Altered neuronal cholesterol uptake in Alzheimer’s linked to APOE4 variant

Researchers at the Sant Pau Research Institute and the Clinical Biochemistry Service at Hospital de Sant Pau, in collaboration with the Spanish Biomedical Research Network in Diabetes and Associated Metabolic Diseases (CIBERDEM), in Barcelona, Spain, have identified a disruption in cholesterol transport mechanism to the brain in patients with Alzheimer’s disease.

The study has shown that lipoproteins in the cerebrospinal fluid of affected individuals exhibit a diminished capacity to deliver cholesterol to neurons. This impairment appears to be associated with the APOE4 genetic variant, which is a known risk factor for the development of Alzheimer’s disease.

“We have long known that people with the APOE4 variant – particularly those who are homozygous – are at much greater risk of developing Alzheimer’s disease,” said Dr Mireia Tondo, lead researcher in the Lipid Disorder Pathophysiology Group at Institut de Recerca Sant Pau.

“However, until now, the mechanisms underlying this association have remained unclear. Our study suggests that the variant may hinder neurons’ ability to absorb cholesterol from the cerebrospinal fluid,” she said.

Cholesterol is essential for neuronal health, supporting membrane formation, synaptic communication and myelin production. Because the blood–brain barrier prevents the uptake of cholesterol from the bloodstream, the brain must synthesise it locally.

“All the cholesterol the brain uses is produced in situ. It is stored in specialised lipoprotein particles that shuttle it from glial cells to neurons. If this transfer fails, neurons may be deprived of the structural and functional components they require,” Dr Tondo explained.

The team analysed cerebrospinal fluid samples from ten patients with Alzheimer’s disease and ten cognitively healthy individuals, all of whom were enrolled in the Sant Pau Initiative on Neurodegeneration (SPIN) cohort. Their evaluation covered two phases of lipid transport: the release of cholesterol from astrocytes into the cerebrospinal fluid and its subsequent uptake by neurons. While cholesterol release appeared unaffected in all participants, uptake by neurons was significantly impaired in those with Alzheimer’s.

To explore the role of genetics, the researchers examined APOE genotype among participants.

“Most patients were heterozygous for APOE4, and we observed a corresponding reduction in cholesterol uptake,” said Dr Tondo.

“We then synthesised recombinant lipoprotein nanoparticles containing either APOE3 or APOE4. In cultured neurons, those carrying APOE4 delivered cholesterol far less efficiently. This led us to believe that the variant may contribute directly to the dysfunction,” she said.

A detailed proteomic analysis of lipoproteins in the cerebrospinal fluid identified 239 associated proteins, 27 of which were altered in patients with Alzheimer’s disease. However, none of the changes involved proteins directly related to cholesterol metabolism.

“This suggests that the lipoprotein system is far more complex than previously understood. Processes such as inflammation, cell adhesion or protein degradation may also play a role in disease progression,” Dr Tondo added.

“Efficient cholesterol delivery is crucial to neuronal integrity,” said Carla Borràs, first author of the study.

“We have shown that this process is impaired in Alzheimer’s disease, particularly among individuals who carry the APOE4 variant. This may increase neuronal vulnerability and accelerate degeneration,” she added.

Dr Tondo emphasised the need for caution in interpretation.

“This research does not establish cholesterol deficiency as a direct cause of Alzheimer’s disease. But it may be one of several contributing factors. It highlights a potentially important avenue of investigation into cerebral lipid metabolism, particularly in those with a genetic predisposition,” she said.

The team has already launched a follow-up study to determine whether the same mechanism occurs in individuals with Down syndrome, a population with heightened genetic risk for Alzheimer’s disease.

“We aim to find out whether impaired neuronal cholesterol uptake is also present in this context.

“Understanding the overlap could guide us towards strategies to delay neurodegeneration by supporting lipid metabolism,” Dr Tondo concluded.

For further reading please visit: 10.1016/j.jlr.2025.100865