ABCA7 variants impact phosphatidylcholine and mitochondria in neurons
Loss-of-function (LoF) variants in the lipid transporter ABCA7 significantly increase Alzheimer's disease risk (odds ratio circa  2), yet the underlying pathogenic mechanisms and specific neural cell types affected remain unclear. To investigate this, we generated a single-nucleus RNA sequencing atlas of 36 human postmortem prefrontal cortex samples, including 12 carriers of ABCA7 LoF variants and 24 matched non-carriers. ABCA7 LoF variants were associated with transcriptional changes across all major neural cell types. Excitatory neurons, which expressed the highest levels of ABCA7, showed significant alterations in oxidative phosphorylation, lipid metabolism, DNA damage responses, and synaptic signaling pathways. ABCA7 LoF-associated transcriptional changes in neurons were similarly perturbed in carriers of the common AD missense variant ABCA7 p.Ala1527Gly (n = 240 controls, 135 carriers) - predicted by molecular dynamics simulations to disrupt ABCA7 structure -, indicating that findings from our study may extend to large portions of the at-risk population. Human induced pluripotent stem cell (iPSC)-derived neurons carrying ABCA7 LoF variants closely recapitulated the transcriptional changes observed in human postmortem neurons. Biochemical experiments further demonstrated that ABCA7 LoF disrupts mitochondrial membrane potential via regulated uncoupling, increases oxidative stress, and alters phospholipid homeostasis in neurons, notably elevating saturated phosphatidylcholine levels. Supplementation with CDP-choline to enhance de novo phosphatidylcholine synthesis effectively reversed these transcriptional changes, restored mitochondrial uncoupling, and reduced oxidative stress. Additionally, CDP-choline normalized amyloid-beta secretion and alleviated neuronal hyperexcitability in ABCA7 LoF neurons. This study provides a detailed transcriptomic profile of ABCA7 LoF-induced changes and highlights phosphatidylcholine metabolism as a key driver in ABCA7-induced risk. Our findings suggest a promising therapeutic approach that may benefit a large proportion of individuals at increased risk for Alzheimer's disease. Overall design: RNA-seq profiling of induced neurons derived from two human isogenic iPSC lines, each homozygous for a distinct ABCA7 loss-of-function variant (p.Tyr622* or p.Glu50fs*3), generated from a parental control line lacking ABCA7 loss-of-function variants. Neurons were collected at Day 28, with or without treatment with CDP-choline during the final 14 days.