A brain proteomic signature of incipient Alzheimer’s disease in young<i>APOE</i>ε4 carriers identifies novel drug targets
Jackson A. Roberts, Vijay R. Varma, Yang An, Sudhir Varma, Julián Candia, Giovanna Fantoni, Vinod Tiwari, Carlos Anerillas, Andrew Williamson, Atsushi Saito, Tina Loeffler, Irene Schilcher, Ruin Moaddel, Mohammed Khadeer, Jacqueline Lovett, Toshiko Tanaka, Olga Pletniková, Juan C. Troncoso, David A. Bennett, Marilyn S. Albert, Kaiwen Yu, Mingming Niu, Vahram Haroutunian, Bin Zhang, Junmin Peng, Deborah L. Croteau, Susan M. Resnick, Myriam Gorospe, Vilhelm A. Bohr, Luigi Ferrucci, Madhav Thambisetty
Abstract
ε4 carriers relative to noncarriers (mean age, 39 ± 6 years). Several of these proteins represent targets of approved and experimental drugs for other indications and were validated using orthogonal methods in independent human brain tissue samples as well as in transgenic AD models. Using cell culture–based phenotypic assays, we showed that drugs targeting the cytokine transducer STAT3 and the Src family tyrosine kinases, YES1 and FYN, rescued molecular phenotypes relevant to AD pathogenesis. Our findings may accelerate the development of effective interventions targeting the earliest molecular triggers of AD.