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Researchers at the University of Southern California and the Max Planck Institute for Human Development in Berlin, Germany have demonstrated that the the noradrenaline and dopamine neurotransmitter systems are involved in age-related memory impairment in different ways. Their work contributes to a better understanding of cognitive aging with and without Alzheimer’s dementia.

“Noradrenaline and dopamine are critical for brain function, but it has been challenging to use magnetic resonance imaging to examine how their functioning changes with age,” said study coauthor and USC Leonard Davis School of Gerontology Professor Mara Mather. “In this study, for the first time we were able to link different types of cognitive functioning to the locus coeruleus – the brain’s source of noradrenaline – versus to brain regions associated with dopamine.”

One of the first signs of the possible later onset of Alzheimer’s dementia is the accumulation of abnormal tau proteins in the brain, which can be detected from the age of around 30. Abnormal tau initially forms in small nuclei, or clusters of cells, in the brainstem that produce neurotransmitters, in particular the neurotransmitters dopamine and noradrenaline. These neurotransmitters ensure the stabilization of synaptic changes in memory-relevant areas of the brain and thus help to retain memories permanently.

With increasing age, abnormal tau proteins spread from these brain nuclei to memory-relevant brain areas, and the dopamine- and noradrenaline-producing cells die off. This in turn leads to age-related cognitive impairment. However, it was previously unclear whether these two neurotransmitters play a different role in age-related cognitive changes.

The researchers used magnetic resonance imaging (MRI) in older adults to show that changes in brain regions that primarily produce noradrenaline were linked to episodic memory. This means that they influence the ability to store events and remember them over longer periods of time. In contrast, changes in regions primarily producing dopamine were linked to working memory, i.e., the ability to retain information for shorter periods of time. The results of their study were published in the journal Nature Aging.

“The aim of our study was to expand our knowledge of the respective roles of dopaminergic and noradrenergic nuclei in memory loss in old age, as these regions are involved in the development of Alzheimer’s dementia,” says study leader Martin Dahl.

Dahl and his research group at the Center for Lifespan Psychology at the Max Planck Institute for Human Development are dedicated to investigating the locus coeruleus, or “blue spot”—a small group of cells deep in the brainstem that is involved in the formation of these neurotransmitters. Its tiny size – barely the size of a fingernail – has prevented it from being studied in living humans for a long time, but researchers have recently been able to do so with the help of special MRI techniques, Dahl explained.

The researchers drew on data from the Berlin Aging Study II (BASE-II) – an ongoing longitudinal study investigating the neuronal, cognitive, physical, and social conditions of successful aging. They evaluated the MRI images of 69 younger participants aged 25 to 40 years and 251 older participants aged 62 to 83 years. In addition, the researchers used the results of cognitive assessments that were collected at several timepoints and allow statements to be made about changes of working and episodic memory as well as intelligence over time.

“In the present study, we used new imaging techniques to decipher the role of declining dopaminergic and noradrenergic neurotransmitters on aging cognition,” Mather said. “Participants were tested on episodic memory (remembering specific information that was learned earlier) and also on working memory (being able to keep a small set of words, numbers, or other items in mind).”

In the future, the researchers plan to link changes in these brain areas to blood-based Alzheimer’s biomarkers and investigate their interplay in the development of Alzheimer’s dementia. The team also plans to extend the scope of their research to other regions of the brain, such as those that produce serotonin, Mather added.

“These neuromodulatory regions appear to play an outsized role, given their small size, in determining cognitive aging trajectories. Thus, they are important targets for interventions that might help avoid their decline,” she said. “Better understanding of how they each contribute to different cognitive functions could help us target interventions based on individual patterns of cognitive decline, for instance.”

News release courtesy of the Max Planck Institute for Human Development. Additional reporting by Beth Newcomb.

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