MAPT and Alzheimer disease: Importantly, all of the pathological changes we studied here were most prominent at Braak stage 3, before an exponential increase in extra-synaptic tau aggregate levels and tau tangle pathology in the pre-frontal cortex, supporting that early synaptic deficits precede neuronal dysfunction and loss in AD, and are mediated by small-diffusible aggregates rather than much larger plaques and tangles.