ABCA7 variants impact phosphatidylcholine and mitochondria in neurons

Djuna von Maydell^{1

2}, Shannon E Wright^{1

2}, Ping-Chieh Pao^{1

2}, Colin Staab^{1

2}, Oisín King^{1

2}, Andrea Spitaleri³, Julia Maeve Bonner^{1

2}, Liwang Liu^{1

2}, Chung Jong Yu^{1

2}, Ching-Chi Chiu^{1

2}, Daniel Leible^{1

2}, Aine Ni Scannail^{1

2}, Mingpei Li^{1

2}, Carles A Boix^{4

5}, Hansruedi Mathys^{1

2

6}, Guillaume Leclerc⁴, Gloria Suella Menchaca^{1

2}, Gwyneth Welch^{1

2}, Agnese Graziosi^{1

2}, Noelle Leary^{1

2}, George Samaan^{1

2}, Manolis Kellis^{4

5}, Li-Huei Tsai^{7

8}

Affiliations

¹ Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA, USA.
² Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA.
³ Department of Medical Biotechnologies and Translational Medicine, University of Milano, Milan, Italy.
⁴ MIT Computer Science and Artificial Intelligence Laboratory, Cambridge, MA, USA.
⁵ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁶ Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA, USA.
⁷ Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA, USA. lhtsai@mit.edu.
⁸ Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA. lhtsai@mit.edu.

PMID: 40931065
DOI: 10.1038/s41586-025-09520-y

ABCA7 variants impact phosphatidylcholine and mitochondria in neurons

Djuna von Maydell et al. Nature. 2025.

. 2025 Sep 10.

doi: 10.1038/s41586-025-09520-y. Online ahead of print.

Authors

Affiliations

¹ Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA, USA.
² Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA.
³ Department of Medical Biotechnologies and Translational Medicine, University of Milano, Milan, Italy.
⁴ MIT Computer Science and Artificial Intelligence Laboratory, Cambridge, MA, USA.
⁵ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁶ Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA, USA.
⁷ Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA, USA. lhtsai@mit.edu.
⁸ Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA. lhtsai@mit.edu.

PMID: 40931065
DOI: 10.1038/s41586-025-09520-y

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 pluripotent stem (iPS)-cell-derived neurons with ABCA7 loss-of-function variants recapitulated these transcriptional changes, displaying impaired mitochondrial function, increased oxidative stress and disrupted phosphatidylcholine metabolism. Supplementation with CDP-choline increased phosphatidylcholine synthesis, reversed these abnormalities and normalized amyloid-β secretion and neuronal hyperexcitability-key Alzheimer's features that are exacerbated by ABCA7 dysfunction. Our results implicate disrupted phosphatidylcholine metabolism in ABCA7-related Alzheimer's risk and highlight a possible therapeutic approach.

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Conflict of interest statement

Competing interests: The authors declare no competing interests.

References

1. Steinberg, S. et al. Loss-of-function variants in ABCA7 confer risk of Alzheimer’s disease. Nat. Genet. 47, 445–447 (2015). - PubMed - DOI
1. Holstege, H. et al. Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer’s disease. Nat. Genet. 54, 1786–1794 (2022). - PubMed - PMC - DOI
1. Kunkle, B. W. et al. Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing. Nat. Genet. 51, 414–430 (2019). - PubMed - PMC - DOI
1. Abe-Dohmae, S. et al. Human ABCA7 supports apolipoprotein-mediated release of cellular cholesterol and phospholipid to generate high density lipoprotein. J. Biol. Chem. 279, 604–611 (2004). - PubMed - DOI
1. Wang, N. et al. ATP-binding cassette transporter A7 (ABCA7) binds apolipoprotein A-I and mediates cellular phospholipid but not cholesterol efflux. J. Biol. Chem. 278, 42906–42912 (2003). - PubMed - DOI

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ABCA7 variants impact phosphatidylcholine and mitochondria in neurons

Affiliations

ABCA7 variants impact phosphatidylcholine and mitochondria in neurons

Authors

Affiliations

Abstract

Conflict of interest statement

References

LinkOut - more resources

Full Text Sources