Preview of the Medifocus Guidebook on: Alzheimer's Disease Updated February 10, 2012

This document is only a SHORT PREVIEW of the Medifocus Guidebook on Alzheimer's Disease. It is intended primarily to give you a general overview of the format and structure of the Guidebook as well as select pages from each major Guidebook section listed in the Table of Contents. To purchase the COMPLETE Medifocus Guidebook on Alzheimer's Disease (154 pages; Updated February 10, 2012), please: Call us at: 800-965-3002 (United States) 301-649-9300 (Outside the United States) Order online through our website: Printed Version Mailed to you and bound for easy reading. Includes free online access to the electronic guidebook for one full year.

Electronic Version Adobe PDF document that can be viewed or printed on any computer Online updates are included for one full year.

Table of Contents
Background Information .................................................................... 8
Introduction ................................................................................................. 8 About Your Medifocus Guidebook ........................................................... 10 Ordering Full-Text Articles ....................................................................... 13

The Intelligent Patient Overview .................................................. 15 Guide to the Medical Literature .................................................... 70
Introduction ............................................................................................... 70 Recent Literature: What Your Doctor Reads ........................................... 71 Review Articles ..................................................................................... 71 General Interest Articles ....................................................................... 84 Drug Therapy Articles ........................................................................ 102 Clinical Trials Articles ........................................................................ 106

Centers of Research ........................................................................... 119

United States ........................................................................................... 121 Other Countries ....................................................................................... 133

Tips on Finding and Choosing a Doctor .................................. 144 Directory of Organizations ............................................................. 150

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1 - Background Information
Introduction
Chronic or life-threatening illnesses can have a devastating impact on both the patient and the family. In today's new world of medicine, many consumers have come to realize that they are the ones who are primarily responsible for their own health care as well as for the health care of their loved ones. When facing a chronic or life-threatening illness, you need to become an educated consumer in order to make an informed health care decision. Essentially that means finding out everything about the illness - the treatment options, the doctors, and the hospitals - so that you can become an educated health care consumer and make the tough decisions. In the past, consumers would go to a library and read everything available about a particular illness or medical condition. In today's world, many turn to the Internet for their medical information needs. The first sites visited are usually the well known health "portals" or disease organizations and support groups which contain a general overview of the condition for the layperson. That's a good start but soon all of the basic information is exhausted and the need for more advanced information still exists. What are the latest "cutting-edge" treatment options? What are the results of the most up-to-date clinical trials? Who are the most notable experts? Where are the top-ranked medical institutions and hospitals? The best source for authoritative medical information in the United States is the National Library of Medicine's medical database called PubMed, that indexes citations and abstracts (brief summaries) of over 7 million articles from more than 3,800 medical journals published worldwide. PubMed was developed for medical professionals and is the primary source utilized by health care providers for keeping up with the latest advances in clinical medicine. A typical PubMed search for a specific disease or condition, however, usually retrieves hundreds or even thousands of "hits" of journal article citations. That's an avalanche of information that needs to be evaluated and transformed into truly useful knowledge. What are the most relevant journal articles? Which ones apply to your specific situation? Which articles are considered to be the most authoritative - the ones your physician would rely on in making clinical decisions? This is where Medifocus.com provides an effective solution. Medifocus.com has developed an extensive library of MediFocus Guidebooks covering a wide spectrum of chronic and life threatening diseases. Each MediFocus Guidebook is a

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high quality, up- to-date digest of "professional-level" medical information consisting of the most relevant citations and abstracts of journal articles published in authoritative, trustworthy medical journals. This information represents the latest advances known to modern medicine for the treatment and management of the condition, including published results from clinical trials. Each Guidebook also includes a valuable index of leading authors and medical institutions as well as a directory of disease organizations and support groups. MediFocus Guidebooks are reviewed, revised and updated every 4-months to ensure that you receive the latest and most up-to-date information about the specific condition.

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About Your MediFocus Guidebook

Introduction
Your MediFocus Guidebook is a valuable resource that represents a comprehensive synthesis of the most up-to-date, advanced medical information published about the condition in well-respected, trustworthy medical journals. It is the same type of professional-level information used by physicians and other health-care professionals to keep abreast of the latest developments in biomedical research and clinical medicine. The Guidebook is intended for patients who have a need for more advanced, in-depth medical information than is generally available to consumers from a variety of other resources. The primary goal of a MediFocus Guidebook is to educate patients and their families about their treatment options so that they can make informed health-care decisions and become active participants in the medical decision making process. The Guidebook production process involves a team of experienced medical research professionals with vast experience in researching the published medical literature. This team approach to the development and production of the MediFocus Guidebooks is designed to ensure the accuracy, completeness, and clinical relevance of the information. The Guidebook is intended to serve as a basis for a more meaningful discussion between patients and their health-care providers in a joint effort to seek the most appropriate course of treatment for the disease.

Guidebook Organization and Content

Section 1 - Background Information
This section provides detailed information about the organization and content of the Guidebook including tips and suggestions for conducting additional research about the condition.

Section 2 - The Intelligent Patient Overview

This section of your MediFocus Guidebook represents a detailed overview of the disease or condition specifically written from the patient's perspective. It is designed to satisfy the basic informational needs of consumers and their families who are confronted with the illness and are facing difficult choices. Important aspects which are addressed in "The Intelligent Patient" section include: The etiology or cause of the disease Signs and symptoms How the condition is diagnosed The current standard of care for the disease Treatment options
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 New developments Important questions to ask your health care provider

Section 3 - Guide to the Medical Literature

This is a roadmap to important and up-to-date medical literature published about the condition from authoritative, trustworthy medical journals. This is the same information that is used by physicians and researchers to keep up with the latest developments and breakthroughs in clinical medicine and biomedical research. A broad spectrum of articles is included in each MediFocus Guidebook to provide information about standard treatments, treatment options, new clinical developments, and advances in research. To facilitate your review and analysis of this information, the articles are grouped by specific categories. A typical MediFocus Guidebook usually contains one or more of the following article groupings: Review Articles: Articles included in this category are broad in scope and are intended to provide the reader with a detailed overview of the condition including such important aspects as its cause, diagnosis, treatment, and new advances. General Interest Articles: These articles are broad in scope and contain supplementary information about the condition that may be of interest to select groups of patients. Drug Therapy: Articles that provide information about the effectiveness of specific drugs or other biological agents for the treatment of the condition. Surgical Therapy: Articles that provide information about specific surgical treatments for the condition. Clinical Trials: Articles in this category summarize studies which compare the safety and efficacy of a new, experimental treatment modality to currently available standard treatments for the condition. In many cases, clinical trials represent the latest advances in the field and may be considered as being on the "cutting edge" of medicine. Some of these experimental treatments may have already been incorporated into clinical practice.

The following information is provided for each of the articles referenced in this section of your MediFocus Guidebook: Article title Author Name(s) Institution where the study was done Journal reference (Volume, page numbers, year of publication)

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 Link to Abstract (brief summary of the actual article) Linking to Abstracts: Most of the medical journal articles referenced in this section of your MediFocus Guidebook include an abstract (brief summary of the actual article) that can be accessed online via the National Library of Medicine's PubMed database. You can easily access the individual abstracts online via PubMed from the "electronic" format of your MediFocus Guidebook by clicking on the corresponding URL address that is provided for each cited article. If you purchased a printed copy of a MediFocus Guidebook, you can still access the article abstracts online by entering the individual URL address for a particular article into your web browser.

Section 4 - Centers of Research

We've compiled a unique directory of doctors, researchers, medical centers, and research institutions with specialized research interest, and in many cases, clinical expertise in the management of the specific medical condition. The "Centers of Research" directory is a valuable resource for quickly identifying and locating leading medical authorities and medical institutions within the United States and other countries that are considered to be at the forefront in clinical research and treatment of the condition. Inclusion of the names of specific doctors, researchers, hospitals, medical centers, or research institutions in this Guidebook does not imply endorsement by Medifocus.com, Inc. or any of its affiliates. Consumers are encouraged to conduct additional research to identify health-care professionals, hospitals, and medical institutions with expertise in providing specific medical advice, guidance, and treatment for this condition.

Section 5 - Tips on Finding and Choosing a Doctor

One of the most important decisions confronting patients who have been diagnosed with a serious medical condition is finding and choosing a qualified physician who will deliver high-level, quality medical care in accordance with curently accepted guidelines and standards of care. Finding the "best" doctor to manage your condition, however, can be a frustrating and time-consuming experience unless you know what you are looking for and how to go about finding it. This section of your Guidebook offers important tips for how to find physicians as well as suggestions for how to make informed choices about choosing a doctor who is right for you.

Section 6 - Directory of Organizations

This section of your Guidebook is a directory of select disease organizations and support groups that are in the business of helping patients and their families by providing access to information, resources, and services. Many of these organizations can answer your questions, enable you to network with other patients, and help you find a doctor in your geographical area who specializes in managing your condition.

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2 - The Intelligent Patient Overview ALZHEIMER'S DISEASE

Introduction
Alzheimer's disease (AD) was first described by a Bavarian psychiatrist and neuropathologist named Alois Alzheimer in 1907. It is defined by the National Institute on Aging as a progressive, irreversible decline in memory, performance of routine tasks, time and space orientation, language and communication skills, abstract thinking, and the ability to learn and carry out mathematical calculations. Other features include personality changes, impaired judgment, and behavioral and psychiatric symptoms. The cognitive changes that occur in AD are not a part of "normal" aging. The most prominent feature of AD is dementia, a general term for a number of syndromes characterized by a decline in intellectual functioning that interferes with normal daily activities and social relationships. The American Psychiatric Association defines dementia as a progressive deterioration in global intellectual ability of such severity that it interferes with social and occupational performance. There are two types of dementia: reversible, which is caused by medication, vitamin imbalances or infection; and irreversible, which is due to a progressive neurodegenerative disorder. Alzheimer's disease is the most common cause of irreversible dementia in individuals over the age of 65, affecting an estimated four to five million persons in the United States. The number is expected to rise significantly as the "baby boomers" generation ages. It is thought to account for up to 70% of cases of dementia worldwide in people over the age of 65. The Centers for Disease Control and Prevention (CDC) estimates that by 2030, there may be 16 million Americans with AD. Alzheimer's disease is always progressive and fatal. People diagnosed with AD survive an average of four to six years after diagnosis, but the duration of the disease ranges from three to (rarely) twenty years. Although the average age of onset of Alzheimer's disease is 65 years or older, there is a type of AD that attacks younger people between the ages of 30-60 that is called young onset Alzheimer's disease. There are approximately 500,000 people in the U.S. with young onset AD. A major challenge for these individuals and their families is that they are at a different stage of life than older AD patients. They may still have school-age children living at home who witness the deteriorating condition of their parent and who may be severely affected emotionally. Individuals with young onset AD may also be employed and/or may be a family's primary wage earner, resulting in major financial disruption for the entire family. There is great concern that the growing number of people with Alzheimer's disease will place a severe strain - physical, emotional, and financial - on increasing numbers of families and caregivers. The overall cost related to AD and necessary care is estimated to be more than $183

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billion per year and the increasing incidence will add a significant burden to the healthcare system in the United States. As the world population ages, AD is expected to be the most overwhelming issue in global health care in this century, since it will affect not only people suffering with AD but the lives of their families and caregivers as well.

What Happens in Alzheimer's Disease?

Alzheimer's disease is characterized primarily by two types of deficits: cognitive deficits which affect functions such as memory, language, planning, attention, and judgment; and behavioral and psychiatric deficits that include wandering, pacing, agitation, depression, anxiety, hallucinations, physical or verbal outbursts, and yelling. The cognitive decline in AD impairs overall function but is not associated with a lack of alertness or delirium. Damage to brain cells in AD begins 10-20 years before the appearance of overt symptoms, such as memory loss. The cellular changes, namely the development of amyloid plaques and neurofibrillary tangles, begin in the area of the brain that is responsible for short-term memory and spread from there. As a result of cellular injury and death, brain tissue in the immediate area begins to shrink (atrophy), and by end-stage AD, the shrinkage is considerable. The doctor who typically treats patients with AD is the primary care physician. Other health care professionals who may be consulted in the course of the disease include neurologists, psychiatrists, psychologists, and social workers.

Mild Cognitive Impairment

Mild cognitive impairment_ (MCI) is a condition in which individuals experience cognitive changes that are greater than expected for their age but not as severe as people diagnosed with AD. Mild cognitive impairment can affect any cognitive function such as language, judgment, reading, or writing, but most commonly affects memory ("amnestic MCI"). For example, occasionally misplacing glasses or forgetting a name is associated with normal aging, but people with MCI may experience these types of impairments more frequently, while still being able to think clearly, solve problems, learn new information, and communicate despite their relatively minor memory loss. They may be able to function independently by compensating for the deficit with lists, reminders, or calendars. People with MCI may experience fear or frustration since they are typically aware of their impairment. According to the American College of Physicians, approximately 20% of the population over 70 years of age is affected by MCI. For some people it remains stable and in others it may even be temporary. However, for a large group of people (slightly less than 50% by some estimates), MCI is a precursor to dementia and a transitional stage from normal aging to Alzheimer's disease. In fact, people whose MCI symptoms are noticeable enough that they seek medical attention are at a higher risk for developing dementia. Although the reason is unknown, more people with MCI develop AD than people without MCI, meaning that MCI places a person at a higher risk for developing AD than people without it. There are no treatments for MCI and management is based on prevention by staying active, socially and mentally, with activities such as learning a new language, or doing puzzles, brain teasers, and memory games.

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The progression of MCI, a "predementia" stage, occurs as the accumulation of AD pathology (amyloid-beta plaques and neurofibrillary tangles) increases in the brain. When the cognitive decline reaches a point where it interferes with daily function, individuals are diagnosed with AD. Because the whole process of progression of cognitive decline in the AD continuum is gradual, it may be difficult for physicians to identify the exact transition from one stage to the next.

Common Types of Dementia

There are different types of dementia, each with a specific etiology, and many of their symptoms overlap. The three most common types of dementia are: Alzheimer's disease Vascular dementia Mixed dementia

Alzheimer's Disease
This is the most common type of dementia and accounts for 60-80% of all cases of dementia. As noted above, it is characterized by difficulty remembering names and recent events, impaired judgment, confusion, depression, poor orientation in time and space, behavior changes, and difficulty walking, speaking, and swallowing.

Vascular Dementia
Vascular dementia is the second most common type of dementia. It is also known as "multi-infarct dementia" (MID), "post-stroke dementia", or "vascular cognitive impairment". Vascular dementia is caused by repeated transient ischemic attacks ("mini-strokes") that result in temporary, partial blockages of the arteries supplying blood to the brain and brief changes in consciousness or sight. These intermittent interruptions of oxygen and nutrients result in brain damage over time and eventually lead to dementia. Symptoms of vascular dementia are varied and typically reflect increasing difficulty performing activities of daily living such as eating or dressing. Additional symptoms may include memory problems, dizziness, lack of concentration, slurred speech, wandering, laughing or crying inappropriately, or difficulty managing finances. Memory may not be as seriously affected as in AD. Symptoms related to impairment in vascular dementia can occur gradually or more suddenly in a stepwise progression. Because vascular dementia is closely associated with heart and blood vessel diseases, it is also considered the most treatable dementia through monitoring of risk factors, such as diet, alcohol, or smoking. Drugs used to treat AD may also be effective in treating vascular dementia. It is thought that MID may either cause or exacerbate Alzheimer's disease in some people. Vascular dementia affects men more than women and occurs usually between the ages of 60-75.

Mixed Dementia
When vascular dementia and AD are both present, the condition is known as mixed dementia. Mixed dementia is clinically significant because the combination of both dementias causes compounded deficits and impairments that have a greater impact on individuals with AD than

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either type alone. Sometimes treating the vascular dementia can result either in improvement of some AD symptoms or in delayed deterioration of cognitive or behavioral function. It is not known exactly how many people suffer from mixed dementia, but the Alzheimer's Association notes that it occurs more often than previously thought. There is evidence that up to 45% percent of brain autopsies of people with dementia show signs of both Alzheimer's disease and vascular dementia. The U.S. Food and Drug Administration (FDA) has not approved any drugs for the management of mixed dementia.

Pathophysiology of Alzheimer's Disease

The brain contains over 100 billion neurons (nerve cells) that communicate with each other through specialized networks that are formed for coordinating various tasks such as movement, learning, memory, or smell. Dendrites are long branching extensions of the neuron that form the connections with other nerve cells. Chemical substances called neurotransmitters carry complex signals back and forth between nerve cells as they flow from the dendrite of one neuron across a synapse to the next neuron. Synapses are minute gaps between nerve cells that permit neurotransmitters to travel rapidly and smoothly throughout the brain, and these signals create the cellular basis for cognition, movement, skills, sensations, and emotions. Much like the components of a factory of well-oiled machines, each individual cell within each network must efficiently carry out its tasks, such as allowing or excluding the entry of certain substances across the cell membrane, producing and excreting waste products, and processing and storing new information. When one part of this complex cellular system fails, it causes a ripple effect. This is what happens in AD: a complex series of events take place over a long period of time resulting in progressive death of brain tissue. There are four changes that take place in the brain in Alzheimer's disease: Neuritic plaques - Dense deposits or clumps of sticky protein fragments called amyloid-beta form between the nerve cells (outside the cell). Amyloid-beta is neurotoxic (poisonous to nerve cells) and leads to cell death. Deposits of amyloid-beta plaques are also found in and around blood vessels in the brain. Neurofibrillary tangles - These are intracellular collections (inside the cell) of twisted protein filaments called tau that destroy the cell from within by causing the collapse of the neuron's chemical transport communication system with other cells. There is a strong correlation between neurofibrillary tangles and cognitive impairment. Reduced levels of acetylcholine - There is a loss of specialized nerve cells deep in the forebrain that produce acetylcholine, a neurotransmitter essential to memory. There are also elevated levels of two enzymes responsible for degrading and destroying available acetylcholine, namely acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). In addition, the levels of two other neurotransmitters, serotonin and norepinephrine, both of which are related to behavioral and cognitive changes, are also reduced in patients with AD. Synaptic and neuronal death - A loss of synapses causes disconnection between the cells that ultimately results in the progressive death of neurons (neurodegeneration). Neurodegeneration is the strongest factor correlated with cognitive impairment.

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The initial step in the development of AD appears to be the formation of amyloid deposits in the brain up to one decade before the first symptoms of dementia appear. The next step is believed to be the formation of neurofibrillary tangles. Eventually there is a loss of synaptic function, followed by neurodegeneration and, finally, brain atrophy. In addition, the continuous reduction of levels of neurotransmitters compounds the dysfunction. Information transfer begins to fail as the number of synapses declines and neurons eventually begin to die off. As this process progresses, symptoms become increasingly more severe. It is believed that already at the stage of mild cognitive impairment (MCI), there is a significant accumulation of plaques and tangles and evidence of neurodegeneration. Plaques and tangles initially form in areas important for learning and memory and then spread outwards, resulting in increasingly reduced cognitive function, significant memory loss, confusion, and behavioral and emotional changes. They usually form first in the entorhinal cortex (important memory center), and then progress to the hippocampus (plays a major role in short-term memory and spatial orientation), amygdala (plays an important role in the processing and memory of emotional reactions), and then diffusely throughout the cortex (responsible for cognition and generating behavior related to incoming sensory information). Symptoms intensify as more areas are affected by the tangles. The visual cortex and motor cortex are usually spared. The development of AD is a complex process and involves multiple factors that interact to cause AD and accelerate its progression. In general, it appears that a combination of factors (in addition to known risk factors) triggers the formation of plaques and tangles, as well as an inflammatory reaction that involves: Microglia - cells that are the main component of the immune defense system in the central nervous system Astrocytes - star-shaped glial cells that play numerous roles in brain cell function Cytokines - inflammatory proteins that are related to the immune response Free radicals - odd unpaired electrons that circulate in the body and attack the nearest cells, causing them to destabilize and release more free radicals The exact mechanism by which all of this happens, the order in which it happens, the precise relationship between risk factors, the actual trigger for the formation of AD, and the role of the inflammatory process in the progression of cell damage and death is unclear at this time, but active research is underway that is studying multiple aspects of the pathophysiology of AD. Some of the areas of active investigation regarding the pathophysiology of AD include: The Roles of Tau Protein Tangles and Amyloid-beta Plaques Tau protein is normally present in axons and dendrites and is directly involved with cell structure, transport of chemicals across the cell membrane, and axonal growth. The addition of a phosphate group to the Tau protein (which occurs in AD) destabilizes the cells and results in a loss of axons, dendrites, and synapses. As the protein tangles accumulate, cell death and synaptic loss increase and neuronal transmission is progressively slowed down and impaired.

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At the same time, there are certain changes that occur in the amyloid precursor protein (APP), a protein that is concentrated in the synapses of neurons. The normal function of APP in the body is unknown, but in Alzheimer's disease APP is abnormally processed and converted to amyloid-beta protein. Amyloid-beta also may stimulate the production of free radicals that results in oxidative stress (the accumulation of destructive free radicals) and cell death. This process has a cascading effect causing diffuse tissue damage. Scientists are investigating the steps that occur in this process, the exact triggers for the formation of neurofibrillary tangles and amyloid-beta plaques, and the relationship with progressive dementia in AD. Cardiovascular Involvement Recent research has shown that as people age, there is a reduced supply of blood to the brain and it may be greater in people who develop AD. It is thought that this greater than average decrease in blood supply may trigger biochemical changes that lead to changes in brain tissue. One possibility is that insufficient blood supply may reduce the amount of nutrients reaching the brain. One of these nutrients is glucose and this may lead to the changes that result in the sticky clumps of tau protein and amyloid-beta. This increasingly clear cardiovascular relationship of poor circulation with the formation of AD opens up many exiting avenues of research and potential treatments. Glucose Metabolism In addition to the reduced supply of glucose to the brain, reduced metabolism of existing glucose in the brain has been noted in some patients with mild cognitive impairment (MCI). It is not clear whether the impaired metabolism of glucose is a cause or effect of cellular changes and how it may be related to the formation of plaques and tangles. Lipids and the Development of Alzheimer's Disease Cholesterol and polyunsaturated fatty acids (PUFAs) are critical for cellular structure and function. It has been shown that individuals with AD have higher levels of cholesterol and decreased levels of polyunsaturated fats in their brain cells than elderly people without AD. The relationship between the increased cholesterol and decreased PUFA and the development of AD is unknown at this time and is an area of active research. Acetylcholine and the Cerebrovascular System A link has been found between the cholinergic cells in the basal forebrain (cells that produce acetylcholine) and the cerebrovascular system. Cholinergic cells project into the cortical blood vessels and the acetylcholine that they produce acts to stimulate or inhibit blood flow. Research has shown that amyloid-beta deposits are also found around cortical blood vessels. Does the reduced blood flow cause the amyloid-beta deposits? Do the amyloid-beta deposits caused by the reduced cholinergic cells or acetylcholine cause further reduction of blood flow? These questions are also the subject of ongoing research.

Incidence of Alzheimer's Disease

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 Approximately 70% of people with dementia have AD. Alzheimer's disease affects approximately five million Americans and up to 20 million people worldwide. The incidence of AD in the U.S. and Europe is expected to at least double by the year 2050. By some estimates, based on census numbers, AD cases may be expected to rise to 15 million cases in the U.S. and 80 million cases worldwide. AD affects approximately 10% of people over the age of 65 and 40% of those over the age of 85. The incidence of AD before the age of 60 accounts for less than 1% of cases worldwide. Considering the fact that the fastest growing segment of the population in the U.S. is people 85 years of age and older, the incidence of AD is expected to have an increasing impact on health care in the U.S.

Risk Factors for Alzheimer's Disease

There are two types of risk factors for Alzheimer's disease (AD), some of which can be managed by individuals and some over which they have no control.

Risk factors that Cannotbe Controlled:

Age - The risk of AD rises exponentially with age and, indeed, age is the greatest risk factor. Risk doubles every five years after age 65 and, by the age of 85, the risk is 50%. The lifetime risk of AD at age 65 without any family history of AD is estimated to be 15%. Family history - People with first-degree relatives with AD are two to three times more likely to develop the disease themselves than people without affected relatives. The risk of developing AD is higher if more than one first-degree relative has or had AD. Genetic predisposition - the apolipoproteinE (APOE) gene on chromosome 19 has been linked to "late-onset" AD, which is the most common form of the disease. Another gene, called SORL1 was identified in 2007. Based on recent research, the National Institutes of Aging estimates that there may be an additional four to seven genes yet to be identified that may be additional risk factors for AD. Despite what is known about the relationship between genetics and the development of AD, genetic testing is not currently recommended. There are two types of genes that play a role in determining whether a person will develop AD, namely: risk genes - These genes elevate the likelihood of developing AD but do not guarantee that it will happen. There are three forms of the APOE gene known as e2, e3, and e4. While everyone inherits one form of the APOE gene from each parent, anyone inheriting the e4 form is at increased risk for AD. If people inherit one copy of APOE-e4, it increases not only the likelihood of developing AD, but at an earlier age than if they inherit e2 or e3. If people inherit two copies of this gene, it increases the likelihood of developing AD even more than if they inherit only one copy of the gene. deterministic genes - anyone who carries these genes is guaranteed to develop AD.

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This situation is rare and has been found so far only in a few hundred extended families. In a minority of cases (one percent or less), AD can be directly traced to a genetic mutation of the gene for the "gene precursor protein" on chromosome 21, the gene for "presenilin 1 protein" on chromosome 4, and the gene for "presenilin 2 protein" on chromosome 1. If any of these mutations are inherited, individuals will develop AD. This is called familial AD and it usually develops before the age of 65 and sometimes as young as age 30.

Gender - Women seem to have a higher risk of developing AD, but investigators are not certain if being female is itself a risk factor because women live longer, or perhaps because of the drop in levels of estrogen (which may be protective against memory loss) following menopause which may predispose women to AD. Mild Cognitive Impairment - MCI is considered to be a "predementia" stage and progression occurs as the accumulation of AD pathology increases in the brain, namely amyloid plaques and neurofibrillary tangles. Approximately 50% of people with MCI develop AD. Traumatic head or brain injury - Moderate to severe head trauma or traumatic brain injury elevates the risk of developing AD. Head injury associated with loss of consciousness or amnesia lasting more than 30 minutes is considered "moderate" and carries twice the risk of developing AD as people with no head injury. If loss of consciousness or amnesia lasts more than 24 hours, the injury is considered "severe" and carries a 4.5 times greater risk of developing AD than people with no head injury.

Risk Factors that Canbe Controlled:

Cardiovascular disease - Elevated cholesterol, high blood pressure (especially in midlife), damage to blood vessels, and stroke, elevate the risk of developing AD. Elevated cholesterol may contribute to AD by inhibiting the ability of the blood to clear unwanted protein fragments from the brain. The combination of cardiovascular risk factors may raise the risk of AD more than each condition alone. Type 2 diabetes - It is thought that elevated levels of sugar in the blood may harm the brain and contribute to the development or exacerbation of AD. A study published in Neurology 2008 (Vol.71(19):pp.1489-1495) concluded that a history of diabetes and/or a history of hypertension were independently associated with a shorter life span in patients with AD. Alzheimer's patients with diabetes were twice as likely to die sooner than AD patients without diabetes. Patients with AD who had high blood pressure were 2.5 times more likely to die sooner than patients with AD who did not have hypertension. This underscores the importance of rigorous management of independent risk factors including Type 2 diabetes and hypertension in patients with AD. Obesity - Obesity in midlife (body mass index of 25 or above) raises the risk of developing AD and also elevates the risk of vascular dementia. To read more about obesity and AD, please click on the following link: http://www.ncbi.nlm.nih.gov/pubmed/21536637 Educational level - Research suggests that individuals with higher levels of education may be less likely to develop AD.

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 Depression or other psychiatric illnesses. Inflammation - The development of protein plaques results in an inflammatory response. The relationship of inflammation to the etiology or exacerbation of AD is currently being investigated. Smoking has been identified as a risk factor for AD. To read more about smoking and AD, please click on the following link: http://www.ncbi.nlm.nih.gov/pubmed/20975015 There are also several environmental factors being studied that may contribute to the development of AD. These include aluminum, zinc, food-borne poisons, and viruses. In a study published in Neurology in 2005 (Volume 65, Issue 4; pp. 545-51), researchers studied four vascular risk factors (diabetes, smoking, hypertension, and heart disease) in 1,138 individuals over a five-year period. Subjects showed no sign of dementia at the beginning of the study. The authors found that diabetes and current smoking were the strongest risk factors for the development of AD, either alone or together, and that hypertension and heart disease alone or in clusters also increased the risk of AD. In addition, the risk of AD increased with the number of vascular risk factors. In people with three or more of these underlying conditions, their risk of developing AD went up nearly 3.5-fold compared with people with none of these risk factors. For more information about this study, please click on the following link: http://www.ncbi.nlm.nih.gov/pubmed/16116114 The Alzheimer's Association notes that African Americans may have a higher risk than Caucasians for developing AD, since they have higher rates of diabetes, hypertension (high blood pressure), elevated cholesterol, and vascular dementia, all of which are significant risk factors for AD.

Atrial Fibrillation and Alzheimer's Disease

In an article published in 2010 in Heart Rhythm (Vol.7(4):pp.433-7), researchers from the Intermountain Medical Center in Murray, Utah reported a link between atrial fibrillation and Alzheimer's disease. Atrial fibrillation is a common heart rhythm disorder (arrhythmia) which occurs when the upper two chambers of the heart (atria) quiver instead of beating synchronously. This irregular heartbeat increases the chances of blood clot formation that can lead to a stroke. Using information gathered from a database of 37,025 people ages 18 and older who were part of the Intermountain Healthcare network, the researchers reported the following major findings: Of the more than 37,000 people included in the study, more than 10,000 (27%) developed atrial fibrillation and 1,535 (4%) developed dementia. Subjects with atrial fibrillation were 44% more likely to develop any type of dementia as compared to subjects without atrial fibrillation. Subjects 70 years old or younger with atrial fibrillation were 130% more likely to develop dementia of the Alzheimer's type. Subjects with both atrial fibrillation and dementia were 61% more likely to die during the five-year study period than subjects with dementia alone.

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Based upon the findings of this study, the Utah researchers concluded that atrial fibrillation appears to be a risk factor for developing Alzheimer's disease with the highest risk noted among people age 70 or younger. Although the exact reason why atrial fibrillation increases the risk of developing AD was not determined by this study, the researchers hypothesized that some patients with atrial fibrillation may have suffered cerebrovascular accidents ("mini-strokes"), which put them at increased risk for developing dementia. The researchers also raised the intriguing possibility that perhaps the development of Alzheimer's disease may be prevented or delayed by managing atrial fibrillation in people ages 70 or younger. For more information about this study, please click on the following link: http://www.ncbi.nlm.nih.gov/pubmed/20122875

Warning Signs of Alzheimer's Disease

While some memory lapses are a part of the normal aging process, those related to AD are more severe than normal and they progress steadily. Even so, distinguishing between normal aging and early AD can be difficult. The Alzheimer's Association notes that some of the warning signs of AD include: Memory loss - Short-term memory loss is one of the most common early signs of dementia. Normal forgetfulness can result in occasionally forgetting a name or an appointment, but the individual with early AD forgets recently learned information more often and is not able to recall the information later. Difficulty performing familiar tasks such as making a phone call or preparing a meal. People with AD seem to lose track of the steps involved in the tasks they set out to perform. Problems with language, such as forgetting simple words or substituting unusual words in their place. Disorientation in time and space, such as getting lost in a familiar neighborhood and not knowing how to get home. Poor or decreased judgment, such as giving away large sums of money to telemarketers or dressing inappropriately for the weather. Problems with abstract thinking such as working with numbers. Misplacing things in unusual locations. Mood or behavior changes, such as rapid mood swings or uncharacteristic behavior for no apparent reason. Personality changes, such as becoming very fearful, suspicious, confused, or dependent. Loss of initiative or motivation, such as sitting in front of the television all day or sleeping more than usual.

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The Intelligent Patient Overview in the complete Medifocus Guidebook on Alzheimer's Disease also includes the following additional sections: Diagnosis of Alzheimer's Disease Treatment Options for Alzheimer's Disease The Role of Complementary Medicine in Alzheimer's Disease Psychosocial Considerations in Alzheimer's Disease Prevention of Alzheimer's Disease New Developments in Alzheimer's Disease Questions to Ask Your Health Care Provider

To Order the Complete Guidebook on Alzheimer's Disease Click Here Or Call 800-965-3002 (USA) or 301-649-9300 (Outside USA)

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3 - Guide to the Medical Literature

Introduction
This section of your MediFocus Guidebook is a comprehensive bibliography of important recent medical literature published about the condition from authoritative, trustworthy medical journals. This is the same information that is used by physicians and researchers to keep up with the latest advances in clinical medicine and biomedical research. A broad spectrum of articles is included in each MediFocus Guidebook to provide information about standard treatments, treatment options, new developments, and advances in research. To facilitate your review and analysis of this information, the articles in this MediFocus Guidebook are grouped in the following categories: Review Articles - 44 Articles General Interest Articles - 59 Articles Drug Therapy Articles - 10 Articles Clinical Trials Articles - 38 Articles

The following information is provided for each of the articles referenced in this section of your MediFocus Guidebook: Title of the article Name of the authors Institution where the study was done Journal reference (Volume, page numbers, year of publication) Link to Abstract (brief summary of the actual article)

Linking to Abstracts: Most of the medical journal articles referenced in this section of your MediFocus Guidebook include an abstract (brief summary of the actual article) that can be accessed online via the National Library of Medicine's PubMed database. You can easily access the individual abstracts online via PubMed from the "electronic" format of your MediFocus Guidebook by clicking on the URI that is provided for each cited article. If you purchased a printed copy of the MediFocus Guidebook, you can still access the abstracts online by entering the individual URI for a particular abstract into your computer's web browser.

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Recent Literature: What Your Doctor Reads

Database: PubMed <July 2009 to January 2012> Review Articles
1.

Diabetes mellitus and Alzheimer's disease: shared pathology and treatment?

Authors: Institution: Journal: Abstract Link: Akter K; Lanza EA; Martin SA; Myronyuk N; Rua M; Raffa RB Temple University School of Pharmacy, Philadelphia, PA19140, USA. Br J Clin Pharmacol. 2011 Mar;71(3):365-76. doi: 10.1111/j.1365-2125.2010.03830.x. http://www.medifocus.com/abstracts.php?gid=NR001&ID=21284695

2.

Memantine in dementia: a review of the current evidence.

Authors: Alonso ME.; Bello MJ.; Lomas J.; Gonzalez-Gomez P.; Arjona D.; De Campos JM.; Gutierrez M.; Isla A.; Vaquero J.; Rey JA.; Herrmann N; Li A; Lanctot K Division of Geriatric Psychiatry, Sunnybrook Health Sciences Centre, Faculty of Medicine, University of Toronto, Canada. Expert Opin Pharmacother. 2011 Apr;12(5):787-800. Epub 2011 Mar 9. http://www.medifocus.com/abstracts.php?gid=NR001&ID=21385152

Institution: Journal: Abstract Link:

3.

Physical exercise alleviates debilities of normal aging and Alzheimer's disease.

Author: Institution: Journal: Abstract Link: Archer T Department of Psychology, University of Gothenburg, Gothenburg, Sweden. Trevor.archer@psy.gu.se Acta Neurol Scand. 2011 Apr;123(4):221-38. doi: 10.1111/j.1600-0404.2010.01412.x. Epub 2010 Sep 29. http://www.medifocus.com/abstracts.php?gid=NR001&ID=20880302

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The Guide to the Medical Literature in the complete Medifocus Guidebook on Alzheimer's Disease includes the following sections: Review Articles - 44 Articles General Interest Articles - 59 Articles Drug Therapy Articles - 10 Articles Clinical Trials Articles - 38 Articles

To Order the Complete Guidebook on Alzheimer's Disease Click Here Or Call 800-965-3002 (USA) or 301-649-9300 (Outside USA)

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4 - Centers of Research
This section of your MediFocus Guidebook is a unique directory of doctors, researchers, medical centers, and research institutions with specialized research interest, and in many cases, clinical expertise in the management of this specific medical condition. The Centers of Research directory is a valuable resource for quickly identifying and locating leading medical authorities and medical institutions within the United States and other countries that are considered to be at the forefront in clinical research and treatment of this disorder. Use the Centers of Research directory to contact, consult, or network with leading experts in the field and to locate a hospital or medical center that can help you. The following information is provided in the Centers of Research directory: Geographic Location United States: the information is divided by individual states listed in alphabetical order. Not all states may be included. Other Countries: information is presented for select countries worldwide listed in alphabetical order. Not all countries may be included.

Names of Authors Select names of individual authors (doctors, researchers, or other health-care professionals) with specialized research interest, and in many cases, clinical expertise in the management of this specific medical condition, who have recently published articles in leading medical journals about the condition. E-mail addresses for individual authors, if listed on their specific publications, is also provided.

Institutional Affiliations Next to each individual author's name is their institutional affiliation (hospital, medical center, or research institution) where the study was conducted as listed in their publication(s). In many cases, information about the specific department within the medical institution where the individual author was located at the time the study was conducted is also provided.

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Centers of Research
United States
AZ - Arizona
Name of Author Aisen PS Caselli RJ Institutional Affiliation Banner Alzheimer's Institute, 901 E Willetta St., Phoenix, AZ 85006, USA. pierre.tariot@bannerhealth.com Department of Neurology, Mayo Clinic Arizona, 13400 East Shea Boulevard, Scottsdale, AZ 85259, USA. Caselli.Richard@Mayo.edu The Cleo Roberts Center for Clinical Research, Banner Sun Health Research Institute, Sun City, Arizona, USA. marwan.sabbagh@bannerhealth.com Department of Neurology, Mayo Clinic, Mayo Clinic Hospital, Phoenix, AZ 85054, USA. Banner Alzheimer's Institute, 901 E Willetta Street, Phoenix, AZ 85006, USA. Adam.fleisher@bannerhealth.com Department of Neurology, Mayo Clinic Arizona, 13400 East Shea Boulevard, Scottsdale, AZ 85259, USA. Caselli.Richard@Mayo.edu Department of Neurology, Mayo Clinic, Mayo Clinic Hospital, Phoenix, AZ 85054, USA. The Cleo Roberts Center for Clinical Research, Banner Sun Health Research Institute, Sun City, Arizona, USA. marwan.sabbagh@bannerhealth.com Banner Sun Health Research Institute, The Cleo Roberts Center for Clinical Research, 10515 West Santa Fe Drive, Sun City, AZ 85351, USA. marwan.sabbagh@bannerhealth.com Banner Sun Health Research Institute, The Cleo Roberts Center for Clinical Research, 10515 West Santa Fe Drive, Sun City, AZ 85351, USA. marwan.sabbagh@bannerhealth.com Banner Alzheimer's Institute, 901 E Willetta St., Phoenix, AZ 85006, USA. pierre.tariot@bannerhealth.com

Cummings J

Demaerschalk BM Fleisher AS Reiman EM

Riordan KC Sabbagh M

Sabbagh MN

Shill HA

Tariot PN

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The Centers of Research in the complete Medifocus Guidebook on Alzheimer's Disease includes the following sections: Centers of Research for relevant states in the United States Centers of Research listed for relevant countries outside the United States To Order the Complete Guidebook on Alzheimer's Disease Click Here Or Call 800-965-3002 (USA) or 301-649-9300 (Outside USA)

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5 - Tips on Finding and Choosing a Doctor

Introduction
One of the most important decisions confronting patients who have been diagnosed with a serious medical condition is finding and choosing a qualified physician who will deliver a high level and quality of medical care in accordance with currently accepted guidelines and standards of care. Finding the "best" doctor to manage your condition, however, can be a frustrating and time-consuming experience unless you know what you are looking for and how to go about finding it. The process of finding and choosing a physician to manage your specific illness or condition is, in some respects, analogous to the process of making a decision about whether or not to invest in a particular stock or mutual fund. After all, you wouldn't invest your hard eared money in a stock or mutual fund without first doing exhaustive research about the stock or fund's past performance, current financial status, and projected future earnings. More than likely you would spend a considerable amount of time and energy doing your own research and consulting with your stock broker before making an informed decision about investing. The same general principle applies to the process of finding and choosing a physician. Although the process requires a considerable investment in terms of both time and energy, the potential payoff can be well worth it--after all, what can be more important than your health and well-being? This section of your Guidebook offers important tips for how to find physicians as well as suggestions for how to make informed choices about choosing a doctor who is right for you.

Tips for Finding Physicians

Finding a highly qualified, competent, and compassionate physician to manage your specific illness or condition takes a lot of hard work and energy but is an investment that is well-worth the effort. It is important to keep in mind that you are not looking for just any general physician but rather for a physician who has expertise in the treatment and management of your specific illness or condition. Here are some suggestions for where you can turn to identify and locate physicians who specialize in managing your disorder: Your Doctor - Your family physician (family medicine or internal medicine specialist) is a good starting point for finding a physician who specializes in your illness. Chances are that your doctor already knows several specialists in your geographic area who specialize in your illness and can recommend several names to you. Your doctor can also provide you with information about their qualifications, training, and hospital affiliations.

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The Tips on Finding and Choosing a Doctor in the complete Medifocus Guidebook on Alzheimer's Disease includes additional information that will assist you in locating a highly qualified and competent physician to manage your specific illness. To Order the Complete Guidebook on Alzheimer's Disease Click Here Or Call 800-965-3002 (USA) or 301-649-9300 (Outside USA)

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6 - Directory of Organizations
Alzheimer's Association
225 North Michigan Avenue 17th Floor Chicago, IL 60601 800.272.3900 info@alz.org www.alz.org

Alzheimer's Disease Research

22512 Gateway Center Drive Clarksburg, MD 20871 800.437.2423 info@ahaf.org www.ahaf.org/alzheimers

Alzheimer's Drug Discovery Foundation

1414 Avenue of the Americas Suite 1502 New York, NY 10019 212.935.2402 hfillit@alzdiscovery.org www.alzdiscovery.org

Alzheimer's Foundation of America

322 8th Avenue 7th Floor New York, NY 10001 866.232.8484 www.alzfdn.org

Alzheimer's Research Forum

82 Devonshire Street S9 Boston, MA 02109 www.alzforum.org

Alzheimer's Weekly
73 Warren Street New York, NY 10007 201.467.4746 www.alzheimersweekly.com

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The Directory of Organizations in the complete Medifocus Guidebook on Alzheimer's Disease includes a list of selected disease organizations and support groups that are helping people diagnosed with Alzheimer's Disease. To Order the Complete Guidebook on Alzheimer's Disease Click Here Or Call 800-965-3002 (USA) or 301-649-9300 (Outside USA)

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This document is only a SHORT PREVIEW of the Medifocus Guidebook on Alzheimer's Disease. It is intended primarily to give you a general overview of the format and structure of the Guidebook as well as select pages from each major Guidebook section listed in the Table of Contents. To purchase the COMPLETE Medifocus Guidebook on Alzheimer's Disease (154 pages; Updated February 10, 2012), please: Call us at: 800-965-3002 (United States) 301-649-9300 (Outside the United States) Order online through our website: Printed Version Mailed to you and bound for easy reading. Includes free online access to the electronic guidebook for one full year.

Electronic Version Adobe PDF document that can be viewed or printed on any computer Online updates are included for one full year.

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Disclaimer
Medifocus.com, Inc. serves only as a clearinghouse for medical health information and does not directly or indirectly practice medicine. Any information provided by Medifocus.com, Inc. is intended solely for educating our clients and should not be construed as medical advice or guidance, which should always be obtained from a licensed physician or other health-care professional. As such, the client assumes full responsibility for the appropriate use of the medical and health information contained in the Guidebook and agrees to hold Medifocus.com, Inc. and any of its third-party providers harmless from any and all claims or actions arising from the clients' use or reliance on the information contained in this Guidebook. Although Medifocus.com, Inc. makes every reasonable attempt to conduct a thorough search of the published medical literature, the possibility always exists that some significant articles may be missed.

Copyright
Copyright 2011, Medifocus.com, Inc. All rights reserved as to the selection, arrangement, formatting, and presentation of the information contained in this report, including our background and introductory information.

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