Cerebrospinal Fluid 7-Ketocholesterol Level is Associated with Amyloid-β42 and White Matter Microstructure in Cognitively Healthy Adults

Ane Iriondo, Maite García-sebastian, Arantzazu Arrospide, Maria Arriba, Sara Aurtenetxe, Myriam Barandiaran, Montserrat Clerigue, Mirian Ecay-torres, Ainara Estanga, Alazne Gabilondo, Andrea Izagirre, Jon Saldias, Mikel Tainta, Jorge Villanua, Kaj Blennow, Henrik Zetterberg, Javier Mar, Beatriz Abad-garcía, Irundika H.k. Dias, Felix M. GoñiPablo Martínez-lage*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Background:Abnormal cholesterol metabolism changes the neuronal membrane and may promote amyloidogenesis. Oxysterols in cerebrospinal fluid (CSF) are related to Alzheimer’s disease (AD) biomarkers in mild cognitive impairment and dementia. Cholesterol turnover is important for axonal and white matter (WM) microstructure maintenance. Objective:We aim to demonstrate that the association of oxysterols, AD biomarkers, and WM microstructure occurs early in asymptomatic individuals. Methods:We studied the association of inter-individual variability of CSF 24-hydroxycholesterol (24-OHC), 27-hydroxycholesterol (27-OHC), 7-ketocholesterol (7-KC), 7β-hydroxycholesterol (7β-OHC), amyloid-β42 (Aβ42), total-tau (t-tau), phosphorylated-tau (p-tau), neurofilament (NfL), and WM microstructure using diffusion tensor imaging, generalized linear models and moderation/mediation analyses in 153 healthy adults. Results:Higher 7-KC levels were related to lower Aβ42, indicative of greater AD pathology (p = 0.041) . Higher 7-KC levels were related to lower fractional anisotropy (FA) and higher mean (MD), axial (AxD), and radial (RD) diffusivity. 7-KC modulated the association between AxD and NfL in the corpus callosum splenium (B = 39.39, p = 0.017), genu (B = 68.64, p = 0.000), and fornix (B = 10.97, p = 0.000). Lower Aβ42 levels were associated to lower FA and higher MD, AxD, and RD in the fornix, corpus callosum, inferior longitudinal fasciculus, and hippocampus. The association between AxD and Aβ42 was moderated by 7K-C (p = 0.048). Conclusion:This study adds clinical evidence to support the role of 7K-C on axonal integrity and the involvement of cholesterol metabolism in the Aβ42 generation process.
Original languageEnglish
Pages (from-to)643-656
Number of pages14
JournalJournal of Alzheimer's disease
Volume76
Issue number2
Early online date6 Jun 2020
DOIs
Publication statusPublished - 21 Jul 2020

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