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 Alzheimer's 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, which are related to neurogenesis and neuroplasticity in AD.