Research has demonstrated that olfactory dysfunction is often an early symptom and a potential biomarker of cognitive decline in neurodegenerative disorders — in particular, Alzheimer’s and Parkinson’s diseases — although the pathophysiology remains unclear. While cognitive decline is most often associated with older populations, concerns regarding long-COVID brain fog and persistent olfactory dysfunction warrant additional investigation to analyze findings among both young and elderly adults.
To home in on data specific to olfactory dysfunction and cognition in a younger demographic, Jonathan Overdevest, MD, an otolaryngologist at NewYork-Presbyterian and Columbia, and his colleagues conducted a scoping review of research evidence focused on a non-elderly population without neurodegenerative diseases. Below, Dr. Overdevest offers insights drawn from their comprehensive literature search.
What interested you in understanding olfactory dysfunction and cognition in younger people?
Our interest stemmed from our work with COVID-related olfactory dysfunction that involved evaluating the association between cognition and loss of smell. Prior to the pandemic, our group and collaborators had demonstrated that loss of olfaction is part of a broader constellation of symptoms that can portend the onset or transition from mild cognitive impairment or early-stage Alzheimer’s to worsening or progression of a patient’s neurodegenerative disease state.
In our COVID-related study, we looked at whether individuals who have a persistent loss of their sense of smell potentially have an increased risk for developing neurocognitive changes. What we experienced during the recruitment for our longitudinal study was that our participants who presented for ongoing smell loss were younger than had typically been evaluated in past studies of neurocognitive function, thus offering a unique opportunity to study smell and neurocognition in this population. With this in mind, we are hoping to further understand this association across the age continuum, beyond the more mature population typically included in studies of olfactory dysfunction and neurocognitive changes.
How did you conduct the literature review and what did it reveal?
Building on the recent inclusion of untreated vision impairment joining hearing loss as a modifiable risk factor for the development of dementia, we were interested in exploring whether the available literature may suggest that other sensory deficits, namely smell loss, may share a similar association. With a renewed interest in dementia prevention, we thus sought to include studies that evaluated smell and cognitive performance in younger, non-elderly adults under 60 years old.
One challenge with disease prevention and intervention, including such efforts in Alzheimer’s and related dementias, is identifying at-risk individuals before many key biomarkers or symptoms are visible. Thus, individual studies often don’t achieve a large enough sample to study this issue, which is why we sought to explore this association by compiling the results of many studies in our scoping review. Ultimately, we identified 167 relevant studies, with 54 selected for data extraction due to minimal biases and clarity of data. Of these, 34 studies contained specific data on individuals between the ages of 18 to 60. The etiologies for loss of smell in these studies were neuropsychiatric disorders (37%), idiopathic causes (25%), type 2 diabetes (7%), trauma (5%), infection (4%), intellectual disability (4%), and other causes (18%). Many of the relevant studies demonstrated mixed results, suggesting that some cognitive domains such as verbal fluency and memory may be associated with olfactory deficits, whereas other domains such as executive function do not seem to trend with olfactory performance. Overall, 21 of the 54 studies demonstrated a positive correlation between olfactory loss and diminished cognitive performance, seven studies demonstrated no association, 25 reported mixed results, and only one reported an inverse association between olfactory loss and cognitive performance.
What additional work is needed to help physicians effectively diagnose and treat olfactory dysfunction?
Compared to widespread and accessible testing options available to evaluate vision and hearing impairments, smell testing standards are not universal, are not well covered by insurance, and thus are often unavailable for patients. Moreover, for individuals with hearing and visual impairments, proper diagnosis is a step toward helping people receive interventional treatment, whereas such treatments don’t yet exist for smell loss. Without these pathways and standardized evaluations, it continues to be more difficult to develop interventions and treatments for olfactory dysfunction. Comprehensive data that can support the history and clinical factors related to olfactory deficits are scarce, which is one of the reasons why we wanted to conduct this literature review.
We also know that there are structural changes in individuals with smell loss, such as olfactory bulb atrophy and decreased representation in the olfactory tract pathways, but again, the psychophysical tests that can help diagnose smell issues are not commonly available in the majority of clinics. While there are tests that can assess an individual’s ability to correctly identify smells and others that can evaluate an individual’s ability to discriminate nuances between odors or measure the threshold odor intensity required for an individual to perceive an odor, the widespread availability of these tests is limited, and more quantitative assessments are not easily deployable or conclusive. To improve the availability and quality of smell tests available for patients, olfactory evaluations should be standardized, there should be identifiable providers for smell testing (similar to optometrists providing vision tests and audiologists conducting hearing tests), and there should be advances in the quantitative character of the tests themselves.
In addition to improving the infrastructure for evaluating olfactory dysfunction, expanding the treatment options for smell loss correction would be a significant improvement from the relatively few options currently in existence. Although anti-inflammatory approaches can potentially be introduced into the nasal cavity, these are not specifically targeted toward the underlying cause of the olfactory dysfunction, where clarity on which molecular mechanisms are driving specific forms of olfactory deficits would provide the insight required to develop targeted therapies. Through our ongoing research, we hope to address this gap in understanding by identifying the critical molecular contributors to the development of olfactory deficits. Once we understand the molecular drivers of why certain individuals and populations develop olfactory dysfunction, we may be able to use this knowledge to proactively reduce the risk of olfactory deficits contributing to cognitive decline.
