Experimental evidence for temporal uncoupling of brain Aβ deposition and neurodegenerative sequelae

Abstract

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

Examining amyloid reduction as a surrogate endpoint through latent class analysis using clinical trial data for dominantly inherited Alzheimer's disease

“…Interestingly, these reductions are in line with the magnitudes observed with donanemab 6,24 and lecanemab 5 . These findings reinforce the importance of considering the rate and extent of amyloid removal in the context of negative clinical trials 29,30 . They provide additional support for the amyloid hypothesis and further validate amyloid reduction as a potential surrogate biomarker.…”

“…5 These findings reinforce the importance of considering the rate and extent of amyloid removal in the context of negative clinical trials. 29,30 They provide additional support for the amyloid hypothesis and further validate amyloid reduction as a potential surrogate biomarker. As an additional point, it is worth mentioning that while we used amyloid PET as the outcome measure to determine the latent classes, other amyloid biomarkers such as CSF Aβ42 can also be used.…”

Cerebrospinal fluid proteomics define the natural history of autosomal dominant Alzheimer’s disease

“…Overproduction of Aβ42 may increase the time between Aβ plaque formation and decreased CSF levels of this marker when compared with mutation noncarriers. It may also affect the point at which Aβ deposition plateaus in ADAD and LOAD 49 , 64 , 65 . In our study, we did not observe a significant effect of APOE ε4 on biomarker changes, consistent with the lack of effect of APOE ε4 on disease onset previously observed in ADAD 66 .…”

Advanced structural brain aging in preclinical autosomal dominant Alzheimer disease

“…BAG was strongly associated with NfL (both CSF and plasma) and only moderately associated with amyloid-β (PET, but not CSF). These observations suggest that MRI estimates of brain age, like NfL, capture a neurodegeneration-related signal in ADAD [ 38 , 63 ]. However, the strong associations between BAG and pTau (in CSF and plasma) are somewhat surprising.…”