text:
A Womans Health
Health & Conditions
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. The Phase III EMERGE clinical trial met its primary endpoint, showing a significant decrease in clinical decline. Biogen plans to file a Biological License Application in the third quarter of 2020.
About Aducanumab
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
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.
Maria Shriver Discusses New Research Efforts
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."
Dementia Defined
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.
No. 1-19
Jboynew
Magnificent article, a debt of gratitude is in order for assembling this! This is clearly one extraordinary post. A debt of gratitude is in order for the important data and experiences you have so given here.
Just School News — Latest and Current Educational Update Portal in Nigeria
Latest and Current Educational Update Portal in Nigeria
www.justschoolnews.com
MarySanchez
A terrific day to start something new and also end up being a successful person, because every person desires it! Do you wish to purchase a brand-new big house, or buy a car, or satisfy your cherished desire? I have introduced a start-up that already collaborates with minimal investment we obtain the optimum revenue! Our customers are always completely satisfied, because we understand how to generate income, and also exactly how to boost them. We want to learn more about you immediately at https://www.gameloginapponline.com
FunCasino | www.funcasino.com | Play for Fun and not Only for Victories | Review
Fun Casino. Because the Most Important Thing is the Player's Mood! About FunCasino Selection of
www.gameloginapponline.com
SmithJohn7
Our platform provides a wide variety of affordable and amazing products. We deliver inspired finds for women, men, kids, auto, gadgets and much more. Discover luxury steals at discounted prices all year long.
Cheapnotic | Online Cheap Shopping
At Cheapnotic Online Store you can purchase the best brands for Men and Women Clothing like cheap clothes, Cheap shoes, cheap bags and Cheap accessories with best quality.
cheapnotic.com
Ugoori
With regularly held employee events, the friendly exchange shall also be fostered aside the working day. https://gigarettes.com/marlboro/46-marlboro-gold.html
Marlboro Gold (Lights) – Free shipping. Cheap UK store.
Get Marlboro Gold (former Lights ) cigarettes online. Classical light taste along with regular king size. Free international delivery for ANY order. Iconic tobacco brand at lowest price.
gigarettes.com
Assignment promised to serve students across the world at a cheap rate assignment writing service. The proficient writers UK are available at this platform. We are the best in meeting deadlines and offer the research-based quality of content.
Assignment Writing Service UK – We serve the best Assignment Writing Service.
Assignment.Org.UK promised to serve students across the world at a cheap rate assignment writing service. The proficient writers UK are available at this platform. We are the best in meeting deadlines and offer the research-based quality of content.
assignment.org.uk
Best Dissertation is the leading UK brand exist in the market to serve students by sharing their academic burden. We excel in producing research-based content for students within a promising time frame. The ardent interest of our organization is to offer cheap dissertation writing service for all students without any discrimination. In the modern age where all niches are become digitalize, we have been striving to spread education by offering fair and immaculate services to students throughout the world.
Dissertation Help UK - Dissertation Writing Service UK - Online Writers UK
Dissertation Writing Service UK Online overcomes all your Dissertation challenges and offers Online Writers UK. Dissertation Help UK with amazing discounts
bestdissertation.co.uk
daphnekoller
Ace My Online Classes is an online class service provider in the US, the company aims to empower students by providing them online assistance regarding their academic issues. You can also ask us to take my online class for me.
jennifercharles
The earliest stages of Alzheimer's basically look like normal old age: mild forgetfulness, for example, is one of the main symptoms. https://startjobs.pk/
Startjobs.pk - Start Your Career In Pakistan As Per Qualification
Startjobs.pk - Government or Private Latest Jobs in Pakistan Today. You can also get Internship, scholarship, & fellowship from Startjobs.pk. It's the only platform which keeps you update regarding the upcoming and current job opening for government & Private jobs.
startjobs.pk
voucherpro
myrabrunson said: There are a lot of Americans are facing Alzheimer's disease. Due to it's viral, a lot of services are providing medical care for this disease. I'll surely write an essay on Alzheimer's Disease for the awareness and with the help of [Cut Rate Writing Service/4dollaressaycom](https://www.4dollaressay.com/) who are professionals in the paper writing.
With the Debenhams Discount Code 20 Off credit card, you earn benefits on every occasion you store on-line or instore. Earn three factors for every £1 you spend at Debenhams, or 1 factor for every £2 you spend anywhere else. As a praise, they will convert the factors (every 3 months) into Debenhams praise Vouchers for in-store use.
Debenhams shipping coverage
Debenhams offers loose wellknown shipping on all orders that exceed $seventy five. you could assume to receive your objects within 10-15 enterprise days. For orders much less than $seventy five, you'll be charged a flat $10 price for shipping.
Debenhams Discount Code 20 Off Returns policy
in case you are disillusioned along with your Debenhams buy, then you may return it within 28 days of the unique transport date. Debenhams best refunds the cost of go back transport if the gadgets had been damaged or incorrect. if you use PayPal to check out, but, the fee carrier reimburses you for the cost of shipping costs.
petewhiddon2
In doing so, it helps the students to demonstrate their skills and abilities to study, comprehend, understand, implement and analyse carefully the given information. These skills are necessary to be successful and effective at any complex or complicated coursework or tasks in any university doing the intensive assignments writing in UAE like a thesis, case study, reports, term paper, research projects and dissertation.
Website: https://www.gulfdissertation.com/
To score a high grade, and/or good marks in any course, you need to Submit Excellent Essays and assignments. Also, you need to ensure that these are always on submitted time. If this is not so, you stand to lose a lot. A well – crafted essay and a neatly executed assignment, submitted on time improve your standing both in the class and in your teacher's eyes.
Website: https://www.writing4u.ae/
AllisonB
I'm so glad there is such ongoing communication and furthering solution focused research regarding Alzheimers, it is a terrible tragedy and results in heartache. Hoping for more voices to arise within the community such as this to offer more help to create great benefit. Allison | https://www.treeservicebrandonmb.com/
This is a fun exercise that many writers use to plunge into who their characters are: the character meets. You can work through a pre-set once-over of requests, or you can think about your very own early, or you can just start forming and take the easy way out. Regard: https://www.writemyessays.org.uk/law-essay.php
Affordable Law Essay Writing Service & Law Essay Help UK
You can avail Law Essay Writing Services UK by Write My Essays. We have professional Law Essay Writer who provides Law Essay help at affordable price.
www.writemyessays.org.uk
heathercarter
That gift is high centered..https://www.smilestreetdentistry.com
Smile Street Pediatric Dentist | Culver City Kids Dentist
Smile Street Pediatric Dentistry is dedicated to creating a healthy smile for your child. Our experienced team focuses on reducing anxiety and creating a fun environment for your child. We can handle all of your children's dentist needs. We continue to strive to be the best pediatric dentist. Call today to get started.
www.smilestreetdentistry.com
Alzheimer's is not the direct cause of their death. The course of Alzheimer's disease varies widely from person to person. Prince-Parker & Associates, Inc. Debt collection harassment?
Alzheimer's is a progressive disorder of the brain and nervous system apparently caused by the buildup of a type of plaque in the brain. Are you facing EOS CCA DEBT COLLECTION HARASSMENT? STOP THE CALLS!? Give us a shout today & get rid of phone harassment from this agency etc.
myrabrunson
There are a lot of Americans are facing Alzheimer's disease. Due to it's viral, a lot of services are providing medical care for this disease. I'll surely write an essay on Alzheimer's Disease for the awareness and with the help of Cut Rate Writing Service/4dollaressaycom who are professionals in the paper writing.
AbdulBasheer
Day by day different kind of disease is rapidly growing in the society that is very harmful to the peoples. Peoples should care to own self and take the safety tips. Now, this post is a discussion about Alzheimer's disease. I have never read this type of disease but after reading this post I am very shocked. I am not feeling well and now I will do struggle for the peoples and give safety tips after researching this. I will give the lesson through my website blog AssignmentHelpAe that always help to the peoples and provide unique information.
Matilda S. Hardin
Truly I truly got influenza this year since this year an infection called swine influenza happens to each individual alongside me which I can check https://www.resumeshelpservice.com/uk-careers-booster-review/ to get quality work. However, I like the inquiry since this sickness is intense. So somebody spare himself from this illness. A debt of gratitude is in order for sharing.
Uk.CareersBooster Review: Best CV Writing Service in UK?
To determine if Uk.CareersBooster.com service is good, we took a closer look at their offers and reputation. ✅ Read detailed review to ensure that you're making a smart investment.
www.resumeshelpservice.com
The Cold Truth: Raynaud's Phenomenon
What your "poor circulation" may really mean
Start 2021 Right: Plan for Cancer Screening and Save Lives!
COVID-19 Should not prevent or delay cancer screening! Early detection is key - latest guidelines and recommendations.
Nearly half of U.S. men actively infected with HPV
HPV commonly infects men and increases the risk of cancer
11 Things You Might Not Know About HPV & Oral Cancer
What are the facts about HPV & oral cancer that you need to know? Longer term follow up confirms safety of HPV vaccine
karisv
January is Cervical Cancer Awareness Month
Cervical cancer prevention, early detection and treatment advances - what every women should know.
Vaccinations roll it slowly - new strains of COVID-19 are emerging.
Caffeine and Urinary Incontinence
Too much caffeine may result in a leaky bladder.
Ask The Doctor: What is Urinary Incontinence?
A physician explains urinary incontinence; signs, symptoms, and treatments.
What Should I Know About Robotic Surgery for Gynecologic Cancer?
Answers to frequently asked questions about robotic surgery for gynecologic cancer.
Managing Your Finances in the Face of Illness
Tax season is upon us - Tips for managing finances, your doctors and insurance company when facing a major illness.


text:
27 migrants confirmed dead in English Channel boat tragedy
FILE PHOTO: Migrants
Published By: Olufunmilola Olukomaiya
French Interior Ministry on Thursday confirmed the death of 27 migrants whose boat capsized in the English Channel on Wednesday.
A spokesperson for the ministry said that the death toll of the tragedy, which was revised down from 31, was still preliminary.
On Wednesday, French Interior Minister Gerald Darmanin had spoken of 31 dead and 33 people on board of the vessel that sank. Two people were rescued, he said.
The spokesperson said nothing conclusive could be said yet about how many people were on board of the boat.
Four smugglers who may have been involved in the failed crossing from France have been arrested.
French President Emmanuel Macron called for a crisis meeting at the European level, saying France would not allow the English Channel to become a graveyard or let smugglers put human lives at risk.
He demanded an immediate increase in resources for the EU's Frontex border protection agency.
A rescue operation was underway in the Channel by air and sea as French and British authorities search for anyone still in the water.
The emergency search was sparked when a fishing boat sounded the alarm earlier on Wednesday, after spotting several people at sea off the coast of France.
Boat mishap: 19 dead, 66 missing
Mexico busts 2 trucks hiding 6 Ghanaians, one Cameroonian, 593 other migrants
Florida Governor DeSantis threatens to dump migrants in Biden's Delaware
Earlier, French Prime Minister Jean Castex said the shipwreck was a "tragedy."
In a tweet, he said his thoughts were with "victims of criminal smugglers who exploit their distress and injury."
British Prime Minister Boris Johnson called on France to step up efforts to stem the flow of migrants crossing the Channel.
He said the tragic incident showed the operations that have taken place to date "haven't been enough," according to PA news agency.
Johnson said he wanted to work with the French authorities to "demolish" the business model of human traffickers who were "literally getting away with murder."
Speaking to broadcasters in Downing Street, Johnson who chaired a meeting of the Government's Cobra civil contingencies committee – said he was "shocked, appalled and deeply saddened" by what had happened.
"What this shows is that the gangs who are sending people to sea in these dangerous crafts will literally stop at nothing," he said.
Johnson suggested the French government had not always approached the problem in the way the British believed it should.
"We've had difficulties persuading some of our partners, particularly the French, to do things in a way that we think the situation deserves.''
Tags: boat accident English Channel Migrants

redpajama_set_name: RedPajamaCommonCrawl


Article Summary: There are always a large amount of medical units that many persons have experienced or purchased before, but they don't really really know the way these work or what these devices can perform for them. When you also look at the normal electrocardiograph sizes, do you know how this instrument can help reduce your problems and different medical sufferings?
Electrocardiograph measurements differ with regards to the type and style of the device. Electrocardiograph sizes are relevant to the medical equipment utilized in offering a transthoracic model of the heart's electric activity. Electrocardiography originates from the German word, Elektrokardiogramm. This was removed from the Greek words such as electro that signifies their relation to electric task, cardio which means heart and chart that way to write.
Electrocardiograph measurements range with regards to the type and style of the device. Electrocardiograph dimensions are applicable to the medical equipment utilized in giving a transthoracic model of the heart's electrical activity. Electrocardiography comes from the German term, Elektrokardiogramm. This was removed from the Greek words such as for instance electro that signifies their relation to electrical activity, cardio meaning center and graph that methods to write.


text:
Home Gaming Dying Light Review – Dead Light Green Light
Dying Light Review – Dead Light Green Light
By Alessandro Barbosa
Zombies have become, for better or worse, a staple in nearly every form of consumable media. They appear in comics, series, films and games, and often take up the same role across the board. These lumbering, clumsy undead often epitomize the need for something fresh, but we're all still pretty content with them hanging around.. In a way, the familiar trope surrounding zombies perfectly sums up Techland's latest title, Dying Light. Like the appearance of the undead, Dying Light doesn't bring any surprises along with it, but remains an enjoyable experience to undertake nonetheless.
Dying Light shares a lot of its DNA with that of traditional zombie lore, which is immediately apparent from the second you start playing. Kyle Crane, an operative for a typically shady governmental organization, is dropped into the once gorgeous city of Harran, which has been quarantined after a massive viral outbreak. The organization in question, the GRE, assigns Crane the task of acting as a triple agent between themselves and the two factions fighting within the city walls, all in the hopes of attaining a file with undisclosed, vital information. There's an underlying sense of conspiracy from the outset, but one that never evolves past the trope it is so heavily relying on, taking predictable steps along a path to a disappointing resolution.
Dying Light is filled with characters, but the sum total of their actual depth couldn't even be compared to a shallow puddle on the street. Kyle Crane in particular is a bland, predictable sculpture of the government agent who just wants to do what's right, while the soldiers on either side of the turf war fall into the buckets listed "angelically good" and "inexplicably evil". It's laughable at times, and I found myself cringing at most of the dialogue you're forced to endure between quests. At one point big bad guy Rias even screams your name into the skies instead of taking a clear opportunity to blow your brains out. It's comically bad.
And while the inhabitants of Harran lack any standout uniqueness, the city outdoes itself. The slums of Harran are gorgeous to behold, especially at low light times such as dusk and dawn. Although inhabited by the undead, it absolutely blossoms with life that makes the lack of any fast travel nearly a non-issue. Becoming familiar with parkour routes and safe back alleys became one of my favourite pass-times thought my campaign, with the sheer amount of detail poured into the design of the city truly paying off. Dying Light is a stunning game, and even more so on a beefy PC. It's a bit jarring when an identical zombie appears just after you've seemingly decapitated him, but for a game this incredibly large (and dense), it's quite remarkable that technical issues are a bit of a rarity.
It's also notable that among the mess of abandoned cars and derelict buildings lie immaculately designed, well thought-out routes for you to run, jump and fall your way through. Dying Light brings together everything that a game like Mirror's Edge was and mashes it together with former Dead Island attempts. You're encouraged to fly rather than fight – rooftops become a safe haven from the hordes below and miss-timing a jump leads to a swift and untimely end. It's interesting that a game primarily focused around zombie horror actually doesn't derive fear from its players through these creatures, but rather through an undeniable sense of vertigo. Gravity is your greatest enemy in Dying Light, and it takes a while for you to truly understand how to tackle it.
While Crane might be a specially trained agent, he has the parkour ability of an infant child at the beginning of the game. He can walk on two feet and jump a fairly standard distance, but that's pretty much it. But like anything in life, practice makes perfect. The more you run and jump, the better Crane becomes at it. The simple act of getting around rewards you with Agility Points, which slowly fill a level meter and unlock more complex, rhythmically sound parkour moves to pull off. Grabbing ledges becomes easier, and before long you'll be stringing together slides with kneecap crunching kicks, sprints with body rattling slams and double jumps with elegant falls into heaps of trash.
Dying Light doesn't make the act of getting around a chore as it usually is in games like this, but rather an absolute pleasure. It takes a little time at first to get used to the brilliant control scheme, but eventually everything just feels natural. Parkour hasn't been nailed this well in a game before, and the few that aim to replicate it in the future would benefit from a peek here and there. The game does somewhat abuse it at times, forcing some incredibly boring climbs up ridiculously high towers, but for the most part you're free to pick your path through Harran and just let loose. It's a fabulous system, and easily the best part of the entire game.
It is, also, one of the only real innovations Techland brings to the table with this brand new IP. Dead Island is famous for its brutal melee combat, and it makes a seamless transition into Dying Light. Weapons range from broken table legs and rusty old wrenches to sharpened machetes and brutally efficient axes, all of which are used to bash in zombie heads and sever limbs. The combat is just as wayward as Dead Island; acutely aimed swings seemingly doing no differentiable damage to wild, less planned ones, although the sheer brutality of it all is gratifying. Heads and blood fly all over the place, and critical hits are rewarded with slow motion close ups and neat little x-ray views of shattered bones. These encounters are rewarded with Power points, which fill up a second skill tree dedicated to increases your undead killing prowess.
These skills increase your stamina, which handicap your ability to swing your weapon endlessly, while others unlock offensive moves such as a ridiculously satisfying drop-kick. These go hand-in-hand with weapon durability, which for once isn't that annoying. Weapons break (often), and the first few hours are insanely frustrating. Not only are the weapons you find bland and weak, they also break extremely quickly, forcing you to hunt around for better coloured, rarer items. It makes some early encounters almost insurmountable, but before long better weapons start surfacing and blueprints unlock a whole new array of customization. Strap on a blowtorch to your favourite knife and cook zombies alive, or add some pressurized gas for a nice little kickback effect. There's a wealth of selection when it comes to dealing death, although it's all wrapped up in cumbersome, confusing menus.
However, it all comes together rather nicely. Although Dying Light encourages you to avoid fights where possible, the times where you are going toe to toe with enemies is undeniably fun. That is, at least, when the sun is up, because at night Dying Light transforms into a whole other game. Larger, more vicious Volatiles roam the streets, and the game is transformed into a light stealth title as you creep around these beasts and head for one of the many safe houses you can unlock. Things get really interesting when one of them is alerted though, as your parkour skills are then called upon and tested properly. You scrabble on the rooftops as the vertically unchallenged enemies chase in quick pursuit, with only the sanctity of UV lights and various traps coming to your aid. The Volatiles are as invulnerable as they are frightening, and being chased by even one is a tense, sweat inducing affair. These moments alone are better than any of the scarce jump scares the game throws at you, relying rather on great enemies and a horrifying sound effects to create true fear.
And while you can simply skip night cycles by hitting the sack at a safe house, you're encouraged to stick it out. Agility and Power points are doubled when the sun goes down, which can fast track your progression in very meaningful ways. The risk comes with dying though, which subtracts points from a third, Survivor trait – and ultimately hinders your most important skill tree. Dying Light strikes a delicate balance between the two, although it may not feel that way in the first few hours. It's probably better to stick to day missions early on, but soon you'll realize that the night isn't as terrible as it seems, and the rewards it brings outweigh the risk (even if ever so slightly).
Although sometimes the game doesn't give you a choice in the matter, plunging you into quests that have to be taken at a certain time of day. Quests in general aren't that thrilling, with most falling prey to the staple fetch quests that open-world titles are so often plagued with. There are a handful of quests that are merely decent rather than outright terrible, but thankfully the mix of combat and movement more than make up for the stale objectives. Still, some clunky shooting segments put a damper on things, and some horrible design choices lead to cheap deaths on a few occasions. It's almost as if Dying Light forgets why it's fun, and then forces you to endure missions that go against what it is at its core.
Thankfully, no matter how terrible the quests, nearly every single one of them can be played with up to three friends. This takes the tense out of certain situations, but injects a different brand of fun into the game at the same time. You might like up-close, silent engagements, while a friend might see firing on red, exploding barrels as the best way to approach things. Having this type of unpredictability (on your side no less) transforms the entire experience of Dying Light, and it almost feels like it's the way it should be played from the start. If you have the choice, bring a few friends along for the ride. Also, don't be afraid to keep Be the Zombie mode one – you never know when someone will decide to assume direct control and chase you all over the slums. Dying Light is a game that often puts its best foot forward, and you'll find it hard to leave Harran when it does.
Unlike Techland's previous titles, Dying Light is an easier game to recommend. Fantastic movement mechanics complement the brutal combat beautifully, and the game on a mechanical level is incredibly engrossing and fun to play. Sadly, there's little else above that to sell. The story and all the characters involved do little to hold your attention, and the mission design does little to surprise.
Dying Light was reviewed on PC
Alessandro Barbosa
Writer, Game Designer, Co-Host on the Checkpoint Chat podcast.
Destiny 2: Where is Xur (and whats he got for sale?) – December 18, 2020
There are still those who are willing to get up at the crack of dusk and boot up their con…
Wonder Woman 1984 review – The superhero movie to save us from 2020
Kervyn Cloete
Taotronic SoundSurge 90 Review – Budget price, surprisingly nice
Darryn Bonthuys
Lego Star Wars AT-AT Walker review – Hoth damn!
Mank Review – A meticulous love letter to 1940s filmmaking
Craig Risi
Airborne Kingdom Review – Let there be flight
There are still those who are willing to get up at the crack of dusk and boot up their console to find him for you. People who'll risk digital life and limb to let you know if Xur is selling a treasure or rubbish. I just so happen to be one of those people. Maybe you're stuck at work and can only log in later tonight. In that case: Where is Xur?
Justin Timberlake is an unlikely father figure in Apple TV+'s drama Palmer
Critical Hit is taking a short break for the rest of 2020, but we'll be back soon!
Riot is working on an MMO set in the League of Legends' Runeterra universe
This new trailer for Wrong Turn 7 proves that some people never learn from their mistakes
And the winner of our Lego Star Wars set is…
One lucky person is about to have an amazing Christmas thanks to this incredible Lego Star Wars set worth R3000!
Win a Lego Star Wars kit worth R3000
Win a copy of Devil May Cry 5: Special Edition!
Win one of five Cadbury #TasteTheAction football hampers!
Critical Hit Game Awards 2020 – The "Other" Awards
Cyberpunk 2077's current consumer catastrophe, explained
Trevor Davies
Critical Hit is built on the idea that we are more than one thing. Are you a hardcore gamer who also enjoys a night out at the movies? Perhaps you're a professional cosplayer who is searching for the perfect burger, or maybe you're just interested in high-end tech and Netflix binging. Covering gaming, entertainment, tech and geek, Critical Hit offers information and critique from a staff of diverse, knowledgeable and fiercely opinionated writers.
You can now pay to level up quicker in Assassin's Creed Valhalla
Former Creed singer Scott Stapp to make his film debut as Frank Sinatra