Accurate Diagnosis of Alzheimer’s Disease Using Specific Breath Volatile Organic Compounds

Whether volatile organic compounds (VOCs) from exhaled breath can be used as a novel biomarker for Alzheimer's disease (AD) diagnosis is unclear. To determine the significantly distinctive VOCs for AD, a total of 970 participants were enrolled, including 60 individuals in data set 1 (AD, 30; controls, 30), 164 individuals in data set 2 (AD, 82; controls, 82), 637 individuals in data set 3 (AD, 31; controls, 606), and 109 individuals in data set 4 (frontotemporal dementia, 19; vascular dementia, 21; Parkinson's disease, 69). The participants in data sets 1, 2, and 4 were from Xiangya Hospital, Central South University. Participants in data set 3 were from a two-year follow-up cohort. VOCs in breath and plasma, neuropsychological scores, plasma p-tau181 levels, metabolites in plasma, and brain functional connectivity were detected. We found that six VOCs were significantly different between the two groups in data set 1 and were verified in data set 2 and data set 3. Ethanol (m/z = 46) and pyrrole (m/z = 67) presented AUC values of 0.907 and 0.895 in data sets 1 and 2 (clinical data sets) and 0.849 and 0.974 in data set 3 (community data set), respectively. The six VOCs were associated with cognitive decline as reflected by neuropsychological tests; five of them were correlated with plasma p-tau181, and these five plasma VOCs were consistently altered as breath VOCs. Correlation between metabolites and five VOCs in plasma was noted, and the five VOCs may originate from blood metabolites. Moreover, four breath VOCs were associated with altered brain connectivity. In conclusion, specific breath VOCs may be used as biomarkers for AD detection.