Olfactory Phenotypes Differentiate Cognitively Unimpaired Seniors from Alzheimer’s Disease and Mild Cognitive Impairment: A Combined Machine Learning and Traditional Statistical Approach

BACKGROUND Olfactory dysfunction (OD) is an early symptom of Alzheimer's disease (AD). However, olfactory testing is not commonly performed to test OD in the setting of AD. OBJECTIVE This work investigates objective OD as a non-invasive biomarker for accurately classifying subjects as cognitively unimpaired (CU), mild cognitive impairment (MCI), and AD. METHODS Patients with MCI (n = 24) and AD (n = 24), and CU (n = 33) controls completed two objective tests of olfaction (Affordable, Rapid, Olfactory Measurement Array -AROMA; Sniffin' Sticks Screening 12 Test -SST12). Demographic and subjective sinonasal and olfaction symptom information was also obtained. Analyses utilized traditional statistics and machine learning to determine olfactory variables, and combinations of variables, of importance for differentiating normal and disease states. RESULTS Inability to correctly identify a scent after detection was a hallmark of MCI/AD. AROMA was superior to SST12 for differentiating MCI from AD. Performance on the clove scent was significantly different between all three groups. AROMA regression modeling yielded six scents with AUC of the ROC of 0.890 (p <  0.001). Random forest model machine learning algorithms considering AROMA olfactory data successfully predicted MCI versus AD disease state. Considering only AROMA data, machine learning algorithms were 87.5%accurate (95%CI 0.4735, 0.9968). Sensitivity and specificity were 100%and 75%, respectively with ROC of 0.875. When considering AROMA and subject demographic and subjective data, the AUC of the ROC increased to 0.9375. CONCLUSION OD differentiates CUs from those with MCI and AD and can accurately predict MCI versus AD. Leveraging OD data may meaningfully guide management and research decisions.