A team of researchers set out to find some answers to Alzheimer’s disease — the most frequent cause of dementia — that affects an estimated 24 million people worldwide. With limited treatment options, scientists are looking for ways to better understand the disease.

Jinsoo Seo, PhD, in the Department of Brain and Cognitive Science at Daegu Gyeongbuk Institute of Science and Technology (DGIST) in South Korea, along with his colleagues, wanted to find out if the APOE4 gene in astrocytes relates to Alzheimer’s disease. The researchers used human-induced stem cells carrying different versions of the APOE gene to make neurons and astrocytes in the lab, and to study their interaction

One hallmark of Alzheimer’s disease is the emergence of so-called beta-amyloid plaques, clumps of beta-amyloid protein accumulating in the brain and thought to be toxic to adjacent neurons. The causes for Alzheimer’s disease and the formation of beta-amyloid plaques are still largely unknown, but genetic studies found a gene called APOE, which is involved in cholesterol metabolism and transport, is linked to Alzheimer’s in the elderly. The APOE gene exists in different versions in people, APOE2, APOE3 and APOE4, but the APO4 gene comes with a relatively higher risk of developing Alzheimer’s.

The researchers found astrocytes carrying the Alzheimer’s disease-associated APOE4 gene released more cholesterol than astrocytes with APOE3.

Curiously, in the brain, it’s mostly the supporting cells called astrocytes rather than the neurons that make ApoE protein, according to the researchers.

The scientists noticed the neurons exposed to higher cholesterol had distinct changes to their cell membranes — the outer layers of the cell which normally contain cholesterol. The high cholesterol content in cell membranes was directly related to the increased production and secretion of beta-amyloid by the neurons. This work illustrates how different versions of the APOE gene in astrocytes can influence beta-amyloid production in neurons, and how cholesterol oversupply from ApoE4 astrocytes might promote the formation of toxic beta-amyloid plaques in Alzheimer’s patients.