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. 2021;79(2):511-530.
doi: 10.3233/JAD-200747.

APOE4 Copy Number-Dependent Proteomic Changes in the Cerebrospinal Fluid

Miles Berger  1   2   3 , Mary Cooter  1 , Alexander S Roesler  1 , Stacey Chung  1 , John Park  1 , Jennifer L Modliszewski  4 , Keith W VanDusen  1 , J Will Thompson  4 , Arthur Moseley  4 , Michael J Devinney  1 , Shayan Smani  1   5 , Ashley Hall  1 , Victor Cai  1   5 , Jeffrey N Browndyke  2   3   6 , Michael W Lutz  7 , David L Corcoran  4 ; and Alzheimer’s Disease Neuroimaging Initiative
Affiliations

APOE4 Copy Number-Dependent Proteomic Changes in the Cerebrospinal Fluid

Miles Berger et al. J Alzheimers Dis. 2021.

Erratum in

  • Erratum to: APOE4 Copy Number-Dependent Proteomic Changes in the Cerebrospinal Fluid.
    Berger M, Cooter M, Roesler AS, Chunga S, Park J, Modliszewski JL, VanDusen KW, Thompson JW, Moseley A, Devinney MJ, Smani S, Hall A, Cai V, Browndyke JN, Lutz MW, Corcoran DL; and Alzheimer’s Disease Neuroimaging Initiative. Berger M, et al. J Alzheimers Dis. 2022;90(3):1339-1340. doi: 10.3233/JAD-229018. J Alzheimers Dis. 2022. PMID: 36373324 Free PMC article. No abstract available.

Abstract

Background: APOE4 has been hypothesized to increase Alzheimer's disease risk by increasing neuroinflammation, though the specific neuroinflammatory pathways involved are unclear.

Objective: Characterize cerebrospinal fluid (CSF) proteomic changes related to APOE4 copy number.

Methods: We analyzed targeted proteomic data from ADNI CSF samples using a linear regression model adjusting for age, sex, and APOE4 copy number, and additional linear models also adjusting for AD clinical status or for CSF Aβ, tau, or p-tau levels. False discovery rate was used to correct for multiple comparisons correction.

Results: Increasing APOE4 copy number was associated with a significant decrease in a CRP peptide level across all five models (q < 0.05 for each), and with significant increases in ALDOA, CH3L1 (YKL-40), and FABPH peptide levels (q < 0.05 for each) except when controlling for AD clinical status or neurodegeneration biomarkers (i.e., CSF tau or p-tau). In all models except the one controlling for CSF Aβ levels, though not statistically significant, there was a consistent inverse direction of association between APOE4 copy number and the levels of all 24 peptides from all 8 different complement proteins measured. The odds of this happening by chance for 24 unrelated peptides would be less than 1 in 16 million.

Conclusion: Increasing APOE4 copy number was associated with decreased CSF CRP levels across all models, and increased CSF ALDOA, CH3L1, and FABH levels when controlling for CSF Aβ levels. Increased APOE4 copy number may also be associated with decreased CSF complement pathway protein levels, a hypothesis for investigation in future studies.

Keywords: Alzheimer disease; C-reactive protein; apolipoprotein E4; biomarker; cerebrospinal fluid; complement activation; mass spectrometry; neurogenic inflammation.

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Conflict of interest statement

Authors’ disclosures available online (https://www.j-alz.com/manuscript-disclosures/20-0747r2).

Figures

Fig. 1
Fig. 1
Volcano Plot of CSF Protein/Peptide Expression by APOE genotype, for the top 20 proteins and the complement cascade proteins in model 1 (A), and for the top 20 proteins and the complement cascade proteins in model 2 (B).
See this image and copyright information in PMC

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