Large Proteomic Study Flags Blood Biomarkers That Could Foretell Dementia

In the hunt for blood biomarkers that predict dementia risk, a large proteomics study has flushed out quarry both old and new. Researchers led by Jin-Tai Yu, Wei Cheng, and Jian-Feng Feng at Fudan University in Shanghai, China, analyzed plasma samples from more than 52,000 cognitively healthy older adults, correlating baseline protein levels with dementia incidence over the next 14 years.

  • Large, prospective proteomic study links blood proteins to dementia risk.
  • Elevated GFAP at baseline predicted all-cause dementia with 89 percent accuracy.
  • Cytokine GDF15 was most highly associated with vascular dementia.

In the February 12 Nature Aging, they report that the known risk proteins GFAP and NfL were the strongest predictors, each more than doubling the odds. The study also pulled out new associations, linking growth differentiation factor 15 (GDF15) to future vascular dementia, and the extracellular matrix protein latent transforming growth factor beta binding protein 2 (LTBP2) to Alzheimer’s disease. Both are members of the TGFβ family of secreted proteins. A handful of other new candidates turned up as well.

Dementia Predictors? A large prospective study linked several plasma proteins to future risk of Alzheimer’s. Top hits: GFAP, NfL, GDF15, and LTBP. [Courtesy of Guo et al., Nature Aging.]

Previous plasma proteome studies had been done in smaller cohorts, or used samples from people who already had dementia, curbing their ability to identify predictive markers (Tanaka et al., 2020; Hye et al., 2006; Walker et al., 2021). For a more comprehensive, prospective view, the authors turned to the U.K. Biobank cohort. This population study enrolled half a million people between age 39 and 70 and has followed them since 2006.

The authors selected 52,645 participants who were cognitively healthy at baseline and had donated blood for proteomic analysis. Their median age at the time was 58; 54 percent were women, 94 percent were white. Over 14 years of follow-up, 691 of them were diagnosed with AD, 285 with vascular dementia, and 441 with other dementia types.

Joint first authors Yu Guo, Jia You, and Yi Zhang mined recently released proteome data from the cohort. The dataset comprised 1,463 plasma proteins measured in baseline blood samples using Olink proteomics technology. Among them, 184 were associated with progression to all-cause dementia, 16 with AD, and 139 with vascular dementia. Notably, the Olink panel did not measure phosphorylated tau isoforms. Plasma p-tau217 is widely regarded as the most promising prognostic biomarker for AD (e.g., Feb 2023 news; Dec 2023 news; Jan 2024 news).

For Alzheimer’s, the top hits after GFAP, NfL, GDF15, and LTBP2 were the extracellular matrix protein brevican, the synaptic protein NPTXR, and CST5, which encodes the protease inhibitor cystatin D (see image above). LTBP2 and CST5 had not been previously linked to the disease.

Elevated GFAP at baseline was the most predictive, associated with a threefold higher risk of developing AD over the next 10 years. When combined with demographic data on sex, age, education, and APOE genotype, plasma GFAP predicted the onset of dementia of any type with 89 percent accuracy, the authors noted. In addition, GFAP was specific for dementia, unlike NfL, which rises in many neurodegenerative conditions.

GFAP may be a useful biomarker for dementia prediction, the authors suggested. However, Oskar Hansson at Lund University, Sweden, noted that GFAP adds no prognostic benefit for AD to models that contain p-tau217 (Mattsson-Carlgren et al., 2023).

For vascular dementia, the top hit was GDF15. It came with a 2.5 times higher risk of developing the disease. This was followed by NfL, GFAP, and matrix metalloprotease 12. Only NfL had been associated previously with vascular dementia. GDF15 is a cytokine that participates in inflammatory pathways, the stress response after cellular injury, and insulin signaling. It has been linked to vascular injury and dementia (McGrath et al., 2020; Walker et al., 2023).—Madolyn Bowman Rogers

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References

News Citations

  1. Paper Alert: Plasma P-tau217 Predicts Future Cognitive Decline
  2. Two New p-Tau217 Blood Tests Join a Crowded Field
  3. Paper Alert: p-Tau217 Blood Test Predicts Plaques, Tangles Over Time

Paper Citations

  1. Tanaka T, Lavery R, Varma V, Fantoni G, Colpo M, Thambisetty M, Candia J, Resnick SM, Bennett DA, Biancotto A, Bandinelli S, Ferrucci L. Plasma proteomic signatures predict dementia and cognitive impairment. Alzheimers Dement (N Y). 2020;6(1):e12018. Epub 2020 May 9 PubMed.
  2. Hye A, Lynham S, Thambisetty M, Causevic M, Campbell J, Byers HL, Hooper C, Rijsdijk F, Tabrizi SJ, Banner S, Shaw CE, Foy C, Poppe M, Archer N, Hamilton G, Powell J, Brown RG, Sham P, Ward M, Lovestone S. Proteome-based plasma biomarkers for Alzheimer's disease. Brain. 2006 Nov;129(Pt 11):3042-50. PubMed.
  3. Walker KA, Chen J, Zhang J, Fornage M, Yang Y, Zhou L, Grams ME, Tin A, Daya N, Hoogeveen RC, Wu A, Sullivan KJ, Ganz P, Zeger SL, Gudmundsson EF, Emilsson V, Launer LJ, Jennings LL, Gudnason V, Chatterjee N, Gottesman RF, Mosley TH, Boerwinkle E, Ballantyne CM, Coresh J. Large-scale plasma proteomic analysis identifies proteins and pathways associated with dementia risk. Nat Aging. 2021 May;1(5):473-489. Epub 2021 May 14 PubMed.
  4. Mattsson-Carlgren N, Salvadó G, Ashton NJ, Tideman P, Stomrud E, Zetterberg H, Ossenkoppele R, Betthauser TJ, Cody KA, Jonaitis EM, Langhough R, Palmqvist S, Blennow K, Janelidze S, Johnson SC, Hansson O. Prediction of Longitudinal Cognitive Decline in Preclinical Alzheimer Disease Using Plasma Biomarkers. JAMA Neurol. 2023 Apr 1;80(4):360-369. PubMed.
  6. Walker KA, Chen J, Shi L, Yang Y, Fornage M, Zhou L, Schlosser P, Surapaneni A, Grams ME, Duggan MR, Peng Z, Gomez GT, Tin A, Hoogeveen RC, Sullivan KJ, Ganz P, Lindbohm JV, Kivimaki M, Nevado-Holgado AJ, Buckley N, Gottesman RF, Mosley TH, Boerwinkle E, Ballantyne CM, Coresh J. Proteomics analysis of plasma from middle-aged adults identifies protein markers of dementia risk in later life. Sci Transl Med. 2023 Jul 19;15(705):eadf5681. PubMed.

Further Reading

Primary Papers

  1. Guo Y, You J, Zhang Y, Liu WS, Huang YY, Zhang YR, Zhang W, Dong Q, Feng JF, Cheng W, Yu JT. Plasma proteomic profiles predict future dementia in healthy adults. Nat Aging. 2024 Feb;4(2):247-260. Epub 2024 Feb 12 PubMed.

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