Circulating Homocysteine and Choroid Plexus Volume Across the Alzheimer's Disease Continuum: Cross-Sectional and Progression-Related Associations.

Overview

1. College of Medical Information and Engineering, Ningxia Medical University, Yinchuan 750004, China; (C.F.); (T.Z.); (Z.L.)
2. School of Public Health, Ningxia Medical University, Yinchuan 750004, China
3. Ningxia Key Laboratory of Environmental Factors and Chronic Disease Control, Yinchuan 750004, China

Abstract

Background: Elevated plasma homocysteine (HCY) is a risk factor for Alzheimer’s disease (AD), but its relationship with structural brain changes across the AD continuum remains unclear. The choroid plexus (CP) regulates cerebrospinal fluid homeostasis and may interface with peripheral metabolic signals. Whether HCY relates to CP structural alterations and disease progression remains unknown. Methods: We analyzed 819 Alzheimer’s Disease Neuroimaging Initiative (ADNI) participants (229 cognitively normal (CN), 397 with mild cognitive impairment (MCI), and 193 with AD dementia). Multinomial logistic regression assessed associations between HCY and diagnosis under stepwise covariate adjustment. Phenotype-wide structural magnetic resonance imaging (MRI) mapping identified HCY-associated signals. Cox models evaluated associations of CP volume (CPV) with CN-to-MCI and MCI-to-AD dementia conversion and whether CPV added prognostic discrimination beyond baseline disease-severity markers. Independent human CP single-nucleus and spatial transcriptomic datasets were reanalyzed to characterize epithelial expression states and their spatial organization in a hypothesis-generating analysis. Results: Higher HCY was associated with MCI and AD dementia; however, the AD association attenuated after adjustment for renal function, vitamin B12, and medications, whereas the MCI association remained stable. CPV was among the HCY-associated MRI signals that persisted after progressive covariate adjustment. Right and bilateral CPV showed model-dependent associations with MCI-to-AD dementia conversion. In the disease-severity sensitivity analysis, larger right and bilateral CPV remained associated with a higher risk of progression from MCI to AD dementia. Single-nucleus analysis identified two CP epithelial states with relatively high expression of one-carbon metabolism-related genes, termed one-carbon metabolism-enriched epithelial state A (OCM-Epi-A) and state B (OCM-Epi-B). Donor-level pseudobulk analysis did not identify pathway enrichment after false discovery rate correction, whereas OCM-Epi-A–like spots were located near endothelial spots more often than expected by chance in three of the four spatial samples. Conclusions: Circulating HCY was associated with larger CPV, and larger CPV showed model-dependent associations with MCI-to-AD dementia progression. Independent transcriptomic reanalysis identified one-carbon metabolism-enriched epithelial states and their spatial organization in postmortem CP tissue, providing hypothesis-generating tissue-level context for the ADNI associations.

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Data Availability Statement

The clinical, neuroimaging, and biomarker data used in this study were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). These data are available to qualified researchers upon application to the ADNI data access committee. The single-nucleus RNA sequencing and spatial transcriptomic datasets reanalyzed in this study are publicly available in the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) under the accession numbers GSE315551 and GSE315553 (BioProject PRJNA1398245). Processed data and customized analytical codes supporting the findings of this study are available from the corresponding author upon reasonable request.

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Recorded: type, language, journal, volume, issue, pages, dates, 6 authors, 6 keywords, 2 funders, 53 references.

Cite

This paper

Feng, C., Zhang, T., Liu, X., Liu, Z., Zhao, Y., & Zhang, P. (2026). Circulating Homocysteine and Choroid Plexus Volume Across the Alzheimer's Disease Continuum: Cross-Sectional and Progression-Related Associations. Biology, 15(16), 1423. https://doi.org/10.3390/biology15161423

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