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Stem cell-derived neurons reflect features of protein networks, neuropathology, and cognitive outcome of their aged human donors
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We have generated a controlled and manipulable resource that captures genetic risk for Alzheimer's disease: iPSC lines from 53 individuals coupled with RNA and proteomic profiling of both iPSC-derived neurons and brain tissue of the same individuals. Data collected for each person include genome sequencing, longitudinal cognitive scores, and quantitative neuropathology. The utility of this resource is exemplified here by analyses of neurons derived from these lines, revealing significant associations between specific Aβ and tau species and the levels of plaque and tangle deposition in the brain and, more importantly, with the trajectory of cognitive decline. Proteins and networks are identified that are associated with AD phenotypes in iPSC neurons, and relevant associations are validated in brain. The data presented establish this iPSC collection as a resource for investigating person-specific processes in the brain that can aid in identifying and validating molecular pathways underlying AD.
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“We detected several SHIP1 binding partners previously identified in other myeloid cells, such as SH3KBP117, GRB218, SHC118, DOK218,19, ARAP120 and CD2AP21 (Figure 1D).”
From INPP5D/SHIP1 regulates endo-lysosomal function and cargo-selective phagocytosis in human microglia (2025) · cites this paper as [17]
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Metadata
- Authors
- Lagomarsino, V. N., Pearse, R. V., Liu, L., Hsieh, Y.-C., Fernandez, M. A., Vinton, E. A., Paull, D., Felsky, D., Tasaki, S., Gaiteri, C., Vardarajan, B., Lee, H., Muratore, C. R., Benoit, C. R., Chou, V., Fancher, S. B., He, A., Merchant, J. P., Duong, D. M., Martinez, H., Zhou, M., Bah, F., Vicent, M. A., Stricker, J. M. S., Xu, J., Dammer, E. B., Levey, A. I., Chibnik, L. B., Menon, V., Seyfried, N. T., De Jager, P. L., Noggle, S., Selkoe, D. J., Bennett, D. A., & Young-Pearse, T. L.
- Affiliations
- Brigham and Women's Hospital (US)
- New York Stem Cell Foundation (US)
- Centre for Addiction and Mental Health (CA)
- Rush University Medical Center (US)
- Columbia University Irving Medical Center (US)
- Emory University (US)
- Harvard University (US)
- ORCID
- Lagomarsino, Valentina N.
- Pearse, Richard V.
- Liu, Lei
- Hsieh, Yi-Chen
- Fernandez, Marty A.
- Vinton, Elizabeth A.
- Paull, Daniel
- Felsky, Daniel
- Tasaki, Shinya
- Gaiteri, Chris
- Vardarajan, Badri
- Lee, Hyo
- Benoit, Courtney R.
- Chou, Vicky
- Merchant, Julie P.
- Duong, Duc M.
- Stricker, Jonathan M.S.
- Xu, Jishu
- Dammer, Eric B.
- Levey, Allan I.
- Chibnik, Lori B.
- Menon, Vilas
- Seyfried, Nicholas T.
- Noggle, Scott
- Selkoe, Dennis J.
- Bennett, David A.
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2021-11
- Volume
- 109
- Issue
- 21
- Pages
- 3402-3420.e9
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC8571042
- OpenAlex
- W3198364341
- Cited by
- 151
- References
- 73
- Citations by year
- 2026: 15 · 2025: 37 · 2024: 36 · 2023: 37 · 2022: 20 · 2021: 6
- FWCI
- 16.97
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 367 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (R21MH118576, R01AG055909, RF1AG057440, R01AG061798, U01AG046170, R21AG056011, U01AG061356, R01NS117446, R01AG061894)
- National Institute on Aging (R01AG30146, R01AG36836, U01AG32984, U01AG46152, R01AG15819, R01AG017917, P30AG10161)
- New York Stem Cell Foundation
- Lawrence Ellison Foundation
- Illinois Department of Public Health
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, iPSC-derived neurons, genetic risk, amyloid-beta, tau protein, amyloid plaques, neurofibrillary tangles, cognitive decline, neuropathology, proteomic profiling, RNA profiling, protein networks, brain tissue
- MeSH terms
- Aged, Alzheimer Disease, Cognition, Humans, Neurons, Amyloid beta-Peptides, tau Proteins, Proteomics, Induced Pluripotent Stem Cells
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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