Soluble cerebral Aβ protofibrils link Aβ plaque pathology to changes in CSF Aβ42/Aβ40 ratios, neurofilament light and tau in Alzheimer’s disease model mice
Emelie Andersson, Nils Lindblom, Shorena Janelidze, Gemma Salvadó, Eleni Gkanatsiou, Linda Söderberg, Christer Möller, Lars Lannfelt, Junyue Ge, Jörg Hanrieder, Kaj Blennow, Tomas Deierborg, Niklas Mattsson, Henrik Zetterberg, Gunnar K. Gouras, Oskar Hansson
Abstract
Abstract The Aβ 42 /Aβ 40 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 Aβ 42 /Aβ 40 ratios in plaques, insoluble fibrillar deposits and soluble protofibrils. A high Aβ 42 /Aβ 40 ratio in soluble protofibrils was the strongest independent predictor of low CSF Aβ 42 /Aβ 40 ratios and high CSF NfL and t-tau concentrations when compared to Aβ 42 /Aβ 40 ratios in plaques and insoluble fibrillar deposits. Furthermore, the Aβ 42 /Aβ 40 ratio in soluble protofibrils fully mediated the associations between the corresponding ratio in plaques and all the investigated CSF biomarkers. In App NL-G-F/NL-G-F knock-in mice, protofibrils fully mediated the association between plaques and the CSF Aβ 42 /Aβ 40 ratio. Together, the results suggest that the Aβ 42 /Aβ 40 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.