SEARCH FOR GENETIC RISK FACTORS IN ALZHEIMER’S DISEASE USING ENDOPHENOTYPES

Jeremy Michael Harris Brigham Young University

MODERN ALZHEIMER’S DISEASE RESEARCH

More than 50,000 deaths per year
Modern research has discovered phenotypes associated with the disease Phenotypes:
 Amyloid

Beta  Apolipoprotein E (ApoE ε4 allele)  Hyperphosporylated Tau Protein (pTau)

CHARACTERISTICS OF ALZHEIMER’S DISEASE

Genetic disorder affecting older individuals
Can progress undiagnosed for years


Cannot be cured due to degenerative nature
Expressions of the disease:
   

Memory Loss Personality shifts Behavioral changes Inability to care for oneself

STATISTICS OF ALZHEIMER’S DISEASE

Study of 313 Alzheimer’s positive individuals:
 63%

female  Mean age of Onset: 67.5  Carrying at least one copy of ApoE ε4: 42%

PHYSICAL MANIFESTATIONS OF ALZHEIMER’S DISEASE

Physical manifestations are not visible until autopsy
Significant decrease in brain matter due to neural tissue decay

TYPES OF ALZHEIMER'S DISEASE

Two types of Alzheimer’s disease, based mainly upon age of onset
 Familial Alzheimer’s disease  Onset prior to age 60  Less than 1% of all AD cases

(FAD)

 Late-Onset Alzheimer’s disease  Onset after age 60  The focus of our research

(LOAD)

AN ENDOPHENOTYPE-BASED APPROACH
Hyperphosphorylated Tau Protein Amyloid Beta Apolipoprotein E

HYPERPHOSPHORYLATED TAU PROTEIN: PTAU

Functional tau proteins stabilize microtubules
When tau is defective, these microtubules fall apart and the tau proteins themselves form neurofibrillary tangles within the brain Higher levels of pTau in the cerebral spinal fluid indicate the rate of progression of Alzheimer’s disease
 

High levels = Fast Moving AD High levels = More neurofibrillary tangles

PTAU AND NEUROFIBRILLARY TANGLES

SIGNIFICANT TAU SNP: RS1868402

Found in the region that encodes tau phosphatase
Evidence that RS1868402 is associated with higher levels of pTau

AMYLOID BETA

Produced by all cells
Most common forms in humans:

 

Aβ40 and Aβ42
Both are normal products of the amyloid precursor protein Aβ42 is linked to Alzheimer’s disease
 

Levels within the cerebral spinal fluid have been shown to correlate to both the presence and progression of AD The amyloid plaques found in the brains of AD patients are from Aβ42

AMYLOID BETA AND ALZHEIMER’S DISEASE

Levels within the cerebral spinal fluid (CSF) may indicate onset of disease

High levels of Aβ in the CSF point to a lower likelihood of developing LOAD Lower levels of Aβ in the CSF point to a greater likelihood of developing LOAD
 

Indicates probable breakdown of Aβ42 Breakdown of Aβ42 leads to accumulation of amyloid plaques in the brain

HUMAN APOLIPOPROTEIN E

Protein essential for lipid transport Synthesized primarily in the liver Also synthesized at a lower rate in the brain

APOLIPOPROTEIN E AND ALZHEIMER’S DISEASE

ApoE is polymorphic

Three isoforms:
  

ApoE2 (Cys at 112 and 158) ApoE3 (Cys-112 and Arg-158) ApoE4 (Arg at 112 and 158)

Three isoforms = three alleles
  

ApoE ε2: Dysfunctional (Atherosclerosis and Hyperlipoproteinema) ApoE ε3: Normal ApoE ε4: Dysfunctional (Alzheimer’s disease)

APOE ε4

Commonly cited as a genetic risk factor for Alzheimer’s disease
 Only

known risk factor for the disease

Possessing even one ApoE ε4 allele increases AD risk 3x

Possessing two ApoE ε4 alleles increases AD risk 8x

APOE ε4 AND ALZHEIMER’S DISEASE RISK
ApoE Genotype
2,2
Least Risk Normal Risk Increased Risk High Risk

2,3 X

3,3

3,4

4,4

2,4

X

X
X X

X

APOE ε4 HYPOTHESIS

ApoE ε4 complexes with Aβ, but cannot transport the Aβ correctly through the blood brain barrier, leaving amyloid plaques in the brain.

THE DATASET

957 Patients and Controls for Aβ
210 Patients and Controls for ApoE ε4


500,000 SNPs per subject
Population was not normally distributed

Use of covariates to identify areas of interest that impact p-values

REDUCING NOISE THROUGH USE OF COVARIATES

Consistently Effective Covariates:
 

Age ApoE Genome

Less Effective Covariates:
 

Clinical Dementia Rating (CDR) Cerebral Spinal Fluid Phospholipase C3 (CSFPC3)

Gender was not an effective covariate

DATA CLEANING AND THE RESULTING DATASET

Amyloid Beta Dataset
 909

Individuals  258,550 SNPs  Final covariates used: Age, CSF Phospholipase C1, C2, and C3

ApoE ε4 Dataset
 210

Individuals  258,550 SNPs  Final covariates used: CDR, ApoE Genome, Age, and CSF Phospholipase C3

LINEAR REGRESSION ANALYSIS ON APOE ε4

MANHATTAN PLOTS: APOE

Three SNPs were found that met the 10-5 criteria
  

RS11102602 RS11931121 RS7792596

SNPs are located on chromosomes 1, 4, and 7, respectively

MANHATTAN PLOTS: AMYLOID BETA

1 SNP was found that met the 10-5 criteria

rs17475516

The SNP is located on chromosome 14

FUTURE DIRECTIONS

Expand the data set to 10 million SNPs
Re-run the analyses Follow any subsequent leads

WHY THIS RESEARCH IS IMPORTANT
Finding SNPs that tie to the phenotypes will help to focus research and more speedily bring about discoveries that can lead to slowing or stopping the progression of Alzheimer’s disease.

TECHNOLOGICAL ADVANCES ARE IMPORTANT