Genetic Screening for Alzheimer’s Disease Thorstensen: Genetic Screening for Alzheimer's Disease 1

Agenda  What is Alzheimer’s Disease (AD)?  Genes associated with AD  The APOE gene Thorstensen: Genetic Screening for Alzheimer's Disease 2

What is Alzheimer’s Disease (AD)?  Type of dementia that causes problems with memory, thinking and behavior  Most common form of dementia  Not a normal part of aging  Worsens over time  Has no current cure, but treatments for symptoms are available and research continues Thorstensen: Genetic Screening for Alzheimer's Disease 3

AD changes the whole brain Thorstensen: Genetic Screening for Alzheimer's Disease 4

The prime suspects for the cause of cell death and tissue loss are plaques and tangles Thorstensen: Genetic Screening for Alzheimer's Disease 5

Genes associated with AD  Four leading genes determined to be causative elements: APP, PS1, PS2 and APOE  Mutations in APP, PS1 and PS2 cause early onset AD (younger than 65 years)  APOE is a risk factor for late onset AD (older than 65 years) Thorstensen: Genetic Screening for Alzheimer's Disease 6

The APOE gene  Present in 30-50% of late onset AD patients  Apolipoprotein E  Secretory protein  Synthesized in the liver  Proposed function:  Amyloid β aggregation and clearance  Intracellular signaling through low-density lipoprotein receptor- related protein (LRP) Thorstensen: Genetic Screening for Alzheimer's Disease 7

Screening and Evaluation of Deleterious SNPs in the APOE Gene of AD  SNP = Single-Nucleotide Polymorphism  nsSNP = nonsynonymous SNP  Several SNPs present in the APOE gene that serve as biomarkers in exploring the genetic basis of AD  Research Goal: Identify deleterious nsSNPs associated with the APOE gene Thorstensen: Genetic Screening for Alzheimer's Disease 8

Why use SNPs, specifically nsSNPs?  SNPs are the most common polymorphisms of DNA sequence variation for mapping complex genetic traits  500,000 SNPs in coding regions of human genome  Several databases of SNPs  nsSNPs cause changes in amino acid residues  These mutations are most likely to cause structural changes therefore altering the function of a protein (like APOE  plaques and tangles) Thorstensen: Genetic Screening for Alzheimer's Disease 9

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Used the Function Analysis and Selection Tool for Single Nucleotide Polymorphisms (FASTSNP) server to detect 7 nsSNPs with high possible functional effects Risk score of 3-4: highly polymorphic Thorstensen: Genetic Screening for Alzheimer's Disease 11

Used the Swiss Protein Data Bank (PDB) viewer to predict mutations in the APOE gene and the Normal Mode Analysis, Deformation, and Refinement (NOMAD-Ref) server to detect 3 mutant- structures with higher total energies and RMSD values compared to the homology modeled structure Deviation in structure implies a functional change Thorstensen: Genetic Screening for Alzheimer's Disease 12

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Must test predicted impact of these nsSNPs using animal models or cell lines to determine if the functionally of the protein has indeed been altered AD has a complex genetic background as well as environmental factors, making research for a cure challenging Thorstensen: Genetic Screening for Alzheimer's Disease 14