Alzheimer’s Disease - Is A Treatment About to be Approved?
by Diana Price, Medical Reviewer Dr. CH Weaver M.D. Editor
Aducanumab (BIIB037) was being developed by as a possible therapy for Alzheimer’s disease (AD) however it was previously determined that there was insufficient evidence supporting the effectiveness of aducanumab in treating the disease and development was halted. Biogen, the developer of the medication has announced that based on a new analyses of data they plan to submit an application to the US Food and Drug Administration seeking approval as a treatment for AD.
Alzheimer’s disease is a progressive neurodegenerative disorder characterized by deposits of protein structures called amyloid in the brain, leading to brain cell death. In Alzheimer’s disease, amyloid aggregates into clumps that can disrupt communication between brain cells and cause their death.
Aducanumab is a monoclonal antibody that targets amyloid and can reduce the number of amyloid plaques that develop in the brain. By reducing the number of amyloid plaques, aducanumab could slow neurodegeneration and disease progression.
Biogen has sponsored several clinical trials, the results of which were not thought to support an FDA approval of aducanumab. The companies press release surprised the market today and patients and investors await release of the new information that the company believes will support its FDA application.
Millions of Americans are affected by Alzheimer’s disease, but most of us are in denial as to the impact of this major—public and personal—health issue. Read on to hear from experts and patients about what we all should know about the disease.
Ask most of your friends and acquaintances what they know about Alzheimer’s disease (AD), and you may be in for a short conversation. Responses from those not personally affected may range from downcast eyes and mournful head shaking to exclamations of “such a sad thing” and “really terrible.” A few brave souls will venture forth with “I do a daily crossword puzzle” or with descriptions of nutritional supplements and Sudoku challenges. Sadly, those who have been personally affected—through the diagnosis of a friend or family member—may not be willing to say much, either, afraid of sharing details of a disease still shrouded by stigma and stifled by a lack of public awareness.
The fact is we should be talking a lot more about AD, which is without doubt a major public health issue today and one we will see explode in coming years. More than 5 million Americans are living with AD today, and that number is projected to reach between 11 and 16 million by 2050.1,2 Despite these high numbers, discussions on the topic to this point have been largely missing from our collective healthcare consciousness.
Harry Johns, president and CEO of the Alzheimer’s Association, says that the lack of dialogue on the topic stems from many of the same issues that inhibited our discussion of cancer for many years. “There is great similarity in the unwillingness to talk about the two diseases,” Johns says, including social stigma and a lack of information about the disease. “People still tend to think of AD as normal aging or a little memory loss. We still today have ignorance and denial.”
In fact, AD is a progressive, degenerative, and fatal disease, and there is no current treatment available to prevent it or to stop its progression. “The fatality part is one thing that people don’t know,” Johns says. “If you are diagnosed with Alzheimer’s disease, you will die with it or of it.” Here are some other statistics Johns says we should all know:
- Someone develops AD every 69 seconds in the United States.
- AD is the sixth underlying cause of death in this country, claiming more lives than diabetes and more lives than breast and prostate cancers combined.
- The costs—human and economic—are huge: there are nearly 15 million AD caregivers in the United States, and the direct and indirect cost of AD and other dementias is $183 billion per year.1
So what can we do? First, we can learn more about AD and about how it affects patients and caregivers. By understanding more about the disease and its impacts on individuals and society, we can move research funding along more rapidly and, ultimately, find a cure. “We have to have the same conversation about Alzheimer’s [as with cancer],” Johns says. “If we can get people to talk about it, we can change investments at the federal level; if we have a conversation about it, we can make a real difference.”
Alzheimer’s Disease 101
Discovered in 1906 by the German psychiatrist and neuropathologist Alois Alzheimer, AD is a progressive degenerative disorder of the central nervous system (the brain and the spinal cord), characterized by memory loss and other cognitive changes that ultimately result in loss of bodily functions and death. There are two types of AD: late-onset Alzheimer’s disease (LOAD) is the most common, with symptoms generally appearing after the age of 65; early-onset Alzheimer’s disease—also known as familial Alzheimer’s disease (FAD)—is more rare. Caused by a gene mutation, FAD is marked by symptoms that appear before age 50 and a strong family history in which 50 percent of every generation develops the disease.
Symptoms of AD, including dementia (see sidebar on page 75), difficulty with problem solving, decreased or poor judgment, and mood changes (see sidebar on page 79 for more signs and symptoms), are the result of nerve cell damage and nerve cell death. The damage to the cells is thought to be, in part, the result of plaques and tangles in the brain resulting from the production and the accumulation of beta-amyloid, a protein fragment that accumulates in (plaques) and among (tangles) nerve cells.
Despite growing knowledge of the pathology, or origins, of the disease, there is still much that researchers don’t know about how and when AD first develops. What has been established through research over the past 30 years, however, is the fact that things are not as black-and-white as originally thought; patients are not healthy one day and demented the next. Rather, biochemical changes that bring on the characteristic symptoms are occurring in the brain far in advance of any cognitive or memory changes.
Laurie Ryan, PhD, program director for Alzheimer’s disease clinical trials at the National Institute on Aging, says, “There is a growing body of evidence that suggests that the underlying pathology precedes the onset of clinical symptoms [of AD] by at least a decade. By the time you get diagnosed with Alzheimer’s, there’s thought to be massive neuronal loss and widespread pathology in the brain.”
Is There a Genetic Link?
At this point no single gene has been linked with the development of LOAD, although the APOE gene has been found to confer a high risk of developing the disease.3 While this gene, and specifically its APOE-e4 variant—which influences age at onset of the disease—can be a genetic predictor, not everyone who is found to carry this gene develops LOAD.
Familial Alzheimer’s disease, which accounts for less than 5 percent of all AD cases, is considered hereditary—children of a parent who has FAD have a 50/50 chance of developing the disease.4 Researchers have linked the development of FAD to mutations in three genes (APP, presenilin 1, and presenilin 2) related to beta-amyloid production.5
Are You at Risk?
The most significant risk factor for AD is age. Most often diagnosed in people over 65, the disease is thought to affect almost half of all Americans over the age of 85.2 This is especially noteworthy in light of the fact that life expectancy continues to rise (it’s almost 80 in the United States now and will be even higher by 2040).6 “We’re really facing a rapidly aging population—and not just the US and other western countries,” Dr. Ryan says. “It’s actually also happening in developing nations as well.”
Other risk factors for AD include family history, head injury, cardiovascular risk factors (high blood pressure, high cholesterol, and high homocysteine), diabetes, diet, social engagement, education, exercise, and social interaction. Although our behavior can affect some of these risk factors, others, like age, are not modifiable.
Research related to lifestyle factors and AD prevention is ongoing, both in animal studies and through observational studies in humans. According to Dr. Ryan, studies to this point have included investigations of links between the Mediterranean diet and AD prevention as well as the impact of exercise, dietary supplements, and social engagement. Despite promising early results from these animal and observational studies, however, there is no significant evidence from clinical trials to support the idea that we can prevent the development of AD by modifying our behavior or by using pharmaceutical interventions or dietary supplements.7
Still, Dr. Ryan cautions that it’s not time to abandon healthy living. “What I tell people is, ‘Can we tell you that exercise can prevent Alzheimer’s? No. But we know that exercise looks like it does a lot of good things for the brain. Healthy lifestyles are not going to hurt you, and it’s something you can do.’” Similarly, though no definitive findings are available regarding dietary modifications, Dr. Ryan encourages a healthy diet for its overall positive benefit and its potential benefit in prevention; and, finally, she says that efforts toward staying socially active and mentally challenged are also a good idea. “Doing crosswords is not going to stop you from getting Alzheimer’s,” she says, “but staying interested and active in new things is important. These are observational studies, but the animal data, I think, is pretty compelling.”
The process of an AD diagnosis most often begins with a primary care physician and likely also includes a neurologist or geriatrician. A diagnosis is generally a multifaceted effort, requiring a detailed patient history, information from family and friends, and physical, neurological, and neuropsychological exams and lab tests.6 Ideally, this process leads to the discovery of criteria specific to AD that distinguish the disease from other forms of dementia (see sidebar at right for information about other types of dementia).
The current criteria, published in April of this year by three expert workgroups spearheaded by the Alzheimer’s Association and the National Institute on Aging of the National Institutes of Health, include cognitive or behavioral symptoms that:
- Interfere with the ability to function at work or at usual activities; and
- Represent a decline from previous levels of functioning and performing; and
- Are not explained by delirium or major psychiatric disorder.
- Cognitive impairment is detected and diagnosed through a combination of (1) history- taking from the patient and a knowledgeable informant and (2) an objective cognitive assessment.
- The cognitive or behavioral impairment involves a minimum of two of the following:
- Impaired ability to acquire and remember new information
- Impaired reasoning and handling of complex tasks, poor judgment
- Impaired visuospatial abilities
- Impaired language function (speaking, reading, writing)
- .Changes in personality, behavior, or comportment8
These criteria represent an important advance in diagnosing AD, says Dr. William Thies, PhD, chief medical and scientific officer at the Alzheimer’s Association: “It is our hope that incorporating scientific knowledge gained and technological advances made over the past quarter century will improve current diagnosis, bring the field closer to earlier detection and treatment, and ultimately lead to effective disease-modifying therapies. Development and publication of these articles is a major landmark in the field.”
But why should we be concerned with diagnosing AD early when there is currently no treatment available? Dr. Ryan says that despite the current lack of treatment, an early diagnosis does provide benefits. “Families have time to plan for the future if we diagnose early,” she says. “You could also have a decrease in healthcare costs if you identify early; and the hope is that when we do have treatments, patients will be able to start these earlier and they will be more effective.”
There is no medication available today that slows or stops the progression of AD. Two treatments, however, have been approved by the Food and Drug Administration to treat the cognitive symptoms of the disease: cholinesterase inhibitors (Aricept® [donepezil], Exelon® [rivastigmine], Razadyne® [galantamine], Cognex® [tacrine]) and memantine (Namenda®). While these treatments do help some patients, the disease ultimately progresses and overwhelms the impact of the medicine (generally in one to two years), leaving patients with no other treatment options.
Dr. Thies says that while the impact of these medications is not significant for everyone affected by AD, the benefit they can provide for some families should not be underestimated. “As a pharmacologist looking at the clinical trial data, my initial response was, This is really underwhelming. But the fact is that being out and talking to lots of people who have observed a loved one with AD, the sort of things I hear are ‘This gave me six more months to talk to my mother’ or ‘This gave me a period of closure with my dad where I could really communicate some things with him.’ That sort of information does not transfer well into clinical trials. We don’t collect that information, and it’s very difficult to quantify. On the other hand, I’ve been convinced in having lots of conversations with people that these drugs do benefit some folks; they don’t benefit everybody, and that’s another cause for dissatisfaction.”
Dr. Ryan acknowledges that these treatments do provide temporary cognitive improvement and deferred decline in some patients but says that the real, significant advance in treatment will occur when a medication is developed that will at least slow the progression of the disease. “If we could slow it down by even five years,” Dr. Ryan says, “people would actually die from other conditions. If they weren’t cognitively impaired, the morbidity associated with Alzheimer’s wouldn’t be as bad. Even just slowing it down would be a huge boost to individuals and society.”
James Cooper, MD, director of the Memory Disorders Clinic and clinical professor of medicine in the Division of Geriatrics and Palliative Care at George Washington University Medical Center, believes that instead of emphasizing the value of current symptomatic treatments, we should instead focus on helping families manage the realities of caregiving and the lifestyle changes that accompany a diagnosis. “I believe we can do more good by encouraging a behavioral treatment approach to AD than with any medications we have,” Dr. Cooper says. Such an approach, which might include support services such as respite care for caregivers, psychological counseling for families, and improved assisted-living and long-term care options, is aimed at improving quality of life. “[These patients] have AD, and they will probably die from it in six to eight years; we need to make them as comfortable as we can. To make them comfortable, we need to make the family and the caregiver comfortable because that’s the interaction in which they live.”
Though there are clearly differing views of the value of current treatment options, there is no doubt that additional and more-effective treatments—aimed at slowing or stopping the progression of the disease, rather than treating symptoms—are needed.
This article presents a very general overview of AD and only skims the surface of the many issues involved in this growing public health concern. Individuals, families, and the federal government will need to dig deeper in coming years as we are forced to come to terms with the size and the scope of this disease and its broad impact. We will need to ask how we, as individuals, want to be cared for; we will need to have honest and open discussions with our families about how AD might affect our lives—and plan accordingly; and we will need to ask our government how it will work to fund research related to AD. These and many more questions await answers, and there is much work to be done.
Advances in Research
New diagnostic tests and more information about the pathology of AD bring hope in the effort to slow or stop the disease.
Patients diagnosed with AD today have few options for treatment, with current medications only treating some of the symptoms some of the time. Still, researchers are hopeful that recent advances in diagnostic testing and continued investigations into the cause of the disease will lead to more and better treatments in the future.
“We’ve made some huge leaps recently, and the name of the game is biomarkers,” says Laurie Ryan, PhD, program director for Alzheimer’s disease clinical trials at the National Institute on Aging. Biochemical biomarkers reflect changes in the brain due to AD, including changes in levels of beta-amyloid and tau—two proteins that form abnormal deposits strongly linked to the disease—in cerebrospinal fluid and, potentially, in blood and urine.6
Dr. Ryan likens these biomarkers to cardiovascular biomarkers that have become common indicators of heart disease. “For cardiovascular disease, we have cholesterol,” Ryan says. “Everyone knows that cholesterol is a risk factor for cardio disease. You identify early; if there’s a problem, you prescribe a statin. If we can identify AD early, then—when we have treatment—we can intervene.”
The next step now that some of these biomarkers have been identified, Dr. Ryan says, is to validate these indicators to allow for earlier diagnosis and potentially more-effective treatment. “We don’t have well-validated markers for AD yet—we don’t have our cholesterol—but we have some that are looking very promising.”
Steven DeKosky, MD, the James Carroll Flippin professor of medical science and the vice president and dean of the University of Virginia School of Medicine, says that the current emphasis on biomarkers is the result of research that has led to our increased understanding of the development of AD. “The natural history of AD is that people who are relatively stable in cognitive status begin to experience cognitive decline, which leads to diagnosis. As the first drugs were developed, we got beyond confirming diagnosis to monitoring effects of therapy. Then we moved back and started being able to identify the disease at earlier and earlier time points, which resulted in a longer care period. Now we have backed up to the point where we are looking at preclinical detection—finding evidence of the disease in the brain before any symptoms are present, in anticipation of medications that could be given to asymptomatic people that would delay emergence of symptoms or slow progression.”
Ultimately, Dr. DeKosky says, biomarkers will truly be valuable when we can move beyond using them as research tools (which is how all such markers start out) and actually help treat the disease that they allow us to diagnose: “It’s very clear that we can identify people who have the amyloid protein deposits in their brains even before they have any symptoms.” Why would you want to be able to do that without a treatment? “It just happens that the research on preclinical detection is a bit ahead of effective treatments,” Dr. DeKosky says. “It has been valuable research to this point, but what will change the game immediately is the first drug that’s effective—and being able to use it in people who have no memory loss but evidence of disease in their brains. To identify them and give medications to stop the disease’s advance will be the great contribution of biomarkers.”
William Thies, PhD, chief medical and scientific officer at the Alzheimer’s Association, believes that the validation of biomarkers that allow for a more specific, early diagnosis of AD will push demand for drugs to treat patients in these early stages. “We’re going to find our first drugs in people with AD or early AD,” Dr. Thies says. “Patients will demand treatments earlier and earlier. Physicians will be more comfortable treating patients who retain as much function as possible.” And, Dr. Thies adds, the development of these drugs is imminent: “We will get to the point in the foreseeable future when we will have the kinds of medications that will make a difference.”
Though you may hear people using the word dementia interchangeably with Alzheimer’s disease, the fact is that dementia is actually a group of symptoms, not a disease. Dementia is generally marked by decreased cognitive (brain) function; it’s progressive, it’s new, it will cause memory loss, and it’s not caused by any other conditions such as depression, metabolic abnormalities, or other medical conditions (heart failure or lung disease, for example).9 Alzheimer’s disease is the most common form of dementia; other types include vascular, Lewy body, frontotemporal lobe, traumatic brain injury, Parkinson’s disease, alcohol, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and human immunodeficiency virus (HIV).
Living with “Big Al”
One couple describes their experience living with Alzheimer’s disease.
“My wife has always been the one in the forefront—the type A personality,” says Jerry Embry, describing his wife of 43 years. “When something needed to get done, everyone went to Libby—and she took the ball and ran with it.”
But about four years ago, Libby began to feel that she could no longer be that go-to person: she was having trouble remembering meetings, she couldn’t complete basic computer tasks, and she found herself getting lost around the town she’d lived in for 25 years.
“It was just so upsetting for me. And I kept thinking to myself, What is wrong with me? Why is this happening?” But the fact is that Libby did have an idea of what was happening, and she was terrified. She had been her father’s caregiver after he had been diagnosed with Alzheimer’s, and she also had memories of her grandfather’s battle with the disease.
Libby decided to retire, hoping that simplifying her life would make a difference. Unfortunately, it soon became clear that things weren’t getting better; in fact, they were getting worse. Having kept most of her concerns to herself, Libby finally told Jerry the extent of her troubles. Though there had been a couple of incidents that had made Jerry aware that there was a bigger problem than Libby had acknowledged, he was surprised when she described the extent of her concern. “I had no earthly idea she had been getting lost,” Jerry says. “So I said, ‘Okay, we’ll go see the doctor.’” And with that initial visit to the family physician, “It was pretty cut and dried,” Jerry says.
Libby was diagnosed with familial Alzheimer’s disease—or, as she likes to say, “Big Al”—in 2007 at the age of 59. Though the initial diagnosis was devastating, she soon realized she had a choice to make. “For two weeks I curled up in the fetal position and bawled. I just couldn’t face it because I knew what was in store—I had seen my dad. But after two weeks, the medication kicked in and I was feeling a little better, and I thought, What am I going to do, just lie here and cry until Big Al comes and takes me away, or am I going to get up and live while I can? And I did.”
Four years later Libby is still learning to navigate her life with Big Al. Medication has made a difference for her, and she feels lucky to still live a very full life. She works part-time in a dress shop, spends time with her children and grandchildren, and still enjoys regular outings with friends. She also works hard to raise awareness about Alzheimer’s disease, traveling to give speeches on the topic and lobbying Congress in Washington, DC.
Still, Libby has hard days. “I forget things all the time,” she says. “I totally forget conversations, and I’m not much good after 7 p.m. Jerry finds me just sitting in a stupor, and he puts me to bed—and I remember none of it. It makes me sad because I know it’s going to get worse and there are going to be really meaningful things that I forget.”
Especially difficult for Libby to contemplate is the idea that she will lose precious time with her grandchildren. She becomes very emotional in describing a conversation she had with her grandson, Synott, when she told him about her diagnosis. “He asked, ‘Nana, do you think you’ll ever forget me?’” Libby says. “And I said, ‘Well, Synott, I will always remember you because you will always be in my heart. And if it ever seems as though I have, you’ll be able to take my hand and look into my eyes and know in your heart that I could never forget you.’” At the conversation’s end, Libby says, Synott told her, “Nana, you’re in every one of my best memories,” and Libby was able to tell him that he was also in every one of hers.
For Jerry the biggest challenge has been accepting that Libby has the disease and acknowledging his wife’s new limitations. “To be quite honest, I’ve had a rough time with this—with accepting it. I forget that Libby’s got this quite often. I forget what she’s going through. I expect things to be like they were 10 years ago, and I know it can’t be. That’s what bugs me so much—that I constantly forget that my wife has got this problem.”
Though the new normal of their life with Big Al has brought its challenges, Libby and Jerry are moving forward, determined to enjoy the time they have together. “I look at things very differently now,” Libby says. “I try to take joy in a lot of the little things—like spending time with my grandkids and things like that. If I forget something minor, I don’t look at it like a big deal anymore; it used to devastate me to know that I’d forgotten, and now I think, That’s minor—I didn’t forget that I played with the grandkids yesterday. I’ve got a great husband and I have great kids and grandkids and wonderful friends who all keep me going.”
Research Funding & Advocacy
The Alzheimer’s Association works to raise awareness and funds.
Harry Johns, president and CEO of the Alzheimer’s Association, is pretty frank when he describes the frustration of AD patients, families, and advocates about the lack of awareness and treatment options available today. “There’s nothing good I can say about this disease,” Johns says. “And there’s nothing much I can say good about what has happened at the federal level about this disease. We need real action, and we don’t have that much time.”
The biggest impediment up to this point, according to Johns, has been a lack of research funding. “The investment on the federal level for cancer research is about $6 billion per year; the NIH [National Institutes of Health] budget for cardiovascular is about $4 billion per year; HIV/AIDS gets around $3 billion per year. For Alzheimer’s it’s $450 million per year. Alzheimer’s disease is disproportionally underinvested.”
Despite the disheartening figures, Johns says, he remains hopeful that research—which has made strides despite the lack of funding—can be propelled by increased public awareness and federal support. “There is a general consensus that we have learned a lot despite the underinvestment,” he says, “and we’re poised to go to other levels if we can get the next investments.”
Recent legislation is a hopeful indicator that lawmakers are ready to direct more resources to AD. In January of this year, President Barack Obama signed the National Alzheimer’s Project Act into law, recognizing the public health crisis that AD represents and creating a national strategic plan for confronting the disease.
The law builds on the work of the Alzheimer’s Association, which, Johns says, is dedicated to accelerating research and bringing about real change in the lives of those affected by the disease. “Our mission is to eliminate the disease through advancement of research, to provide enhanced care and support for those affected, and to reduce the risk of dementia through the promotion of brain health.” The ultimate goal? A world without Alzheimer’s disease.
The largest private, nonprofit funder of Alzheimer’s research, the Alzheimer’s Association provides information, support, and advocacy opportunities for patients and caregivers. The organization’s website (www.alz.org) provides valuable background information about the disease, highlights breaking news about research, hosts message boards, and provides links to a 24-hour hotline, among other resources for patients and caregivers. In addition, local chapters across the country provide support groups and educational workshops.
Eleven million Americans today provide care for a family member or friend with Alzheimer’s disease. For those caregivers, making the choice—or having the choice thrust upon them—to care for a person living with Alzheimer’s is life changing.
Harry Johns, president and CEO of the Alzheimer’s Association, says that for many caregivers, caring for an Alzheimer’s patient is an all-encompassing, 24-hour job. “Caregivers often give up time at work, lose jobs, spend their own money, and lose their own health.” There’s a reason, he says, that one of the most popular books about Alzheimer’s caregiving is called The 36-Hour Day (by Nancy L. Mace and Peter V. Rabins; Johns Hopkins University Press, 2006).
The challenges are indeed significant, especially because of the often long-term nature of the role, says Howard Gleckman, author of Caring for Our Parents: Inspiring Stories of Families Seeking New Solutions to America’s Most Urgent Health Crisis (St. Martin’s Press, 2009) and resident fellow at The Urban Institute. The duration of care for dementia patients is quite a bit longer than that required by other frail elderly populations, Gleckman says, with one-third of dementia patients requiring care for five years or more. This extended period of caregiving takes a major toll on many aspects of caregivers’ lives, affecting them physically, emotionally, and financially.
Physically, caregivers are regularly transferring patients from one place to another—including from the bed to a chair or wheelchair, back and forth to the bathroom, and in and out of the shower. This type of caregiving can also be particularly challenging emotionally, Gleckman says: “There’s frustration because you’re trying to help and are getting nothing obvious back [from the patient].” And because much of the time involved in caregiving each day for an Alzheimer’s patient revolves around watching and waiting for a potential fall or another issue, there is constant stress related to waiting for the next emergency. “It’s much more difficult to be doing nothing for a patient than to be productively helping,” he says.
Because of the near-constant vigilance required of the caregiver, isolation becomes an issue; friends often withdraw, and it’s difficult to get out of the house. “The world becomes smaller and smaller for caregivers and patients,” Gleckman says, and the result is high rates of depression. The financial impact on caregivers is also substantial. “One of the things people don’t think about much is the consequences on caregivers, not just in terms of their current situation but in terms of the future,” Gleckman says. “Quitting a job means no income in the present and less put away for retirement and less for Social Security.”
For caregivers in this role, respite care—short-term temporary relief that allows the caregiver an emotional and physical break—can be critical. Depending on the caregiver’s location and financial resources, respite care options might include adult day care or a home health aid or other in-home care provider. Attending a caregiver support group can also be very helpful, allowing caregivers to share their experiences and get support from others who are in a similar situation. For caregivers who have trouble getting away, the Alzheimer’s Association staffs a 24-hour helpline at (800) 272-3900.
- Alzheimer’s Association. 2011 Alzheimer’s disease facts and figures. Alzheimer’s and Dementia. 2011;7(2):12-45.
- Hebert LE, Scherr PA, Bienias JL, Bennett DA, Evans DA. Alzheimer disease in the US population. Archives of Neurology. 2003;60:1119-22.
- Bird TD. Genetic aspects of Alzheimer’s disease. Genetics in Medicine. 2008;10(4): 231-39.
- Timashenka Geiger A, Morgan O, Meyer K, Skelton K, eds. The Shriver Report: A Woman’s Nation Takes on Alzheimer’s: A Study by Maria Shriver and the Alzheimer’s Association. Alzheimer’s Association; 2010.