A Bioinformatics Investigation of Genetic Mutations
Causing Alzheimer’s Disease

Dannielle Skander

Introduction
Alzheimer’s disease is a devastating disease that is estimated to affect more
than 5 million Americans currently1. It is estimated to effect approximately 47 million
people worldwide, only to have this number continue to increase to 76 million by 20302.
Alzheimer’s disease is most common in Western Europe, with North America falling
close behind, and is least common in Africa3. In this thesis study, I will be examining
various genetic risk factors associated with Alzheimer’s disease and their prevalence in
different populations.
Cost of Alzheimer’s disease to Society
Alzheimer’s disease is the most expensive disease in America, costing more
than cancer and heart disease4. The cost of caring for patients in 2016 was
approximately $236 billion3. The global cost is about $604 billion2 but is estimated to
increase to $1.1 trillion by 20501. In addition to the costs of society, caregivers also
have a huge cost. Caregivers spend approximately $9.7 billion of their own in extra
health care costs for their patient. They give around 17.9 billion hours of unpaid care3
and these hours value over $230 billion1. Patients with Alzheimer ’s disease, in the last
five years of life, spend much more than patients with cancer or heart disease. On
average, they spend approximately $111,000 more4. The cost to society, the patients
and the caregivers will continue to rise as more people develop Alzheimer’s disease.

Avg Spent in Millions of Dollars

Average Money Spent by Patient Yearly
350
300

287

250

175

200

173

150
100
50
0
Alzheimer's

Heart Disease

Cancer

Condition

5

Figure 1: Average money spent by patients having Alzheimer’s, heart disease and cancer .

The history of Alzheimer’s disease
Alzheimer’s disease was discovered by Alois Azheimer in 19066. Alzheimer was
a psychiatrist and neuroanatomist during his time working at the Frankfurt Psychiatric
Hospital. He discovered Alzheimer’s disease after he observed one of his patients,
Auguste D7. She was well until March 1901 when her husband said she developed
paranoia and started having difficulties handling money and remembering things8. This
patient also developed some personality changes6. When Alois Alzheimer observed
her, he said she had severely impaired recall memory and could not recall something
she had just said moments before8. After her death, Alzheimer was able do to an
autopsy using some brain material. He discovered changes in cell and tissue structures
in the brain, which are now known as plaques and neurofibrillary tangles9. Another one
of the patients, Josef F, was diagnosed with Alzheimer’s upon his death. When
Alzheimer looked at the brain, he found only plaques and no neurofibrillary tangles.

Alzheimer diagnosed both patients, among others, with Alzheimer’s despite the slight
difference in brain material. In later years, scientists and doctors have reexamined the
patient’s brain material and found that Alzheimer was correct in diagnosing them both
patients with the disease. Scientists determined that the difference in brain alterations
found was due to the development of the disease7.
When Dr. Alzheimer did an autopsy on his patient, he noticed shrinkage and
abnormal deposits around the neurons6. After significant technological and scientific
advances, scientists were able to study the brain of Alzheimer’s patients in much more
detail than before. In 1984, the plaques Dr. Alzheimer noted were found to be beta
amyloid protein plaques. A few years later in 1986 scientists found out that the tangles
were made of the tau protein7 . These will be discussed below.

Figure 2: Picture of a healthy brain vs. a brain with Alzheimer’s Disease
Changes, Alzheimer's Association, 2011

10

obtained by More Brain

Pathophysiology of Alzheimer’s disease
Alzheimer’s is a devastating irreversible disease affecting neurons in the brain.
The damage normally starts in the hippocampus, which is very important for memory
formation, and spreads from there. The connections between neurons will weaken and
because of this, the neurons will eventually die. As described above, the disease is
characterized by plaques, made of the amyloid protein, and neurofibrillary tangles,
consisting of the tau protein, in the brain. The amount of the tau protein found in the
neurofibrillary tangles is proportionate to the degree of memory loss a patient
experiences. Scientists are not certain about the exact function the amyloid plaques
play, but they believe that the high concentration of plaques found on the hippocampus
and cerebral cortex in Alzheimer’s patients plays a role in the neuronal degenerative
process11 Figure 2 illustrates the tangles and plaques that are found in the brain of a
patient with Alzheimer’s disease.

Figure 3: Brain plaques and tangles. Left side is a normal brain and the right side is the amyloid plaques
12

and neurofibirillary tangles found in the brain of an Alzheimer’s patient . Picture obtained by BrightFocus
Foundation.

Activated glial cells surround the amyloid plaques in diseased patients; these
cells are responsible for secreting a large amount of inflammatory molecules, such as
pro-inflammatory cytokines, chemokines, and reactive oxygen species (ROS)13. The
molecules released impair the normal neurophysiologic conditions, causing problems
relating to cognition, learning and memory. Other biological processes, such as
dysfunction of lysosomal/proteasomal degredation, mitochondrial dysfunction and
oxidative stress, have been associated with the disease 14.
This is a progressive disease, which means that as the disease progresses
through the brain, the symptoms and damage done keep worsening. The most common
symptom is memory loss11. Some other symptoms in addition to memory loss are
personality and behavioral changes, impaired judgement, wandering, paranoia and
language problems9. The symptoms may not be experienced by all patients and if
experienced, may not be experienced to the same degree.
One hypothesis about the pathogenesis of the disease is the amyloid cascade
hypothesis. This hypothesis describes the cleavage of the amyloid precursor protein
(APP) which leads to overproduction, oligomerization, and later the deposition of the
amyloid beta protein aggregates in the central nervous system15. The oligomerization is
amyloid beta (A!) is thought to initiate the sequence of events that cause the
degeneration of neuronal synapses. This degeneration causes inflammation and the
death of many neurons.
T Lymphocytes are thought to play an important role in the neuroinflammatory
processes of Alzheimer’s. There are increased levels of peripheral T cells in
postmortem brains of patients when compared to brain tissue from other

neurodegenerative diseases. While scientists believe T cells play a role, they cannot yet
tell if it is a damaging or helping affect. T cells specific for A!1-40 are found in healthy
individuals but T cells specific for A!1-42 are found in individuals with the disease15.
Genes associated with Alzheimer’s disease
There are two categories of Alzheimer’s disease, early onset and late onset.
Early onset happens earlier in life and is believed to be caused by genetic mutations.
Patients that are diagnosed with early onset Alzheimer’s may also experience
myoclonus, which is muscle twitching and spasm 16. Late onset Alzheimer’s typically
occurs after the age of 65 and is not definitely known to be caused by genetic
mutations, although there are genetic risk factors involved. Three genes have been
identified to date that, when mutated, can cause early-onset Alzheimer’s disease. These
genes are Presenilin 1, presenilin 2, and apolipoprotein E.
The normal functions of presenilin 1 (PSN1) include autophagy, maintenance of
calcium homeostasis and the meditation of correct interactions between the
endoplasmic reticulum and mitochondria 17. PSN 1 also has functions concerning the
amyloid protein. The amyloid plaques that are characteristic of Alzheimer’s disease are
formed by the accumulation of amyloid-beta, a neurotoxin that is produced by the
breakage of amyloid-beta precursor protein (APP) 18. Presenilin 1 induces this breakage
when the gene is mutated. Inheriting a mutation in the presenilin 1 (PSN1) gene
guarantees that a person will develop Alzheimer’s disease.
A deficiency of presenilin 2 (PSN 2) is associated with inflammatory effects in
microglia 19. When neuroinflammation of microglia occurs, neurotoxic and

neuroprotective consequences occur to the central nervous system. Scientists believe
that the loss of PSN 2 functions contribute to the inflammatory characteristics of
Alzheimer’s disease. A mutation in the presenilin 2 (PSN2) gene gives a 95% chance of
developing the disease20. Both PSN1 and PSN 2 genes also code for proteolytic
enzymes that cleave APP into the amyloid-beta and other fragments, hence why there
is a build up when there is a mutation in the genes 14.
The last gene scientists know to be associated with Alzheimer’s disease is the
apolipoprotein E (ApoE) gene21. There are three forms of the gene that a person can
inherit, namely, the e2, e3, and e4 forms. The e4 form gives the person the highest
chance of developing Alzheimer’s 20. If a person inherits only one copy, they are three
times as highly (compared to e3) to develop the disease but if they inherit two copies,
their chances increase eight to twelve fold. The most prevalent genetic risk factor for the
disease is the e4 allele of the gene22. The functions of the gene include lipid transport
throughout the body and damaged tissue repair23. The gene also plays a role in
neuronal development and plasticity and has an effect on the nutrient intake
conditions24.
There have been a multitude of other studies conducted on genes possibly
associated with late-onset Alzheimer’s disease. Several of the genes identified,
including CDK5, LMO4, PTEN and TGFβ 1, increase the abnormal protein aggregation
and other characteristics consistent with that of the disease 14. These are similar to the
effects seen with mutations in ApoE. A further nine genes that are important for the
pathology of Alzheimer’s disease were identified in 2016. These 9 new loci involve the

genes ABCA7, BIN1, CASS4, CD33, MEF2C, MS4A6A, PICALM, SORL1 and
ZCWPW114.
Prognosis
Alzheimer’s disease starts to become noticeable around age 65. The difference
in average life expectancies between different populations will have an effect on the
number of individuals that live to express the disease. Africa, where the average life
expectancy is only 51, may not see as much of the disease because the people are not
living to an age where symptoms become noticeable (Figure 4). The life expectancy will
be taken into account when considering the prevalence of Alzheimer’s disease in the
different populations included in this study.

Life Expectancies
81

75

79
68

Years

51

EAS

EUR

AFR

AMR

SAS

Populations

25

Figure 4: Average life expectancies of different populations . EAS-Eastern Asia; EUR-Europe, AFRAfrica, AMR-America, SAS-Southern Asia

There is currently no treatment for Alzheimer’s disease. There is a lack of
knowledge about the disease and a lack of early Alzheimer’s disease biomarkers, which
together hinders the treatment of the disease15. When treatments are introduced, the
disease has already spread enough throughout the brain to interfere with daily tasks.
Doctors can prescribe drugs that slow down the progression of the disease, but the
efficacy of the drug may vary between patients. Other drugs that doctors prescribe deal
with the symptoms that patients have, such as for their sleeping and anxiety problems.

Methods
Dataset: Genetic information was obtained from the dbSNP Short Genetic
Variation database at the National Center for Biotechnology Information. Data was
collected on single nucleotide polymorphisms (SNPs) within the presenilin 1 (PSN1),
presenilin 2 (PSN2), and apolipoprotein E (ApoE) genes.
Analysis: Each SNP allele was categorized according to the effects that they
had on protein function and disease phenotype, and those most likely to result in
disease were chosen for further study. Frequency data was obtained for each SNP
allele, and the Hardy Weinberg equation (p2+2pq+q2) was used to calculate the
percentage of people estimated to have the mutation. This was calculated for different
sub-populations (EAS-Eastern Asia; EUR-Europe, AFR-Africa, AMR-America, SASSouthern Asia), where data was available. Data on the current number of individuals
living in each population was obtained (Worldometers.info), as well as the percentage of
the population over 65 (data.worldbank.org), and these were used to calculate the
predicted number of affected individuals in each population.

Results
Presenilin 1, presenilin 2 and apolipoprotein E were the three genes chosen for
this study. A database search was performed to identify genetic variation (SNPs) within
the genes, and SNP frequencies in different populations. When the NCBI database was
searched for presenilin 2 mutations for Homo sapiens was searched, no results were
found. For this reason, Presenilin 2 was left out of the research.
When looking at the NCBI database, the results were limited to Homo sapiens.
The results were further limited to missense, nonsense and frameshift mutations,
excluding synonymous mutations. In synonymous mutations there is a single nucleotide
change but the change does not affect the amino acid produced. A missense mutation
is a mutation where one nucleotide is changed, changing the amino acid produced but
not affecting the rest of the protein, while a nonsense mutation is a mutation in which a
single nucleotide change created a stop codon, causing the rest of the protein sequence
to be lost. In frameshift mutations, one nucleotide is added or deleted so the rest of the
nucleotides shift over, thus changing the entire protein from that point on. The hits
focused on were the ones that had any clinical significance and the ones that produced
data for different populations, Eastern Asia (EAS), Europe (EUR), Africa (AFR), America
(AMR) and Southern Asia (SAS). Data was also collected on the number of individuals
in each population, as well as the number of individual over 65, the age at which
Alzheimer’s typically appears.
The Hardy Weinberg equation, p2+2pq+q2, was used to calculate the expected
frequency of the genetic mutation. The equation describes and predicts genotype
frequencies given a specific allele frequency. P is the variable used for the dominant

allele and q is for the recessive allele. The p2 term describes the homozygous dominant
individuals, the 2pq is the heterozygous individuals and the q2 is the homozygous
recessive individuals. Only the first section, p2+2pq was used because this disease is
dominant. This frequency was multiplied by the current number of individuals in the
population to get the projected number of individuals that have the mutation (Figure 6
and 7, blue bars). To get a better estimate of the number of people in each population
with Alzheimer’s disease, I multiplied the projected number of people by the percentage
of individuals in each population living over 65 (Figure 6 and 7, orange bars). The life
expectancy factor decreased the amount of people having the disease because most
people will not be living to an age where the symptoms become prevalent.
The total number of individuals with each mutation is an upper bound estimate.
The formula P(A∩B∩C) less then or equal to P(A)+P(B)+P(C)-P(A ∩C)-P(A ∩B)P(B ∩C)+P(A ∩B ∩C) is used to calculate the exact number of individual with the

mutations. Because we do not have enough on the likelihood that a patient has another
genetic mutation on top of the one they already have, we cannot go any further then the
upper bound estimate. This estimate is the most amount of people that will have the
mutation. We assume that because the genetic mutations are not exclusive, this
number will be smaller.

Figure 5: Venn Diagram showing the intersection of (A ∩B ∩C)

ApoE:
I identified 240 SNPs in the ApoE gene. Of these many were excluded, because they
were synonymous mutations and would not affect the protein produced, and 35 nonsynonymous (missense, non-sense, frameshift) mutations were chosen for further
study.

ApoE mutation & life expectancy
# of people affected millions

597.7
600
500
400

287.5

300
200

27.7

100
0

217.4
41.7

23

76.4

12.3 11 0.594

# affect (hardy weinberg)

EAS
287.5

EUR
217.4

AFR
597.7

AMR
76.4

SAS
11

# affected after life expectancy

27.7

41.7

23

12.3

0.594

population
# affect (hardy weinberg)

# affected after life expectancy

Figure 6: The number of individuals having the Apo E mutation that will be affected after life expectancy is
taken into consideration

The ApoE mutation is expected to affect 104,306,378.6 individuals within the Eastern
Asia, Europe, Africa, America and Southern Asia populations. The number of individuals
affected by the mutation significantly drops once life expectancy is introduced as a
variable.

Table 1: The exact number of individuals expected to have Alzheimer’s in each population after life
expectancy is introduced.

ApoE Mutation (population)
Population
EAS
EUR
AFR
AMR
SAS
TOTAL

Number of people with Alzheimer’s
27,654,193.53
41,716,996.54
23,041,663.99
11,299,062.9
594,461.6691
104,306,378.7

All of the known pathogenic mutations for Apo E were gathered from the database.
Allele frequencies were given and used to calculate the expected frequency of affected
individuals (homozygous dominant and heterozygous, from the Hardy-Weinberg
equation) for the given population. Table 2 is the frequency of each mutation for the
world population for the pathogenic cases. Only pathogenic cases were analyzed for
table 2.

Table 2: The frequencies for all Apo E mutation data found for aggregated populations

Frequencies for Apo E mutations with aggregated populations
Mutation number
Frequency
1
0.001648%
2
0.003294%
3
0.003560%
4
0.008859%
5
0.086159%
6
0.039966%
7
0.020089%

PSN 1:
I identified 209 SNPs in the PSN1 gene. Of these many were excluded, because they
were synonymous mutations and would not affect the protein produced, and 15 nonsynonymous (missense, non-sense, frameshift) mutations were chosen for further
study.

# of people affected in millions

PSN1 Mutation & Life Expectancy
30
25
20

10.3

15
10

2.5

5
0

# affect (hardy weinberg)
# affected after life
expectancy

25.9

2

0 0

4.1

5.1
0.61

0.276

EAS
25.9

EUR
10.3

AFR
0

AMR
4.1

SAS
5.1

2.5

2

0

0.61

0.276

population
# affect (hardy weinberg)

# affected after life expectancy

Figure 7: the number of individuals having the PSN1 mutation that will be affected after life expectancy is
taken into consideration

The PSN1 mutation is expected to affect 5,362,974.684 individuals within the Eastern
Asia, Europe, America and Southern Asia populations. There are no individuals in the
African population affected by mutations in the PSN 1 gene. The number of individuals

affected by the mutation significantly drops once life expectancy is introduced as a
variable.
Table 3: The exact number of individuals expected to have Alzheimer’s in each population after life
expectancy is introduced

PSN1 Mutation (after life expectancy)
Population
EAS
EUR
AFR
AMR
SAS
Total

Number of people with Alzheimer’s
2,493,154.959
1,982,707.613
0
610,297.185
276,814.9267
5,362,974.684

All of the known pathogenic mutations for PSN1 were gathered from the database.
Allele frequencies were given and used to calculate the Hardy Weinberg frequency for
the given population. Table 4 is the frequency of each mutation for the world population
for the pathogenic cases. Only pathogenic cases were analyzed for table 4.

Table 4: The frequencies for all PSN1 mutation data found for aggregated

Frequencies for PSN1 mutations with aggregated populations
Mutation number
Frequency
1
0.003294%
2
0.001648%

Discussion
I project that the ApoE mutation will affect approximately 104,306,378.7
individuals and the PSN1 mutation will affect approximately 5,362,974.684 individuals
across the nation. The total number of individuals I project that will be affected by either
of these mutations is 109,669,353.4. This number is based on the current world
population and will fluctuate with the change in world population. This approximation of
109 is an upper bound estimate of the number of individuals having Alzheimer’s. The
109 million is based on the assumption that each person in the world can only have one
mutation causing the disease, which we know is not true. For example, person A could
have three mutations that cause Alzheimer’s but in my data, I am considering her as 3
different people with the disease because of her three mutations. This projection is also
assuming that every missense, nonsense and frameshift mutation is pathogenic, which
might not be the case. Depending on where the mutation occurs on the protein, it may
or may not have a pathogenic effect. Current literature estimates that there will be 76
million people worldly having the disease2. This is significantly smaller than my
projection, most likely due to my estimate being an upper bound and assuming every
mutation to be pathogenic.
The individuals that comprise each population in the database could also skew
the data. It is unlikely that the sampling is completely random so it may not be sampling
every population equally. The African population is seeing a zero frequency for one
mutation which could be caused by the lack of resources in this area. There may be
only a small number of individuals capable of getting their genome sequenced, so the

sample may not accurately represent the genetic variation present in the entire
population.
Current literature shows Europe having the highest prevalency of Alzhiemer’s
with America following behind3. My data supports Europe having the highest but does
not support America being in second. According to the data I produced, Eastern Asia
would be the second. I would expect that Southern Asia and Africa would not spend as
much time, money or resources on Alzheimer’s disease research than Europe, America
or Eastern Asia would. After life expectancy was factored in, the number of individuals
dropped significantly for Eastern Asia and Africa. If the health care improves in these
parts of the world, they should see an increase in the life expectancies. If these life
expectancies increase to about 65, they will see much more people with the disease. At
that time, I would expect Eastern Asia and Africa to spend more resources and time on
the disease.
Natural selection is the differential reproduction of genotypes. It unlikely to have
been taking place for any mutations in PSN1 or ApoE for any population, given that
Alzheimer’s is a relatively recent finding, first identified only in 1906. The symptoms of
the disease occur later in life, after a reproductive age. While natural selection is
probably not happening, selection might be; selection here being the choosing whether
to reproduce or not. People are now getting to see their parents and grandparent
develop the disease because the life expectancies are much better than they used to
be. Seeing this, people might choose to get genetic testing done to see if they have a
mutation in PSN1, PSN2, or ApoE.

One problematic issue with Alzheimer’s disease is that there is no cure, but the
treatment would need to start years before symptoms become noticeable. Classical
gene therapy is when scientists are able to delete an entire gene out of the DNA. This
would not be beneficial to patients with Alzheimer’s because the genes that cause the
disease have very important functions. If the gene was lost, the patient could have a
multitude of other problems. One possible future treatment could be the CRISPR
technology. CRISPR uses a protein, CAS 9, and guide RNA to edit genes26. The protein
and guide RNA go into the DNA, find the mutated section of DNA, remove the damaged
part and replace with the correct set. The benefit to this is that the genes are not
completely lost, and therefore, do not lose their entire function.
Alzheimer’s disease currently costs the nation a total of $604 billion2,
which isn’t including the $9.7 billion extra that families pay for care takers and other
health costs3. Because the number of patients with the disease are expected to
increase, so is the cost to the nation. The cost is estimated to be about $1.1 trillion by
20501 if the prevalence does not decrease. The nation, especially regions such as
eastern Asia and Europe, needs to increase their efforts on finding a cure for the
disease. Specifically, I believe the focus should be more on the ApoE gene because it
affects a significantly higher amount of people across the nation. A cure would
significantly help decrease the amount of people having the disease and consequently,
the cost to society.

Function
frame shift
missense
frame shift
missense
nonsense
nonsense
frame shift

Appendix. Data Tables
Allele
GG
C
G
G
T
A

"correct" allele
G
G
A
T
C
-

Amino
Glu
Arg
lle
Ser
Ser

"correct" amino codon position amino position A
Val
2
288
Gly
1
280 NA
Asp
3
232 NA
Asn
2
229 NA
Tyr
3
220 NA
Gln
1
216
Ala
3
168 NA

Results from PSN1, pathogenic group

T
C
G
(GG)0.00001647
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
0.00000824 0.99999177
NA
NA
NA

population
0.99998355 ExAc aggregated
NA
NA
NA
NA
NA
NA
NA
NA
ExAc aggregated
NA

NA

p2+2pq
0.003294%
NA
NA
NA
NA
0.001648%
NA

33015753

33015729

868 rs142248153

903 rs543405986

927 rs576075856

missense

missense

missense

G

A

G

A

G

A

Ser

Arg

Val

Asn

Gly

Met

2

1

1

264

276

284

"correct"
"correct codon amino
allele allele
amino " amino position position A
G
A
Ser
Asn
2
329

33015788

Chromosome mRNA
Clinical
position position Cluster ID Sig
Function
33014755
1063 rs534306255
missense

Results for PSN 1 population, part 1

T
C
G
1
0
1
0
1
0
0.99859995
0.0014
1
0
0.99997526 0.00002471
1
0
1
0
1
0
0.99859995
0.0014
1
0
0.99998355 0.00001647
0
1
0
1
0
1
0
1
0.001 0.99899995
0.00000824 0.99999177
1
0
0.99900001
0.001
1
0
1
0
1
0
0.99995881 0.00004118

- Population
EAS
EUR
AFR
AMR
SAS
ExAc aggregated
EAS
EUR
AFR
AMR
SAS
ExAc aggregated
EAS
EUR
AFR
AMR
SAS
ExAc aggregated
EAS
EUR
AFR
AMR
SAS
ExAc aggregated

% of
population factor life
p2+2pq
expectancy
# of pop
# affected over 65
0 1623153468
0
9.62%
0
0 739107476
0
19.19%
0
0 1237666164
0
3.86%
0
0.279804% 362456416 1014167.55
14.79% 149995.38
0 63688069
0
5.42%
0
0.004942%
0 1623153468
0
0
0 739107476
0
0
0 1237666164
0
0
0.279804% 362456416 1014167.55
149995.38
0 63688069
0
0
0.003294%
0 1623153468
0
0
0 739107476
0
0
0 1237666164
0
0
0 362456416
0
0
0.19990% 63688069 127312.45
6899.0617
0.001648%
0 1623153468
0
0
0.1999% 739107476 1477475.84
283527.614
0 1237666164
0
0
0 362456416
0
0
0 63688069
0
0
0.008236%

33017588

33017523

33017477

33015703

636 rs186325627

701 rs546177345

747 rs181671227

953 rs72555746

missense

synonymous C

missense

C

A

synonymous A

A

T

G

G

His

Asp

Ile

Gly

Asn

Asp

Val

Gly

Results for PSN 1 population, part 2
3

292
0.002
0.004
0
0.0029
0.0399
0.00762692
0.00265487
0.0025

208 0.99900001
1
1
1
1
0.99999177

224

3

187

1

1

0.005
0.995
0
1
0
1
0
1
0
1
0.00013178 0.99986821

1
0.99799997
1
1
1
0.99998355

0.99800003
0.99599999
1
0.99710006
0.9601
0.99237305
0.99734515
0.9975

0.001
0
0
0
0
0.00000824
0
0.002
0
0
0
0.00001647

EAS
EUR
AFR
AMR
SAS
ExAc aggregated
ESP Cohort
CSAgilent
EAS
EUR
AFR
AMR
SAS
ExAc aggregated
EAS
EUR
AFR
AMR
SAS
ExAc aggregated
EAS
EUR
AFR
AMR
SAS
ExAc aggregated

0.3996%
0.7984%
0
0.579159%
7.82080%
1.51957%
0.530269%
0.499375%
0.9975%
0
0
0
0
0.026354%
0.1999%
0
0
0
0

0
0.39960%
0
0
0
0.003294%

1623153468
0
739107476 2953473.47
1237666164
0
362456416
0
63688069
0

1623153468 3244683.78
739107476
0
1237666164
0
362456416
0
63688069
0

1623153468 16190955.8
739107476
0
1237666164
0
362456416
0
63688069
0

1623153468 6486121.26
739107476 5901034.09
1237666164
0
362456416 2099198.95
63688069 4980916.5

0
566771.559
0
0
0

312073.686
0
0
0
0

1557246.13
0
0
0
0

623835.143
1132408.44
0
310387.557
269915.865

Chromosome position mRNA Position Cluster ID

Clinical Sig

G

Lys

Gly

1

21

# affected

0

# of pop

0

p2+2pq

0.1999%

739107476

0

Population

EAS

0

1237666164

0

-

0.99900001

EUR

0

362456416

0

G

1

AFR

0

63688069

C
0.001

1

AMR

0

T
0

1

SAS

0

1623153468 3244683.78
0

1

739107476

1623153468

Function allele "correct" allele amino "correct" amino codon position amino position A
missense A

0

0.99993408

0

177 rs121918392 pathogenic; Alzheimer's disease, hyperlipoproteinemia type 3, liboprotein, glomerulopathy, sea blue histocyte disease

0

EAS

44907777

0.00006592

1

ExAc Aggregated 0.013184%
0

1

242

228 NA

151

0.0000443 0.99995571

0.00003747

31

2

246

1

0

Leu

2

Glu

0

0

Trp

1

Lys

0.79840%

1237666164

0

Met

Pro

G

207 rs201672011 pathogenic; Alzheimer's disease, hyperlipoproteinemia type 3, liboprotein, glomerulopathy, sea blue histocyte disease

EAS

0

63688069

362456416

-

Arg

missense A

44907807

1237666164 19866027.1

EUR

0

0

0

AFR

0

63688069

0

ExAc Aggregated 0.029646%
1

0.004

AMR

0
0.99599999

0

SAS

ExAc Aggregated 0.001648%

1

0

C

Gln

0.7321997

0.0869

0.1037

0.2678

0.8449001 0.15509999

ExAc Aggregated

SAS

AMR

AFR

EUR

EAS

19.0418%

16.6248%

19.6646%

46.3883%

28.6144%

16.5152%

362456416 71275604.4

1237666164

739107476

1623153468

574132293

211491170

268067042

63688069 10588014.1

0.9131

NA

ExAc Aggregated 0.008859%

ExAc Aggregated ?????

NA NA

ExAc Aggregated 0.003560%

0.89630002

NA

0.99998218

0.89976752 0.10023248
NA

0.99996251

NA

739107476 5901034.09
1

0

ExAc Aggregated 0.480436%

1

0.99759495 0.00240507

1.29577%

0.265310%

G

Cys

ExAc Aggregated 0.003294%

ESP Cohort

44908601

480 rs587778876 untested, major depressive disorder, unipolar depression, seasonal affective disorder

missense A

C

0.00001647

CSAgilent

44908645

504 rs429358

nonsense A

C

ExAc Aggregated ??????

0.0065

44908660

567 rs587778877 untested, major depressive disorder, unipolar depression, seasonal affective disorder

missense A

0.00000824

0.99867254 0.00132743

44908684

799 rs121918396 pathogenic; Alzheimer's disease, hyperlipoproteinemia type 3, liboprotein, glomerulopathy, sea blue histocyte disease

missense T

0.99349999

44908747

841 rs267606663 pathogenic; Alzheimer's disease, hyperlipoproteinemia type 3, liboprotein, glomerulopathy, sea blue histocyte disease

0.99999177

44908979

852 rs121918395 pathogenic; Alzheimer's disease, hyperlipoproteinemia type 3, liboprotein, glomerulopathy, sea blue histocyte disease

0.0863

44909021

pathogenic; Alzheimer's disease, hyperlipoproteinemia type 3, liboprotein, glomerulopathy, sea blue histocyte disease

44909032

0.0000178

1623153468

1.60512%

NA

EUR

NA NA

AFR

NA

1

46

143

NA

0.99919999

1

60 0.99998355
NA

0

2

102

0.008

Arg

1

117 NA

362456416 2099198.95

Leu

2

NA

0
Cys

Thr

1

NA NA

0.579159%

Pro

Pro

NA

AMR

C

Ala

Ala

NA

SAS

T

Gln

NA

0.997100006

missense T

A

Thr

122 NA

0.91369998

0.0029

missense C

C

1

130

1

pathogenic; Alzheimer's disease, hyperlipoproteinemia type 3, liboprotein, glomerulopathy, sea blue histocyte disease

243 rs121918399 pathogenic; Alzheimer's disease, hyperlipoproteinemia type 3, liboprotein, glomerulopathy, sea blue histocyte disease

missense G

G

Leu

1

0.9995817

253 rs769452

missense A

Met

Cys

0
44907843

294 rs28931576 pathogenic; Alzheimer's disease, hyperlipoproteinemia type 3, liboprotein, glomerulopathy, sea blue histocyte disease

missense A

C

Arg

0.00014828
44907853

421 rs11083750 other, Alzheimer's disease, hyperlipoproteinemia type 3, lipoprotein glomerulopathy, sea blue histocyte disease

missense A

T

0.00000824 0.99999177

44907894

465 rs28931577 pathogenic; Alzheimer's disease, hyperlipoproteinemia type 3, liboprotein, glomerulopathy, sea blue histocyte disease

missense C

Results from Apo E pathogenic, part 1

0

0

ExAc Aggregated 0.086159%

0.59910%

739107476

0

254 0.00043089 0.99956912

0

1237666164

0

2

EAS

0

63688069

362456416

Val

EUR

0

Glu

0.99700004

AFR

0

T

1

AMR

missense A

0.003

1

SAS

877 rs199768005 pathogenic; Alzheimer's disease, hyperlipoproteinemia type 3, liboprotein, glomerulopathy, sea blue histocyte disease

0

1

ExAc Aggregated 0.031669%

44909057

0

1

0

1623153468 9724312.43

0

0.99984163

0.59910%

262

0

EAS

1

0.00015836

0.99700004

EAS

4.93750%

0

0

739107476

1623153468

0

0

1623153468 9724312.43

0.003

Glu

263

Lys

1

G

Glu

0

missense A

Lys

739107476

900 rs140808909 pathogenic; Alzheimer's disease, hyperlipoproteinemia type 3, liboprotein, glomerulopathy, sea blue histocyte disease

G

0

44909080

missense A

EUR

903 rs190853081 pathogenic; Alzheimer's disease, hyperlipoproteinemia type 3, liboprotein, glomerulopathy, sea blue histocyte disease

1

0

44909083

0

1237666164

269

NA NA
NA
ExAc Aggregated 0.020089%

1

EUR

NA NA
NA
ExAc Aggregated ?????
0

AFR

1237666164 61109766.8

1

0.025 0.97499996

0

362456416 4192315.89

63688069

0

1.15664%

308983494

AMR

1623153468

SAS

739107476 89602738.4

1

19.0360%

1237666164

0

12.1231%

NA
NA

SAS
8.60640%
ExAc Aggregated 7.06637%
NA NA
NA

EAS

NA NA
NA NA

ExAc Aggregated 0.245369%
NA NA
NA

19.5212%

NA
NA

EUR

0.9370004

0.8998

AFR

362456416 33684597.1

NA
NA
0.0626

9.29342%

0.1002

0.1029 0.89709997

AMR

0.044 0.95600003
0.03597911 0.96402091
NA
NA
NA

63688069 5481249.97

241607287

0.0476 0.95239997

0.0058 0.99419999

0

NA
NA
NA
0.00003587 0.99996412

NA
NA
0.00010045

0

292 NA
NA
314 0.99989957

AFR

1

152 NA
154

1

2
1

163

0.0012276 0.99877238
NA
NA
NA

0

Arg

2
1

163 NA

NA
NA

0

Arg
Ser

1

164 NA
170 NA

63688069
Gly

Pro
Cys

2

176

362456416

His
Arg

Arg

1
1

0

C

Gln
Ser

Pro

1

0

G
A

Cys

Glu
Ala

AMR

missense G

C
T

His

Arg

SAS

921 rs267606661 pathogenic; Alzheimer's disease, hyperlipoproteinemia type 3, liboprotein, glomerulopathy, sea blue histocyte disease

missense A
missense C

C

Gln
Pro

1

991 rs121918398 pathogenic; Alzheimer's disease, hyperlipoproteinemia type 3, liboprotein, glomerulopathy, sea blue histocyte disease
1056 rs28931579 pathogenic; Alzheimer's disease, hyperlipoproteinemia type 3, liboprotein, glomerulopathy, sea blue histocyte disease

missense A
missense A

C

Cys

0

571 rs28931578 pathogenic; Alzheimer's disease, hyperlipoproteinemia type 3, liboprotein, glomerulopathy, sea blue histocyte disease
576 rs121918393 pathogenic; Alzheimer's disease, hyperlipoproteinemia type 3, liboprotein, glomerulopathy, sea blue histocyte disease

missense T

G
G

ExAc Aggregated 0.031663%

44909101

pathogenic; Alzheimer's disease, hyperlipoproteinemia type 3, liboprotein, glomerulopathy, sea blue histocyte disease

missense A

C

160 NA

1

44909171
44909236

603 rs769455

missense C
missense C

1

0

44908751
44908756

604 rs121918397 pathogenic; Alzheimer's disease, hyperlipoproteinemia type 3, liboprotein, glomerulopathy, sea blue histocyte disease

missense T

Arg

ExAc Aggregated 0.039966%
ExAc Aggregated ?????

44908783

pathogenic; Alzheimer's disease, hyperlipoproteinemia type 3, liboprotein, glomerulopathy, sea blue histocyte disease

606 rs121918394 pathogenic; Alzheimer's disease, hyperlipoproteinemia type 3, liboprotein, glomerulopathy, sea blue histocyte disease
624 rs267606662 pathogenic; Alzheimer's disease, hyperlipoproteinemia type 3, liboprotein, glomerulopathy, sea blue histocyte disease

Cys

0.99984169

44908784

642 rs7412

C

0.00019985

44908786
44908804

missense T

0.99980015
0.00000833 0.99999166

44908822

594 rs387906567 pathogenic, familial type 3 hyperlipoproteinemia

0.00015833

44908774

Results from Apo E pathogenic, part 2

44907777

44907768

44906664

207 rs201672011

177 rs121918392

168 rs533904656

159 rs559532612

chromosome mRNA
position
position Cluster ID
44906655
147 rs144354013

44907807

Clinical
"correct"
"correct" codon amino
Sig
position position A
Function allele allele
amino amino
T
C
G
missense G
A
Ala
Thr
1
11
1
0
1
0
1
0
0.99859995
0.0014
1
0
0.99995881 0.00004118
0.99998355
0.00001647
0.99900001
0.001
missense A
G
Thr
Ala
1
14
0
1
0
1
0
1
0.0014 0.99859995
0
1
missense A
G
Thr
Ala
1
18
0.003
0.99700004
0
1
0
1
0
1
0
1
0.00010714
0.99989283
0.00001649 0.99998349
pathogenic;
missense
Alzheimer's
A
disease,
G
hyperlipoproteinemia
Lys
Gly
type 3,
1 liboprotein,
21
glomerulopathy,
0.001
sea blue histocyte0.99900001
disease
0
1
0
1
0
1
0
1
0.00006592
0.99993408
pathogenic;
missense
Alzheimer's
A
disease,
G
hyperlipoproteinemia
Lys
Glu
type 3,
1 liboprotein,
31
glomerulopathy,
0
sea blue histocyte disease 1
0
1
0.008
0.99919999
0.0029
0.99710001
0
1
0.00014828
0.9995817

Results from Apo E population, part 1

population
EAS
EUR
AFR
AMR
SAS
ExAcAggregated
ExAcAggregated
CSAgilent
EAS
EUR
AFR
AMR
SAS
EAS
EUR
AFR
AMR
SAS
ExAcAggregated
ExAcAggregated
EAS
EUR
AFR
AMR
SAS
ExAc Aggregated
EAS
EUR
AFR
AMR
SAS
ExAc Aggregated

factor life
p2+2pq
pop #
# affected expectancy
?????
1623153468
?????
739107476
?????
1237666164
0.279804%
362456416 1014167.55 149954.814
????
63688069
?????
0.003294%
?????
0 1623153468
0
0
0
739107476
0
0
0 1237666164
0
0
0.279804%
362456416 1014167.55 149954.814
0
63688069
0
0
0.599100% 1623153468 9724312.43 935284.37
0
739107476
0
0
0 1237666164
0
0
0
362456416
0
0
0
63688069
0
0
0.021427%
??????
0.1999% 1623153468 3244683.78 312073.686
0
739107476
0
0
0 1237666164
0
0
0
362456416
0
0
0
63688069
0
0
0.013184%
0 1623153468
0
0
0
739107476
0
0
1.60512% 1237666164 19866027.1 765835.345
0.579159%
362456416 2099198.95 310387.557
0
63688069
0
0
0.029646%

44907853

44907908

44908542

44908592

44908684

253 rs769452
pathogenic;
missense
Alzheimer's
C
disease,
T
hyperlipoproteinemia
Pro
Leu
type 3,
2 liboprotein,
46
glomerulopathy, sea1blue histocyte
0 disease
0.99599999
0.004
1
0
1
0
1
0
0.99759495 0.00240507
0.99867254 0.00132743
0.99349999
0.0065
308 rs370594287
missense C
?
His
?
3
64
0.001 0.99900001
0
1
0
1
0
1
0.001 0.9989995
0.0014826 0.99985176
0.00000824
0.99999177
362 rs557845700
missense T
G
Ile
Met
3
82
0
1
0
1
0
1
0.0014
0.99859995
0
1
412 rs577618688
missense G
A
Arg
Gln
2
99
1
0
1
0
0.99849999
0.0015
1
0
1
0
0.99997526
0.00002471
504 rs429358
pathogenic;
missense
Alzheimer's
C
disease,
T
hyperlipoproteinemia
Arg
Cys
type 3,
1 liboprotein,
130
glomerulopathy,
0.91369998
sea blue histocyte
0.0863 disease
0.8449001 0.15509999
0.7321997
0.2678
0.89630002
0.1037
0.9131
0.0869
0.89976752 0.10023248

Results from Apo E population, part 2

EAS
EUR
AFR
AMR
SAS
ExAc Aggregated
ESP Cohort
CSAgilent
EAS
EUR
AFR
AMR
SAS
ExAc Aggregated
ExAc Aggregated
EAS
EUR
AFR
AMR
SAS
EAS
EUR
AFR
AMR
SAS
ExAc Aggregated
EAS
EUR
AFR
AMR
SAS
ExAc Aggregated

0
0.79840%
0
0
0
0.480436%
0.265310%
1.29578%
0.1999%
0
0
0
0.19990%
0.296696%
?????
0
0
0
0.279804%
0
0
0
0.299775%
0
0
0.004942%
16.5152%
28.6140%
46.3883%
19.6646%
16.6248%
19.0418%

1623153468
0
0
739107476 5901034.09 1132408.44
1237666164
0
0
362456416
0
0
63688069
0
0

1623153468 3244683.78 312073.686
739107476
0
0
1237666164
0
0
362456416
0
0
63688069 127312.45 6899.0617

1623153468
0
0
739107476
0
0
1237666164
0
0
362456416 1014167.55 149954.814
63688069
0
0
1623153468
0
0
739107476
0
0
1237666164 3710213.74 143028.74
362456416
0
0
63688069
0
0

1623153468 268067042 25782688.1
739107476 211488213 40584588.1
1237666164 574132293 22132799.9
362456416 71275604.4 10538810.9
63688069 10588014.1 573764.484

44908750

44908708

44908705

44908690

570 rs531939919

528 rs543363163

525 rs573658040

510 rs11542041

missense T

missense A

missense T

missense A

C

G

C

T

Trp

Ser

Cys

Ser

Arg

Gly

Arg

Cys

1

1

1

1

Results from Apo E population, part 3
132

137

138

152

0.001
0
0
0
0
0.0000088

0
1
0
1
0.0008 0.99919999
0
1
0
1
0.0000174 0.9999826
0
1
0
1
0
1
0
1
0.001 0.99899995
0.0000176 0.99998242

0
1
0
1
0
1
0
1
0.001 0.99899995
0.0000178 0.99998218

0.99900001
1
1
1
1
0.99999188

EAS
EUR
AFR
AMR
SAS
ExAc Aggregated
EAS
EUR
AFR
AMR
SAS
ExAc Aggregated
EAS
EUR
AFR
AMR
SAS
ExAc Aggregated
EAS
EUR
AFR
AMR
SAS
ExAc Aggregated

?????
?????
?????
?????
?????
?????
0
0
0
0
0.19990%
0.003520%
0.1999%
0
0
0
0
0.001760%
0
0
0
0
0.19990%
0.003560%

1623153468
739107476
1237666164
362456416
63688069

1623153468
739107476
1237666164
362456416
63688069

0
0
0
0
0
0
0
0
127312.45 6899.0617

0
0
0
0
0
0
0
0
127312.45 6899.0617

1623153468 3244683.78 312073.686
739107476
0
0
1237666164
0
0
362456416
0
0
63688069
0
0

1623153468
739107476
1237666164
362456416
63688069

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Alzheimer's Association. .
2. Alzheimer’s Association. (2014). Alzheimer's and Dementia: Global Resources.
Alzheimer's Association. .
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.
4. Alzheimer’s Association. (2017). Fact Sheet. Alzheimer's Association.
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5. Alzheimer’s Association. (2017). Fact Sheet: Costs of Alzheimer’s to Medicare
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7161>.
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.
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.
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