Lower Plasma Serotonin is Associated with Higher Amyloid Burden, Hippocampal Atrophy, and Cognitive decline in Alzheimer's Disease: A 24-Month Longitudinal Study.

Yingbo Han, Li Liu, Li Chang, Xiaomin Ge, Qianqian Chen, Qian Li, Hehua Li, Wenchao Li, Alzheimer’s Disease Neuroimaging Initiative

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Article in Journal of molecular neuroscience : MN, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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1 · What the graph read from it

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5 · Who and what money

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9 authors.

Yingbo HanDepartment of Neurology, Henan medical Key Laboratory of Neurology, Henan Joint International Laboratory of Neurorestoratology for Senile Dementia, Henan Key Laboratory of Neurorestoratology and Protein modification, First Affiliated Hospital of Henan Medical University, Xinxiang, 453100, Henan, China.

Li LiuDepartment of Neurology, Henan medical Key Laboratory of Neurology, Henan Joint International Laboratory of Neurorestoratology for Senile Dementia, Henan Key Laboratory of Neurorestoratology and Protein modification, First Affiliated Hospital of Henan Medical University, Xinxiang, 453100, Henan, China.

Li ChangDepartment of Neurology, Henan medical Key Laboratory of Neurology, Henan Joint International Laboratory of Neurorestoratology for Senile Dementia, Henan Key Laboratory of Neurorestoratology and Protein modification, First Affiliated Hospital of Henan Medical University, Xinxiang, 453100, Henan, China.

Xiaomin GeDepartment of Neurology, Henan medical Key Laboratory of Neurology, Henan Joint International Laboratory of Neurorestoratology for Senile Dementia, Henan Key Laboratory of Neurorestoratology and Protein modification, First Affiliated Hospital of Henan Medical University, Xinxiang, 453100, Henan, China.

Qianqian ChenDepartment of Neurology, Henan medical Key Laboratory of Neurology, Henan Joint International Laboratory of Neurorestoratology for Senile Dementia, Henan Key Laboratory of Neurorestoratology and Protein modification, First Affiliated Hospital of Henan Medical University, Xinxiang, 453100, Henan, China.

Qian LiDepartment of Neurology, Henan medical Key Laboratory of Neurology, Henan Joint International Laboratory of Neurorestoratology for Senile Dementia, Henan Key Laboratory of Neurorestoratology and Protein modification, First Affiliated Hospital of Henan Medical University, Xinxiang, 453100, Henan, China.

Hehua LiDepartment of Neurology, Henan medical Key Laboratory of Neurology, Henan Joint International Laboratory of Neurorestoratology for Senile Dementia, Henan Key Laboratory of Neurorestoratology and Protein modification, First Affiliated Hospital of Henan Medical University, Xinxiang, 453100, Henan, China.

Wenchao LiDepartment of Neurosurgery, Henan medical Key Laboratory of Neurology, Henan Joint International Laboratory of Neurorestoratology for Senile Dementia, Henan Key Laboratory of Neurorestoratology and Protein modification, First Affiliated Hospital of Henan Medical University, Xinxiang, 453100, Henan, China. liwenchao01202022@163.com.ORCID http://orcid.org/0000-0002-9388-9261

Alzheimer’s Disease Neuroimaging Initiative

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

This study investigated longitudinal plasma serotonin dynamics across the Alzheimer's disease (AD) continuum (cognitively normal [CN], mild cognitive impairment [MCI], and AD) to determine whether baseline serotonin and its 24-month change are associated with CSF amyloid-β (Aβ42), tau biomarkers, amyloid PET burden, structural brain integrity, and cognitive decline. Data from 959 ADNI participants (CN = 306, MCI = 421, AD = 232) with baseline and 24-month follow-up were analyzed. Measures included plasma serotonin, CSF biomarkers (Aβ42, total tau, p-tau181), florbetapir PET, MRI (hippocampal volume, cortical thickness), and cognitive tests (MMSE, ADAS-Cog 11, CDR-SB). Group differences were tested using ANOVA or Kruskal-Wallis, and associations were examined via partial correlations and mixed-effects models adjusted for age, sex, education, and APOE ε4, with FDR correction. The results revealed that baseline plasma serotonin levels showed a stepwise decline across the clinical continuum (CN > MCI > AD; p ≤ 0.05), consistent with progressive serotonergic dysregulation. In AD participants, higher baseline serotonin was significantly associated with less amyloid pathology and preserved brain structure, including higher CSF Aβ42 (β = 0.28, FDR p = 0.01), lower florbetapir PET SUVR (β = -0.31, FDR p = 0.02), and larger hippocampal volume (β = 0.33, FDR p = 0.02). Higher serotonin was also linked to better cognitive performance (MMSE: β = 0.22, FDR p = 0.02; ADAS-Cog 11: β = -0.24, FDR p = 0.02). Longitudinally, decreases in serotonin over 24 months in AD were associated with worsening amyloid burden (ΔPET SUVR: β = -0.29, FDR p = 0.02) and accelerated hippocampal atrophy (β = 0.32, FDR p = 0.01). Baseline serotonin predicted smaller 24-month declines in CSF Aβ42 (β = 0.28, FDR p = 0.01) and reduced hippocampal volume loss (β = 0.31, FDR p = 0.01). In CN and MCI groups, associations between serotonin and AD biomarkers or cognitive outcomes were not significant after FDR correction. On the whole, lower plasma serotonin levels are linked to amyloid pathology, hippocampal neurodegeneration, and cognitive decline in AD, supporting serotonin's potential as a stage-specific biomarker and mechanistic contributor to disease progression. Integrative longitudinal studies are needed to clarify causality and evaluate serotonergic pathways as therapeutic targets.

Indexed as

Alzheimer DiseaseCognitive DysfunctionHippocampusSerotoninAgedAged, 80 and overAmyloid beta-PeptidesAtrophyBiomarkersFemaleHumansLongitudinal StudiesMalePeptide FragmentsPositron-Emission Tomographytau ProteinsAmyloid beta-Peptidesamyloid beta-protein (1-42)BiomarkersPeptide FragmentsSerotonintau ProteinsAlzheimer’s diseaseAmyloid-βCognitive functionHippocampal atrophyPlasma biomarkersSerotonin

Identifiers

PMID41770485

DOI10.3389/fimmu.2025.1646740

What Socratic holds

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.