Year: 2018
Type: article
Abstract: Objective Previous studies suggest that the brain‐derived neurotrophic factor (BDNF) Val66Met (rs6265) polymorphism may influence symptom onset in Alzheimer's disease (AD). Our recent cross‐sectional findings suggest that Met66 may influence clinical expression in dominantly inherited AD (DIAD) through its effects on tau. However, it remains unclear whether carriage of Met66 in DIAD results in faster increases in cerebrospinal fluid (CSF) tau and ptau181, and whether these increases are associated with accelerated brain volume loss and memory decline. Methods A total of 211 subjects (101 mutation noncarriers, 110 mutation carriers), who were cognitively normal, as defined by a Clinical Dementia Rating global score of 0, completed assessments of cognitive function, neuroimaging, and CSF sampling over 3.5 years as part of the Dominantly Inherited Alzheimer's Network. Results In mutation carriers, Met66 carriers showed faster memory decline (4×), hippocampal volume loss (16×), and CSF tau and ptau181increases (6×) than Val66 homozygotes.BDNFdid not influence rates of cortical β‐amyloid accumulation or change in CSF Aβ42levels in mutation carriers. In mutation noncarriers,BDNFgenotype had no effect on change in cognition, brain volume, cortical β‐amyloid accumulation, or change in any CSF measures of tau, ptau181, and CSF Aβ42. Interpretation As in sporadic AD, the deleterious effects of β‐amyloid on cognitive function, brain volume loss, and CSF tau in DIAD mutation carriers are less in Val66 homozygotes. TheBDNFVal66Met polymorphism should be considered as a potential moderator of clinical trial outcomes in current treatment and prevention trials in DIAD and sporadic AD. Ann Neurol 2018;84:424–435
Source: Annals of Neurology
DOI: 10.1002/ana.25299
Authors: Yen Ying Lim, Jason Hassenstab, Alison Goate, Anne M. Fagan, Tammie L.S. Benzinger, Carlos Cruchaga, Eric McDade, Jasmeer Chhatwal, Johannes Levin, Martin R. Farlow, Neill R. Graff‐Radford, Christoph Laske, Colin L. Masters, Stephen Salloway, Peter Schofield, John C. Morris, Paul Maruff, Randall J. Bateman, on behalf of the Dominantly Inherited Alzheimer Network
Institutions: Florey Institute of Neuroscience and Mental Health, Washington University in St. Louis, Icahn School of Medicine at Mount Sinai, Brigham and Women's Hospital, Harvard University, Massachusetts General Hospital, Ludwig-Maximilians-Universität München, Indiana University Indianapolis, Indiana University School of Medicine, Mayo Clinic, Mayo Clinic in Florida, German Center for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Brown University, UNSW Sydney, Neuroscience Research Australia
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Funders: Korea Health Industry Development Institute, Deutsches Zentrum für Neurodegenerative Erkrankungen, National Institutes of Health, National Health and Medical Research Council, National Institute on Aging, National Institute of Biomedical Imaging and Bioengineering, National Center for Advancing Translational Sciences
Awards: G1309605592, G2117308036, G2202404319, G2824222223, G2880069213, G40706755, G4427631003, A multi-cohort investigation of the effects of BDNF Val66Met on tau, neurodegeneration and cognition in preclinical Alzheimer’s disease, Dominantly Inherited Alzheimer Network, G587293260, Alzheimer's Disease Research Center, Washington University Institute of Clinical and Translational Sciences, Dominantly Inherited Alzheimer Network, Genetic mechanisms that moderate effects of Aß accumulation in preclinical Alzheimer's disease, National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD)
OpenAlex ID: W2883960573