Neurosciences | Results indicate that a variant of the APOE gene affects the progression of the neurodegenerative disease through inflammation of the brain
*By Oberdan Rodrigo Schumann
*First published May 11, 2023
*Photo: João Pedro Ferrari Souza/Personal Archive
The causes of the onset and progression of Alzheimer’s disease (AD), which accounts for approximately 70% of dementia cases worldwide, are still little understood by medicine. Some of its risk factors are known: habits such as tobacco smoking, diseases such as diabetes, and genetic factors are examples in this regard. A few measures that help prevent it are also known, such as physical activity and mental exercise. The current treatments for Alzheimer’s patients are symptomatic, i.e. they do not stop or even retard the progression of the disease.
The research study “APOEε4 associates with microglial activation independently of Aβ plaques and tau tangles”, conducted by João Pedro Ferrari Souza, a doctoral student in UFRGS’ Graduate Research Program in Biological Sciences: Biochemistry (PPGBIOQ), addresses the main genetic risk factor for Alzheimer’s disease: the e4 variant of the APOE gene, which encodes polyprotein E. Its results register the first clinical evidence of the influence of this gene on the progression of Alzheimer’s through inflammation of the brain.
“Our results suggest that treatments seeking to reduce inflammation of the brain can potentially help contain the progression of Alzheimer’s disease, especially in patients who carry the APOE4 gene,” Souza explains. The study resulted in an article published in Science Advances in early April. “This article guarantees that the study will be read by important researchers and that it will be a basis for future research on the disease,” he emphasizes.
Glial cells and the APOE gene
In PPGBIOQ, Souza is supervised by professor Eduardo Zimmer, of UFRGS’ Department of Pharmacology. “Professor Zimmer has been long researching a specific type of cell, glial cells. And my research project was always aimed at a deeper understanding about the influence of such glial cells on Alzheimer’s disease,” he adds.
Glial cells are the main producers of polyprotein E in the human brain. This protein is expressed by the APOE gene, which has three variants: APOE3, carried by most of the world’s population; APOE2, which has a protective effect against Alzheimer’s disease; and lastly, APOE4, considered the greatest risk factor for the development of the disease.
“Even if we know this, we don’t understand very well the mechanisms by which APOE4 increases the risk for Alzheimer’s disease. Full comprehension of such mechanisms is very important because of two reasons: first, we need to understand the natural progression of the disease, and secondly, we need to develop treatments,” Souza stresses.
Neuroinflammation and its relationship with Alzheimer’s disease
Alzheimer’s disease occurs mainly when two types of proteins – amyloids and tau proteins – build up in the brain and start to harm it, causing neuronal cell death and a series of illnesses, such as atrophy. These aggressions activate a type of glial cell called microglia. In turn, these defense cells cause the brain to enter a state of neuroinflammation, which contributes directly to the progression and acceleration of the disease.
Although studies using animal subjects have been carried out, Souza’s research shows the first evidence in humans supporting that APOE4 causes AD progression and neuroinflammation.
“There is still a lot to be studied and validated, but the research results so far obtained suggest that anti-inflammatory treatments can possibly reduce the progression of AD, especially in patients that have this e4 variant. Apparently, this needs to be done in the earliest moments of the disease, when the pathological process starts occurring in the brain”
João Pedro Ferrari Souza
Next steps
Souza carried out his research during a sandwich doctorate at the University of Pittsburgh, in the United States. There, he studied a more clinical part of his advisor’s work to understand how glial cells affect Alzheimer’s disease in humans.
The partnership between the University of Pittsburgh and Canada’s McGill University was crucial to the activities of the research. “McGill has a great patient cohort that allows several biological markers for Alzheimer’s disease to be followed up,” Souza explains.
To Souza, the next steps involve carrying out research on the reduction of inflammation of the brain and understanding its consequences for the Alzheimer patient. Furthermore, he points out that studies on APOE are far from over. “It can be said that the variant has a manifold contribution. Our line of research seeks to understand a bit more the many contributions of this gene to the disease,” he concludes.
Translated into English by Daniel Senna Irgang, undergraduate student enrolled in the course “Supervised Translation Training II (English)” of the Undergraduate Program in Language and Literature, under the supervision and translation revision of Professor Elizamari R. Becker (P.h.D.).