Finding their way home: How brain modeling could help Alzheimer’s patients
By Wendy Sutton
For the millions living with Alzheimer’s disease, finding their way home can become an overwhelming challenge, even in their own familiar neighborhoods.
This spatial disorientation, often called wandering, reflects a breakdown in the brain’s internal navigation system: a complex computational network that most of us rely on without realizing.
Omar Ahmed, associate professor of psychology at the University of Michigan, is working to understand how that system functions and why it fails in those with Alzheimer’s and many living with Parkinson’s. His lab combines experimental neuroscience with computational modeling to identify the brain regions, neurons and calculations that allow humans and many other animals to orient themselves and navigate through the world.
Many species, including humans, navigate using a process called dead reckoning, an internal sense of direction that continuously updates as we move, without reliance on external cues. A person standing on their street intuitively knows which direction their house is because the brain is constantly making that calculation.
Central to this process is the retrosplenial cortex, a region of the brain that appears fundamental for computing the angles that connect location A to location B. Damage to this region, whether from hemorrhages or glioblastoma, produces the same disorientation seen in patients with Alzheimer’s and Parkinson’s.
To understand the computations underlying navigation, Ahmed’s team first had to do extensive experimental work recording and characterizing every type of neuron in the retrosplenial cortex.
Read the full article in the Michigan Institute for Computational Discovery and Engineering Spring 2026 Magazine: https://micde.umich.edu/finding-their-way-home-how-brain-modeling-could-help-alzheimers-patients
“This is the brain saying, ‘Hey, that wasn’t active enough, so let’s put more synapses in’. The brain wants to operate at a set point. So if you take it below that point, it’s going to find ways to fix that less active state. Using psychedelics in a temporary capacity can rescue synaptic activity in Alzheimer’s mouse models, and that could not have been understood without the computational model.”
What they found was unexpected. The region contains a unique class of neuron found nowhere else in the brain.
These uniquely small neurons fire constantly, making the retrosplenial cortex one of the most metabolically demanding regions in the human brain. This constant firing is likely due to the continuous calculations being run, which are critical to survival.
A mouse in an open field that sees a predator’s shadow has less than one second to turn in the optimal direction and run for shelter. A wrong turn could be fatal. Ahmed believes this existential pressure is why these neurons demand such extraordinary metabolic resources.
Outside of the retrosplenial cortex, a separate class of neurons called head-direction cells encode which direction a person is pointing in the world, updating continuously as the head turns. The unique retrosplenial neurons are positioned to receive input from these head-direction cells through optimally positioned dendrites, branch-like extensions that carry signals toward a nerve cell’s body.
Using computational modeling, Ahmed’s team determined that the unique retrosplenial neurons take the incoming head‑direction signal to maintain a continuous, internal sense of orientation through multiple turns. This tracking includes not only the direction the head is facing, but where various markers are, such as the sun or home.
The team’s models allow them to simulate neuron behavior under conditions that would be impossible to test experimentally in real time. This ability to remove different factors and change ratios is critical because neurons are part of such a complex system.
To better understand why these neurons fail, Ahmed and his team are examining what a retrosplenial neuron looks like in a mouse model of Alzheimer’s. Physiologically, they appear nearly normal. The difference is a measurable decrease in the number of inputs coming from the head-direction cells.
“In Alzheimer’s, we often hear about amyloid plaques and tau tangles,” Ahmed said. “But these are just making synaptic connections worsen over time. At its core, Alzheimer’s disease is a synaptic deficit. That means that these neurons are getting fewer inputs from the head-direction cells. So the question becomes, how do we restore that?”
That question led Ahmed’s lab to investigate whether psychedelic compounds might have the answer. Funded by the University of Michigan’s Eisenberg Family Depression Center and the National Institutes of Health, the lab is uncovering whether those compounds can reverse the navigational deficits seen in Alzheimer’s.
Psychedelic drugs have already demonstrated clinical promise for treating major depression. In controlled clinical settings, using controlled doses, a single treatment can reduce symptoms for years by increasing the number of synaptic inputs in the prefrontal cortex.
Similarly, because Alzheimer’s is a synaptic deficit, Ahmed’s lab is exploring whether the same mechanism applies to the navigational deficit in Alzheimer’s.
When the brain is in the acute phase after the psychedelic drug is administered, Ahmed’s team has shown that neurons enter a state of decreased excitability, contrary to prior assumptions.
Just as physical exercise damages muscle fibers and the body responds by rebuilding them stronger, the brain detects this dampened excitability state and responds by building back more robust synaptic connections. This process is thought to be one reason why improvements from psychedelic treatment have been observed for years after a single session.
“This is the brain saying, ‘Hey, that wasn’t active enough, so let’s put more synapses in,’” Ahmed said. “The brain wants to operate at a set point. So if you take it below that point, it’s going to find ways to fix that less active state. Using psychedelics in a temporary capacity can rescue synaptic activity in Alzheimer’s mouse models, and that could not have been understood without the computational model.”
In a disease that can make even familiar places feel unknown, Ahmed’s research is leading to a new understanding of how the brain might find its way home again.