People often ask the question: Is Alzheimer’s hereditary? In this blog, we’ll shed light on the genetic link to Alzheimer’s Disease through the gene ApoE4 and the role ApoE4 plays to increase the risk of Alzheimer’s.
Here the Key Takeaways:
- The ApoE4 gene variant is the most common genetic link to Alzheimer’s.
- ApoE4 increases the amount of misfolded Abeta and Tau proteins in the brain, thus facilitating the development of Alzheimer’s.
- Evidence suggests an excess of misfolded proteins in the brain, such as Abeta, Tau, and Synuclein, can cause Alzheimer’s Disease and other progressive dementias.
- ApoE4 may worsen the damage caused by misfolded Tau tangles.
This excess damage from ApoE4 and misfolded Tau occurs more frequently in women.
The ApoE gene encodes proteins that transport lipids in and out of cells. Humans all carry two copies of ApoE, which comes in three (3) different forms:
Individuals who carry two copies of the ApoE-2 gene have a significantly reduced risk of Alzheimer’s.
The ApoE4 form appears in approximately 14% of people overall.
About 40% of Alzheimer’s patients carry one or two copies of ApoE4.
How Does ApoE4 Increase Alzheimer’s Risk?
- Having one copy of the ApoE4 gene increases the risk of developing Alzheimer’s by approximately three-fold.
- Having two copies of ApoE4 increases the probability of Alzheimer’s by roughly 10-fold.
- ApoE may also play a role in the capture and degradation of misfolded proteins in addition to carrying lipids.
What’s Misfolded Protein or Prion?
Proteins are linear chains composed of building blocks called amino acids. Each linear protein chain folds naturally into a unique three-dimensional shape. Some proteins can misfold into one or more alternative forms.
Occasionally, these alternative misfolded shapes may lead to disease. Even more rarely, the misfolded proteins may induce the standard forms of the protein to misfold as well.
Prions are misfolded proteins that replicate and spread disease by inducing misfolding of native proteins. One prion can turn into more than billions over several years. Prions can also move directly from cell to cell or through the blood or spinal fluid (CSF).
Prions are the cause of Mad Cow Disease in cattle and Creutzfeld-Jacob Disease in people.
Prion-like replication appears to play a role in the progression of both Alzheimer’s and Parkinson’s Diseases. Unlike Mad Cow Disease, the prion-like properties observed in Alzheimer’s and Parkinson’s are not infectious and cannot spread between people.
Learn more about misfolded proteins here.
How ApoE4 Relate to Misfolded Abeta, Tau, and Synuclein?
Alzheimer’s appears to be caused by the misfolding of two different proteins: Abeta and Tau, which cause neurodegeneration and plaque formation and tangles in the brain. The plaque represents large insoluble clumps of misfolded Abeta between brain cells, and tangles represent insoluble clumps of Tau within these cells.
ApoE4 increases the amounts of both misfolded Abeta and Tau in the brain. In the case of Abeta, ApoE4 slows the degradation and elimination of misfolded Abeta aggregates. ApoE4 also binds directly to Abeta and may increase misfolding. ApoE4 can also misfold and often appears in plaque with misfolded Abeta.
ApoE4 binds to Tau may facilitate its misfolding. Misfolded Tau attached to ApoE4 is more damaging to the brain than misfolded Tau alone.
Does ApoE4 Increase Parkinson’s Risk?
Parkinson’s Disease results from the misfolding of another brain protein called Synuclein. There’s no evidence at present suggesting that ApoE4 is associated with either Parkinson’s or with misfolding of Synuclein.
In summary, research has shown that ApoE4 plays a crucial role in increasing misfolded forms of Abeta and Tau proteins, which cause neurodegeneration and symptoms of Alzheimer’s.
Does ApoE4 Affect Men Vs. Women Differently?
For unknown reasons, ApoE4 affects women more severely than men.
Several clues suggest that women respond more unfavorably to Tau tangles than men in the presence of ApoE4. Similar numbers of Tau tangles in ApoE4 women lead to more severe disease than in women expressing the ApoE2 or ApoE3 genes.