People with a gene variant called APOE4 have a higher risk of developing late-onset Alzheimer’s disease: APOE4 is three times more common among Alzheimer’s patients than it is among the general population. However, little is known about why this version of the APOE gene, which is normally involved in metabolism and transport of fatty molecules such as cholesterol, confers higher risk for Alzheimer’s.
To shed light on this question, MIT neuroscientists have performed a comprehensive study of APOE4 and the more common form of the gene, APOE3. Studying brain cells derived from a type of induced human stem cells, the researchers found that APOE4 promotes the accumulation of the beta amyloid proteins that cause the characteristic plaques seen in the brains of Alzheimer’s patients.
“APOE4 influences every cell type that we studied, to facilitate the development of Alzheimer’s pathology, especially amyloid accumulation,” says Li-Huei Tsai, director of MIT’s Picower Institute for Learning and Memory and the senior author of the study.
The researchers also found that they could eliminate the signs of Alzheimer’s in brain cells with APOE4 by editing the gene to turn it into the APOE3 variant.
Picower Institute Research Scientist Yuan-Ta Lin and former postdoc Jinsoo Seo are the lead authors of the paper, which appears in the May 31 online edition of Neuron.
APOE, also called apolipoprotein E, comes in three variants, known as 2, 3, and 4. APOE binds to cholesterol and lipids in cells’ environments, enabling the cells to absorb the lipids. In the brain, cells known as astrocytes produce lipids, which are then secreted and taken up by neurons with the help of APOE.