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Key Gene in Alzheimer Disease Tied to Cholesterol Accumulation in the Brain
The APOE4 gene, considered the strongest risk factor for Alzheimer disease (AD), alters the way cholesterol moves around the brain, which likely contributes to cognitive impairment associated with the disease. Researchers from the Icahn School of Medicine at Mount Sinai, New York, New York, and the Massachusetts Institute of Technology, Cambridge, Massachusetts, published their findings in Nature.
“By identifying ways APOE4 mediates the risk of Alzheimer [disease], we’ve opened new pathways to both treat and prevent the disease through a much-needed nonamyloid strategy,” said study co-lead author Joel Blanchard, PhD, assistant professor of neuroscience, and cell, developmental, and regenerative biology, at the Icahn School of Medicine.
The study involved single-nuclei RNA sequencing of the postmortem prefrontal cortex of 32 human brains from people with and without APOE4.
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“Since APOE4 is present in approximately 50% of people with Alzheimer [disease], 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 Alzheimer disease population,” said Dr Blanchard. “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.”
In people with the APOE4 gene, 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, according to the study. The cholesterol accumulation reduced myelination and hindered electrical communication within the brain, potentially leading to learning and memory dysfunction.
Pharmacological intervention to reduce the effect improved learning and memory in mice with APOE4 Alzheimer disease, the study showed.
“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,” said Dr Blanchard. “This has clear implications for treating and also identifying those at risk for developing Alzheimer disease.
In addition to drugs that facilitate cholesterol transport, Dr Blanchard noted, other interventions designed to restore cholesterol equilibrium in the brain, including dietary and lifestyle changes, may also increase cognitive reserve in people with the APOE4 gene.
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