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Effect of BDNF Val66Met Polymorphism on Hippocampal Subfield Volumes and Compensatory Interaction with APOE-ε4

Natalia Vilor-Tejedor, Grégory Operto, Tavia E Evans, Carles Falcon, Marta Crous-Bou, Carolina Minguillón, Raffaele Cacciaglia, Marta Milà-Alomà, Oriol Grau-Rivera, Marc Suárez-Calvet, Diego Garrido-Martín, Sebastián Morán, Manel Esteller, Hieab H Adams, José Luis Molinuevo, Roderic Guigó, Juan Domingo Gispert, ALFA Study


Background: Current evidence supports the involvement of brain-derived neurotrophic factor (BDNF) Val66Met polymorphism, and the ε4 allele of APOE gene in hippocampal-dependent functions. Previous studies on the association of Val66Met with whole hippocampal volume included patients of a variety of disorders. However, it remains to be elucidated whether there is an impact of BDNF Val66Met polymorphism on the volumes of the hippocampal subfield volumes (HSv) in cognitively unimpaired (CU) individuals, and the interactive effect with the APOE-ε4 status.

Methods: BDNF Val66Met and APOE genotypes were determined in a sample of 430 CU late/middle-aged participants from the ALFA study (ALzheimer and FAmilies). Participants underwent a brain 3D-T1-weighted MRI scan, and volumes of the HSv were determined using Freesurfer (v6.0). The effects of the BDNF Val66Met genotype on the HSv were assessed using general linear models corrected by age, gender, education, number of APOE-ε4 alleles and total intracranial volume. We also investigated whether the association between APOE-ε4 allele and HSv were modified by BDNF Val66Met genotypes.

Results: BDNF Val66Met carriers showed larger bilateral volumes of the subiculum subfield. In addition, HSv reductions associated with APOE-ε4 allele were significantly moderated by BDNF Val66Met status. BDNF Met carriers who were also APOE-ε4 homozygous showed patterns of higher HSv than BDNF Val carriers.

Conclusion: To our knowledge, the present study is the first to show that carrying the BDNF Val66Met polymorphisms partially compensates the decreased on HSv associated with APOE-ε4 in middle-age cognitively unimpaired individuals.

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Vilor-Tejedor N, Operto G, Evans TE, Falcon C, Crous-Bou M, Minguillón C, Cacciaglia R, Milà-Alomà M, Grau-Rivera O, Suárez-Calvet M, Garrido-Martín D, Morán S, Esteller M, Adams HH, Molinuevo JL, Guigó R, Gispert JD; ALFA Study. Effect of BDNF Val66Met on hippocampal subfields volumes and compensatory interaction with APOE-ε4 in middle-age cognitively unimpaired individuals from the ALFA study. Brain Struct Funct. 2020 Nov;225(8):2331-2345. doi: 10.1007/s00429-020-02125-3. Epub 2020 Aug 17. PMID: 32804326; PMCID: PMC7544723.