A gene variant that causes Alzheimer's disease severely affects the brain

The gene variation of Apolipoprotein E (APOE), called APOE4, is one of the largest risk factors in developing Alzheimer’s disease, increasing the risk for the disease greatly. It has largely been unknown as to why this is the case. People can be tested for the gene and take action to limit their risk.

A study has revealed answers, linking APOE4 with defective cholesterol processing in the brain. This leads to defects in the insulating sheaths that surround nerve fibers. The changes can cause memory and learning deficits. The study also said that drugs that restore the cholesterol processing could treat Alzheimer’s.

The research from the study was published recently in the journal Nature.

The research

The study combines evidence from the brains of mice that had the disease with both postmortem human brains and lab-based human brain cultures. The research would show when individuals had one or two copies of APOE4, instead of the more common APOE3 variant, also called oligodendrocytes.

Deficiency of the myelin, a fatty insulation, may be a contributing factor causing Alzheimer’s. This is because communications among neurons are degraded without the correct myelination.

The research team, led by Li-Huei Tsai, a professor and director of The Picower Institute for Learning and Memory and the Aging Brain Initiative at MIT, found unique ways that APOE4 disrupts how lipids—fat molecules—are handled by parts of the brain that include neurons.

The team identified compounds that appear in the lab to correct the problems, that could possibly lead to future treatment plans.

The research elaborates on the prior work by providing analysis across various major brain cell types using single nucleus RNA sequencing (snRNAseq) in postmortem brains to compare gene expressions between APOE4 and APOE3. "This paper shows very clearly from the snRNAseq of postmortem human brains in a genotype specific manner that APOE4 influences different brain cell types very distinctly,” said Tsai.

“We see convergence of lipid metabolism being disrupted, but when you really look into further detail at the kind of lipid pathways being disturbed in different brain cell types, they are all different,” he continued.

The study

The researchers used postmortem human brain samples from the Religious Orders Study and the Rush Memory and Aging Project. The snRNAseq results used in the study contained more than 160,000 individual cells of 11 different types from the prefrontal cortex of 32 people—12 with two APOE3 copies, 12 with one copy of each APOE3 and APOE4, and eight with two APOE4 copies.

The APOE3/3 and APOE3/4 were sorted by Alzheimer’s diagnosis, gender, and age, while all APOE4/4 variant carriers did have Alzheimer’s. Five out of eight APOE 4/4 carriers were female.

The results

Although some results reflected known characteristics of Alzheimer’s, others were new. For example, one particularly new pattern showed that the more APOE4-carrying oligodendrocytes (lipid rich substance in the nervous system) and individuals had, the greater the effect and expression of cholesterol synthesis genes and disruptions to cholesterol transport.

To comprehend the reasoning behind the results, the researchers created lab cell cultures of oligodendrocytes engineered to differ by the variant APOE3 or APOE4. The APOE4 oligodendrocytes did not myelinate (produce layers of myelin wrapping around the neuronal axons, acting as a layer of insulation) the neurons as well as the APOE3 did.

The researchers treated the APOE4-carrying cells in mice with the drug cyclodextrin, which replicates cholesterol removal. This process helped to restore myelin development. This suggested an association between improved myelination and improved perception. Although cyclodextrin may not be able to correct lipid imbalances within the brain, the researchers are hopeful that better therapies and treatment options can one day emerge to fight the disease.