@article{cf5a02a2baaf48149da21b850acb6c2b,
title = "BDNF Val66Met moderates memory impairment, hippocampal function and tau in preclinical autosomal dominant Alzheimer's disease",
abstract = "See Rogaeva and Schmitt-Ulms (doi:10.1093/aww201) for a scientific commentary on this article. The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism is implicated in synaptic excitation and neuronal integrity, and has previously been shown to moderate amyloid-β-related memory decline and hippocampal atrophy in preclinical sporadic Alzheimer's disease. However, the effect of BDNF in autosomal dominant Alzheimer's disease is unknown. We aimed to determine the effect of BDNF Val66Met on cognitive function, hippocampal function, tau and amyloid-β in preclinical autosomal dominant Alzheimer's disease. We explored effects of apolipoprotein E (APOE) ϵ4 on these relationships. The Dominantly Inherited Alzheimer Network conducted clinical, neuropsychological, genetic, biomarker and neuroimaging measures at baseline in 131 mutation non-carriers and 143 preclinical autosomal dominant Alzheimer's disease mutation carriers on average 12 years before clinical symptom onset. BDNF genotype data were obtained for mutation carriers (95 Val66 homozygotes, 48 Met66 carriers). Among preclinical mutation carriers, Met66 carriers had worse memory performance, lower hippocampal glucose metabolism and increased levels of cerebrospinal fluid tau and phosphorylated tau (p-tau) than Val66 homozygotes. Cortical amyloid-β and cerebrospinal fluid amyloid-β42 levels were significantly different from non-carriers but did not differ between preclinical mutation carrier Val66 homozygotes and Met66 carriers. There was an effect of APOE on amyloid-β levels, but not cognitive function, glucose metabolism or tau. As in sporadic Alzheimer's disease, the deleterious effects of amyloid-β on memory, hippocampal function, and tau in preclinical autosomal dominant Alzheimer's disease mutation carriers are greater in Met66 carriers. To date, this is the only genetic factor found to moderate downstream effects of amyloid-β in autosomal dominant Alzheimer's disease.",
keywords = "Alzheimer's disease, amyloid-β, dementia, genetics, tau",
author = "Lim, {Yen Ying} and Jason Hassenstab and Carlos Cruchaga and Alison Goate and Fagan, {Anne M.} and Benzinger, {Tammie L.S.} and Paul Maruff and Snyder, {Peter J.} and Masters, {Colin L.} and Ricardo Allegri and Jasmeer Chhatwal and Farlow, {Martin R.} and Graff-Radford, {Neill R.} and Christoph Laske and Johannes Levin and Eric McDade and Ringman, {John M.} and Martin Rossor and Stephen Salloway and Schofield, {Peter R.} and Holtzman, {David M.} and Morris, {John C.} and Bateman, {Randall J.}",
note = "Funding Information: Data collection and sharing for this project was supported by The Dominantly Inherited Alzheimer's Network (DIAN, U19AG032438) funded by the National Institute on Aging (NIA) and the German Center for Neurodegenerative Diseases (DZNE). This work was also supported by the NIHR Queen Square Dementia Biomedical Research Unit and the MRC Dementias Platform UK (MR/L023784/1 and MR/009076/1). We thank the Genome Technology Access Center in the Department of Genetics at Washington University School of Medicine for help with genomic analysis. The Center is partially supported by NCI Cancer Center Support Grant #P30 CA91842 to the Siteman Cancer Center and by ICTS/CTSA Grant# UL1TR000448 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. Data and/or tissue generated from DIAN fibroblasts (or IPSCs) and/or exome chip sequencing was supported by the DIAN-TU Pharma Consortium, (the DIAN-TU Pharma Consortium, http://dian-tu.wustl. edu/en/pharma-consortium-members/). This publication is solely the responsibility of the authors and does not necessarily represent the official view of NCRR or NIH. JP Chhatwal is supported by K23-AG049087. YY Lim is supported by the Alzheimer's Australia Dementia Research Fellowship, the Yulgilbar Alzheimer's Research Program, and the NHMRC-ARC Dementia Research Development Fellowship. Publisher Copyright: {\textcopyright} 2016 The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.",
year = "2016",
month = oct,
day = "1",
doi = "10.1093/brain/aww200",
language = "English (US)",
volume = "139",
pages = "2766--2777",
journal = "Brain",
issn = "0006-8950",
publisher = "Oxford University Press",
number = "10",
}