Dopamine deficiency found to drive memory impairment in Alzheimer’s disease, suggests study

Why do memories fade in Alzheimer’s disease – and can they be restored?

University of California, Irvine researchers have uncovered a key mechanism underlying memory loss, showing for the first time that dopamine dysfunction in the entorhinal cortex, a critical memory-related brain region, contributes directly to impaired memory formation.

The study, published today in Nature Neuroscience, identifies a previously unrecognized role for dopamine in Alzheimer’s-related cognitive decline and points to potential therapeutic strategies using existing drugs such as Levodopa.

Memory allows us to connect experiences – linking a smell to a place or a sound to an event. While research has established that memory formation depends on the medial temporal lobe, often referred to as the brain’s “memory center,” the precise neural mechanisms that break down in Alzheimer’s disease have remained unclear.

Researchers led by Kei Igarashi, Chancellor’s Fellow and associate professor of anatomy and neurobiology at the UC Irvine School of Medicine, focused on the entorhinal cortex, a key gateway to the hippocampus that plays a central role in memory. In earlier published work, the team discovered that dopamine is essential for memory formation in this region. In the present study, they investigated whether disruption of this dopamine system contributes to memory impairment in Alzheimer’s disease.

Using a mouse model of Alzheimer’s disease, the researchers found that dopamine levels in the entorhinal cortex were reduced to less than one-fifth of normal levels, and neurons no longer responded appropriately to stimuli that should be learned.

To determine whether restoring dopamine could rescue memory function, the team increased dopamine levels in the entorhinal cortex using optogenetic techniques. This intervention restored the mice’s ability to form memories. Importantly, administration of Levodopa – a drug widely used to treat Parkinson’s disease – also normalized neural activity and improved memory performance.

“We did not initially expect dopamine to be affected in Alzheimer’s disease,” Igarashi said. “However, as the evidence accumulated, it became clear that dopamine dysfunction plays a central role in memory impairment.”

Alzheimer’s disease affects tens of millions of people worldwide, and effective treatments remain limited. Current approaches have largely focused on removing toxic proteins such as amyloid-beta and tau from the brain, but these strategies often fail to restore memory once neuronal dysfunction has occurred.

This discovery provides an important new piece in understanding how memory circuits break down in Alzheimer’s disease and lays the groundwork for developing dopamine-based therapies. As associative memory declines early in the disease, targeting its underlying neural mechanisms may offer a promising path toward slowing cognitive decline.

Reference:

Nakagawa, T., Xie, J.L., Park, K. et al. Early dopamine disruption in the entorhinal cortex of a knock-in model of Alzheimer’s disease. Nat Neurosci (2026). https://doi.org/10.1038/s41593-026-02260-w