A single-cell atlas of ABCA7 loss-of-function reveals lipid disruptions, mitochondrial dysfunction and DNA damage in neurons

Abstract ABCA7 loss-of-function (LoF) variants dramatically increase the risk of Alzheimer’s disease (AD), yet the pathogenic mechanisms and the cell types affected by this loss remain largely unknown. Here, we performed single-nuclear RNA sequencing of 36 human post-mortem samples from the prefrontal cortex (PFC) of ABCA7 LoF carriers and matched control individuals. ABCA7 LoF variants were associated with perturbed gene clusters in all major cell types. Excitatory neurons, which expressed the highest levels of ABCA7, showed profound perturbations in gene clusters related to lipid metabolism, mitochondrial function, DNA damage, and NF-kB signaling. Given the known role of ABCA7 as a lipid transporter, we reasoned that ABCA7 LoF may mediate neuronal dysfunction by altering the lipidome, and evaluated lipid changes by untargeted mass-spectrometry. Indeed, ABCA7 LoF in post-mortem human PFC and iPSC-derived neurons showed widespread changes to the lipidome, including increased triacylglycerides and altered abundance of multiple phospholipid species. Consistent with these observations, assays on post-mortem human PFC and iPSC-derived ABCA7 LoF neurons (iNs) showed increased levels of mitochondrial dysfunction, DNA damage, and NF-kB activation, suggesting that ABCA7 LoF is a causal mediator of these disruptions in neurons. This study provides a detailed atlas of ABCA7 LoF in the human brain and suggests that lipid dysregulation in neurons may be an underlying insult by which ABCA7 LoF increases AD risk. One-Sentence Summary ABCA7 loss-of-function, associated with increased risk for Alzheimer’s, causes mitochondrial dysfunction, DNA damage, and lipid disruptions in neurons.