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

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 App^{NL-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.