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

Article type: Research Article

Authors: Iriondo, Ane^a | García-Sebastian, Maite^a | Arrospide, Arantzazu^{b; c} | Arriba, Maria^a | Aurtenetxe, Sara^a | Barandiaran, Myriam^a | Clerigue, Montserrat^a | Ecay-Torres, Mirian^a | Estanga, Ainara^a | Gabilondo, Alazne^a | Izagirre, Andrea^{a; d} | Saldias, Jon^a | Tainta, Mikel^a | Villanua, Jorge^a | Blennow, Kaj^{e; f} | Zetterberg, Henrik^{e; f; g; h} | Mar, Javier^{b; c} | Abad-García, Beatrizⁱ | Dias, Irundika H.K.^j | Goñi, Felix M.^k | Martínez-Lage, Pablo^{a; *}

Affiliations: [a] Center for Research and Advanced Therapies, CITA-Alzheimer Foundation, Donostia-San Sebastian, Gipuzkoa, Spain | [b] Gipuzkoa Primary Care – Integrated Health Care Organizations Research Unit, Alto Deba Integrated Health Care Organisation, Nafarroa Hiribidea, Arrasate, Gipuzkoa, Spain | [c] Biodonostia Health Research Institute, Paseo Doctor Begiristain, Donostia, San Sebastian, Spain | [d] Department of Nursing II, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), Spain | [e] Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden | [f] Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden | [g] Department of Neurodegenerative Disease, UCL Institute of Neurology, London, United Kingdom | [h] UK Dementia Research Institute at UCL, London, United Kingdom | [i] Central Analysis Service, Faculty of Science and Technology, University of the Basque Country (UPV/EHU), Leioa, Bizkaia, Spain | [j] Aston Medical Research Institute, Aston Medical School, Aston University, Birmingham, UK | [k] Departamento de Bioquímica, University of the Basque Country (UPV/EHU) and Instituto Biofisika (CSIC, UPV/EHU), Leioa, Bizkaia, Spain

Correspondence: [*] Correspondence to: Pablo Martinez-Lage, PhD, Fundación CITA-Alzheimer Fundazioa, Parque Científico tecnológico de Gipuzkoa, S.A., Mikeletegi 71, bajo 20009 Donostia-San Sebastian (Gipuzkoa), Spain. Tel.: +34 943 021 792; E-mail: pmlage@cita-alzheimer.org.

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.

Keywords: Amyloid-β , cerebrospinal fluid, diffusion tensor imaging, oxysterols, white matter

DOI: 10.3233/JAD-200105

Journal: Journal of Alzheimer's Disease, vol. 76, no. 2, pp. 643-656, 2020