Alzheimer’s: The Disease That Steals Your Mind

Ajouté : 2026-06-05

[00:00:00]In 2007 in Aichi Prefecture in Japan, an elderly man with Alzheimer's disease left home during the kind of gap every caregiver knows and every caregiver dreads. It was a few minutes when someone turns away, answers the door, washes the dish, tries to, you know, go about their day. But he was 91 years old and his wife, also elderly, had been helping to care for him through the long progression of his illness. His family had tried to prepare for the danger of wandering in the only way they knew how.

[00:00:28]According to Japanese reporting, identifying information had been sewn into his clothing so that if he became lost, strangers could read it and help guide him home. That morning, he managed to walk to a nearby station, board a train, and later entered the track area of another station along the line. He didn't come home. Then the second shock.

[00:00:47]JL Central, one of Japan's largest rail companies, sued his family. The company sought damages for the delays and disruption caused on its lines that day.

[00:00:55]and lower courts initially found the family members liable for that loss.

[00:00:59]Holy [ __ ] train company, you [ __ ] savages. Allegedly, the case climbed slowly through the Japanese legal system until it reached the country's Supreme Court. At stake was a question much larger than one family or one morning at a rural station. When dementia destroys a person's ability to judge risk, who becomes responsible for every door, every street, every platform edge, every impossible moment of supervision? Who exactly is we? So, the man at the center of that case we just mentioned, had lived a long life in Nichi Prefecture, and by 2007, his Alzheimer's disease had advanced to the point where he could no longer be safely left alone for long.

[00:01:38]His wife, then in her 80s, was his primary caregiver, and family members tried to share what they could of the watching and the worrying. Japanese reporting from Asarah Shimban later traced what happened on the day he disappeared when a brief lapse in supervision opened a door that should have stayed closed. He boarded a train from Obi Station, traveled a short distance, and ended up in the track area of Kioa Station where he was killed in an incident involving a passing train.

[00:02:03]JR Central calculated its losses from the resulting delays, and they went looking for someone to pay up. The company demanded roughly 7.2 million yen in damages from the dead man's relatives, arguing that the family had failed in its duty to supervise him. A district court agreed with the railway, and so did the high court on first appeal, leaving the widow and her son legally on the hook for a moment of inattention in a years'slong marathon of care. The judgment alarmed dementia advocates and aging policy experts across Japan because if that ruling stood, every family caring for a relative with cognitive decline would be one open door away from financial ruin.

[00:02:40]In March 2016, after years of appeals, the Supreme Court of Japan reversed the lower decisions and freed the family from liability. Though the legal reasoning left as many questions open as it closed. So this is where our story really begins and it's also where the larger argument of this episode begins as well. Dementia is a medical diagnosis, sure, but it is also a stress test that reaches far beyond the clinic and into the lives of everyone connected to the person who's changing. It tests hospitals and homemade, courts and insurance companies, drug regulators and nursing homes, neighbors who notice and neighbors who look away and entire aging societies trying to decide how much risk a free person is allowed to carry. The IG case is one family's tragedy and it is also a question the rest of the world hasn't yet answered. Now, before we go any further, it helps to be rather precise about what we're actually talking about today because the word dementia gets used loosely in ways that obscure what is happening inside a human brain. Dementia is not a single disease and it is not a normal part of getting older. Even though its risk does rise sharply with age, the World Health Organization describes it as a syndrome which means a recognizable pattern of symptoms produced by a range of underlying diseases and injuries that damage the brain over time. Those symptoms typically include progressive problems with memory, thinking, language, judgment, behavior, [music] and the ordinary tasks of daily life like dressing, cooking, or handling money. The damage is biological. It's rooted in the death of brain cells and the breakdown of the networks that connect them. And at present, most forms cannot be cured and cannot be reversed.

[00:04:23]Alzheimer's disease is the most common cause, accounting for somewhere between 60 and 70% of cases worldwide, which is why the two terms often get tangled together in everyday speech. Vascular dementia caused by strokes and damaged blood vessels in the brain is another major form. and so are Louisibody dementia and fronttotemporal dementia, each with its own pattern of symptoms and progression. A person can also have more than one type at once, which complicates both diagnosis and treatment in ways that families rarely hear about until they're deep inside it. And here's the thing, normal aging can mean slower recall, the missing name that surfaces an hour later, the keys left on the wrong shelf. I must be aging. Dementia though is something different because it steadily strips away the ability to live independently and to make sense of the ordinary world. The US Centers for Disease Control put it plainly on its public-f facing pages. Alzheimer's and other dementias are not a normal part of aging even though older adults are far more likely to develop them. And one last note on language before we get into the thick of it. Throughout this episode, we're going to speak of people living with dementia because that is the framing now used by major health bodies and advocacy groups and because it keeps the person visible inside the diagnosis.

[00:05:37]A person with Alzheimer's is still a person often for many years after the first signs appear. And that fact will matter for almost every story that we cover today. Okay. So, if we zoom out from just [music] the one case we looked at so far, the numbers become rather difficult to comprehend. The World Health Organization, the WHO, estimates that around 57 million people were living with dementia worldwide in 2021 with nearly 10 million new cases added every year. It's also one of the leading causes of disability and dependence among older adults on the planet. And the curve is bending upward rather than down. A forecast published in the Lancet Public Health by researchers at the Institute for Health Metrics and Evaluation Projects said that the global figure could reach roughly 152.8 8 million people by the year 2050. That's not that long away. This increase is driven largely by population aging, which means more and more people surviving long enough to enter the years when dementia risk climbs. The biggest proportional rises are expected to be in parts of North Africa, the Middle East, and subsaharan Africa, regions where health systems have far fewer resources to absorb the load. The financial weight is already absolutely staggering. The WHO, who has put the global cost of dementia at around $1.3 trillion US as of 2019, a figure that includes formal medical care, and the vast informal labor of families. Roughly half of that cost is [music] care provided by relatives and friends who are not paid for the hours they give, the sleep they lose, and the careers they shrink to keep someone safe at home. When economists try to price that work at even modest wage rates, the total dwarfs the budgets of entire national health systems. Women carry the burden twice over in most countries. They are more likely to be diagnosed with dementia in later life, partly because they live longer on average, and they are also more likely to be the daughter, wife, or sister who steps in to provide unpaid care for someone else. Studies cited by the WHO suggest that women provide the majority of informal dementia care hours globally, often while still holding paid jobs or raising children of their own.

[00:07:40]Japan, where we started today, sits at the leading edge of this demographic curve with one of the oldest populations on Earth and a dementia case load that has already reshaped its courts, its trains, and its towns. Every other age in society is following along that same path just a few decades behind which is one reason cases like the one in H keep drawing international attention. All right. So to understand why a 91year-old man in 2007 could walk out of his house and see into a court case. We have to go back more than a century to a hospital in Frankfurt in Germany and to a woman whose name medicine has never quite let go of. In November 1901, a 51-year-old patient named Augusta was admitted to Stardish.

[00:08:27]Oh my god, Germany. Starts an Fure E point.

[00:08:34]I'm sorry. I'm sorry. I took German at school, but uh I was never very good at it. This is the city's institution for the mentally ill and the epileptic. Her husband could no longer manage her at home. She was confused, fearful, and increasingly unable to recognize the people and objects around her. Though she was still, by the standards of the day, a young woman, her doctor was Aloy Alzheimer, a 37-year-old psychiatrist with a strong interest in the physical structure of the brain. He recorded her case in unusual detail, sitting with her, asking her questions, writing down her answers in clinical notebooks that would later be rediscovered and studied by historians of medicine. In one exchange preserved in those notes, August was asked to write her own name.

[00:09:15]And after several failed attempts, she said in German Mik Veron, which translates as I have lost myself, which is [ __ ] chilling.

[00:09:26]Augusta died in April 1906 after years of decline inside the institution. An Alzheimer asked for a brain to be sent to his laboratory in Munich for examination. Under the microscope, he saw two strange features in the tissue.

[00:09:39]dense clumps of protein scattered between the nerve cells and twisted fibers tangled inside them. In a lecture delivered in November of that same year, he described what he had found in her case, linking her devastating symptoms in life to these specific physical changes in death. The presentation did not cause an immediate sensation, and the audience reportedly moved on to other topics afterwards without much discussion. But a few years later in 1910, the influential psychiatrist Emil Craraperlin included the condition in his major textbook and gave it the name by which the world knows it today, Alzheimer's disease after the doctor who had described August's brain. Now, the patient herself, the woman who had said she was lost, faded from public record for most of the 20th century until her original file was rediscovered in the 1990s and her face, her words, and her suffering returned to the story that bears her doctor's name. For most of the 20th century, what Aloy Alzheimer had described under his microscope sat in a strange medical limbo. Doctors knew the pathology existed, but in everyday practice when an older person began to forget names and wander into different rooms, the diagnosis written down was usually sil carried the weight of inevitability.

[00:10:51]Rather than being a disease, families absorbed that change in silence at home without help because there was nothing useful to call it and nothing useful to do. That began to shift though in April 1976 when the neurologist Robert Katsman published an editorial in the Archives of Neurology arguing that Alzheimer's disease and so-called scenile dementia were the same illness separated only by the age which symptoms appeared. Catsman went further, calling the combined condition a major killer that had been hidden inside death certificates listing pneumonia, heart failure, or simple old age. The National Institute on Aging had been established two years earlier in 1974. A Catsman's argument gave the new institute a clear scientific target to pursue. In 1980, a Chicago businessman named Jerome Stone, whose wife Evelyn had been diagnosed with Alzheimer's, [music] brought together a handful of small family support groups and founded what became the Alzheimer's Association. The organization gave caregivers a place to call, researchers a constituency to fund, and the disease itself a name that ordinary Americans could finally use without shame. Still, for most of the 80s, an Alzheimer's diagnosis remained something families whispered about rather than announced. The wall came down in public on November the 5th, 1994, when former United States President Ronald Reagan released a handwritten letter to the American people. He was 83 years old, 5 years out of the White House, and he wrote that doctors had told him that he was one of the millions of Americans who would be afflicted with Alzheimer's disease.

[00:12:22]Quoting him, I now begin the journey that will lead me into the sunset of my life. end quote. And he also said that by speaking openly that he might promote greater awareness of the condition.

[00:12:34]Reagan lived another decade inside that diagnosis, mostly out of public view, and he died in June 2004 at the age of 93. His letter did something that medical journals and advocacy brochures had not managed on their own because it placed the disease inside one of the most recognizable lives of the century and asked the country to look directly at it. After 1994, donations to dementia research climbed. News coverage expanded and the word Alzheimer's started appearing in obituaries that had previously offered only a long illness.

[00:13:05]To understand what Reagan was describing, it helps to picture the human brain as this vast web of around 86 billion nerve cells. Each one talking to thousands of others through tiny junctions called sinapses. Every memory you hold, every face you recognize, every sentence you understand is carried across that web by chemical and electrical signals firing in patterns built up over a lifetime. Alzheimer's disease is at its core the slow corrosion of that web from inside the brain tissue itself. Two proteins sit at the center of the story and they're the same two structures that alloys Alzheimer drew from August Deita's brain in 1906. The first is amaloid beta, a sticky protein fragment that begins to clump together in the spaces between neurons, forming the dense plaques he saw scattered through a cortex. The second is tao, a protein that normally helps stabilize the internal scaffolding of a healthy nerve cell, but which in disease folds wrong and twists into tangled fibers inside the neuron itself.

[00:14:07]Researchers still argue about which protein damages the brain first and how exactly each one drives the disease. But the broad sequence is now reasonably well established. Amaloid begins to accumulate in the brain 10 to 20 years before any symptoms appear. Often while the person is still working, driving, raising a family, and feeling entirely well. Towel pathology follows, spreading from region to region in a pattern that researchers have mapped through hundreds of postmortem studies. As these proteins accumulate, the brain's immune cells called [music] micro ga switch into an inflammatory state and begin damaging the very tissue that they were meant to protect.

[00:14:40]Sinapses are pruned away faster than they [music] could be rebuilt, and the connections that hold memories together start to thin out. The earliest losses concentrate in a small seahorse-shaped structure deep in the temporal lobe called the hippocampus, which acts as the brain's gateway for forming new memories. That's why the first symptom that most families notice is not forgetting a child at home, but forgetting a conversation from an hour ago or asking the same question three times in an afternoon. Old memories laid down decades earlier remain accessible for a long time because they live in distributed networks across the cortex.

[00:15:14]While the machinery for laying down new ones [music] is being dismantled first. As the disease spreads outward from the hippocampus [music] and into the rest of the cortex. Language begins to fray.

[00:15:23]Navigation fails and judgment erodess in ways that are obvious to relatives long before they're obvious to the patient.

[00:15:29]In the late stages of Alzheimer's, the damage reaches regions of the brain that control swallowing, balance, and basic bodily regulation. People lose the ability to walk safely, then to eat without choking, and eventually [music] to fight off the infections that follow when a body can no longer move or clear its own lungs. Most people with Alzheimer's don't die from plaques and the tangles directly. They die from pneumonia, from falls, from the cascade of failures that follows when the brain can no longer manage the body that it's inside. That's why specialists beginning with a 2009 paper widely covered by Time magazine pushed to have Alzheimer's recognized as a terminal illness on the same conceptual footing as advanced cancer [music] or endstage heart failure. The proteins alloys Alzheimer drew in his notebook century ago are still the proteins at the center of today's drug trials, today's PET scans, and today's blood tests. August data's brain in that sense has never really left the lab. Now Alzheimer's accounts for roughly 60 to 70% of dementia cases worldwide according to the WHO. But the remaining share is made up of conditions that look similar from the outside while behaving very very differently inside the brain. Treating every case of cognitive decline as Alzheimer's is one of the most common mistakes that families and even some clinicians make and it can lead to wrong medications, wrong expectations, and wrong plans for the years ahead. Vascular dementia is the second most common form and it's caused by damage to the blood vessels that keep brain tissue alive. A major stroke can trigger it suddenly, leaving a person marketkedly changed within hours. But more often, it builds up through a series of small, sometimes silent strokes and through the narrowing of tiny vessels deep inside the [music] brain. Families often describe vascular dementia as a staircase rather than a slope with long stable periods broken by sudden drops in ability after each new vascular event. Louisi body dementia is named after the abnormal clumps of a protein called alpha sinucleene that collect inside neurons. The same protein that drives Parkinson's disease in a different distribution. People with Louisbody dementia often experience vivid visual hallucinations early in the illness along with dramatic fluctuations in alertness from one hour to the next.

[00:17:38][music] Movement symptoms similar to Parkinson such as stiffness, tremor, and a shuffling walk frequently appear alongside the cognitive changes, and sensitivity to certain antiscychotic drugs can make standard psychiatric treatment dangerous. Fronttotemporal dementia attacks [music] a different territory of the brain. the frontal and temporal loes. And it often strikes earlier in life than Alzheimer's, sometimes in the 50s, even the 40s and 40 next year is terrifying because the frontal loes govern personality, judgment, and social behavior. The first signs are not usually memory loss at all. A previously cautious accountant might begin making reckless purchases. A gentle patient might become coarse or aggressive. A fluent speaker might start losing words and grammar while still remembering exactly where they parked their car. Then there's mixed dementia, which research increasingly suggests may be the rule rather than the exception in older patients. Autopsy studies have found that many people diagnosed in life with Alzheimer's also carried significant vascular damage or Louis bodies or both layered together inside their brain. The neat textbook categories, they blur in real life, which is part of why diagnosis is a lot harder than it sounds. A handful of rarer conditions can also produce dementia, including crude yakob disease, a rapidly progressing pron disorder that can kill within months rather than years. We've made a video about it.

[00:19:01]It'sing terrifying. These edge cases matter in the clinical sense, but they make up a tiny fraction of the global case load. The practical point is that the single word dementia hides at least four distinct biological stories. And the right care for one can definitely be the wrong care for another. And that difference is going to matter a lot when later in today's episode we come back to Robin Williams and the misdiagnosis that shadowed the final year of his life. But for now, let's jump to the spring of 2011. Pat Summit was 58 years old and the most decorated coach in the history of American college basketball. Over 38 seasons at the University of Tennessee, she had won 198 games and eight national championships with the Lady Voss. And she was known across the sport for a level of mental precision that bordered on legend. She remembered plays from a decade earlier. She remembered the families of every player she had ever recruited and she ran practices with the exactness of someone who never lost track of a single detail. That spring, she began losing track of the details.

[00:20:05]Keys went missing. Names slipped. Plays she had drawn up a thousand [music] times grew unfamiliar on the whiteboard.

[00:20:11]And the friction she felt inside her own thinking was unlike anything she had known her whole life. She went to the Mayo Clinic for evaluation in May 2011, and the doctors there diagnosed her with early onset Alzheimer's disease. She was 59. On August the 23rd, 2011, Summit announced the diagnosis publicly through a statement released by the university.

[00:20:32]She coached one final season with significant support from her staff, retired in April 2012 with the title of head coach Emiratus, and founded the Pats Summit Foundation to fund Alzheimer's research and patient services. She died on June 28th, 2016 at the age of 64 from complications of the disease. Now, her story is useful because the signs she first noticed are the [music] signs that most families miss, dismiss, or rationalize for months and sometimes years before anyone consults a doctor. The World Health Organization and the US Centers for Disease Control described an overlapping cluster of early symptoms that tend to appear in the months and years before a formal diagnosis. People begin repeating the same questions in a single conversation, losing track of what day or season [music] it is, struggling to find ordinary words like watch or stairs, and mishandling familiar tasks such as paying a recurring bill or following a recipe that they've cooked for decades. Personality changes are also a part of the picture, and they can be subtler than the memory lapses. A sociable person may start withdrawing from gatherings that they used to enjoy.

[00:21:37]A patient person may become unusually irritable and a careful person may begin making decisions, especially financial decisions that close family members find baffling. Families tend to explain these changes through almost anything else first, reaching for grief, retirement, hearing loss, medication, side effects, or simple stress before they reach for the terrifying possibility of dementia.

[00:21:59]Now there is an intermediate stage that researchers call mild cognitive impairment [music] where measurable changes in memory or thinking are present but daily life still functions more or less normally. Not everyone with mild cognitive impairment goes on to develop dementia and some people remain stable for years or even improve when an underlying cause is identified and treated. The threshold that most clinicians use for a dementia diagnosis is functional. Meaning the changes have begun to interfere with independent living in a way that another person can clearly observe. None of this means that an occasional lost word or misplaced phone is a sight of the disease and a single video on the internet is definitely not the right tool for diagnosis. Okay. What Pat Summit did by going to a specialist as soon as she sensed the friction inside her own coaching is what every major dementia organization recommends. Early evaluation can identify reversible causes, slow the progression in some cases, and give the person time to make decisions about their own life while they still can hold a pen. Confirming a dementia diagnosis is harder than most families expect when they first walk into a neurologist's office. There's no single blood test, no quick scan that returns a yes [music] or no.

[00:23:10]Historically, a definitive diagnosis of Alzheimer's disease could only be made after death. When a pathologist examine the brain for the plaques and tangles that Allies Alzheimer [music] first drew in 1906, doctors working with patients have to assemble the diagnosis from a whole lot of smaller pieces. The process usually begins with a detailed history taken from both the patient and a close family member because people in the early stages of dementia often underestimate or hide the changes that they're experiencing. Clinicians administer standardized cognitive tests that measure memory, attention, language, and visual skills. [music] They look for patterns of impairment that fit one disease better than another. Blood work checks for treatable conditions such as thyroid deficiency, vitamin B12 deficiency, certain infections, brain imaging with MRI or CT scans rules out tumors, strokes, and a condition called normal pressure hydrocheilis uh that can mimic dementia closely. That last category is really important because a meaningful minority of patients who arrive looking like they have dementia actually have something else driving their symptoms. Depression in older adults can blunt memory and concentration so severely that it has its own clinical nickname pseudo dementia and it often improves dramatically with treatment. Certain medications, especially those with anticolinergic effect, can produce confusion that lifts within weeks of stopping the drug. Sleep apnea, alcohol use, and chronic urinary tract infections can all push an older brain into a [music] state that looks alarmingly like early Alzheimer's until the underlying issue is addressed. The biomarker era is changing this picture in real time. PET scans can now detect amaloid plaques in the living brain.

[00:24:46]Cerebral spinal fluid drawn through a lumbar puncture can be analyzed for amaloid and tow. And blood tests for Alzheimer's pathology have moved from research laboratories into early clinical use in several countries. These tools allow specialists to identify the disease earlier and more confidently than at any other point in history. They also raise difficult new questions about whether people want to know they carry the pathology years before symptoms begin. Misdiagnosis remains a serious risk particularly for Louisibody dementia and fronttotemporal dementia which can be mistaken for psychiatric illness, Parkinson's disease or simple personality change for years before the correct label is applied. Specialists at memory clinics see patients who have been on the wrong medications for half a decade because the original diagnosis was Alzheimer's when the underlying disease was actually something else entirely. A diagnosis once made sets a long sequence of decisions in motion that most families have never thought through. Driving privileges have to be evaluated sometimes by the state, sometimes by a frank conversation at the kitchen table. Power of attorney, healthcare proxies, and advanced directives need to be drafted while the person still has the legal capacity to sign them. Financial accounts may need new safeguards, and conversations about long-term care, whether at home or in a facility, have to start years before they will actually be needed. We will return to those decisions later in today's episode when we look at what happened to one family in California after their diagnosis arrived. So stay tuned. But with a diagnosis in hand, the next question every family asks is the obvious one. What can medicine actually do? The honest answer in 2024 is that we can do more than we could in 1990 and also less than the headlines often suggest. So the first drug specifically approved in the United States for Alzheimer's disease was tacin cleared by the FDA in 1993 under the brand name Cognax. It worked by slowing the breakdown of acetylcholine, a neurotransmitter that nerve cells use to talk to one another and that runs short in Alzheimer brains. Tacine produced modest cognitive benefits in some patients, but it also carried a significant risk of liver toxicity and many people simply could not tolerate it for long. By the early 2010s, it had been pulled from the US market, eclipsed by newer drugs in the same family that were easier on the liver. Those newer drugs are the colon eststerase inhibitors most families today have actually heard of. Donna Brazil marketed as ariscept and approved in 1996 along with rivastamine and gallantamine both approved later in the decade. They work along the same general principle as tacine boosting available aceticoline to support the failing communication between neurons. For some patients, especially in mild to moderate Alzheimer's, these medications produce a measurable improvement in memory and daily function that can last for months or sometimes a few years. For others, the benefits small or absent, and the side effects, including nausea, diarrhea, and slowed heart rate, outweigh whatever gain there might be.

[00:27:42]In October 2003, the FDA approved a fourth drug, meantine, also sold as Nmena, for moderate to severe Alzheimer cases. Meantine works on a different chemical pathway, blunting overactivity of a brain chemical called glutamate that in excess appears to damage neurons. It's often added on top of a colon eststerase inhibitor in the later stages of the disease and the combination has become a standard part of treatment in many memory clinics around the world. And here's the part the families have to hit clearly even when it's hard. None of these medications stops Alzheimer's disease and none of them brings back the neurons that have already died. The plaque continues to accumulate. The tangles continue to spread and the underlying biology grinds relentlessly forward regardless of which pill you take in the morning. What these drugs can do in the patients who respond to them is lift the symptoms slightly for a window of time, buying months of clearer conversation or steadier routine before the disease reasserts itself. This is why supportive care has remained the backbone of dementia treatment for decades, not as an afterthought, but as the main event.

[00:28:48]Consistent daily routines reduce confusion. Familiar environments reduce agitation. And trained caregivers, whether family members or professionals, can prevent the falls, infections, and crises that often determine how long someone actually lives when they have the [music] disease. Speech therapy, physical therapy, and structured activities have all been shown to help maintain function longer than medication alone. The WHO in its 2025 fact sheet on dementia continues to frame care, not cure, as the central reality of treatment worldwide. It was inside that frustrating gap between drugs that soften symptoms and disease that kept advancing that the next chapter of Alzheimer's research took shape. So in 1984, two researchers named George Glenner and Cain Wong working at the University of California, San Diego, isolated and sequenced the protein that made up the dense plaques alloys Alzheimer had drawn almost 80 years earlier. They named it beta amaloid and their work opened a chemical door that the entire field would pour through over the following decades. Two years later in 1986, several laboratories independently identified the tangled fibers inside neurons as twisted forms of a protein called to completing the molecular pair at the heart of the disease. What came next was a hypothesis that has dominated Alzheimer's research ever since. often called the amaloid cascade hypothesis. The idea first articulated formally in the early 1990s is that the abnormal buildup of beta amaloid is the initiating event in Alzheimer's disease [music] and that everything else including the towangles and inflammation and the eventual death of neurons flows downstream from that first protein that's gone wrong. If amaloid is the upstream cause, then clearing amaloid from the brain should slow or stop the disease. And the pharmaceutical companies have spent tens of billions of dollars over 30 years trying to do exactly that. For most of those 30 years, the trials failed. Drug after drug reduced amaloid in the brain without producing meaningful improvement in patients and a generation of researchers began openly questioning whether the field had bet too much on a single molecule. Skeptics argued that amaloid might be a byproduct of the disease rather than its driver or that intervening at the plaque stage was simply too late for someone who was already losing memory. What kept the amaloid hypothesis alive through those failures was genetics and specifically a small number of families in which Alzheimer's disease passes down through the generations like clockwork. In the early 90s, researchers identified mutations in a gene called AP, which codes for the amaloid precursor protein in families where members reliably developed Alzheimer's in their 40s or 50s. Soon afterward, mutations in two related genes, Pressinelin 1 and Preinel 2, were linked to similar early onset inherited forms of the disease, and all three genes turned out to affect how amaloid is produced and processed in the brain. A separate genetic discovery, the AOE epsilon 4 variants, kind of pleased that I know how to say that little symbol there on my teleprompter, identified in 1993, did not cause Alzheimer's outright, but significantly raise the risk of developing the more common late onset form. People who inherit one copy of a poe epsilon 4 are at elevated risk, and those who inherit two copies face risk levels several times higher than the general population. The genetic evidence pointed again and again back toward amaloid biology. Now, the most striking population in this story is in the rural highlands of Antiochia in northwestern Colombia, where an extended family of around 6,000 related individuals carries a specific pre-enoline 1 mutation known as E280A, often called the PISA mutation. Carriers reliably develop mild cognitive impairment in their mid-4s and full dementia by their early 50s in a pattern that has been documented across generations by Colombian neurologist Francisco Leera and his collaborators since the 1980s. The PISER cohort has become one of the most important populations in global Alzheimer's research and prevention trials in this family testing whether anti-amaloid treatments started before symptoms can delay the disease that their genes otherwise guarantee. This is the science that sits behind the diagnosis Pat Summit received in her 50s. Most early onset Alzheimer's is not inherited in the same dramatic pattern as the pace families. But the existence of those families and the genes they carry is part of why amaloid has remained at the center of the field even after so many failed drugs. The bet was scientific. It was expensive. And by the early 2020s, it was about to face its sharpest public crisis yet. In July 2022, the journal Science published [music] an investigation by reporter Charles Pillar that shook the Alzheimer's research community in a way nothing had in years.

[00:33:30]The reporting centered on Sylvane Len, neuroscientist at the University of Minnesota and on a 2006 paper he had co-authored in the journal nature that had been cited thousands of times by other researchers in the field. [music] The paper identified a specific subspecies of amaloid called a beta star 56 [music] as a possible toxic agent driving memory loss in animal models of Alzheimer's disease. The investigation was triggered by a Vanderbilt University neuroscientist named Matthew Shrag, who had been hired to examine images in scientific papers as part of a separate dispute over a different outsiders [music] experimental drug. Shrag began noticing what looked like duplicated and altered bands in western blot images, laboratory pictures that researchers used to show the presence of specific proteins in their experiments. He compiled his findings and shared them with science, which then [music] commissioned independent image analysts and Alzheimer's researchers to review those same papers. The reviewers concluded that images in multiple lesser papers showed signs of manipulation raising serious questions about the underlying data on a beta star 56. In the months that followed, journals issued expressions of concern. Corrections were published, and the 2006 Nature paper was eventually retracted in 2024 after an extended review process by the journal and the author's institution. Len disputed aspects of the allegations through his university, and the formal investigations into research misconduct moved at the slow pace that such inquiries always do. And here's what the episode did not prove. The questioned images concerned a specific amaloid subspecies a beta star 56 that some researchers have pursued as a potential drug target and the doubts cast on those particular results undermined that specific line of work. The broader amalite hypothesis builds on genetic evidence from a pre-enoline mutations and on decades of independent biochemical research did not rest on Len's images and was not refuted by their problems. Senior Alzheimer's researchers quoted in the science investigation made that point repeatedly even as they acknowledge the damage to public trust. What the episode did expose was how much weight a single visually striking finding can carry in a field hungry for a clear culprit and how long it can take [music] for image problems to surface in peer-reviewed literature that processes tens of thousands of figures every year. Matthew Shrag became a reluctant public figure in the scientific integrity work and his methods including careful sideby-side image comparison were soon being applied to papers in other corners of bienson.

[00:35:55]The a beta star 56 story slid out of the foreground of Alzheimer's research and the field's attention turned back to the broader question of whether any anti-amaloid drug could actually help a living patient. That question was about to receive its loudest and most contested answer in a generation inside the conference rooms of the US Food and Drug Administration. So, while the FDA was preparing for its first major modern decision on an Alzheimer's drug, a country music star was already writing the most public diary of the disease that American audiences had ever seen, [music] Glenn Campbell, the guitarist and singer behind Rinstone Cowboy and Witchita Lineman, was diagnosed with Alzheimer's disease in 2011 at the age of 75. and his family chose unusually to announce it before he stepped onto the road for one last run of shows that became known as the Goodbye Tour which ran from 2011 into 2012 and stretched longer than anyone had initially planned because Campbell was still on most nights able to play. His children played alongside him in the touring band, queuing him into songs, covering the moments when the lyrics slipped and standing close enough on stage to guide him back to the verse if he lost his place. Audiences came knowing what they were watching and the reviews from that tour describe a strange double experience of seeing a musician disappear and remain in the same evening. In 2014, the documentary Gun Campbell I'll Be directed by James Kee brought cameras inside the tour and inside the family home. The film showed Campbell forgetting interviews moments after giving them, asking his wife the same questions across a single afternoon and then walking onto a stage and playing intricate guitar solos that his hands seemed to remember even when his conscious mind did not. Procedural memory, that's the kind stored in motor circuits built up over a lifetime of practice, is often preserved longer in Alzheimer's than the explicit memory for names and dates. That's why athletes and musicians can sometimes perform skills that they can no longer describe. The film also captured the harder moments away from the stage, including a neurological examination of the Mayo Clinic in which Campbell could not consistently identify the year or the building he was sitting in. His wife Kim and his children appear throughout the documentary as the everyday infrastructure of his continued performing life, managing medications and travel, and the dozens of small accommodations that kept him safe on tour. The film closed its theatrical run with a song called I'm Not Going to Miss You, which Campbell recorded after his diagnosis and which his coowwriter Julian Raymond has described as his direct response to the disease. The lyric is unsparing about what was coming and what had already gone. Written from the perspective of someone who knows he will eventually lose the person that he is singing to. The song was nominated for an Academy Award for best original song in 2015 and won a Grammy that same year for best country song. Kembell continued recording until his voice and stamina would no longer allowed it and he died on August the 8th, 2017 at the age of 81 after several years out of the public eye in long-term memory care.

[00:38:43]Now, a brief note just before we get into this next section. We're going to be discussing the death of the actor Robin Williams back in 2014, and we will do so clinically focused on what his autopsy revealed about a particular form of dementia. If this is difficult to hear, please feel free to skip ahead.

[00:38:59]And if you're struggling, help's always available. Robin Williams was 63 years old when he died on August the 11th, 2014 at his home in Northern California.

[00:39:08]And the months leading up to his death had been some of the most medically confusing of his life. In May of that year, he'd been diagnosed with Parkinson's disease, and he had spoken privately with friends and family about the tremors, the stiffness, and the rising anxiety that had been disrupting his work and his sleep for many months.

[00:39:22]The Parkinson's label gave a name to some of what he was experiencing, but it did not account for the full range of symptoms his family later described in detail. The autopsy performed by the Marin County Coroner revealed something his doctors had not been able to see during his life. Williams had diffuse Louis body disease, an aggressive form of the same pathology that drives Louis body dementia with widespread deposits of the protein alphasine nucleon throughout his brain stem, his lyic system, and his cortex. Louisibody dementia is the second most common form of progressive dementia after Alzheimer's disease and its symptoms include vivid visual hallucinations, traumatic fluctuations in attention and alertness from hour to hour, movement problems similar to Parkinson's and a severe sleep disorder in which people act out their dreams physically. In September 2016, Williams' widow, Susan Schneider Williams, published a personal essay in the journal Neurology titled The Terrorist Inside My Husband's Brain.

[00:40:17]She wrote about watching her husband move through what she counted as more than 40 symptoms in the final year of his life, including paranoia, delusions, insomnia, gastrointestinal distress, and sudden lapses in his ability to remember lines on set. She described doctors searching for explanations, one symptom at a time, never assembling them into the single diagnosis that the autopsy would later confirm. Her essay made several careful points that have shaped how clinicians now talk about the disease publicly. Louisibody dementia is frequently mistaken for Parkinson's disease and Alzheimer's disease or for primary psychiatric illness and the wrong diagnosis can lead to the wrong medications. Some of those medications can actually be dangerous in Louisibody patients because of their severe sensitivity to certain antiscychotic drugs. She also argued that the depression often described as a cause of suffering in such cases can itself be a symptom of the underlying neurological disease rather than a separate condition layered on top of it. The Louis Body Dementia Association reported a sharp rise in family inquiries in the months after Williams' death and again after his widow's essay appeared in neurology.

[00:41:19]For many caregivers, the public accounts of a famous patient navigating misdiagnosis put a name to symptoms they had been trying to describe to their own doctors for years without success. The condition remains underrecognized in primary care and specialist memory clinics continue to see patients who arrive with files full of older incorrect labels. But let's step away from the famous names for a moment and into an ordinary home in an ordinary suburb because this is of course where most dementia care actually happens. The World Health Organization estimates that informal caregivers, meaning family members and friends who are not paid for the work, provide on average 5 hours of care per day to a person living with dementia and that women provide roughly 70% of those caregiving hours worldwide.

[00:42:05]Those [snorts] numbers are large and clean on the page, and they flatten an experience that lived from the inside is made of thousands of small refusals to walk away. Consider the medication schedule taped to the refrigerator, the one with the highlighter marks and the times written in capital letters because a misdose at 6:00 in the evening means a worse night at 3:00 in the morning.

[00:42:24]Consider the locks installed on the insides of cabinets that once held only pots and pans because the person you love has begun mistaking dish soap for something drinkable. Consider the front door that now has a chain higher than eye level because last winter your father walked out in his pajamas and was found four streets away by a neighbor who recognized him only because they'd gone to the same church for 30 years.

[00:42:46]Caregivers describe a particular kind of exhaustion that is not exactly physical and not exactly emotional and that does not lift after a single night of rest because no single night of rest is ever uninterrupted. The same question gets asked at 11:00 in the evening, then at 1:00 in the morning, and then at 3. And the patient asking it is genuinely encountering it as new every time.

[00:43:09]Saying, "I already told you," does no good, and it often makes things worse.

[00:43:13]So caregivers learn to answer the same question with the same calm voice for the eighth time before sunrise. The role expands far beyond bedside care. It's territory most family members never train for. They become medication managers, safety monitors, insurance negotiators, financial planners, legal proxies, and the emotional shock absorbers for every other relative who calls to ask how things are going without offering to come and help. They learn to interpret behaviors that doctors call neurossychiatric symptoms and the rest of the world might simply call frightening. These include agitation, suspicion, and sometimes accusations aimed at the people doing the most to keep them safe. Researchers and clinicians have a name for the particular grief that runs through this work and they call it anticipatory grief. It is the experience of mourning someone who is still in the room with you, still drinking coffee at the kitchen table, still recognizable in flashes that arrive without warning and leave the same way. Caregiver depression rates are elevated compared to the general population in studies cited by major dementia organizations and the risks rise with the duration of caregiving and the severity of the patients symptoms. Speaking of caregivers as heroes, which the press often does, can obscure a more important fact about the work they do. The burden they carry is not the existence of their loved one who remains a person worthy of care for as long as the disease allows.

[00:44:35]The burden is the inadequate support around them, the patchwork of services and insurance rules and restbite programs that families have to assemble on their own while also keeping someone alive. For many families, there comes a point where the home arrangement stops being sustainable and the search begins for somewhere else. In the United States and much of the English-speaking world, that search usually leads to a category of facility known as assisted living, often with a specialized wing or program marketed under the name of memory care.

[00:45:02]These businesses present themselves as a middle ground between independent living and a traditional nursing home designed for people who need supervision and help with daily activities without requiring hospital level medical care. The marketing materials are familiar to anyone who has toured one of these places under pressure. Brochers [music] describe secure units with coded doors that prevent wandering, structured daily routines designed to reduce confusion, staff trained in dementia specific communication, and activities calibrated to the cognitive abilities of residents.

[00:45:32]Many facilities, they're physically attractive with landscaped courtyards, dining rooms that aim for the feel of a restaurant, and private or semi-private apartments that families can decorate with familiar furniture from home. The regulatory reality behind those brochures is more complicated than most families realize at the point of move in. In a 2013 investigation by ProPublica and the PBS series Frontline, reporter AC Thompson documented that in many US states, assisted living is regulated more like housing than like healthcare with rules that vary substantially from one jurisdiction to the next. Minimum staffing ratios are not always set by law. Training requirements for direct care workers are often modest and [music] oversight inspections can be infrequent compared with the inspections required of skilled nursing facilities. That structural gap is more important for dementia residents than for almost any other population because people with moderate to advanced dementia are frequently unable to report neglect or abuse to anyone outside the building. A resident who cannot remember whether they were repositioned in bed cannot tell a family member during a Sunday visit that they were left in the same chair from breakfast to dinner.

[00:46:35]Residents who cannot reliably describe pain cannot alert staff to a developing infection until it's become a medical emergency. Families almost always choose facilities under the worst possible conditions for clear thinking. The decision usually arrives after a fall, after a wandering incident, after a hospitalization, or after a caregiver has reached a point of physical collapse. And it has to be made in days or weeks rather than in months of careful comparison. Cost pressures sharpen the urgency further because in much of the United States, assisted living is paid for out of personal savings and home equity rather than through Medicare and families are watching the meter run from the moment they sign up. It was inside this industry under these conditions that a woman named Joan Boyce moved into a facility called Emerald Hills [music] in Orin, California. This was in September 2008. And let's look into it now. Joan Boyce was 81 when she was diagnosed with Alzheimer's disease, and her family had reached the point at which keeping her safely at home was just no longer possible. Emerald Hills was operated by the Emiratus Corporation, then one of the largest assisted living chains in the United States, and the facility offered a dedicated memory care unit that the family understood to be staffed and equipped for residents at Jones level of cognitive decline. The Boyce family later said in court filings that the admissions process had reassured them their mother would receive the supervision and physical care that she could no longer provide for herself.

[00:47:58]Joan Boyce lived at Emerald Hills for approximately 3 months. And during that period, according to the evidence presented at trial, she developed multiple pressure ulcers, including a severe wound on her lower back that progressed to a stage which underlying tissue was exposed. Pressure ulcers, also called bed sores, develop when a person is left in the same position for too long without being repositioned and any mobile or partially mobile residents. They are a recognized and largely preventable complication of inadequate nursing care. Joan was hospitalized, transferred out of the facility, and died in early 2009 with the pressure ulcers and resulting complications cited in court as substantial factors in her death. Her family filed suit against Emirates Corporation alleging elder abuse, negligence, and wrongful death. and the case went to trial in Sacramento County Superior Court in 2013. ProPublica and Frontline, working in parallel with the litigation, reported on internal company practices the plaintiff's attorneys argued had contributed to the conditions at Emerald Hills, including staffing levels that the family's lawyers said were inadequate to the acuity of the residents the facility had accepted.

[00:49:01]Emiratus disputed the characterization of its operations and defended the care provided the facility throughout the proceedings. In May 2013, the jury returned a verdict in favor of the Boyce family, finding Emiritus liable for elder abuse, negligence, and wrongful death, and awarding compensatory impunitive damages that initially totaled hundreds of millions of dollars.

[00:49:19]The trial judge later reduced the award substantially, and in June 2013, the court upheld a final judgment of roughly 23 million US, as reported by KC and the Associated Press. The judge's ruling included pointed language about the company's conduct, and the verdict became one of the most prominent assisted living elder abuse judgments in recent American legal history. And just a note on the corporate timeline here for accuracy, in 2014, after the boy verdict, Emiritus Corporation was acquired by Brookdale Senior Living, which became the largest senior living operator in the US through that merger.

[00:49:51]The findings of fact in the Boyce case belong to Emmeritus, the company that operated Emerald Hills at the time Joan lived there. and reporting on the case attributes the conduct accordingly rather than extending it to the acquiring company that took on the operations afterward. Always good for us to cover our legal bases. The harder question raised by the verdict is the one regulators and families have wrestled with in the decades since. How does an industry built around the promise of safety for cognitively vulnerable residents produce cases like Joan Boyce's at all? and what specific regulatory changes have followed in the states where such cases have been documented. Reform proposals after the ProPublica and frontline reporting included stricter staffing rules, mandatory dementia training, and clearer admissions criteria for memory care units, but uptakers varied widely by state, and federal oversight of assisted living remains far thinner than the oversight of skilled nursing facilities funded by Medicare and Medicaid. All right, so it was a while ago, but let's return to that morning in Achi and to the man whose family had sewn identification into the lining of his clothes. By the time his case reached the Supreme Court of Japan in 2016, Lur Court had already ruled twice that his relatives owed JR Central money for the disruption his health had caused on the rail line. The Nagoya District Court in 2013 ordered the family to pay the full 7.2 million yen, and the Nagoya High Court in 2014 reduced that figure to around 3.6 6 million yen while keeping the wife on the hook for her husband's actions. The widow at the center of this case was 85 years old at the time of the incident and she had her own care needs that limited how closely she could shadow her husband through the house.

[00:51:26]Her eldest son, who shared legal responsibility under the high court's reasoning, lived hundreds of kilometers away in Yokohama and had not been physically present that day. The lower courts had nonetheless held that a spouse with a statutory duty of supervision could be liable when a person judged incapable of responsibility caused damage to a third party. On March the 1st, 2016, the Supreme Court reversed those decisions and ruled that the family was not automatically liable for the railways losses. The judgment as reported by the Asahi Shiman and Jcast News did not say that families with a relative living with dementia could never bear responsibility for harm caused by that relative. No, it said that liability had to be assessed case by case looking at the actual living arrangement, the physical capacity of the caregiver and the practical possibility of supervision under real conditions. For the widow in HI, the court found those conditions made automatic liability unreasonable.

[00:52:20]She was elderly. She was frail and the idea that she could have prevented her 91-year-old husband from leaving the house during a brief lapse stretched the legal duty of supervision past the point where it matched daily life. The son in Yokohama, the court reasoned, could not be treated as a constant supervisor of a father that he did not live with. And here's the thing, the ruling landed in a country where the scale of dementia related wandering has already moved far beyond the courtroom. The National Police Agency of Japan reported that more than 10,000 people with dementia were recorded as missing in 2015 and that figure has risen in subsequent annual reports as the population has aged further. Municipalities from Fukoka to Sai have built volunteer search networks, drills with local schools and registries where families can submit photographs and physical descriptions in advance. Some towns have experimented with QR coded stickers placed on fingernails or clothing which a stranger can scan to contact a registered caregiver. Others have funded GPS enabled shoes through local welfare budgets. Dementia advocates in Japan welcomed the 2016 ruling as a recognition that the duty of care could not rest entirely on exhausted spouses and distant children. Legal scholars writing in Japanese law journals after the decision noted that the court had left open the question of who if not the family should bear the residual cost of incidents like the one at Kioa station.

[00:53:37]Jail Central walked away from the case without compensation and the railway has not in public statements pursued similar [music] claims against caregivers in subsequent wandering deaths along its lines. The widow died a few years after the ruling out of the public eye and her name was kept out of most reporting at the family's request. The legal precedent that her case said continues to be cited in Japanese tort textbooks under the heading of supervisory liability for persons lacking capacity.

[00:54:02]So families can't do it alone and courts can't fix it after the fact. What does the society actually build for people living with dementia? Well, two answers have taken shape over the last two decades. One behind a wall and one without one. The wall belongs to Dehulog, a residential complex in the town of Vasp in the Netherlands which opened in December 2009 on the site of a former traditional nursing home. The facility was designed by the nonprofit Vivium Zorg Group for residents with severe dementia, and it houses roughly 150 to 170 people across a cluster of small homes built around streets, a square, a supermarket, a cafe, in a theater. Staff work in ordinary clothes rather than uniforms. Residents shop for groceries with assistance, and the perimeter is secured so the residents can move freely inside the village without being able to wander into traffic outside. The model does not claim to cure dementia or slow its biology. The leadership at Hogawake has been careful in interviews to push back against journalists who describe it as a miracle. What it changes is simply the environment around the disease so that a resident who wants to walk meets a familiar street rather than a car on a highway. Lissa McFarer writing in the New Yorker in October 2018 called the approach a system of comforting fictions and her piece explored the ethical question of whether arranging a simulated normal life of people who could no longer follow the real one is a form of kindness or a form of deception.

[00:55:31]The question doesn't have a settled answer and hog inspired projects have since opened in countries from Denmark to Canada with varying degrees of fidelity to the original design. Critics point out that the per resident cost is substantial and the Dutch long-term care markets makes the model possible in ways that do not transfer easily to countries with thinner public insurance. Outside the wall, a different strategy has spread more widely under the banner of dementia friendly communities. Japan launched Ninisho Support Caravan in 2005, a national program that trains ordinary citizens in basic dementia awareness through short courses run by local governments and community groups.

[00:56:08]The Japanese Ministry of Health, Labor, and Welfare has reported that more than 14 million people have completed the training by early 2020, including bank tellers, bus drivers, school children, and convenience store staff. The United Kingdom built a parallel program called Dementia Friends, launched by the Alzheimer Society in 2013, which by its own published figures has trained several million people in England, Wales, and Northern Ireland. Francis piloted village land projects in the town of Dax in the southwest which opened in 2020 with a layout influenced by Hogavik but funded through a mix of public and departmental support. Each program rests on the same underlying bet that a shopkeeper who recognizes confusion can guide the customer home rather than calling the police on someone who's forgotten where they parked. The ethical tensions inside these programs are real and unresolved.

[00:56:55]GPS trackers and QR identification tags raise privacy questions for people who can no longer consent to being monitored and the line between protection and surveillance grows thinner as the technology improves. Now advocates argue that the alternative, the death at Koa Station and the lawsuit that followed it [music] sets a clear floor under what civic infrastructure for dementia has to look like. So, in April 2016, in a nursing home in the Netherlands, a 74-year-old woman with severe Alzheimer's disease was given a lethal dose of medication by her physician in accordance with the Dutch euthanasia law and with an advanced directive that she had written years earlier while still legally competent. The case became the first prosecution of a doctor under the Netherlands's termination of life on request and assisted suicide act since the law took effect in 2002. The patient and the doctor were not named in public records and reporting in the Washington Post and Dutch outlets has referred to them only by role. The woman had been diagnosed with Alzheimer's several years earlier and she had drafted a written directive requesting euthanasia when her suffering became unbearable and when she could no longer recognize her family.

[00:58:02]The directive was reviewed by her general practitioner and updated as her condition changed. And by 2016, she had moved into residential care because her husband could no longer manage her at home. By the time the procedure was carried out, she was no longer able to consistently affirm or refuse the request that she had written years earlier. Dutch prosecutors charged the physician, a geriatrician who had taken over a care at the nursing home, with failing to verify the patients current wishes adequately before proceeding. The case proceeded through the Hague District Court in 2019, and on September the 11th of that year, the court acquitted the doctor of all charges. The judges ruled that the physician had acted with due care under the law, that the advanced directive was valid, and that requiring renewed consent from a patient already in advanced dementia would have rendered the directive meaningless. In April 2020, the Dutch Supreme Court upheld the acquitt and clarified that doctors carrying out euthanasia under a written advanced directive in advanced dementia would not face criminal liability where statutory due care criteria were met. The Royal Dutch Medical Association subsequently updated its professional guidance on advanced directives in dementia, setting out how physicians should document conversations and assess suffering when the patient can no longer speak for themselves. The legal question was resolved within the Dutch system. The philosophical question wasn't because courts aren't about philosophy. The case sits on this fault line that runs through modern medical ethics and it's been argued on both sides by people acting in good faith. On one side is the principle of prior autonomy which holds that a person of sound mind has the right to bind their future self to decisions about a life that they can foresee but not yet inhabit. The directive is on this view the only voice the earlier self will ever have once the disease has progressed and ignoring it is a different kind of abandonment. On the other side is the principle of present vulnerability which holds that the person in the bed is the person who matters now and that someone who can no longer affirm a past decision cannot meaningfully be said to be exercising it. Disability advocates and some palative care physicians have argued that advanced directives in dementia risk treating cognitive change itself as a fate worse than death and that the framework can pressure patients toward early decisions they may not make if better care were available. The Netherlands permits this procedure only under strict statutory conditions and most countries do not permit it at all in cases of advanced dementia, including most jurisdictions in North America and most of the European Union. A Lemon comparison published in April 2024 set out how France, Belgium, Spain, and other neighbors draw the line in different places along the spectrum. The Dutch case did not resolve the underlying ethical question for any of them and it remains one of the sharpest unresolved questions in the medicine of cognitive decline. Now dementia is not just a clinical question anymore. It's also become a planning question for finance ministries. The World Health Organization put the global cost of dementia at roughly$ 1.3 trillion US in 2019 with about half of that figure representing the unpaid labor of family members rather than build medical care.

[01:01:10]Projections cited in the same WHO materials suggest that the annual total will continue to climb as the global case load moves towards 153 million people by 2050. Governments have been writing plans against those numbers for more than a decade now with varying degrees of follow-through. In the United States, President Barack Obama signed the National Alzheimer's Project Act into law on January the 4th, 2011, creating a federal coordinating structure and committing the country to a national plan with the stated goal of preventing or effectively treating Alzheimer's disease by 2025. The act required annual updates and a standing advisory council and federal Alzheimer's research funding through the National Institutes of Health rose substantially in the years that followed. Though the 2025 treatment goal arrived without being met, Japan moved on a parallel track with the orange plan launched by the Ministry of Health, Labor, and Welfare in 2012 and updated as the New Orange plan in January 2015. The plan sets numerical targets for early diagnosis, for the [music] expansion of community support centers and for the training of citizens through the ninchi show support caravan that we mentioned earlier. The United Kingdom announced the prime minister's challenge on dementia under David Cameron in March 2012 with a refreshed version challenge on dementia 2020 published 3 years later. At the international level, the World Health Assembly adopted the global action plan on the public health response to dementia 2017 to 2025 in May 2017, asking member states to coordinate work across awareness, risk reduction, diagnosis, and caregiver support. The G8 Dementia Summit hosted by the UK in December 2013 had set the political tone for that decade by committing participating governments to accelerate research with reporting in the BMJ describing an ambition framed around finding a disease modifying treatment by 2025. Behind all of these documents sits a workforce problem that no plan has yet solved. You see, there are not enough trained dementia caregivers for the 57 million people already living with the disease, let alone for the 153 million projected by midentury. And care worker turnover in the United States and the United Kingdom routinely runs above 30% annually in published industry surveys.

[01:03:19]Wages in direct care work remain low across most high-income countries.

[01:03:23]Immigration restrictions have tightened the supply of foreignb born caregivers in several economies and lower inome countries face the steepest projected increases in cases with the thinnest existing infrastructure. Now the honest list of open questions in dementia science is longer than the list of settled facts and the field has grown more candid about that in recent years.

[01:03:43]One of the most stubborn puzzles concerns the relationship between brain pathology and lived symptoms because autopsy studies have repeatedly identified people who died with extensive amaloid plaques and towangle while remaining cognitively intact into their final months. Other patients decline rapidly with relatively modest pathology and no current biomarker reliably predicts which path an individual will follow. The amaloid hypothesis itself has taken hits even from drugs that did exactly what the theory predicted. Solomab, an antibbody developed by Eli Lily that targets soluble amaloid, failed to show meaningful clinical benefit across the [music] expedition trials and was reported in 2023 to have missed its end points in the A4 prevention study in people with early amaloid accumulation.

[01:04:28]The failures do not refute the broader hypothesis, but they complicated the simplest version of it and they pushed researchers to look at tow inflammation and vascular contributions with renewed attention. A newer line of inquiry concerns the GLP-p1 receptor agonist, the class of drugs that include semiglutide and that has reshaped the treatment of diabetes and obesity over the last few years. Novo Nordisk has been running phase 3 trials called evoke and evoke plus testing oral semiglutide in early Alzheimer's disease with results expected to be out in the coming years. Whether a drug developed for blood sugar will turn out to influence the trajectory of dementia is a genuine unknown at the time we're making this video. Hopefully, we'll have an update for you in the future. Biomarker testing has created its own ethical territory that medicine has not yet mapped completely as well. Blood tests for amaloid and tow are moving rapidly into wider clinical use. And they make it possible to tell a healthy 55-year-old that they are very likely to develop Alzheimer's disease in the decades ahead at a moment when no treatment can reliably change the outcome. Specialists in memory clinics report that some patients want that information and others absolutely don't. The field is still working out how to offer testing responsibly under those conditions.

[01:05:41]Incident data adds one more layer of uncertainty to the picture. Several large studies in high-income countries, including the Framingham Heart Study cohort and analysis from the United Kingdom, have suggested that age specific dementia incidents has been declining in recent decades, possibly because of better cardiovascular health and rising education levels. Other regions, particularly parts of Asia and subsaharan Africa, are seeing rising age specific rates alongside the demographic surge, and the global total continues to climb even when individual risk at a given age may be falling. So, let's return one last time today to Frankfurt in November 1901 and to the consulting room where Alloys Alzheimer sat across from his 51-year-old patient with a notebook open on the table between them.

[01:06:28]He had asked her to write her own name and after several attempts that did not resolve into letters, Augusta [music] said in German mikurin.

[01:06:38]The phrase translates to, [music] "I have lost myself." And it appears in the case notes that historians of medicine recovered from the Frankfurt archive in the '90s. She said it more than a 100 years ago, before the disease that would eventually carry her doctor's name had been described in any textbook. She said it before Emil Crapelin would borrow that name in 1910. Before George Glenner and Cain Wong would isolate beta amalloid in 1984, before the Colombian families in Antiochia would be enrolled in prevention trials, and before any of the drugs, lawsuits, national plans, or ethics cases in this episode even existed. There are about 57 million people living with dementia in the world today, according to the WHO. The projection from the Institute for Health Metrics and Evaluation puts that figure at 153 million by 2050. Each of those numbers contains a sentence very much like the one August wrote down in a doctor's office in Frankfurt in a language her doctor understood on a day that she could no longer write her own name. The Supreme Court of Japan ruling in March 2016 didn't answer the question that this episode opened with at Kioa Station. It said that the answer cannot be a single exhausted spouse alone in a house holding the door closed. And on that note, very personal one for those people, we'll end today's video.