R406W is a change that affects the C-terminal region of the tau protein, a part that is important for maintaining the protein’s overall structure and the way it behaves.
In many families, the symptoms noticed first are related to memory, which is why R406W can resemble Alzheimer’s disease early on. This memory-led pattern is one of its more consistent features, though behavior, movement, and language can also become involved as time goes on. Penetrance is high, and variability across families is also high — even relatives carrying the same change can differ, with some showing memory-led changes and others more behavioral changes, reflecting which brain regions are affected.
In the brain, R406W leads to the build-up of aggregates containing both forms of tau (3R and 4R), and tends to affect the hippocampus and nearby temporal regions tied to memory. Interestingly, the tau filaments in R406W fold in the same way as those seen in Alzheimer’s disease.
R406W is one of the better-studied MAPT changes, with strong clinical, imaging, and pathology data, and many model systems — including cell and animal models — available to researchers.
References -
Hutton M, et al. (1998). Nature 393:702–705. — The original discovery that R406W and other MAPT mutations cause inherited FTD. https://pubmed.ncbi.nlm.nih.gov/9641683/
Ygland E, et al. (2018). Alzheimer’s Research & Therapy 10:2. — Combines data on 63 reported carriers; describes the memory-led, slowly progressing pattern. https://pubmed.ncbi.nlm.nih.gov/29370822/
Sato C, et al. (2021). Annals of Clinical and Translational Neurology 8:1817–1830. — Shows R406W produces Alzheimer-like tau biomarker changes without amyloid. https://pubmed.ncbi.nlm.nih.gov/34339118/
Qi C, et al. (2025). Nature Structural & Molecular Biology. — Cryo-EM showing R406W tau filaments share the Alzheimer fold. https://pubmed.ncbi.nlm.nih.gov/40050476/
Alzforum. MAPT R406W — continuously updated overview of clinical features, pathology, and research models. https://www.alzforum.org/mutations/mapt-r406w
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