A possible explanation has been found in a study why apoE4, the most significant genetic risk factor associated with Alzheimer’s disease, fails to protect the brain from inflammation.
Alzheimer’s disease is characterized by accumulation of amyloid-β protein plaques, chronic inflammation, and impaired nerve function in the brain. The most significant genetic risk factor for this disease is apoE4, a variant of apolipoprotein E, which is known among others to hasten the onset of the disease. While more than half of all individuals with Alzheimer’s disease carry this variant, the exact effect of apoE4 on disease progression is still unknown.
A study recently completed at the University of Helsinki in Finland identified a more accurate link between the apoE4 gene and the part of the human immune system that underlies, among other things, Alzheimer’s disease. This is known as the complement system, and it contributes to the destruction of foreign cells and easily triggers an inflammatory response in the body.
“We found that apoE4 binds poorly to factor H, a regulatory factor of immunity. Factor H molecules are critical in preventing complement-mediated inflammation,” said Karita Haapasalo, the study’s principal investigator who leads the Inflammation and Infection research group at the University of Helsinki.
“Normally, apoE binds factor H to amyloid-β aggregates in the brain, thereby reducing local inflammation. But apoE4 is not,” he said.
This leads to the accumulation of harmful amyloid-β aggregates and inflammation in the brain.
According to Haapasalo, the binding of factor H to apoE4 could present a potential solution for preventing changes in the brain that lead to the onset of Alzheimer’s disease. Further research will soon be carried out to look for these connecting molecules.
The amyloid-β aggregates associated with Alzheimer’s disease begin to form in the brain decades before the diagnosis of memory impairment. Because the mechanisms underlying these changes are not well understood, drug development is focused on stopping or slowing down the changes that have already occurred.
“The drugs currently used do not prevent the onset of the disease itself,” says Haapasalo.
Alzheimer’s disease is a slowly developing memory disorder with more than 10 million new cases each year. As the population ages, the number of patients with this disease will increase significantly. In the future, Alzheimer’s disease will add to human suffering, as well as a public health and economic burden.
“Determining the molecular mechanisms that influence the onset of Alzheimer’s disease is important for developing drugs and curative therapies in the future.”
The study, published in the journal EMBO Reports, was conducted using an experimental cell culture model and investigated brain biopsy samples from patients with idiopathic normal pressure hydrocephalus (iNPH) syndrome, in collaboration with the University of Eastern Finland, Kuopio University Hospital and international research organizations.