CoChat
Sign Up
Cited by 78Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

APOE ε4 carriers share immune-related proteomic changes across neurodegenerative diseases

Open access
Shvetcov, Artur, Johnson, Erik C. B., Winchester, Laura M., Walker, Keenan A., Wilkins, Heather M., Thompson, Terri G., Rothstein, Jeffrey D., Krish, Varsha +6 more·2025·Nature Medicine
DOI 10.1038/s41591-025-03835-zPMC PMC12353839
Open this paper in CoChat — free accountOpen PDF

Abstract

The APOE ε4 genetic variant is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD) and is increasingly being implicated in other neurodegenerative diseases. Using the Global Neurodegeneration Proteomics Consortium SomaScan dataset covering 1,346 cerebrospinal fluid (CSF) and 9,924 plasma samples, we used machine learning-based proteome profiling to identify an APOE ε4 proteomic signature shared across individuals with AD, frontotemporal dementia (FTD), Parkinson’s disease dementia (PDD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS) and nonimpaired controls. This signature was enriched in pro-inflammatory immune and infection pathways as well as immune cells, including monocytes, T cells and natural killer cells. Analysis of the dorsolateral prefrontal cortex proteome for 262 donors from the Accelerating Medicines Partnership for AD UPenn Proteomics Study revealed a consistent APOE ε4 phenotype, independent of neurodegenerative pathology, including amyloid-β tau and gliosis for all diseases, as well as TDP-43 in ALS and FTD cases, and α-synuclein in PD and PDD cases. While systemic proteomic changes were consistent across APOE ε4 carriers, their relationship with clinical and lifestyle factors, such as hypertension and smoking, varied by disease. These findings suggest APOE ε4 confers a systemic biological vulnerability that is necessary but not sufficient for neurodegeneration, emphasizing the need to consider gene–environment interactions. Overall, our study reveals a conserved APOE ε4-associated pro-inflammatory immune signature persistent across the brain, CSF and plasma irrespective of neurodegenerative disease, highlighting a fundamental, disease-independent biological vulnerability to neurodegeneration. This work reframes APOE ε4 as a pleiotropic immune modulator rather than an AD-specific risk gene, providing a foundation for precision biomarker development and early intervention strategies across neurodegenerative diseases.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/s41591-025-03835-z

Cites

14 of 14 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Recent work identified inflammatory signatures in APOE ε4/ε4 across brain, CSF, and plasma using high-powered cohorts.

    “This is underscored by recent work, which identified inflammatory signatures in APOE ε4/ε4 across brain, CSF, and plasma using high‐powered cohorts. 78”

    From Plasma extracellular vesicles from <i>APOE3</i> Christchurch carriers display a protective phenotype in early stages of autosomal dominant Alzheimer's disease (2026) · cites this paper as [78]

    The Discussion reports a pro-inflammatory APOE ε4-associated proteomic signature across brain, CSF and plasma, and Methods > Participants describes a large cohort of 11,270 people. However, the reported cross-tissue finding concerns ε4 carriers, including both heterozygotes and homozygotes; the paper does not establish it specifically for ε4/ε4 individuals across all three tissues. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 70

  1. [1]Belloy, M. E., Napolioni, V. & Greicius, M. D. A quarter century of APOE and Alzheimer’s disease: progress to date and the path forward. Neuron 101, 820–838 (2019). 30844401 PMC6407643
  2. [2]Fabre, S. F. et al. Clinic-based cases with frontotemporal dementia show increased cerebrospinal fluid tau and high apolipoprotein E ε4 frequency, but no tau gene mutations. Exp. Neurol. 168, 413–418 (2001). 11259129
  3. [3]Bernardi, L. et al. The effects of APOE and tau gene variability on risk of frontotemporal dementia. Neurobiol. Aging 27, 702–709 (2006). 15904995
  4. [4]Rubino, E. et al. Apolipoprotein E polymorphisms in frontotemporal lobar degeneration: a meta-analysis. Alzheimer’s Dement. 9, 706–713 (2013). 23688578
  5. [5]Ferrari, R. et al. Genetic architecture of sporadic frontotemporal dementia and overlap with Alzheimer’s and Parkinson’s diseases. J. Neurol. Neurosurg. Psychiatry 88, 152–164 (2017). 27899424 PMC5237405
  6. [6]Koriath, C. et al. ApoE4 lowers age at onset in patients with frontotemporal dementia and tauopathy independent of amyloid-β copathology. Alzheimer’s Dement. (Amst.) 11, 277–280 (2019). 30949567 PMC6430720
  7. [7]Li, Y. J. et al. Apolipoprotein E controls the risk and age at onset of Parkinson’s disease. Neurology 62, 2005–2009 (2004). 15184605
  8. [8]Ibanez, L. et al. Functional genomic analyses uncover APOE-mediated regulation of brain and cerebrospinal fluid β-amyloid levels in Parkinson disease. Acta Neuropathol. Commun. 8, 196 (2020). 33213513 PMC7678051
  9. [9]Drory, V. E., Birnbaum, M., Korczyn, A. D. & Chapman, J. Association of APOE ε4 allele with survival in amyotrophic lateral sclerosis. J. Neurol. Sci. 190, 17–20 (2001). 11574101
  10. [10]Zetterberg, H., Jacobsson, J., Rosengren, L., Blennow, K. & Andersen, P. A. Association of APOE with age at onset of sporadic amyotrophic lateral sclerosis. J. Neurol. Sci. 273, 67–69 (2008). 18656208
  11. [11]Real, R. et al. Association between the LRP1B and APOE loci and the development of Parkinson’s disease dementia. Brain 146, 1873–1887 (2022). PMC10151192 36348503
  12. [12]Mata, I. F. et al. APOE, MAPT, and SNCA genes and cognitive performance in Parkinson disease. JAMA Neurol. 71, 1405–1412 (2014). 25178429 PMC4227942
  13. [13]Szwedo, A. A. et al. GBA and APOE impact cognitive decline in Parkinson’s disease: a 10-year population-based study. Mov. Disord. 37, 1016–1027 (2022). 35106798 PMC9362732
  14. [14]Tan, M. M. X. et al. Genome-wide association studies of cognitive and motor progression in Parkinson’s disease. Mov. Disord. 36, 424–433 (2021). 33111402 PMC9053517
  15. [15]Tsuang, D. et al. APOE ε4 increases risk for dementia in pure synucleinopathies. JAMA Neurol. 70, 223–228 (2013). 23407718 PMC3580799
  16. [16]Jo, S. et al. The role of APOE in cognitive trajectories and motor decline in Parkinson’s disease. Sci. Rep. 11, 7819 (2021). 33837234 PMC8035327
  17. [17]Shvetcov, A. et al. Proteome profiling of cerebrospinal fluid using machine learning shows a unique protein signature associated with APOE4 genotype. Aging Cell 24, e14439 (2025). 39722190 PMC11984689
  18. [18]Mi, H., Muruganujan, A., Casagrande, J. T. & Thomas, P. D. Large-scale gene function analysis with PANTHER classification system. Nat. Protoc. 8, 1551–1566 (2019). PMC6519453 23868073
  19. [19]Uhlen, M. et al. A genome-wide transcriptomic analysis of protein-coding genes in human blood cells. Science 366, 6472 (2019). 31857451
  20. [20]Martinez-Martinez, A. B. et al. Beyond the CNS: the many peripheral roles of APOE. Neurobiol. Dis. 138, 104809 (2020). 32087284 PMC7195217
  21. [21]Butterworth, R. F. The liver-brain axis in liver failure: neuroinflammation and encephalopathy. Nat. Rev. Gastroenterol. Hepatol. 10, 522–528 (2013). 23817325
  22. [22]Sebastiani, P. et al. A serum protein signature of APOE genotypes in centenarians. Aging Cell 18, e13023 (2019). 31385390 PMC6826130
  23. [23]Fouquet, M., Besson, F. L., Gonneaud, J., La Joie, R. & Chetelat, G. Imaging brain effects of APOE4 in cognitively normal individuals across the lifespan. Neuropsychol. Rev. 24, 290–299 (2014). 25146994
  24. [25]Mishra, S. et al. Longitudinal brain imaging in preclinical Alzheimer disease: impact of APOE ε4 genotype. Brain 141, 1828–1839 (2018). 29672664 PMC5972633
  25. [26]Robinson, J. L. et al. Neurodegenerative disease concomitant proteinopathies are prevalent, age-related, and APOE4-associated. Brain 141, 2181–2193 (2018). 29878075 PMC6022546
  26. [27]Han, J.-D. J. et al. Evidence for dynamically organized modularity in the yeast protein–protein interaction network. Nature 430, 88–93 (2004). 15190252
  27. [28]Imam, F. et al. The Global Neurodegeneration Proteomics Consortium: biomarker and drug target discovery for common neurodegenerative diseases and aging. Nat. Med. 10.1038/s41591-025-03834-0 (2025). PMC12353841 40665048 · DOI
  28. [29]Van Exel, E. et al. Effect of APOE ε4 allele on survival and fertility in an adverse environment. PLoS ONE 12, e0179497 (2017). 28683096 PMC5500260
  29. [30]Martin, G. M. APOE alleles and lipophylic pathogens. Neurobiol. Aging 20, 441–443 (1999). 10604437
  30. [31]Finch, C. E. & Sapolsky, R. M. The evolution of Alzheimer disease, the reproductive schedule, and apoE isoforms. Neurobiol. Aging 20, 407–428 (1999). 10604433
  31. [32]Tuminello, E. R. & Han, D. S. The apolipoprotein E antagonistic pleiotropy hypothesis: review and recommendations. Int. J. Alzheimer’s Dis. 2011, 726197 (2011). 21423560 PMC3056453
  32. [33]Gale, S. C. et al. APOε4 is associated with enhanced in vivo innate immune responses in humans. J. Allergy Clin. Immunol. 134, 127–134 (2015). PMC4125509 24655576
  33. [34]Fernandez-Calle, R. et al. APOE in the bullseye of neurodegenerative diseases: impact of the APOE genotype in Alzhiemer’s disease pathology and brain diseases. Mol. Neurodegener. 17, 62 (2022). 36153580 PMC9509584
  34. [36]Gallagher, M. D. & Chen-Plotkin, A. S. The post-GWAS era: from association to function. Am. J. Hum. Genet. 102, 717–730 (2018). 29727686 PMC5986732
  35. [37]Ashton, N. J. et al. A multicentre validation study of the diagnostic value of plasma neurofilament light. Nat. Commun. 12, 3400 (2021). 34099648 PMC8185001
  36. [38]Gotze, K. et al. Plasma neurofilament light chain as prognostic marker of cognitive decline in neurodegenerative diseases, a clinical setting study. Alzheimer’s Res. Ther. 16, 231 (2024). 39427171 PMC11490051
  37. [39]Lin, Y.-S., Lee, W.-J., Wang, S.-J. & Fuh, J.-L. Levels of plasma neurofilament light chain and cognitive function in patients with Alzheimer or Parkinson disease. Sci. Rep. 8, 17368 (2018). 30478269 PMC6255914
  38. [40]Malek-Ahmadi, M. et al. Plasma NfL is associated with the APOE ε4 allele, brain imaging measurements of neurodegeneration, and lower recall memory scores in cognitively unimpaired late-middle-aged and older adults. Alzheimer’s Res. Ther. 15, 74 (2023). 37038190 PMC10084600
  39. [41]Frick, E. A. et al. Serum proteomics reveal APOE-ε4-dependent and APOE-ε4-independent protein signatures in Alzheimer’s disease. Nat. Aging 4, 1446–1464 (2024). 39169269 PMC11485263
  40. [42]Mattson, N., Andreassen, O. A., Zetterberg, H., Blennow, K. & Alzheimer’s Disease Neuroimaging Initiative. Association of plasma neurofilament light with neurodegeneration in patients with Alzheimer disease. JAMA Neurol. 74, 557–566 (2017). 28346578 PMC5822204
  41. [43]Rutledge, J. et al. Comprehensive proteomics of CSF, plasma, and urine identify DDC and other biomarkers of early Parkinson’s disease. Acta Neuropathol. 147, 52 (2024). 38467937 PMC10927779
  42. [45]Montagne, A. et al. APOE4 leads to blood–brain barrier dysfunction predictive cognitive decline. Nature 581, 71–76 (2020). 32376954 PMC7250000
  43. [46]Sweeney, M. D., Montagne, A., Sagare, A. P., Nation, D. A. & Zlokovic, B. V. Broken blood–brain barrier in Alzheimer’s disease and other neurodegenerative disorders. Nat. Rev. Neurol. 15, 133–150 (2019). PMC5829048 29377008
  44. [47]Ziegler-Heitbrock, L. The CD14 + and CD16 + blood monocytes: their role in infection and inflammation. J. Leukoc. Biol. 81, 584–592 (2007). 17135573
  45. [48]Wong, K. L. et al. The three human monocyte subsets: implications for health and disease. Immunol. Res. 53, 41–57 (2012). 22430559
  46. [50]Hayday, A. C. γδ Cells: a right time and a right place for a conserved third way of protection. Annu. Rev. Immunoloy 18, 975–1026 (2000). 10837080
  47. [52]Lanier, L. L. NK cell recognition. Annu. Rev. Immunoloy 23, 225–274 (2005). 15771571
  48. [53]Filippini, N. et al. Distinct patterns of brain activity in young carriers of the APOE-ε4 allele. Proc. Natl Acad. Sci. USA 106, 7209–7214 (2009). 19357304 PMC2678478
  49. [55]Andre, C. et al. Reduced rapid eye movement sleep in late middle-aged and older apolipoprotein E ε4 allele carriers. Sleep 47, zsae094 (2024). 38634644 PMC11236949
  50. [57]Seeley, W. W., Crawford, R. K., Zhou, J., Miller, B. L. & Greicius, M. D. Neurodegenerative diseases target large-scale human brain networks. Neuron 62, 42–52 (2009). 19376066 PMC2691647
  51. [58]Ramanan, V. K. & Saykin, A. J. Pathways to neurodegeneration: mechanistic insights from GWAS in Alzheimer’s disease, Parkinson’s disease, and related disorders. Am. J. Neurodegener. Dis. 2, 145–175 (2013). 24093081 PMC3783830
  52. [59]Harris, K. et al. The impact of routine vaccinations on Alzheimer’s disease risk in persons 65 years and older: a claims-based cohort study using propensity score matching. J. Alzheimer’s Dis. 95, 703–718 (2023). 37574727 PMC10578243
  53. [61]Eyting, M. et al. A natural experiment on the effect of herpes zoster vaccination on dementia. Nature 641, 438–446 (2025). 40175543 PMC12058522
  54. [62]Taquet, M., Dercon, Q., Todd, J. A. & Harrison, P. J. The recombinant shingles vaccine is associated with lower risk of dementia. Nat. Med. 30, 2777–2781 (2024). 39053634 PMC11485228
  55. [66]Dunk, M. M. et al. Relationships between APOE, type 2 diabetes, and cardiovascular disease in postmenopausal women. J. Gerontol. A Biol. Sci. Med. Sci. 80, glae246 (2025). 39364911 PMC11775828
  56. [67]Lahoz, C. et al. Apolipoprotein E genotype and cardiovascular disease in Framingham Heart Study. Atherosclerosis 154, 529–537 (2001). 11257253
  57. [69]Carroll, C. et al. Addressing comorbidities in people with Parkinson’s disease: considerations from an expert panel. J. Parkinson’s Dis. 14, 53–63 (2024). 38217610 PMC10836549
  58. [70]Mirra, S. S. et al. The Consortium to Establish a Registry for Alzheimer’s disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer’s disease. Neurology 41, 479–486 (1991). 2011243
  59. [73]Ince, P. G., Lowe, J. & Shaw, P. J. Review. Neuropathol. Appl. Neurobiol. 24, 104–117 (1998). 9634206
  60. [75]Williams, S. A. et al. Plasma protein patterns as comprehensive indicators of health. Nat. Med. 25, 1851–1857 (2019). 31792462 PMC6922049
  61. [76]Johnson, E. C. B. et al. Large-scale proteomic analysis of Alzheimer’s disease brain and cerebrospinal fluid reveals early changes in energy metabolism associated with microglia and astrocyte activation. Nat. Med. 26, 769–780 (2020). 32284590 PMC7405761
  62. [77]Ross, B. C. Mutual information between discrete and continuous data sets. PLoS ONE 9, e87357 (2014). 24586270 PMC3929353
  63. [78]Fayyad, U. M. & Irani, K. B. Multi-interval discretization of continuous-valued attributes for classification learning. In Proc.13th International Joint Conference on Uncertainty in Artificial Intelligence 1022–1027 (1993).
  64. [79]Wickham, H. ggplot2: Elegant Graphics for Data Analysis (Springer-Verlag, 2016).
  65. [80]Xia, J., Benner, M. J. & Hancock, R. E. W. NetworkAnalyst—integrative approaches for protein–protein interaction network analysis and visual exploration. Nucleic Acids Res. 42, W167–W174 (2014). 24861621 PMC4086107
  66. [81]Xia, J., Gill, E. & Hancock, R. E. W. NetworkAnalyst for statistical, visual and network-based approaches for meta-analysis of expression data. Nat. Protoc. 10, 823–844 (2015). 25950236
  67. [82]Zhou, G. et al. NetworkAnalyst 3.0: a visual analytics platform for comprehensive gene expression profiling and meta-analysis. Nucleic Acids Res. 47, W234–W241 (2019). 30931480 PMC6602507
  68. [83]Orchard, S. et al. Protein interaction data curation—the International Molecular Exchange Consortium (IMEx). Nat. Methods 9, 345–350 (2013). PMC3703241 22453911
  69. [84]Breuer, K. et al. InnateDB: systems biology of innate immunity and beyond—recent updates and continuing curation. Nucleic Acids Res. 41, 1228–1233 (2013). PMC3531080 23180781
  70. [85]Kanehisa, M. & Goto, S. KEGG: Kyoto Encyclopedia of Genes and Genomes. Nucleic Acids Res. 38, 27–30 (2000). PMC102409 10592173

Cited by

Sorted by citations

Authors
Shvetcov, A., Johnson, E. C. B., Winchester, L. M., Walker, K. A., Wilkins, H. M., Thompson, T. G., Rothstein, J. D., Krish, V., Imam, F. B., The Global Neurodegeneration Proteomics Consortium (GNPC), Burns, J. M., Swerdlow, R. H., Slawson, C., & Finney, C. A.
Affiliations
  • The University of Sydney (AU)
  • Emory University (US)
  • University of Oxford (GB)
  • National Institute on Aging (US)
  • University of Kansas (US)
  • Johns Hopkins University (US)
  • Gates Ventures (US)
Corresponding author
  • Shvetcov, Artur
  • Finney, Caitlin A.
ORCID
Venue
Nature Medicine
Publisher
Springer Science and Business Media LLC
Published
2025-07-15
Volume
31
Issue
8
Pages
2590-2601
ISSN
  • 1078-8956 (ISSN-L)
  • 1546-170X
DOI
10.1038/s41591-025-03835-z
PMC
PMC12353839
OpenAlex
W4412451589
Cited by
78
References
14
Citations by year
2026: 54 · 2025: 23 · 2021: 1
FWCI
49.55
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Medicine (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • Department of Health | National Health and Medical Research Council (MRF2040081)
  • Neil & Norma Hill Foundation Annemarie & Arturo Gandioli-Fumagali Foundation Perpetual Foundation - John Williams Endowment Hillcrest Foundation
  • U.S. Department of Health & Human Services | National Institutes of Health (K08AG08604, R01AG089497, P50AG025688, P30AG072973, R21TR003589, R01AG07816, U19AG068054, R35NS132179, R01AG064227)
  • Alzheimer's Research UK
  • Alzheimer's Association (23AARG-1023)
  • Answer ALS Foundation Robert Packard Center for ALS Research at Johns Hopkins University
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
APOE ε4, neurodegenerative diseases, Alzheimer's disease, frontotemporal dementia, Parkinson's disease dementia, Parkinson's disease, amyotrophic lateral sclerosis, cerebrospinal fluid proteomics, plasma proteomics, dorsolateral prefrontal cortex, immune signatures, pro-inflammatory pathways, monocytes, T cells, natural killer cells, gene-environment interaction, biomarkers, hypertension, smoking
MeSH terms
Aged, Alzheimer Disease, Amyotrophic Lateral Sclerosis, Female, Heterozygote, Humans, Male, Middle Aged, Parkinson Disease, tau Proteins, Neurodegenerative Diseases, Proteome, Proteomics, alpha-Synuclein, Apolipoprotein E4, Frontotemporal Dementia

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.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review