Tuebingen: Researchers Reminisce, Predict at Alzheimer Centennial
On Saturday, 3 November, 1906, Alois Alzheimer traveled from Munich, where he lived and worked, to Tuebingen. That afternoon, he was to address the 37th convention of Southwestern German psychiatrists, who were then called, cruelly, “Irrenaerzte” (“insanity doctors, alienists”). Eighty-eight colleagues filled the auditorium in the Clinic of Psychiatry at the University of Tuebingen, including Franz Nissl of tissue stain and Nissl body fame, and the child psychologist C. G. Jung. To them, Alzheimer presented his first, signature case of the disease that his boss Emil Kraepelin would later name in honor of his protégée. Alzheimer recounted in meticulous detail how Auguste D’s unusual disease had progressed. He also projected images of the plaques and tangles that he spotted in her brain after she had died in Frankfurt and he’d had her brain shipped in a wooden crate by train to Munich. Alas, his prescient observations met with deafening silence. No one asked a question. The local newspaper, Tuebinger Chronik, laconically noted Alzheimer’s talk in one sentence: “Private docent Dr. Alzheimer (Munich) reported a curious, severe disease process that caused significant shrinkage of nerve cells within 4.5 years.” The newspaper devoted most of its convention coverage to more fashionable issues in psychiatry at the time: hypnotic sleep to cure anxiety, childhood trauma as the cause of adult melancholy, and more generally an impassioned debate about Sigmund Freud and psychoanalysis. As a group, psychiatrists were not ready to contemplate disturbances of the mind as specific organic diseases of the brain.
One hundred years and 20 million patients later, 180 scientists and guests from all over the world met in the same graceful building on a hillside above the medieval town of Tuebingen to commemorate Alzheimer’s achievement in three days of public and scientific events. Led by Mathias Jucker, at the Hertie Institute in Tuebingen, the organizers decided to host the conference in the historic clinic. Because seating there is limited, the organizers were unable to invite as many scientists as they wished. To share the event more widely, they have made an on-demand video stream of both full days of scientific talks freely available for download. For this reason, this news story will not cover any presentation in detail. Rather, it offers tidbits of the flavor and themes at this unique event. This story aims chiefly to remind busy scientists why it’s well worth their time to forgo cherished evening reruns of Law and Order, or even to give up a perfectly good day in the lab, and instead watch this program.
The first day afforded a luxury in which young investigators can rarely indulge: a look back in time to the early pioneers in AD research, with talks given by Robert Terry himself, looking fit and feisty as ever, along with colleagues who worked with him. The second day featured current concepts and a session that expressly encouraged wild predictions about the future. This session offered hilarity as some speakers hedged for fear of “making an elephant’s ass out of themselves,” while others proclaimed themselves perfectly happy to do so and prophesied away.
Some talks were emotional as pioneers shared memories of colleagues who have passed away. Some illuminated historical context as speakers quizzed each other on how they interpreted their key findings in the conceptual framework of the time. Be transported back to a time when research was conducted—quelle horreure!—without computers, without PubMed, without Western blots or antibodies. You will find animated discussion about what people thought in those early days when the data stared them in the face but the implications had not been worked out yet. For a look back, a look around, and then a look to the future, readers may want to consider running the program in lunch hours and journal clubs and discussing it with their students and postdocs. Importantly, watch the program to remind yourself of the many colleagues who coauthored the milestone discoveries listed in the program, or who were independently working on the very same problem.
Here are some selected historic teasers. Terry recalled Robert Katzman’s 1976 editorial in Archives of Neurology that attracted neurologists and biochemists to a small field that had before been the province of neuropathologists including Henry Wisniewski. Katzman spread the idea that early onset AD and what was called senile dementia are largely one disease. This put AD on the map as a public health issue and set the stage for the founding of the National Institute on Aging and a steep increase in research funding under its AD program director Zaven Khatchaturian, who helped build a national AD research infrastructure. Khalid Iqbal dug up original data on early work to isolate tangles gathered before the advent of now-ubiquitous techniques such as immunoprecipitation. Peter Davies recalled scientists’ excitement when they began to understand the cholinergic deficit in AD. The first chance of treatment emerged on the horizon as the scientists hoped to repeat the success of the Viennese physician-researcher Oleh Hornykiewicz, who experimented with clinical use of L-dopa and laid the groundwork for the subsequent introduction in 1967 of oral L-dopa as the first effective drug to treat a neurodegenerative disease. Davies recalled how his collaborators experimented in the clinic, treating AD patients with choline bought from a pharmacy across the street. The subsequent development of today’s widely used cholinesterase inhibitors is history, though they help less with AD than L-dopa does with PD.
A special highlight of the conference was the appearance of Cai’ne Wong, who published his seminal work isolating β amyloid while he was a technician with George Glenner. Wong had left science for a career in writing, and most AD researchers working today have never seen him. In his search for original research records, Wong discovered that many had been inadvertently destroyed a few years after Glenner’s lab was disbanded following his early death from a systemic amyloidosis. Glenner was a competitor of Colin Masters, but also a frequent collaborator, as Masters himself noted in Tuebingen. Indeed, the two had met to basically divvy up the prize, deciding that Glenner would go after vessel amyloid and Masters after the core plaques.
Wong also said that Glenner was so disenchanted with the journals Nature and Science that he did not even consider submitting his seminal discovery to them, publishing it instead in Biochem & Biophy Research Communications. In absentia, Nature or Science editors suffered repeated stabs on the familiar theme that they don’t always know a good thing when they see it. Take heart, researchers everywhere; you are in good company! For example, few American AD researchers know that Jean-Pierre Brion at the Free University of Brussels Medical School published a landmark paper on tau protein in neurofibrillary tangles as early as 1985, three years before Michel Goedert confirmed and extended his findings. Why? Nature had snubbed Brion and he then decided against English altogether, publishing instead in French in Archives de Biologie (Bruxelles). And not all will know that as early as 1987, before proteasomal degradation was understood, Yasuo Ihara already showed that ubiquitin is an integral part of neurofibrillary tangles. (In their defense, this last finding the Science editors were prepared for.)
Also already in the 1980s, imaging hippocampal atrophy for an early diagnosis of AD began to take shape with the pioneering work of Mony de Leon, first with CT but soon after with MRI and PET. Sadly, one of his more important papers appeared in PNAS on September 11, 2001, just as he, a New Yorker, saw the towers fall, de Leon told the audience.
Konrad Beyreuther is credited with breaking, by an inch, the tape across the publication finish line in the fierce 1986 race to clone the APP gene. Other groups who hotly pursued APP include Dmitry Goldgaber and Carlton Gajdusek, Rudi Tanzi and Rachael Neve (both published a day after Beyreuther), Nikolaos Robakis and Henry Wisniewski, Barbara Cordell (who filed a patent), and also Carmela Abraham, Dennis Selkoe, and Huntington Potter, who instead cloned the amyloid plaque component α1-antichymotrypsin. These rivalries were recalled when Beyreuther noted the day and minute when his group first knew they had the right clone (23 October 1986, 11:12 p.m.), and Goldgaber recalled his research leading up to the clone he presented at that year’s Society for Neuroscience conference in Washington, D.C. At the time, the field considered APP cleavage mostly abnormal. That began to change in 1992, when Christian Haass and colleagues in Dennis Selkoe’s group showed that cells throughout the body normally make and secrete the Aβ peptide. The next big prize many labs are chasing these days is a high-resolution crystal structure of APP, or of presenilin and other γ-secretase complex components.
A theme that reached from the historic session into the future concepts session is the idea of genetic heterogeneity in neurodegenerative disease. Peter St. George-Hyslop started the thought when he chose to speak about it rather than about the finding he is best known for, that is, the discovery of the presenilin 1 gene. His earlier realization, published in 1990, that changes in several different genes can cause Alzheimer disease, broadened the field and has been widely borne out. Other speakers extended the notion to speculate that neurodegeneration will in the future be considered a spectrum disorder. Christine van Broeckhoven suggested that forms of hemorrhagic stroke, Alzheimer disease, and frontotemporal dementias can be reasonably seen as occurring on a continuum, and Monique Breteler noted that overlaps between these different origins of dementia are seen at the level of imaging and human symptoms. Furthermore, Virginia Lee outlined significant overlap at the level of pathology across a range of dementing disorders involving the proteins tau and α-synuclein.
The future session saw talk about prevention. Breteler cautioned that population-based prevention strategies eventually will have to deal with the way dementia occurs most often, that is, mixed up with numerous comorbidities. She urged that ways be developed to treat dementia in community populations, not just AD in carefully defined and selected groups as is done for clinical trials. Another prediction is that we will be able to deal with AD much like doctors handle atherosclerotic cardiovascular disease these days: use a simple, fluid-based test to screen people for their risk of developing AD and prescribe a preventive medicine, if needed. Nick Fox held out the provocative notion that we will carry data about our brain on memory sticks, that is, that we will obtain high-resolution brain scans periodically in mid-life that will alert us to the first signs of atrophy or metabolic loss and tell us when to intervene therapeutically. Such scans would represent a sort of reverse growth chart of the brain from the ones used in routine pediatric care. No matter which vision the speakers favored, they agreed that the field needs to find designs for smaller, faster, cheaper prevention trials than the ones considered the gold standard today. An urgent priority toward that goal is that a biomarker be validated in the context of a clinical trial. Then it could be accepted as a surrogate outcome first in small, focused intervention trials, and eventually serve to shorten prevention trials. All this will still take at least two decades, Breteler estimated.
The amyloid hypothesis continues to dominate the field, perhaps even more so now that its first fruits are being put to the test in the clinic. Even while this is happening, however, John Hardy called on the field to consider alternative explanations of the available data. He said he is troubled by “too much good news” in that amyloid deposition is all too easy to treat in mice, even as the leap from mice to humans seems as questionable as ever. Efforts to translate mouse treatments to humans have either failed, shown feeble effects, or are still underway. Hardy urged that the field not take clinical success of the amyloid hypothesis for granted and put effort into developing more rigorous alternatives. Two ideas Hardy considered worth exploring are the presenilin inhibition hypothesis advanced by Jie Shen and others, and a little-noticed suggestion that Aβ serves a role in sealing blood vessels, advanced by Craig Atwood and colleagues. A geneticist, Hardy also urged his colleagues not to assume that genetics will be able to explain all risk for neurodegenerative disease, but to take the power of stochastic events into account as well. The conference closed with a plea from Bengt Winblad not to dismiss people with advanced AD as being beyond help. Even in a completely mute state, the person remains, and deserves the best care to the end. The conference dinner welcomed conference-goers at the same restaurant that the 37th psychiatry convention had patronized in 1906. And the event closed with Harald Steiner’s announcement that the Hans and Ilse Breuer Foundation will award its 2007 Alzheimer research prize to Eva-Maria Mandelkow to advance her research on the role of tau protein.
If these morsels alone didn’t whet your appetite to take in two full days of talks, consider this: watching the show will arm you with enough AD trivia to shine at lab beer hours for some time to come. For example, find out what’s up with King Kong wrestling a recalcitrant tau protein. Find out why Peter Davies’s coworkers didn’t inhale when they ran their first attempts at AD therapy. While taking down your Halloween decorations, discover why Konrad Beyreuther and Colin Masters once held hands over Kraepelin’s grave. Did you know antibodies in Dennis Selkoe’s lab have female names? (To find out why: ask Carmela Abraham.) You will hear that Beyreuther’s lab discovered they had a full-length clone of a membrane protein on 3 November 1986, the same day Alzheimer presented in Tuebingen. Find out why Christine van Broeckhoven showed up for her lecture flanked by security guards. To end on a serious and celebratory note, find out why van Broeckhoven’s outsized likeness shone down on travelers this year at Charles de Gaulle airport in Paris. (Hint: major award.)—Gabrielle Strobel.
Everyone with even a passing interest in Alzheimer disease has seen a sepia-toned photograph of its namesake like the one on last week’s cover of Science magazine. A fatherly, pensive man with a mustache, sometimes a cigar, photographed from his right side and often with hands folded in his lap as was customary for sitting portraits at the time. But there is much more to Alois Alzheimer, and participants at the Alzheimer 100 Centennial conference, held 3-6 November in Tuebingen (where Alzheimer studied for a semester), were treated to a glimpse or two.
Conference co-organizer Konrad Maurer directs the Clinic for Psychiatry and Psychotherapy at the Johann Wolfgang Goethe University of Frankfurt, where Alzheimer worked when he met his patient Auguste Deter. Maurer and his wife Ulrike are a fountain of knowledge about the man, his work, and his time. They took conventioneers on a tour to the house in the Bavarian town of Marktbreit at the river Main, where Alzheimer was born on 14 June 1864 as one of eight children to a notary at the royal regional court. (When Alzheimer’s older brother Karl was born, Karl’s mother died. Alzheimer’s father waited the year that social custom required before he married her twin sister. Karl and Alois indeed look so alike that on some photographs it’s nearly impossible to tell them apart, were it not for a scar on the left cheek that Alois sustained during a fencing duel in his student fraternity.) Ulrike Maurer restored Alois’ birth house as a museum in the style of Alzheimer’s time. The notes below are taken from the tour and from Alois Alzheimer, His Life and Work with Text and Photographs, Konrad and Ulrike Maurer (Pre Press Print Production Service, Marburg, 2002, ISBN 3-935966-05-09).
Alzheimer disease has become one of the most widely known eponyms for any human illness. One might think that the man behind it focused on it exclusively throughout his career. But that’s far from true. Alzheimer worked on an astonishing range of diseases of the mind, and published equally widely. He was deeply tied into clinical service at his successive places of work in the cities of Frankfurt, Heidelberg, Munich, and Breslau; part of his distinction lies in the fact that, in addition to his load as a hands-on physician and administrator, he studied everything that caught his interest. A dissertation, completed in Wuerzburg, on the topic of ceruminal glands (better known as the source of earwax), got him started in histology and microscopy, but the topic could not hold his curiosity. His first position as assistant physician brought him to the Lunatic Asylum of Frankfurt, an institution directed years earlier by Heinrich Hoffman, the author of the children’s book Struwwelpeter. In the grandiose, fairy-tale building that housed the asylum, Alzheimer worked under Emil Sioli, who would later ship Auguste D.’s brain to Alzheimer in Munich, and with Franz Nissl, who became a close collaborator and friend.
Alzheimer and Nissl studied autopsy tissue of hundreds of different psychiatric cases. Even then, they both believed that mental diseases are brain diseases, and that organic, that is, anatomic/pathologic correlates could be found that would allow a much more specific classification than existed at the time. Alzheimer also was convinced that the symptoms he saw in his patients represented a far greater number of distinct mental illnesses than the current categories suggested. His time in Frankfurt, from 1888 to 1903, was prolific. He published 23 papers, on topics ranging from arteriosclerotic atrophy of the brain (Alzheimer believed that arteriosclerosis caused what is now considered the late-onset form of AD), to what was then called progressive paralysis. He published on alcoholic delirium, meningoencephalitis, epilepsy, and gliosis. Even then, he tried to grasp an anatomic and pathologic basis of psychosis, a challenge that would confound pathologists for decades to come.
Alzheimer also brought his perspective to his work as a forensic psychiatrist. One vignette that shows how modern he was is his early behavioral psychology experimentation with a shoe fetishist. The man became aroused at the sight of ladies’ footwear and, according to Konrad Maurer, had been picked up in a hotel, where guests used to leave their shoes in the corridor overnight for cleaning. Alzheimer arranged to have a women’s shoe placed discretely near the man, observed him as he became restless, and meticulously noted his mood (somber that evening) and his pulse (elevated from the usual 85 to 125 per minute).
While in Frankfurt, Alzheimer treated a wealthy diamond merchant who in 1892 died from progressive paralysis. This type of diagnosis was common at the time. A few years later it would prove to be a consequence of syphilis and became a signature example for an infectious origin of mental illness. In 1894, Alzheimer married the merchant’s widow, Cecilie Geisenheimer. The marriage appears to have been happy and produced three children. Unlike some others who become independently wealthy, Alzheimer did not slow down in his work at all. On the contrary, he used his independence to focus freely on his research, and indeed decided to forgo a salary in his later job in Munich and to pay some of his lab members out of his own pocket. Without this independence, the Maurers’ book notes, he might not have been able to prevail against the current of psychoanalytic thinking in his time.
On 25 November 1901, a 51-year old Frankfurt resident entered the lunatic asylum, and Alzheimer himself wrote her admission papers. The Maurers’ biography reprints four neatly handwritten pages in which Alzheimer carefully documented his examination of this women, Auguste Deter. On 23 December 1995, Konrad Maurer had found her case file containing the original admission and eventual pathology documents at the University of Frankfurt, where they had been misplaced for decades. The admission papers reveal Alzheimer’s gentle probing of her various cognitive domains. They record her disturbed behavior (hitting other patients, screaming), as well as conversations that reveal her memory loss, confusion, and her despair. Auguste’s husband told Alzheimer that she first became suspicious and jealous of a neighbor. (According to Maurer, the husband married this neighbor a year after Auguste’s death.) Alzheimer added to her file until June 1902. When she died on 8 April 1906 from sepsis following bedsores, Alzheimer had long since moved briefly to Heidelberg and then on to Munich. He became highly regarded for his research on alcohol addiction and his approach to alcoholism therapy, and explored many other conditions as well. It is remarkable, then, how amid all these changes and distractions, Alzheimer maintained his interest in this particular woman and had her brain sent so he could examine it. After he had analyzed Auguste D.’s brain, the original slides disappeared, only to resurface, decades later in 1997, in a Munich university basement.
In Munich, Alzheimer worked with Kraepelin, the foremost German psychiatrist of his time. There, Alzheimer obtained his habilitation, an obligatory final step of academic qualification in Germany, with a thesis on the histologic analysis of cortical pathology in 320 separate cases of mental disorders, all of which he dissected, prepared, and drew himself. Kraepelin wrote about this work that Alzheimer proved pathological anatomy to be an indispensable tool for research of mental disorders, and that his work excelled in how it maintained a close relationship between anatomy and clinical observation. In Munich, Alzheimer stood out for his international group, hiring scientists from all over Europe and from the U.S. and Argentina. He mentored investigators who would become known in their own right, including Hans-Gerhard Creutzfeldt and Alfons Jakob, F. H. Lewy, and Gaetano Perusini. He was known as warmhearted, unassuming, available to his students and protégées, but a poor lecturer.
In Munich, Alzheimer published 31 papers. They include not only his most famous one describing Auguste D. (Alzheimer, 1907), but also a paper in 1911 on his second patient, Johann F. This case may have prompted Kraepelin, in a psychiatry textbook he published in 1909, to coin the term “Alzheimer disease” for what Alzheimer and his colleagues had until then called presenile dementia, writes Hans Kluenemann, who has tracked Johann F.’s pedigree (Kluenemann et al., 2002). Ironically, Johann F.’s case does not fit the classic pathologic definition of Alzheimer disease, since he had only amyloid plaques, no tangles. By 1909, Alzheimer and Perusini had published their analysis of five AD patients.
During this period, too, Alzheimer published widely, from reports on Wallerian degeneration of peripheral nerves and on Huntington disease to controversial societal issues such as abortion in mentally ill people. He was ahead of his time in many ways. He defended the interests of mentally handicapped people. He argued that a biology-based characterization of mental illnesses would become possible once the structure of the normal cortex was better known, and that the current absence of evidence was not evidence of absence. And he contributed to a public debate that led, eventually, to the founding of the Max-Planck Institute of Psychiatry in Munich.
In 1912 Alzheimer moved to the Silesian Friedrich-Wilhelm University in Breslau, but on his way there fell sick with an infectious angina from which he never fully recovered. He produced 19 more scientific papers in the next three years. Notable among his last contributions is a 1915 paper titled “Der Krieg und die Nerven.” Released by the Breslau publishing house von Preuf & Jünger in 1915, a year after World War 1 had begun, it described what would later be called post-traumatic stress disorder (PTSD) in soldiers. On 15 December 1915, Alois Alzheimer died at the age of 51. He was buried next to his wife in Frankfurt.—Gabrielle Strobel.
Alois Alzheimer was born in this house in Marktbreit
Image credit: Carmela Abraham
The nameplate on the house prompts...
Image credit: Carmela Abraham
...Ben Wolozin to pay homage to St. Alzheimer.
Image credit: Carmela Abraham
Seeing what the master saw: fans peer through one of Alois Alzheimer's personal microscopes. Virginia Lee.
Image credit: Gabrielle Strobel
Colin Masters.
Image credit: Gabrielle Strobel
Carl Cotman.
Image credit: Gabrielle Strobel
Alison Goate.
Image credit: Carmela Abraham
Mony de Leon.
Image credit: Gabrielle Strobel
Lary Walker.
Image credit: Gabrielle Strobel
Mony de Leon and colleague in front of the Hotel Loewe, Bavaria's oldest, in Marktbreit.
Image credit: Carmela Abraham
(L to R) Alison Goate, Colin Masters, Ben Wolozin, Eckhart Mandelkow, Carmela Abraham, and Eva-Maria Mandelkow.
Image credit: Carmela Abraham
In the living room of Alzheimer's birth house, Eva-Maria Mandelkow, John Trojanowski, and Frost White in front of Alois Alzheimer's family portrait with his wife Cecilie Geisenheimer and their three children.
Image credit: Jacqueline Mervaillie
Creighton (Tony) Phelps.
Image credit: Jacqueline Mervaillie
Virginia Lee, Alison Goate, Frost White, Ben Wolozin, and Eva-Maria Mandelkow.
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