The number one Alzheimer's risk factor

The protein ApoE4 is considered the most important genetic risk factor for Alzheimer's disease.

One of the central questions in Alzheimer's research is related to an unspectacular protein. It is called ApoE4, about 15 percent of people have it - and it is precisely this group that has a significantly higher risk of developing Alzheimer's in old age. Researchers have been trying to find out for many years, why this is so and what exactly this protein does in the brain . Step by step, they are getting closer to the puzzle, but they have not yet been able to decipher the mechanisms once and for all.

A distinct form of Alzheimer’s?

A study from 2024 (Fortea et al., Nature Medicine) even suggests that ApoE4 is more than “just” a risk factor: If this mutation is present twice in the genome (i.e. not only on a single chromosome, but also on the corresponding counterpart), then this seems to lead – in most cases –  to the development of Alzheimer’s disease. The double mutation (also referred to as “ApoE4 homozygosity”) would therefore be triggering a distinct, genetically determined form of Alzheimer’s.

Delivery service

ApoE is the abbreviation for Apolipo protein. In humans, it occurs in three gene variants: ApoE2, ApoE3 and ApoE4. This protein is something of a delivery service for the human brain: it brings important nutrients to the nerve cells, such as polyunsaturated fatty acids. Among other things, these are found in the membranes that surround the nerve cells. Certain unsaturated fatty acids are also converted into messenger substances - so-called endocannabinoids - which regulate numerous functions of the central nervous system. The Apolipo proteins thus play a supporting role in brain function. All three types perform the transport function equally well. They differ only in the extent to which the risk of Alzheimer's disease is pronounced: for ApoE4, it is twelve times higher than for ApoE3.

To solve this puzzle, the researchers are taking a close look at the molecular processes in which the protein is involved. For example the endocytosis: this is the name given to the process by which ApoE enters the interior of nerve cells. They dock onto a membrane receptor called sortilin, which then transports the ApoE onward. This endocytosis is vital for the brain: if it doesn't work and therefore too few unsaturated fatty acids arrive in the nerve cells, they atrophy and are susceptible to inflammation.

Researchers from the DZNE have found a possible explanation for the problems with ApoE4. Usually, ApoE binds to the receptor sortilin, which transports it along with the charged fatty acids into the cell interior and immediately returns to the cell surface to introduce new ApoE. This happens many times an hour to ensure that the nerve cells are well supplied with the urgently needed fatty acids. With ApoE4, however, this process comes to a standstill: The receptor sortilin binds the protein normally and brings it into the cell interior - but there, however, it clumps together and therefore cannot return to the cell surface. As a result, endocytosis comes to a standstill, no more new fatty acids enter the cell interior, and the nerve cells die. This is where a novel therapy could come in: Researchers are trying to develop a drug that prevents this clumping.

However, ApoE also has an effect on amyloid deposition in plaques: ApoE glues amyloid together and therefore accelerates its aggregation and deposition. ApoE4, the most important risk factor for Alzheimer's disease, causes amyloid to aggregate to a much greater extent than the other two ApoE variants*. ApoE itself is massively produced by microglial cells that are in direct contact with plaques. Therefore, they seem to pump ApoE into the plaque outright.