Early on in the 2014 award-winning film, Still Alice, the title character, Alice, who will soon be diagnosed with early-onset Alzheimer’s disease, loses her way during her daily run—suddenly unable to navigate a route and place she once knew very well. People with Alzheimer’s disease show similar issues with wayfinding and spatial navigation in the early stages of this debilitating neurodegenerative disorder. They also often show deficits in olfactory function, sense of smell, but it wasn’t clear how, or even if, these two wholly different symptoms might be related. A new study from researchers at McGill University helps to connect these symptoms and and the brain regions underlying them—potentially offering new insights into the role of smell in Alzheimer’s disease.

Navigating by smell alone

When most consider smell’s role in navigation, they think of animals—a rat sniffing out a piece of cheese or a dog using his nose to help find his way home.  While it is easy to think of humans relying predominantly on vision to help us navigate the world, all of our senses help us make our way.

“There’s no one sensory modality that tells us where we are,” says Daniel Dombeck, a neurobiologist at Northwestern University. “We use all of our senses, including vision and olfaction, to tell us where we are in space. But we don’t really know how all of these senses come together to do that.”

We also don’t know if only a single sense can provide enough information to successfully navigate. To see whether or not olfaction would be sufficient for rats to move in space, Dombeck and colleagues created a virtual reality system that allowed them to deliver specific odor cues to animals moving on a treadmill while removing all other sensory cues. They found, to their surprise, that the rats were able to navigate in this virtual world and used the same cells in the hippocampus seen when the animals used visual navigation strategies as they did so. The results were published on 26 February 2018 in Nature Communications.

“Just with olfactory cues, these animals could determine where they are, to a pretty high degree of precision—almost as good as they can with just visual cues,” he says. “It gives us some interesting targets to better understand what role smell may play in navigation.”

Different abilities, overlapping brain regions

If we understood better how smell and navigation are linked, we might better understand the pathologies that lead to Alzheimer’s disease and other disorders. Véronique Bohbot, a neuroscientist at McGill University, says that her goal, in looking at olfaction, was to “untangle” its role in Alzheimer’s disease.

“We know that Alzheimer’s disease begins in the hippocampus and the entorhinal cortex, an area of the brain involved with processing olfactory information, early on,” she says. “There seemed like there had to be a link there.”

Simultaneously, Bohbot’s former graduate student, Louisa Dahmani, now a post-doctoral fellow at Harvard Medical School, noted that similar brain regions, including the hippocampus, the brain’s long-term memory center, and the medial orbitofrontal cortex (mOFC), an area implicated in olfaction, kept popping up in studies separately investigating smell and spatial memory.

“These two very different functions seemed to rely on similar brain regions,” she says. “And we see impairments in these two functions co-occuring in diseases like Alzheimer’s and also in schizophrenia. So we wanted to study the question more directly.”

To investigate a potential link, Bohbot, Dahmani, and colleagues used structural magnetic resonance imaging (MRI) to look at the brains of 57 people as they completed a variety of spatial memory tasks, and, separately, identified a variety of different smells. The researchers discovered that participants who had a talent for spatial memory were also quite good at identifying smells—and, additionally, they tended to have a bigger right hippocampus as well as a thicker left mOFC. In a second experiment, the group looked at patients with damage to the mOFC and found they had issues with both the smell identification and spatial memory tasks. The results were published in 16 October 2018 in Nature Communications.

Dahmani says the findings that both tasks rely on mOFC suggest that these systems evolved in the brain at the same time.

“There has been a standing hypothesis that the olfactory system and the navigational system evolved together around the same time—and this study does provide some evidence towards that, even though we didn’t directly test that question,” she says. “The need to navigate and the need to interact with chemical stimuli is something that the whole animal kingdom seems to have in common.”

Moving forward

Dombeck says that Bohbot and Dahmani’s findings give him some new targets to test in his own research.

“It would be interesting to target the orbitofrontal cortex and look at animal’s abilities to discriminate between different odors and see if that correlates with how well they can learn to navigate these olfactory worlds,” he says. “It gives us new connections that we can probe more deeply to understand how the brain puts together sensory information so we can navigate our environments.”

Bohbot hopes to look at the brain’s olfactory areas to provide early biomarkers to identify who may be at risk for developing Alzheimer’s disease. She would like to further probe the links between smell and navigation to better understand their relationship and why they may go awry in disease.

“The early detection of a problem is fundamental to one day finding a cure. It’s possible we could do a simple smell test and then a more comprehensive navigation test to help us identify who is at risk,” she says. “Then we have a target population for intervention before clinical dysfunction begins.”