Comparison of Commonly Measured Plasma and Cerebrospinal Fluid Proteins and Their Significance for the Characterization of Cognitive Impairment Status

Article type: Research Article

Authors: Rehman, Habbiburr^a | Ang, Ting Fang Alvin^{b; c} | Tao, Qiushan^d | Espenilla, Arielle Lauren^{g; h} | Au, Rhoda^{a; b; c; h; i; j} | Farrer, Lindsay A.^{a; c; f; g; h; i; j} | Zhang, Xiaoling^{a; g; h; i; j; *} | Qiu, Wei Qiao^{b; c; d; e; j; *} | for the Alzheimer’s Disease Neuroimaging Initiative¹

Affiliations: [a] Department of Medicine (Biomedical Genetics), Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA | [b] Department of Anatomy & Neurobiology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA | [c] Department of Neurology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA | [d] Department of Pharmacology & Experimental Therapeutics, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA | [e] Department of Psychiatry, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA | [f] Department of Ophthalmology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA | [g] Department of Biostatistics and Boston University School of Public Health, Boston, MA, USA | [h] Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA | [i] Framingham Heart Study, Boston University School of Medicine, Framingham, MA, USA | [j] Alzheimer’s Disease Research Center, Boston University School of Medicine, Boston, MA, USA

Correspondence: [*] Correspondence to: Wendy Wei Qiao Qiu, MD, PhD, Boston University School of Medicine, 72 East Concord Street, R-623D, Boston, MA 02118, USA. E-mail: wqiu67@bu.edu. and Xiaoling Zhang, MD, PhD, Boston University School of Medicine, 72 East Concord Street, E223, Boston, MA 02118, USA. E-mail: zhangxl@bu.edu.

Note: [1] Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (https://adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf.

Abstract: Background:Although cerebrospinal fluid (CSF) amyloid-β42 peptide (Aβ42) and phosphorylated tau (p-tau) and blood p-tau are valuable for differential diagnosis of Alzheimer’s disease (AD) from cognitively normal (CN) there is a lack of validated biomarkers for mild cognitive impairment (MCI). Objective:This study sought to determine how plasma and CSF protein markers compared in the characterization of MCI and AD status. Methods:This cohort study included Alzheimer’s Disease Neuroimaging Initiative (ADNI) participants who had baseline levels of 75 proteins measured commonly in plasma and CSF (257 total, 46 CN, 143 MCI, and 68 AD). Logistic regression, least absolute shrinkage and selection operator (LASSO) and Random Forest (RF) methods were used to identify the protein candidates for the disease classification. Results:We observed that six plasma proteins panel (APOE, AMBP, C3, IL16, IGFBP2, APOD) outperformed the seven CSF proteins panel (VEGFA, HGF, PRL, FABP3, FGF4, CD40, RETN) as well as AD markers (CSF p-tau and Aβ42) to distinguish the MCI from AD [area under the curve (AUC) = 0.75 (plasma proteins), AUC = 0.60 (CSF proteins) and AUC = 0.56 (CSF p-tau and Aβ42)]. Also, these six plasma proteins performed better than the CSF proteins and were in line with CSF p-tau and Aβ42 in differentiating CN versus MCI subjects [AUC = 0.89 (plasma proteins), AUC = 0.85 (CSF proteins) and AUC = 0.89 (CSF p-tau and Aβ42)]. These results were adjusted for age, sex, education, and APOE ϵ4 genotype. Conclusions:This study suggests that the combination of 6 plasma proteins can serve as an effective marker for differentiating MCI from AD and CN.

Keywords: Alzheimer’s disease, biomarkers, mild cognitive impairment, proteins

DOI: 10.3233/JAD-230837

Journal: Journal of Alzheimer's Disease, vol. 97, no. 2, pp. 621-633, 2024