Mount Sinai and MIT Researchers Uncover Link Between a Key Gene for Alzheimer’s Disease and Cholesterol Build-Up in the Brain
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,” says co-lead author Joel Blanchard, PhD, Assistant Professor of Neuroscience, and Cell, Developmental and Regenerative Biology, at Icahn Mount Sinai. “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.”
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.”
About the Icahn School of Medicine at Mount Sinai
The Icahn School of Medicine at Mount Sinai is internationally renowned for its outstanding research, educational, and clinical care programs. It is the sole academic partner for the eight member hospitals* of the Mount Sinai Health System, one of the largest academic health systems in the United States, providing care to a large and diverse patient population.
Ranked 14th nationwide in National Institutes of Health (NIH) funding and among the 99th percentile in research dollars per investigator according to the Association of American Medical Colleges, Icahn Mount Sinai has a talented, productive, and successful faculty. More than 3,000 full-time scientists, educators and clinicians work within and across 34 academic departments and 35 multidisciplinary institutes, a structure that facilitates tremendous collaboration and synergy. Our emphasis on translational research and therapeutics is evident in such diverse areas as genomics/big data, virology, neuroscience, cardiology, geriatrics, as well as gastrointestinal and liver diseases.
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About the Mount Sinai Health System
Mount Sinai Health System is one of the largest academic medical systems in the New York metro area, with more than 43,000 employees working across eight hospitals, over 400 outpatient practices, nearly 300 labs, a school of nursing, and a leading school of medicine and graduate education. Mount Sinai advances health for all people, everywhere, by taking on the most complex health care challenges of our time — discovering and applying new scientific learning and knowledge; developing safer, more effective treatments; educating the next generation of medical leaders and innovators; and supporting local communities by delivering high-quality care to all who need it.
Through the integration of its hospitals, labs, and schools, Mount Sinai offers comprehensive health care solutions from birth through geriatrics, leveraging innovative approaches such as artificial intelligence and informatics while keeping patients’ medical and emotional needs at the center of all treatment. The Health System includes approximately 7,300 primary and specialty care physicians; 13 joint-venture outpatient surgery centers throughout the five boroughs of New York City, Westchester, Long Island, and Florida; and more than 30 affiliated community health centers. We are consistently ranked by U.S. News & World Report's Best Hospitals, receiving high "Honor Roll" status, and are highly ranked: No. 1 in Geriatrics and top 20 in Cardiology/Heart Surgery, Diabetes/Endocrinology, Gastroenterology/GI Surgery, Neurology/Neurosurgery, Orthopedics, Pulmonology/Lung Surgery, Rehabilitation, and Urology. New York Eye and Ear Infirmary of Mount Sinai is ranked No. 12 in Ophthalmology. U.S. News & World Report’s “Best Children’s Hospitals” ranks Mount Sinai Kravis Children's Hospital among the country’s best in several pediatric specialties.