Effect of BDNF Val66Met on hippocampal subfields volumes and compensatory interaction with APOE-ε4 in middle-age cognitively unimpaired individuals from the ALFA study

Abstract

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.

Genetic Influences on Hippocampal Subfields

“…Three studies specifically explored the association between hippocampal subfield volumetry and BDNF (brain-derived neurotrophic factor) Val66Met (rs6265) polymorphism. 36-38 Frodl et al (2014) showed significant interaction effects between BDNF Val66Met genotypes and childhood adversity within hippocampal subfields in a sample involving individuals diagnosed with MDD. On the one hand, the study highlighted that Met allele carriers with childhood adversity had smaller subfield volumes than Val allele homozygotes, where the most reduced volumes were specific for CA2/3 (β = −0.28, p = 0.015).…”

Distinct Patterns Link the BDNF Val66Met Polymorphism to Alzheimer’s Disease Pathology

“…Previous studies have shown an association of lower serum BDNF to widespread A␤ 42 in PET studies [6] and faster disease progression in Met carriers, and this effect is magnified by the presence of an Apolipoprotein E (APOE) 4 allele [7,8]. On the other hand, clinically healthy Val-Val individuals showed lower hippocampal volume compared to heterozygotes and with a dose-response effect with the number of APOE 4 alleles [9]. Older meta-analyses in both healthy and neuropsychiatric populations found no effects of Val66Met on brain volume.…”

Deciphering the Effect of Different Genetic Variants on Hippocampal Subfield Volumes in the General Population

“…It was also shown that Aβ oligomers exert a toxic influence on synaptic transmission by affecting synaptic long-term potentiation, as well as long-term depression, and might promote synapse loss in the hippocampus [ 15 ]. However, recent studies suggest that this effect might be compensated by the presence of one BDNF Met allele [ 16 , 17 ], but results on this remain controversial.…”

“…BDNF itself is a neuronal growth factor that plays an important role in the induction of neuronal sprouting and differentiation, and is highly expressed in the hippocampus [ 18 , 19 ]. Especially, the single-nucleotide polymorphism BDNF Val 66 Met, which causes a valine (Val) to methionine (Met) substitution at codon 66 of the BDNF protein, is of high interest because of its known influence on hippocampal functions [ 16 ]. It has also been associated with AD and depression in the past [ 20 , 21 ].…”

“…Studies in rodents and humans suggested that carriers of the BDNF Met allele show lower hippocampal volumes [ 19 , 22 ]. The differential expression of BDNF in different hippocampal regions might also suggest a distinct impact of the Val 66 Met polymorphism on hippocampal subfield volumes [ 16 ]. Despite these results, a joint analysis of the relation between Val 66 Met and hippocampal volumes in healthy subjects revealed no significant effect [ 19 ], and a further meta-analysis of neuropsychiatric patients showed no genotype-dependent effects [ 23 ].…”