A Novel Peptidome Technology for the Diagnosis of Mild Cognitive Impairment and Alzheimer’s Disease by Selected Reaction Monitoring

Article type: Research Article

Authors: Fukui, Yusuke^a | Tadokoro, Koh^a | Hamada, Minaki^b | Asada, Kyoichi^b | Lee, Lyang-Ja^b | Tachiki, Hidehisa^b | Morihara, Ryuta^a | Abe, Koji^c | Yamashita, Toru^{a; *}

Affiliations: [a] Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Kitaku, Okayama, Japan | [b] Protosera, Inc., KENTO Innovation Park NK, Settsu, Osaka, Japan | [c] Department of Neurology, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan

Correspondence: [*] Correspondence to: Dr. Toru Yamashita, Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmacy, 2-5-1 Shikata-cho, Okayama 700-8558, Japan. Tel.: +81 86 235 7365; Fax: +81 86 235 7368; E-mail: [email protected].

Abstract: Background:With the aging of populations worldwide, Alzheimer’s disease (AD) has become a concern due to its high prevalence and the continued lack of established treatments. Early diagnosis is required as a preventive intervention to modify the disease’s progression. In our previous study, we performed peptidomic analysis of serum samples obtained from AD patients and age-matched healthy subjects to seek peptide biomarker candidates for AD by using BLOTCHIP-MS analysis, and identified four peptides as AD biomarker candidates. Objective:The objective was to validate the serum biomarker peptides to distinguish mild cognitive impairment (MCI) and AD in comparison to cognitively healthy controls using a new peptidome technology, the Dementia Risk Test. Methods:We enrolled 195 subjects with normal cognitive function (NC; n = 70), MCI (n = 55), and AD (n = 70), The concentrations of cognitive impairment marker peptides (Fibrinogen α chain (FAC), Fibrinogen β chain (FBC), Plasma protease C1 inhibitor (PPC1I), α2-HS-glycoprotein (AHSG)) were quantified by using a selected reaction monitoring assay based on liquid chromatography-MS/MS. Results:The present study confirmed that three peptides, FAC, FBC, and PPC1I, were significantly upregulated during the onset of AD. This three-peptide set was both highly sensitive in determining AD (sensitivity: 85.7%, specificity: 95.7%, AUC: 0.900) and useful in distinguishing MCI (sensitivity: 61.8%, specificity: 98.6%, AUC: 0.824) from NC. Conclusions:In this validation study, we confirmed the high diagnostic potential of the three peptides identified in our previous study as candidate serum biomarkers for AD. The Dementia Risk Test may be a powerful tool for detecting AD-related pathological changes.

Keywords: Alzheimer’s disease, biochemical marker, dementia risk test, liquid chromatography-MS/MS, mild cognitive impairment, peptidome, selected reaction monitoring

DOI: 10.3233/JAD-230915

Journal: Journal of Alzheimer's Disease, vol. 100, no. 1, pp. 219-228, 2024