Jacob Eft
4/25/21
EXSC-305
Alzheimer’s Disease
Introduction
Alzheimer’s is the onset of cognitive and functional decline associated with old age.
Alzheimer’s is the 6th leading cause of death in the United States. Early and accurate diagnosis
are key to this disease. This disease can frequently go undiagnosed or misdiagnosed and can be
very problematic and costly as the disease progresses. It is expected that Alzheimer’s Disease
diagnoses will rise 35% by 2030, and triple by 2050. In the beginning stages of the disease, an
individual will begin to lose the ability to create and store new memories.
As the disease progresses you will begin to see changes in behavior and cognitive
function. When someone has Alzheimer’s, you will see a change in amyloid precursor protein
(APP), and production of the APP fragment beta-amyloid (Aβ) along with hyperphosphorylated
tau protein. These chemical changes cause a loss of synaptic strength, synaptic loss, and
neurodegeneration. There are licensed treatments that can help to alleviate Alzheimer’s
symptoms, but there is still a major need for better understanding of the disease so we can create
treatments that will modify the disease. There is reliable research right now that we are using to
correctly identify risk factors and protective measurements, but further research is needed to see
how substantially these protective measurements can lower the risks.
Etiology/Physiology
There are two main neurological explanations to how Alzheimer’s Disease affects the
brain. It is mainly characterized by hard, insoluble plaques, made up of beta-amyloid (Aβ),
between the nerve cells in the cerebral cortex of the brain. Beta-amyloid is a protein fragment
from a larger protein known as an amyloid precursor protein (APP). APP is important to the
survival of neurons as it helps them repair themselves after any damage. But, when Alzheimer’s
is present, enzymes cut APP into fragments, resulting in beta-amyloid, that clump together onto
non-nerve cells and form plaques as seen on Figure 1. These plaques then interfere with the
brain's ability to function properly, resulting in damaging effects.
On the other hand, Alzheimer’s Disease can also be the effect of neurofibrillary tangles
within a nerve cell. Healthy neurons promote nutrient transportation by a system of
microtubules. Those microtubules contain a protein called tau. When Alzheimer’s Disease is
present, the protein, tau, is abnormal and becomes tangled with other tau strands, causing the
microtubules to collapse. With no microtubules, nutrient transport between cells stops,
eventually causing the death of those cells.
Figure 1. Blocking of the neurotransmitter by beta-amyloid (Aβ) clumps, effecting its ability to
send messages throughout the brain.
Signs and Symptoms
Researchers estimate there are more than 47 million people with dementia in the world,
and 60%-80% of those with dementia have Alzheimer’s. The biggest factor in Alzheimer’s is
age, as the risk of Alzheimer’s doubles every 6.3 years. Signs and symptoms of this disease can
begin years before diagnosis. In these years before diagnosis, people will begin to see changes in
mood, anxiety, and sleep. Once diagnosed, there are 3 different stages of Alzheimer’s. The first
stage will normally last 2-4 years. In this stage of the disease, patients will start to show
symptoms of dementia that might include mild memory lapses and problems finding the right
words.
The second stage is the longest, which can sometimes last up to 10 years. During this
stage, the patient could begin to experience different behavioral changes such as irritability,
depression, and anxiety. In addition, patients may begin to experience increasing memory loss,
difficulty reading, writing, thinking logically, and more. During the third and final stage of
Alzheimer’s Disease, the patient may begin to have little or no ability to take care of themselves
and may have trouble performing normal daily activities. This may include losing the ability to
communicate and control bodily functions. Patients can also experience dysphagia, which is
having difficulty swallowing. The final stage of Alzheimer’s Disease can last one to three years.
Recognizing the signs and symptoms early is key to diagnosis, with diseases like this early
recognition is key.
Diagnosis
An accurate and early diagnosis is key when it comes to Alzheimer’s. With early
diagnosis, families of the patient will be able to plan their future life and finances. At this time,
Alzheimer’s disease can only be definitively diagnosed once the patient has died. When
diagnosing a living person with Alzheimer’s, you must have a detailed history of the individual’s
symptoms, and what course those symptoms have taken in recent history. When taking this
history, the clinician must receive the history from the patient as well as some of the people he is
close with. This detailed history will help to reveal the patient’s cognitive impairments, social
function, occupational function, instrumental function, and a neuropsychological assessment
must be completed. When a clinical diagnosis is made, it must use criteria such as NINCDSADRDA (National Institute of Neurological and Communicative Disorders and Stroke and the
Alzheimer's Disease and Related Disorders Association). This criteria has good specificity and
sensitivity of over 80% when distinguishing patients with Alzheimer’s vs people without
dementia. The NINCDS-ADRDA however is less accurate when distinguishing Alzheimer’s vs
other types of dementia with a rate of 22-88%. Based on research and evidence, a CT or MRI
should be used to detect lesions or diseases inside the scull that could contribute to Alzheimer’s
symptoms. There are new tests coming out that can find Tau protein and Aβ peptides in the
spinal fluid. There is still a high degree of variability with the spinal fluid tests and will need to
be standardized before they can become more reliable.
Another way that has recently been approved by the FDA is noninvasive. This new
technique utilizes a specialized PET scan to detect the florbetapir tracer. The tracer will reveal
amyloid-β (Aβ) peptides in the plaques in the patient’s brain. This new method had a specificity
rate of up to 100% and a sensitivity rate of up to 96%. It took nearly a decade from the time the
first tracer was made at the University of Pittsburgh, to the time it was finally approved by the
FDA. The only current issue with this diagnostic method, is the price for patients. The cost of
this method is very expensive, and most insurance companies will not pay to have it done.
Currently, the majority of patients undergoing this diagnostic method are doing so through
various clinical trials.
Treatment
In order to treat Alzheimer’s as effectively as possible, treatment must begin as
soon as a diagnosis is made. Upon starting treatment after diagnosis, an assessment must be
made of the patient’s everyday life and the family around them, information, services, and
support should be provided to the patient and their family to help them live their lives. One class
of drugs used is antipsychotic drugs. These drugs are used to treat agitation, aggression, and
psychosis in patients with Alzheimer’s. Side effects with these drugs include sedation,
parkinsonism, chest infections, ankle oedema, and an increased risk of stroke and death. Because
these side effects are so severe, potential risks should be compared to the benefits. There is
currently no established benefit to these drugs, as large trials have shown little to no benefit to
these drugs. There is non-medicinal alternative therapy instead of taking these medications.
Examples of these therapies include social interaction, person-centered care training,
aromatherapy, and exercise.
Another treatment for Alzheimer’s is active immunotherapy and passive
immunotherapy. Active immunotherapy uses fragments of the amyloid-β (Aβ) protein to clear
the amyloid-β (Aβ) protein and improve behavior. The issue with this, is that this treatment was
effective in mice, but in human patients the treatment was able to clear some of the amyloid-β
(Aβ) protein but was not as clear cut as the mice. Passive immunotherapy uses antibodies of the
amyloid-β (Aβ) protein to clear the protein from the brain. This trial was again effective in mice,
and trials are currently underway in humans. There is speculation with this method that the
antibodies will not be able to make it past the blood brain barrier.
There have been many drug trials to try to help treat patients with Alzheimer’s,
however many of these drug trials have failed to effectively treat Alzheimer’s patients. One
group of drugs currently undergoing clinical trials are aggregation inhibitors. These drugs are
designed to process, aggregate, and clear amyloid-β (Aβ) from pathways in the brain. One drug
called Tramiprosate failed its clinical trial, but other drugs are in phase 2 of their clinical trial and
are currently showing positive results to move to phase 3. Current Researchers believe that these
drugs that target the amyloid-β (Aβ) protein are more effective for early Alzheimer’s when
compared to later Alzheimer’s. Currently there are no drugs that have proven effects in the
treatment of Alzheimer’s. Part of the reason we do not have an effective treatment yet, is how
many are currently undergoing clinical trials. When a drug undergoes a clinical trial, there is
only a very small chance it will be approved, and this goes for drugs of all forms. Because of
this, there is an urgent need for more drugs to be developed and therefore to undergo clinical
trials.
One future treatment approach for Alzheimer’s patients may be to strengthen and
enhance the connections and networks in the brain. This approach would treat and enhance
cognitive function in Alzheimer’s patients. There are also clinical trials currently underway that
involve asymptomatic patients with predispositions to Alzheimer’s. these clinical trials are being
assessed for biomarkers and objective testing for clinical outcomes. Another future approach by
researchers at Massachusetts Institute of Technology, found that the use of gamma-frequency
oscillations was able to reduce the amyloid-β (Aβ) protein deposition and improve cognitive
function in mice. This trial method was done by using a non-invasive 40 Hz photic stimulator to
entrain the desired frequency in the mouse. This method of treatment is still in very early stages
of a clinical trial, and there is currently no information on if this is effective or not in humans.
Risk factors/Alzheimer’s in West Virginia
Some of the risk factors with Alzheimer’s are also areas where the people of West
Virginia tend to struggle. Risk Factors for Alzheimer’s include smoking, hypertension, high
cholesterol, obesity, poor nutrition, physical inactivity, and diabetes. The population of West
Virginia ranks within the top 5 in smoking, hypertension, high cholesterol, obesity, and diabetes.
West Virginian’s also rank in the top 3 for poor nutrition, hypertension, and high cholesterol.
Research has shown that patients with both Alzheimer’s and high blood pressure had a
significant decrease in blood flow to the brain, making them more susceptible to the neurological
effects of Alzheimer’s.
One study shows that patients with high cholesterol were 66% more likely to be
diagnosed with Alzheimer’s. West Virginia ranks number 1 for high blood pressure in the US.
Poor nutrition is a key risk factor with Alzheimer’s. Maintaining a good diet is essential for
people who may be predisposed to the disease. Making sure someone has a good diet is essential
to helping maintain a healthy weight, cholesterol and glucose levels, and blood pressure. A good
diet should include plenty of fruits, vegetables, grains, and fish. Eating fish has been shown to
lower risk of cardiovascular disease and ultimately, Alzheimer’s Disease.
Conclusion
Alzheimer’s disease is becoming very common in our society, and yet very unknown at
the same time. This is such a complex disease that it is very difficult to treat and diagnose a
patient when they have it. As of right now, the only way to 100% diagnose the disease is after
the patient has passed away. Alzheimer’s Disease is different from other diseases because of how
long the disease affects you. Patients can be in different stages of the disease for many years at a
time. Patients can also have the disease years before they are officially diagnosed. Treatment
options for the disease are very limited, and not vey effective. Much more research is still needed
to find a clinical treatment method. With so many risk factors involved with this disease, and it
being so hard to treat, when patients are diagnosed their lives and their families’ lives will be
affected for the rest of the patient’s life.
Sources
Atri, A. (2019, January 29). The Alzheimer's Disease Clinical Spectrum: Diagnosis and
Management. https://www.sciencedirect.com/science/article/pii/S0025712518301317
Ballard, C., Ballard, C., Gauthier, S., Corbett, A., Brayne, C., Aarsland, D., & Jones, E. (2011,
March 2) Alzheimer's disease https://www.thelancet.com/action/showPdf?pii=S01406736%2810%2961349-9
Chancellor, Bree, Duncan, Angel, and Chatterjee, Anjan. ‘Art Therapy for Alzheimer’s Disease
and Other Dementias’. (2014, January 1) : 1 – 11.
https://content.iospress.com/articles/journal-of-alzheimers-disease/jad131295
DeTure, M. A., & Dickson, D. W. (2019). The neuropathological diagnosis of alzheimer's
disease. Molecular Neurodegeneration, 14(1), 32.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6679484/pdf/13024_2019_Article_333.pdf
Hane, F. T., Robinson, M., Lee, B. Y., Bai, O., Leonenko, Z., & Albert, M. S. (2017). Recent
progress in alzheimer’s disease research, part 3: Diagnosis and treatment IOS Press.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5389048/pdf/jad-57-jad160907.pdf
Tan, Chen-Chen, Yu, Jin-Tai, and Tan, Lan. ‘Biomarkers for Preclinical Alzheimer’s Disease’.
(2014, January 1) : 1051 – 1069 https://content.iospress.com/articles/journal-of-alzheimersdisease/jad140843
Thoenen, E., Curtis, C., Bazzle, N., Slemp, C., Christy, D., Doria, J. C., . . . Light, T. (2011,
May). An Overview of Dementia: The Growing Crisis in West Virginia.
http://www.wvdhhr.org/bph/hsc/pubs/other/Dementia_an_overview_2010/Dementia.pdf
Weller, J., & Budson, A. (2018, August 1). Current understanding of alzheimer’s disease
diagnosis and treatment F1000 Research Ltd.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6073093/pdf/f1000research-7-15791.pdf