Julianne Kim

Mrs. Saha
Indep Res GT
25 April 2022
Primary Research Final

Through meta-analysis, a series of five articles were closely analyzed and compared to determine
if the hypothesis of targeting amyloid-β will prevent cell death and alleviate the neurological
damage associated with Alzheimer’s disease. The data suggests that amyloid-β accumulation
alone does not cause neurodegeneration as it can occur in cognitively normal individuals, and
could be a sign of normal aging.

The five articles analyzed all oppose the idea of amyloid-β as an effective target for Alzheimer's
treatment. The second article comes from Penn Medicine News, “Measuring the Brain’s Amyloid
Buildup Less Effective in Identifying Severity.” Through their study, large amounts of amyloid
plaques were present in healthy, non-demented individuals. Conversely, the intended removal of
amyloid-β from the brains of patients with Alzheimer’s disease led to no change in or even
worsened cognitive performance (Ingeno). The fourth article comes from Medical News Today,
“What Causes Alzheimer's? Not Toxic Amyloid.” While people with mild cognitive impairment
had higher quantities of amyloid-β in their brains at the beginning of the study, this protein did
not seem to build up any faster in these participants than it did in cognitively healthy individuals
(Cohut). The fifth article comes from The Jackson Laboratory, “Moving Beyond Amyloid to
Treat Alzheimer’s Disease.” It was found that blocking amyloid-β is not a viable target for
therapy, and its presence alone is not sufficient to cause Alzheimer’s. After a certain stage, their
elimination will be ineffective in slowing disease progression (Wanner). These sources believe
amyloid-β fails to reflect levels of brain function and therefore may be of limited value when
facing patients with cognitive decline.

While articles one and three share the same viewpoint, in addition, they speculate that the
aggregation of amyloid-β is the first step thought to trigger a cascade of disease-causing
processes. The first article comes from Stanford Medicine News, “Scientists Reveal How
Beta-Amyloid May Cause Alzheimer's.” Although amyloid-β begins destroying synapses before
plaque accumulation, the protein PirB is a high-affinity receptor and leads soluble amyloid-β
clusters to stick to PirB quite powerfully (Goldman). This trips off a cascade of biochemical
activities, impeding the ability of synapses to strengthen when engaged and promoting its
weakening. The third article comes from Nature, “The Amyloid Hypothesis on Trial.” It found
that amyloid-β interacts to promote the formation of tau tangles, which then damage neurons and
cognition. Cognitive symptoms are linked more closely to the number and location of tau tangles
than they are to the same characteristics of amyloid-β plaques (Makin). These sources believe
 amyloid-β is just the first step to inducing Alzheimer's pathology, and proteins resembling PirB
and tau-tangles trigger the cognitive impairment associated with the disease.

Meta-analysis compared numerous articles in order to identify whether the protein amyloid-β
primarily induced Alzheimer's pathology. When looking into the five articles, if targeting the
protein did prevent cell death, it was subsequent to uncover how the synapse functioned
differently and propose possible treatment plans. If targeting the synapse did not prevent cell
death, it was important to understand why and uncover methods that would prevent cell death
in Alzheimer's patients.

Although researchers have argued that targeting amyloid-β supported by the amyloid hypothesis
has proven to be the main cause of Alzheimer’s disease, failed clinical trials and research studies
have indicated that the presence of amyloid-β alone is insufficient in causing Alzheimer’s, and
after a certain stage, their elimination will be ineffective in slowing disease progression.
Additionally, the data concluding the articles revealed that the failure of certain drugs like
amyloid-β to meet clinical endpoints could mean that they have targeted the wrong biomarker,
but could also signify that the drugs were being administered too late on symptomatic patients to
have any remarkable effect.

Primary Document Analysis Chart

Julianne Kim Howard High School, 2022

Document: #1 #2 #3
1. Type of Website Website Website
Document
(Format)
Date(s) of Sep. 19, 2013 Aug. 6, 2019 July. 25, 2018
2. Document
3. Source Stanford Medicine News Penn Medicine News Nature

Author/Creator Bruce Goldman - writer Lauren Ingeno Simon Makin- writer

4. (Position)
5. Document A. Position on the -Beta-amyloid begins -Amyloid imaging does -The aggregation of
Information Role of destroying synapses before not reflect levels of beta-amyloid
Beta-Amyloid in plaque accumulation, brain function, therefore is the first step thought to
Alzheimer's leading to nerve cell death. it may be of limited trigger a cascade of
Disease -Protein “PirB” impedes value for assessing disease-causing
the ability of synapses to patients with cognitive processes such as tau-tangle
strengthen when engaged decline. formation, synapse
and promotes weakening. -FDG-PET is a more dysfunction
sensitive indicator of and cell death.
cognitive decline.
B. Research being -Carla Shatz (PhD, -Andrew Newberg (MD, -Michel Goedert
Conducted professor of neurobiology professor of Radiology (neuroscientist at
(conductors, and biology, senior author at Thomas Jefferson the University of Cambridge,
participants, of the study) University, co-principal UK)
setting, etc.) investigator)
 conducts research in mice
strain at Harvard
University.
C. Evidence -“Her team bred the
Supporting Alzheimer’s-genes-carryin
Research g strain with the
PirB-lacking strain to
create hybrids.
Experimentation showed
that the brains of young
“Alzheimer’s mice” in
which PirB was absent
retained as much
synaptic-strength-
shifting flexibility as those
of normal mice.
PirB-lacking Alzheimer’s
mice also performed as
well in adulthood as
normal mice did on
well-established tests of
memory, while their
otherwise identical
PirB-expressing peers
suffered substantial
synapse and memory loss.”
D. Research Findings -PirB, is a high-affinity
and Overall receptor for beta-amyloid
Conclusion in its “soluble cluster”
form, meaning that soluble
beta-amyloid clusters stick
to PirB quite powerfully.
This trips off a cascade of
biochemical activities
culminating in the
destruction of synapses.
E. Possible -Argument over whether
Doubts/Concerns blocking PirB or removing
the protein would be more
efficient/safer in reducing
neurological impairment.
F. Plans for Future -Create drugs that block
Alzheimer’s beta-amyloid’s binding to
Research/Clinical PirB on nerve-cell surfaces
Trials during earlier stages of the
disease.
evaluated 63 -Michael Murphy
individuals: 19 with (neuroscientist at the
clinically diagnosed University of Kentucky in
Alzheimer’s disease, 23 Lexington)
with mild cognitive -John Hardy (neurogeneticist
impairment, and 21 at University College
healthy individuals. London, and pioneer of the
amyloid hypothesis)
-“Large amounts of -“Cognitive symptoms are
amyloid plaques were linked more closely to the
present in healthy, number and location of tau
non-demented tangles than they
individuals. are to the same
Conversely… characteristics of amyloid-β
the intended removal of plaques.’’
amyloid from the brains -“Experiments in mice and
of patients with human cell lines show that
Alzheimer’s disease led human tau is required for
to no change in, or even some of the neuronal damage
worsened, cognitive associated with the
performance.” disease to occur.”
-“The correlation -“Positron emission
between low cognitive tomography scans of the
performance and high brain reveal that
levels of amyloid was plaques can begin to form
significantly weaker decades before cognitive
than the correlation symptoms appear, and that
between FDG and low amyloid-β levels might
cognitive performance have plateaued by the time
for all groups included that patients enter trials.”
in the study.”
-Amyloid imaging can -Beta-amyloid accelerates the
reveal disease, but it is formation of tau tangles,
incapable of which causes more damage
differentiating between to neurons.
patients who have very -Drugs for patients are being
mild or very severe given at the wrong point in
symptoms. the progression of
Alzheimer’s
disease.
-FDG-PET may not be a -Plaques are found in the
perfect diagnostic tool. brains of many elderly
people with normal
cognition.
-FDG-PET is currently -Attack both beta-amyloid
the best available and tau tangles through drug
method for monitoring treatments/therapies.
symptoms of dementia -Test drugs targeting
and looking at brain beta-amyloid and tau tangles
function. in people who are
at risk of Alzheimer’s prior
to developing symptoms.
6. Lack of -May be other avenues of -How does FDG-PET -Other worthwhile targets
Information destruction affecting the measure cognitive (inflammation, synapse
synapses. deficiency, leading them dysfunction, cell death, etc.).
to a diagnosis?

Document: #4 #5
1. Type of Website Website
Document
(Format)
Date(s) of Jan. 4, 2020 June. 30, 2020
2. Document
3. Source Medical News Today The Jackson Laboratory
(JAX)
Author/Creator Maria Cohut Mark Wanner
4. (Position)
5. Document A. Position on the -The buildup of -Beta-amyloid buildup
Information Role of beta-amyloid has is only one part of a
Beta-Amyloid in associations with much larger collection
Alzheimer's Alzheimer’s, however it of processes that lead to
Disease may not actually cause the Alzheimer’s
condition. progression.

B. Research being -Prof. Mark Bondi (senior -Jackson Laboratory

Conducted author of study paper that
(conductors, appears in Neurology)
participants, evaluated a total of 747
setting, etc.) participants: 305
cognitively healthy, 289
with mild cognitive
impairment, and 153
displaying “objectively-
defined subtle cognitive
difficulties (Obj-SCD),” at
the University of California
San Diego School of
Medicine and the Veterans
Affairs San Diego
Healthcare System.
C. Evidence -“Prof. Bondi and the team
Supporting found that beta-amyloid
Research built up at a faster rate in
the participants with
Obj-SCD compared with
those who were deemed
cognitively healthy…these
individuals experienced a
thinning of brain matter in a
region called the entorhinal
cortex…this brain region
plays a role in memory and
spatial orientation.”
research program is
exploring multiple
aspects of Alzheimer’s,
conducting the latest
study recruiting
volunteers with a rare
genetic mutation that
meant they would
develop dementia.
-“When the trial began,
they were all still
symptom-free. It was
conducted over five
years and involved
monthly infusions or
injections of one of two
experimental drugs
targeting beta-amyloid
for each participant. The
result? The drugs did
nothing to stop or even
slow down the rate of
 -“While people with mild
cognitive impairment had
higher quantities of
beta-amyloid in their brains
at the beginning of the
study, this protein did not
seem to build up any faster
in these participants than it
did in cognitively healthy
individuals.”
D. Research -Cognitive changes may be
Findings and occurring before significant
Overall levels of amyloid have
Conclusion accumulated.
-Beta-amyloid does not
rapidly accumulate through
age.
E. Possible -Mild cognitive impairment
Doubts/Concerns does develop into dementia
in a significant number of
people.
-Biomarkers that measure
proteins such as
beta-amyloid
continue to be highly
expensive, inaccessible for
clinical use, or not available
to those with certain
medical conditions.
F. Plans for Future -Focus on treatment targets
Alzheimer’s of pathologies other than
Research/Clinical amyloid, such as tau, that
Trials are more highly associated
with the thinking and
memory difficulties that
impact people’s lives.
-New study’s findings
could help change the
emergence of biomarkers
by refocusing the research
approach on more subtle
markers of Alzheimer’s,
such as those assessing for
Obj-SCD.
6. Lack of -How did researchers
Information characterize Obj-SCD
participants? Was there a
certain cognitive
cognitive decline in the
subjects.”
-Blocking beta-amyloid
is not a viable target for
therapy.
-The presence of beta-
amyloid alone is not
sufficient to cause
Alzheimer’s, and after a
certain stage, their
elimination will be
ineffective in slowing
disease progression.
-Environmental and
behavioral factors such
as diet and exercise, the
interplay between beta
amyloid, tau, the
immune system, brain
vasculature, and other
factors could all
potentially be
contributors to the
disease.
-Treatment may need to
occur extremely early in
disease development
(years or even decades
before any symptoms
appear) to be effective.
-Countless number of
possible factors
(environmental/behavior
 deficit/diagnosis at which a al factors, tau tangles,
person needed to reach in vascular disease, etc.).
order to qualify?

Through meta-analysis, it is implied through these conclusions that amyloid-β accumulation does
not cause neurodegeneration. The research established that plaques occur in cognitively normal
individuals and could be a sign of normal aging. Furthermore, several other protein fragments
involving tau-tangles, as well as Pir-B, have demonstrated to be more competent and effective
treatment alternatives. The findings preceding the meta-analysis research have proposed the plan
for conducting clinical trials where researchers are targeting tau-tangles and Pir-B in patients
who are at risk of Alzheimer’s prior to developing symptoms.