Ane Iriondo1, Maite García-Sebastian1, Arantzazu Arrospide2,3, Maria Arriba1, Sara Aurtenetxe1, Myriam Barandiaran1, Montserrat Clerigue1, Mirian Ecay-Torres1, Ainara Estanga1, Alazne Gabilondo1, Andrea Izagirre1,4, Jon Saldias1, Mikel Tainta1, Jorge Villanua1, Kaj Blennow5,6, Henrik Zetterberg5,6,7,8, Javier Mar2,3, Beatriz Abad-García9, Irundika H K Dias10, Felix M Goñi11, Pablo Martínez-Lage1. 1. Center for Research and Advanced Therapies, CITA-Alzheimer Foundation, Donostia-San Sebastian, Gipuzkoa, Spain. 2. Gipuzkoa Primary Care - Integrated Health Care Organizations Research Unit, Alto Deba Integrated Health Care Organisation, Nafarroa Hiribidea, Arrasate, Gipuzkoa, Spain. 3. Biodonostia Health Research Institute, Paseo Doctor Begiristain, Donostia, San Sebastian, Spain. 4. Department of Nursing II, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), Spain. 5. Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden. 6. Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden. 7. Department of Neurodegenerative Disease, UCL Institute of Neurology, London, United Kingdom. 8. UK Dementia Research Institute at UCL, London, United Kingdom. 9. Central Analysis Service, Faculty of Science and Technology, University of the Basque Country (UPV/EHU), Leioa, Bizkaia, Spain. 10. Aston Medical Research Institute, Aston Medical School, Aston University, Birmingham, UK. 11. Departamento de Bioquímica, University of the Basque Country (UPV/EHU) and Instituto Biofisika (CSIC, UPV/EHU), Leioa, Bizkaia, Spain.
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.
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.
Entities:
Keywords:
Amyloid-βzzm321990; cerebrospinal fluid; diffusion tensor imaging; oxysterols; white matter