How Rare Variants of the ABCA7 Gene Influence Alzheimer’s Disease Development

Recent research conducted by scientists at MIT has shed light on the role of rare gene variants, specifically in the ABCA7 gene, in contributing to Alzheimer's disease. This groundbreaking study reveals that certain dysfunctional versions of ABCA7, which are present in a very small segment of the population, significantly elevate the risk of developing this neurodegenerative disorder.

The ABCA7 gene encodes a protein crucial for the transportation of lipids across cell membranes, an essential process in maintaining healthy brain function. Mutations in this gene interfere with lipid metabolism, leading to alterations in cell membrane integrity and neuronal health. The study found that these mutations cause neurons to become hyperexcitable and enter a stressed state, which can result in DNA damage and other cellular dysfunctions.

Remarkably, the scientists discovered that these detrimental effects could be mitigated through the application of choline, a vital nutrient involved in the synthesis of cell membranes. Treatment with choline restored normal gene expression patterns and reduced neuronal hyperexcitability and amyloid beta production—protein aggregates that form plaques characteristic of Alzheimer’s pathology. This suggests that dietary supplementation with choline might offer a protective benefit.

The research team analyzed tissue samples from the Religious Orders Study/Memory and Aging Project, identifying individuals carrying rare ABCA7 variants. Single-cell RNA sequencing of neurons from these individuals revealed that many affected genes are involved in lipid metabolism, DNA repair, and energy production. In laboratory models, introducing these variants into neurons confirmed alterations in mitochondrial function, lipid processing, and increased oxidative stress.

Furthermore, experiments demonstrated that supplementing neurons with CDP-choline, a precursor to phosphatidylcholine, normalized mitochondrial function and lowered amyloid beta levels in brain organoids. These findings suggest that interventions targeting lipid metabolism could potentially slow or prevent the progression of Alzheimer’s disease in at-risk individuals.

This research aligns with previous findings about the APOE4 gene, another major genetic risk factor for Alzheimer’s, which also impairs lipid processing in brain cells. Importantly, the study highlights that even common variants of ABCA7—present in approximately 18% of the population—may have subtle effects on lipid metabolism that contribute to disease risk.

Overall, the study emphasizes the crucial relationship between lipid homeostasis and neuronal health and opens avenues for new therapeutic strategies focusing on metabolic regulation to combat Alzheimer’s disease.