Figure 1 |. Putative role of tau and microglia in resilience.

a | In individuals with Alzheimer disease (AD), tau, which is largely bound to axonal microtubules in normal conditions, detaches from microtubules, becomes hyperphosphorylated and misfolded, and coalesces into neurofibrillary tangles in the neuronal soma. In individuals with clinically manifest AD, soluble hyperphosphorylated tau species are mis-targeted and preferentially accumulate within the synaptic compartment in parallel with microglial cell activation. Over time, these changes are associated with the most frequently observed tissue injury response in AD brains, that is, neuronal cell death and synaptic loss. b | In the brains of ‘resilient’ individuals, a negligible accumulation of soluble hyperphosphorylated tau in synapses and a suppressed inflammatory brain response have been observed. These features are associated with the preservation of neurons and synapses amid a burden of plaques and tangles equal to that observed in the brains of individuals with clinically manifest AD. This differential tissue response to the progressive accumulation of plaques and tangles in individuals with clinically manifest AD and resilient individuals is likely to contribute to their widely divergent clinical phenotypes.