Understanding Human Brain Resilience to Alzheimer’s Pathology


Not everyone with a significant burden of classic Alzheimer’s disease neuropathological changes (e.g., plaques and tangles) experiences comparable cognitive decline or has the typical tissue responses of neuronal and synaptic derangement. Identifying predictive markers of such natural protection and understanding the underlying mechanisms involved may hold key clues to developing novel cognitive sparing therapies in the elderly. This project will perform 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 (N=54), cognitively intact individuals whose postmortem exam demonstrated significant amounts of AD changes (“resilient”) (N=59), and typical demented AD patients (N=53). The vast majority of these cases were followed prospectively for years, with extensive clinical information available and a short interval between the last detailed cognitive assessment and death, making this large set of brains unique and particularly informative.

Our previous work has allowed us to rigorously demonstrate that plaques and tangles do not inevitably result in neuronal and synaptic derangement and impaired cognition in all cases (Perez-Nievas et al., 2013). We also have gained significant insight into the events that appear to be more proximate correlates to neuronal changes and cognitive impairment than just the presence of plaques and tangles, including activation of GSK-beta enzyme and soluble phosphor-tau accrual in synapses and neuroinflammation. The identification of a histologic and biochemical “signature” characteristic of human brain resilience to AD pathology will be used to understand the hierarchy of events that results in cognitive impairment in the presence of plaques and tangles. The ultimate goal is to identify druggable pathways and molecular targets linked to brain resilience to AD pathology, and eventually to test novel meaningful interventions. We think the studies proposed here will provide valuable hints to identify novel targets and better disease-modifying treatments for AD. Given the evidence for neuroinflammation as a critical mediator in other neurodegenerative disorders, such therapies may have wide potential benefits.

Funding to Date



Pathological Pathways and Systems, Translational Research


Teresa Gomez-Isla, M.D.