Scientists have identified a breakdown in cholesterol transport to neurons in Alzheimer’s disease, a defect linked to the high-risk APOE4 variant.
Researchers from the Sant Pau Research Institute (IR Sant Pau), the Clinical Biochemistry Service at Hospital de Sant Pau, and the Spanish Biomedical Research Network in Diabetes and Associated Metabolic Diseases (CIBERDEM) have uncovered an important disruption in how cholesterol reaches the brain in people with Alzheimer’s disease.
Their work shows that lipoproteins in the cerebrospinal fluid of affected patients are less effective at supplying cholesterol to neurons, a problem that may be connected to the APOE4 genetic variant, one of the strongest known risk factors for Alzheimer’s. The study appears in the Journal of Lipid Research.
According to Dr. Mireia Tondo, researcher in the Lipid Disorder Pathophysiology Group at IR Sant Pau and lead author of the project, “We’ve long known that people with the APOE4 variant—especially in the homozygous form—have a much higher risk of developing Alzheimer’s, but until now, the reasons for this weren’t well understood. Our study suggests that one contributing factor may be that neurons, in the presence of this variant, have a harder time absorbing cholesterol delivered through the cerebrospinal fluid.”
Cholesterol: Essential for Neuronal Viability
Cholesterol is a vital molecule for proper neuronal function. It plays a key role in membrane formation, synaptic transmission, and myelin production. Unlike other organs, the brain does not receive cholesterol from the bloodstream due to the protective blood–brain barrier. “All the cholesterol the brain needs is produced locally,” explains Dr. Tondo, “and it’s stored in specific lipoprotein particles that transport it from glial cells to neurons. If this process fails, the neuron may not receive the structural and functional resources it needs.”
The research team analyzed cerebrospinal fluid samples from 10 patients with Alzheimer’s disease and 10 individuals without the disease, all part of the Sant Pau Initiative on Neurodegeneration (SPIN) cohort. They evaluated two stages of cerebral lipid transport: first, the ability of astrocytes to release cholesterol into the cerebrospinal fluid, and second, the ability of neurons to absorb this cholesterol. The results showed that astrocyte cholesterol release was similar in all participants, but neuronal uptake was clearly impaired in patients with Alzheimer’s.
Based on these findings, the team sought to determine whether this defect was related to genetics. “Most of the patients in our sample were heterozygous for the APOE4 variant, and we observed lower cholesterol uptake in them. So we decided to go further and create recombinant lipoprotein nanoparticles, identical except for containing either APOE3 or APOE4,” Dr. Tondo explains. “When we tested them in cultured neurons, those containing APOE4 delivered cholesterol much less efficiently. This led us to believe that this variant may directly contribute to the dysfunction we observed.”
Protein Alterations and Functional Implications
The researchers also performed a detailed proteomic analysis of the cerebrospinal fluid lipoproteins. They identified 239 proteins associated with these particles, of which 27 were altered in Alzheimer’s patients. Interestingly, none of these differences directly involved proteins related to cholesterol metabolism. “This finding tells us that the lipoprotein system is far more complex than we thought, and that other mechanisms—such as inflammation, cell adhesion, or protein degradation—may also influence disease progression,” adds Dr. Tondo.
“Efficient delivery of cholesterol to neurons is essential for their function and maintenance. Our results show that this process is impaired in Alzheimer’s disease, particularly in the presence of the APOE4 variant,” says Carla Borràs, the study’s first author. “This may contribute to neuronal vulnerability and progressive degeneration.”
This research was made possible through collaboration between the lipid metabolism group and the Memory Unit at Sant Pau, an international reference center in the clinical and biomolecular study of dementias. Additional contributors included researchers from the Spanish Biomedical Research Network in Neurodegenerative Diseases (CIBERNED), the Spanish National Center for Cardiovascular Research (CNIC), the Biomedical Research Network in Cardiovascular Diseases (CIBERCV), and the Catalan Institute of Nanoscience and Nanotechnology (ICN2).
Dr. Tondo stresses the importance of cautious interpretation: “This study does not prove that cholesterol deficiency is the direct cause of the disease, but it may be one of the factors contributing to neuronal damage. In any case, it opens a very interesting line of research into cerebral lipid metabolism, especially in people with genetic risk.”
The research group is already working on a new study to see whether this mechanism is also impaired in people with Down syndrome, a population with genetic risk for developing Alzheimer’s. “We want to know whether the problem with neuronal cholesterol uptake also exists in this other genetic context. This could help us understand whether there are common mechanisms and whether improving lipid metabolism could be a way to delay neurodegeneration,” concludes Dr. Tondo.
Reference: “Cerebrospinal fluid lipoprotein-mediated cholesterol delivery to neurons is impaired in Alzheimer’s disease and involves APOE4” by Carla Borràs, Marina Canyelles, David Santos, Noemí Rotllan, Estefanía Núñez, Jesús Vázquez, Daniel Maspoch, Mary Cano-Sarabia, Qi Zhao, Maria Carmona-Iragui, Sònia Sirisi, Alberto Lleó, Juan Fortea, Daniel Alcolea, Francisco Blanco-Vaca, Joan Carles Escolà-Gil and Mireia Tondo, 21 July 2025, Journal of Lipid Research.
DOI: 10.1016/j.jlr.2025.100865
Funding: This work was partially funded by the Instituto de Salud Carlos III (ISCIII), part of the Spanish Ministry of Economic Affairs and Digital Transformation, and by the European Regional Development Fund (FEDER) under the slogan “A way of making Europe,” through projects PI21/00140, PI23/00232, PI18/0035, PI22/00758, JR22/00003, INT21/00073, PI20/01473, and PI23/01786.
The study was also funded by the U.S. National Institutes of Health (NIH) through grants R01 AG056850, R21 AG056974, R01 AG061566, R01 AG081394, and R61 AG066543, as well as by the Tatiana Pérez de Guzmán el Bueno Foundation through grant IIBSP-DOW-2020-151, and the European Union’s Horizon 2020 Research and Innovation Framework Programme (H2020-SC1-BHC-2018-2020).
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1 Comment
“We’ve long known that people with the APOE4 variant—especially in the homozygous form—have a much higher risk of developing Alzheimer’s, but until now, the reasons for this weren’t well understood.”
A least one reason is well understood. Having the APOE4 variant makes it easier for HSV1 (the cold sore virus) to cross the blood-brain barrier. HSV1 is one of the top risk factors for dementia; having it increases the odds ratio by 2.5 fold. The longer one has HSV1, the higher their risk of dementia. And according to an anecdotal analysis of 8000 people with HSV1 compared to 25000 age-and-sex-matched controls, taking anti-herpetic drugs to treat oral cold sores resulted in 90% lower risk of dementia.
The mechanism for HSV1 causing dementia is well known too. Amyloid-beta has anti-pathogenic purposes; it gets produced to fight viruses like HSV1.
The trouble is that Alzheimer’s has a range of risk factors like HSV1, APOE4, poor circulation, poor mitochondrial health, glutamate excitoxicity, inflammation, altered methylation…but virtually all the research just focuses on addressing one factor at a time. It’s like a car needing its alternator, starter solenoid and battery replaced, then being disappointed when just replacing the battery doesn’t fix it.