Summary: For decades, Alzheimer’s research has focused almost exclusively on toxic proteins like amyloid-beta and tau. However, a new study has identified a new culprit: dopamine dysfunction in the entorhinal cortex.
Researchers discovered that dopamine levels in this critical “memory gateway” drop to less than one-fifth of normal levels in Alzheimer’s models, preventing neurons from encoding new experiences. Most significantly, the study proved that memory could be restored using Levodopa, a common drug already FDA-approved for Parkinson’s disease.
Key Facts
- The Dopamine Drop: Dopamine levels in the entorhinal cortex were found to be reduced by over 80%, leaving neurons unable to respond to stimuli or form associative memories.
- Restoring Memory: Using both light-based (optogenetic) tools and the drug Levodopa, researchers successfully “rescued” memory function in mice, allowing them to learn and remember again.
- Circuit vs. Protein: While current treatments try to clear out protein plaques, this approach focuses on fixing the neuronal circuits that have already become dysfunctional.
- Repurposed Potential: Because Levodopa is already widely used for Parkinson’s, this discovery opens an immediate path for clinical trials to see if it can slow or reverse early memory loss in human Alzheimer’s patients.
Source: UC Irvine
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.
The research team also included Tatsuki Nakagawa, Jiayun L. Xie, Kiwon Park, Kai Cao, Marjan Savadkohighodjanaki, Yutian J. Zhang, Heechul Jun, Ayana Ichii, Jason Y. Lee, Shogo Soma, Yasmeen K. Medhat, at UC Irvine Department of Anatomy & Neurobiology; and Takaomi C. Saido, RIKEN Center for Brain Science, Japan.
Funding: This work was supported by NIH R01 grants from the National Institutes of Health (R01MH121736, R01AG063864, R01AG066806, R01AG086441, R01MH137156, RF1AG091584), a BrightFocus Foundation Research Grant (A2019380S), an Alzheimer’s Association Research Grant (AARG-17-532932), a Brain Research Foundation Grant (BRFSG-2017-04), a New Vision Research Award (CCAD201902), and a PRESTO grant from the Japan Science and Technology Agency (JPMJPR2481) to K.M.I. T.N. was supported by an Alzheimer’s Association Research Fellowship (AARF-22-923955) and a BrightFocus Foundation Fellowship Grant (A2022018F).
Key Questions Answered:
A: While dopamine is famous for reward, it also acts as a “save button” in the brain’s memory centers. Without enough dopamine in the entorhinal cortex, your brain can’t “stamp” a new experience into your long-term memory, which is why events seem to vanish in Alzheimer’s.
A: It’s a very promising possibility. This study showed that Levodopa normalized neural activity and improved memory performance. Since the drug is already safety-tested and available, it could theoretically be fast-tracked for Alzheimer’s research.
A: They still matter, but they might be the “arsonists” that started the fire. Even after you put out the fire (remove the proteins), the “house” (the dopamine circuit) is still damaged. This research suggests we need to repair the circuits to actually get the memory back.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this Alzheimer’s disease research news
Author: Carly Murphy
Source: UC Irvine
Contact: Carly Murphy – UC Irvine
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Early dopamine disruption in the entorhinal cortex of a knock-in model of Alzheimer’s disease” by Tatsuki Nakagawa, Jiayun L. Xie, Kiwon Park, Kai Cao, Marjan Savadkohighodjanaki, Yutian J. Zhang, Heechul Jun, Ayana Ichii, Jason Y. Lee, Shogo Soma, Yasmeen K. Medhat, Takaomi C. Saido & Kei M. Igarashi. Nature Neuroscience
DOI:10.1038/s41593-026-02260-w
Abstract
Early dopamine disruption in the entorhinal cortex of a knock-in model of Alzheimer’s disease
The entorhinal cortex is a critical brain area for memory formation, while also the region exhibiting the earliest histological and functional alterations in Alzheimer’s disease (AD).
The entorhinal cortex therefore has been long hypothesized as one of the originating brain areas of AD pathophysiology, although circuit mechanisms causing its selective vulnerability remain poorly understood.
Here we show that dopamine neurons projecting their axons to the lateral entorhinal cortex (LEC), critical for memory formation in healthy brains, become dysfunctional from the early pathological stage and cause associative memory impairments in amyloid precursor protein knock-in mice.
Dopamine dysfunction led to the disruption of associative memory encoding of LEC layer 2/3. Optogenetic reactivation of LEC dopamine fibers rescued associative learning behavior. L-DOPA treatment restored memory encoding of LEC neurons and associative memory of amyloid precursor protein knock-in mice.
These results suggest early dysfunction of LEC-projecting dopamine neurons underlie memory impairment in AD from early stages, pointing to a need for clinical investigation of LEC dopamine in patients with AD.
