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Cited by 35Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

ABCA7 variants impact phosphatidylcholine and mitochondria in neurons

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von Maydell, Djuna, Wright, Shannon E., Pao, Ping-Chieh, Staab, Colin, King, Oisín, Spitaleri, Andrea, Bonner, Julia Maeve, Liu, Liwang +15 more·2025·Nature
DOI 10.1038/s41586-025-09520-yPMC PMC12611789
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Abstract

Abstract Loss-of-function (LoF) variants in the lipid transporter ABCA7 significantly increase Alzheimer’s disease risk (odds ratio ≈ 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 dynamic 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- β 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.

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  • Lipid droplets have been associated with AD risk genes beyond APOE (PICALM and INPP5D in microglia and ABCA7 in neurons), suggesting convergent biology across risk genes.

    “Interestingly, lipid droplets have now been associated with AD risk genes beyond APOE (PICALM and INPP5D in microglia and ABCA7 in neurons), suggesting convergent biology across risk genes11,31,32.”

    From APOE genotypes differentially remodel the astrocytic lipid droplet proteome to shape lipid droplet dynamics (2026) · cites this paper as [32]

    The ‘ABCA7 LoF alters PC balance’ section reports accumulation of neutral lipids, including triglycerides, in ABCA7 loss-of-function neurons. The Discussion also links ABCA7-related lipid disruption with work on APOE4. Our copy does not show that the accumulated lipids form lipid droplets, so it supports the neuronal lipid-metabolism link but not the specific lipid-droplet association. (LLM, conf=0.82)

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Authors
von Maydell, D., Wright, S. E., Pao, P.-C., Staab, C., King, O., Spitaleri, A., Bonner, J. M., Liu, L., Yu, C. J., Chiu, C.-C., Leible, D., Ni Scannail, A., Li, M., Boix, C. A., Mathys, H., Leclerc, G., Menchaca, G. S., Welch, G., Graziosi, A., Leary, N., Samaan, G., Kellis, M., & Tsai, L.-H.
Affiliations
  • Massachusetts Institute of Technology (US)
  • University of Milan (IT)
  • Broad Institute (US)
  • University of Pittsburgh (US)
  • MIT Computer Science and Artificial Intelligence Laboratory (US)
Corresponding author
Tsai, Li-Huei
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2025-09-10
Volume
647
Issue
8089
Pages
462-471
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/s41586-025-09520-y
PMC
PMC12611789
OpenAlex
W4414090303
Cited by
35
References
18
Citations by year
2026: 27 · 2025: 5 · 2024: 2 · 2023: 1
FWCI
17.95
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by-nd)
  • Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, cc-by-sa)
  • Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
Funders
National Institute on Aging (RF1AG054012, RF1AG062377, RF1AG054321, R56AG081376, RF1AG075901, P30AG072975)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
ABCA7, Alzheimer's disease, loss-of-function mutations, phosphatidylcholine metabolism, lipid metabolism, mitochondrial dysfunction, excitatory neurons, DNA repair, synaptic signalling, amyloid-beta secretion, neuronal hyperexcitability, oxidative stress, iPSC-derived neurons, single-nucleus RNA sequencing

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