Summary: For decades, Alzheimer’s research has largely targeted toxic proteins such as amyloid-beta and tau. A new study from UC Irvine identifies a different contributing factor: early dopamine dysfunction in the entorhinal cortex, a critical brain region for forming new memories.
Researchers report that dopamine levels in this memory gateway drop to under 20% of normal in an Alzheimer’s mouse model, preventing neurons from encoding new experiences. Crucially, the team demonstrated that memory function could be restored using Levodopa, a drug already approved for Parkinson’s disease.
Key Facts
- Severe Dopamine Loss: Dopamine in the entorhinal cortex was reduced by more than 80%, leaving neurons unresponsive to stimuli needed for associative memory formation.
- Memory Rescue: Both optogenetic stimulation of dopamine fibers and administration of Levodopa reinstated normal neural activity and allowed mice to learn and remember again.
- Circuit Repair vs. Protein Clearance: Unlike approaches that aim to clear amyloid and tau, this strategy targets the neuronal circuits already damaged in Alzheimer’s disease.
- Clinical Potential: Because Levodopa is an established, FDA-approved therapy for Parkinson’s, these findings could accelerate translational research to evaluate dopamine-based treatments for early memory loss in people with Alzheimer’s.
Source: UC Irvine
Why do memories fade in Alzheimer’s disease, and is restoration possible?
UC Irvine researchers reveal a previously unrecognized mechanism: early loss of dopamine signaling in the entorhinal cortex directly undermines the brain’s ability to encode new memories.
Published in Nature Neuroscience, the study offers new insight into cognitive decline by showing that dopamine disruption in a specific memory-related circuit contributes to Alzheimer’s-associated memory impairment and suggests a practical therapeutic avenue using existing medications like Levodopa.
Memory depends on linking sensations and experiences — for example, associating a smell with a place or a sound with an event. Although the medial temporal lobe has long been recognized as essential for memory, the exact circuit-level breakdowns that lead to memory loss in Alzheimer’s have been unclear.
Led by Kei Igarashi, Chancellor’s Fellow and associate professor of anatomy and neurobiology at the UC Irvine School of Medicine, the team focused on the entorhinal cortex, the primary gateway to the hippocampus and a central node for forming associative memories.
Building on prior work showing that dopamine supports memory formation in this region, the researchers tested whether impairment of the dopamine system contributes to Alzheimer’s-related memory deficits. Using an amyloid precursor protein knock-in mouse model, they measured dopamine levels and neuronal responses in the lateral entorhinal cortex (LEC).
They found dramatic depletion of dopamine — to less than a fifth of normal concentrations — and observed that LEC neurons no longer encoded stimuli that should form associative memories. To test reversibility, the investigators used optogenetic stimulation to reactivate dopamine inputs to the LEC, which restored associative learning behavior. Administration of Levodopa likewise normalized LEC neural responses and improved memory performance in the mice.
“We did not initially expect dopamine to be affected in Alzheimer’s disease,” Igarashi said. “But as our data accumulated, it became clear that early dopamine dysfunction in the entorhinal cortex plays a central role in disrupting memory.”
Alzheimer’s disease impacts tens of millions worldwide and remains without broadly effective treatments to restore lost memory. Many current therapies aim to remove protein aggregates such as amyloid-beta and tau, yet clearing these proteins does not always recover memory once circuits are damaged. This study highlights the need to repair or restore circuit function — specifically LEC-projecting dopamine neurons — to recover memory capabilities.
By pinpointing an early, reversible circuit deficit, the findings support further clinical investigation of dopamine-targeted interventions for early-stage Alzheimer’s. Because Levodopa is already in clinical use for Parkinson’s disease, it may provide a practical path for early trials assessing whether dopamine restoration can slow or reverse cognitive decline in humans.
The research team includes 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 (UC Irvine Department of Anatomy & Neurobiology), and Takaomi C. Saido (RIKEN Center for Brain Science, Japan).
Funding: This work received support from multiple NIH R01 grants (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: Dopamine is widely known for reward signaling, but it also functions as a neural “save” signal in memory regions. Sufficient dopamine in the entorhinal cortex is required for marking new experiences so they can be consolidated into long-term memory. When dopamine is lost, the brain fails to encode those experiences effectively, which contributes to memory loss in Alzheimer’s.
A: The results are encouraging. In this mouse model, Levodopa restored neural activity and improved associative memory. Because Levodopa has an established safety profile for Parkinson’s disease, it may be feasible to test its effects on early cognitive symptoms in controlled clinical studies for Alzheimer’s patients.
A: Amyloid and tau remain important factors in Alzheimer’s pathology. The study suggests these proteins may initiate damage, while dopamine circuit dysfunction represents a downstream, functionally critical problem. Clearing proteins may not be enough; repairing or compensating for damaged circuits will likely be essential to restore memory.
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 essential for memory formation and shows some of the earliest structural and functional changes in Alzheimer’s disease (AD). Despite this, the circuit-level reasons for its selective vulnerability have remained unclear.
This study demonstrates that dopamine neurons projecting to the lateral entorhinal cortex (LEC), which are vital for healthy memory encoding, become dysfunctional at early pathological stages in an amyloid precursor protein knock-in mouse model. That dysfunction disrupts associative memory encoding in LEC layer 2/3 neurons.
Optogenetic reactivation of dopamine fibers to the LEC rescued associative learning, and treatment with L-DOPA restored memory encoding in LEC neurons as well as associative memory performance in the model mice.
These results indicate that early dysfunction of LEC-projecting dopamine neurons contributes to memory impairment in AD and support the need for clinical investigation of LEC dopamine signaling in patients with Alzheimer’s disease.