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Lim, Yen Ying; Hassenstab, Jason; Cruchaga, Carlos; Goate, Alison; Fagan, Anne M.; Benzinger, Tammie L. S.; Maruff, Paul; Snyder, Peter J.; Masters, Colin L.; Allegri, Ricardo; Chhatwal, Jasmeer; Farlow, Martin R.; Graff-Radford, Neill R.; Laske, Christoph; Levin, Johannes; McDade, Eric; Ringman, John M.; Rossor, Martin; Salloway, Stephen; Schofield, Peter R.; Holtzman, David M.; Morris, John C.; Bateman, Randall J. (2016): BDNF Val66Met moderates memory impairment, hippocampal function and tau in preclinical autosomal dominant Alzheimer's disease. In: Brain, Vol. 139: pp. 2766-2777
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Abstract

The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism modulates A beta+ related memory decline in sporadic Alzheimer's disease. Yen Ying Lim et al. report that this polymorphism also affects outcomes in autosomal dominant Alzheimer's disease. Met66 carriers show greater dysfunction in cognition, glucose metabolism and tau, with implications for clinical trial design.See Rogaeva and Schmitt-Ulms (doi:related-article ext-link-type="doi" id="RA3" related-article-type="companion" xlink:href="10.1093/brain/aww201"10.1093/aww201related-article) for a scientific commentary on this article. The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism modulates A beta+ related memory decline in sporadic Alzheimer's disease. Yen Ying Lim et al. report that this polymorphism also affects outcomes in autosomal dominant Alzheimer's disease. Met66 carriers show greater dysfunction in cognition, glucose metabolism and tau, with implications for clinical trial design.The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism is implicated in synaptic excitation and neuronal integrity, and has previously been shown to moderate amyloid-beta-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-beta in preclinical autosomal dominant Alzheimer's disease. We explored effects of apolipoprotein E (APOE) epsilon 4 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 Val(66) homozygotes, 48 Met(66) carriers). Among preclinical mutation carriers, Met(66) carriers had worse memory performance, lower hippocampal glucose metabolism and increased levels of cerebrospinal fluid tau and phosphorylated tau (p-tau) than Val(66) homozygotes. Cortical amyloid-beta and cerebrospinal fluid amyloid-beta(42) levels were significantly different from non-carriers but did not differ between preclinical mutation carrier Val(66) homozygotes and Met(66) carriers. There was an effect of APOE on amyloid-beta levels, but not cognitive function, glucose metabolism or tau. As in sporadic Alzheimer's disease, the deleterious effects of amyloid-beta on memory, hippocampal function, and tau in preclinical autosomal dominant Alzheimer's disease mutation carriers are greater in Met(66) carriers. To date, this is the only genetic factor found to moderate downstream effects of amyloid-beta in autosomal dominant Alzheimer's disease.