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The Problem of Alzheimer's: How Science, Culture, and Politics Turned a Rare Disease into a Crisis and What We Can Do About It
Karlawish, Jason

Introduction: The Disease of the Century
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She had a problem with memory—the ability to recall new information. And she had problems with the ability to plan, sequence, and organize a task, what psychologists call executive function, a term that describes the adult brain’s capacity to conduct itself, to orchestrate its myriad of cognitive abilities—such as memory, language, and attention—into a song of yourself.
Part 1: Alzheimer’s Unbound
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Dementia in a sense is a disease of autonomy, and the lives of persons with it are an extended conversation over a question: “What’s a good life when you’re losing your ability to determine that life for yourself?” 2
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Memory is the earliest symptom because the hippocampus is often affected earliest by the disease.
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Drug companies saw a large and promising market for a treatment that could prevent Alzheimer’s. They began testing drugs in persons with MCI. Unfortunately, none of these studies discovered an effective drug.
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The absence of a drug treatment only amplified clinicians’ frustration with MCI, especially busy primary care clinicians. Why devote precious time to diagnose a condition that isn’t causing obvious harm, might not get worse, and has no treatment? To them, MCI seemed a presumptuous medicalization of aging.
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Amyloid is like a term from geometry such as “triangle.” It describes the unique shape of a protein. Just as there are several types of triangles—obtuse, equilateral, and right angled, for example—there are several types of amyloid proteins.
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if he’d simply thought over Congo red’s structure, he could have predicted this negative result before he’d sacrificed a single rat. Congo red is charged, and the border patrol of the blood-brain barrier doesn’t admit charged molecules.
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a revolution in psychiatry. America was embracing a new zeitgeist, and not just in psychiatry. Mental illness was the result of disorders in how neurons communicated or, in a word, neurotransmission.
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The psychiatrist Peter Kramer’s bestselling Listening to Prozac made the case that brain diseases were caused by imbalances in neurotransmitters. Suicide was, for example, conceptualized as a “serotonin problem.”
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“Positive PiB uptake” became a shorthand for the detection of amyloid in a living person’s brain. Also like MCI (mild cognitive impairment), PiB was revolutionary. PiB wasn’t simply a radiotracer. It was an idea at the vanguard of a new way of thinking about Alzheimer’s disease. A single word captured the collective scientific imagination: “biomarkers.” The term describes biological measures of a disease in action. PiB was among a growing set of technologies that measured Alzheimer’s biomarkers in the brains of living humans.
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just how precisely MRI can quantify brain atrophy: 4 percent per year in a person with Alzheimer’s disease compared to 1 percent in a person without Alzheimer’s disease.
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By 2013, the Alzheimer’s Association reported in its annual Facts and Figures Report that they estimated 5.2 million people in the United States had dementia caused by Alzheimer’s disease and as many as 8 million, MCI. 4
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A 2011 Centers for Disease Control and Prevention study estimated 16 million Americans had cognitive impairment. 5 All
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Physicians didn’t have effective pharmacologic treatments for the disease. They just had better ways to diagnose and talk about it.
Part 2: The Birth of Alzheimer’s Disease
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Senility was a convergence of physical, social, and psychological causes, some combination of aging neurons, social isolation, vascular disease, and unresolved psychological conflicts. It was a kind of degenerative adolescence leading to a second childhood of infantile dependence. We were without any understanding of the biology of what was happening to an aging neuron. Aging was dark magic.
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Slowly and then all at once, senility disappeared. In its place was Alzheimer’s disease, and it seemed to be everywhere. The commonly accepted explanation for why this happened is demography. For much of human history, there weren’t a lot of old people, and so there weren’t many older adults with disabling cognitive and behavioral problems.
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Older adults who were disabled from cognitive and behavioral problems transformed from the senile elderly into patients whose disease became inflamed by the rhetoric of a crisis that is bound to bankrupt nations’ economies.
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Scientists can be divided into two types: foxes and hedgehogs. Foxes follow ideas and so wander across fields of study and methods. Hedgehogs never leave the field where they were born. They patiently focus on a topic and a method.
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Alzheimer and Sioli were a participant in an emerging revolution in psychiatry and the definition of psychiatric diseases. Their inspiration was the work of the eminent nineteenth-century German physician Rudolf Virchow, who advocated careful dissection and microscopic study of tissues as the method to discover the causes of disease such as cancer. The psychiatrists wanted to apply these same approaches to diseases of the brain.
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called themselves alienists to capture their role in treating the socially isolated, or alienated, asylum patient—
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Alzheimer was among a small cadre of clinician-scientists who sought to classify and understand mental illnesses as the consequence of organic diseases in the brain.
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this revolution was quite dependent on the stability, well-being, and support of their asylums, a circumstance that faced substantial challenges after the spectacular destruction of World War I and the economic and social upheavals that followed imperial Germany’s defeat.
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By the dawn of the twentieth century, German psychiatry had arrived at an auspicious moment. Technologies such as Nissl’s stain, asylums with built-in laboratories and university linkages, and a German-speaking scientific intelligentsia would soon converge to make the discovery of Alzheimer’s disease possible.
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something made visible courtesy of the recent advances in stains developed by Nissl. Alzheimer saw fibrils inside and outside her neurons and “minute miliary foci which are caused by a deposition of a special substance in the cortex.”
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This statement, that senile and presenile dementias may in fact be the same disease, was utterly revolutionary.
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Kraepelin’s system to classify psychiatric diseases dominated early twentieth-century psychiatry worldwide. It was disseminated in multiple editions of his canonical text Compendium of Psychiatry: For the Use of Students and Physicians. The eighth edition included Alzheimer’s 1907 case report, naming it “Alzheimer’s disease.”
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Psychiatric illness, Kraepelin asserted, could and should be grounded with the same approach as diseases of the body; that is, a careful description of the essential clinical features tightly correlated with clinical outcomes and, ideally, the findings from pathology.
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As the twentieth century unfolded, Dr. Alzheimer’s 1907 and 1911 case reports and Fischer’s work were all forgotten, of interest only to the few neurologists who specialized in cognitive disorders.
Highlight(blue) - 9. Alois Alzheimer: An Unwitting Revolutionary > Location 1879
The dominant theory was that senility was the end stage not of a disease but instead of a hodgepodge of causes—a breakdown in a psychodynamic balance among various pathologies, including vascular disease, personality, and, most importantly, relentlessly aging neurons. Senility was a difficult, unavoidable natural event. Like the winter, there wasn’t much to do except bundle up and tough it out.
Highlight(blue) - 10. Oblivion, or War and Madness > Location 1923
Psychiatric clinical-pathological research required resources: physicians with time to undertake research instead of patient care, subjects with well-documented case histories and brain tissue, and a lab with microscopes and other equipment. The lack of sustained and steady access to these resources was one reason why Alzheimer’s disease remained stuck as the unusual disease of the cerebral cortex that he presented after lunch at the 1906 meeting in Tübingen. Other factors were at work as well. One of them was present the very afternoon after Alzheimer stepped away from the lectern: Sigmund Freud’s psychodynamic theory of mental illness.
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This theory posited that mental illness was a disease of the mind caused by suppressed traumas. Freud identified suppressed childhood sexual traumas as a main culprit.
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Hundreds of thousands of cases of neurasthenia, or “shell shock,” became case studies on the effects of trauma on otherwise healthy brains. Despite any physical wound, young men were blind, tremulous, mute, or paralyzed. The Battle of the Somme left some thirty thousand cases. They were living, brain-damaged proof that trauma to the psyche—to the mind—causes mental illness. Freudianism—or more generally a psychodynamic theory of mental illness and its treatment—not only gained legitimacy, but it also dominated other theories of psychiatric illness. Alzheimer’s revolutionary idea that presenile and senile dementia might be caused by a distinct, biological disease was supplanted by a more urgent and overwhelming crisis.
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In the aftermath of World War I, German psychiatry and neurology began to collapse under the weight of anti-Semitism and Nazi eugenics.
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By war’s end, Kraepelin and his textbook were cast aside. The Royal Psychiatric Clinic of Munich where Alzheimer and Perusini had worked and trained psychiatrists in the clinical-pathologic model of psychiatric disease was a reputational cesspool and an academic wasteland. Alzheimer’s disease was a casualty of war and madness.
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postwar America. There, a set of medical, social, and cultural forces collectively kept the problem of dementia in older adults hidden from both medical and public concern.
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Freud and psychodynamic theories about stress as a cause of pervasive mental illnesses and the focus on “neuroses” (that is, anxiety and depression) enthralled not only the profession of psychiatry but all of American culture.
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After the war, as psychiatrists described themselves as Freudians (none chose the moniker “Kraepelinian”), America was swept up in variations on Freudianism. Freud himself would have been devastated. He hated America. Psychodynamic theories of disease and the application of the talking cure to treat them gained wide acceptance in America. By 1976, membership in the American Psychiatric Association had grown from 4,400 in 1948 to 27,000, and the chairs of most departments of psychiatry were proponents of a psychoanalytic definition of mental illness and its treatment.
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This practice of psychiatry had little reason to care about persons with senility.
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This model led to treatments that mixed biological interventions—including electroconvulsive therapy and sedative medications—and social and psychological interventions to reduce stress. It dominated psychiatry’s understanding of dementia in older adults and sustained the distinction between senile and presenile dementia.
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The mantra to both define and diagnose a neurological disease was “find the lesion.”
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the stereotypical description of senile dementia was a patient with a “normal” neurological exam, meaning normal motor, sensory, and reflexes. It was the cognitive and emotional exam that was abnormal, an exam that was more the practice of psychiatry than neurology. Therapeutically, unlike psychiatry with its talking cures, neurology was a comparatively bleak field. For much of the twentieth century, few brain diseases, save for infections such as syphilis, were treatable. The discoveries of dopamine for Parkinson’s and antiepileptic drugs were among the few breakthroughs that allowed a neurologist to treat the symptoms of these disabling and untreatable diseases.
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sustained them began to fall apart. As the twentieth century drew to a close, progressive, self-made, forward-looking America—where “go-ahead” isn’t just a direction of travel but also a command for how to live—began to think differently about living with senility, whether as patient or family. It became a big medical problem. Curing the problem of senility would become the means for all Americans—young and old—to continue to go ahead. But first senility needed to be rebranded from an extreme state of aging into a disease to be diagnosed, treated, and, ideally, cured.
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IN APRIL 1976, with the publication of an essay, Alois Alzheimer’s unusual disease of the cerebral cortex, one of the rare causes of the uncommon “presenile dementias,” became a prevalent and malignant killer of older adults.
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Katzman’s point was that the data were good enough to support a revolutionary claim. Older adults’ dementia was not caused by senility—an extreme stage of aging—but rather by a disease. Dipping into epidemiology, he estimated there could be as many as 1.2 million patients with the newly redefined Alzheimer’s disease and that it was the fifth leading cause of death. His numbers suggested a burden of disease on par with cancer and heart disease. He closed with a call to action. “Senile as well as pre-senile forms of Alzheimer are a single disease, a disease whose etiology must be determined, whose course must be aborted, and ultimately a disease to be prevented.”
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From the hyperfocused vantage of the molecular ultrastructure of the amyloid plaque, senility looked a lot like Alzheimer’s disease.
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At meetings of neurologists and psychiatrists, he started to buttonhole colleagues to test out an idea. Senile dementia isn’t an extreme end stage of aging. It’s a disease like Parkinson’s disease. They listened and encouraged him. By 1976, he decided he was ready to become an Alzheimer’s disease activist.
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The timing of his editorial’s publication was auspicious. Psychodynamic Freudian theories of brain disease were collapsing and being replaced with “biological psychiatry” and its promise that hard sciences of molecular biology, neurochemistry, and genetics could lead to treatments for psychiatric and neurological illnesses with the same precision as treatments for cancer and heart disease.
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A new ethic was emerging that was changing societal expectations of being an adult. Characteristics such as race, gender, sexuality, and even age were becoming less and less acceptable as the organizing principle for what a person could or could not choose to do, such as where they ate lunch, lived, went to school, or the job they worked at. For older adults, this meant upending beliefs that the elderly are passive, quiet, dull, and unproductive. Treating an older adult based on these beliefs should be replaced with respecting each person’s exercise of her self-determination, her autonomy to create a life as she desired. Society had a duty to respect each person’s autonomy and remove barriers to her self-determination. This ethical revolution made unpalatable the idea that with aging, loss of the abilities to make decisions and live independently was just a natural—and so normal—part of life.
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In October 1980, the nationally syndicated advice columnist Abigail Van Buren had received a letter from “DESPERATE IN NY.” Dear Abby, About two years ago, I began to notice a change in my husband. He became increasingly forgetful and easily confused, even though he was only 50 … We saw several doctors before one finally seemed familiar with my husband’s condition. He told us he had Alzheimer’s disease, for which there is no known cure. Alzheimer’s disease occurs in people as young as 40 and 50 as well as in some older people. 1 Desperate went on to explain that her husband, although in excellent health, had memory problems so bad he could not drive, had to quit work, and needed to be watched every minute. Sometimes he seemed normal, but then he was once again dependent and forgetful. “I feel so helpless. How do others cope with this disease?” Abby began her reply: “You are not alone.” In a few years, these four words would be the opener of caregiver support groups across the nation. She explained that “there are now groups of concerned friends and relatives who have banded together to provide support, develop and disseminate helpful information and encourage much needed research in Alzheimer’s disease.” She gave Desperate a simple instruction. Send a stamped, self-addressed envelope to Alzheimer’s Disease and Related Disorders Association. The address was 32 Broadway, New York, New York. Lonnie Wollin’s office was the official address for the association because Lonnie used this address in the articles of incorporation and office for the Alzheimer Disease Society, the not-for-profit Lonnie established in 1978. The office had a desk and one staff person.
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DESPERATE IN NY was also proof of Jerry Stone’s influence, power, connections, and relentlessly strategic approach to address a problem. He called on a friend who was a friend of Abby’s. The letter was staged. Jerry Stone was DESPERATE IN NY.
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national public opinion poll that found Alzheimer’s disease was the fifth most feared and serious disease in the United States. “It is extremely doubtful,” he explained, “if Alzheimer’s disease would have been listed even just two years ago in such a poll.” 1
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convincing Congress to fund research for a cure for Alzheimer’s disease.
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The problem was a divided Congress. It agreed to fund the NIH to support research to discover a cure. It could not agree on how to care for persons with Alzheimer’s disease. The idea of social insurance for long-term care, to support the costs of interventions such as an adult day care program and the time spent caregiving, exposed ideologically charged flash points.
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At the same time that Alzheimer’s was coming of age, so, too, was another equally young and frightening disease: the human immunodeficiency virus, or HIV, the cause of the deadly acquired immune deficiency syndrome, or AIDS. The first cases were reported in 1981.
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What they desperately wanted was a treatment for the mind, a pill that would preserve the person—or even better—bring back the person who was lost.
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Cognex, Aricept, and later Exelon and Razadyne were all members of a class of drugs called cholinesterase inhibitors. Their effect was to increase levels of a protein called acetylcholine in the brain.
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The problem then and still today in America is that an effective intervention is not a treatment unless it has a business model.
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It was an epidemic that without a cure will leave America caring for millions of disabled older adults. We didn’t fight polio by building iron lungs, they argued. We discovered a vaccine. So, too, with Alzheimer’s disease. We could build more nursing homes or we could discover a cure. Forty years later, there is no cure.
Part 3: Living Well in the House of Alzheimer’s
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two events recast senility as a disease. The first was scientific advances in electron microscopy and biochemistry. These allowed physicians to point to specific and visible things—such as proteinopathies of amyloid and tau—rather than aging as the cause of older adults’ progressive and disabling cognitive impairments. The second was advances in ethics.
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Alzheimer’s has been caught up in deeply partisan battles over the proper role of the state to support the lives of Americans, the role of women, the responsibilities of the family, and the politics of welfare.
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It was the best of care and the worst of care. It was uncoordinated care. It was a medical fun house run by madmen.
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Alzheimer’s disease doctors however don’t have the armamentarium of treatments that cardiologists and oncologists have.
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In the United States, funds to care for patients are driven by payments for prescriptions for surgical and drug treatments. Alzheimer’s care is in the awkward position of not having a comparable business model. The richest nation in the world does not have a viable market to support this care. Simply put, a clinician can’t make a living as an Alzheimer’s doctor because the reimbursement from insurance cannot support a physician’s most essential resource: time.
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clinicians based in a community hospital and dedicated to taking care of patients. They relied on the revenue from clinical care, which meant the funds collected from billing Medicare.
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the care of a high volume of relatively healthy adults (the leaders of clinical operations describe this volume as “the churn”) generates revenue that then offsets the losses from the time needed to care for the more complicated older adults.
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the United States only supports long-term care for chronically ill and disabled citizens who can prove they are impoverished and so qualify for Medicaid.
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Her training director, the eminent physician and epidemiologist Alvin Feinstein, dismissed her research proposal, explaining that he couldn’t think of a topic less interesting to anyone than older people becoming confused in the hospital, and also there was nothing to be done about it.
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An older adult free of delirium at admission developed it because of four things present on the day of admission: impaired vision, dementia, dehydration, and severe illness. Each of these added to an older adult’s risk of transforming from being alert and attentive when she came into the hospital to deteriorating into a state of frightened inattention and confusion.
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five noxious insults and events following hospital admission independently conspired to cause delirium. 5 Physical restraints that kept the patient from moving about, a urinary catheter that also restrained the patient (and also increased the risk of a bladder infection), adding three or more medications (among the most common were psychoactive medications, especially sedatives for sleep), low blood proteins suggestive of malnutrition, and, finally, harms from the things doctors did, their diagnostic procedures or treatments.
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The devastating confusion older adults experience in the hospital was not like the winter, something that just happens, but the consequence of a cascade of events and, like polio, it was preventable.
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a pill with a business model to propel it into practice.
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Each patient instigated a constant back-and-forth over who would have charge of an acutely ill older adult with dementia and a broken hip. The longer the patient waited in the emergency room, the sicker she became, and the clinicians’ approach to caring for her became more and more risk averse. The anesthesiologists insisted on a cardiology consult and the cardiologist then ordered tests, and so surgery was further delayed. Fluids were limited so as to avoid heart failure. The now-dehydrated patient developed worsening kidney function. As a result, once-safe doses of medications became toxic. Not surprisingly, delirium often ensued and as it did, antipsychotic or sedative medications were prescribed, and so they became even sicker.
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Robert Katzman’s 1976 essay was a call to change the way medicine and society thought about senility, to see it not as an extreme stage of aging but as a disease worthy of medical attention. The next—and tragically delayed—step in this revolution has been the recognition that to care for these millions of patients and their families, we need to change.
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He and his colleagues weren’t really studying the disease. They were studying their representation of the disease.
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The diagnosis and care of older adults with cognitive problems is a talk-intensive practice,
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PiB, the imaging agent for amyloid,
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enzymes that precipitated the cascade of events that broke amyloid into toxic fragments that then accumulated into plaques.
Highlight(blue) - 22. Hope in a Plan > Location 4425
At best, this drug slowed the disease. The benefit to patients was modest, perhaps a few months’ delay before a person cascaded downward from being inefficient in her daily activities to being disabled and needing a caregiver to monitor and help her.
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Beta-amyloid—the protein at the core of the senile plaque that Robert Katzman described in his April 1976 editorial and that Glenner and Wong sequenced eight years later, that PiB imaged and that Schenk cleared with his immunotherapy approach—wasn’t the cause of Alzheimer’s disease. It was therefore the wrong target for treatment.
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This gargantuan mismatch between the disease engineered in mice versus the disease in humans suggested that the field was in a sense captured in the costly service of raising and caring for thousands and thousands of mice rather than spending those dollars on studies of humans with the actual disease.
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Alzheimer’s disease is like cancer. It isn’t one disease but many (some spoke of “Alzheimer’s diseases”). And like cancer, we should expect we’re going to discover better treatments, but we’re not going to drug our way out of this complicated enormity of a problem.
Part 4: A Humanitarian Problem
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At the start of internship, I explained to my elderly patients how their elevated pressure was their aging body’s “natural response” in order to push blood through their hardened arteries. By the end of internship, I told my patients something quite different. What was once considered normal cardiac aging was now a disease called systolic hypertension of the elderly. I prescribed medication to lower their elevated blood pressure. Fast-forward three years to my fellowship in geriatric medicine. Nearly all my patients were on antihypertensive medications.
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As people survive their heart attack, as heart failure and some cancers become chronic diseases, people are living into their eighties and beyond. This is the age of dementia.
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As my colleagues discover how to diagnose and treat the disease before a person has dementia or even MCI, the diagnosis of Alzheimer’s disease will spread to include a stage defined not by cognitive decline but instead by biomarkers and only biomarkers. A 2018 study estimated that as many as 46.7 million persons have this “preclinical Alzheimer’s disease,” a term that describes a diagnosis before cognitive impairment. 1 The net effect of biomarker discoveries is that each of us is more and more likely to learn we are at risk of dementia—or at risk of becoming a caregiver. Or both.
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The complexity of Alzheimer’s disease (really diseases), the lack of a simple and single “druggable target” so that we might tame it like influenza, measles or polio, the threat of chronic escalating disabilities, the staggering costs of time and task, the stigmas that corrupt dignity and identity together converge on a call to action. Nations must tackle the Alzheimer’s problem as a humanitarian problem.
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Framingham, became a treasure chest of data to explain the natural history of heart disease, one of the twentieth century’s greatest killers. Framingham was among the key studies to demonstrate that the rise in blood pressure seen commonly in aging was not “normal” but rather the sign of disabling, deadly events to come, namely a stroke or heart attack.
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Cognitive reserve is a biological argument for a public policy. To prevent dementia, we ought to make a robust investment in public education and other cognitively stimulating venues such as museums and cultural centers.
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We also haven’t discovered the right combination of tests to accurately measure an individual’s risk of developing dementia.
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a common theme among people with elevated amyloid. The result was different from other medical tests because the disease this test foretold was not an attack on the body but on the mind and her self-determination and identity.
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one of the most common hazards of living with dementia, getting lost on a hot day and suffering dehydration and the ensuing devastating cascade of life-threatening complications such as delirium.
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With technologies like these, we may still have an only partly treatable disease, but at least, for a while, we won’t be disabled. They’re a kind of cognitive prosthetic, devices to fill in the gaps in our ability to remember, orient ourselves to time and place, or negotiate a space. They are in a sense parts of our extended mind.
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numerous recastings of what we called the problem (first insanity, then senility, and then dementia, perhaps someday amyloidosis with tauopathy, etc.),
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This pattern of bereavement among caregivers of those with dementia is precisely the opposite of the experience of caregivers of people dying from cancer and other diseases that typically ravage the body but spare the mind.
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There is, in a sense, a caesura, an interruption, between living with and dying of the disease, and this space is so vast and mysterious that physicians don’t see either Alzheimer’s disease or dementia as causes of death. They routinely don’t list them as a cause of death on the death certificate they’re required to complete, preferring instead to list causes such as pneumonia, sepsis, or complications of a hip fracture. The first time I recorded “Alzheimer’s disease” as the cause of death, the nurse who stood beside me at the desk in the nursing home candidly volunteered: “I didn’t know people died of Alzheimer’s disease.”