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Abstract
Shame on the
National Institute on Aging (NIA) for sponsoring a new way of defining
Alzheimer's disease based on biomarkers (plaques and tangles). Heiko Braak in
2011 after dissecting 2,332 brains ranging in age from 1 to 100 found that only
10 cases had complete absence of Alzheimer's disease related biology. Every person
over 25 years of age had Alzheimer's disease biomarkers. The new framework
sponsored by the NIA makes every older person liable for a diagnosis of
Alzheimer's disease. The pharmaceutical connections of most researchers
involved brings into question the intent of this framework. This article
details the scientific argument against using biology as the only indicator of
the disease while ignoring the clinical aspects. The conclusion advocates for a
careful reassessment of an emerging eugenics movement where biological markers
are becoming more readily relied on when the science supporting these
indicators remains incomplete.
Introduction
After more than a
century of research the National Institute on Aging and the Alzheimer’s
Association (NIA-AA) are yet again reverting to the original century-old
definition of Alzheimer’s disease. A definition which Emil Kraepelin—Alois
Alzheimer’s supervisor—hastily formalized as a “new disease” in 1911. Published
in 2018, this recycled definition is the NIA-AA latest Research Framework: Toward a biological definition of Alzheimer’s
disease and was headed by Clifford Jack (referred to from now on as the
Framework; Jack, et al, 2018).
The Framework
relies on the plaques and tangles as the signature of Alzheimer’s disease,
while overall neurological damage defines severity of Alzheimer’s disease. This
time around, in contrast to the earlier 2011 Guidelines (Jack et al, 2011),
this Framework ignores the clinical features of the disease. This is important
because for the first time the clinical aspect of the disease—what we think of
as Alzheimer’s disease which is how it is expressed through loss of memory,
changes in mental capacities and even mood and personality changes—will be
ignored in preference to its biological clues. By doing so the authors usher in
a new dawn of disease classification. This new biological definition is based
on three types of information: [A] amyloid beta deposition, [T] pathologic tau,
and [N] neurodegeneration. Referred to as the AT(N) [see note below for a more
detailed description].
With eight
different AT(N) biomarker types this Framework is un-wielding in its confusion.
But the confusion is not in its complexity but in its logic. The authors make
the illogical and unsubstantiated claim that “A biological rather than a
syndromal definition of AD [Alzheimer’s disease] is a logical step toward
greater understanding of the mechanisms underlying its clinical expression.”
(Jack, et al, 2018; p.536). That Alzheimer’s disease can only be diagnosed
through these biological markers (biomarkers) while ignoring the real disease,
its clinical expression. The authors argue that the clinical and
neuropathological features of the disease are “…two very different entities…”
(Jack, et al, 2018; p.536) and that “…cognitive symptoms are not an ideal way
to define AD [Alzheimer’s disease]” (Jack, et al, 2018; p538). As a vehicle for
scientific exploration, understanding and ultimately cure Alzheimer’s disease,
the Framework ignores science, obfuscates methodology, and fudges outcomes in
order to drive through an agenda based on pharmaceutical (in contrast to
scientific) considerations. This paper lays out the argument for this
assertion. There are serious repercussions from this approach but it is the
lack of scientific rigor that will eventually expose this approach for what it
is, a sham. This paper exposes the lack of scientific methodology utilized by
the NIA-AA in reaching their conclusion.
A clinical
disease—a disease that is experienced or has observed consequences—is now being
argued to be exclusively a biological disease. But Alzheimer’s disease is only
important because it is a clinical disease. If everyone that has the biomarkers
do not express the disease then there would be no interest in research. It is
of no consequence what the biology is if the disease is not experienced or
observed. By reversing this truism, that the biology is more importantly than
the outcome of the disease, the authors are transforming how we look at health
and ill-health. A transformation that
the authors of the Framework concede is a “…a profound shift in thinking.”
(Jack, et al, 2018; p.538.) The profound shift is also found in the lack of
scientific method employed. But the authors protect this radicalism “…dementia
is not a “disease” but rather is a syndrome composed of signs and symptoms that
can be caused by multiple diseases, one of which is AD” (Jack, et al, 2018;
p.538). Admitting that what they are studying can be one of many causes of
Alzheimer’s disease and “The fact that most dementia is multifactorial presents
a challenge both for diagnosis and treatment.” (Jack, et al, 2018; p.545). We
are guaranteed no scientific road map in this Framework. The authors also
acknowledge that we do not know how to start: “Cut points must be determined,
and age norming biomarker cut points is controversial.” (Jack, et al, 2018;
p.550) “The distinction between normal aging and age-related disease has been
debated for decades…and we do not presume to settle this here.” (Jack, et al,
2018; p.550). Again, the Framework provides no structure for research on the
real issues of aging, despite mounting evidence that dementia is not part of
the normal aging process (e.g., Nelson, et al, 2011). We still do not have a
framework for studying diseases related to aging as pathology rather than as
aging. For a research framework the authors were laisse faire when it came to dictating “The committee avoided
taking a proscriptive approach to these methodologic issues under the
assumption that this was best left to expert work groups and individual
research centers.” (Jack, et al, 2018;
p.551). But research centers do not determine these methodological issues,
their sole objective in their research company—whether private or
university-based laboratories—is to gain funding or monetize a cure.
That biology
contributes to and is part of the process of Alzheimer’s disease is not
contested. But to argue that the biology—the biological markers of the disease,
its neuropathology—is purely the disease contradicts a wealth of evidence. The
Framework is more of a research policy rather than a scientific paper and is
therefore devoid of scientific merit. It was published even though biomarkers
density and cutoff points through “universal standards have not yet been
established.” (Jack, et al, 2018; p.551).
The Framework’s
proposition is premature and wrong. It ensures that all older adults have
Alzheimer’s disease. Older adults that do not have plaques and tangles in their
brains have not been identified. As a result, older adults are automatically
branded as suffering Alzheimer’s disease which makes this new approach
ageist. And such sensitivities are
overwhelmed by the hubris of the authors when they admit that “Up to 60% of CU
[cognitive unimpaired] individuals over age 80 years have AD [Alzheimer’s
disease] neuropathologic changes at autopsy or by biomarkers…Thus, using a
clinical diagnosis of ‘AD’ to ascertain absence of disease is associated with
an error rate exceeding 50% in the elderly.” (Jack, et al, 2018; p.552).
“However, it is increasingly recognized that neurodegeneration/ injury, even in
classic AD [Alzheimer’s disease] brain regions, also occurs in non-AD
conditions. This is particularly so in elderly individuals where comorbidities
are common.” (Jack, et al, 2018; p.539).
The same Framework conceded a high rate of false negatives, with ten to
thirty percent of autopsies of individuals with Alzheimer’s disease do not show
these biomarkers. While among those still alive, a similar proportion of
Alzheimer’s disease patients have normal amyloid PET or CSF Ab42 studies (Jack,
et al, 2018). While in contrast there are many false positives, with thirty to
forty percent of cognitively unimpaired elderly persons having the biomarkers
at autopsy and at PET and CSF screenings (cited in Jack, et al, 2018). Averaging
ten to forty percent false positive and false negatives does not form a solid
foundation to develop a purely biomarker theory of Alzheimer’s disease. But if
there is one study that should demolish the validity of this Framework is the
study conducted in 2011 by Heiko Braak and his colleagues from the University
of Ulm, in Germany. They looked at 2,332 brains of people that died from
various causes from a number of different hospitals. The sample was not random,
and a convenience sample, but t also included children. This is the first time
that children’s brains were studied for dementia. From this study only 10
brains showed a complete lack of disease (less than half one percent) (Braak,
et al, 2011). All of these cases where in people aged 23 years and younger. By
the Framework’s criteria, all adults already have Alzheimer’s disease. Such
criterion makes no sense unless you are a pharmaceutical company. In research defining
all adults as suffering a disease limits the capacity to differentiate and limits
what you could study. The criterion becomes unreliable with an adult
population.
In addition, there
is also a statistical problem to add to the biological problem. Older adults tend
to have more neurological variances then younger adult populations. Such
variance become greater among the older population—known as heteroscedasticity.
Making a specific diagnosis becomes increasingly more difficult among older
populations. For neurologists separating Alzheimer’s disease from other
co-existing neurological diseases becomes very difficult and impossible in most
cases. Dementia among older adults might have outward behavioral similarities,
but the inward clinical expressions are very different because there are so
many other co-morbidities present. For example, it is rare with older adults
that a brain disease occurs in isolation from other type of (non-cognitive)
diseases such as depression (Wagner et al, 2011) and anxiety (Guziak & Smith,
2014). While multiple comorbidities exist, isolating the disease includes both
a clinical problem as well as a neurological one (Qui, DeRonchin & Fratiglioni,
2007). As a result, most dementias are misdiagnosed (Nielsen, 2011; Black &
Simpson, 2014; Sayegh & Knight, 2013).
Explaining why a
U.S. federal agency—the National Institute on Aging (NIA)—established to
address the health needs of older adults, is pushing for an erroneous approach
to study Alzheimer’s disease that will wrongly identify a disease among all of
its constituents—older adults—attests to the overwhelming power of the
pharmacological industry in subverting the NIA’s primary and sole
task—protecting older adults. A cursory look at the business affiliation of
some of the primary authors of the Framework identifies thousands of conflicts
of interest (Jack et al, 2018; supplemental material).
There are both
political as well as methodological/statistical deficits and to understand both
it is important to understand the context why such conscious mistakes are
propagated.
History
Summarizing
research on dementia remains elusive because there is an abundance of research
being produced across many technical disciplines. Driven exclusively by money,
whether private pharmacological investments or federal and (international)
states funding, research is mostly directed at monetizing a cure. There are
some notable exceptions. Details of such work, some more impressive than
others, divert researchers from an overview of the general health of the
research itself. In 2017, Gill Livingston and her colleagues in reviewing
dementia prevention, intervention, and care report that “…around 35% of
dementia is attributable to a combination of these nine risk factors; early
education up to age 11 or 12, hypertension, obesity, hearing loss and
later-life depression, diabetes, physical inactivity, smoking and social
isolation.” (Livingston, et al, 2017; p.14) While at the same time arguing that
in comparison, eliminating the main genetic correlate (Apolipoprotein E) will
only result in a 7% reduction in incidence. There is a resistance to
acknowledging that what will truly cure, or at least delay dementia and
Alzheimer’s disease is preventive care and lifestyle choices. That
pharmacological interests benefit from this resistance is not by chance.
After enormous
resources invested over the last 100 years to research Alzheimer’s disease—and
providing the sole impetus for the establishment of the U.S. National Institute
on Aging (NIA)—we are nowhere closer to understanding Alzheimer’s disease. Nor
does anyone have any semblance of how to stop and cure the disease (for review
see: Whitehouse, 2014; The, 2016; Garrett & Valle, 2016). Research remains
disorganized, clinicians remain confused, and the public has become
increasingly worried (for review see: Ballenger, 2017; Garrett & Valle,
2015). Although there are many potential alternate approaches to developing
research guidelines on Alzheimer’s disease (for review see: Weuve, et al, 2015;
Jessen, et al, 2014; Bennett, et al, 2015; Au, et al 2015; Snyder, et al, 2016;
Garrett, 2017) we are back again to the original definition of the disease.
Historical evidence informs us that it was wrong then, and scientific evidence
informs us that it remains wrong today.
A century ago
Alois Alzheimer published a case study where he identified plaques and tangles
in the brain of a young woman of 51 years. This was not a new observation, nor
was it unique. It was known that most people with dementia had the same brain
malformations, including the majority with senile (relating to old age)
dementia. This was such a non-event that Alzheimer’s initial attempt at
publishing these observations in 1906 failed because it was not scientifically
worthy, and it took a year for these observations to be published (Dahm, 2006).
However, three years after this initial observation Emil Kraepelin—Alzheimer’s
supervisor at the Munich clinic—included this observation of plaques and
tangles in “young” patients as ‘Alzheimer’s disease’ in the eighth edition of
his book Psychiatrie. Against the
overwhelming evidence from the scientific community, a new disease was created.
We do not know
Kraepelin’s motive for such hurried and ill-informed decision. However, the
fact that his neurological clinic in Munich was in competition with the one in
Prague likely played a role. The Prague clinic was headed by the much more
accomplished Arnold Pick, who already had published more than 350 scientific
papers and a textbook of neuropathology (Kertesz & Kalvach, 1996). More
importantly, Arnold Pick already identified Pick's disease and the Pick bodies
in dementia as a result of buildup of tau proteins (unknown at the time) in
neurons defined as "Pick bodies.” In contrast Kraepelin and Alzheimer had
no academic imprint in this area. Pick’s Prague clinic also included the highly
accomplished neurologist Oskar Fischer who was the first to identify Amyloid
Beta plaques which became known as Fisher Plaques. Both Fischer and Alzheimer
had published observations that identified plaques and tangles, both using the
same methodology of reduced silver staining technique developed in 1902 by Max
Bielschowsky (Goedert, 2008). At a time, leading up to 1918, when the Weimar
Republic was declared, ushering in a time of nationalism and emerging Nazi
movement—the Jewish Fischer and Pick in concert with all other contemporary
researchers, argued that Alzheimer’s disease was not a new disease. Politically
Pick and Fischer were on the wrong side of emerging nationalism and anti-Semitic
swell. It could be argued that politics outplayed science. By enshrining
Alzheimer’s disease as a new disease—in contradiction to the overwhelming
scientific evidence against a new disease—Kraepelin established a political
aspect of Alzheimer’s disease and gained kudos for his newly established 2017
Munich clinic (now named Max Planck Institute for Psychiatry in Munich) to the
detriment of the Prague clinic.
Fast forward in
time, the second political event that falsely promoted the uniqueness of this
disease came about with the creation of the U.S. National Institute on Aging.
In 1974 Public Law 93-296 established the National Institute on Aging and in
1976 Robert (Bob) Butler was appointed its first director. The political theatre
behind the scene revealed the true purpose of the NIA. Despite Butler’s
interest in age inequity—having published a 1969 paper that defined “ageism”
and then in 1976 he published a Pulitzer winning book Why Survive?: Being Old in America—Butler’s focus was always on
neurological diseases. Butler confessed: ‘‘I decided that we had to make it
[Alzheimer’s disease] a household word…And I call it the health politics of
anguish.’’ (Fox, 1989; p. 82). By using Alzheimer’s disease to promote NIA’s
mission, Alzheimer’s disease again become political. This involved a radical
change. NIA’s founding members realized that politically, they needed something
more than ‘diseases of older adults’ to validate their new institute to
Congress. President Nixon at the time in rejecting the first proposal for the
establishment of the NIA must have agreed with Congress that “we are not in the
business of curing aging.” Congress saw
diseases of older adults as inevitable, one that required care rather than
cure. Dementia was also ill-defined,
broad, and too diffuse a term to get Congress excited. In response and playing
the “health politics of anguish” the founders of the NIA ingeniously focused on
Alzheimer’s disease. Thanks to Kraepelin, Alzheimer’s disease provided a
biomedical disease that can be approached as a biologically-determined
disease—a real disease.
There was one
problem with this approach: by definition, Alzheimer’s disease was primarily a
disease of younger people and not a disease of older adults. There were very
few patients suffering from real Alzheimer’s disease in the 1970s. In fact, Robert Katzman himself in the 1976
article reports that cases were so few that “Precise epidemiological
information [on Alzheimer’s disease] is not available…” (Katzman, 1976; p.378).
It was becoming apparent that most patients with clinically defined senile
dementia—onset of disease after 65 years—have very similar pathological changes
in their brains as patients with Alzheimer's disease (Ballenger, 2006). A century of criticism, arguing that dementia
and Alzheimer’s disease are one and the same thing, was suddenly being recognized
(Robertson, 1990). It became politically expedient now to ignore what Kraepelin
and Alzheimer argued for and to admit that Alzheimer’s disease is not uniquely
different from senile dementia. Katzman & Karasu (1975) already started
eroding the distinction between dementia and Alzheimer’s disease and, as a
result, the two constructs were merged. However, rather than changing the name
of Alzheimer’s disease to senile dementia—because the establishment of the NIA
relied on the banner of a neurological disease—the name Alzheimer's disease was
retained and broadened significantly to include senile dementia (Katzman, 1976;
Katzman & Bick, 2000). This proved extremely beneficial in the politics of
anguish. An editorial by Robert Katzman in the April 1976 Archives of Neurology
altered the balance (Katzman, 1976). In the short two-page article (plus
references), Katzman made the argument for subsuming senile dementia under
Alzheimer’s disease. It was not even peer-reviewed, again a political rather
than a scientific discussion. Katzman’s political conjectures projected
Alzheimer's disease as being the fourth or fifth most common cause of death in
the United States. Overnight Alzheimer’s disease “became” a national public
health issue. As Kraepelin “created” Alzheimer’s disease, Katzman “transformed”
the disease into a public health menace.
Hubris plays a
role again, Robert Katzman was not shy in acknowledging the importance of his
usurping of senile dementia: "I think there's no question that that's my
major contribution. Of the 115 papers I've written, that two-page editorial is
clearly the most important." (Fox, 1989, p. 73). Now, the fate of
Alzheimer’s disease became intricately woven with the promotion of the NIA. The
creation of the NIA depended on Alzheimer’s disease gaining prominence and
national attention. Without the banner of a disease, Congress was not going to
fund research on aging. The ageist attitude was—and remains to this day—that
aging is not important by itself. The founding fathers of the NIA knew that
they needed constituents to bring the mission of the NIA to Congress, and that
meant using Alzheimer’s disease as a lure. All they had to do was to persuade
the general public that Alzheimer’s disease research was not only a national
priority—as well as the NIA’s—but that it was their priority as well. The
growth of locally-based Alzheimer’s associations was essential in order to
bring public pressure on local and national representatives to support NIA’s
mission. This required a symbiotic
relationship—one that has endured to this day. With all of this political
activity, science was overlooked.
It took more than
80 years for a quasi-theory to be developed to explain Alzheimer’s disease. The
Amyloid Cascade hypothesis (Hardy & Higgins 1992) proposed that the
accumulation of two misfolded proteins—amyloid-Ī² peptide and tau tangles—in the
brain was Alzheimer’s disease signature pathology (Karran, Mercken & De
Strooper, 2011). Even by 1992, it was dead on arrival, existing evidence
already refuted this hypothesis, and researchers working in the field knew this.
Deposition of
amyloid (A4) protein deposits were (variably) present in 66% autopsies on adults
over 65 years of age with progressive supranuclear palsy, 57% with Parkinson's
disease, 40% with Huntington's chorea and in elderly patients with frontal lobe
dementia (Mann & Jones,1990; Ross & Poirier, 2004). A signature
biomarker that is shared by other diseases is not a signature but a rubber
stamp. By 1990 researchers were arguing that the “Amyloid deposition in elderly
persons may thus relate more to certain aspects of ageing and genetics than to
AD [Alzheimer’s disease], per se.” (Mann & Jones, 1990; p. 68). Two years later, despite these stark
anomalies, the Amyloid Cascade hypothesis become hallowed knowledge and formed
the basis for nearly all of the neurological work in Alzheimer’s
disease—including the genetic creation of special (transgenic) mice whose brain
is contaminated with amyloid plaques and tau tangles that form the basis for
testing of all pharmacological interventions.
Repeating History
Based on the
amyloid cascade hypothesis (Hardy and Higgins, 1992), active immunization
against amyloid-Ī²42 peptide was proposed as a treatment. But so far, all types
of ‘amyloid’ trials have failed.
In the active
amyloid-Ī²42 immunization clinical trial by Elan Pharmaceuticals (AN1792),
researchers were successful at clearing the amyloid-Ī²42 that formed the
plaques. The immunization trials show that amyloid can be cleared from the
brain. The clearance of visible plaques was seen as a revolution, the “holy grail”
that the new Framework is resurrecting. The problem is that cognition was not
improved (Hock et al., 2003; Bayer et al., 2005; Gilman et al., 2005). In fact,
longer term follow-up revealed continuing cognitive decline despite removal of
plaques (Holmes et al., 2008). The argument is that it is possible that the
damage has already been done and therefore the clearing of the plaques is
inconsequential to the residue of the disease.
Another approach
was related to inflammation response. There was observational evidence that
inflammation is part of the disease process. The discovery that patients with
rheumatoid arthritics who regularly consume non-steroid anti-inflammatory drugs
(NSAIDs), had lower rates of Alzheimer’s disease (e.g., Andersen, et al, 1995).
However, the anti-inflammatory drug R‐flurbuprofen
trial conducted by Myriad Genetics was stopped. Although stage two showed some
promise, the outcomes in stage three proved non-significant. It was not clear
whether the concentration was sufficient (800 mg) and whether the effects of
the drug were too diffuse and non-specific. It is not possible to interpret the
outcome of the trial in any useful way. More recent studies with NSAIDs on
reducing the incidence of Alzheimer’s disease have proven inconclusive (Wang,
et al, 2015; Miguel-Ćlvarez et al, 2015.) Best interpretation is that a daily
dose of generic ibuprofen reduces the likelihood of Alzheimer’s disease. These
studies did however leave one possible interpretation. That the lack of
outcomes could be due to the disease already being present and therefore the intervention
could not prevent it. Again, the argument being proposed is that there is a
need to catch the disease much earlier (McGeer, Rogers & McGeer, 2016.) The
Framework complies with this hypothesis. But there is a problem in logic.
If by removing
amyloid-Ī² in patients resulted in poorer performance on cognitive testing in
human trials (Gilman et al, 2005; Boche et al, 2010; Dodart et al, 2002) then
the plaques cannot be the disease (Iqbal, Liu & Gong, 2014). Therefore, if one of the signature disease of
Alzheimer’s disease is found not to cause Alzheimer’s disease then something
else must cause the dementing features that we observe. Boche et al (2010) concludes that; “However,
the continuing progression of cognitive decline in AD patients after Abeta
immunisation [plaques] may be explained by its lack of apparent effect on
tangles [tau].” (p.13). The results are clear, the amyloid-Ī²42 are precursors
to the real disease which is the tau tangles. It could be that there are
unknown, or hidden precursors. But the Framework does not address the
possibility that Alzheimer’s disease is caused by biomarkers that we perhaps
have not yet identified or know about.
The Tau Influence
Given these
setbacks, the only way that the Amyloid Cascade hypothesis can survive is
through two interpretations. One is that we need to treat the disease at
earlier pre-clinical stage, and secondly to develop safer immunization of
amyloid-Ī²42 since this seems to be the precursors to the tau tangles which
might be the cause of the clinical disease. But this strategy has not fared
well in the past. In 2018, Stefano Cappa with the Institute for Advanced
Studies, Pavia Italy remarked that the competing “tau hypothesis” shares most
of the conceptual assumptions of the amyloid approach—the idea that the
development of Alzheimer’s disease could be stopped or delayed by interfering
with the biology, in this case the formation of neurofibrillary
tangles—pathologic Tau (Cappa, 2018).
Despite
reservations, resources have been diverted to the next big thing—stopping Tau
from becoming a problem in the brain. There are four ways this protein becomes
toxic and so far, there are attempts to limit two of these (phosphorylation and
glycosylation.) Although these are showing positive results in animal studies
(Lim et al., 2000) and in reducing risk of Alzheimer’s disease (Szekely et al.,
2004), so far, the results have been insignificant and diffuse (Li, Kaida-Yip & Zabel, 2018).
While there are
treatments that attempt to immunize, and therefore stop the formation of tau,
these therapies have similarly shown some success at clearing the tau but
without the desired clinical outcome. It seems that the theory is wrong from
the start. The biology—tangles and tau as the neuropathology—might contribute,
moderate and/or mediate the disease, but it is unlikely to be the disease
itself. However, reliance by relying on the objectives of the Framework’s
stated ambition of clearing the amyloid-Ī²42 and tau tangles, then we have
succeeded: Mission Accomplished. Especially if we remove the clinical outcome
by ignoring the observation that individuals’ dementing behavior does not improve
(Boche et al, 2010).
But judging
success on neurology and ignoring clinical evidence is superficial. If clearing
the amyloid-Ī²42 and tau tangles results in the patient retaining the clinical
disease i.e., suffering from memory disorders, personality changes, and
impaired reasoning., then we have failed. The public does not want clean brains
they want the “abnormal” behavior to go away. Any approach that ignores these
realities of success is doomed even if the objectives of the Framework are
successful.
The clinical
aspect of the disease deserves attention. The Framework specifies that; “…[a]
person has an AD [Alzheimer’s disease] biomarker profile, we cannot know if the
cognitive deficit is attributable to AD alone or to other potential
comorbidities in addition…different cognitive stages may be present in the
population among people with the same biomarker profile” (Jack et al, 2018;
p.546) Not only does the Framework not address the clinical aspect, but it
argues against the role of biomarkers in the clinical expression of the
disease.
Following the
lead of Bruno Dubois with the University Pierre & Marie Curie, Paris—and
colleagues with the International Working Group (IWG) and also with the
NIA-AA—there already was a movement to improve upon the existing Guidelines of
2011 (Jack et al 2011) and improving upon the clinical diagnosis of Alzheimer’s
disease (DuBois et al, 2014). This was the right approach. The initial
Guidelines, although not without criticism (e.g. Weuve et al, 2015; Garrett &
Valle, 2014), proposed that Alzheimer’s disease progresses on a continuum with
three stages (Jack et al., 2011). The first is an early, pre-clinical stage
with no symptoms (Sperling et al., 2011), followed by a middle stage of mild
cognitive impairment (MCI) (Albert et al., 2011), followed by a final stage of
Alzheimer’s dementia (McKhann et al., 2011). An additional update focuses on
the criteria for identifying Alzheimer’s related changes at autopsy (Hyman et
al., 2012). These further improvements on the original guidelines were
concerned with the clinical application of their work. Importantly they were
aware of how Alzheimer’s disease can have atypical forms, mixed diseases and
can have a preclinical presence.
By ignoring all
of these aspects of the disease, ignoring the scientific literature that negate
the simplicity of the Amyloid Cascade hypothesis and the similarly ill-fated
tau-cascade hypothesis, and focusing purely on the biology—regardless of the
clinical aspects—the Framework is attempting not just to define a new diagnosis
of Alzheimer’s disease it is trying to reengineer how we define diseases.
Nosology
How we classify
diseases have always relied on their clinical expression except for now. In
2008 the National Institute of Mental Health (NIMH) introduced Research Domain
Criteria (RDoC), a new classification of diseases—nosology. It was especially
promoted by the NIMH then director Thomas Insel, who has now migrated to Google
Life Sciences which in the Google empire has become a full-fledged member of
Mountain View's Alphabet Inc., and taken on a new name: Verily, a for profit
health company.
The RDoC baptism
in 2013 coincided with the publication of the DSM-5— Diagnostic and Statistical
Manual of Mental Disorders the definitive reference for diagnosing psychiatric
disease sponsored by the American Psychiatric Association—which itself heralded
a radical diagnostic departure is moving towards more dimensionality of disease
(no longer binary), relying on more biological indicators and an emphasis on
pharmacological outcomes. The implicit assumption in DSM-5 and explicitly
stated in RDoC is that behavioral/mental/clinical disorders are manifestations
of biological/neurological disorders. Bad behavior is nothing more than
biological expressions. Fixing the biology will fix the problem. Thomas Insel
himself argued that the explicit emphasis of RDoC is to “yield new and better
targets for treatment.” (Insel, 2013)
While demoting the importance of understanding the disease, it elevates
the search for a cure. An illogical approach. Underwhelming the scientific
method in favor of a panacea, one that accommodates an economic imperative.
A backlash of
criticism ensued (e.g., Nemeroff, Weinberger & Rutter, 2013; Peterson,
2015; Weinberger, Glick & Klein, 2015) but despite evidence against this
approach, RDoC gained legitimacy. RDoC’s biological determinism was promoted by
the success of how easy it was for the public and scientists to believe that
Alzheimer’s disease was determined by a simple disease, a biological
malfunction. The history of Alzheimer’s disease laid the foundation for a new
way of biological determinism that has not been seen since the height of the
eugenics movement in 1923 when the American Eugenics Society was founded. But
this emphasis on biology is unfounded. There is no evidence that biology
exclusively determines Alzheimer’s disease or any other mental disorders.
Eugenics Versus Science
In May 2016, in a
short eight-page report in Nature Biotechnology, Rong Chen, Stephen Friend and
Eric Schadt from the Icahn School of Medicine at Mount Sinai, New York, and their
colleagues reversed our idea about genetic determinism. This small revolution
proved to be radical because by association, this also unhinges biological
determinism—the belief that biology determines all your traits (Chen, et al,
2016).
What they did is
to apply scientific method to examining commonly held beliefs about disease.
Usually genetic investigations focus on a group with a disease and then
identifying genes that are different in this group from the rest of the
(control) population. By comparing this group with a control group, they can
single-out a gene that “caused” this difference. Sometimes geneticists hit
lucky and find only one gene that is different between the two groups. In such
circumstances this single gene follows Mendelian laws in how it affects people.
Mendelian laws are named after the monk Gregor Johann Mendel who between 1856
and 1863 discovered the mathematics of heritability. Using this methodology,
scientists have subsequently identified 584 Mendelian diseases: where one gene
causes a specific disease. For the first time the validity of this assumption
was being tested. The results were unexpected and revolutionary.
Rong Chen and his
colleagues screened for 874 genes among 589,306 individuals. They identified
15,597 individuals who had genes for debilitating diseases but they did not
express the disease—they were genetically infected but did not show it. After
rigorous elimination of candidates for various technical and theoretical
reasons, 13 individuals had genetic disorders for: cystic fibrosis,
Smith-Lemli-Opitz syndrome, familial dysautonomia, epidermolysis bullosa
simplex, Pfeiffer syndrome, autoimmune polyendocrinopathy syndrome, acampomelic
campomelic dysplasia and atelosteogenesis. For over fifty years it was believed
throughout the scientific community that having one of these genes results in a
debilitating disease. But for these lucky 13 adults they were completely
normal. They did not express the disease. This single paper heralds the death
of biological determinism. What this informs us is that even Mendelian disease
are mediated or moderated by something other than genetics or biology. We know
very little about what can moderate and mediate this process.
The Framework
usurps the RDoC mission. But despite the change in name, the aim similarly
dictates biomarkers as diseases. But science contradicts this assumption. The
NIA-AA Framework relies exclusively on biological markers even though “None of
the biomarkers are as sensitive as direct examination of tissue at autopsy.”
(Jack, et al, 2018; p.544) The reliability of the tools we have to measure
these biomarkers are questionable; “a negative amyloid PET scan should not be
equated with the complete absence of Ab [amyloid-Ī²42] in the brain or even with
absent or sparse neuritic plaques [tau tangles]…pathologic tau that can be
present in the brain below the in vivo tau PET detectable threshold is unknown
at this time.” (Jack, et al, 2018; p.544). The tools we have are unreliable,
but even more worrisome, they lack of validity—they are useless. We have to
judge how sensible choosing neurological degradation to define degradation when
“the number of neurons or neuronal processes that must be lost to detect
atrophy on MRI or hypometabolism on FDG PET is not known.” (Jack, et al, 2018;
p. 544). These anomalies must have been identified in the Framework to placate
critics, but they succeed in highlighting the lack of robustness of the theory
they are proposing. Even if we accept that this aim is to focus on cure, how
reliable is this approach to help cure Alzheimer’s disease when these
biomarkers are known to relate (cause?) other diseases.
The AT(N)
biomarkers are not an exclusive signature of Alzheimer’s disease alone. “In any individual, the proportion of
observed neurodegeneration/injury that can be attributed to AD [Alzheimer’s
disease] versus other possible comorbid conditions (most of which have no
extant biomarker) is unknown.” (Jack, et al, 2018; p. 543). These admissions
pose serious scientific flaws that expose this Framework to failure. There is
also no connection between these biomarkers as the authors confess: “The AT(N)
biomarker system does not imply a specific order of events nor does it imply
causality.” (Jack, et al, 2018; p. 541.) And even though the authors refrain
from using the clinical expression, their only means of validating the disease
is through its clinical expression: “The rate of cognitive decline is
significantly greater for cognitively impaired and CU [cognitively unimpaired]
individuals who have abnormalities in both an amyloid biomarker and a second
biomarker type (which could be CSF T-tau or P-tau, atrophy, or hypometabolism)
in comparison to individuals who have neither or only one of these biomarker
abnormalities.” (Jack, et al, 2018; p.541-2). There is not one study that can
prove that “…biomarkers predict greater likelihood of and more rapid cognitive
decline” (Jack, et al, 2018; p.542). It is likely, but the science has not been
done, and science cannot be prejudged.
Ignoring Science
The disclaimer is
that this framework is “…for research purposes only…” Defining a research framework through an
international publication under the auspices of a U.S. National Institutes is
unnecessary. A research directive can easily have been issued through a Request
for Proposal directive. As with the 2011 guidelines, again issued by the
NIA-AA, the effect was that the then newly proposed clinical
continuum—pre-clinical/Mild Cognitive Impairment/Alzheimer’s disease—was
adopted by clinicians throughout. Given the research importance, the Framework
will similarly be (haphazardly and unevenly) adopted across the clinical field.
Such duplicity remains worrisome. A truly research framework would approach it
through scientific methods, not through self-serving selection of cherry-picked
facts designed to look progressive. Especially one that serves the pharmacological
industry.
A scientific
study would establish the follow: What are the correlates of dementia (both
biological and clinical.) Other "mis-folded" proteins are present in
brains, some 34 proteins can mis-fold, why focus on just two? If Alzheimer's
disease is an amyloid problem why not look at this under amyloidosis instead of
separately? Why are some mis-folded
proteins useful? A longitudinal study of chemical changes in the brain,
particular attention to the effect of physical and psychological trauma and the
brain. This establishes all the parameters. A theory must at least include all
of these parameters. If there is a focus on just two biomarkers, the
amyloid-Ī²42 and the tau neuritic tangles then how many people (of all ages)
have these biomarkers, what is the tipping point and what is the cut-off point
where it is clinically expressed through dementia (or other clinical
disease)? You cannot do this science
without the clinical aspect of the disease.
But the main
failure of the Framework is not its lack of scientific rigor, it is its lack of
scientific insight. The brain is the most complex entity in the universe, no
other system or organ is as complex. Valid competing explanations for dementia
invariably treat the brain as a complex system, and therefore any disease is
expressed through the breakdown of complex systems. For example, in older
people there are changes in resilience, reduction in body temperature, hormone
changes (especially for women) all of which affect the blood-brain-barrier and
other biological systems that protect the brain from infections. With reduced
resilience, the brain receives an onslaught of bacterial, fungal, viral, metal,
and other invasions that the brain experiences difficulty in coping. The plaques
and the tangles in this scenario are responses to this attack. The frameworks
exclusive focus on these biomarkers does not elucidate the many different
dynamic processes of infection. Science first needs a theory. Observations are
not made in a vacuum.
Science is a
method, based on theory. There is no such thing as scientific fact, only
observations obtained through scientific method. A theory accomplishes three
primary things. First it summarizes all existing information, without ignoring
anomalies. It explains all that is observed. Secondly a theory predicts. Thirdly
a theory generates hypotheses that are open to testing and refutation. We can
test a theory through its many parts. During this stage of testing, the method
of science is to test the smallest number of variables against the most
discreet outcome. This stage relies on a good methodology and accurate
statistics. Most science fails here.
Science is
reliant on constant replication in order to ascertain the relationship that we
are observing is indeed real (i.e. true). The likelihood that a research
finding is indeed true depends on three indicators: the prior probability of it
being true (before doing the study), the statistical power of the study, and
the level of statistical significance (Wacholder et al, 2004; Risch, 2000).
Because most studies do not follow these requirements, focusing instead on
statistical significance alone, Ioannidis argues most current published research
findings are false (Ioannidis, 2005). We are creating false science and
building upon an edifice of falsehoods.
This level of
unawareness is further fueled by attempts to find a cure before understanding
what we are trying to cure. Such applied science, however noble, is not
science. Science is a method used to understand a phenomenon. It is not
predetermined. With the new target to develop a cure for Alzheimer’s disease by
2025 (Cummings et al 2016) we continue to ignore “—incomplete understanding of
AD pathogenesis, the multifactorial etiology and complex pathophysiology of the
disease, the slowly progressive nature of AD, and the high level of comorbidity
occurring in the elderly population.” (Sugino et al 2015). We are kicking the
can down the road. We will find ourselves in the same spot in a century from
today and we will be reading the same kind of criticism as we are here.
Conclusion
Arnold Pick saw
dementia as “. . . a mosaic of localized partial dementias. . .” (Tilney, 1919,
p. 35), Alzheimer’s disease is likely caused by a mosaic that includes: viral
(HIV/AIDS, herpes simplex virus type I, varicella zoster virus,
cytomegalovirus, Epstein-Barr virus), bacteria (syphilis and
lyme-disease/borrelia), parasites (toxoplasmosis, cryptococcosis and neurocysticercosis),
fungi (Candida glabrata), infections (possibly prions), and vascular (stroke,
multiple-infarct dementia, hydrocephalus, injury and brain tumors)(Garrett & Valle, 2014).
There are
processes that promote and delay the infection and the spread of infection.
Primarily the Blood-Brain-Barrier (e.g., Deane, et al 2009), inflammation
(e.g., Lee, et al 2000), vascular (e.g., DiMarco, et al, 2015), White Matter
(e.g., Serrano-Pozo, et al, 2011) and many other dynamic processing in the brain.
Such models already exist (e.g., among many others see Schelke, et al 2018).
The brain is
complex and science is nowhere close to understanding the mechanics let alone
curing specific diseases. Shortchanging science in order to get to a quick fix
is demeaning to scientists and defrauds humanity. We will end up in the same position a hundred
years from now.
We end with a
warning that was predicted more than 100 years ago. Such consequences were
predicted in 1911 by Gaetano Perusini, one of the brilliant researchers working
with Alois Alzheimer, when he wrote: “[scientists] who amuse themselves with
anatomically localizing the location of conscience, the will and related
matters, would find a good playground, in which the tangles, for instance,
might offer the most clear-cut explanation for the disorientation observed in
the senile demented patient…” (Perusini, 1910, p 144).
Older adults have
truly become a playground for a new wave of eugenics. Ignoring the
sociological, psychological and social context of the disease. Shame on the
National Institute on Aging.
© USA Copyrighted 2018 Mario D. Garrett
Note:
A= Biomarkers of Ab plaques in the cortex of the brain. Measured by injecting a radioactive material—ligand—that attaches to the plaques and then imaged using Positron-Emission Tomography-PET. Or measured by low Ab42 in the cerebrospinal fluid (CSF).
T= Biomarkers of fibrillar tau. Measured by injecting a radioactive material—ligand—that attaches to the tau and then imaged using Positron-Emission Tomography-PET. Or measured by elevated phosphorylated tau (P-tau) in the cerebrospinal fluid (CSF).
-->
N=Biomarkers of neurodegeneration or neuronal injury. Measured by elevated phosphorylated tau (P-tau) in the cerebrospinal fluid (CSF). Measuring metabolism in the brain by injecting Fluorodeoxyglucose (FDG) which is a radioactive chemical that is taken up by cells as if it is glucose and then measuring activity with Positron-Emission Tomography-PET. Hypometabolism is not defined. In additional the measure include atrophy as measured by Magnetic Resonance Imaging (MRI). Atrophy is not defined.
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