ABCA7 variants impact phosphatidylcholine and mitochondria in neurons.

ABSTRACT: Loss-of-function variants in the lipid transporter ABCA7 substantially increase the risk of Alzheimer's disease^1,2, yet how they impact cellular states to drive disease remains unclear. Here, using single-nucleus RNA-sequencing analysis of human brain samples, we identified widespread gene expression changes across multiple neural cell types associated with rare ABCA7 loss-of-function variants. Excitatory neurons, which expressed the highest levels of ABCA7, showed disrupted lipid metabolism, mitochondrial function, DNA repair and synaptic signalling pathways. Similar transcriptional disruptions occurred in neurons carrying the common Alzheimer's-associated variant ABCA7 p.Ala1527Gly³, predicted by molecular dynamics simulations to alter the ABCA7 structure. Induced p

SUBMITTER: von Maydell D 

PROVIDER: S-EPMC12611789 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature