Anosmia Can Warn Us of More Than Just COVID

COVID-19 knocks out smell and taste so often and so abruptly that it can serve as an early warning of virus surges. Now, according to researchers from the Alzheimer’s Association International Conference, persistent anosmia 3 to 6 months after SARS-CoV-2 infection best predicted which older adults from the Andes mountains of Argentina had cognitive impairment.

Only longer-term follow-up will show if these cognitive losses resolve or progress as dementia. We should be unsettled that other researchers at the same meeting found that elderly patients hospitalized with COVID-19 who had toxic-metabolic encephalopathy also had some of the same plasma markers found in Alzheimer’s and neuroinflammatory conditions: tau, phosphorylated tau, neurofilament light, glial fibrillary acid protein, and ubiquitin carboxyl-terminal hydrolase L1.

Apart from COVID-19, anosmia often precedes Alzheimer’s and other neurodegenerative conditions. Even in young, healthy people, smell somehow connects with cognitive function. Why?

Smell drives memory like no other sensation. The musty odor of printer’s ink rockets me back to the Linotype press shop for my high school newspaper. All of us have similar smell-soaked memories. Smell enriches our lives in unseen ways, deepening our experience of food, flowers, friends, foes.

People who lose smell, whether from COVID-19, another infection, or trauma, complain of a flatness to living, a loss of zest. No smell of coffee, of bakeries, of a lover’s perfume. Years ago, I saw a patient whose traumatic anosmia disabled him from being a fire inspector, as he could no longer smell smoke. And over the years, countless anosmia patients have mourned with me the loss of food’s bouquet, restricted to the primary tastes of the tongue: sweet, sour, bitter, salt, and umami.

COVID-19 may attack the supporting “sustentacular” cells in the nasal epithelium, which carry abundant ACE2 receptors. This appears to knock out smell (and a good part of taste) for days to weeks, but some people lose smell for months. At autopsy, COVID-19 patients showed microvascular inflammation in the olfactory bulb and in other brain connections, though no evidence of SARS-CoV-2 infection was found in tissue samples. Perhaps on the less frequent occasions when COVID-19 somehow inflames the olfactory brain, this causes the prolonged anosmia found in many long COVID cases. Even this longer anosmia usually resolves, but perhaps leaves longer-lasting or permanent changes elsewhere in the brain.

From the nasal epithelium, olfactory neurons cross the cribriform plate to synapse on the olfactory bulb within the brain, which then connects directly to piriform cortex, the amygdala, and the entorhinal cortex. Smell is the only sensation that bypasses relay stations in the thalamus to connect directly with memory, emotion, and our visceral sense of self. Piriform cortex connects to the orbitofrontal cortex, where smell information integrates with other sensory modalities and emotion states, where you learn to enjoy certain foods and avoid unpleasant smells, but also learn to tell a gentle caress from a harsh wallop.

So, smell connects richly to memory, learning, and other brain functions. Functional MRI in people with traumatic anosmia demonstrates widespread reduced activation in orbitofrontal cortex, insula, and medial temporal structures involved in memory. And even in apparently healthy young people who did not have COVID-19, reduced smell, as measured by odor identification and discrimination, impacted frontal executive functions.

Olfactory information then connects from orbitofrontal cortex to insula and anterior cingulate, where our internal milieu — how I feel, what I feel — connects to the external world of sight, sound, touch, and smell.

The rich exterior world mirrors our complex inner world, built on body feelings layered with external and internal smell notes. Smell reminds the body of itself — waft of sweat, of breath within our mask, but without knowing it we also smell pheromones, potent chemical signals sent from one body to another. We understand more about pheromones in animals, but clear human signals of dominance, of availability reinforce our behavior by smell texts that our brain reads, while we think it’s our heart.

Smell provides a sense of place and of others, knit together with a feeling of me in the world. Data, in the key of smell, waft into our insular cortex where it joins with other body feelings and builds our sense of who we are and how we connect to the world of people and of environments.

Easy to imagine, then, how this system could be rewired by the plaques and tangles of Alzheimer’s and other neurodegenerative conditions, confounding social cues and draining the vital juice from daily living. Will COVID-19 produce cognitive losses that resolve, or progress into dementia?

As the damaged systems try to reboot, many COVID-19 patients complain of parosmias, distortions of usual smell and taste which are usually disagreeable. The Alzheimer’s patient usually gets something less dramatic: a gradual fading of bouquet, leaving some patients with an insatiable urge for sweet or salty foods. To track the progress or resolution of neuropsychiatric sequelae of COVID, an international consortium hopes to better understand the natural history of post-acute sequelae of SARS-CoV-2 (PASC) or long COVID.

Smell training shines a ray of hope. Prior to COVID-19, some patients with anosmia partially regained sensitivity by training with standard vials of specific smells. Now, with COVID-19, many people, including fine chefs and wine experts, are trying desperately to regain their palates. After 6 weeks of smell training, a randomized study demonstrated objective improvements in smell discrimination and sensitivity (in people who did not have COVID-19), along with MRI evidence of enhanced cortical thickness in right inferior frontal gyrus, bilateral fusiform gyri, and right entorhinal cortex. This measured increase in cortical thickness does not necessarily imply changes in any cognitive functions beyond the smell sense itself. However, preliminary studies suggest that smell training may improve cognitive scores in people with aging-related cognitive decline.

Could refining our own sense of smell protect against dementia? A course on wine tasting, or perfume appreciation, or any training that enhances our smell awareness, at least would make life a little richer, and maybe would somehow forfend the darkness to come.

James Santiago Grisolía, MD, is a clinical neurologist practicing in San Diego and is the Stroke Medical Director for Scripps Mercy Hospital, Chula Vista campus. Grisolía is also editor of the San Diego County Medical Society’s monthly magazine, San Diego Physician.