through the use of these assays, levels of Abeta have been measured in cellular and animal systems, in the brain in AD, and in plasma and cerebrospinal fluid in humans. These assays now make it feasible to monitor the effects of manipulations aimed at decreasing amyloid. As is discussed, these types of measurements may be applied to making the diagnosis of AD or to following the effects of treatment.

Immunization Against Amyloid

Another approach to lowering levels of Abeta in the brain is to enhance its removal, or clearance. There are several enzymes within and outside cells that are capable of breaking down Abeta, and cells, such as microglia, can clear extracellular Abeta. These various mechanisms of removal of Abeta are complex and their relative contributions are incompletely understood. Nevertheless, a remarkable recent series of experiments using APP transgenic mice has stimulated much interest in Abeta clearance. Mice were immunized with Abeta and developed high titers of antibodies against Abeta. Control groups included mice that were not immunized, and mice immunized with a different peptide. When immunization with Abeta was started in young mice and continued on a regular basis, there was a dramatic decrease in Abeta levels in the brain and in the formation of amyloid plaques. If immunization was started in adult mice, when amyloid deposition into plaques has already occurred, the outcome compared with control animals was prevention of further plaque development and possibly diminution of the number or size of existing plaques. These effects were not simply nonspecific by-products of immunization: mice immunized with amyloid A, a peptide capable of binding to amyloid deposits, developed a strong antibody titer but still developed extensive Abeta amyloid deposits in the brain. The mechanism whereby these immunization experiments attenuated amyloid is presumably related to the antibodies against Abeta. These are capable of crossing the blood-brain barrier to some extent, and bind to extracellular Abeta. They then seem to enhance the clearance of a pool of Abeta, most likely by cells, such as microglia, as shown in further studies in which passive immunization using antibodies against Abeta was also effective at enhancing clearance of Abeta. It is not clear whether a strategy of active or passive immunization will be successful in humans with AD. Nevertheless the initial results in mice were dramatic, and immunization with Abeta seems to be safe in mice and other animals, so that early human clinical testing has begun.

Many further approaches to increase Abeta clearance or block the aggregation of Abeta are also under study. Several compounds have been shown to decrease Abeta aggregation, although none is yet ready for use in clinical trials. The amyloid hypothesis of AD is going to receive comprehensive testing in the near future.

Other Treatment Approaches to Alzheimer's Disease

A strong case can be made for Abeta as being causally related to AD. Many other mechanisms have been implicated in AD. It is possible that these are downstream of Abeta or act as propagating factors in the amyloid cascade. Alternatively, Abeta could be a marker that is closely linked to as yet unidentified pathways that cause neuronal dysfunction in AD without being directly causative. In either event, it may be fruitful to explore these other mechanisms as treatment opportunities. Evidence for these treatment targets stems from diverse sources, including epidemiologic studies in AD, analyses of brains of AD patients, and studies into pathways of neurodegeneration. A few of these pathways are highlighted because they provide targets that may be tested as treatment for AD very shortly. Novel approaches to treating AD include the following:

• Decreasing Abeta production
• beta-secretase inhibition
• gamma-secretase inhibition
• Increasing alpha-secretase cleavage of APP
• Increasing clearance of Abeta
• Immunization
• Treatment with antibodies against Abeta
• Decreasing aggregation of Abeta
• Decreasing oxidation
• Decreasing inflammation (NSAIDs)
• Altering tau phosphorylation
• Blocking apoptosis

Gene therapy

Neural prAbeta leads to cellular damage only after deposits of amyloid have triggered inflammation. Several clinical and epidemiologic studies have found that patients with AD had lower levels of use of certain types of anti-inflammatory medications than age-matched controls. These associations have most strongly implicated nonsteroidal anti-inflammatory drugs (NSAIDs) as potentially protecting against AD. NSAIDs are relatively nonselective in their effects on inhibiting various enzymes important in producing inflammatory mediators. Nonselectivity also correlates with gastrointestinal side effects of these drugs. More selective anti-inflammatory agents have recently been developed that inhibit the enzyme cyclooxygenase 2. Such medications are free of gastrointestinal side effects and have been shown to be highly potent in the treatment of such conditions as arthritis. In an APP transgenic mouse model of Abeta deposition, administration of NSAIDs resulted in a decrease in amyloid deposition. A controlled clinical trial of prednisone, a more potent anti-inflammatory agent than NSAIDs, failed to show slowing of clinical progression of AD. Cyclooxygenase 2 inhibitors and NSAIDs are now entering clinical trials for AD.

Oxidative Damage

In aging and a host of neurodegenerative diseases, including AD, there is much evidence for oxidative damage. Markers of oxidation are readily found in plaques, tangles, DNA, proteins, and lipids in the brain in AD. Epidemiologic studies suggest that use of antioxidants, such as vitamin E and vitamin C, may protect elderly individuals from developing AD. A placebo-controlled clinical trial of vitamin E (at a high dose of 2000 IU/d), selegiline (an inhibitor of the enzyme monoamine oxidase B), or both, in patients with moderately severe AD found that treatment with either vitamin E or selegiline delayed the time to reach key clinical milestones, such as death, institutionalization, or loss of basic activities of daily living. Treatment did not alter the rate of cognitive decline, but the level of cognitive impairment at entry reduced the chances of finding this type of effect. Further studies of vitamin E and other antioxidants are needed, with treatment initiated at different stages of AD. Different antioxidants gain access to specific cellular compartments, for example lipid-rich membranes, mitochondria, or the cytosol, and may vary in the types of oxidative stress that they combat. Combinations of antioxidants may be better than single agents, and will be explored in future treatment trials in AD.

Estrogen Deficiency in Women

Among groups of elderly people, AD seems to be more common in women than in men, even after taking into account the greater life expectancy of women. This increased risk may be caused by chronic effects on the brain of estrogen deficiency after menopause. Neurons in the brain have receptors for estrogen, and changes in synaptic structure and brain function have been shown in experimental animals after estrogen depletion. Several epidemiologic studies have found that women who take estrogen supplements seem to have a lower risk of AD than those who do not. Short-term studies suggest that estrogen treatment in postmenopausal women leads to improvement of mood and performance on several types of cognitive tests. One placebo-controlled clinical trial has examined the use of estrogen treatment for 12 months in postmenopausal women with AD who had undergone hysterectomy. In this study, groups of patients receiving estrogen treatment or placebo did not differ significantly in cognitive test performance. Similar negative findings came from single-center studies. There does not seem to be a beneficial effect of estrogen in treating established AD. It remains an open question whether estrogen replacement can prevent or delay the onset of AD if started earlier. Long-term studies are under way to examine whether estrogen replacement has protective effects against AD.

Neurofibrillary Tangles

Tangles are aggregates of proteins, comprising mainly the tau protein. In AD, tau forms insoluble filaments, usually paired helical filaments that coalesce into larger structures that can occupy much of the cell body of neurons. Tau is normally quite soluble and the cellular events that result in filament formation are not well understood. A key normal function of tau is to promote the bundling of neurofilaments in axonal processes of neurons. The extent to which tau promotes this activity depends on the degree of phosphate incorporated into tau. As a result of cellular signaling, a variety of kinase enzymes regulate tau phosphorylation, whereas several phosphatases control the removal of phosphate. In paired helical filaments, tau is highly phosphorylated. If the phosphorylation precedes tangle formation and results from aberrant cellular signaling, then it may be possible to alter the balance and decrease the risk of paired helical filaments formation. Lithium, used in the treatment of bipolar depression, activates signaling pathways that lead to a net removal of phosphate from tau and can protect cultured neurons from toxicity caused by Abeta. Although lithium may be impractical for treating patients with AD, novel drugs with similar actions could be developed. Alternatively, if other factors within neurons are necessary to seed tau into filaments, then these could become targets for treatment.

Apoliprotein E

As discussed previously, apo E is a lipoprotein that is genetically associated with AD. It is not certain how the e4 version of apo E promotes AD. Relative to apo E e3, e4 shows different properties, for example altered binding to Abeta, which may result in decreased clearance, different affinity of binding to tau, reduced antioxidant capacity, and altered transport of cholesterol and lipids needed for neuronal membrane remodeling. It is possible that altering levels of apo E, cholesterol, or lipids in the brain may have beneficial effects in AD.

Protecting Neurons from Death

In many circumstances, cell death is an active process that follows a program of cellular events, and requires the activation of enzymes (called caspases) that break down DNA and proteins. In neurodegenerative disorders, such as AD, activation of this cellular program may be responsible for neuronal death. Much evidence implicates caspases in neuronal death in AD. Inhibitors of some of the key enzymes and activators of cell death have been developed and confer neuroprotection in cell or animal models of neuron loss.

Replacing Neurons: Stem Cells

The long-held idea that neurons in the adult human brain do not divide has now been overthrown. In some brain areas, neuronal precursor cells have been discovered. They are capable of division and of being grown in culture, and have the potential of being grafted into damaged brain, where they may be induced to mature and extend connections to adjacent neurons. The feasibility of neuron grafting in general is currently being explored in animal models.

Combinations of Treatment in Alzheimer's Disease

Many of the targets described previously are not mutually exclusive. By analogy with cancer treatment, where combination therapy using several drugs, or drugs plus irradiation, has led to some successes, optimizing the treatment of AD to slow the progression of disease may require combining different treatment modalities. For example, in addition to lowering amyloid production or its aggregation, also strengthening antioxidant mechanisms and decreasing inflammatory responses may achieve the best results.

When to Initiate Disease-Modifying Treatment for Alzheimer's Disease

The progression of AD is marked by a spreading burden of pathologic changes. It is not clear whether all of these are irreversible. Loss of neurons leading to atrophy of key hippocampal, temporal, and cortical areas in the brain is presumably irreversible. The accumulation of highly insoluble tangles within neurons most likely profoundly impairs neuron function. As with any disease process, it makes sense to initiate treatment as early as possible. Some neuropathology studies suggest that the hallmark lesions of AD, plaques and tangles, can be found in the brains of people in their 50s, and most likely antedate the earliest symptoms of dementia by 15 years or more. If this is the case, then treatment may need to be initiated among people in their 50s or earlier to have the full impact.

More detailed recent studies have measured the burden of pathologic change in brains of individuals who were carefully clinically characterized shortly before death. In these studies, people who were not demented show minimal loss of neurons in vulnerable areas, such as the hippocampus over an age range spanning 50 to 80. Low counts of neurofibrillary tangles and a small degree of amyloid deposition are evident. Once very mild dementia begins, the pathologic picture changes. Neurons are lost in certain layers within the hippocampus. Amyloid deposition becomes more apparent and is associated with higher numbers of tangles. It is possible that steps associated with amyloid deposition accelerate the formation of tangles. There are several implications of these studies. First, there is neuronal loss even at this early stage of AD, when symptoms relate mainly to memory impairment. If we were to arrest the progression of AD completely at this stage, it is possible that the neuron loss would remain irreversible and memory loss would persist. So, as a general principle, if an effective treatment for AD exists, it needs to be initiated as early as possible. Second, it may be possible to intervene closer to the time of acceleration of pathology, if we can predict when someone is approaching a vulnerable age. If we cannot make predictions about the extent of risk of AD among asymptomatic elderly individuals, then we are obliged to treat a large number of individuals for many years to prevent AD--a shotgun approach.

Early Diagnosis

Much attention is being focused on diagnosing AD at a very early symptomatic stage. Psychometric test methods that probe memory acquisition, and tests of complex reasoning and problem solving are effective at detecting early abnormalities, as reviewed by Salmon elsewhere in this issue. Systematic interview of a knowledgeable informant may also be very sensitive in detecting significant decline. Screening for early cognitive decline requires use of sensitive instruments and rating questionnaires by primary practitioners, and education of the general public about the importance of early identification of dementia.

Mild Cognitive Impairment

The clinical diagnosis of AD requires lengthy evaluation of patients and integrating supportive information with the exclusion of other causes of dementia. Definite confirmation of AD can only be obtained at autopsy. At a stage of mild impairment, the clinical diagnosis is difficult, because deficits in cognition and functional abilities are subtle. The term mild cognitive impairment (MCI) has been proposed by investigators at the Mayo Clinic to describe what may be a transition between normal cognitive abilities and clearly recognizable AD. Memory difficulty is the usual symptom, recognized by patients or others, and detected by sensitive tests of memory. The forgetfulness is mild enough so there is little or no compromise of daily function. Screening cognitive tests are insensitive in these patients, who usually score above standard cutoff points for dementia. On the Mini-Mental State Examination, scores of 24 or higher (out of 30) are typical. Potential causes of cognitive impairment, such as depression or head trauma, should be ruled out. Follow-up studies of patients with MCI show that 8% to 15% per year show progression to clinically unambiguous dementia and meet a diagnosis of AD. This is higher than the incidence of AD in the population at large. In patients who die at the stage of MCI, AD changes are commonly found in brain regions, such as the hippocampus and entorhinal cortex, which play important roles in memory acquisition. Other researchers have given names, such as mild or questionable dementia, to patients with the clinical picture of MCI. Predicting which patients at this prodromal stage already harbor AD pathology and initiating early treatment is now being explored in diagnostic and treatment studies.

Biologic Markers as Aids to Diagnosis and Treatment in Alzheimer's Disease

To assist in early diagnosis and to provide tools to help to follow patients with AD, biologic markers are being investigated. Several types of markers show promise at this stage. Neuroimaging provides many ways to map the structure or function of the brain, and recent advances have improved the precision of measuring changes, as discussed in detail by DeCarli elsewhere in this issue. For example, tests such as MR imaging can be used to compute the volume of the brain or substructures, such as the hippocampus, and atrophy can be quantified.

Atrophy of either the whole brain or of temporal lobe structures is apparent in many patients even at a stage of MCI. If two serial imaging studies are obtained over an interval of about 1 year, the rate of progressive decline of total brain or hippocampal volume can be measured and seems clearly to discriminate patients with MCI from normal aging. Brain metabolism as imaged by positron emission tomography or single photon emission CT can identify areas of cortical hypometabolism in the temporoparietal region as a marker in patients with AD. The concentration of N-acetyl aspartate, an amino acid marker of neuronal number or density, can be measured in sectors of the brain by MR spectroscopy and is decreased in AD.

Biochemical markers related to pathologic changes in the brain in AD can be measured in the cerebrospinal fluid (CSF), and several abnormalities occur in AD. Tau is an important protein related to the cellular skeleton of neurons. In AD insoluble aggregates of tau form in neurons and are the chief constituent of tangles. CSF levels of tau are increased in about 70% to 90% of patients with AD compared with nondemented elderly controls. Levels of tau are not related to level of severity or duration of dementia; high tau levels have been found in many patients with very mild dementia or MCI. CSF tau is also elevated in non-AD conditions with neuronal death or damage, such as acute stroke or Creutzfeld-Jakob disease, which reduces the value of tau for differential diagnosis. Assays are now being tested that measure phospho-tau, because tau in NFT is highly phosphorylated. CSF phospho-tau levels seem to have greater disease specificity than total tau. As discussed previously, longer forms of Abeta ending at amino acid 42 are implicated in AD. The levels of Abeta42 in CSF are significantly decreased in patients with AD relative to controls and measuring both Abeta and tau increases diagnostic accuracy compared with either one alone. There is preliminary evidence for some markers being altered in blood in AD. For example, isoprostanes are stable prostaglandin metabolites that reflect oxidative processes. Their levels are increased in plasma, urine, and CSF of AD patients relative to controls.

How to Measure Effects of Disease-Modifying Treatment in Alzheimer's Disease

Medication trials for AD at present use clinical outcome measures, such as patients' performance on overall cognitive tests or batteries of psychometric tests to measure cognition, and information gained from informants or caregivers to assess global change, functional abilities, and behavior. Although these methods are robust enough to use in multicenter studies and provide measures of the extent of medication effect that may be relevant to clinical practice, they show a high extent of variability on retesting over time. For example, the Mini-Mental State Examination score declines by an average of three to four points per year in patients with AD, but the variability of change is at least as high as this average. In patients with MCI, the extent of change of cognition over time is slow and small. Clinical trials of patients with MCI require detailed assessment batteries and long follow-up periods to detect medication effects.

If novel treatments are developed and tested at the earliest stages of AD or even presymptomatically, then as an alternative to clinical assessment methods, biologic markers, such as a neuroimaging index of structure or function or biochemical markers in CSF or plasma, could be used to provide evidence of biologic efficacy of the treatment approach. This could lead to shorter and smaller initial clinical studies, and facilitate the testing of different doses of medications or of combination therapy. Even though biologic markers may show evidence of treatment efficacy in this way, the clinical effect size of the treatment ultimately needs to be calibrated using more widely used clinical outcome measures.

Prevention

Primary prevention of AD requires treating large numbers of people years before the earliest clinical changes of AD are noticeable. The latent period between AD pathology developing in the brain and its clinical expression is not known. Primary prevention could require many years of treatment. Medications suitable for this approach need to be inexpensive, safe, and well tolerated.

Clues from epidemiologic and case-control studies of AD have suggested that certain medications or supplements may alter the risk of developing AD. These include NSAIDS, estrogen in women, and vitamins E and C. All of these do meet the requirement of ease of use and are inexpensive. Primary prevention trials are currently under way using estrogen and gingko biloba. Because primary prevention studies for AD need large numbers of subjects and lengthy follow-up, they are much more expensive than conventional trials among symptomatic patients. If the propagation stage of AD is largely irreversible, then primary prevention or initiating treatment at a stage of MCI may become the only realistic times to intervene with disease-modifying treatment. Treatment approaches that target Abeta production or clearance will provide information to help to address this important question.

Summary

Recent scientific and clinical advances have raised hopes for developing rational treatment approaches for AD. The most promising treatment target is Abeta, and approaches to decrease the production or enhance the clearance of Abeta are already entering early human clinical trials. Cellular and animal models provide important tools to assess treatments that target Abeta before human studies begin. Early diagnosis and treatment intervention are priorities in effectively slowing the progression of AD or delaying progression from a stage of MCI to overt dementia. Biologic markers obtained from neuroimaging techniques and biochemical measures in blood and CSF may enhance early diagnosis and provide novel means of following treatment effects. Primary prevention of AD requires much larger studies, and ideally will use treatment approaches that target initiating mechanisms of disease.

References

1. Afford S, Randhawa S: Apoptosis. Mol Pathol 53:55, 2000
2. Aisen PS, Davis KL, Berg JD, et al: A randomized controlled trial of prednisone in Alzheimer's disease: Alzheimer's Disease Cooperative Study. Neurology 54:588, 2000 Full Text
3. Akiyama H, Barger S, Barnum S, et al: Inflammation and Alzheimer's disease. Neurobiol Aging 21:383, 2000 Abstract
4. Alvarez G, Munoz-Montano JR, Satrustegui J, et al: Lithium protects cultured neurons against beta-amyloid-induced neurodegeneration. FEBS Lett 453:260, 1999 Abstract
5. Andreasen N, Minthon L, Clarberg A, et al: Sensitivity, specificity, and stability of CSF-tau in AD in a community-based patient sample. Neurology 53:1488, 1999 Full Text
6. Bard F, Cannon C, Barbour R, et al: Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat Med 6:916, 2000 Abstract
7. Borchelt DR, Thinakaran G, Eckman CE, et al: Familial Alzheimer's disease-linked presenilin 1 variants elevate As1-42/1-40 ratio in vitro and in vivo. Neuron 17:1005, 1996 Abstract
8. Braak H, Braak E: Neuropathological staging of Alzheimer related changes. Acta Neuropathol 82:239, 1991 Abstract
9. Brazil MI, Chung H, Maxfield FR: Effects of incorporation of immunoglobulin G and complement component C1q on uptake and degradation of Alzheimer's disease amyloid fibrils by microglia. J Biol Chem 275:16941, 2000 Abstract
10. Buxbaum JD, Liu KN, Luo Y, et al: Evidence that tumor necrosis factor alpha converting enzyme is involved in regulated alpha-secretase cleavage of the Alzheimer amyloid protein precursor. J Biol Chem 273:27765, 1998 Abstract
11. Corder EH, Saunders AM, Strittmatter WJ, et al: Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 261:921, 1993 Abstract
12. Daly E, Zaitchik D, Copeland M, et al: Predicting conversion to Alzheimer disease using standardized clinical information. Arch Neurol 57:675, 2000 Abstract
13. De Strooper B, Saftig P, Craessaerts K, et al: Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature 391:387, 1998 Abstract
14. Eikelenboom P, Rozemuller AJ, Hoozemans JJ, et al: Neuroinflammation and Alzheimer disease: Clinical and therapeutic implications. Alzheimer Dis Assoc Disord 14(suppl 1):S54, 2000 Abstract
15. Findeis MA: Approaches to discovery and characterization of inhibitors of amyloid beta-peptide polymerization. Biochim Biophys Acta 1502:76, 2000 Abstract
16. Fox NC, Cousens S, Scahill R, et al: Using serial registered brain magnetic resonance imaging to measure disease progression in Alzheimer disease: Power calculations and estimates of sample size to detect treatment effects. Arch Neurol 57:339, 2000 Abstract
17. Frautschy SA, Cole GM, Baird A: Phagocytosis and deposition of vascular beta-amyloid in rat brains injected with Alzheimer beta-amyloid. Am J Pathol 140:1389, 1992 Abstract
18. Galasko D, Chang L, Motter R, et al: High cerebrospinal fluid tau and low amyloid beta42 levels in the clinical diagnosis of Alzheimer disease and relation to apolipoprotein E genotype. Arch Neurol 55:937, 1998 Abstract
19. Games D, Adams D, Alessandrini R, et al: Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein. Nature 373:523, 1995 Abstract
20. Hardy J: Amyloid, the presenilins, and Alzheimer's disease. Trends Neurosci 20:154, 1997 Abstract
21. Haroutunian V, Perl DP, Purohit DP: Regional distribution of neuritic plaques in the nondemented elderly and subjects with very mild Alzheimer disease. Arch Neurol 55:1185, 1998 Abstract
22. Henderson VW: Estrogen, cognition, and a woman's risk of Alzheimer's disease. Am J Med 103:11S, 1997 Abstract
23. Henderson VW, Paganini-Hill A, Miller BL, et al: Estrogen for Alzheimer's disease in women: Randomized, double-blind, placebo-controlled trial. Neurology 54:295, 2000 Full Text
24. Holcomb LA, Gordon MN, Jantzen P, et al: Behavioral changes in transgenic mice expressing both amyloid precursor protein and presenilin-1 mutations: Lack of association with amyloid deposits. Behav Genet 29:177, 1999 Abstract
25. Holtzman DM, Fagan AM, Mackey B, et al: Apolipoprotein E facilitates neuritic and cerebrovascular plaque formation in an Alzheimer's disease model. Ann Neurol 47:739, 2000 Abstract
26. Hsiao K, Chapman P, Nilsen S, et al: Correlative memory deficits, A-beta elevation, and amyloid Plaques in transgenic mice. Science 274:99, 1996 Abstract
27. Hulstaert F, Blennow K, Ivanoiu A, et al: Improved discrimination of AD patients using beta-amyloid1-42 and tau levels in CSF. Neurology 52:1555, 1999 Full Text
28. Ishiguro K, Ohno H, Arai H, et al: Phosphorylated tau in human cerebrospinal fluid is a diagnostic marker for Alzheimer's disease. Neurosci Lett 270:91, 1999 Abstract
29. Jack CR Jr, Petersen RC, Xu YC, et al: Prediction of AD with MRI-based hippocampal volume in mild cognitive impairment. Neurology 52:1397, 1999 Full Text
30. Jarrett JT, Lansbury PT Jr: Seeding "one-dimensional crystallization" of amyloid: A pathogenic mechanism in Alzheimer's disease and scrapie? Cell 73:1055, 1993 Citation
31. Johnson KA, Jones K, Holman BL, et al: Preclinical prediction of Alzheimer's disease using SPECT. Neurology 50:1563, 1998 Full Text
32. Kimberly WT, Xia W, Rahmati T, et al: The transmembrane aspartates in presenilin 1 and 2 are obligatory for gamma-secretase activity and amyloid beta-protein generation. J Biol Chem 275:3173, 2000 Abstract
33. Lambert MP, Barlow AK, Chromy BA, et al: Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins. Proc Natl Acad Sci USA 95:6448, 1998 Abstract
34. Lim GP, Yang F, Chu T, et al: Ibuprofen suppresses plaque patholgy and inflammation in a mouse model for Alzheimer's disease. J Neurosci 20:5709, 2000 Abstract
35. Lorenzo A, Yankner BA: beta-amyloid neurotoxicity requires fibril formation and is inhibited by Congo Red. Proc Natl Acad Sci USA 91:12243, 1994 Abstract
36. Mandelkow EM, Mandelkow E: Tau in Alzheimer's disease. Trends Cell Biol 8:425, 1998 Abstract
37. Markesbery WR, Carney JM: Oxidative alterations in Alzheimer's disease. Brain Pathol 9:133, 1999 Abstract
38. Masters CL, Simms G, Weinmann NA, et al: Amyloid plaque core protein in Alzheimer's disease and Down's syndrome. Proc Natl Acad Sci USA 82:4245, 1985 Abstract
39. McGeer PL, Schulzer M, McGeer EG: Arthritis and anti-inflammatory agents as possible protective factors for Alzheimer's disease: A review of 17 epidemiologic studies. Neurology 47:425, 1996 Full Text
40. Morris MC, Beckett LA, Scherr PA, et al: Vitamin E and vitamin C supplement use and risk of incident Alzheimer disease. Alzheimer Dis Assoc Disord 12:121, 1998 Abstract
41. Mucke L, Masliah E, Yu GQ, et al: High-level neuronal expression of abeta 1-42 in wild-type human amyloid protein precursor transgenic mice: Synaptotoxicity without plaque formation. J Neurosci 20:4050, 2000 Abstract
42. Mufson EJ, Chen EY, Cochran EJ, et al: Entorhinal cortex beta-amyloid load in individuals with mild cognitive impairment. Exp Neurol 158:469, 1999 Abstract
43. Mulnard RA, Cotman CW, Kawas C, et al: Estrogen replacement therapy for treatment of mild to moderate Alzheimer disease: A randomized controlled trial. Alzheimer's Disease Cooperative Study. JAMA 283:1007, 2000 Abstract
44. Murphy MP, Uljon SN, Fraser PE, et al: Presenilin 1 regulates pharmacologically distinct {gamma}-secretase activities: Implications for the role of PS in {gamma}-secretase cleavage. J Biol Chem 275:26277, 2000 Abstract
45. Naslund J, Haroutunian V, Mohs R, et al: Correlation between elevated levels of amyloid beta-peptide in the brain and cognitive decline. JAMA 283:1571, 2000 Abstract
46. Nitsch RM, Slack BE, Wurtman RJ, et al: Release of Alzheimer amyloid precursor derivatives stimulated by activation of muscarinic acetylcholine receptors. Science 258:304, 1992 Abstract
47. Otto M, Wiltfang J, Tumani H, et al: Elevated levels of tau-protein in cerebrospinal fluid of patients with Creutzfeldt-Jakob disease. Neurosci Lett 225:210, 1997 Abstract
48. Paleologos M, Cumming RG, Lazarus R, et al: Cohort study of vitamin C intake and cognitive impairment. Am J Epidemiol 148:45, 1998 Abstract
49. Petersen RC, Smith GE, Waring SC, et al: Mild cognitive impairment: Clinical characterization and outcome. Arch Neurol 56:303, 1999 Abstract
50. Pike CJ, Burdick D, Walencewicz AJ, et al: Neurodegeneration induced by beta-amyloid peptides in vitro: The role of peptide assembly state. J Neurosci 13:1676, 1993
51. Pratico D, Clark CC, Lee V-M, et al: Increased isoprostane biosynthesis in Alzheimer's disease: Correlation of a specific non invasive index of lipid peroxidation with disease severity. Neurobiol Aging 21(suppl 1):S220, 2000 Citation
52. Price DL, Sisodia SS: Mutant genes in familial Alzheimer's disease and transgenic models. Annu Rev Neurosci 21:479, 1998 Abstract
53. Price JL, Morris JC: Tangles and plaques in nondemented aging and "preclinical" Alzheimer's disease. Ann Neurol 45:358, 1999 Abstract
54. Roher AE, Chaney MO, Kuo YM, et al: Morphology and toxicity of Abeta-1-42 dimmer derived from neuritic and vascular amyloid deposits of Alzheimer's disease. J Biol Chem 271:20631, 1996 Abstract
55. Sano M, Ernesto C, Thomas RG, et al: A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer's disease. The Alzheimer's Disease Cooperative Study. N Engl J Med 336:1216, 1997 Abstract
56. Saunders AM, Strittmatter WJ, Schmechel D, et al: Association of apolipoprotein E allele e4 with late-onset familial and sporadic Alzheimer's disease. Neurology 43:1467, 1993 Abstract
57. Schenk D, Barbour R, Dunn W, et al: Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 400:173, 1999 Abstract
58. Schenk DB, Seubert P, Lieberburg I, et al: beta-peptide immunization: A possible new treatment for Alzheimer's disease. Arch Neurol 57:934, 2000 Citation
59. Scheuner D, Eckman C, Jensen M, et al: Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease. Nat Med 2:864, 1996 Abstract
60. Schuff N, Amend D, Ezekiel F, et al: Changes of hippocampal N-acetyl aspartate and volume in Alzheimer's disease: A proton MR spectroscopic imaging and MRI study. Neurology 49:1513, 1997 Full Text
61. Selkoe DJ: Translating cell biology into therapeutic advances in Alzheimer's disease. Nature 399(6738 suppl):A23, 1999 Abstract
62. Seubert P, Vigo-Pelfrey C, Esch F, et al: Isolation and quantification of soluble Alzheimer's beta-peptide from biological fluids. Nature 359:325, 1992 Abstract
63. Shoji M, Golde TE, Ghiso J, et al: Production of the Alzheimer amyloid beta protein by normal proteolytic processing. Science 258:126, 1992 Abstract
64. Sinha S, Lieberburg I: Cellular mechanisms of beta-amyloid prduction and secretion. Proc Natl Acad Sci USA 96:11049, 1999 Abstract
65. Skoog I, Gustafson D: HRT and dementia. J Epidemiol Biostat 4:227, 1999 Abstract
66. Skovronsky DM, More DB, Milla ME, et al: Protein kinase C-dependent alpha-secretase competes with beta-secretase cleavage of amyloid-beta precursor protein in the trans-Golgi network. J Biol Chem 275:2568, 2000 Abstract
67. St George-Hyslop PH: Molecular genetics of Alzheimer's disease. Biol Psychiatry 47:183, 2000 Abstract
68. Vanmechelen E, Vanderstichele H, Davidsson P, et al: Quantification of tau phosphorylated at threonine 181 in human cerebrospinal fluid: A sandwich ELISA with a synthetic phosphopeptide for standardization. Neurosci Lett 285:49, 2000 Abstract
69. Vassar R, Bennett BD, Babu-Khan S, et al: Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286:735, 1999 Abstract
70. Vekrellis K, Ye Z, Qiu WQ, et al: Neurons regulate extracellular levels of amyloid beta-protein via proteolysis by insulin-degrading enzyme. J Neurosci 20:1657, 2000 Abstract
71. Walker LC, Pahnke J, Madauss M, et al: Apolipoprotein E4 promotes the early deposition of Abeta42 and then Abeta40 in the elderly. Acta Neuropathol (Berl) 100:36, 2000 Abstract
72. Wang PN, Liao SQ, Liu RS, et al: Effects of estrogen on cognition, mood, and cerebral blood flow in AD: A controlled study. Neurology 54:2061, 2000 Full Text
73. Weisgraber KH, Mahley RW: Human apolipoprotein E: The Alzheimer's disease connection. FASEB J 10:1485, 1996 Abstract
74. Wellington CL, Hayden MR: Caspases and neurodegeneration: On the cutting edge of new therapeutic approaches. Clin Genet 57:1, 2000 Abstract
75. Whitehouse PJ, Kittner B, Roessner M, et al: Clinical trial designs for demonstrating disease-course-altering effects in dementia. Alzheimer Dis Assoc Disord 12:281, 1998 Abstract
76. Wolfe MS, De Los Angeles J, Miller DD, et al: Are presenilins intramembrane-cleaving proteases?
77. Implications for the molecular mechanism of Alzheimer's disease. Biochemistry 38:11223, 1999 Abstract
78. Yu G, Nishimura M, Arawaka S, et al: Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and betaAPP processing. Nature 407:48, 2000 Abstract

Source: www.mdconsult.com

Journal Abstracts 1) Alzheimer's disease. Accurate and early diagnosis in the primary care setting.

Marin DB, Sewell MC, Schlechter A.
Geriatrics 2002 Feb;57(2):36-40; quiz 43

Department of Psychiatry, Division of Geriatric Psychiatry, Mount Sinai School of Medicine, New York, NY, USA.

Alzheimer's disease is the most common dementia type and is characterized by a gradual, progressive decline in multiple areas of cognition and function. Early diagnosis is key because it can initiate the process of patients and family adapting to and managing disease symptoms. Moreover, certain pharmacologic interventions can impede symptom progression and significantly improve quality of life. A spectrum of basic tests and instruments make clinical diagnosis of AD attainable in the primary care setting. Treatment with cholinesterase inhibitors is targeted toward cognitive enhancement. Neuroprotection involves delaying dementia progression and remains experimental. Problematic cases should be referred.

Source: PubMed

2) Proposal of criteria for clinical diagnosis of mild cognitive impairment, dementia and Alzheimer's disease

Robles A, Del Ser T, Alom J, Pena-Casanova J.
Neurologia 2002 Jan;17(1):17-32

Servicio de Neurologia. Hospital Clinico Universitario. Santiago de Compostela. La Coruna. Spain.

The most widely accepted criteria for Alzheimer's disease (AD) diagnosis (NINCDS-ADRDA and DSM-IV) do not allow to differentiate accurately between AD and other degenerative dementias which have recently formulated criteria for its clinical diagnosis. Therefore, it is necessary to bring AD diagnostic criteria up to date in order to optimise their specificity, by assessing its most specific clinical manifestations, its most representative markers and those features typical of other diseases which are usually taken into account for a differential diagnosis.According to the latest reports on the subject, the disturbances suffered by memory, behaviour and the rest of cognitive and executive functions must be equally considered when establishing the syndromic diagnosis of dementia; this will always require the coexistence of an evident functional impairment. Due to this, the concepts of "dementia" and "mild cognitive impairment" should be clearly distinguished. For the time being, AD can only be diagnosed when dementia has been proved and this shows a series of cognitive, behavioural and neurological features which are representative of it. Nevertheless, some diagnostic markers appear to be precocious and specific enough to try to identify those patients who suffer from mild cognitive impairment due to an incipient stage of AD. We are suggesting some criteria for the clinical diagnosis of dementia, mild cognitive impairment and AD that seem to be more detail

Source: PubMed

Journal Abstracts

1) A randomized, double-blind, placebo-controlled study of the efficacy and safety of donepezil in patients with Alzheimer's disease in the nursing home setting. Tariot PN, Cummings JL, Katz IR, Mintzer J, Perdomo CA, Schwam EM, Whalen E.
J Am Geriatr Soc 2001 Dec;49(12):1590-9

Department of Psychiatry, University of Rochester Medical Center, Monroe Community Hospital, Rochester, New York 14620, USA.

OBJECTIVES: To evaluate the safety and efficacy of donepezil in the management of patients with Alzheimer's disease (AD) residing in nursing home facilities.

DESIGN: Twenty-four-week, randomized, multicenter, parallel-group, double-blind, placebo-controlled trial.

SETTING: Twenty-seven nursing homes across the United States.

PARTICIPANTS: Two hundred eight nursing home patients with a diagnosis of probable or possible AD, or AD with cerebrovascular disease; mean Mini-Mental State Examination (MMSE) score 14.4; mean age 85.7.

MEASUREMENTS: The primary outcome measure was the Neuropsychiatric Inventory-Nursing Home Version (NPI-NH). Secondary efficacy measures were the Clinical Dementia Rating (Nursing Home Version)-Sum of the Boxes (CDR-SB), MMSE, and the Physical Self-Maintenance Scale (PSMS). Safety was monitored by physical examinations, vital signs, clinical laboratory tests, electrocardiograms (ECGs), and treatment-emergent adverse events (AEs).

RESULTS: Eighty-two percent of donepezil- and 74% of placebo-treated patients completed the trial. Eleven percent of donepezil- and 18% of placebo-treated patients withdrew because of AEs. Mean NPI-NH 12-item total scores improved relative to baseline for both groups, with no significant differences observed between the groups at any assessment. Mean change from baseline CDR-SB total score improved significantly with donepezil compared with placebo at Week 24 (P < .05). The change in CDR-SB total score was not influenced by age. Differences in mean change from baseline on the MMSE favored donepezil over placebo at Weeks 8, 16, and 20 (P < .05). No significant differences were observed between the groups on the PSMS. Overall rates of occurrence and severity of AEs were similar between the two groups (97% placebo, 96% donepezil). Gastrointestinal AEs occurred more frequently in donepezil-treated patients. In general, AEs were similar in older and younger donepezil-treated patients, with the majority of patients experiencing only AEs that were transient and mild or moderate in severity. Weight loss was reported as an AE more frequently in older patients, although a loss at last visit of >or=7% of screening weight occurred at the same rate in older and younger patients (9% of donepezil- and 6% of placebo-treated patients). No significant differences between groups in vital sign changes, bradycardia, or rates of clinically significant laboratory or ECG abnormalities were observed. C

CONCLUSION: Patients treated with donepezil maintained or improved in cognition and overall dementia severity in contrast to placebo-treated patients who declined during the 6-month treatment period. The safety and tolerability profile was comparable with that reported in outpatient studies of donepezil. These findings also suggest that advanced age, comorbid illnesses, and high concomitant medication usage should not be barriers to donepezil treatment. Given the apparent improvement in behavior in the placebo group, and the high use of concomitant medications in both groups, the impact of donepezil on behavior in the nursing home setting is unresolved and merits further investigation. In summary, effects on cognition, overall dementia severity, and safety and tolerability findings are consistent with previous findings in outpatients and support the use of donepezil in patients with AD who reside in nursing homes.

Source - PubMed

2) Olanzapine in the treatment of anxiety symptoms due to Alzheimer's disease: a post hoc analysis.

Mintzer J, Faison W, Street JS, Sutton VK, Breier A.
Int J Geriatr Psychiatry 2001 Dec; 16 Suppl 1:S71-7

Medical University of South Carolina, Alzheimer's Research and Clinical Programs Charleston, SC 29406-6076, USA. mintzerj@musc.edu

OBJECTIVES: To assess the efficacy and tolerability of olanzapine in the treatment of significant anxiety symptoms in patients with AD.

METHODS: A post hoc analysis of a previously published study was performed. Those post hoc analysis evaluated the response to treatment with olanzapine of a subgroup of AD patients presenting with significant symptoms of anxiety. Patients were considered to have significant symptoms of anxiety if their baseline in the Nursing home version of the Neuropsychiatric Instrument NPI/NH anxiety scores were > or = 2. The analysis included 120 patients.

RESULTS: Patients receiving olanzapine 5 mg/d were statistically significantly improved on the NPI/NH Anxiety item compared to those receiving placebo (olanzapine, 5 mg/d: -3.72; placebo: -1.67; p = 0.034). In the group of patients with clinically significant anxiety, somnolence was the only treatment-emergent event that was statistically different in any olanzapine treatment group compared with placebo (olanzapine 5 mg/d: 9 patients [25%], p = 0.034; 10 mg/d: 7 [23%], p =

0.054; 15 mg/d: 7 [26%], p = 0.050; placebo: 1 [3.7%]). When controlling for treatment-emergent somnolence, the improvement in anxiety in the olanzapine 5 mg/d group remained statistically significant (p = 0.049).

CONCLUSIONS: These findings suggest that olanzapine could be a safe and effective treatment for anxiety in Alzheimer's disease. Copyright 2001 John Wiley & Sons, Ltd.

Source - PubMed

1) J C Morris,
Alzheimer's Disease Research Center,
Washington University School of Medicine,
4488 Forest Park Ave.,
Suite 130, St Louis
MO 63178,
USA.

2) M Grundman,
Alzheimer's Disease Cooperative Study,
Department of Neurosciences,
University of California, San Diego.
mgrundman@ucsd.edu.

3) O L Lopez,
Alzheimer's Disease Research Center,
Departments of Psychiatry and Neurology,
University of Pittsburgh,
Pittsburgh, PA
USA.

4)J G Csernansky,
Alzheimer's Disease Research Center and the Department of Psychiatry,
Washington University School of Medicine, St. Louis
MO 63110.
Email: csernanj@medicine.wust.edu

5)T A Ala,
Alzheimer's Treatment and Research Center,
Department of Neurology,
University of Minnesota,
HealthPartners Regions Hospital,
St. Paul, MN
USA.
Email: tala@siumed.edu

6) G K Gouras,
Laboratory of Molecular and Cellular Neuroscience and Fisher Center
for Research on Alzheimer's Disease
The Rockefeller University New York
New York 10021
USA.
Email: gkgouras@mail.med.cornell.edu