TAU is the main disease driver in Alzheimer’s and many other sporadic and genetic tauopathies. TAU is differently spliced, the role of individual splice-isoforms unclear. Murine Mapt-KO mice are healthy, and protected from Alzheimer’s, but no such case has been reported in humans. Using gnomad database, we here demonstrate that the only isoform expressed during fetal human brain development is intolerant to mutation, while other brain and peripheral nervous system TAU isoforms are dispensable. With TAU targeted therapies for Alzheimer’s and other tauopathies on the rise, we caution that TAU is essential human brain development.

Genetic and sporadic forms of tauopathies, the most prevalent of which is Alzheimer’s Disease, are a scourge of the aging society, and in case of genetic forms, can also affect children and young adults. All tauopathies share ectopic expression, mislocalization, or aggregation of the microtubule associated protein TAU, encoded by the MAPT gene. As TAU is a neuronal protein widely expressed in the CNS, the overwhelming majority of tauopathies are neurological disorders. They are characterized by cognitive dysfunction often leading to dementia, and are frequently accompanied by movement abnormalities such as parkinsonism. Tauopathies can lead to severe neurological deficits and premature death. For some tauopathies there is a clear genetic cause and/ or an epigenetic contribution. However, for several others the disease etiology is unclear, with few tauopathies being environmentally triggered. Here we review current knowledge of tauopathies listing known genetic and important sporadic forms of this disease. Further, we discuss how DNA methylation as a major epigenetic mechanism emerges to be involved in the disease pathophysiology of Alzheimer’s, and related genetic and non-genetic tauopathies. Finally, we debate the application of epigenetic signatures in peripheral blood samples as diagnostic tool and usage of epigenetic therapy strategies for these diseases.