A gene recognized as the strongest risk factor for Alzheimer's disease (AD) alters the way cholesterol moves around the brain and as we age, this altered movement likely contributes to loss of learning and memory, a team of researchers from the Icahn School of Medicine at Mount Sinai and the Massachusetts Institute of Technology (MIT) reports.
The change in cholesterol processing brought about by the gene, APOE4, may play a central role in Alzheimer's disease-related cognitive impairments, and pharmacological intervention to reduce this effect improved learning and memory in mice with APOE4 Alzheimer's disease, the researchers said. The study was published online November 16 in Nature.
Since APOE4 is present in aproximately 50 percent of people with Alzheimer's, we realized that deciphering its molecular and cellular pathways could help us to better understand the pathogenesis of the disease and reveal new therapeutic strategies for a large portion of the AD population. We learned that APOE4 causes gene expression changes across all cell types of the human brain and significantly alters signaling pathways associated with cholesterol balance and transport."
Joel Blanchard, PhD, Co-Lead Author, Assistant Professor of Neuroscience, and Cell, Developmental and Regenerative Biology, at Icahn Mount Sinai
The study was initiated while Dr. Blanchard was a postdoctoral fellow at The Picower Institute for Learning and Memory in the laboratory of Li-Huei Tsai, PhD, Picower Professor of Neuroscience at MIT and senior author of the paper. They continued the work as a collaboration when Dr. Blanchard joined Mount Sinai as a faculty member in 2021.
"Mounting evidence shows that APOE4 disrupts how different brain cells process lipids including cholesterol and that this underlying biology may contribute significantly to the pathology of Alzheimer's disease," Dr. Tsai said. "This insight suggests that in a large population of patients, lipid regulation may be a worthwhile target in the urgent search for potential interventions."
Dr. Blanchard and co-lead authors Leyla Akay, and Djuna von Maydell, graduate students at MIT, and Jose Davila Velderrain, PhD, research group leader at Human Technopole, performed single-nuclei RNA sequencing of the postmortem prefrontal cortex of 32 human brains from individuals with and without APOE4. The researchers found that in patients with APOE4, cholesterol was aberrantly deposited in oligodendrocytes, the cells responsible for producing myelin, a fatty insulating structure that sheaths neurons and facilitates electrical communication between different parts of the brain. This accumulation of cholesterol in APOE4 oligodendrocytes led to reduced myelination, hindering electrical communitation within the brain and potentially leading to learning and memory dysfunction.
Previous studies have documented myelin damage in many individuals before the onset of Alzheimer's disease symptoms, and found that reduced myelin volume in the fourth and fifth decades of life predicts a higher probability of cognitive impairment decades later. The Mount Sinai-MIT team is the first to establish a functional link between APOE4, myelination, and memory loss.
"It's interesting to speculate from our work that dysregulation of cholesterol-related processes in the oligodendrocytes causes a reduction in myelin early in the lives of APOE4 carriers, rendering them particularly vulnerable to amyloid and tau-mediated neurotoxicity that accumulates later on. This has clear implications for treating and also identifying those at risk for developing AD," says Dr. Blanchard, who is an investigator in the Black Family Stem Cell Institute, The Friedman Brain Institute, and The Ronald M. Loeb Center for Alzheimer's Disease at Mount Sinai.
APOE4 is associated with increased deposition of amyloid-β proteins that clump together to form plaques, and neurofibrillary tangles of the tau protein, both of which collect between neurons and disrupt their communications function. While prior research has suggested a link between Alzheimer's disease and the interaction of abnormal tau and amyloid-β, it is still not known if these proteins are the cause or the consequence of AD.
The connection uncovered by Mount Sinai and MIT researchers between APOE4 and cholesterol imbalance could potentially open the door to new therapeutic solutions for a disease known to afflict one in ten Americans over the age of 65.
Dr. Blanchard said that in addition to drugs that facilitate cholesterol transport, other interventions designed to restore cholesterol equilibrium in the brain-;including dietary and lifestyle-;might also increase cognitive reserves in individuals with the APOE4 gene. "By identifying ways APOE4 mediates the risk of Alzheimer's," he says, "we've opened new pathways to both treat and prevent the disease through a much-needed non-amyloid strategy."
Blanchard, J.W., et al. (2022) APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes. Nature. doi.org/10.1038/s41586-022-05439-w.