The Aβ42/Aβ40 ratio in the cerebrospinal fluid (CSF) and the concentrations of neurofilament light (NfL) and total tau (t-tau) are changed
The Aβ42/Aβ40 ratio in the cerebrospinal fluid (CSF) and the concentrations of neurofilament light (NfL) and total tau (t-tau) are changed in the early stages of Alzheimer’s disease (AD)1, but their neurobiological correlates are not entirely understood. Here, we used 5xFAD transgenic mice to investigate the associations between these CSF biomarkers and measures of cerebral Aβ, including Aβ42/Aβ40 ratios in plaques, insoluble fibrillar deposits and soluble protofibrils. A high Aβ42/Aβ40 ratio in soluble protofibrils was the strongest independent predictor of low CSF Aβ42/Aβ40 ratios and high CSF NfL and t-tau concentrations when compared to Aβ42/Aβ40 ratios in plaques and insoluble fibrillar deposits. Furthermore, the Aβ42/Aβ40 ratio in soluble protofibrils fully mediated the associations between the corresponding ratio in plaques and all the investigated CSF biomarkers. In AppNL-G-F/NL-G-F knock-in mice, protofibrils fully mediated the association between plaques and the CSF Aβ42/Aβ40 ratio. Together, the results suggest that the Aβ42/Aβ40 ratio in CSF might better reflect brain levels of soluble Aβ protofibrils than insoluble Aβ fibrils in plaques in AD. Furthermore, elevated concentrations of NfL and t-tau in CSF might be triggered by increased brain levels of soluble Aβ protofibrils.
Lund University, Faculty of Medicine, Department of Clinical Sciences, Malmö, Clinical Memory Research, Lunds universitet, Medicinska fakulteten, Institutionen för kliniska vetenskaper, Malmö, Klinisk minnesforskning, Originator, Lund University, Profile areas and other strong research environments, Strategic research areas (SRA), MultiPark: Multidisciplinary research focused on Parkinson´s disease, Lunds universitet, Profilområden och andra starka forskningsmiljöer, Strategiska forskningsområden (SFO), MultiPark: Multidisciplinary research focused on Parkinson´s disease, Originator, Lund University, Faculty of Medicine, Department of Experimental Medical Science, Experimental Dementia Research, Lunds universitet, Medicinska fakulteten, Institutionen för experimentell medicinsk vetenskap, Experimentell demensforskning, Originator, Lund University, Profile areas and other strong research environments, Lund University Profile areas, LU Profile Area: Proactive Ageing, Lunds universitet, Profilområden och andra starka forskningsmiljöer, Lunds universitets profilområden, LU profilområde: Proaktivt åldrande, Originator, Lund University, Faculty of Medicine, Department of Experimental Medical Science, Neuroinflammation, Lunds universitet, Medicinska fakulteten, Institutionen för experimentell medicinsk vetenskap, Neuroinflammation, Originator, Lund University, Faculty of Medicine, WCMM-Wallenberg Centre for Molecular Medicine, Lunds universitet, Medicinska fakulteten, WCMM- Wallenberg center för molekylär medicinsk forskning, Originator, Lund University, Faculty of Medicine, Department of Clinical Sciences, Lund, Section IV, Neurology, Lund, Brain Injury After Cardiac Arrest, Lunds universitet, Medicinska fakulteten, Institutionen för kliniska vetenskaper, Lund, Sektion IV, Neurologi, Lund, Brain Injury After Cardiac Arrest, Originator
