Tracking down a missing trigger for Alzheimer's disease by mass spectrometric imaging based on brain network analysis

Alzheimer's disease (AD) has been proposed to begin in a cryptic form long before clinical symptoms appear. If this is the case, there might be an initial trigger leading to AD that we have not yet seen. Such a trigger might occur far away from the brain regions that are currently identified as affected sites, and might start long before either functional or histological changes are apparent. How might we detect this putative trigger? In this chapter, I propose an experimental approach using matrix-assisted laser desorption ionization (MALDI)-based imaging mass spectrometry (IMS), combined with pathological and functional connectivity studies, to track down the initial trigger of AD. The deficits in AD brains do not spread randomly, and even though we do not know where to find the initial deficit or which biomolecule is involved, the brain region where the initial change occurs is surely connected functionally to the brain regions that subsequently show detectable damage. Therefore, MALDI IMS taking account of the brain's functional connectivity and the spread of AD symptoms should be a powerful strategy for uncovering molecular signatures related to the AD trigger(s).