Brain HealthABCA7 Alzheimer's Gene Disrupts Brain Cell Lipids and Mitochondria
Scientists at MIT used single-nucleus RNA sequencing of human post-mortem brain tissue to map how loss-of-function variants in ABCA7 — a strong Alzheimer's risk gene — disrupt cell biology across multiple brain cell types. Excitatory neurons, which express the highest ABCA7 levels, showed the most damage: disrupted lipid metabolism, impaired mitochondrial function, elevated oxidative stress, and reduced synaptic signaling. Experiments in iPSC-derived neurons with ABCA7 variants confirmed these changes and revealed a specific breakdown in phosphatidylcholine synthesis. Remarkably, supplementing these neurons with CDP-choline restored phosphatidylcholine levels, normalized mitochondrial function, reduced amyloid-beta secretion, and reversed neuronal hyperexcitability — pointing to a potential therapeutic strategy for a major genetic subtype of Alzheimer's disease.
