Dopamine deficiency contributes to Alzheimer's disease memory impairment

An international research team led by Professor Kei Igarashi and Assistant Professor Tatsuki Nakagawa of Graduate School of Medicine at Tohoku University, and the University of California, Irvine, revealed that lack of dopamine in the entorhinal cortex causes memory impairment in Alzheimer's disease (AD). They also found that increasing the dopamine level in the entorhinal cortex by administering existing dopamine therapeutics such as Levodopa could recover the memory of AD mice. The findings were published in Nature Neuroscience.

It is known that the part of the brain damaged in early AD patients is not the hippocampus, which controls memory, but the adjacent entorhinal cortex. However, it was unclear which of the neurons in it were damaged. In 2021, the research team found that neurons in the entorhinal cortex receive dopamine to form memories.

Earlier brain studies had examined in detail the roles of dopamine in the striatum, a brain part responsible for body movement. Levodopa, which supplements dopamine, has been approved as a treatment for Parkinson's disease. The team assumed that decrease in dopamine in the entorhinal cortex was the cause of memory impairment in AD and conducted a study to verify this assumption.

First, olfactory memory was tested using AD mice (amyloid precursor protein knock-in mice) prone to accumulate amyloid-β in their brains. Mice are highly capable of discriminating between different odors, so healthy mice can easily memorize odors, but AD mice cannot. When dopamine levels in the entorhinal cortex were measured during the sniffing behavior, AD mice showed reduced levels of dopamine, which were about one-fifth of those in healthy mice.

Electrophysiological recordings of neural activity in the entorhinal cortex showed that neurons in AD mice were unable to respond properly to the odors they were supposed to remember. In a therapeutic experiment, when dopamine in the entorhinal cortex was increased by an optogenetic approach, AD mice were able to memorize odors again. Administration of Levodopa also restored the neural activity in the entorhinal cortex to the normal level and improved memory in AD mice.

Nakagawa said, "Optogenetic approaches were new to our laboratory, so we had to test various conditions until we could get the desired effect in therapeutic experiments." The findings suggest that lack of dopamine in the entorhinal cortex is one of the causes of memory impairment in AD, and that therapies inducing dopamine increase may relieve memory impairment.

Igarashi said, "In the future, I would like to collaborate with clinical researchers to find out whether AD patients actually have decreased dopamine levels in the entorhinal cortex, and if so, whether Levodopa is effective for improving their symptoms."

Journal Information
Publication: Nature Neuroscience
Title: Early dopamine disruption in the entorhinal cortex of a knock-in model of Alzheimer's disease
DOI: 10.1038/s41593-026-02260-w