Serotonin Enhances Neurogenesis Biomarkers, Hippocampal Volumes, and Cognitive Functions in Alzheimer's Disease

Research on serotonin reveals a lack of consensus regarding its role in brain volume, especially concerning biomarkers linked to neurogenesis and neuroplasticity, such as ciliary neurotrophic factor (CNTF), fibroblast growth factor 4 (FGF-4), bone morphogenetic protein 6 (BMP-6), and matrix metalloproteinase-1 (MMP-1) in Alzheimers disease (AD). This study aimed to investigate the influence of serotonin on brain structure and hippocampal volumes in relation to cognitive functions in AD, as well as its link with biomarkers like CNTF, FGF-4, BMP-6, and MMP-1. Data from the ADNI included 133 AD participants. Cognitive function was assessed using CDR-SB, serotonin levels were measured with the Biocrates AbsoluteIDQ p180 kit and UPLC-MS/MS, and neurotrophic factors and biomarkers were quantified using multiplex targeted proteomics. Voxel-Based Morphometry (VBM) analyzed gray matter volume changes via MRI. Statistical analyses employed Pearson correlation and Bootstrap methods, with p-values < 0.05 or 0.01 considered significant. The analysis revealed a significant positive correlation between serotonin levels and total brain volume (r = 0.179, p = 0.039) and hippocampal volumes (right: r = 0.181, p = 0.037; left: r = 0.217, p = 0.012). Besides, higher serotonin levels were associated with improved cognitive function, evidenced by a negative correlation with CDR-SB scores (r = -0.198, p = 0.023). Furthermore, total brain volume and hippocampal volumes showed significant negative correlations with CDR-SB scores, indicating that greater cognitive impairment was associated with reduced brain volume (total: r = -0.223, p = 0.010; left: r = -0.246, p = 0.004; right: r = -0.308, p < 0.001). Finally, serotonin levels were positively correlated with BMP-6 (r = 0.173, p = 0.047), CNTF (r = 0.216, p = 0.013), FGF-4 (r = 0.176, p = 0.043), and MMP-1 (r = 0.202, p = 0.019), suggesting a link between serotonin and neurogenesis and neuroplasticity. In conclusion, increased serotonin levels are associated with improved cognitive function, increased brain volume, and elevated levels of neurotrophic factors and biomarkers--specifically CNTF, FGF-4, BMP-6, and MMP-1--that are related to neurogenesis and neuroplasticity in AD. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=106 SRC="FIGDIR/small/616371v1_ufig1.gif" ALT="Figure 1"> View larger version (19K): org.highwire.dtl.DTLVardef@c020eaorg.highwire.dtl.DTLVardef@1b104e2org.highwire.dtl.DTLVardef@b7bc5borg.highwire.dtl.DTLVardef@aeffdc_HPS_FORMAT_FIGEXP M_FIG C_FIG Serotonin plays a key role in cognitive function, with higher levels linked to increased brain and hippocampal volumes and better cognitive performance, as shown by lower CDR-SB scores (indicating less cognitive impairment). In addition, serotonin is positively associated with neurotrophic factors and biomarkers like ciliary neurotrophic factor (CNTF), fibroblast growth factor 4 (FGF-4), bone morphogenetic protein 6 (BMP-6), and matrix metalloproteinase-1 (MMP-1), which are involved in neurogenesis and neuroplasticity. These findings suggest that elevated serotonin levels contribute to brain health, cognitive function, and the promotion of neural growth and plasticity, particularly in Alzheimers disease (AD).