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Association of BDNF Val66Met With Tau Hyperphosphorylation and Cognition in Dominantly Inherited Alzheimer Disease

2022; American Medical Association; Volume: 79; Issue: 3 Linguagem: Inglês

10.1001/jamaneurol.2021.5181

2168-6157

Yen Ying Lim, Paul Maruff, Nicolas R. Barthélemy, Alison Goate, Jason Hassenstab, Chihiro Sato, Anne M. Fagan, Tammie L.S. Benzinger, Chengjie Xiong, Carlos Cruchaga, Johannes Levin, Martin R. Farlow, Neill R. Graff‐Radford, Christoph Laske, Colin L. Masters, Stephen Salloway, Peter R. Schofield, John C. Morris, Randall J. Bateman, Eric McDade, Jasmeer P. Chhatwal, Colleen Fitzpatrick, Courtney Bodge, Stephen Salloway, Chrismary De La Cruz, Jill Goldman, Arlene Mejia, Katie Neimeyer, James M. Noble, Samantha L. Gardener, Ralph N. Martins, Hamid R. Sohrabi, Kevin Taddei, Kathleen Carter, Duc M. Duong, Erik C. B. Johnson, Allan I. Levey, Lingyan Ping, Nick Seyfried, Susanne Gräber‐Sultan, Lisa M. Häsler, Anna Hofmann, Mathias Jucker, Stephan Käser, Elke Kuder-Buletta, Christoph Laske, Oliver Preische, Anna Diffenbacher, Yakushev Igor, Johannes Levin, Jonathan Vöglein, Ulricke Obermüller, Bianca Esposito, Alison Goate, Alan E. Renton, Jared R. Brosch, Jill Buck, Marty Farlow, Bernardino Ghetti, Ricardo Allegri, Patricio Chrem, Noelia Egido, Christian Haass, Estrella Morenas‐Rodríguez, Brigitte Nuscher, Gregory S. Day, Neill R. Graff‐Radford, Morgan Graham, Sochenda Stephens, Clifford R. Jack, Jacob Bechara, William S. Brooks, Peter R. Schofield, Aki Araki, Takeshi Ikeuchi, Kensaku Kasuga, Kenji Ishii, Hisako Fujii, Michio Senda, Hiroyuki Shimada, Ryoko Ihara, Akemi Nagamatsu, Yoshiki Niimi, J. Maxwell Douglas, Nick C. Fox, Miguel L. Grilo, Cath Mummery, Antoinette O’Connor, Colin L. Masters, Robert A. Koeppe, Sarah Berman, Sarah B. Goldberg, Snežana Ikonomović, William E. Klunk, Oscar L. López, James M. Mountz, Neelesh K. Nadkarni, Riddhi Patira, Lori Smith, Beth E. Snitz, Sarah Thompson, Elise A. Weamer, Neal Scott Mason, Helena Chui, John M. Ringman, Sarah Adams, Nicolas R. Barthélemy, Randall J. Bateman, Tammie L.S. Benzinger, Susan E. Brandon, Virginia Buckles, Lisa Cash, Charlie Chen, Jasmin Chua, Carlos Cruchaga, Darcy Denner, Aylin Dincer, Tamara Donahue, Anne M. Fagan, Becca Feldman, Shaney Flores, Erin Franklin, Nelly Friedrichsen, Alyssa Gonzalez, Brian A. Gordon, Julia Gray, Emily Gremminger, Alex Groves, Jason Hassenstab, Cortaiga Hellm, Elizabeth Herries, Laura Hoechst-Swisher, David M. Holtzman, Russ C. Hornbeck, Gina Jerome, Celeste M. Karch, Sarah Keefe, Deb Koudelis, Yan Li, Jacob I. Marsh, Rita Martinez, Kwasi G. Mawuenyega, Austin McCullough, Eric McDade, John C. Morris, Joanne Norton, Richard J. Perrin, Kristine Shady, Wendy Sigurdson, Jennifer A. Smith, Peter Wang, Qing Wang, Chengjie Xiong, Jinbin Xu, Xu Xiong,

Tryptophan and brain disorders

Allelic variation in the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism moderates increases in cerebrospinal fluid (CSF) levels of tau and phosphorylated tau 181 (p-tau181), measured using immunoassay, and cognitive decline in presymptomatic dominantly inherited Alzheimer disease (DIAD). Advances in mass spectrometry show that CSF tau phosphorylation occupancy at threonine 181 and 217 (p-tau181/tau181, p-tau217/tau217) increases with initial β-amyloid (Aβ) aggregation, while phosphorylation occupancy at threonine 205 (p-tau205/tau205) and level of total tau increase when brain atrophy and clinical symptoms become evident.To determine whether site-specific tau phosphorylation occupancy (ratio of phosphorylated to unphosphorylated tau) is associated with BDNF Val66Met in presymptomatic and symptomatic DIAD.This cross-sectional cohort study included participants from the Dominantly Inherited Alzheimer Network (DIAN) and Aβ-positive cognitively normal older adults in the Alzheimer's Disease Neuroimaging Initiative (ADNI). Data were collected from 2009 through 2018 at multicenter clinical sites in the United States, United Kingdom, and Australia, with no follow-up. DIAN participants provided a CSF sample and completed clinical and cognitive assessments. Data analysis was conducted between March 2020 and March 2021.Mass spectrometry analysis was used to determine site-specific tau phosphorylation level; tau levels were also measured using immunoassay. Episodic memory and global cognitive composites were computed.Of 374 study participants, 144 were mutation noncarriers, 156 were presymptomatic mutation carriers, and 74 were symptomatic carriers. Of the 527 participants in the network, 153 were excluded because their CSF sample, BDNF status, or both were unavailable. Also included were 125 Aβ-positive cognitively normal older adults in the ADNI. The mean (SD) age of DIAD participants was 38.7 (10.9) years; 43% were women. The mean (SD) age of participants with preclinical sporadic AD was 74.8 (5.6) years; 52% were women. In presymptomatic mutation carriers, compared with Val66 homozygotes, Met66 carriers showed significantly poorer episodic memory (d = 0.62; 95% CI, 0.28-0.95), lower hippocampal volume (d = 0.40; 95% CI, 0.09-0.71), and higher p-tau217/tau217 (d = 0.64; 95% CI, 0.30-0.97), p-tau181/tau181 (d = 0.65; 95% CI, 0.32-0.99), and mass spectrometry total tau (d = 0.43; 95% CI, 0.10-0.76). In symptomatic mutation carriers, Met66 carriers showed significantly poorer global cognition (d = 1.17; 95% CI, 0.65-1.66) and higher p-tau217/tau217 (d = 0.53; 95% CI, 0.05-1.01), mass spectrometry total tau (d = 0.78; 95% CI, 0.28-1.25), and p-tau205/tau205 (d = 0.97; 95% CI, 0.46-1.45), when compared with Val66 homozygotes. In preclinical sporadic AD, Met66 carriers showed poorer episodic memory (d = 0.39; 95% CI, 0.00-0.77) and higher total tau (d = 0.45; 95% CI, 0.07-0.84) and p-tau181 (d = 0.46; 95% CI, 0.07-0.85).In DIAD, clinical disease stage and BDNF Met66 were associated with cognitive impairment and levels of site-specific tau phosphorylation. This suggests that pharmacological strategies designed to increase neurotrophic support in the presymptomatic stages of AD may be beneficial.