Serotonin System Degeneration Mapped in Mild Cognitive Impairment


A new study correlates reduced serotonin transporter and increased amyloid-ß deposition with cognitive deficits in mild cognitive impairment, suggesting a role for serotonergics in early Alzheimer disease.


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A reduction in serotonin transporter (5-HTT) in parts of the brain involved with executive function, emotion, and memory has been detected in persons with mild cognitive impairment (MCI).

In a new study comparing a group with MCI to healthy, age-matched controls, this marker of serotonin system degeneration in those with MCI and cortical deposition of amyloid-ß were both correlated with cognitive impairment associated with progression to Alzheimer disease (AD).1

Although the investigators emphasize that correlation of lower serotonin transporter levels with the development of MCI does not show causation, it does suggest a potential therapeutic role for serotonergic medication in early, preclinical stages of AD.

“The correlation we observed between lower serotonin transporters and memory problems in MCI is important because we may have identified a brain chemical that we can safely target that may improve cognitive deficits and, potentially, depressive symptoms," stated Gwenn Smith, PhD, Department of Psychiatry and Behavioral Sciences, Division of Geriatric Psychiatry and Neuropsychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, in a press release from Johns Hopkins Medicine.2

"If we can show that serotonin loss over time is directly involved in the transition from MCI to AD, recently developed antidepressant medications may be an effective way to improve memory deficits and depressive symptoms and, thus, may be a powerful way forward to slow disease progression," Smith indicated.

Smith and colleagues employed positron emission tomography (PET) imaging of 5-HTT and amyloid-ß, structural magnetic resonance imaging (MRI), and neuropsychological assessments in the study of 49 participants with MCI and 45 healthy controls. Participants with MCI were enrolled if they had a Clinical Dementia Rating Scale (CDR) score of 0.5 (consistent with MCI) and a score of at least 1 standard deviation below the mean on auditory-verbal and/or visual-spatial memory tests for executive function.

The investigators found lower 5-HTT in cortical, striatal, and limbic regions, and higher amyloid-ß deposition in the cortical region in those with MCI. The investigators note that associations found between memory measures and higher amyloid-ß in the amygdala and entorhinal cortex were unexpected, as there are relatively low concentrations of amyloid-ß in these regions.

The lower 5-HTT, particularly in limbic regions, was correlated with greater deficits in auditory-verbal and visual-spatial memory; and with the semantic (category-guided) fluency testing for executive functioning. There was no correlation, however, with the phonemic (letter-guided) fluency tests.

"The greater associations between semantic than phonemic fluency with greater neuropathology (indicated by) 5-HTT loss and amyloid-ß deposition in the MCI group would be expected," Smith et al explain, "given the greater semantic relative to phonemic fluency deficits reported in the early stages of AD."

Smith et al suggest that decreased 5-HTT in MCI reflects progressive loss of serotonin terminals and cell bodies and posit there could be secondary effects on other neurotransmitters modulated by serotonin, such as dopamine, acetylcholine, glutamate, and gamma-aminobutyric acid.

"The primary and secondary effects of serotonin degeneration would potentially have an impact on cognition and the emergence of neuropsychiatric symptoms over the course of MCI," they indicate.

Emerging Evidence Supports Serotonergics in MCI

Smith et al also found evidence in studies with transgenic amyloid mouse models that suggests a potential therapeutic role of serotonergics in preclinical stages of AD.3 In these animal models, serotonin receptor modulators (5-HT4 agonists and 5-HT6 antagonists) have been shown to block amyloid-ß pathology and to initially, albeit transiently, prevent memory deficits and/or improve memory function.4 Further, selective serotonin reuptake inhibitors have been demonstrated to decrease amyloid-ß in cerebrospinal fluid in both mouse models and in humans without cognitive deficits.5

Smith et al also point out that, although most clinical studies of serotonergics in AD and MCI have targeted neuropsychiatric symptoms, there is emerging evidence of beneficial effect on cognitive deficits in MCI. In one cited study, domain-specific improvements were found in attention, memory, and executive function.6

"(That) study suggests that treatments targeting on serotonin receptors that are less affected than 5-HTT could represent a more effective serotonergic intervention target for improving cognition," Smith et al related.

From their own findings linking reduced 5-HTT in MCI to deficits in auditory-verbal and visual-spatial memory and to semantic fluency, the investigators posit that serotonin system degeneration contributes to cognitive deficits as well as emergence of neuropsychiatric symptoms. They anticipate conducting additional studies with PET imaging, including of the Tau protein, to evaluate the associations over time.

"A greater understanding of the relationship of serotonin degeneration to other aspects of AD pathology in preclinical AD is important to determine whether serotonergic agents may have a potential role as an intervention or prevention target for cognitive deficits and neuropsychiatric symptoms," Smith et al indicated.

Dr Bender reports on medical innovations and advances in practice and edits presentations for news and professional education publications. He previously taught and mentored pharmacy and medical students, and he provided and managed pharmacy care and drug information services.


1. Smith GS, Kuwabara H, Yan H, et al. Serotonin degeneration and amyloid-ß deposition in mild cognitive impairment: relationship to cognitive deficits. J Alzheimers Dis. 2023;96(1):215-227.

2. Study suggests serotonin loss may contribute to cognitive decline in the early stages of Alzheimer's disease. Johns Hopkins Medicine. Press release. December 7, 2023. Accessed January 16, 2024.

3. Liu Y, Yoo M-J, Savonenko A, et al. Amyloid pathology is associated with progressive monoaminergic neurodegeneration in a transgenic mouse model of Alzheimer's disease. J Neurosci. 2008;28(51):13805-23814.

4. Claeysen S, Bockaert J, Giannoni P. Serotonin: a new hope in Alzheimer’s disease? ACS Chem Neurosci. 2015;6(7):940-943.

5. Sheline YI, West T, Yarasheski K, et al. An antidepressant decreases CSF Aß production in healthy individuals and in transgenic AD mice. Sci Transl Med. 2014;6(236):236re4.

6. Tan SN, Tan C. Vortioxetine improves cognition in mild cognitive impairment. Int Clin Psychopharmacol. 2021;36(6):279-287.

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