Pre-Alzheimer's Memory Problems Linked to Loss of Serotonin

People with fewer happy chemicals in their brain might be at greater risk of neurodegeneration from Alzheimer's disease, according to new research.

Of people with mild cognitive impairment, those with lower levels of serotonin—a neurotransmitter associated with positive mood, appetite and sleep—were found to have increased memory problems, the Journal of Alzheimer's Disease, a peer-review journal, published.

The study therefore revealed that participants who already had mild cognitive impairment (MCI) had already lost brain structures that transported serotonin.

"Serotonin plays a significant role in normal brain function and modulates fundamental behaviors, including mood, sleep, appetite, and cognition. Degeneration of the serotonin system has been observed in previous studies in Alzheimer's and patients with MCI," Gwenn Smith, a professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine, told Newsweek. "Studies of animal models of Alzheimer's have shown that serotonin degeneration occurs before the development of widespread beta-amyloid protein deposition."

Alzheimer's disease degenerates the brain, eventually leading to the development of dementia. The disease is associated with the build-up of several proteins called amyloid and tau, which clump up into plaques and tangles, and affect the brain's functions. Around 5.8 million adults live with Alzheimer's disease and other dementias in the United States, according to the Centers for Disease Control and Prevention (CDC).

MCI is the stage before Alzheimer's fully kicks in, and is associated with forgetfulness, loss of sense of smell, and struggling to remember words. MCI may not always lead to full-blown Alzheimer's, but is often a precursor stage, meaning that it is an important stage for early interventions.

"In this study, we found brain region-specific changes in correlations of beta-amyloid and serotonin transporter with auditory verbal (words) and visual spatial (shapes) memory and verbal fluency (retrieval of words based on categories)," Smith said. "We tested a statistical model of memory and verbal fluency deficits that included beta-amyloid protein and gray matter volumes. We found that adding serotonin transporter imaging data to this model improved the fit of the model significantly, suggesting that serotonin degeneration has a role in memory problems in addition to the beta-amyloid protein and the loss of gray matter in the brain."

However, the authors stress that these results only show a correlation between lower serotonin transporter levels and memory problems in MCI, which does not necessarily mean that serotonin or lack thereof plays a role in the progression of MCI to Alzheimer's.

In the study, the authors performed positron emission tomography (PET) scans on the brains of over 90 adults with and without mild cognitive impairment between 2009 and 2022, looking at serotonin transporter levels and the amount of amyloid-beta protein (Aβ) in the brain. Amyloid is one of the protein structures that build up in the brain and cause dementia.

They found that patients with MCI had up to 25 percent lower levels of serotonin transporters in some regions of the brain, specifically those involved in executive function, emotion, and memory. They also had higher amyloid levels than the control group.

"The serotonin transporters are affected because the nerve cells that produce serotonin and the projections of these neurons to other brain regions are vulnerable to neurodegeneration. While we do not have direct evidence in humans, the loss of serotonin may result in lower levels of brain chemicals linked to serotonin or a decreased capacity of nerve cells to compensate in response to neurodegenerative processes," Smith said.

The researchers hope that they can further investigate how serotonin is linked to Alzheimer's in the hope that it could be targeted in the treatment of the disease.

"MCI is a preclinical stage of Alzheimer's disease. Individuals with MCI progress to an Alzheimer's disease diagnosis, based on cognitive and functional decline, due to an increase in accumulation of abnormal proteins (amyloid and tau) and a loss of synapses associated with brain chemicals. We do not yet know why this occurs or if the changes in brain chemical occur as a consequence of the build-up of proteins or from an independent disease process. We and others have shown that serotonergic medications such as antidepressants can improve memory. We are studying more recently developed serotonergic medications that may be more effective," Smith said.

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Update 12/12/23, 11:07 a.m. ET: This article was updated to add comments from Smith.