What role does cholesterol play in hereditary Alzheimer's?

BarcelonaAt least one in six cases of Alzheimer's disease has genetic causes. Specifically, those with two copies of a gene called APOE4 have a greater than 95% chance of developing the signs of this dementia between the ages of 60 and 65. Now, researchers at the Sant Pau Research Institute have discovered in a study that these individuals have a key alteration that could explain why they have such a high risk of developing the disease: their neurons do not properly absorb cholesterol, which is very important for the maintenance and function of our brains. For the Catalan researchers, these conclusions, published in the journal Journal of Lipid Research This Wednesday, they open new avenues for intervention in the treatment of this disease.

The authors' hypothesis is that the APOE4 genetic variant alters the efficiency with which neurons capture the cholesterol they need to function, which could promote their dysfunction and degeneration. Cholesterol is a vital molecule for the proper functioning of neurons, since it intervenes in the formation of their membranes, in synaptic transmission, and in the production of myelin, a substance made of fat and water without which communication between neurons would be slow and defective. However, the brain does not receive cholesterol from the blood, like other organs, but rather produces it locally and stores it in particles that transport it to the neurons. If this process fails, the neuron may not receive the structural and functional resources it needs.

Less ability to absorb cholesterol

Researchers analyzed cerebrospinal fluid samples from ten patients with Alzheimer's and ten people without the disease and evaluated two stages of this process, in which proteins transport cholesterol to neurons for their proper function. One of the stages they analyzed is when neurons must uptake cholesterol, and they observed that in patients with Alzheimer's, neurons did not have the same capacity to do so as those of healthy people. In fact, the authors warn that neuronal uptake in Alzheimer's patients "was clearly compromised."

Given these results, the research team wanted to understand whether this defect was related to genetics and found that most of the patients in the sample had two copies of the APOE4 gene. Furthermore, upon analyzing the results in depth, they saw that cholesterol uptake was lower in patients with this genetic variant. However, Mireia Tondo, a researcher at IR Sant Pau and first author of the study, warns that the research's conclusions do not allow us to affirm that cholesterol deficiency is the direct cause of the disease, but it "could be one of the factors that contribute to neuronal damage," and maintains that the study opens "a very interesting line of genetic exploration."