Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
[Preprint]. 2024 Jun 13:2024.06.11.24308706.
doi: 10.1101/2024.06.11.24308706.

Alzheimer's disease CSF biomarkers correlate with early pathology and alterations in neuronal and glial gene expression

Ali S Ropri  1   2 , Tiffany G Lam  1   2 , Vrinda Kalia  3 , Heather M Buchanan  1   2 , Anne Marie W Bartosch  1   2 , Elliot H H Youth  1   2 , Harrison Xiao  1   2 , Sophie K Ross  1   2 , Anu Jain  4 , Jayanta K Chakrabarty  4 , Min Suk Kang  2   5 , Deborah Boyett  6 , Eleonora F Spinazzi  6 , Gail Iodice  7 , Robert A McGovern  8 , Lawrence S Honig  2   5 , Lewis M Brown  4 , Gary W Miller  3 , Guy M McKhann  6 , Andrew F Teich  1   2   5
Affiliations

Alzheimer's disease CSF biomarkers correlate with early pathology and alterations in neuronal and glial gene expression

Ali S Ropri et al. medRxiv. .

Update in

Abstract

Introduction: Normal pressure hydrocephalus (NPH) patients undergoing cortical shunting frequently show early AD pathology on cortical biopsy, which is predictive of progression to clinical AD. The objective of this study was to use samples from this cohort to identify CSF biomarkers for AD-related CNS pathophysiologic changes using tissue and fluids with early pathology, free of post-mortem artifact.

Methods: We analyzed Simoa, proteomic, and metabolomic CSF data from 81 patients with previously documented pathologic and transcriptomic changes.

Results: AD pathology on biopsy correlates with CSF β-amyloid-40/42, neurofilament light chain (NfL), and phospho-tau-181(p-tau181)/β-amyloid-42, while several gene expression modules correlate with NfL. Proteomic analysis highlights 7 core proteins that correlate with pathology and gene expression changes on biopsy, and metabolomic analysis of CSF identifies disease-relevant groups that correlate with biopsy data..

Discussion: As additional biomarkers are added to AD diagnostic panels, our work provides insight into the CNS pathophysiology these markers are tracking.

Keywords: Alzheimer’s disease; CSF; biomarkers; metabolomics; proteomics.

PubMed Disclaimer

Conflict of interest statement

Declaration of Interests/Conflicts: LSH reports grants from NIH, New York State Dept of Health, Lewy Body Disease Association, CurePSP, Abbvie, Acumen, Alector, Biogen, Bristol-Myer Squibb, Cognition, EIP, Eisai, Genentech/Roche, Janssen/Johnson and Johnson, Transposon Therapeutics, UCB, and Vaccinex, as well as consulting fees from Biogen, Corium, Eisai, Genentech/Roche, and New Amsterdam, Payment or honoraria from Eisai Pharmaceuticals, Medscape, and Biogen, Payment for expert testimony from Monsanto and legal firms, support for attending meetings and/or travel from Eisai Pharmaceuticals, participation on a data safety monitoring or advisory board from Prevail Therapeutics/Lilly, Cortexyme, and Eisai, and a leadership role in the Alzheimer’s Association. GWM reports grant funding from NIH, CancerUK, Department of Defense (USAMRAA), Alley Corp, and SPARK-NS. AFT reports grant funding from NIH and Regeneron, stock ownership in Biogen and Ionis, paid committee work for DOD and NIH, and unpaid committee work for the Alzheimer’s Association. RAM reports grants from NIH, Minnesota Partnership for Biotechnology and Genomics, Minnesota Robotics Institute, and MnDRIVE Data Science Initiative. GMM reports grants from NIH, consulting with Koh Young Inc and NeuroOne Technologies, participation on the Medronic SLATE trial Publication Committee, and leadership/committee roles in the Neurosurgical Society of America, AANS, and ASSFN. LMB reports support from NIH. The other authors have nothing to report.

Figures

Figure 1 –
Figure 1 –. AD pathology, gene expression modules, and AD CSF Simoa markers co-correlate
A) Top ontology groups characterizing our four modules reproduced from [10]. Saddlebrown and mediumpurple3 are both enriched for immune response ontology groups, and this is consistent with additional analysis using cell-type specific gene lists that showed that both modules are enriched for microglial genes [10]. We previously showed that the saddlebrown module is enriched for disease associated microglial (DAM) genes identified in AD mouse models, while mediumpurple3 is enriched for homeostatic genes, and this is consistent with saddlebrown positively correlating with AD pathology and mediumpurple3 negatively correlating with AD pathology. The darkgrey module is enriched for neuronal genes, and orange is enriched for astrocytic genes, although this enrichment is less obvious from its ontology analysis. B) Our four modules correlate with quantified β-amyloid and tau pathology on the 81 biopsies with CSF similarly to the correlations reported in [10]. For this study, we also added quantified GFAP staining, and correlations with the four modules are shown. In all three cases, FDR adjusted p-values are shown. C) Correlations of histologic data and gene expression modules with CSF Simoa measurements of AD biomarkers. * = FDR adjusted p-value < 0.05 (each column adjusted separately). All correlations shown in this figure are Spearman’s rank correlation coefficient. See text for details, and Supplementary Tables 3 and 4 for numbers used in this figure. The n for each Simoa analysis is variable due to some sample failure. In summary, 78 samples have CSF Aβ40/42 values, 80 have CSF ptau 181 values, 77 have CSF ptau 181/Aβ42 values, 80 have CSF tau values, and all 81 have CSF NfL values. GFAP staining was also only achieved on 80 samples. All other analyses here and in the rest of the study are completed on all 81 samples.
Figure 2 –
Figure 2 –. CSF proteomics data correlates with biopsy pathology and gene expression modules.
Seven core proteins are shown that pass our filters for reproducibility (see Methods). In A) we show the Spearman’s correlations of these proteins with the eigengene of the four modules and quantified β-amyloid, tau, and GFAP on biopsy. * = p-values < 0.05. In B) we show Spearman's correlation of 81 CSF samples with YKL-40 ELISA values vs. saddlebrown and orange module eigengenes and NPTXR ELISA values vs. darkgrey and mediumpurple3 module eigengenes. r and p values indicated. See Supplementary Tables 5 and 6 for numbers related to this figure.
Figure 3 –
Figure 3 –. CSF YKL-40 correlates with microglial and astrocytic genes.
Shown are the hub genes for the orange and saddlebrown modules, with astrocytic genes highlighted for orange and microglial genes highlighted for saddlebrown. Both modules correlate with CSF YKL-40. The mean gene expression vector of the astrocytic genes from orange and microglial genes from saddlebrown also correlate with YKL-40, supporting a role for these genes in the relationship between brain pathophysiology and CSF YKL-40. See Supplementary Table 7 for numbers used in this figure.
Figure 4 –
Figure 4 –. CSF metabolomics highlights AD relevant pathways.
We analyzed our CSF with high-resolution mass spectroscopy-based metabolomics in order to identify any biological pathways that may correspond to early AD pathology in brain tissue using mummichog (see Methods). Representative pathways that are predicted to be altered in tandem with AD histology and gene expression changes are shown. * = FDR p-values < 0.05. See Supplementary Table 8 for numbers used in this figure.
See this image and copyright information in PMC

Similar articles

See all similar articles

References

    1. Oliveira LM, Nitrini R, Roman GC. Normal-pressure hydrocephalus: A critical review. Dement Neuropsychol. 2019;13:133–43. - PMC - PubMed
    1. Williams MA, Malm J. Diagnosis and Treatment of Idiopathic Normal Pressure Hydrocephalus. Continuum (Minneap Minn). 2016;22:579–99. - PMC - PubMed
    1. Borgesen SE, Gjerris F. The predictive value of conductance to outflow of CSF in normal pressure hydrocephalus. Brain. 1982;105:65–86. - PubMed
    1. Symon L, Dorsch NW. Use of long-term intracranial pressure measurement to assess hydrocephalic patients prior to shunt surgery. Journal of neurosurgery. 1975;42:258–73. - PubMed
    1. McGovern RA, Nelp TB, Kelly KM, Chan AK, Mazzoni P, Sheth SA, et al. Predicting Cognitive Improvement in Normal Pressure Hydrocephalus Patients Using Preoperative Neuropsychological Testing and Cerebrospinal Fluid Biomarkers. Neurosurgery. 2019;85:E662–E9. - PubMed

Publication types