International Journal of Engineering and Advanced Research Technology (IJEART)
ISSN: 2454-9290, Volume-1, Issue-6, December 2015
Multifratal Analysis of the Pathogenesis of
Alzheimer Disease
Tong-han Lan, Zi-yang Lan, Xiao Li, Hao Cai, Fei fei Yu
AbstractIn this paper the fractal analysis method is
introduced to characterize the self-similarity of DNA sequences.
Using this method, four whole genomes of the pathogenesis of
Alzheimers Disease provided by NCBI are analyzed. the
pathogenesis of Alzheimers Disease were exhibited multifractal
characteristics when calculating the probability measure for
four difference the pathogenesis sequences of each base
indidually.From the results we find that Renyi dimension range
between 0.0090 to 3.5043. the multifractal characteristic
properties in the whole the pathogenesis of Alzheimers Disease
are verified. The results of this paper suggest that the the
multifractal characteristic property is one of the natural
properties that DNA sequences possess, and is directly related to
the structure and function of the whole DNA molecule.
Index Termsmutilfractal,pathogenesis of Alzheimers
Disease,Renyi dimension
I. INTRODUCTION
Alzheimers disease (AD) is the most common form of
dementia and the most frequent degenerative brain disorder
encountered in old age, The risk of developing AD
substantially increases after 65 years of age [1]. AD is quickly
becoming one of the major universal healthcare
problems.While the cause of this disease remains unknown,
there is evidence for substantial genetic influence [1]-[5].
With the unclear pathogenesis, several hypotheses about the
pathogenesis of AD, such as the Abnormal protein
hypothesis, cholinergic hypothesis, oxidative stress theory
and the estrogen hypothesis, etc. were proposed. Mutations in
three genes, a myloid precursorprote in ( APP ), presenilin 1
and 2( PSEN1 , PSEN2 ), result in an early onset, autosomal
dominant form of the disease beginning in the third or fourth
decade. The 4 allele of apolipoprotein E (APOE) increases
the risk of both sporadic and familial AD occurring later in
life around the sixth decade. Each of these genes is involved
in the production or processing of the amyloid peptide,
which is deposited in the brain as dense plaques that are
characteristic of the disease [3]. Today, however, there are
neither precise diagnostic approaches nor effective
therapeutic agents available for Alzheimer disease.
In the past decade or so there has been a ground swell of
interest in unraveling the mysteries of DNA. In order to
distinguish coding regions from non-coding ones, many
approaches have been proposed[6]-[11], at the same times,
the nonlinear scaling method, such as complexity(12)and
fractal analysis[13][17]were used. The wordfractal was
coined by Benoit Mandelbrot in the late 1970s,but objects
now defined as fractal in form have been known to artists and
mathematicians for centuries. Mandelbrots definition---a set
whose hausdorff dimension is not integeris clear in
13
mathematical terms. In addition, related concepts are those of
self-similarity and sub-divisibility. The length of the coastline
of Britain or the length of the perimeter of the Koch curve
increases as we measure it at finer spatial resolution.The use
of fractal analysis has been applied to many field[17].
The main purpose of this paper is to analyze the
pathogenesis of Alzheimer Disease by means of fratal
method.DNA research has previously focused on searching
for low level patterns directly visible within the
sequence,while ignoring high level patterns.The multifractal
analysis of the pathogenesis of Alzheimers Disease is
intended to demonstrate that a higer level of pattern
information may be availible within the the pathogenesis of
Alzheimers Disease[18].Thus the research has technically
significance.
This paper is divided into four parts: the first part is the
introduction of the pathogenesis of Alzheimer Disease and
DNA series analysis basic state; in the second part we briefly
review materials and the fratal method; the third and four part
are the results and discussion.
II. MATERIALS AND METHODS
A. Data Resources
We will use the tools of the World Wide Web to search the
GenBank DNA sequence database
(http://www.ncbi.nlm.nih.gov). Homo sapiens amyloid
beta (A4) precursor protein (APP), RefSeqGene on
chromosome 21(NCBI Reference Sequence: NG_007376.1,
GI:166795291); Homo sapiens apolipoprotein E (APOE),
RefSeqGene on chromosome 19(NCBI Reference Sequence:
NG_007084.2, GI:163954918); Mus musculus presenilin-1
gene, alternatively spliced transcripts, complete
cds,GenBank: AF007560.1, GI:2463667; Mus musculus
presenilin-2 gene,strain 129X1/SvJ chromosome 12
CRA_211000022007779, whole genome shotgun
sequence,GenBank: AAHY01101600.1, GI:69874353.
B. Mapping rule
n
A DNA sequence i (i=1,2,,L)of length L is comprised
a series of 4 types of base as follows: adenine(A); thymine(T);
guanine(G); and cytosine(C). In order to apply numerical
methods to nucleotide sequence, We can also use(-2,-1,1,2) to
replace {A,G,C,T},We expect it to reveal more information
than one dimensional DNA walk [19].
C. Fractal analysis
The use of fractal analysis has been applied to many
fields[Kins94],such as ion channel kinetics analysis etal,
Fractals are sets which exhibit self-similar properties at
different scales and are characterized by their fractal
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 Multifratal Analysis of the Pathogenesis of Alzheimer Disease

dimension. The wordfractal was coined by Benoit 1.0

80 0.8
Mandelbrot in the late 1970s,but objects now defined as 60
Brown noise
0.6

fractal in form have been known to artists and mathematicians 0.4

y(n)

y(n)
40
0.2
for centuries. Mandelbrots definition---a set whose 20
0.0
white noise
hausdorff dimension is not integeris clear in mathematical 0 -0.2

terms. In addition, related concepts are those of self-similarity 0 2000 4000

n
6000 8000 10000 4000 4400n 4800 5200

and sub-divisibility. The length of the coastline of Britain or Fig2.shown brown noise and white noise
the length of the perimeter of the Koch curve increases as we
measure it at finer spatial resolution.The use of fractal C. Calculation of probabilities
analysis has been applied to many field[19]-[21]. We can also use(-2,-1,1,2) to replace {A,G,C,T},The
approach implemented is to calculate the probabilities for
each individual base of the pathogenesis of Alzheimer
D. Multifractal Dimension
Disease separately,Fig 3 show the pathogenesis of Alzheimer
In practice,it is more useful to consider a signal as a Disease difference base at window 100 condition probability
multifractal, namely considering of more than one distribution.The results defer guass distribution.
fractal.Using Renyi dimension can provide comprehension of 20
apolipoprotein E
adenine(A) 20 apolipoprotein E
400
APP
600

500
window length 100 guanine(G) adenine(A)
window length 100
APP

complexity within the signal.The Renyi dimension is defined

guanine(G)
15 window length 100 window length 100
15 400

Number

number
300

Number
Number
10 300
10 200

as(1)[19].Where r is the volume element size,Nr is the 5

0
5 100

0
200

100

number of volume elements for a given volume element 0.10 0.20 0.30
probability
0.40 0.1 0.2 0.3
probability
0.4 0.5 0.0 0.1 0.2 0.3
probability
0.4 0.5 0.6 0.0 0.1 0.2 0.3
probability
0.4 0.5

size,Pj is the probability of occurrence within a given volume 30

25
apolipoprotein E
thymine(T)
window length 100
25

20
apolipoprotein E
cytosine(C)
window length 100
500
APP
cytosine(C) 400 APP
thymine(T)

element. The q value can be considered as a fractal dimension

window length 100
20 400

Number
window length 100

Number
15
300

Number

Number
15 300
10
10 200
200

index. 5 5
100

0
100

0
0.1 0.2 0.3 0.4 0.5 0.1 0.2 0.3 0.4 0.5
Nr probability probability 0.0 0.1 0.2 0.3
probability
0.4 0.1 0.2 0.3 0.4 0.5 0.6

log p
probability

q 80
presenilin-1
adenine(A)
80 presenilin-1
200

presenilin-2
250
presenilin-2
60 guanine(G) adenine(A) guanine(G)
j window length 100
60
window length 100 150 window length 100 200 window length 100

1
Number

Number

Number
j 1

Number
Dq lim
40 150
100
40
100
20 50

r 0 q 1
20
50

log r (1) 0.1 0.2 0.3

probability
0.4 0.5 0.1 0.2 0.3
probability
0.4
0
0.2 0.3
probability
0.4 0.5
0
0.10 0.20
probability
0.30

100
presenilin-1 250
80 presenilin-1
80 thymine(T) cytosine(C) presenilin-2
window length 100 window length 100 cytosine(C)
200 window length 100 presenilin-2
60 150
Number

Number
60 thymine(T)
window length 100

Number
150

III. RESULTS

Number
40 40 100
100
20 20 50
50

A useful way of analyzing patchiness arising from the 0.1 0.2 0.3 0.4
probability
0.5
0.1 0.2 0.3
probability
0.4 0.05 0.10 0.15 0.20 0.25
probability
0.30 0.35
0
0.1 0.2 0.3 0.4
probability
0.5 0.6

heterogeneous purine-pyrimidine content is DNA walk, Fig 3 show the pathogenesis of Alzheimer Disease
defined as above 2.2 mapping rulers. The displacement of difference base at window 100 condition probability
n
y ( n) u
i 1
i
contribution.
walker after n steps, y(n) is defined as and D. Estimating the multifractal dimension
will display on a graph of y(n) vs n .
We compute Renyi dimension for difference the
pathogenesis of Alzheimer Disease of the four bases.The
A. The characteristic of DNA walk results were shown as Fig 4. Renyi dimension for the amyloid
We find apparent patchiness in real DNA sequencesboth beta precursor protein (APP)between 0.0090 to 3.5043, Renyi
in the noncoding and coding regions. Figure1 shows a dimension for apolipoprotein E between0.0023 to 1.7731,
representative DNA walk for four different of the Renyi dimension for presenilin-1 gene between0.0028
pathogenesis of Alzheimer Disease DNA sequences. to2.6578 , Renyi dimension for presenilin-2 gene
amyloid beta
between0.0217 to 3.0965.
600 3 precursor protein
15x10
400 apolipoprotein E (APOE)
Y(n)

10 4
Y(n)

200 2
APOESERIES
3
amyloid beta (A4) precursor protein 1.5
0 5 2
1
y

-200
y

1
0 0.5

0
3
0 2 4 6 8 10x10
3 0 50 100 150 200 250x10 0
n n -1
5 -0.5
5
3000 5000 4 50
40 4 50
3 40
2500 presenilin-1 30 3 30
4000 presenilin-2 x 2
10
20
2 20
2000 1 q x 10
Y(n)

0 q
1 0
3000
Y(n)

1500
1000 2000
3
500 1000 presenilin1 4
2.5 presenilin2
0 0 2 3
3 3
0 10 20 30 40x10 0 20 40 n 60 80 100x10 1.5
n 2
y

1
y

1
Fig1. shows a representative DNA walk for four different 0.5

0 0

of the pathogenesis of Alzheimer Disease DNA sequences. -0.5

5 -1
5
4 50
40 4 50
3 30 40
3 30
2 20
x 10 x 2 20
q
1 0 10 q
1 0

B. The characteristic of brown noise and white noise Fig 4.shown Renyi dimension for difference the
We use simulation method and produce two series,namely pathogenesis of Alzheimer Disease
brown noise and white noise , The displacement of walker
after n steps y(n) is used, Fig2.shown brown noise and white E. After Sliding window compute multifractal dimension
noise walker. Multifractal characteristic of {A,G,C,T}computed over

14 www.ijeart.com
 International Journal of Engineering and Advanced Research Technology (IJEART)
ISSN: 2454-9290, Volume-1, Issue-6, December 2015
100 moving windows with a window size of 128 and offset of promote transcriptional activation, while others form the
1 was shown in Fig.5 for the amyloid beta precursor protein protein basis of the amyloid plaques found in the brains of
(APP), Multifractal value of A between 0.0357 to 1.0883, patients with Alzheimer disease. Mutations in this gene have
Multifractal value of G between 0.0345 to1.1860, been implicated in autosomal dominant Alzheimer disease
Multifractal value of C between 0.0245 to 0.9557, and cerebroarterial amyloidosis. Multiple transcript variants
Multifractal value of T between 0.0220 to 1.1364.The encoding several different isoforms have been found for this
similary apolipoprotein E presenilin-1 gene and gene[22].Chylomicron remnants and very low density
presenilin-2 gene of Multifractal characteristic of {A,G,C,T} lipoprotein (VLDL) remnants are rapidly removed from the
can be computed. circulation by receptor-mediated endocytosis in the liver.
Multifractal characteristic of A
Multifractal characteristic of G Apolipoprotein E, a main apoprotein of the chylomicron,
0.2
0.4
binds to a specific receptor on liver cells and peripheral
0

-0.2
0.2 cells.ApoE is essential for the normal catabolism of
0
-0.4
triglyceride-rich lipoprotein constituents[23].act. these
-Dq

-0.2
-0.6
-Dq

-0.4
-0.8

-1 -0.6 properties are considered to be related to the construction of

-0.8
-1.2
60

40
100
-1
60
the higher order structure of the DNA molecule.
80
20
20
40
60
40
60
80
100
This paper is preliminary with respect to the multifractal
q 0 0 20 40
re

q 0 0
20
re
characteristic Exist in potential relevance to the pathogenesis
of Alzheimers Disease. Its aim is to provide the means for the
Multifractal characteristic of C

Multifractal characteristic of T

0.4

0.2 0.2
analysis of the multifractal characteristic properties of DNA
-0.2
0

-0.2
0
sequences.although the research resuls ahown the multifractal
characteristic Exist the pathogenesis of Alzheimers Disease,
-Dq

-0.4 -0.4
-Dq

-0.6 -0.6

-0.8

-1
-0.8

-1
This may led to series of questions, what is the physical
60

40
80
100
-1.2
60
100
phenomena and possible mechanism of the pathogenesis of
Alzheimers Disease ? How to categorize different types of
60
20 40
40 80
20 60
0 0 20 40
q re 20
q 0 0
re
the pathogenesis of Alzheimers Disease, how to understand
Fig.5 shown Multifractal characteristic of the function of the pathogenesis of Alzheimers Disease, how
{A,G,C,T}computed over 100 moving windows with a to build the pathogenesis of Alzheimers Disease kinetics
window size of 128 and offset of 1. model systematically? Although the data tell us that the
multifractal characteristic does exist in the pathogenesis of
Alzheimers Disease, we will still think about the physical
IV. DISCUSSION properties of the pathogenesis of Alzheimers Disease.what
Multifractal analysis was applied to analysize amyloid beta kind of distribution form do these the pathogenesis of
precursor protein apolipoprotein E presenilin-1 and Alzheimers Disease have? All these studies should be the
presenilin-2 the sequences of the pathogenesis of Alzheimers future direction of research.
Disease. the pathogenesis of Alzheimers Disease were
exhibited multifractal characteristics,at the same times,it was ACKNOWLEDGMENT
calculated the probability measure for four difference the This project was supported by China National Nature
pathogenesis sequences of each base indidually.From the Science Foundation No:30470413, No:31160200.Hubei
results we find that Renyi dimension range between 0.0090 to province Nature Science Foundation No:2004ABA220 and
3.5043.After Sliding window compute multifractal China Postdoctoral Science Foundation. We are also indebted
dimension,Multifractal characteristic of {A,G,C,T}computed to sir lan zi yang for his valuable support and helpful
over 100 moving windows with a window size of 128 and discussions.
offset of 1 , for the amyloid beta precursor protein (APP),
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Tong-han Lan,Gongnongbin Road, Jiangan District Wuhan 430012,P R

China
Zi-yang Lan, Gongnongbin Road, Jiangan District Wuhan 430012,P R
China
Xiao Li, Gongnongbin Road, Jiangan District Wuhan 430012,P R China
Hao Cai, Gongnongbin Road, Jiangan District Wuhan 430012,P R
China
Fei fei Yu Gongnongbin Road, Jiangan District Wuhan 430012,P R
China

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