What are the most promising treatment options available for patients

with Alzheimer's disease?

Todd Laffaye

Senior Project Advisor: Lauren Lucky

Abstract

Alzheimer's disease is one of the most devastating and detrimental crises we face in the world
today. It is incurable, making it a death sentence filled with confusion, forgetfulness, and pain for
those affected. Over the years, the fight for a cure has intensified and thus the higher number of
pharmaceuticals and treatment options being investigated has lead to a new chapter of
Alzheimer's treatment development. In this paper, I explore and analyse the treatment methods
and pharmaceuticals currently in development for Alzheimer's treatment to identify which is the
most promising. This research is based primarily on meta-analysis and data from 2017 or later.
Based on currently existing research, the drug aducanumab seems to be the most promising for
Alzheimer's disease treatment. It is an effective, safe, and disease-modifying drug that improves
cognition. Aducanumab has shown the most potential to aid those suffering from Alzheimer’s
and potentially end the disease’s crisis in the following years. To do this, aducanumab must first
complete phase three clinical trials before it can become available on the market for treatment.
However, due to the complexity of the disease, further research is needed for pharmaceuticals
that can treat more than one main hallmark for a full-fledged treatment.

12th Grade Humanities

Animas High School
5 March 2017
Laffaye

1
Laffaye

Part​ ​I:​ ​Introduction

From 2010, the cost of dementia care has increased by 35% to US$818 billion dollars in

2015, affecting over 48 million people worldwide. By 2030, it is estimated that dementia will

affect over 74 million people and have a cost of over US$2 trillion dollars (Shih-Ya Hung 10).

Dementia is one of the great modern pandemics and Alzheimer's disease (AD) is the most

common form of dementia, accounting for the sixth leading cause of death in the United States

according to the Center For Disease Control. Currently, it is estimated that one in ten people are

affected by Alzheimer's disease. AD is incurable; a diagnosis of AD is a death sentence.

However, not all hope is lost. As the number of expected AD patients grows, so does the funding

for clinical trials of new drugs from Congress. This has caused a massive influx in the number of

new drugs and treatment methods in development for AD specifically.

Within this paper, it is important to understand the difference between dementia and

Alzheimer's disease. Dementia is an umbrella term that defines the symptoms associated with

neurological degeneration, whereas Alzheimer's disease specifically relates the cause of

dementia and the specific symptoms seen in AD patients due to the pathophysiological changes

seen in an AD-affected brain (Forester). By understanding these pathophysiological changes,

researchers are able to target specific hallmarks of AD and create treatment pharmaceuticals in

an attempt to change the progression of the disease. With so many different pharmaceuticals,

each working in a variety of ways and levels of complexity, it seems as though a few currently

stand above the others and show more promise for future AD treatment. Based on the most

current research and clinical data, the most promising treatment method for AD is by targeting

2
Laffaye

beta-amyloid (Aβ) aggregates, and furthermore, the most promising treatment option available

for patients with Alzheimer's disease is the drug aducanumab.

Part​ ​II:​ ​Historical​ ​Context

Alzheimer's disease is not a recent discovery. AD is named after Dr. Alois Alzheimer,

who noticed changes in the brain tissue of a woman who had died of an unusual mental illness in

1906. He found many abnormal clumps (now called amyloid plaques (Aβ)) and bundles of

tangled fibers (now called neurofibrillary tangles (NFTs)), which are now considered two of the

main hallmarks of AD (U.S. Department of Health). It is not known how AD spreads through the

brain, although it is known that these hallmarks usually start to develop in the hippocampus,

where they then spread to the amygdala, temporal lobe, frontal lobe, parietal lobe, occipital lobe,

cerebellum, and down though the deep brain to the brainstem, where eventually the pons and the

medulla oblongata (the part of the brain that controls the heart and lungs) necrose (the cells die),

causing patient death (Tender Rose Dementia Care Specialists). The last drug to pass the clinical

trial process and become publicly available was memantine. It was approved by the U.S. Food

and Drug Administration (FDA) in 2003. It works similarly to the other 3 drugs which have

passed clinical trials and become publicly available for AD, which are donepezil, galantamine,

and rivastigmine. These drugs work to enhance the acetylcholine (a neurotransmitter) response in

patients with AD, which can lead to improved cognitive function. However, this does not change

the progression of the disease. All four of these drugs (memantine, donepezil, galantamine, and

rivastigmine) are symptomatic drugs, not disease-modify drugs, thus they do not treat the disease

in a conventional sense. In its current state, AD treatment can be thought of being ​equivalent to

3
Laffaye

the stage that cancer treatment was in the 1970s to 1990s (Forester). The majority of drugs

currently in development either do more damage than good, effecting both healthy and diseased

areas of the brain, or do not do enough to change the progression of the disease.

In my research, I analyzed many drugs currently in the clinical trial process for the

United States. Clinical trials have 4 phases, and in order to understand how far a drug is in its

development, it is important to understand each step of the clinical trial process. For most AD

pharmaceuticals, before being brought into the clinical trial process, they are first created and

tested on mice models in a lab. Once showing effectiveness and safety in mice, the clinical trial

process begins. Phase one studies are designed to determine the effects of the pharmaceutical on

humans. This includes how it is absorbed, metabolized, excreted and how it interacts in relation

to the human body. This phase also investigates side effects related to dosage. If a drug passes

phase one, it then moves into a slightly larger phase two trial. This is where effectiveness is

tested. These trials are often randomised and blinded. They utilize a placebo drug to be compared

against the new drug in question to provide pharmaceutical companies and the FDA with

comparative information about the relative safety and effectiveness of the drug in testing. If a

drug passes here, it then moves into phase three. Phase three is the make or break point for drugs

in development. These are large scale tests that involve randomized and almost always double

blinded testing against placebo to provide pharmaceutical companies and the FDA with a more

thorough understanding of the effectiveness of the drug and the possible any side effects. Phase

three usually takes several years, but if a drug passes phase 3, pharmaceutical companies can

then request that the FDA make that drug publically available on the market. Phase four usually

comes after this, where the drug is compared with other drugs already on the market. Long-term

4
Laffaye

effectiveness is also analysed. Results from phase four testing can cause a drug to be taken off

the market or become more strictly regulated.

In the context of Alzheimer's disease, it is important to remember that it is a unique form

of dementia, with many different hallmarks that are unique to the pathophysiology (conditions

and changes associated with disease or injury) related to AD. These are the hallmarks of AD:

The first hallmark is lowered acetylcholine levels (leading to cognition loss). The second

hallmark is higher glutamate levels that are caused by excitotoxicity (the pathological process

that causes neuronal damage and death by the overactivations of receptors from the

neurotransmitter glutamate). Glutamate in such high levels is cytotoxic (toxic to living cells).

The third hallmark is the aggregation of extracellular amyloid-β (Aβ plaque which causes

neuronal death). Amyloid is a protein that is normally found throughout the body, however, in

AD the protein divides improperly which creates a form called beta-amyloid which is toxic to

neurons. The fourth hallmark is the formation of neurofibrillary tangles (NFTs) from the

hyperphosphorylation (over phosphorylation) of tau (a protein that stabilizes microtubes), which

causes neuronal death. Normally, every neuron contains long fibers made of proteins which act

as scaffolds and transports for nutrients. In AD, these fibers become twisted and tangled. This

causes neurons to become unable to transport nutrients properly, leading to death (Rutgers

University). The fifth hallmark is neuroinflammation. This is seen as neurons die, and causes

even more neuronal death and swelling in the brain. The two main hallmarks of AD are the

aggregation of Aβ and the formation of NFTs, as these are commonly considered to be the most

detrimental and specific to AD.

5
Laffaye

As technology has progressed, there have been many technological advancements which

make identifying these hallmarks and the study of treatment options for AD possible. Magnetic

resonance imaging and x-ray imaging (MRI/CAT scans) are used to help rule out other diseases

when looking for AD. Positron emission tomography (PET scans) can show reduced cell activity

in certain areas in patients with AD. Structural imaging is also used to show the decrease in brain

volume in patients with AD and Aβ imaging can be used to monitor levels of Aβ in AD brains.

These imaging techniques are also used to help prove the effectiveness of drugs in clinical trials.

Part III: Research and Analysis

Section A: Treatment Methods

For Alzheimer's disease, there are many different targets for methods of treatment. These

are the 15 most common methods for AD treatment, each of which focuses on a specific AD

hallmark within a group. Within the acetylcholine-related group, there is the enhancement of the

acetylcholine response by acetylcholinesterase (​an enzyme that causes rapid hydrolysis

(chemical breakdown) ​inhibitors, the enhancement of acetylcholine response by using 5-HT6

receptor antagonists (drug that bonds to and blocks a receptor), the enhancement of the

acetylcholine response using H3 receptor antagonists, and the enhancement of the acetylcholine

response by a7 nicotinic acetylcholine receptor agonists (Shih-Ya Hung 2-6). For glutamate,

there is the inhibition of glutamate cytotoxicity by Nmethyl-D-aspartate (NMDA) receptor

antagonists or glutamate release inhibitors (Shih-Ya Hung 6). For the beta-amyloid (Aβ) related

group, there is the inhibition of Aβ production by β-secretase (BACE) inhibitors, the inhibition

of Aβ production by y-secretase inhibitors or modulators, and the clearance of Aβ by active or

6
Laffaye

passive immunotherapy (Shih-Ya Hung 6-8). Active immunotherapy stimulates the body's own

immune system, while passive immunotherapy utilizes immune system components like

antibodies which are created outside of the body. Within the tau-related group, there is the

enhancement of microtubule stabilization by tau stabilizers, the prevention of tau aggregation by

tau aggregation inhibitors, and the enhancement of phosphorylated-tau clearance by active

immunotherapy (Shih-Ya Hung 8-9). There are also the methods of the inhibition of

neuroinflammation and the utilization of nasal insulin and calcium channel blocker (Shih-Ya

Hung 9). These are considered non conventional methods.

These various targets for treatment methods can be categorized into 4 main categories:

Neurotransmitter related, Aβ related, tau-related, and other. However, within the context of this

paper, for analysing specific drugs I will be using these 6 categories of broad treatment target

methods: Methods that enhance the acetylcholine response, methods that are Aβ related, methods

that involve the inhibition of glutamate, methods that are tau-related, methods that are

neuroinflammation related, and non conventional. Of these 6 categories, I believe beta-amyloid

(Aβ) targeted treatment methods are the most advanced and developed after an analysis of each

treatment method target and specific drugs that have been developed for each. These are the

reasons why I believe other treatment methods are inferior to Aβ targeted treatment methods.

Section B: Acetylcholine

Firstly, when looking at methods revolving around the enhancement of the acetylcholine

response, it needs to be known that acetylcholine response treatment does not cure AD in the

conventional sense. This means that enhancing acetylcholine levels does not necessarily change

7
Laffaye

the progression of AD (Forester). Rather, acetylcholine is used to improve cognition in patients

with AD. Three of the four drugs already available for AD are related to acetylcholine. These

drugs are donepezil, galantamine, and rivastigmine. They do not cure AD or slow disease

progression significantly, instead, they help treat the symptoms associated with AD (loss of

cognitive function). This is where the distinction between symptomatic and disease-modifying

pharmaceuticals is so important to understanding AD treatment. For a disease to be treated in the

conventional sense, the progression of the disease has to be changed. Pharmaceuticals can be

differentiated between symptomatic and disease-modifying based on what hallmarks they act on

and how they work. For example, these pharmaceuticals that work to enhance acetylcholine

response (donepezil, galantamine, and rivastigmine) only work while patients are on the

medication. They also target a symptom and not an underlying cause. Although lowered

acetylcholine response is a hallmark of AD, it is most likely caused by Aβ plaque or tau. We

know enhancing acetylcholine response does not change the progression of the disease, thus it

can not conveniently treat/cure AD. For a pharmaceutical to be considered disease-modifying,

the drug must “alter the course of the illness, changing the pathophysiology of the brain”

(Forester). Acetylcholine-related treatments do not do this.

Moreover, other recently developed acetylcholine treatment pharmaceuticals such as

idalopirdine, ABT-288, GSK239512, and encenicline have failed. Idalopirdine did not meet

primary efficacy endpoints vs. placebo. ABT-288 failed due to a lack of clinical efficacy. The

drug K239512 failed due to a lack of improvements in memory testing, and encenicline actually

improves acetylcholine levels and cognitive function, but was put on hold by FDA for side

8
Laffaye

effects (Shih-Ya Hung 2-6). All in all, acetylcholine-related treatments are not disease-modifying

and have had a string of recent failures, meaning these methods not the most promising.

Section C: Glutamate

Next, when looking at glutamate-related treatment methods, there is simply not enough

research on glutamate in relation to AD treatment compared to other hallmarks. There have also

only been a handful of drugs have ever been created for this treatment method and they do not

work well. For context, glutamate is a neurotransmitter that sends chemical messages in the brain

by exciting neurons. In AD, glutamate levels are increased by excessive activation of (NMDA)

receptors (Shih-Ya Hung 6). Glutamate at such high levels is cytotoxic, causing neuronal death.

Glutamate treatment may be disease-modifying, but it is likely not as effective as Aβ or

tau-related treatment methods because they are considered the two main hallmarks of AD.

Regardless, it is believed that glutamate treatment methods “may enhance the localized

vulnerability of neurons in a manner consistent with AD neuropathology” (Shih-Ya Hung 6),

which makes them a palpable treatment target. However, palpable is not the same as promising.

The only one of the four drugs that have been passed by the FDA that is not related to

acetylcholine enhancement is the drug memantine, which is a glutamate-related treatment

method (Forester). This is also the most recent drug to be passed by the FDA, but there is a

catch. Although memantine is available for AD treatment, this is not the disease it was

conventionally meant for (Shih-Ya Hung 6). Furthermore, as stated in the article “Drug

Candidates in Clinical Trials for Alzheimer's Disease”, author Shih-Ya Hung states that,

9
Laffaye

Memantine cannot prevent neuronal loss, worsening of dementia or modify the disease

progression. Despite never receiving formal approval for the early stages of AD,

memantine is frequently prescribed at this stage. Its clinical usefulness in mild AD is

controversial, with conflicting reports from meta-analyses. (6)

Due to this information, memantine cannot be considered a promising treatment method. One of

the only other drugs for AD utilizing glutamate treatment methodology is riluzole (for patients

already on donepezil). In mice, riluzole increased glutamate reuptake and decreased glutamate

release in the hippocampus. It also decreases tau levels (Shih-Ya Hung 6). Riluzole finished a

phase two clinical trial in 2017 for AD. Riluzole also recently finished phase 3 clinical trials for

the treatment of both Parkinson's and Huntington's diseases. Both programs had negative results

and were discontinued (Alzforum). Because memantine has very controversial effects for AD

and riluzole had negative results for two other diseases, as well as only showing positive effects

in mice models, glutamate-related treatment methods can not be considered the most promising.

Section D: Tau

Tau-related treatment methods are different from both acetylcholine and

glutamate-related treatment methods in the sense that tau is one of the main hallmarks of AD

which has the full potential to be disease-modifying with an effective pharmaceutical. Tau is a

protein that is a stabilizer of microtubes. Within neurons in AD, tau becomes

hyperphosphorylated and causes the formation of neurofibrillary tangles (NFTs) which leads to

neuronal death. NFTs comprise of aggregated and misfolded tau protein caused by this

hyperphosphorylation (Grüninger 1). As stated by author F. Grüninger in the article “Invited

10
Laffaye

Review: Drug Development for Tauopathies”, “In drug development terms, prevention of

development of NFTs or clearance of NFTs from the brain should result in cognitive benefits”

(1). However, the issue with the tau-related treatment methods is that drugs in development

related to tau and neurofibrillary tangles present vast side effects and are also ineffective because

tau is intracellular (inside cells), making it hard to target. Also, most drugs related to tau

treatment are too early in development to tell relative effectiveness. As stated by Brent P.

Forester, MD, MSc. Chief, Division of Geriatric Psychiatry and Site Director, Harvard Medical

School Psychiatry Core Clerkship, McLean Hospital, “Tau is a good 8-10 years behind Aβ

targeted treatment options” (Forester). This further supports why Aβ targeted treatment methods

are the most advanced. Furthermore, the complexity of targeting tau and thus NFTs means most

drugs that show promise in mice models do not show similar results in the human clinical trial

process. For example, in mice trials, the drug bapineuzumab was shown to effectively reduce

cerebrospinal fluid (CSF) phosphorylated tau protein concentration in mice brains (Abushouk et

al. 12), however, these effects were not seen in humans and there were vast side effects present.

In the article “Bapineuzumab for Mild to Moderate Alzheimer's Disease: A Meta-analysis of

Randomized Controlled Trials”, author Abushouk et al. found that, “…the bapineuzumab group

was not superior to the placebo group in terms of change from baseline in Alzheimer’s disease

assessment scale” (12). He then continues by saying, “Regarding safety, bapineuzumab increased

the risk of serious treatment-emergent adverse events and cerebral vasogenic edema” (12). In

conclusion, he says, “Considering the lack of clinical efficacy, combined with the significant

association with serious adverse events, bapineuzumab should not be used to treat patients with

mild to moderate AD” (12). Not only was a similar positive effect not seen in human clinical

11
Laffaye

trials compared to mice trials, but serious treatment adverse events and cerebral vasogenic edema

and serious issues. Other tau-related treatment method pharmaceuticals such as epothilone D and

rember also failed due to side effects and lack of clinical efficiency. In the article “Dyrk1

Inhibition Improves Alzheimer's Disease-Like Pathology”, author Branca et al. states that,

We found that chronic Dyrk1 inhibition reversed cognitive deficits in AD mice. These

effects were associated with a reduction in amyloid-b (Ab) and tau pathology.

Mechanistically, Dyrk1 inhibition reduced APP and insoluble tau phosphorylation. The

reduction in APP phosphorylation increased its turnover and decreased Ab levels. These

results suggest that targeting Dyrk1 could represent a new viable therapeutic approach for

AD. (1)

Although it is true that Dyrk1 does show potential, it has never been tested in the clinical trial

process, only on mice, and could likely have a similar outcome to bapineuzumab. Other

pharmaceuticals that work slightly differently, working to enhance phosphorylated-tau clearance

via active immunotherapy such as AADvac-1 and ACI-35 are too early in development to tell

how promising they may be. AADvac-1 is in phase two clinical trials and ACI-35 is in phase one

(Alzforum). The only drug to over make it to phase three clinical trials was the drug TRx0237.

Like these other tau-related pharmaceuticals, TRx0237 missed its co-primary endpoints. It also

had side effects that changed the color of pee and poop for patents and was thus discontinued

(National Library Medicine). Due to the vast side effects, difficulty of targeting intracellular tau,

and ineffectiveness of recent drugs related to tau treatment methods, they are not the most

promising for AD treatment.

12
Laffaye

Section E: Neuroinflammation

Neuroinflammation related treatment methods do not necessarily cure AD, rather they

reduce the negative side effects that come with a strong immune response. Neuroinflammation is

related to the pathophysiology of AD and these drugs work to prevent cell death caused by

inflammation, but not by the main hallmarks of AD itself (Aβ and tau). In AD, Aβ deposition

activates microglia, which triggers neuroinflammation. This neuroinflammation is what causes

neuronal death and cognitive deficits (Veerappan et al. 4). Due to this, drugs that work off

neuroinflammation related treatment methods can be thought of as more symptomatic drugs

rather than disease-modifying. In the article “Inhibition of Ikkβ by Celastrol and Its Analogues”

by author Veerappan et al., the drug celastrol is discussed. It works by inhibiting IKKβ, an

enzyme that controls NF-kB activation. This can be used to help control and reduce

inflammatory responses in patients with AD. In this article, Veerappan et al. states that,

“Although celastrol has been shown to be neuroprotective, it is toxic at increased concentration

which is evident from its apoptotic and anti-cancer activity in many cancer cells” (5). Even

though celastrol was found to be effective in a rat model of AD, improving memory and

suppressing damage done on neurons by the nervous system and preventing cell death, it is noted

that celastrol is toxic in high concentration and thus research is currently being done to try and

change the structure of celastrol so it can be less toxic and more effective for AD treatment in

humans (Veerappan). However, due to the toxicity and the fact that these results are not from

human clinical trials, at its current state celastrol is not as promising as other pharmaceuticals

that work off Aβ related treatment methods. Another pharmaceutical that is based on

neuroinflammation treatment methods is the drug azeliragon. Azeliragon is in phase three

13
Laffaye

clinical trials, but it is not a disease-modifying drug (like all neuroinflammation treatment

method related drugs). Another drug called alzhemed failed to show clinical efficacy in 2007.

Ibuprofen was also tested for AD treatment and it showed no significant change and also gave

patients negative side effects. The drug called fluruzan also failed because it did not change

primary outcomes in mild AD (Shih-Ya Hung 9). All in all, neuroinflammation related methods

are still of clinical benefit, just not as much as an actual disease-modifying treatment method

because they are symptomatic drugs and therefore not the most promising for AD treatment.

Section F: Non Conventional

In the world of AD treatment, there are also treatment methods which do not necessarily

a line with any of the conventional treatment method categories. Many of these are not

necessarily disease-modifying or effective. For simplicity, I will only talk about vitamin D2

supplementation and calcium channel blockers. Firstly, vitamin D2 supplementation was thought

to have clinical benefit related to AD because poor vitamin D nutrition is linked to dementia

(Stein et al. 1). After doing the first ever randomized controlled trial (RCT) for vitamin D2

supplementation effect for AD patients, in the article “A Randomized Controlled Trial of

High-Dose Vitamin D2”, author Stein et al. found that,

In conclusion, despite reports that dementia is associated with poor vitamin D nutrition,

we found no benefit for cognition or disability from adding high-dose vitamin D to

ongoing low-dose vitamin D supplementation. Furthermore, despite reports in unblinded

studies of improvement in cognition with nasal insulin in AD, we found no benefit from

nasal insulin acutely or over 48 h. (7)

14
Laffaye

This means that although vitamin D2 supplementation is a good thing in general, for AD it did

not seem to have any effect on the specific pathophysiology of the disease. It is also definitely

not disease-modifying.

The idea of calcium channel blockers for AD treatment was brought up because it was

found that an influx of calcium is cytotoxic (Nimmrich 1), meaning that blocking calcium

channels could have clinical benefit. In the article “Calcium Channel Blockers and Dementia” by

author Nimmrich, it was found that,

Nimodipine was reported to improve both cognitive and behavioural symptoms in

patients with so-called chronic organic brain syndrome or AD. Improvement in memory

deficits and attention was observed in more than the 70% of patients with age-related

dementias in postmarketing surveillance studies in Europe. (4)

Although this does not necessarily point to disease modification, their other findings did. It was

also found that,

...calcium channel blockers such as nilvadipine and nitrendipine may also reduce the

accumulation of Aβ in the brain of APP-overexpressing mice (Paris et al., 2011). In this

respect, calcium channel blockers may not only function at the level of Aβ toxicity but

may even prevent production (or enhance clearance) of the toxic peptide. (4)

This was a big discovery, but the effect of this drug has on Aβ has not been tested on humans, so

similarly to bapineuzumab this effect may not be the same for humans as it was found in mice.

Therefore, both vitamin D2 supplementation and calcium channel blockers are not the most

promising for AD treatment.

15
Laffaye

Section G: Aβ

Next, when looking at Aβ targeted treatment methods, based on my research I have found

that drugs related to Aβ targeted treatment methods are the most promising, more than

acetylcholine, glutamate, tau, neuroinflammation, and non conventional treatment method

targets. This is because Aβ targeted treatment methods are the only treatment methods that have

the ability to alter the progression of AD with drugs in phase three or higher clinical trials. Other

treatment methods with the ability to alter the progression of the disease with drugs in phase

three clinical trials have failed to meet endpoints and did not pass the clinical trial process. For

example, related to​ ​Aβ, there are the pharmaceuticals E2609, AZD3293, CNP520 and

JNJ-54861911 to name a few that “have shown satisfactory pharmacokinetics and encouraging

clinical data” (Shih-Ya Hung 6-8). These are all currently in phase three trials, meaning each of

them could have huge potential as disease-modifying pharmaceuticals. Also, there is the drug

crenezumab which is able to “recognizes oligomeric and fibrillar Aβ species and amyloid

plaques with high affinity, and monomeric Aβ with low affinity” (Shih-Ya Hung 8). This drug is

also in a phase three clinical trials with huge potential. However, these drugs do not seem to be

as promising as one Aβ targeted treatment method pharmaceutical in specific, the drug

aducanumab.

Section H: Aducanumab

Similar to E2609, AZD3293, CNP520, JNJ-54861911, and crenezumab, aducanumab is

disease-modifying. This means it has the potential to change the progression of AD and treat it in

the conventional sense. More so, aducanumab is the most advanced and most promising of these

16
Laffaye

potentially disease-modifying pharmaceuticals. Aducanumab utilizes the specific treatment

method of Aβ targeted treatment via passive immunotherapy. In relation to other treatment

methods, passive anti-Aβ immunization is the most advanced strategy for treating AD (Shih-Ya

Hung 7). The only other phase three drug that utilizes this same method is crenezumab.

Moreover, aducanumab is more advanced than crenezumab because “Research into human B

cells that react with Aß aggregates led to the development of aducanumab, and preclinical

studies with mice found that the antibody was able to cross the blood-brain barrier and clear Aß

from plaque bearing brains” (Brown University 1). This was a huge breakthrough for the

development of aducanumab and shows how it behaves in a state-of-the-art manner. In phase

two clinical trials, a phase looking for safety specifically, it was actually found that aducanumab

was disease-modifying in a dose-dependent manner (Brown University 2). Aducanumab also

showed a high level of success in mice models before the clinical trial process. Unlike

bapineuzumab, that high level of success is backed up by clinical results from the human clinical

trial process. In the article “Data Suggest Antibody's Clinical Benefit in Treatment of

Alzheimer's Disease” by Brown University, it is stated that, “A year of monthly infusions of the

human monoclonal antibody aducanumab reduced amyloid-ß (Aß) plaques in patients with

prodromal or mild Alzheimer’s disease, and resulted in a slowing of clinical decline in these

patients...” (1). Results like this from a phase two study which shows a pharmaceuticals ability to

be disease-modifying are extremely promising. The article also states that according to Jeff

Sevigny, et al., “Considering that it may have taken up to 20 years for Aß to have accumulated to

the levels in these patients at study entry, the observed kinetics of Aß removal within a 12-month

time period appears encouraging for a disease-modifying treatment for patients with Alzheimer’s

17
Laffaye

disease” (2). This quote shows just how promising early clinical trial data is for aducanumab in

terms of disease altercation. Similar results for disease altercation have not been seen for any

other pharmaceutical. When asking Brent P. Forester, MD, MSc, what drugs he thinks are most

promising for Alzheimer's treatment, he said, “Aducanumab is currently the most promising

treatment option” (Forester). This shows that top-level researchers and experts in the field are in

agreement. To back up his claims, he stated aducanumab is different than other Aβ targeted

pharmaceuticals because over the past ten to twelve years, other drugs have targeted Aβ too late,

when AD is already in the moderate stage. Aducanumab is different and more promising because

it can intervene early when patients are pre-symptomatic. This is huge because Aβ is often found

in AD brains up to 17 years before symptoms (Forester).

Not only can aducanumab target Aβ while patients are pre-symptomatic, but it also has

very limited and easy to control side effects. Because aducanumab is an antibody, when it binds

to Aβ it creates an immune response, meaning it can be followed by excessive accumulation of

immune cells, causing brain swelling. Additionally, vascular Aβ causes microbleeds, which can

be identified as amyloid-related imaging (ari) E and (ari) H (Forester). After brain imaging,

patient’s brains can either look like they just had a stroke or look completely normal. However,

the risk for these side effects is relatively low (Forester). Moreover, this risk is even further

reduced by genetic screening for a gene called aop4. This is because researchers were able to

find a direct correlation between side effects and the speed of which doses of aducanumab are

increased from start of treatment to maximum effective dose. Therefore, if the speed is slowed of

increasing increments of drug dose for patients with aop4, side effects virtually stop and any

patient can reach maximum effective dose eventually (Forester). This is absolutely incredible,

18
Laffaye

effectively eliminating the side effects that come with aducanumab and making the drug

available and well tolerated for anyone with AD.

Additionally, aducanumab is available and is currently in two phase three clinical trials

internationally, which are recruiting patients until June of 2018 (Alzforum). If aducanumab

continues showing as much promise as it has, phase three will be finished by mid-2020 and the

drug could hit the market anytime afterward.

Part IV: Discussion and Conclusions

In conclusion, after analysing each group of treatment method based on hallmark,

specific treatment methods, and specific pharmaceuticals within those treatment methods, I

believe the most promising treatment option available for patients with Alzheimer's disease is the

drug aducanumab. Aducanumab targets Aβ plaques, one of the main hallmarks of AD which has

the most promise for pharmaceutical development and disease modification. It utilizes passive

immunotherapy, one of the most advanced specific treatment methods. It has the ability to

remove Aβ plaques pre-symptomatically, improve cognitive function and change the progression

of the disease. It also has reduced side effects with proper gene screening. It is the only drug in

the clinical trial process for AD treatment which is disease-modifying and in phase three or

higher. Therefore, it is currently the most promising for AD treatment when compared to other

pharmaceuticals and treatment methods.

Past research into this topic may look very different than my research. This is because

new drugs are being developed constantly for AD treatment. Before aducanumab was developed,

a different pharmaceutical would have been the most promising, and in the future a new drug or

19
Laffaye

treatment method may become more promising than aducanumab. However, currently, studies

have shown aducanumab is the most promising. Most sources I used analysed recent work and

were published in 2017 or sooner. In such a fast-changing field current research is key. The

larger implications of my research are that finding a pharmaceutical that can treat AD in the

conventional sense would be a huge accomplishment. AD would no longer be a death sentence

and billions of dollars could be saved annually. Aducanumab is currently showing promise to be

able to do that.

Just because theses larger implications are huge and very positive for the future of AD

treatment, it is important to remember that diseases are complex. AD has many hallmarks and

although targeting one of the main ones like Aβ (as aducanumab has done) is beneficial, it will

not address the other hallmarks. Neurofibrillary tangles are still a main hallmark of AD. Future

investigation into hyperphosphorylated tau and NFTs will likely need to be done to enhance our

ability to treat AD. The future investigation into symptomatic treatments such as

neurotransmitter related will also enhance our ability to symptomatically treat AD and improve

the quality of life of those affected.

Although future treatments will likely aim to target multiple hallmarks, currently the

most promising treatment option available for patients with Alzheimer's disease only targets one

hallmark. The drug aducanumab has been shown to do what others currently can’t. Hopefully,

with future research and the combination of other pharmaceuticals and medical discoveries,

aducanumab can help bring an end to the AD crisis.

20
Laffaye

Works Cited

221AD302 “Phase 3 Study of Aducanumab (BIIB037) in Early Alzheimer's

Disease.”​Clinicaltrials.gov​, National Library of Medicine, 19 Feb. 2018,

clinicaltrials.gov/ct2/show/NCT02484547?term=BIIB037&rank=4.

“AADvac-1.” Alzforum, Biomedical Research Forum, ​www.alzforum.org/therapeutics/aadvac-1​.

Abushouk, Abdelrahman Ibrahim, et al. "Bapineuzumab for Mild to Moderate Alzheimer's

Disease: A Meta-Analysis of Randomized Controlled Trials." BMC Neurology, vol. 17,

04 Apr. 2017, pp. 1-13. EBSCOhost, doi:10.1186/s12883-017-0850-1.

“ACI-35.” ​Alzforum​, Biomedical Research Forum, www.alzforum.org/therapeutics/aci-35.

“Aducanumab.” ​ALZFORUM​, Biomedical Research Forum,

www.alzforum.org/therapeutics/aducanumab.

“Alzheimer's Disease Fact Sheet.” ​National Institute on Aging​, U.S. Department of Health and

Human Services, 17 Aug. 2017, www.nia.nih.gov/health/alzheimers-disease-fact-sheet.

Branca, Caterina, et al. "Dyrk1 Inhibition Improves Alzheimer's Disease-Like Pathology." Aging

Cell, vol. 16, no. 5, Oct. 2017, pp. 1146-1154. EBSCOhost, doi:10.1111/acel.12648.

"Data Suggest Antibody's Clinical Benefit in Treatment of Alzheimer's Disease." Brown

University Psychopharmacology Update, vol. 28, no. 1, Jan. 2017, pp. 1-5. EBSCOhost,

doi:10.1002/pu.30195.

Grüninger, Fiona. "Invited Review: Drug Development for Tauopathies." Neuropathology &

Applied Neurobiology, vol. 41, no. 1, Feb. 2015, pp. 81-96. EBSCOhost,

doi:10.1111/nan.12192.

21
Laffaye

Laffaye, Todd A, and Brent P. Forester. “Interview on Treatment Options for AD.” 7 Feb. 2018.

“LMTM.” ​Alzforum​, Biomedical Research Forum, www.alzforum.org/therapeutics/lmtm.

Myers, Catherine E. “Memory Loss & The Brain.” ​Memory Loss & the Brain​, Rutgers

University, 2006, www.memorylossonline.com/glossary/neurofibrillarytangles.html.

Nimmrich, V and A Eckert. "Calcium Channel Blockers and Dementia." British Journal of

Pharmacology, vol. 169, no. 6, 15 July 2013, pp. 1203-1210. EBSCOhost,

doi:10.1111/bph.12240.

“Riluzole.” ​Alzforum​, Biomedical Research Forum, ​www.alzforum.org/therapeutics/riluzole​.

Shih-Ya, Hung and Fu Wen-Mei. "Drug Candidates in Clinical Trials for Alzheimer's Disease."

Journal of Biomedical Science, vol. 24, 19 July 2017, pp. 1-12. EBSCOhost,

doi:10.1186/s12929-017-0355-7.

Stein, Mark S, et al. "A Randomized Controlled Trial of High-Dose Vitamin D2 Followed by

Intranasal Insulin in Alzheimer's Disease." Journal of Alzheimer's Disease, vol. 26, no. 3,

Aug. 2011, pp. 477-484. EBSCOhost,

search.ebscohost.com/login.aspx?direct=true&db=aph&AN=65504250&site=ehost-live.

“Understand Alzheimer's Disease in 3 Minutes.” Tender Rose Dementia Care Specialists, 2010.

Youtube​, www.youtube.com/watch?v=Eq_Er-tqPsA.

Veerappan, Karpagam, et al. "Inhibition of Ikkβ by Celastrol and Its Analogues – an in Silico

and in Vitro Approach." Pharmaceutical Biology, vol. 55, no. 1, Dec. 2017, pp. 368-373.

EBSCOhost, doi:10.1080/13880209.2016.1241809.

22