Researchers at the Massachusetts Institute of Technology (MIT) have unveiled how rare variants of the ABCA7 gene contribute to a high risk of developing Alzheimer’s. A study published this week in the journal Nature showcases the therapeutic potential of these findings for a broader population.
While mutations that result in a complete loss of function of the ABCA7 protein are rare, they are one of the strongest known genetic risk factors for Alzheimer’s disease, doubling the chances of an individual carrying these variants developing the neurodegenerative disease as they age. The ABCA7 protein is known to be responsible for transporting lipids across the cell membrane, but the exact link between its function and the development of Alzheimer’s has long remained unclear.
For the first time, MIT researchers have described the cascade of effects that these rare mutations have on neurons, including a disruption of lipid metabolism that results in hyperexcitable neurons that are more likely to accumulate the amyloid beta plaques that characterize Alzheimer’s. These effects were found to be reversible when treating neurons with choline, a precursor to the neurotransmitter acetylcholine and an important structural component of cell membranes.
“We found pretty strikingly that when we treated these cells with choline, a lot of the transcriptional defects were reversed,” said Djuna von Maydell, graduate student at MIT and lead author of the study. “We also found that the hyperexcitability phenotype and elevated amyloid beta peptides that we observed in neurons that lost ABCA7 was reduced after treatment.”
Among more than 1,200 patient tissue samples in the Religious Orders Study/Memory and Aging Project (ROSMAP), a study tracking aging and dementia over time, von Maydell and colleagues identified 12 samples from individuals with loss of function variants of ABCA7. Using single-cell RNA sequencing, they compared these samples to that of 24 matched controls to generate a transcriptional atlas of the effects of ABCA7 mutations in each cell type within the brain.
Results showed that excitatory neurons expressed the highest levels of ABCA7 protein. When this protein was missing, the neurons showed alterations in the synthesis of lipids and mitochondrial function, along with increased cellular stress. Neurons are known to rely on mitochondria to meet their high energy demands, and their dysfunction has been previously linked to aging and neurodegeneration processes. The cellular stress observed could also contribute to DNA damage and inflammation commonly seen in the brains of Alzheimer’s patients
In particular, mutations in ABCA7 affected the levels of phosphatidylcholine, a type of lipid present in cell membranes, including mitochondrial membranes. Treatment with choline, a precursor of phosphatidylcholine, reversed many of these transcriptional changes in neurons grown in vitro.
A previous study had shown that changes in phosphatidylcholine levels are linked to the development of Alzheimer’s in patients carrying the APOE4 genetic variant, a well-known risk factor that is present in about 15% of the population. Taken together, these results seem to suggest that disruptions to lipid metabolism are central to the development of Alzheimer’s and potentially shared across other risk factors, opening up the possibility of preventive treatments that are effective in a broader population.
“There’s more work to be done in this direction, but this suggests that ABCA7 dysfunction might play an important role in a much larger part of the population than just people who carry the rare variants,” said von Maydell.
“From APOE4 to ABCA7 loss of function, my lab demonstrates that disruption of lipid homeostasis leads to the development of Alzheimer’s-related pathology, and that restoring lipid homeostasis, such as through choline supplementation, can ameliorate these pathological phenotypes,” said Li-Huei Tsai, PhD, professor of neuroscience and director of the Picower Institute for Learning and Memory at MIT and senior author of the study.
Tsai and colleagues believe that supplementation with choline, which is naturally found in eggs, meat, and fish among other foods, could be an effective preventive treatment for individuals carrying high-risk mutations. In collaboration with the University of Texas and MD Anderson Cancer Center, the researchers are now running a clinical trial testing the effects of choline supplements in patients who carry the APOE4 variant.