Role of Genetics in AD – Alondra PimentelThere are 4 genes loc.docx

Role of Genetics in AD – Alondra Pimentel
There are 4 genes located on different chromosomes associated
with Alzheimer’s disease – these genes are an autosomal
dominant or a sporadic inheritance. Although extensive studies
have shown there is a genetic component in both early-onset and
late-onset Alzheimer’s, it has also been found that other factors
contribute to the disease. This includes sex, aging,
environmental factors, and other unidentified genetic risks.2
Figure 1 The four genes and their respective chromosomes
associated with Alzheimer’s disease.3
· Amyloid Precursor Protein (APP)
· Chromosome: 21q21
· Inheritance: Autosomal Dominant
· APP missense mutations have been found in 85 families,
though only about 10-15% of these mutations account for the
presence of early-onset familial AD.2
· This gene is an integral membrane protein and is concentrated
in the synapses of neurons. Although its function is unknown it
is associated with synapse formation regulation and the ability
of the nervous system to adapt to changes in the environment.2
· Apolipoprotein E (APOE)
· Chromosome: 19q13.32
· Inheritance: Sporadic
· APOE plays a role in the metabolism of cholesterol and
triglycerides throughout the body.2
· APOE comes in different alleles: ε2, ε3, and ε4.
· ε2: rare, and is usually associated with a much later
occurrence of Alzheimer’s disease when compared to someone
with a different APOE gene.1
· ε3: this is the most common allele and doesn’t affect risk in
this disease.1

· ε4: this gene increases the risk of getting the disease and at an
earlier age. The most APOE ε4 genes one can have is 2 – the
more you have the greater the risk.1
· Presenilin 1 (PSEN1)
· Mutations in this gene are the most common cause of EOAD,
accounting for 18-50% of familial cases.2
· The missense mutation in this gene causes the most severe
form of EOAD, characterized by progressive dementia and
parkinsonism.2
· PSEN1 forms the catalytic core of the γ-secretase complex.2
· Presenilin 2 (PSEN2)
· Unlike PSEN1, missense mutations in this gene are a rare
cause of EOAD, affecting individuals much later in life in
comparison.2
· This gene is found highly expressed in neurons and the
mutations associated affects the way in which APP is cut by γ-
secretase.2
References:
1. Alzheimer's Disease Genetics Fact Sheet. (2015, August 30).
Retrieved from https://www.nia.nih.gov/health/alzheimers-
disease-genetics-fact-sheet.
2. Bekris, L. M., Yu, C. E., Bird, T. D., & Tsuang, D. W.
(2010). Genetics of Alzheimer disease. Journal of geriatric
psychiatry and neurology, 23(4), 213–227.
doi:10.1177/0891988710383571
3. Stavljenic–Rukavina, A. (2004). Molecular Mechanisms in
Alzheimer's Disease.

IHP 510 Module Four Worksheet
For this task, you will complete a SWOT analysis to determine
the strengths, weaknesses, opportunities, and threats of a
specific healthcare organization’s service or product. Based on
your SWOT analysis, you will then propose an additional
service or product to market for the organization, while also
comparing your additional service or product to a competing
healthcare organization’s service or product.
This task is designed to provide practice for the analysis,
service proposal, and competition analysis that you will
complete as part of Final Project Milestone Two in Module
Five.
To complete this worksheet, first review the module resources.
Next, review the following webpages. Select one of the
organizations and one of its product or services to analyze:
· Mayo Clinic: Products and Services
· Johns Hopkins Medicine
· Cleveland Clinic: Institutes and Departments
Complete the following sections for the organization’s service
or product that you chose.
Part I. Complete the SWOT for the selected organization.
1. List at least 3 strengths and explain what makes them
strengths.

2. List at least 3 weaknesses and explain what makes them
weaknesses.
3. List at least 3 opportunities and explain what makes them
opportunities.
4. List at least 3 threats and explain what makes them threats.
5. After completing the SWOT components for the chosen
organization, address the following:
What additional service or product would you propose to market
for this organization? Why?
In making your proposal, identify a competing healthcare
organization’s similar service or product—one that you think is
effective. Below, identify the service/product and briefly
describe why you feel it is successful.
Be sure to apply instructor feedback on this worksheet task to
your Final Project Milestone Two, due in Module Five,
especially the sections on the situational analysis, service
proposal, and competition analysis that you will need to
consider when completing your final healthcare marketing and
communication plan.

IHP 510 Module Four Worksheet Guidelines and Rubric
Conducting a SWOT Analysis, Considering the Competition,
and Making a Proposal
Overview: For this task, you will complete a SWOT analysis to
determine the strengths, weaknesses, opportunities, and threats
of a specific healthcare
organization’s service or product. Based on your SWOT
analysis, you will then propose an additional service or product
to market for the organization, while also
comparing it to a competing healthcare organization’s service or
product. This task is designed to provide practice for the
analysis, service proposal, and
competition analysis that you will complete as part of Final
Project Milestone Two in Module Five.
Prompt: Complete the Module Four Worksheet by addressing
the following critical elements:
○ Identify three strengths for the healthcare organization’s
service or product that you chose, explaining what makes these
elements strengths.
○ Identify three weaknesses for the healthcare organization’s
service or product that you chose, explaining what makes these
elements
weaknesses. Identify three opportunities for the healthcare
organization’s service or product that you chose, explaining

what makes these
elements opportunities.
○ Identify three threats for the healthcare organization’s service
or product that you chose, explaining what makes these
elements threats.
product would you propose to market for this organization?
Why?
identify a competing healthcare organization’s similar service
or product—one that you think is
effective. Briefly describe why you feel it is successful.
Rubric
Be sure to apply instructor feedback on this worksheet task to
your Final Project Milestone Two due in Module Five—
especially the sections on the situational
analysis, service proposal, and competition analysis that you
will need to consider when completing your final healthcare
marketing and communication plan.
Critical Elements Exemplary (100%) Proficient (90%) Needs
Improvement (70%) Not Evident (0%) Value
SWOT: Strengths Meets “Proficient” criteria and
demonstrates keen insight into
what makes the elements
strengths
Identifies strengths, explaining
what makes them strengths

Identifies strengths, explaining
what makes them strengths,
but response has gaps in detail,
clarity, or logic
Does not identify strengths,
explaining what makes them
strengths
16
SWOT: Weaknesses Meets “Proficient” criteria and
weaknesses
Identifies weaknesses,
weaknesses
Identifies weaknesses,
weaknesses, but response has
gaps in detail, clarity, or logic
Does not identify weaknesses,
weaknesses
16
https://learn.snhu.edu/d2l/lor/viewer/view.d2l?ou=6606&loIdent
Id=6396

SWOT: Opportunities Meets “Proficient” criteria and
opportunities
Identifies opportunities,
opportunities
Identifies opportunities,
opportunities, but response
has gaps in detail, clarity, or
logic
Does not identify
opportunities, explaining what
makes them opportunities
16
SWOT: Threats Meets “Proficient” criteria and
threats
Identifies threats, explaining
what makes them threats
Identifies threats, explaining
what makes them threats, but
response has gaps in detail,
clarity, or logic
Does not identify threats,

threats
16
Additional
Service/Product
Meets “Proficient” criteria and
demonstrates sophisticated
understanding of the needs for
services and products of
healthcare organizations
Proposes an additional service
or product to market for the
healthcare organization,
providing rationale
Proposes an additional service
or product to market for the
healthcare organization,
providing rationale, but
response has gaps in detail,
clarity, or logic
Does not propose an additional
service or product to market
for the healthcare organization
16
Competing
Service/Product
Meets “Proficient” criteria and

demonstrates sophisticated
understanding of what makes
services and products effective
in healthcare organizations
Identifies a competing
healthcare organization’s
similar service or product,
describing why it is effective
Identifies a competing
similar service or product,
describing why it is effective,
but response has gaps in detail,
clarity, or logic
Does not identify a competing
similar service or product
16
Articulation of
Response
Submission is free of errors
related to citations, grammar,
spelling, syntax, and
organization and is presented
in a professional and easy-to-
read format
Submission has no major errors
spelling, syntax, or organization

Submission has major errors
spelling, syntax, or
organization that negatively
impact readability and
articulation of main ideas
Submission has critical errors
spelling, syntax, or organization
that prevent understanding of
ideas
4
Total 100%
Uzma Chohan-Weber 11/20/2019
Drug Therapies for Alzheimer’s Disease (Carlson and Birkett,
2017)
Individuals affected with Alzheimer’s Disease experience a
buildup of amyloid plaques in the brain, which consist of the
dense protein beta-amyloid, created by the beta-secretase
enzyme. Additionally, these individuals have neurofibrillary
tangles which are composed of dying neurons that contain
intracellular accumulations of twisted filaments tau protein.
This buildup of beta-amyloid and tau contribute to the
degeneration of the brain. As a result of these factors, drug
therapies that affect beta-amyloid and tau proteins present the
best areas of research to treat the cause of the disease or slow
its progression.
Beta-Amyloid – Posiphen (Lahiri et al., 2006)

Posiphen is one of the drugs currently being studied that
focuses on lowering of beta-amyloid, which is a protein present
in abnormally high levels in the brain of people with
Alzheimer’s disease. In this study, posiphen was tested in vitro
using cultured human neuroblastoma cells and in vivo using a
mouse animal model. The goal of the study was to investigate
if posiphen (Figure 1) would lower both beta-amyloid (Aβ) and
beta-amyloid precursor protein (APP) over different dose levels.
Figure 1, Chemical structure of posiphen
Beta-Amyloid – Atabecestat (Timmers et al., 2018)
Atabecestat (JNJ-54861911) is one of the drugs currently being
studied that focuses on inhibiting the beta-secretase enzyme
from making beta-amyloid. This enzyme is what creates beta-
amyloid. Inhibition of this enzyme is a key factor in the
treatment and prevention of Alzheimer’s Disease. In this study,
atabecestat (Figure 2) was tested in an in vivo clinical trial
using human patients with early phase Alzheimer’s Disease.
The goal of the study was to investigate the pharmacodynamics
activity as a proof of mechanism of atabecestat to inhibit beta-
secretase in patients with mild cognitive impairment due to
Alzheimer’s Disease.
Figure 2, Chemical structure of atabecestat
Tau Protein – AADvac1 (Novak et al., 2018)
AADvac1 is a vaccine being studied that focuses on targeting
tau proteins through immunotherapy. Tau proteins are the main
component of tangles, which is an abnormality in the brain of
patients with Alzheimer’s disease. In this study, AADvac1
(Axon Peptide 108) was tested in an in vivo clinical trial using
human patients with mild to moderate Alzheimer’s disease who
had completed a preceding phase 1 study. The goal of the study
was to prove long-term safety of AADvac1 and analyzing the
performance of the vaccine.

Results – Posiphen (Lahiri et al., 2006)
This graph shows the effects of posiphen on beta-amyloid
precursor protein (APP) and beta-amyloid (Aβ) in vitro in
human SK-N-SH cells. The data shows that posiphen both dose
and time dependently lowered both APP and Aβ levels by
reducing the synthesis rate. All dose levels reduced both APP
(graph A) and Aβ (graph B) as compared with controls. A
different drug pheneserine was also investigated as part of the
study, also showing reduction compared to controls.
This graph shows the effects of posiphen on beta-amyloid
precursor protein (APP) and beta-amyloid (Aβ) in vivo in mice.
The data shows that posiphen dose dependently lowered both
APP and Aβ levels by reducing the synthesis rate, similar to the
in vitro results. All dose levels reduced both APP and Aβ as
compared with controls. A different drug pheneserine was also
investigated as part of the study, also showing reduction
compared to controls.
The authors concluded that posiphen, like phenserine, can lower
beta amyloid and represents a drug candidate for Alzheimer’s
disease treatment.
Results – Atabecestat (Timmers et al., 2018)
The above charts show the percent change from baseline in
cerebrospinal fluid (CSF) and plasma amyloid-β 1–40 (Aβ1–40)
at day 28 for both treatment groups (Caucasian patients with
early AD and Japanese patients with preclinical AD). Both the
atabecestat 10 mg and 50 mg dose groups showed reductions in
beta amyloid levels from baseline in the CSF and Aβ1–40 levels
and other Aβ fragments as compared to placebo in both
treatment groups.
Results – AADvac1 (Novak et al., 2018)

This graph shows the antibody response to AADvac1 over 96
weeks of treatment. The values show the 95% confidence
interval of the mean titres. Bold weeks indicate the points of
AADvac1 vaccine treatment. The light gray shows the values
obtained in the first in-human study and the white shows the
sustained antibody response in the follow up study.
The authors concluded that a more frequent booster dose
regimen of AADvac1 was needed. Slower brain atrophy in the
MRI data and a reduction in cognitive assessment decline was
observed in patients with high titres. The conclusion of the
study was that additional clinical trials were required to
establish proof of clinical efficacy. The follow up ADAMANT
Phase II study for AADvac1 was recently completed (un-
published), confirming the safety profile and a statistically
significant impact on neurodegeneration.
References:
Carlson N, Birkett M (2017) Physiology of Behavior. Boston,
MA: Pearson.
Lahiri DK, Chen D, Maloney B, Holloway HW, Yu QS, Utsuki
T, Giordano T, et al. (2006) The experimental Alzheimer's
disease drug posiphen [(+)-phenserine] lowers amyloid-beta
peptide levels in cell culture and mice. J Pharmacol Exp Ther.
320(1):386-96. doi:10.1124/jpet.106.112102
Timmers M, Streffer JR, Russu A, Tominaga Y, Shimizu H,
Shiraishi A, Tatikola K, et al. (2018) Pharmacodynamics of
atabecestat (JNJ-54861911), an oral BACE1 inhibitor in patients
with early Alzheimer's disease: randomized, double-blind,
placebo-controlled study. Alzheimers Res Ther. 10(1):85.
doi:10.1186/s13195-018-0415-6.
Novak P, Schmidt R, Kontsekova E, Kovacech B, Smolek T,
Katina S, Fialova L, et al. (2018) FUNDAMANT: an
interventional 72-week phase 1 follow-up study of AADvac1, an
active immunotherapy against tau protein pathology in
Alzheimer's disease. Alzheimers Res Ther. 10(1):108. doi:
10.1186/s13195-018-0436-1.

Axon announces positive results from Phase II ADAMANT trial
for AADvac1 in Alzheimer’s Disease. (n.d.) Axon
Neuroscience. Retrieved on 11/20/2019 from: http://www.axon-
neuroscience.eu/docs/press_release_Axon_announces_positive_r
esult_9-9-2019.pdf
Gene Therapies for AD
What is nerve growth factor?
Nerve growth factor, also called NGF, is a type of neurotrophin.
Neurotrophins monitor neuronal cells for abnormal stimuli that
could be harmful to the nervous system. They also assist in the
maintenance of function, development, survival, and death of
neurons (Squire, 2009). In order to conduct studies in drug
therapies for Alzheimer’s disease, we must first dig deeper in
understanding the mechanisms of Alzheimer’s on the genetic
level. This can also lead us to gene therapies.
Figure 1 (Choi et al., 2014)
On the chart in figure 1, three gene therapies are summarized,
containing the type of cell, the gene involved, the subjects used,
and the results of the trials.
According to the third treatment listed in the chart above
(Figure 1), neural stem cell-expressing NGF that were
transplanted into the hippocampus region of mice subjects
exhibiting a symptom of cognitive deficit showed protective
factors of the neurons (Choi et al., 2014).
Study: TDP-43 inhibitory peptide – (Gao et al., 2019)

TDP-43 is the TAR DNA-binding protein 43. Proteinopathy of
TDP-43 has become increasingly known as a major feature of
Alzheimer’s disease. In this study, the mitochondria were used
to attack the TDP-43 neurotoxicity in Alzheimer’s disease
induced mice. To measure cognitive and motor function in the
mice after administration of the inhibitory peptide, a series of
tests were used (open-field tests, muscle strength tasks, etc.).
By using an inhibitory peptide for TDP-43, the major symptoms
of AD, neuronal loss and behavioral abnormalities, can be
reduced.
Results and Discussion:
Figure 2
The schematic model (Figure 1) shows the pathology of AD in
the transgenic mice as well as the administration of the
inhibitory peptide (PM1) and the following behavioral tests that
measured cognition and motor function. After inducing the
effects of AD in transgenic mice by augmenting TDP-43 in the
mitochondria, there were mixed results:
By inhibiting the TDP-43 localization in the mitochondria, the
TDP-43 proteinopathy process was reduced as well as other
mitochondrial abnormalities.
Figure 3
The Aβ plaque deposition remained unchanged in older mice
after administering the PM1. Figure 2 shows no difference in
plaque formation between the control PM (induced AD
symptoms but no treatment) and the PM1. However, there was
protection against neuronal loss and gliosis. Gliosis is the
destruction of glial cells, which assist in the insulation of
neurons.

Improved cognition and motor functions were expressed in older
mice after the administration of the PM1. Cognitive
deterioration in young mice was prevented by PM1 as well.
These studies have shown the potential of gene therapy in not
only reducing the progression, but also restoring deteriorated
parts of the nervous system.
References:
Choi, S. S., Lee, S.-R., Kim, S. U., & Lee, H. J. (2014).
Alzheimers Disease and Stem Cell
Therapy. Experimental Neurobiology, 23(1), 45. doi:
10.5607/en.2014.23.1.45
Gao, J., Wang, L., Gao, C., Arakawa, H., Perry, G., & Wang, X.
(2019). TDP-43 inhibitory
peptide alleviates neurodegeneration and memory loss in an
APP transgenic mouse model for Alzheimers
disease. Biochimica Et Biophysica Acta (BBA) - Molecular
Basis of Disease, 1866(1), 165580. doi:
10.1016/j.bbadis.2019.165580
Squire, L. R. (2009). Encyclopedia of neuroscience.
Amsterdam: Elsevier, Acad. Press.

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