DRUG DISCOVERY

Alzheimer’s Disease:
A Smoking Gun with No Suspect“Insanity is doing thesame thing over and overagain and expecting adifferent result.” It is notexactly clear who coinedthat phrase, but anyone
frustrated with Alzheimer’s
disease research in thelast 30 years certainly
could have.

Beta-Amyloid — The Smoking Gun
For the past three decades, beta-amyloid has been the assumed culprit of Alzheimer’s disease(AD). Consequently, a significant amount of research and industry resources have been deployedto understanding how it causes the disease, which has reached epidemic proportions(Alzheimer’s Association).
Beta-amyloid is a protein fragment that builds up in the brains of AD patients creating sticky clumpsof plaque that disrupt communication between brain cells and eventually kills them.
The association between a patient with dementia and the buildup of amyloid plaques in thebrain was first described by Dr. Alois Alzheimer in 1906. However, it wasn’t until 1984 thatbeta-amyloid was considered a diagnostic marker and target for AD treatment due to the workof Dr. George Glenner at University of California San Diego. Dr. Glenner created a brain bankto study the diseased brains of patients who were suspected to have died from AD. Afterdiscovering beta-amyloid deposits in over 90% of diseased brains, he characterized the protein
as “a novel cerebrovascular amyloid protein,” responsible for the brain plaques in AD and a prime
suspect in triggering nerve cell damage.

Alzheimer’s Disease: A Smoking Gun with No Suspect

Publication Counts by Year
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2k
1k0
1967

1972

1977

1982

1987

1992

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2007

Despite such a clear link between AD and the buildup ofbeta-amyloid plaques, researchers and drug companies
have not been successful in developing an effective therapy
that targets beta-amyloid.

Beta-amyloidEnzymes
Cell membrane

It wasn’t until 1984 that beta-amyloid wasconsidered a diagnostic marker and target
for Alzheimer’s disease treatment due tothe work of George Glenner at Universityof California San Diego.

2

Based on Dr. Glenner’s findings,
beta-amyloid became a natural focus ofresearch on AD. Since then, the numberof publications on this biomarker has
skyrocketed (Figure 1).

2012

2017

Fig 1. The
number ofresearchpublications
on the role ofbeta-amyloidin AD from
1967–2017.
Chart courtesyof Amplion.

more than 100 beta-amyloid targeted drugs
that have failed to adequately treat AD. While
it is possible that the studies evaluating thesedrugs were not well designed, or that thedrugs were given too late in the AD process,some scientists think the beta-amyloid
protein is not a true cause of AD.
Despite the mountain of failures, there are
currently several studies targeting betaamyloid. The results from these studies will
either vindicate supporters of the beta-amyloid
hypothesis or suggest that chasing this theoryfor the past 30 years was likely a big mistake.

One of the biggest dissenters of thebeta-amyloid hypothesis is Dr. George Perry,
Proponents of the beta-amyloid hypothesis
a neuroscientist at the University of Texas
point to three main lines of evidence toat San Antonio. Dr. Perry champions thesupport its association with AD:
alternative hypothesis that oxidative stressis the primary culprit of AD. He argues that
1. The identification of rare genes thatwhile beta-amyloid may build up in response
increase beta-amyloid production andalmost guarantee the development of AD. to oxidative stress, it is not the root causeof the disease. Controversially, he has
2. Mice that develop amyloid plaques alsodeclared the beta-amyloid hypothesis
develop behaviors that mimic human“dead,” and has further commented on
dementia and AD.
the misdirection of AD research.
3. Individuals with Down syndrome havethree copies of the gene that carries
Beta-Amyloid as a Biomarker
the beta-amyloid protein and often
Although treatments based on beta-amyloid
develop AD by middle age.
have not yielded positive results, it is still used
as a biomarker to confirm AD. Beta-amyloid isA Contrarian View of thefound in the cerebrospinal fluid (CSF), which
Beta-Amyloid Hypothesis
surrounds the brain and spinal cord in aclosed system encapsulated by a thin tissue
Despite such a clear link between AD
membrane called the meninges. Removing
and the buildup of beta-amyloid plaques,
CSF is an invasive procedure that is normallyresearchers and drug companies have not
performed by inserting a needle into the spine
been successful in developing an effective(spinal tap), the brain (ventricular puncture), or
therapy that targets beta-amyloid. Currently,a growing group of scientists are questioning on rare occasions, in the base of the back of
the skull (cisternal puncture).
the decades old theory as there have been

© 2018 Bio-Rad Laboratories, Inc.

Alzheimer’s Disease: A Smoking Gun with No Suspect

Tau is also being
investigated as a potential
therapeutic target inclinical studies. However,as with beta-amyloid, thepharmaceutical industry
has not made progresswith bringing tau-based
therapies into approved
clinical use.

Beta-amyloid plaque deposits in thebrain occur through cleavage of thelarge amyloid-precursor protein (APP) bysecretases (enzymes that break downAPP). When sampling the CSF in patientswith AD, low levels of beta-amyloid areobserved because it is being aggregatedand deposited in the brain as plaques andis therefore unavailable to circulate freely in
the CSF.

Other AD Biomarkers
Another clinically accepted, CSF-based
biomarker used to confirm AD is the tau
protein. Tau is found in neuronal microtubules,
which maintain the structure of the cell, and iselevated in the CSF of patients with AD. Tauproteins cause tangles that lodge themselvesin the brain, thus preventing nutrients andother essential supplies from moving throughthe cell, resulting in cell death.
Tau is also being investigated as apotential therapeutic target in clinicalstudies. However, as with beta-amyloid,
the pharmaceutical industry has not madeprogress with bringing tau-based therapies
into approved clinical use.
Magnetic resonance imaging (MRI) andpositron emission tomography (PET) arealso currently accepted methods used toclinically diagnose AD. MRI is used to detect

Alzheimer’s disease is sometimes referred to as type 3 diabetes since patients with type2 diabetes are twice as likely to develop Alzheimer’s disease as those without.

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structural changes in the brain due to AD.
The loss of neurons, synapses, and othersigns of compromised nerve cells can bedetected with MRI, but it is often too late in
the disease process to intervene (Sohmaand Kokai 2016). PET reflects metabolic
deficits due to synaptic dysfunction andpossibly tau-mediated neuronal injury(Vemuri and Jack 2010).
The clinical standard of care for AD
diagnosis relies on beta-amyloid, tau, MRI,and PET analyses. Although these arevalid diagnostic tools, they are either very
invasive or expensive. Furthermore, noneof these methods can detect preclinical AD
with the required sensitivity and specificity.
Therefore, less invasive biomarkers may be
a more accessible alternative.

Emerging Biomarkers in AD
Macrophage migration inhibitory factor (MIF)
is a pro-inflammatory protein that can bemeasured in the blood and CSF. MIF plays
a role in the body’s immune response andinsulin regulation. It is involved in the responseof brain glial cells to the build-up of abnormal
proteins during AD. Scientists believe that
inhibition of MIF activity caused by glycation(bonding of sugar to protein) could be thetipping point in AD progression.
Glycation reduces the effectiveness ofMIF, which suggests a link between blood
sugar levels and AD. Accordingly, AD issometimes referred to as type 3 diabetes
since patients with type 2 diabetes are twice
as likely to develop AD as those without.
Type 2 diabetes is caused by insulin
resistance, which is the cell’s inability touse insulin to metabolize glucose. Insulin
is needed to provide energy to the brain
by facilitating the absorption of glucose
by neurons, thus making them stronger.
Without insulin, the brain will not get theglucose it needs to function properly. Overconsumption of sugar requires beta cells
to continuously produce insulin until they
become resistant due to overuse. As aresult, brain cells that are insulin resistant do
not get the nutrients they require, ultimately
leading to cell death and AD.
Biomarker profiling is another approachthat has been applied in recent years todiagnose AD as well as other diseases.
Single biomarker assays in AD are3

Alzheimer’s Disease: A Smoking Gun with No Suspect

challenging to establish since they are
multifactorial and complex. Profiling involves
sampling a number of different markers andapplying machine learning and sophisticatedstatistical models to discern which of themarkers, when evaluated together, arepredictive of AD in a patient. Using this typeof model also allows researchers to explore
blood-based markers, which are usually lessspecific than CSF markers since they are
not localized to the brain. However, blood
sampling is far less invasive than puncturing
the spinal cord to obtain CSF and can be
performed outside of clinical settings.
A novel and completely noninvasive
sampling method that has been studied
for its potential application in AD biomarker
profiling is analysis of saliva. Developing
accurate and sensitive biomarkers in saliva
would be ideal for screening individuals atgreatest risk of developing AD. A recent
study tested the saliva of 29 adults withmild cognitive impairment, AD, or a control

group of healthy individuals (Yilmaz et al.
2017). The researchers positively identified
and accurately quantified 57 metabolites
indicative of AD. Some of the observed
variances in the biomarkers were significant,and the researchers were able to makepredictions as to individuals with the highest
risk of developing AD.

References

Conclusion

Vemuri P and Jack CR Jr (2010). Role of structural MRI
in Alzheimer’s disease. Alzheimers Res Ther 2, 23.

AD is a complex, multifactorial diseaseof the brain that may overlap withmalfunctions of other organ systems.
Developing valid biomarkers for diagnosis
has been achieved, but there is still a needfor less expensive and invasive diagnostic
methods as well as the ability for earlier
diagnosis in order to enhance prevention
and treatment. Treatments currently
approved only address symptoms, andthe primary suspects at the root of a cure,beta-amyloid and tau, have been studied
extensively with no resulting therapies.

Yilmaz A et al. (2017). Diagnostic biomarkers of
Alzheimer’s disease as identified in saliva using 1H
NMR-based metabolomics. J Alzheimers Dis 58,355–359.

Alzheimer’s Association. Alzheimer’s Disease — A
Public Health Crisis. cdc.gov/aging/aginginfo/pdfs/
Module1-Alzheimers-Disease-Public-Health-Crisis.pdf,
accessed May 15, 2018.
Sohma H and Kokai Y (2016). Plasma biomarkers in
Alzheimer’s disease. In Update on Dementia, D. Moretti,ed. (IntechOpen), intechopen.com/books/update-ondementia/plasma-biomarkers-in-alzheimer-s-disease,accessed May 15, 2018.

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