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

The earliest defining event in the pathogenesis of Alzheimer´s disease (AD) is the intracerebral deposition of Abeta, which starts at least 20 years before the onset of dementia. The link between Abeta and downstream neurodegeneration leading to dementia remains unclear, a critical gap in knowledge at a time when clinical trials are increasingly shifting to pre-symptomatic disease stages. Consequently, the design of preventive treatment strategies based on biomarkers remains an important challenge. Here, we have analyzed CSF samples from 21.5-month-old APPPS1 and WT mice, with and without BACE inhibition from 1.5 to 21.5 months, using mass spectrometry-based label-free quantification of proteins. Life-long BACE inhibition showed a partial rescue of several CSF protein markers for neurodegeneration such as NEFL and inflammation such as Trem2 or Cst7.