*4.6. MRI Acquisition*

We used a 1.5- or 3-Tesla magnetic resonance scanner (MAGNETOM Avanto, Siemens Healthcare, Erlangen, Germany or Ingenia, Philips Healthcare, Best, The Netherlands) with three-dimensional volumetric acquisition of a T1-weighted gradient echo sequence (repetition time range/echo time range, 6.5 ms/3.2 ms; field of view [frequency × phase], 240 mm × 240 mm; matrix, 256 × 256; contiguous axial slices of 1.5 mm thickness).

### *4.7. Image Processing*

For all image processes, we used PMOD software version 3.7 (PMOD Technologies Ltd., Zurich, Switzerland) [29]. Acquired 11C-PBB3 and 11C-PiB images were transformed into standard brain and then SUVR images were reconstructed with the midbrain as the reference region using the frame summation of dynamics of the image for 30 to 50 min after 11C-PBB3 injection and for 50 to 70 min after 11C-PiB injection. The SUVR level of each volume of interest (VOI) was calculated in a manually set region of interest (ROI) as shown in Supplementary Figure S1.

### *4.8. Statistical Analysis*

To quantitatively evaluate tau accumulation, SUVR values relative to the midbrain were calculated in each ROI. Statistically, the value of FAD (Osaka) was regarded as significantly high when it was higher than the average by more than 2 SD (standard deviation) in SAD patients and HCs.

## **5. Conclusions**

Here, we report a patient with familial AD who had heavy tau burden in the cerebral cortex and cerebellum with only a negligible amount of Aβ. The unprecedented observations support our hypothesis that Aβ, probably in oligomers, induces tau accumulation and neuronal degeneration without forming senile plaques.

**Supplementary Materials:** The following are available online at http://www.mdpi.com/1422-0067/21/12/4443/s1, Figure S1: Region of interest (ROI).

**Author Contributions:** H.S. (Hiroyuki Shimada): Clinical management; S.M., J.T., A.T.: Imaging and statistical analysis; J.K., Y.W. (Yasuhiro Wada), A.M., Y.W. (Yasuyoshi Watanabe): Tracer preparation; H.S. (Hitoshi Shimada), M.H., T.S.: Tracer supply and funding; T.T.: Basic research to support this study; Y.I.: General management and writing the manuscript. All authors have read and agreed to the published version of the manuscript.

**Funding:** NIRS/QST grant (Japan Agency for Medical Research and Development 16768966).

**Acknowledgments:** The authors thank M. Ando and N. Kotani (Osaka City University) for psychological tests. The present study was financially supported by the NIRS/QST grant (Japan Agency for Medical Research and Development 16768966) in which Osaka City University was involved as a collaborating facility.

**Conflicts of Interest:** Authors H.S. (Hitoshi Shimada), M.H., and T.S. possess patent royalty of PBB3.
