Abstract Body

The rate of progression of Alzheimer disease varies substantially across patients, yet it is uncertain why there are such marked individual differences. We explored the possibility that differences in tau propagation might contribute to this variability, and are also exploring other possible drivers of decline: apoE genotype, vascular pathological co-occurrence, and inflammatory changes.

We measured tau propagation of cortical soluble tau, measured from frozen autopsy material derived from patients who had been followed longitudinally at our Center. We measured bioactivity in an in vitro test, and found increased bioactivity in the individuals who had had a faster rate of progression. These both also correlated with biophysical properties of tau, specific patterns of post translational modifications as assessed by mass spectroscopy (with Dr Judith Steen), and ability to “seed” tau aggregates in a mouse model. We are currently studying the specific post translational modifications and trying to understand both their role in altering propagation kinetics as well as the activation of the enzymes responsible for specific PTMs, and to extend the assays to the hundred fold smaller amounts of bioactive tau present in AD patient lumbar spinal fluid.