{"id":95696,"date":"2026-10-12T00:01:00","date_gmt":"2026-10-12T06:01:00","guid":{"rendered":"https:\/\/www.opinionpublica.tv\/portada\/?p=95696"},"modified":"2026-10-11T16:09:50","modified_gmt":"2026-10-11T22:09:50","slug":"will-we-ever-understand-dementia","status":"publish","type":"post","link":"https:\/\/www.opinionpublica.tv\/portada\/will-we-ever-understand-dementia\/","title":{"rendered":"Will we ever understand dementia?"},"content":{"rendered":"\n
\"Will<\/figure>\n\n\n\n

Since the days of Dr. Alzheimer himself, there has been a dream that severe senility might have an explanation \u2014 and a cure. The search for both has never been more urgent.<\/p>\n\n\n\n

The story of the science of dementia began on an autumn day in 1891, when a 71-year-old man was admitted to the psychiatric hospital at the University of Prague. The man, referred to as August H. in his medical file, had periods of freezing up mentally, sometimes fainting and not coming to for several minutes. More recently, he had been prone to fits of rage, and even threatened his wife with a knife, shouting that he was going to kill her.<\/p>\n\n\n\n

The case caught the attention of the director of the clinic, Arnold Pick. After August H. died, Pick\u2019s team examined his brain, dividing it into sections and weighing them and checking for abnormalities. The brain seemed essentially normal except for signs of decay, or atrophy, in one self-contained place: the left temporal lobe.<\/p>\n\n\n\n

This was quite likely the first recorded moment that a scientist, staring at a piece of brain tissue, saw dementia as a problem to be understood and solved, rather than a natural, unavoidable part of aging. Until then, almost everyone, including Pick himself, had taken it as an article of faith that dementia, or senility, was a generalized condition, the sign of a brain in overall decline. But after seeing August H.\u2019s brain, Pick began to search for and document other dementia cases in which the problem wasn\u2019t aging, but this specific part of the brain that was starting to lose function and misfire.<\/p>\n\n\n\n

His observations might have fallen into obscurity had they not come to the attention of one of his counterparts in Germany \u2014 Alois Alzheimer.<\/p>\n\n\n\n

Pick\u2019s clinic, in Prague, existed far from Germany\u2019s well-known neurology centers. But Alzheimer was plugged in to a community of cutting-edge researchers in Frankfurt and, later, Munich, specialists in microscopy and histology who could analyze sections of a brain under a microscope by staining the samples on glass slides.<\/p>\n\n\n\n

While Pick\u2019s consequential patient was August H., Alzheimer\u2019s was a woman named Auguste D. She arrived at the Frankfurt hospital where Alzheimer worked in 1901, when she was only 51 years old. Out of nowhere, it seemed, she had flown into fits of jealousy toward her husband, then suffered a rapid loss of memory. She got lost in her own apartment, carried things back and forth incessantly and then hid them, and became convinced someone was trying to kill her. After she died in 1906, Alzheimer found something strange in her brain cells, which he examined under a microscope.<\/p>\n\n\n\n

In the center of an otherwise almost normal cell, Alzheimer noticed \u201cone or several fibrils,\u201d or what we now call tangles, and in the cell\u2019s outer layers he saw \u201cnumerous small miliary foci,\u201d or what are now called plaques. \u201cAll in all,\u201d Alzheimer concluded in a 1907 paper, \u201cwe have to face a peculiar disease process.\u201d<\/p>\n\n\n\n

The plaques and tangles identified by Alzheimer remain the most compelling and mysterious aspects of what we now call Alzheimer\u2019s disease. On a slide, under a microscope, the plaques (later found to be made of a protein called beta-amyloid) looked like little blotches, darker in the center and wispier on the edges. The tangles (now known to be proteins called tau) looked like little curly threads that interwove, bundled together and bunched up in any number of ways.<\/p>\n\n\n\n

To Alzheimer, these plaques and tangles seemed like interlopers, clogging the cells of a brain and causing disease, though he had no evidence that this was really the case; he could only compare them with the brains of people who had died without brain disorders, which were free from these intrusions. Alzheimer didn\u2019t know how the plaques and tangles had gotten into those brain cells, why they were there, how to get rid of them or even whether anyone should try.<\/p>\n\n\n\n

Today dementia is estimated to affect more than 55 million people worldwide, and nearly 10 million cases are added every year. By 2050 \u2014 as populations age and the power of diagnosis improves \u2014 that number is projected to rise as high as 139 million. We\u2019re already on our way to becoming a society of caregivers, looking after an aging population unable to support itself.<\/p>\n\n\n\n

And yet, in a sense, we understand little more about the plaques and tangles of Alzheimer\u2019s disease than we did 120 years ago, when Alois Alzheimer first noticed them. In recent years, we may have even lost ground. A decades-long consensus about the meaning of those plaques and tangles has collapsed as treatments built on those theories have failed, reopening what now must be understood as one of the most urgent unsolved problems in medical science: What is dementia, and how can we possibly slow its advance and reduce its terrible toll?<\/p>\n\n\n\n

From the start, Alzheimer\u2019s disease had a very fluid definition. Alois Alzheimer\u2019s second major patient, known as Johann F., had only plaques in his brain, no tangles. If Alzheimer\u2019s was a single disease, why did affected brains often look so different from one another? And there remained the question of the cases Pick had been collecting. In 1911, Alzheimer re-examined two of Pick\u2019s cases and found something very different between plaques and tangles: tiny spherical orbs, clear with spots in the middle that would later be called Pick bodies.<\/p>\n\n\n\n

As a diagnosis, Pick\u2019s disease \u2014 now classified as a form of frontotemporal dementia, or FTD \u2014 was as elusive as Alzheimer\u2019s. \u201cEach case suggests new problems,\u201d the German psychiatrist Anton von Braunm\u00fchl said in 1928. And even if scientists wanted to further investigate these new diseases, there was no way to diagnose them with certainty before patients died, much less provide a cure.<\/p>\n\n\n\n

This sense of futility was not the only reason that little progress was made. This was the age of Freud, with neurology upstaged by psychoanalysis; in sanitariums and hospitals and clinics, brain science was becoming pass\u00e9. But as the century progressed, the human race, at least in the wealthy world, was experiencing something revolutionary. Thanks in large part to the development of antibiotics to fight life-threatening bacterial infections, the average life span was increasing. And as humans lived longer, many more of them were developing problems with memory and cognition.<\/p>\n\n\n\n

Finally, a growing number of neurologists started to suggest a paradigm shift. Why should dementia be seen as a natural inevitability of aging? Why couldn\u2019t it, one day, be cured?<\/p>\n\n\n\n

In 1976, a neurologist named Robert Katzman published an article in Archives of Neurology titled \u201cThe Prevalence and Malignancy of Alzheimer Disease: A Major Killer,\u201d in which he argued that the distinction between garden-variety senility and Alzheimer\u2019s disease \u2014 which, for decades, was considered a rare condition \u2014 ought to be dropped entirely. If most of the world\u2019s millions of dementia cases were recategorized as Alzheimer\u2019s, Katzman wrote, the disease would automatically qualify as the fourth or fifth most common cause of death in America.<\/p>\n\n\n\n

In one elegant semantic flourish, the scientific community had a new nemesis \u2014 a medical menace, like cancer or heart disease, to obsess over and build entire systems of research and drug development around. The campaign worked. By the 1980s, \u201cAlzheimer\u2019s\u201d had become a household word. Alzheimer\u2019s disease became neuroscience\u2019s public enemy No. 1. Between 1976 and 1989, the National Institute on Aging\u2019s annual budget for Alzheimer\u2019s research surged to $222 million from about $20 million.<\/p>\n\n\n\n

But once this new war on Alzheimer\u2019s was underway, there were unintended consequences. Nearly every dementia disorder was now assumed to be Alzheimer\u2019s \u2014 and since there was still no test for Alzheimer\u2019s, other than an autopsy, how could you prove any doctor wrong? Misdiagnosis became something close to the norm. In one 1993 study, 18 of 21 patients found to have a rarer type of dementia had first been wrongly thought to have Alzheimer\u2019s.<\/p>\n\n\n\n

The scientific community had traded one gross generalization for another. Whether you called it senility or Alzheimer\u2019s, you were denying something essential and subtle about dementia that researchers took years to understand \u2014 something Pick and Alzheimer both knew: Dementia is not just one thing.<\/p>\n\n\n\n

By the 1990s, two camps had emerged: Those who blamed the tau protein for Alzheimer\u2019s were nicknamed tauists, and those who considered the beta-amyloid protein to be the culprit were called baptists. The debate between the tauists and baptists became one of the most prominent story lines of neuroscience \u2014 even as the baptists had clearly taken the lead. In 1991, the geneticist John Hardy and his colleagues isolated a mutation in a gene that produces the so-called amyloid precursor protein in people with Alzheimer\u2019s.<\/p>\n\n\n\n

That was good enough for most of those in the field to become born-again baptists: Most researchers and pharmaceutical companies went all in on attacking the beta-amyloid protein. Their case was strengthened in the late 1990s when two more genetic mutations, known as presenilin and APOE, seemed to confirm the connection.<\/p>\n\n\n\n

After that, the baptist consensus locked in, and the funding spigot turned on. Developing a new neurodegenerative drug through Phase 3 clinical trials can cost upward of $2 billion. And this wasn\u2019t just one drug. Over several decades, the pharmaceutical industry has sunk easily tens of billions of dollars into drugs targeting amyloid proteins, all with little effect. Other approaches were crowded out \u2014 not just in the pharma world, but in academia, which needs pharma support to get results. Generations of researchers experienced that chilling effect directly.<\/p>\n\n\n\n

\u201cIf you worked on tau, they would kill your career and you would wind up not getting funded,\u201d said Dr. John Crary, a neuropathologist who runs the brain bank at Mount Sinai Medical Center. \u201cYou would wind up at the V.A., or worse, in Worcester \u2014 not at Harvard, right?\u201d<\/p>\n\n\n\n

The consensus around amyloid turned any other attack on dementia into a sideshow. Tau tangles were considered at best a secondary aftereffect and, at worst, an \u201cartifact\u201d \u2014 the word scientists use to describe something they think doesn\u2019t matter at all.<\/p>\n\n\n\n

In the late 1990s, when three different research teams successfully linked FTD to the MAPT gene that produces tau, the baptist camp didn\u2019t back down. Instead, they argued that because amyloid seemed to show up first in the brain, tau must be a sign of the final stages of Alzheimer\u2019s disease. Tau is the bullet, one saying went, but amyloid is the gun. Without a gun, the murder can\u2019t happen.<\/p>\n\n\n\n

And yet, every year someone seemed to identify a new tau-related brain condition: many cases of FTD, dementia with Lewy bodies, corticobasal degeneration, argyrophilic grain disease, chronic traumatic encephalopathy, atypical forms of Parkinson\u2019s disease, certain strains of A.L.S. The overproduced protein in these conditions is tau.<\/p>\n\n\n\n

Gun or no gun, the bullet seemed to be doing just fine on its own.<\/p>\n\n\n\n

Slowly, the importance of non-Alzheimer\u2019s cases became undeniable. In the 1980s, Alzheimer\u2019s was assumed to be 85 percent of all dementias. But that percentage has been nose-diving ever since. Dr. Crary quoted Dr. Rusty Hays, a prominent neuropathologist, whom he once heard say: \u201cIt used to be easy \u2014 you saw plaques and tangles and you were done. It was Alzheimer\u2019s.\u201d Those days are over.<\/p>\n\n\n\n

The amyloid camp did score a victory when the Food and Drug Administration approved lecanemab, a drug infusion that showed evidence of removing amyloid plaques from the brain; a second, similar drug, called donanemab, followed. The trouble was, the positive results of these drugs were so marginal \u2014 and the risks so considerable, including brain swelling and bleeding \u2014 that researchers became divided on whether they ought to be celebrating at all. The most shocking reversal came from one of the forefathers of the amyloid hypothesis, Dr. John Hardy.<\/p>\n\n\n\n

\u201cWhen we found amyloid mutations, I thought, and the field thought, that sorting out amyloid was to sort out dementia,\u201d Dr. Hardy said in 2022. \u201cWe do not think that anymore.\u201d<\/p>\n\n\n\n

For the last six years, a convention space in a major city somewhere on the globe has attracted hundreds of attendees of the Tau Global Conference, an international gathering of scientists and drug developers focused on disorders of the tau gene. Dozens of papers are presented over several days, and the venue\u2019s hallways are packed with several hundred placards displaying the most recent tau-related research findings, battling a dozen or more different conditions where tau is implicated: Alzheimer\u2019s, Parkinson\u2019s, FTD, A.L.S. and even traumatic brain injury and chronic traumatic encephalopathy.<\/p>\n\n\n\n

After decades of being passed over, tau, here at least, is the belle of the ball. More than half a dozen teams are working on tau-reducing drugs now, with the earliest results showing hope for slowing the symptoms of dementia. But just as tau is having its moment, it might be time to call off the debate entirely.<\/p>\n\n\n\n

In the wake of the collapse of the amyloid hypothesis, there\u2019s a renewed drive to understand not just tau, but a wealth of other factors in the development of dementia. Two more proteins, TDP-43 and alpha-synuclein, are now connected with late-in-life memory loss and cognitive decline, respectively, for people with Alzheimer\u2019s and even those without Alzheimer\u2019s. \u201cI don\u2019t think anyone, even the most fervent, would tell you that if you could just get the right amyloid lowering you will cure this,\u201d said Dr. Bruce Miller, director of the Memory and Aging Center at the University of California, San Francisco.<\/p>\n\n\n\n

Going after so many different proteins calls for stopping the mutated genes that are overproducing those proteins. (CRISPR is one option among many possible gene therapies, all of which face the challenge of safely getting past the blood-brain barrier, the membrane that protects the brain from outside infections.) The gene called APOE offers the clearest genetic biomarker for hereditary risk for Alzheimer\u2019s; researchers are focused on finding ways to manipulate that gene to help stop the disease in its tracks. Other gene therapies could bolster or trigger our immune systems to help the body clear out proteins that would otherwise clump up in the brain.<\/p>\n\n\n\n

Beyond Alzheimer\u2019s, people are living so long now that it isn\u2019t uncommon to die with two or even three different neurodegenerative conditions. Once these conditions can be accurately predicted with biomarkers, many foresee the day when there could be a precision-medicine approach for dementia, tailoring treatments to each patient\u2019s specific genetic issues the way that many cancers are treated now. Patients with high amyloid or tau or TDP-43 numbers could receive treatments the same way patients take statins for high cholesterol.<\/p>\n\n\n\n

Above all, the acknowledgment of the genetic nuance in dementia is fueling a slightly more sober sense of optimism than the fervor of the baptists and tauists. A recent overview of the Alzheimer\u2019s literature in the journal Cell offers \u201chope for a future where AD is not only treatable but also preventable,\u201d while still acknowledging the condition\u2019s \u201ccomplex pathologic underpinnings.\u201d<\/p>\n\n\n\n

This, after all, was Arnold Pick\u2019s insight: that dementia is many things. What if we could nip these complex problems in the bud genetically, before the crippling health care costs and heartbreaking losses \u2014 before the ones we love lose much of what makes them who they are?<\/p>\n\n\n\n

\u201cWith the gene carriers, you can get in very early, maybe even before any age-related change is happening, any pathology is present at all,\u201d Dr. Miller said. \u201cI think it\u2019s going to be a really huge decade. We\u2019re just beginning.\u201d<\/p>\n\n\n\n