Wandering and getting lost is common among individuals with Alzheimer's disease, but what causes this disoriented behavior? New research reveals that it may be down to the buildup of an Alzheimer's-related protein, which interferes with the brain's GPS.

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Researchers suggest that a buildup of the protein tau may interfere with the brain's GPS.

The study reveals that the accumulation of a protein called tau, which is considered a hallmark of Alzheimer's disease, can damage nerve cells in the brain that help us to navigate our surroundings.

Co-study leader Dr. Karen Duff - of the Taub Institute for Research on Alzheimer's Disease and the Aging Brain at Columbia University Medical Center (CUMC) in New York - and colleagues publish their findings in the journal Neuron.

Alzheimer's disease is the most common form of dementia, accounting for around 60-80 percent of all cases.

The condition is characterized by a decline in cognitive functions, such as memory, learning, and problem-solving. People with Alzheimer's may also experience disorientation and behavioral changes, which can sometimes lead to wandering.

According to the Alzheimer's Association, approximately 6 in 10 people with the disease wander; they might have trouble recalling their name or address while out and about, or be unable to recognize their surroundings. This can put them at risk of injury.

Previous studies have suggested that wandering and other disoriented behaviors in Alzheimer's disease arise as a result of changes in the entorhinal cortex (EC), which is a brain structure involved in memory and navigation.

Dr. Duff and colleagues note that in Alzheimer's disease, the EC is one of the first areas of the brain to be affected by the buildup of tau - a protein that can twist and form "tangles" that are harmful to nerve cells.

However, precisely how tau can lead to problems with navigation has been unclear - until now.

Tau may reduce grid cells' ability to 'fire'

For their study, Dr. Duff and colleagues wanted to determine how tau affects grid cells, which are nerve cells in the EC that act as the brain's GPS. As we move through space, grid cells transmit electrical signals that create an internal map, helping us to navigate our environment.

To reach their findings, the researchers monitored the grid cells in two groups of older mice as they performed a series of spatial cognitive tasks. One group of mice had been genetically engineered to express tau in the EC, while the other group consisted of normal mice.

The researchers found that the tau-expressing mice were much less likely to be able to navigate their surroundings than the normal mice, indicating that tau interferes with grid cell function in the EC.

Further investigation of the rodents' brains showed that tau only destroyed or interfered with excitatory cells in the EC, not inhibitory cells. Excitatory cells are cells that transmit electrical signals, or "fire," while inhibitory cells suppress such signals.

According to the team, this finding suggests that tau reduces grid cells' ability to fire, making navigation difficult.

"It appears that tau pathology spared the inhibitory cells, disturbing the balance between excitatory and inhibitory cells and misaligning the animals' grid fields," says co-first study author Hongjun Fu, Ph.D., also of the Taub Institute.

Findings may advance Alzheimer's diagnosis and treatment

According to Dr. Eric Kandel, Kavli professor of brain science at CUMC, the team's study "clearly shows that tau pathology, beginning in the entorhinal cortex, can lead to deficits in grid cell firing and underlies the deterioration of spatial cognition that we see in human Alzheimer's disease."

He adds that this could further our understanding of the brain changes that arise in the early stages of Alzheimer's.

Furthermore, the researchers believe their findings indicate that deep brain stimulation and other therapies that target specific nerve cells have the potential to treat spatial disorientation in people with Alzheimer's.

However, study co-author Gustavo A. Rodriguez, Ph.D., also of the Taub Institute, notes that there is much more we need to learn about the role of grid cells in Alzheimer's.

"We don't yet know what percentage of healthy grid cells are needed for proper navigation or whether this system is rescuable once it has been compromised," he explains.

Still, Dr. Duff is confident that their discovery has the potential to benefit the millions of people living with Alzheimer's disease.

"[...] our findings suggest that it may be possible to develop navigation-based cognitive tests for diagnosing Alzheimer's disease in its initial stages. And if we can diagnose the disease early, we can start to give therapeutics earlier, when they may have a greater impact."

Dr. Karen Duff

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