Alzheimer Disease. The Changing View

398 Pages·2000·5.51 MB·English

by  Robert Katzman and Katherine Bick (Auth.)

In 1977, the editors of this volume, in collaboration \vith our
colleague Dr. Robert Terry, organized a 3-day ^vorkshop/conference in
Bethesda, Maryland, on Alzheimer disease and related disorders under the
sponsorship of three of the National Institutes of Health: the National Insti
tute of Neurological and Communicative Disorders and Stroke, the National
Institute on Aging, and the National Institute of Mental Health — a confer
ence that was highly successful. We had two goals. The first was to reach
consensus that Alzheimer disease (AD) was not just a relatively rare neurode
generative disorder of the presenium, but was the major cause of dementia in
the elderly in developed countries. The second quite different goal was to
bring together investigators w^ho had already made important contributions to
the field and others ^vhom we sought to recruit to the field in order to help
"jump-start" research in AD.
Twenty years later, the two of us, gratified by the explosive success of the
field of AD research and in the growth of the Alzheimer's Association —
initially formed shortly after the workshop/conference — thought we should
document the work and views of the pioneers whose efforts in the 20 years pre
ceding this conference had brought the subject into modern biology. The tool
we use is oral history. We have interviewed 23 of the major participants in the
scientific and health care advances that occurred in the period between 1960
and 1980. This series of intervievv^s — intervie^ws that touch both on the human
and on the scientific aspects of the advances that each has made — constitutes
xii PREFACE
this volume. Because the words of our intervie^vees Avill be of interest to a
broad audience of scientists, chnicians, and family members, we have tried to
provide help from time to time in editors' notes, selected references, and read
ing lists, but the words are those of the intervie^wed. We hope that our readers
will enjoy the stories that are told.
We grouped the interviev^s to begin ^vith the pioneer ^work of the 1960s
that applied modern biology to the AD brain and developed a prospective clin
ical—neuropathological approach that demonstrated the identity of AD and
senile dementia. During the seventies, further advances occurred w^ith the
development of experimental approaches, studies of the role of genetics, cul
minating in the discovery of the major role of cholinergic deficits in the AD
brain. Again in the sixties, as the numbers of AD victims — patients and their
families — increased, innovative care arrangements were introduced.
Clinicians began to standardize diagnostic approaches. As it became under
stood that AD was the most important cause of dementia in the elderly,
epidemiological studies took on new meaning, and the extent of the public
health impact of AD was recognized. These societal changes served as a major
impetus for the formation and success of the Alzheimer's Association. The
changing vie^vs in medical thinking over this time span become evident w^hen
one contrasts the description of the term "chronic organic brain syndrome"
used for dementing diseases in the 1952 D lag nod tic and Statutlcal Manual of the
American Pdychiatric Addociation (DSM 1) with the appearance of a straightfor-
^vard definition of dementia in the 1980 version (DSM III).
Readers ^vill discover that the authors prefer the term "Alzheimer
disease' but have used "Alzheimer's disease' whenever the interview^ee or
organization used that term. We have used British spelling in the interview's
^vith our British colleagues and American spelling elsew^here.
We wish to call the reader's attention to three accounts that overlap
aspects of our narrative but from different perspectives: Patrick J. Fox's 1989
detailed article, "From Senility to Alzheimer's Disease: The Rise of the
Alzheimer's Disease Movement" [Milbank Q 67(1), 58-102 (1989)]; Daniel A.
Pollen's intriguing book, Hannah^d Heird: The Quedt for the Genetic Origind of
Alzheimer^d Di^eade, Oxford Univ. Press, New York, 1993; and Peter J.
Whitehouse, Konrad Maurer, and Jesse F. Ballenger (eds), Co nceptd of Alzheimer
Dideade: Biological^ Clinical and Cultural Ferdpecti^edy Johns Hopkins Univ. Press,
Baltimore, 2000.
With regard to the current status of Alzheimer disease, the reader may
wish to consult the following general reading:
Katzman, R., and Fox, P. (1999). The Avorldwide impact of dementia in the next fifty
years. In "Epidemiology of Alzheimer's Disease: From Gene to Prevention" (R.
Mayeux and Y. Christen, eds.). Springer-Verlag, New^ York.
Teriy, R D., Katzman, R, Bick, K. L., and Sisodia, S. (eds.) (1999), "Alzheimer Dis
ease," 2nd ed., Lippincott-Williams & Wilkins, Baltimore.
ACKNOWLEDGMENTS xiii
Acknowledgments
We tkank our interview^ees for their cooperation and patience. We are in
debted to our editor at Academic Press, Jasna Markovac, Exlitor in Chief of
Biomedical Sciences, for her enthusiasm and encouragement in our undertak
ing. Marge Lorang, our Eklitorial Coordinator, has been an especially sensitive
interpreter of our goals for the project. Working ^vith her has been a pleasant
and profitable experience. We are grateful to Sue Johnson, Dr. Katzman's ad
ministrative assistant, for cheerfully keeping us organized during the flow of
the many iterations of the interviews and for faciliating the retrieval of histori
cal information. Robert Katzman thanks Nancy Katzman for her constant
support in this as in so many other ventures.
In dedicating this book, Katherine Bick pays tribute to the inspiration of
the late professor Luigi Amaducci, ^who sparked her historical interests.
Robert Katzman dedicates this book to Nancy's mother, Elsie Anderson Bern
stein, Avho so dearly loved life, but who lost the last decade of her o^vn life to
Alzheimer disease. This experience with the reality of Alzheimer disease
played a major role in shifting his career focus to the dementing illnesses.
Chapter 1
SETTING TIE STAGE
Alzheimer disease (AD), the most common neurodegenerative disorder in our
society, accounts for two-thirds of the cases of age-related (senile) dementia.
AD is characterized by a progressive, ultimately fatal dementia. The best cur
rent estimates are that there are between 3.2 and A million cases in the United
States today. It may be reasonably argued that AD is the fourth most impor
tant cause of death. As our society continues to age, one can project that in
the year 2050, new^ly diagnosed cases of AD will equal those of all cancers
combined (1).
Yet only 40 years ago the importance of AD v^as ignored. Textbooks of
neurology and psychiatry devoted only sentences or a paragraph or two to the
disorder. This book traces the scientific, clinical, and societal events that led to
the recognition of the importance of AD in the interval between 1960 and
1980, presented though the medium of oral history. By 1980 the importance of
AD w^as recognized in the scientific community, scientific interest in AD had
become widespread, an active Alzheimer's Association had been formed, and
the National Institutes of Health (NIH) began seriously to fund AD research.
ALZHEIMER DESCRIBES HIS
CLASSIC CASE
The long hiatus between Alzheimer's 1907 publication of his classic case (2)
and the events in the 1960s now seems anomalous as the importance of the
1907 paper was immediately recognized. Kraepelins 1910 text (3) used the
term "Alzheimer's disease" to describe cases ^vith the pathological features
described by Alzheimer appearing in the presenium. The presenium w^as
considered to be ages AS to 60 years, although some later writers upped the
age to 66. Cases occurring later in life with similar (although some argued not
identical) pathology w^ere classified as senile dementia or senile psychosis.
Alois Alzheimer's major M^ork on "general paralysis," the contemporary
term for neurosjrphilis, no doubt contributed to his sensitivity to the unusual
2 1. SETTING THE STAGE
presentation that he sav^^ in Auguste D., the \vonian admitted to the Frankfurt
Insane Asylum in 1901 ^vho died in 1906. Auguste D.'s chnical course and the
pathological examination of her nervous system ^vere the key elements that
led Alzheimer to describe her case briefly at the psychiatrists' meeting in
Tubingen in 1906. Hippius (4) reports Alzheimer's comments, from 1895, that
his interest in psychiatry stemmed from his first position after his final exami
nations as the medical "traveling companion of a mentally ill lady.''
Auguste D.'s clinical presentation and the subsequent neuropathological
studies carried out by Alzheimer and Perusini provided the raw material for
Emil Kraepelin's designation in 1910 of this peculiar pattern as Alzheimer's dis
ease. The scientific literature around the turn of the 20th century was replete
with discussions of the putative etiologies of the various impaired mental states
seen in the elderly. Discovery of the spirochete that caused the devastation
of neurosyphilis, particularly w^hen it presented as a progressive dementia
(general paresis, as neurosyphilis M^as called then), stimulated search for like
causes of the other psychogeriatric conditions. Such explorations ^vere made
possible by the application of new dyes and impregnation techniques that
revealed the intimate details of the neuronal structure. Alzheimer's friends and
colleagues (such as Franz Nissl in Heidelberg and Emil Kraepelin, who
recruited Alzheimer to Munich from Heidelberg) and his rivals (such as Oskar
Fischer in Arnold Pick's group in Prague) were all part of a close circle of
European researchers who met at meetings, edited scholarly journals, and
argued passionately about the issues of the causes and trademarks of brain
disease.
In 1898 Alzheimer published a lengthy paper on senile dementias of
various etiologies with emphasis on those related to atheromatous vascular
disease (5). In that paper he referred to "dementia praesenilis" as a subgroup
^vithin or an atypical form of senile dementia, distinguished by a preexisting
mental feebleness and an earlier manifestation. In his 1911 paper, Alzheimer
(6) reported once more on the clinical and morphological changes seen in
presenile diffuse brain atrophy and recognized clearly their morphological
correspondence to those seen in senile dementia. He discussed the views of his
colleagues Perusini and Simchowitz as well as those of Fischer, to whom he
gave generous credit for his emphasis on the importance of the plaques in the
histology of senile dementia. Many of these early papers, \vritten in German,
have been translated and reviewed in a book by Dr. Bick (7).
Alzheimer's unique contribution to the disease that bears his name ^vas
the demonstration of the structures that are now called neurofibrillary tangles
and the recognition that they were important markers of a disease process.
His colleague Gaetano Perusini's camera lucida dra^vings of the many dra
matic shapes he sa^v in the histological preparations of the original Alzheimer
case are models of careful representation (8). In the first brief presentation at
Tubingen, Alzheimer described the thickening of the intracellular fibrils and
their unique response to silver impregnation methods, ^th the eventual total
THE FOLLOW-ON FROM ALZHEIMER'S WORK 3
disruption of the nerve cell and the skeleton of the "tangled bundle of fibrils''
as the only remnant.
The other hallmark of the disease, the senile or neuritic plaque, had first
been reported in the brains of old people affected by epilepsy by Blocq and
Marinesco working in Paris in 1892 (9) and discussed in detail by Redlich as
"miliary sclerosis" in 1892 (10). The term "miliary" comes from the Latin v^ord
for the grain millet and was used to describe lesions or tubercles that had
the size and shape of millet seeds. Fischer's publication in 1907 (11) expanded
the description of these structures, v^hich he considered proliferative phenom
ena and called miliary or glandular necrosis. Alzheimer disagreed with Fischer's
interpretation that they ^were the "most important anatomical substrate of pres
byophrenia." He concluded that they w^ere not the cause of senile dementia but
an accompaniment of senile involution (aging) of the nervous system.
Alzheimer disease is unique in that two such different pathologies, the
plaque and tangle, are its hallmarks. Neuropathologists and others have argued
throughout the 20th century as to the relative importance of these two findings.
Although today most remembered for his neuropathological contribu
tions, Alzheimer considered himself primarily a clinician and aWays S3cw the
neuropathological laboratory studies as basic know^ledge that ^vas to be
applied in the service of the clinic. The third floor laboratory that Alzheimer
established in Munich trained a w^hole generation of international colleagues
in his approach. Not only did he emphasize the importance of clinical w^ork
underpinned by careful pathological correlations, he encouraged the develop
ment of animal models to test ideas about etiology and pathogenesis.
Alzheimer ^vas a v^elcoming and generous host and inspired young peo
ple from many countries ^who came to his laboratory. For example, he gave the
task of the complete workup of the case of Auguste D. to Gaetano Perusini
who came to work with him from Italy and w^ho published the full description
as the sole author in 1911 in the journal edited by Nissl and Alzheimer. Sev
eral times during his career Alzheimer competed for clinical directorships.
When the opportunity came to take up the post of Director and Professor of
Psychiatry at Breslau in 1912, he did not hesitate to leave the Munich labora
tory behind, despite Kraepelin's misgivings that this might mean the end of
Alzheimer's researches. Sadly, that proved to be the case, but lingering ill
health, rather than diminished interest, ^was probably to blame. Alzheimer's
untimely death in 1915 (probably of bacterial endocarditis) ended a brilliant
scientific and clinical career.
THE FOLLOW-ON FROM
ALZHEIMER'S WORK
From the time of the publication of the first case in 1907 throughout the early
years, almost all of the publications about AD came from the people vv^ho had
4 1. SETTING THE STAGE
either direct or first-generation connections ^vith the Alzheimer laboratory in
Munich. Solomon Fuller studied for some years ^vith Alzheimer and later
published clinical-pathological studies from the Westborough State Hospital
in Massachusetts. He reported details of the 13 cases known as AD in 1911
(12). Publications in the United States called the condition senile dementia
before the original Alzheimer report, e.g. Pickett (1903, 13), reported on 200
"true senile dements" from Philadelphia Hospital. Ho^vever, in 1911 (14),
Barrett, at the University of Michigan, Avas ^vriting about AD and in 1913
commented that "it has become difficult to limit disease processes by age
periods," as Alzheimer himself had said.
Alzheimer's colleague from 1907 to 1910, Teofil Simchovs^itz introduced
the term "senile plaque" and described granulo-vacuolar degenerations in the
brains of patients with senile dementia in his 1911 paper (15). Alzheimer
described at some length in his 1911 paper the response of the core of
the plaque to various staining techniques and concluded that it ^vas an unor
ganized mass w^hose appearance is different with different stains and w^hich
sometimes has a structure that resembles fine crystals. He thought that the
evidence supported the view that the core ^vas a deposit of an unkno^vn
metabolic product in the cerebral cortex. Arguments as to \vhether the plaque
components were produced in dltu—Alzheimer's conjecture -—or arrived in the
cerebral cortex from the systemic circulation^—^as Gellerstedt (16) thought
most likely ^—Mrere prominent in the literature for many years. In 1927 (17),
Diviy reported that his careful studies on the center of the plaque indicated
that its reactions were shared with those of amyloid. He w^as a^vare of the
lack of chemical specificity of both silver impregnation and Congo red
staining and added polarization optical studies to his tests. In 1934, Diviy
(18) pointed out that both the cores and the tangles were congophilic with
polarized light and remarked that this suggested a common origin for the
two. Congophilic angiopathy ^vas first named by Pantelakis in 1954 (19), but
credit for its full description should go to Scholz in Munich in 1938 (20).
Scholz found the same characteristics ^ metachromasia ^vith basic aniline
dyes, Congo red staining, intense birefringence under polarized light after
Congo red, and positive iodine reactions ^—^in the deposits in the cerebral
vessel avails and concluded that they vv^ere the same as the plaque cores. He
called the vessel inclusions "drusige Entartung" (plaque-like degeneration)
and rejected the idea that these indicated amyloidosis of the brain comparable
to systemic amyloid disease. The traditions of the German school w^ere
continued in the papers from this era with extended descriptions of the
clinical course of the illness and detailed reports of numerous histological
preparations. Griinthal's paper (21) on a histopathological clinical study
of AD, w^hich became a classic in the field, added 13 more pathologically
studied cases to the record of AD. He mentions that these add to the 20
he found in the literature. A review of the early history can also be found in
Bick (22).
Is ALZHEIMER DISEASE STRICTLY A PRESENILE DEMENTIA? 5
Is ALZHEIMER
DISEASE STRICTLY A
PRESENILE DEMENTIA?
During the first third of the 20th century the major discriminating factor in di
agnosis seems to have been the age of the patient. Malamud and Lo^venberg
discussed this restriction and concluded on the basis of their experience that
"if cases cHnically and pathologically typical of Alzheimer's disease do occur at
different ages, Kraepelin's idea that this disease may really be independent of
the senile group must be seriously considered"(23).
Jervis and Soltz (24), discussing cases with onset prior to age 45,
agreed M^ith Griinthal that from the pathological viewpoint alone, AD cannot
be differentiated from senile dementia, but the clinical symptomatology, which
constitutes a solid unit, must play an important role in the final diagnosis of
AD. In general, the greater severity of the clinical presentation of the prese
nile disease and the focality of the triad of agnosia, apraxia, and aphasia were
interpreted as another support for the distinction between presenile and senile
dementias.
This point of vie^v ^vas continued by David Rothschild, a
Canadian—American physician, trained in pathology and psychoanalysis in
Germany, w^ho devoted most of his efforts during the 1930s and 1940s to
investigating the relationship between Alzheimer disease and senile dementia
(25,26). Rothschild had an interesting link to Alzheimer in that he trained in
Hamburg in Jakob's laboratory and Jakob in turn had trained in Alzheimer's
laboratory. He argued from his case material that, although the lesions and
their regional distributions in the presenile AD brain and in "senile dementia"
v^ere similar, the number of lesions \vas often greater in presenile cases and
the progression of dementia and involvement of language ^vere more severe in
the younger cases.
Rothschild did make several potentially important contributions: con
trary to the accepted dogma of his era, he asserted and provided evidence that
senile dementia (of the Alzheimer type) could be differentiated both clinically
and pathologically from dementia due to atherosclerotic vascular disease, not
ing that there are cases ^vith both lesions present, a finding 25 years ahead of
its time. He described in detail nonatherosclerotic lesions in blood vessel ^valls
in some cases of presenile AD and "senile dementia," clearly congophilic or
amyloid angiopathy, but he did not use Congo Red to study his tissue and did
not refer in any of his papers to Divry's 1924 discovery of amyloid in the
Alzheimer plaque, an important missed opportunity, as amyloid angiopathy
may account for 10 to 20% of strokes today. In regard to the issue of ^vhether
Alzheimer disease and "senile dementia" Avere identical, he presented evidence
from his more detailed analysis of the distribution of lesions in the brains of
both groups that could ^vell have been interpreted as evidence for their
6 1. SETTING THE STAGE
identity. Unfortunately, he pulled back from this conclusion, stating, "While
-we do not subscribe to the conceptions that Alzheimer's disease is merely a va
riety of senile dementia, the fact that it sho^vs histologic changes essentially
similar to the lesions present in the latter disease suggests that similar factors
may operate in the two conditions."
Rothschild also sought to explain the existence of plaques and tangles
in the brain of some cognitively normal elderly. At first he considered the
possibility that this might be due to a "unusually strong compensatory capa
city of the patient," a predecessor of the concept of brain reserve, but he aban
doned this approach to ascribe at least part of the development of dementia
in the elderly to psychological causes! Perhaps his training in psychoanalysis
or the post World War II popularity of "psychosomatic medicine" colored
his vie^vs.
The identity of Alzheimer disease and senile dementia ^was asserted
unequivocally in 1948 by R. D. Newton (27), Avho was fully a^ware of Roth
schild's papers. Newton's own review of the literature led him to a quite differ
ent opinion, that senile dementia and AD were identical. Newton noted that
among patients \vith AD pathology there Avas a ^vide variation in symptoms
unrelated to their age and that there were consistent histological differences
between those with onset before and those with onset after age 65. Although
Newton is widely cited today for his prescient conclusion, he was simply
ignored by other investigators until 1968, when Blessed, Tomlinson, and Roth
verified this conclusion in their classic, quantitative prospective study of the
relationship of pathological lesions to cognitive changes during life (28).
AND THE ROLE OF STROKES?
We have noted that an additional confound in the United States w^as the em
phasis on cerebral atherosclerosis and cerebrovascular events as a cause of
late life dementia. Walter Alvarez, a gastroenterologist and a pioneer geriatri
cian, headed the gastrointestinal division at the Mayo Clinic for 25 years
(1926 to 1950) and w^as considered by many to be the most prominent
internist of his day. Prior to joining the Mayo Clinic he focused on the impor
tance of statistical techniques and helped establish a department of biometry
and statistics at the Mayo Clinic. How^ever, he was best knov^n as the author
for over 20 years of a widely published syndicated column. His first book,
"Nervous Indigestion," published in 1930, was a best seller and his 1951 book
on "The Neuroses" almost reached that status. He often interpreted symptoms
not understood by medicine of his day (or today for that matter) as psychoso
matic. In 1946 (29), however, he published an extraordinary paper on demen
tia in the elderly that did not attribute his cases to psychosomatic causes but
rather to small strokes. In the paper entitled "Cerebral arteriosclerosis Avith
small commonly unrecognized apoplexies," Alvarez noted, "one of the com
monest diseases of man is a slow petering out tow^ard the end of life, and one
''CHRONIC ORGANIC BRAIN SYNDROME" 7
of the commonest \v^ays of petering out is that in ^v^hich the brain is slo^vly
destroyed by the repeated thrombosis of small sclerotic blood vessels." This
article, published a decade before C. Miller Fisher's classic paper, ^was based
on clinical pathological data in seven patients, including two of his relatives
for M^hom he had life-long histories, and ^vas an excellent description of the
lacunar state. Alvarez's impact on American physicians w^as immediate, and
for the next three decades his explanation vv^as readily accepted by practicing
physicians w^ho w^ould attribute progressive dementia in the elderly to "stiff
pipes" and small strokes.
ESCAPING VIA LABELING
DEMENTIA AS "CHRONIC
ORGANIC BRAIN SYNDROME"
The chaotic situation created by these conflicting views (and similar uncer
tainties in other areas of mental disorders) posed a problem for American
psychiatrists. FoUo^ving World War II, the US government began construct
ing Veterans Administration Hospitals ^vith large psychiatric facilities
throughout the country. A uniform nomenclature ^vas needed. The American
Psychiatric Association responded with their 1952 "Diagnostic and Statistical
Manual," no^w referred to as DSM-L In DSM-I the term "organic brain
syndrome" was introduced. This inclusive term covered all of the dementing
illnesses and also delirious states. Within this broad umbrella, the category,
"chronic organic brain disease" subsumed not only presenile AD and senile
dementia and other neurodegenerative disorders that lead to dementia, but
also vascular dementia and progressive infectious disorders, including those
that would later be termed the "prion diseases." This very broad, nonspecific
terminology w^as embraced by many clinicians outside of the United States,
although a few in Great Britain preferred the equally nonspecific concept of
"brain failure." Such terms provided a comfortable cover in the absence of an
agreed upon understanding of the underlying diseases.
This new nomenclature did not arouse the interests of investigators. In
1966, the first year covered by the National Library of Medicine's electronic
index "Medline," there were just 10 citations to Alzheimer disease in peer-
revicM^ed scientific and medical journals ^world^vide and only 18 citations to
"senile dementia." By 1980, the number of citations to AD had increased
sixfold to 113. These numbers can be compared to the 1998 Medline that cited
2238 articles on Alzheimer disease, but only 71 on "senile dementia."
A major turnaround in scientific and lay interest in Alzheimer disease
had occurred by 1980. In that year the American Psychiatric Association's
third revision of their "Diagnostic and Statistical Manual," DSM-III, recog
nized Alzheimer disease as a leading cause of dementia in the elderly. The