Progression of mild cognitive impairment (MCI) to Alzheimer’s disease (AD) dementia can be predicted by clinical features and a combination of biomarkers may increase the predictive power. In the present study, we investigated whether the combination of olfactory function and plasma neuronal-derived exosome (NDE) Aβ_1–42 can best predict progression to AD dementia.

87 MCI patients were enrolled and received the cognitive assessment at 2-year and 3-year follow-up to reevaluate cognition. In the meanwhile, 80 healthy controls and 88 AD dementia patients were enrolled at baseline as well to evaluate the diagnose value in cross-section. Olfactory function was evaluated with the sniffin sticks (SS-16) and Aβ_1–42 levels in NDEs were determined by ELISA. Logistic regression was performed to evaluate the risk factors for cognitive decline in MCI at 2-year and 3-year revisits.

In the cross cohort, lower SS-16 scores and higher Aβ_1–42 levels in NDEs were found in MCI and AD dementia compared to healthy controls. For the longitudinal set, 8 MCI individuals developed AD dementia within 2 years, and 16 MCI individuals developed AD dementia within 3 years. The two parameter-combination of SS-16 scores and Aβ_1–42 level in NDEs showed better prediction in the conversion of MCI to AD dementia at 2-year and 3-year revisit. Moreover, after a 3-year follow-up, SS-16 scores also significantly predicted the conversion to AD dementia, where lower scores were associated with a 10-fold increased risk of developing AD dementia (p = 0.006). Similarly, higher Aβ_1–42 levels in NDEs in patients with MCI increased the risk of developing AD dementia by 8.5-fold (p = 0.002).

A combination of two biomarkers of NDEs (Aβ_1–42) and SS-16 predicted the conversion of MCI to AD dementia more accurately in combination. These findings have critical implications for understanding the pathophysiology of AD dementia and for developing preventative treatments for cognitive decline.