Yen Ying Lim1, Jason Hassenstab2, Alison Goate3, Anne M Fagan2, Tammie L S Benzinger4, Carlos Cruchaga5, Eric McDade2, Jasmeer Chhatwal6,7, Johannes Levin8, Martin R Farlow9, Neill R Graff-Radford10, Christoph Laske11,12, Colin L Masters1, Stephen Salloway13, Peter Schofield14,15, John C Morris2, Paul Maruff1,16, Randall J Bateman2. 1. The Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia. 2. Department of Neurology, Washington University in St Louis, St Louis, MO. 3. Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY. 4. Department of Radiology, Washington University in St Louis, St Louis, MO. 5. Department of Psychiatry, Washington University in St Louis, St Louis, MO. 6. Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA. 7. Center for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA. 8. Department of Neurology, University of Munich, Munich, Germany. 9. Department of Neurology, Indiana University School of Medicine, Indianapolis, IN. 10. Department of Neurology, Mayo Clinic, Jacksonville, FL. 11. German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany. 12. Section for Dementia Research, Department of Cellular Neurology, Hertie Institute for Clinical Brain Research and Department of Psychiatry and Psychotherapy, University of Tübingen, Tübingen, Germany. 13. Department of Neurology, Warren Alpert Medical School of Brown University, Providence, RI. 14. Neuroscience Research Australia, Sydney, NSW, Australia. 15. School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia. 16. Cogstate Ltd, Melbourne, Victoria, Australia.
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 ptau181 increases (6×) than Val66 homozygotes. BDNF did not influence rates of cortical β-amyloid accumulation or change in CSF Aβ42 levels in mutation carriers. In mutation noncarriers, BDNF genotype 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. The BDNF Val66Met 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.
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 ptau181 increases (6×) than Val66 homozygotes. BDNF did not influence rates of cortical β-amyloid accumulation or change in CSF Aβ42 levels in mutation carriers. In mutation noncarriers, BDNF genotype 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. The BDNFVal66Met 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.
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