New Alzheimer’s research shows declining levels of serotonin—the brain chemical linked to memory—could trigger the start of dementia. The finding from Johns Hopkins University School of Medicine opens the possibility of staying the onset of dementia and Alzheimer’s Disease by preventing the loss of serotonin or introducing a substitute.
The research team, led by Dr. Gwenn Smith and Dr. Alena Savonenko, was curious about recent work also out of Johns Hopkins that linked declining serotonin levels in mice with an increase in brain protein clumps. These “amyloid” protein clumps are commonly found in Alzheimer’s patients.
Dr. Smith’s research team recruited participants with known mild memory loss and a group of similarly-aged healthy counterparts. While some memory loss and lower serotonin levels are common in older people, the first group had all been diagnosed with mild cognitive impairment, or a slight decline in memory for sequences, organization, and related words. The average age of all participants was 66 with a mix of males and females.
Both groups underwent PET and MRI brain scans where a chemical tracker helped identify levels of the serotonin transporter SERT. By measuring SERT, the researchers could observe the amount of serotonin in the brain, normally a difficult task.
Participants were also scored on verbal memory tests. The participant’s SERT level was compared to the memory test scores to determine if there was a correlation between serotonin levels and memory loss.
In every case, patients with lower verbal memory scores (on average 37 percent lower) also had lower levels of the SERT serotonin transporter (18 percent less). In short, the research points to low serotonin levels as a cause of Alzheimer’s and dementia, rather than an effect. It was previously unclear if low serotonin levels in Alzheimer’s patients were an effect of the disease or caused the disease. However, because the research participants had only mild cognitive impairment with no specific signs of dementia, but also had low serotonin levels similar to Alzheimer’s patients, those levels appear to be a cause.
This finding may adjust Alzheimer’s treatment research to focus on limiting serotonin loss or offering a replacement, according to Dr. Smith. "Now that we have more evidence that serotonin is a chemical that appears affected early in cognitive decline, we suspect that increasing serotonin function in the brain could prevent memory loss from getting worse and slow disease progression," said Dr. Smith.
What is Serotonin?
In brief, serotonin is a chemical that sends signals between nerves. It’s found in the brain, bowels, nervous system, and blood. It serves a number of known functions, include regulation of mood, appetite, and digestion, blood clotting, sleep, sexual desire, and—importantly for Alzheimer’s patients—memory recall.
Changes in serotonin levels are studied for their link to depression, migraines, obesity, and Parkinson’s disease, though some researchers believe the chemical’s prevalence in the body could make it responsible for a host more functions and negative symptoms. For example, studies have even linked serotonin to bone metabolism, breast milk production, and liver regeneration.
Importantly, the serotonin found in the blood is different from the serotonin produced in the brain. The two cannot cross over because of the “blood-brain barrier” which is a membrane that prevents circulating blood from interacting with the brain and fluids in the brain.
It’s believed lower levels of brain serotonin may be caused by brain swelling, use of alcohol, age, and even diet. However, while levels of blood serotonin can be measured, there is no current method for measuring levels of the chemical in the brain. Rather, researchers often study protein SERT during brain scans.
SERT is a transporter that helps serotonin move throughout the brain. This protein not only helps serotonin deliver messages throughout the brain but also takes the serotonin back to the messaging center when its task is completed. Without SERT, serotonin is lost after sending signals, causing the levels of serotonin in the brain to go down.
Treatments for Abnormal Serotonin Levels
The most common treatment for low levels of serotonin is SSRI drugs, or selective serotonin reuptake inhibitors. SSRI drugs, like Prozac, were developed as antidepressants. SSRIs limit the body’s ability to reabsorb serotonin, thereby increasing the overall levels of serotonin in the brain. This is done by preventing the SERT from taking serotonin back to the message center after use.
Once lower levels of serotonin were linked with Alzheimer’s and given high levels of depression linked with memory loss and agitation, SSRIs began to be used with Alzheimer’s patients. However, Dr. Smith believes her recent study may explain why SSRIs have been largely ineffective with Alzheimer’s patients; because these patients have such low levels of serotonin, the drug was unable to effectively target any serotonin to prevent reuptake.
Because of limitations in testing serotonin levels in the brain, the science of how treatments targeted at brain serotonin work is still largely speculation. For example, scientists are still unclear on how SSRI, exactly, work to limit the activity of SERT. Other treatments for low brain serotonin levels include light therapy, psychotherapy, exercise, and diet.
Measuring Declining Memory and Cognitive Loss
Given the study’s findings, the Johns Hopkins team is now focused on how increasing serotonin levels may limit or prevent dementia in patients with only mild cognitive loss. Indeed, identifying cognitive loss early has been on the minds of Alzheimer’s researches as a way to track the disease’s progression. To identify cognitive loss, two tests are most common: Brief Visuospatial Memory Test (BVMT) and the California Verbal Learning Test (CVLT).
The BVMT measures visual and special recollection by showing a grid with varied designs and then asking participants to recreate the designs from memory. A longer-term recall is then measured by asking participants to complete the design again after 25 minutes of “distraction” tasks.
The CVLT measures episodic learning and memory by asking participants to recall as many words as possible from a list of 16 topic-based words, such as fruits. The amount and order of the recalled words indicate how the participant memorizes new facts. In older people, both tests were used in Dr. Smith’s research test.
Patients with advanced Alzheimer’s are sometimes tested with the NAB List test. As a variant on the CVLT, this test asks participants to remember a list of words they read three times. In some instances of the test, there is a short or long period of distraction prior to asking for a recall.
Next Steps in Alzheimer’s Serotonin Research
The results from Dr. Smith and her team spurred two new avenues for research. First, it’s possible the PET method used in the study could be effective for tracking the progression of Alzheimer’s, by tracking the ebb and flow of serotonin to measure levels. This may be done in conjunction with detecting the build-up of Alzheimer’s protein amyloid.
Second, it may be possible to target some or all of the 14 receptors that measure the level of brain serotonin to encourage increased levels. Dr. Smith is tracking the number of experimental drugs focused on these receptors as an alternative to SSRIs. A full review of the research and findings are available in the September 2017 issue of Neurobiology of Disease.