Experimental evidence for temporal uncoupling of brain Aß deposition and neurodegenerative sequelae.

Brain Aß deposition is a key early event in the pathogenesis of Alzheimer´s disease (AD), but the long presymptomatic phase and poor correlation between Aß deposition and clinical symptoms remain puzzling. To elucidate the dependency of downstream pathologies on Aß, we analyzed the trajectories of cerebral Aß accumulation, Aß seeding activity, and neurofilament light chain (NfL) in the CSF (a biomarker of neurodegeneration) in Aß-precursor protein transgenic mice. We find that Aß deposition increases linearly until it reaches an apparent plateau at a late age, while Aß seeding activity increases more rapidly and reaches a plateau earlier, coinciding with the onset of a robust increase of CSF NfL. Short-term inhibition of Aß generation in amyloid-laden mice reduced Aß deposition and associated glial changes, but failed to reduce Aß seeding activity, and CSF NfL continued to increase although at a slower pace. When short-term or long-term inhibition of Aß generation was started at pre-amyloid stages, CSF NfL did not increase despite some Aß deposition, microglial activation, and robust brain Aß seeding activity. A dissociation of Aß load and CSF NfL trajectories was also found in familial AD, consistent with the view that Aß aggregation is not kinetically coupled to neurotoxicity. Rather, neurodegeneration starts when Aß seeding activity is saturated and before Aß deposition reaches critical (half-maximal) levels, a phenomenon reminiscent of the two pathogenic phases in prion disease.