Low serum serotonin is associated with functional decline, mild behavioural impairment and brain atrophy in dementia-free subjects
Authors: Sim Ming Ann , Liao Yingqi , Chan Siew Pang , Tan Eugene S J , Kan Cheuk Ni , Chong Joyce R , Chai Yuek Ling , Venketasubramanian Narayanaswamy , Tan Boon Yeow , Hilal Saima , Xu Xin , Chen Christopher L H , Lai Mitchell K P 
Published: January 2025

Abstract
Brain serotonin dysregulation is associated with dementia and neuropsychiatric symptomology. However, the prognostic utility of circulating serotonin levels in detecting features of prodromal dementia including functional decline, cognitive impairment, mild behavioural impairment and brain atrophy remains unclear. In this prospective study of memory clinic subjects followed-up for ≤5 years, dementia-free subjects, classified as having no cognitive impairment or cognitive impairment, no dementia at baseline, underwent annual neuropsychological assessments including Montreal Cognitive Assessment, Global Cognition Z-scores and Clinical Dementia Rating Scale Global Scores (where a ≥ 0.5 increment from baseline denotes functional decline). Mild behavioural impairment was measured using baseline and annual Neuropsychiatric Inventory assessments, while brain atrophy was evaluated using cortical and medial temporal atrophy scores from baseline MRI scans. Baseline serum serotonin was then associated with the neuropsychological and neuroimaging measures cross-sectionally and longitudinally. Furthermore, associations of serum serotonin with cross-sectional brain atrophy scores were studied. Of the 191 elderly subjects included in the study, 63 (33.0%) had no cognitive impairment while 128 (67.0%) had cognitive impairment, no dementia. Fourteen subjects (9.0%) showed baseline mild behavioural impairment. Compared with the highest tertile, subjects within the lowest tertile of serotonin had greater Cortical Atrophy scores (adjusted odds ratio = 2.54, 95% confidence interval=1.22–5.30, P = 0.013). Serotonin levels were not significantly associated with cross-sectional neuropsychological or mild behavioural impairment scores (all P &gt; 0.05). Of the 181 subjects with longitudinal cognitive follow-up (median duration 60.0 months), 56 (30.9%) developed functional decline, while incident mild behavioural impairment occurred in 26/119 (21.8%) subjects. Compared with the highest tertile, lower serotonin levels were associated with higher hazards of functional decline (lowest tertile: adjusted hazards ratio = 2.15, 95% confidence interval = 1.04–4.44, P = 0.039), and incident mild behavioural impairment (lowest tertile: adjusted hazards ratio = 3.82, 95% confidence interval = 1.13–12.87, P = 0.031, middle tertile: adjusted hazards ratio = 3.56, 95% confidence interval =1.05–12.15, P = 0.042). The association between the lowest serotonin tertile and functional decline was mediated via its effect on incident mild behavioural impairment (adjusted odds ratio = 3.96, 95% confidence interval = 1.15–13.61, P = 0.029). In conclusion, low circulating serotonin may be associated with cortical atrophy at baseline, as well as act as an early prognostic marker for functional decline and mild behavioural impairment in elderly, dementia-free subjects.