Polymorphism of brain derived neurotrophic factor influences β amyloid load in cognitively intact apolipoprotein E ε4 carriers

Abstract

Aside from apolipoprotein E (APOE), genetic risk factors for β amyloid deposition in cognitively intact individuals remain to be identified. Brain derived neurotrophic factor (BDNF) modulates neural plasticity, which has been implicated in Alzheimer's disease. We examined in cognitively normal older adults whether the BDNF codon 66 polymorphism affects β amyloid burden and the relationship between β amyloid burden and cognitive scores, and how this relates to the effect of APOE. Amyloid load was measured by means of (18)F-flutemetamol PET in 64 community-recruited cognitively intact individuals (mean age 66, S.D. 5.1). Recruitment was stratified according to a factorial design with APOE (ε4 allele present vs absent) and BDNF (met allele at codon 66 present vs absent) as factors. Individuals in the four resulting cells were matched by the number of cases, age, and gender. Among the APOE ε4 carriers, BDNF met positive subjects had a significantly higher amyloid load than BDNF met negative subjects, while BDNF met carrier status did not have an effect in APOE ε4 noncarriers. This interaction effect was localized to precuneus, orbitofrontal cortex, gyrus rectus, and lateral prefrontal cortex. In the APOE ε4/BDNF met carriers, a significant inverse relationship existed between episodic memory scores and amyloid burden but not in any of the other groups. This hypothesis-generating experiment highlights a potential role of BDNF polymorphisms in the preclinical phase of β amyloid deposition and also suggests that BDNF codon 66 polymorphisms may influence resilience against β amyloid-related effects on cognition.

Keywords: AD, Alzheimer's disease; APOE; APOE, apolipoprotein E; Alzheimer; Amyloid PET; BDNF; BDNF, brain-derived neurotrophic factor; Flutemetamol; MRI, magnetic resonance imaging; PET, positron emission tomography; PVC, partial volume correction; SUVR, standardized uptake value ratio; SUVRcomp, SUVR in composite cortical volume of interest; VOI, volume-of-interest; met, methionine; val, valine.

Fig. 1

Distribution of ¹⁸F-flutemetamol retention levels for the different genetic groups. X axis: age in years; Y axis: SUVR_comp.

Fig. 2

Effects of BDNF and APOE genotypes on amyloid deposition measured by SUVR_comp. (A) SUVR_comp in the different genetic subgroups. (B) Further differentiation depending on APOE and BDNF subgroups.

Fig. 3

Statistical parametric map of the main effect of APOE (A) and the interaction effect between APOE and BDNF (B). (A) Main effect of APOE genotype: increased ¹⁸F-flutemetamol retention in APOE ε4 + ve carriers compared to APOE ε4 − ve carriers in the posterior cingulate. (B) Interaction effect between BDNF and APOE: increased ¹⁸F-flutemetamol retention in the precuneus, orbitofrontal cortex, gyrus rectus, middle frontal gyrus, and inferior frontal sulcus. Images are displayed at voxel-level P < 0.001, only clusters that reached corrected cluster-level P < 0.05 are shown. SPM t maps are projected onto axial, sagittal, and coronal sections of the SPM8 standard single subject T1 template and as SPM8 glass brain views.

Fig. 4

Correlation between amyloid ligand retention and AVLT delayed recall (DR) and total learning (TL) scores. (A) Negative correlation between SUVR_comp values and AVLT DR scores in the BDNF met + ve/APOE ε4 + ve group (red line). (B) Negative correlation between SUVR_comp values and AVLT TL scores in the BDNF met + ve/APOE ε4 + ve (red line). SUVR_comp (Y axis) plotted by AVLT DR or TL scores (X axis): BDNF met + ve/APOE ε4 + ve (red triangles), BDNF met − ve/APOE ε4 + ve (blue squares), BDNF met + ve/APOE ε4 − ve (red circles) and BDNF met − ve/APOE ε4 − ve (blue diamonds). When the correlation does not reach significance, no regression line is shown.