Amanda Clewley
University of New Hampshire- Manchester

The purpose of this project is to explore the predictive genomic testing that has been performed as it relates to the APOE gene and its effect on Alzheimer’s disease risk as well as to evaluate the importance of the test’s predictive value. This was achieved through analysis of review articles, primary articles and the 23andMe genomics website. The direct-to-consumer personal genomics company 23andMe determines the Alzheimer’s disease risk of its consumers using only the APOE variant (23andMe, n.d.). Although APOE is the most studied and best known predictor for AD risk, it is not the only variant associated with the disease, nor can AD be entirely contributed to the APOE ε4 allele. Other factors including epigenetics and environmental influences may also play a role in the development of the disease (Bennett et al, 2015). Due to concerns put forth by the FDA, 23andMe no longer provides most health disease risk data, including results for Alzheimer’s disease (Zettler et al, 2014).

  • Alzheimer’s disease (AD) is the most significant form of dementia present in the United States today.
  • Late-onset Alzheimer’s disease is a type of dementia that is rising in prevalence due to the increasing number of the American elderly population.
  • Symptoms of AD develop slowly, leading to complete loss of cognitive function and death.
  • Patients with late-onset Alzheimer’s disease usually start developing memory loss following middle age. Early-onset Alzheimer’s disease is marked by the onset of symptoms before or during middle age.
  • Alzheimer’s disease is associated with significant health-care costs.
  • Brain pathology for AD includes β-amyloid protein plaques (figure 1) and neurofibrillary tangles (figure 2) (Reitz 2015)

Amyloid Plaques Image.jpg
Figure 1- Amyloid plaques. Reproduced with permission from CC license. Retrieved from
Neurofibrillary Tangles Image.jpg
Figure 2- Neurofibillary tangles. Reproduced with permission from CC license. Retrieved from

The APOE gene:
  • APOE is the most significant gene associated with Alzheimer’s disease and can be linked to β-amyloid plaques as well as other brain pathology that may contribute to the disease (Wolf et al, 2013).
  • The APOE gene is found on chromosome 19 and is involved with lipid transport.
  • APOE is the best established genetic risk factor for Alzheimer’s disease (Reitz, 2015).
  • The APOE gene encodes for a protein called apolipoprotein E referred to as apoE (Wolf et al, 2013).
Amino acid at location 112
Amino acid at location 158
Frequency in US
  • APOE has three alleles that are referred to as APOEε2, ε3 and ε4 (Reitz, 2015).
    • There are two main variations of apoE, found at amino acids 112 and 158.
    • The ε2 variant has the amino acid cysteine at both locations.
      • APOEε2 constitutes about 10% frequency in the United States.
      • Those with the APOE ε2 gene may be at a lower risk for developing the disease (Wolf et al, 2013).
    • APOEε3 includes one cysteine amino acid (location 112) and one arginine amino acid found at 158.
      • The most common allele is the APOE ε3 at 70% of the US population.
    • The ε4 allele is marked by arginine at both variable locations.
      • The frequency of the APOEε4 variant in the US is 20% (Wolf et al, 2013).
      • APOEε4 is the variant linked to an increased risk of developing AD and a decreased age of developing symptoms (Reitz, 2015).
      • There is a structural difference in the apoE4 protein due to the arginine variant which may account for the association of the gene with AD pathology (Wolf et al, 2013).
      • People with one copy of APOEε4 are thought to have a 2-3 times risk of developing AD.
      • People with two ε4 alleles may have over a 5 times increase in risk (Reitz, 2015).
      • APOEε4 may contribute to cognitive and memory impairment.
      • APOEε4 is only significantly linked to the development of AD in non-Hispanic whites of European descent.
        • Studies involving other ethnic groups have not shown consistent results (Reitz, 2015).

The Roles of APOE:
  • APOE is primarily associated with the formation of β-amyloid plaques in neural tissue; however APOE may have multiple roles outside of the development of β-amyloid in the pathogenesis of Alzheimer’s disease.
  • ApoE functions as lipid transport in the liver and brain.
  • It is not yet known what effect the structural change in apoE4 has on the transportation of lipid in brain cells and how that relates to risk for AD.
  • There has been shown to be a link between apoE and pathology related to tau proteins.Studies have shown a decreased metabolism of glucose by brain cells in healthy subjects with the APOEε4 allele.
    • When phosphoylated, tau proteins can form tangled structures with other cytoskeleton proteins.
    • High levels of apoe4 expression have been linked to the formation of these neurofibrillary tangles and death in mice.
    • Lower levels of the variant gene expression in mice have correlated with inhibition of learning and memory.

  • ApoE4 may impair intracellular trafficking and the function of the mitochondria and may damage astrocytes which support neuron function.
  • Patients with AD show a decreased function of the blood-brain barrier which has great impacts on brain function.Research has connected apoE4 with the promotion of inflammation in the innate immune system.
    • ApoE4 has an effect on the vasculature of the brain and is associated with a number of cerebrovascular conditions.
    • This may be due to the inefficient clearance of β-amyloid associated with the impairment of the blood-brain barrier.

  • ApoE4 has also been associated with hyperlipidema and heart disease (Wolf et al, 2013).

Other Genes linked to Alzheimer's Disease:
  • There are many other genes besides APOE with implications in Alzheimer’s disease.
  • A large Genome Wide Association (GWA) study has been done using 75,000 non-Hispanic white participants of European ancestry.
    • This study identified 23 genes that related to Alzheimer’s disease risk.
    • The genes were primarily involved in the immune system response and inflammation, lipid metabolism and movement of molecules within and out of the cell.
    • The variants found in this study account for a large portion of the disease risk factors compared to the APOE gene and other previously known markers.
  • APP is a gene with implications in early-onset Alzheimer’s disease.
    • APP is located on chromosome 21 and therefore may be related to an increase in the likelihood of those with Down syndrome to develop AD.
    • APP normally codes for a trans-membrane protein.
    • Mutation in APP is involved with increased β-amyloid plaques.
  • The PSEN1 and PSEN2 genes are involved with cleavage of β-amyloid peptide chains.
    • Improper cleavage of β-amyloid due to mutations in PSEN1 and PSEN2 has been linked to Alzheimer’s disease.
  • ADAM10 is a gene involved with regulation of the APP region.TREM2 and TREML2 are genes related to the immune system with have been found to have a role in AD (Reitz, 2015).
    • Variants in ADAM10 are shown to contribute to an increase in β-amyloid plaques due to improper cleavage of the protein.

Diagnostic Testing for Alzheimer's Disease:
  • There are several diagnostic tests that are currently used to screen for Alzheimer’s disease.
  • One test that is currently being used is for the levels of β-amyloid in blood plasma.β-amyloid and tau protein can also be tested for in cerebral spinal fluid and relate to AD risk.
    • While there does seem to be a link between elevated plasma β-amyloid and AD it is not conclusive.

  • MRI testing is performed to test for AD risk. Brain atrophy and the presence of β-amyloid plaques in PET scans are associated with an AD diagnosis.
  • There is no effective therapy for Alzheimer’s disease despite research done during the past 20 years.
  • There have been recent unsuccessful trials regarding the treatment of β-amyloid deposition in patients with mild to moderate AD.
    • This may be due to the ineffectiveness of treating β-amyloid plaques after they have already been deposited in someone with current symptoms of AD.
  • Genetic testing may help the treatment of AD in guiding effective therapies for their specific condition.
    • Learning more about the genetic risk factors that contribute to AD could improve prediction and diagnosis of AD and lead to more personalized medical treatment.
    • However, at this point the known variants only account for a small portion of Alzheimer’s disease risk.
    • Research outside of the work done with associated SNP’s such as further work with GWAS, whole-genome sequencing and whole-exome sequencing studies and research involving other ethnic groups still must be done.
    • Genetic risk variants also need to be weighed with environmental factors in order to get a better understanding of an individual’s disease risk (Reitz, 2015).

Next: Materials and Methods
Broader Impacts
Acknowledgments and Literature Cited