About 50–70% of people aged 65 years or older exhibit olfactory impairment (OI) (1). OI has been observed in patients with neurodegenerative diseases (NDDs) such as Alzheimer's disease (2), Parkinson's disease (PD) (3), or progressive supranuclear palsy (4); therefore, OI might be an early biomarker for a broad spectrum of NDDs. For example, in the neuropathological progression of PD, the olfactory bulb and the anterior olfactory nucleus are one of the first lesions within the central nervous system during the pathogenesis of PD. The lesions would continue to extend into more remote olfactory sites during the three to four pathological stages onward (5). Thus, olfactory impairment might be a manifestation and a potential diagnostic marker for early PD (6). Published literature indicates that OI is associated not only with NDDs, but also with increased mortality. A few longitudinal studies have shown an excessive relative risk for mortality as high as 20–112% in the elderly with OI, adjusted for age, sex, and other covariates (7, 8). Some studies have demonstrated the OI-mortality relationship in the middle-aged group (9, 10). In addition, some evidence indicates that the NDD is one of the leading causes of death and probably would overtake cancer by 2040 as the top one killer (11). Therefore, the NDD was considered as a possible mediator in the relationship between OI and mortality and explains the relationship partly (8, 12, 13).

However, the question arises as whether OI could proceed with the onset of neuropathological lesions or simply cause or potentiate by the neuropathologies (14)? Furthermore, cognitive performance at baseline may also tangle with the relationship (15), which makes the question even more complicated. So far, few studies have addressed the question and the findings remain controversial because of the diverse study design and data analysis method. In this study, we analyzed data collected from the prospective phase of the 10-year follow-up of the Shanghai Aging Study (SAS) to explore the mediation effect of NDDs on the OI-mortality relationship.

Olfactory dysfunction is reported as the only sensory, which has been associated with mortality, when compared with hearing or visual impairment (2). Although the OI-mortality relationship has been identified independently from incidence of dementia (7), current findings support the relationships between OI, NDDs, and mortality risk and some studies have further shown that cognitive function might be a potential mediator in the relationship (3, 12, 13). Devanand et al. found that the OI-mortality association was weaker when controlled for dementia, yet still statistically significant (13). Liu et al. showed that dementia could account for 22% of the higher 10-year mortality linked to poor olfactory function (3). Our findings have confirmed that OI was associated with mortality in older adults during a 9.4-year follow-up and the association was even stronger in the NDDs participants.

We also found that failure to identify certain odors, especially coffee or rose, was associated with a higher mortality risk and the association was mediated by NDDs. Failure to identify a specific odor-like coffee was also suggestive of reduced survival in another study (25); however, failure to smell rose has not been reported for this potential connection. The mediation of NDDs on the associations of coffee is weak. One hypothetical explanation for the absence or weak mediation of NDDs might be that OI happened, while the clinical cognitive function is not yet affected and, thus, undiagnosed (26); postmortem markers of NDDs existing in the brains of subjects without a diagnosis of NDDs have supported this speculation (27).

There are several strengths in this study. First, although a causal relationship between OI and mortality and the mediation by NDDs cannot be established in the observational study, the study design and the sequential happening of the exposure, mediator, and outcome have ruled out a reversed conclusion. Second, cognitive function at baseline has been controlled in this study. Third, abundant demographic and medical historical variables collected in the SAS offered us a unique opportunity to use the four-way decomposition method to attribute effects to interaction and to assess mediation. The four-way decomposition methods used in published related literature were essentially special cases of the four-way decomposition. The four-way decomposition method could provide maximum insight into how much of an effect is mediated by a potential mediator in an exposure-mediation-outcome causal pathway (23).

Limitations of this study cannot be ignored. First, besides the complicated diagnosis procedure of cognitive impairment, we defined participants with other NDDs only based on their medical records, not used standard inclusion/exclusion criteria. Some participants might have NDDs, but they ignored that and did not go to see doctors. So, the NDDs in this study might be underestimated. On the other hand, there may be misdiagnosis existed because NDDs diagnoses on the medical records were made by doctors from different levels of hospitals. Second, NDDs include a large spectrum of disorders with remarkable differences. In this study, it is not appropriate to take dementia, MCI, and PD into account as the homogeneous NDD. Third, the instrument we used to assess the olfactory function only has 12 sticks for 12 odors. This limited us in seeking odors that were more sensitive than these 12. Fourth, the SSST-12 evaluated the olfactory identification, which cannot completely present the olfactory function. Together with the odor discrimination, detection thresholds should be administered to define the olfactory impairment. Fifth, this study was an observational study with relatively small sample size. The association and the mediation effects resulting from the statistical analysis only could reflect the phenomenon or clue. Future studies should focus on the biological mechanism, which could deeply explain our findings.

This study indicated that OI was associated with the long-term mortality in older adults and the association was even stronger in those with NDDs. Failure to identify coffee or rose was associated with a higher mortality risk and the association was mediated by NDDs. This study result suggests a potential signal for predicting survival in the elderly, especially those with NDDs. The findings need to be further confirmed with larger cohort studies or with interventional design.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by the Shanghai Aging Study was approved by the Medical Ethical Committee of Huashan Hospital, Fudan University, Shanghai, China (approval number: 2009-195). The patients/participants provided their written informed consent to participate in this study.

YC and DD contributed to the design of the study, data analysis and interpretation, and drafting of the manuscript. ZX contributed drafting of the manuscript and data analysis. ZX, WW, and QZ contributed to the data collection of the study. All authors contributed to the critical revision of the manuscript for important intellectual content.

DD and QZ were supported by grants from the Shanghai Municipal Science and Technology Major Project (No. 2018SHZDZX01), the ZJ Lab, National Natural Science Foundation of China (81773513), and the State Key Laboratory of Neurobiology and Frontiers Center for Brain Science of Ministry of Education, Fudan University. The funding agencies had no role in the design of this study and will not have any role during its execution, analyses, interpretation of the data, or decision to submit results.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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