Neuroscience. 2026 Sep 4:S0306-4522(26)00613-5. doi: 10.1016/j.neuroscience.2026.09.005. Online ahead of print.
ABSTRACT
Both serum serotonin and cardiovascular-risk (CVR) burden are implicated in Alzheimer's disease (AD)-related vascular and neurodegenerative processes, yet their interrelationship across the AD continuum remains unclear. This cross-sectional study examined whether serum serotonin was associated with three complementary measures of CVR burden across the AD continuum and according to CSF amyloid status in 428 participants (138 cognitively normal [CN] individuals, 206 participants with mild cognitive impairment [MCI], and 84 participants with AD), using covariate-adjusted regression models with FDR correction. Following covariate-adjusted analyses, serum serotonin declined progressively from CN to MCI and AD, whereas all CVR measures were higher in MCI and AD than in CN participants. Among participants with MCI and pooled amyloid-positive (Aβ+) participants, greater CVR burden was consistently associated with lower serum serotonin across the Framingham Risk Score (FRS), pooled PCA-derived CVR score, and cohort-specific PCA-derived CVR score. Together, these within-group findings suggest that lower serum serotonin accompanies greater vascular-risk burden in clinically and biologically vulnerable individuals. However, CVR × diagnosis and CVR × amyloid-status interaction tests were not significant after FDR correction. Besides, lower serum serotonin and greater CVR burden were separately associated with poorer cognitive and functional outcomes in both MCI and Aβ+ participants. In short, greater CVR burden was associated with lower serum serotonin, particularly within MCI and Aβ+ groups, and both factors were related to less favorable clinical outcomes, underscoring the need for longitudinal and mechanistic studies to define serotonin's role at the vascular-neurodegenerative interface in AD.
PMID:42697521 | DOI:10.1016/j.neuroscience.2026.09.005