In the healthy brain, the 3R and 4R isoforms are equivalently expressed.46 In Alzheimer’s brain, there is a decrease in 3R tau isoform or increase in 4R tau levels resulting in shift in the ratio of 4R-tau to 3R-tau.47,48 Our observation demonstrated that light 3R and intense 4R labelled neurons observed in substantia nigra of MMD and PD were similar to a pattern that existed in temporal cortex of Alzheimer’s disease (Supplementary Fig. 6), indicating that unequal 3R and 4R tau expression was associated with neurodegeneration. This evidence concerns the gene MAPT and early-onset autosomal dominant Alzheimer disease.