Abstract Body

Although it is widely assumed that plaques and tangles are causally related to the cognitive symptoms in Alzheimer's disease (AD), observations from multiple studies suggest that relationships between plaques, tangles and cognition are not particularly strong and do not suffice to reliably predict clinical outcome at individual level. Increasing evidence suggests that not everyone with brain AD pathology will experience cognitive decline during their lifetime, and some individuals may be resilient to the insult of amyloid and tau deposition in their brains. Understanding the mechanisms underlying such natural protection has the potential of providing valuable hints to identify novel targets and better disease modifying treatments for AD. We conducted detailed quantitative pathologic and biochemical studies in a large series of human postmortem tissue samples to define these mechanisms, through comparisons between individuals cognitively intact at the time of death whose brains were free of substantial AD pathology at postmortem, cognitively intact individuals whose postmortem exam demonstrated significant amounts of AD changes (resilient), and typical demented AD patients. We found that hyperphosphorylation and mislocalization of soluble tau to synapses and neuroinflammation are better predictors of the anatomical collapse of synapses and neurons, and thus cognitive impairment, than plaques and tangles. Future investigations directed to further define the molecular mechanisms as well as individual genetic and epigenetic factors that, beyond plaques and tangles, drive differential clinical fates and rates of cognitive decline have the potential to accurately predict the future for an individual and the need and optimal timing for intervention.