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Brain. 2016 Oct;139(Pt 10):2766-2777. Epub 2016 Aug 12.

BDNF Val66Met moderates memory impairment, hippocampal function and tau in preclinical autosomal dominant Alzheimer's disease.

Author information

1
1 The Florey Institute, The University of Melbourne, Parkville, Victoria, Australia yen.lim@florey.edu.au.
2
2 Department of Neurology, Washington University in St. Louis, St. Louis, MO, USA.
3
3 Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, USA.
4
4 Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
5
5 Department of Radiology, Washington University in St. Louis, St. Louis, MO, USA.
6
1 The Florey Institute, The University of Melbourne, Parkville, Victoria, Australia 6 Cogstate Ltd., Melbourne, Victoria, Australia.
7
7 Department of Neurology, Warren Alpert Medical School of Brown University, Providence, RI, USA.
8
1 The Florey Institute, The University of Melbourne, Parkville, Victoria, Australia.
9
8 Ageing and Memory Center, Instituto de Investigaciones Neurologicas "Raúl Carrea" (FLENI), Buenos Aires, Argentina.
10
9 Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA 10 Center for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
11
11 Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, USA.
12
12 Department of Neurology, Mayo Clinic Jacksonville, FL, USA.
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13 German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany 14 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.
14
15 Department of Neurology, University of Munich, Munich, Germany.
15
16 Memory and Aging Center, Keck School of Medicine of the University of Southern California, CA, USA.
16
17 Dementia Research Centre, Department of Neurodegenerative Diseases, UCL Institute of Neurology, London, UK.
17
18 Neuroscience Research Australia, Sydney, NSW, Australia 19 School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia.

Abstract

SEE ROGAEVA AND SCHMITT-ULMS DOI101093/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

PMID:
27521573
PMCID:
PMC5815565
DOI:
10.1093/brain/aww200
[Indexed for MEDLINE]
Free PMC Article

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