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 18F-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.

BDNF Val66Met predicts cognitive decline in the Wisconsin Registry for Alzheimer's Prevention

“…37 Other groups have noted similar moderating effects of Ab and BDNF on cognition in older adults. 38 This interaction between Ab and the BDNF Val66Met polymorphism adds further support for the potential role the BDNF protein has in moderating Ab production, thus protecting cognitive function. Animal studies have indicated that BDNF regulates sorting protein-related receptor with A-type repeats, a known modulator of Ab precursor protein trafficking and processing, via extracellular signalregulated protein kinase stimulation, suggesting that BDNF could deter amyloid production.…”

Automated Quantification of 18F-Flutemetamol PET Activity for Categorizing Scans as Negative or Positive for Brain Amyloid: Concordance with Visual Image Reads

“…All participants gave written informed consent that was approved by the Internal Review Board of each participating institution. We grouped subjects into 3 cohorts: an autopsy cohort (n 5 68) comprising terminally ill patients with subsequent postmortem confirmation of brain amyloid status; a test cohort (n 5 172) comprising 33 patients with clinically probable Alzheimer disease, 80 patients with mild cognitive impairment, and 59 healthy volunteers; and a healthy cohort comprising 105 healthy volunteers from 3 studies (7,13,14).…”

Amyloid imaging in cognitively normal older adults: comparison between 18F-flutemetamol and 11C-Pittsburgh compound B

“…Inclusion was stratified for two genetic factors: BDNF ! 5 (met allele present or absent) and APOE (ε4 allele present or absent), as this cohort was part of a larger 18 F-flutemetamol study in healthy controls of the interactions between these polymorphisms [16,17] frames were realigned and summed for both data sets separately. The individual's 18 Fflutemetamol and 11 C-PIB PET summed images were co-registered to the subject's T1-weighted structural MRI.…”

“…The spatially standardised volumes of interest (VOIs) were identical for 18 Fflutemetamol and for 11 C-PIB image analysis. The cerebellar GM was defined based on the automated anatomical labelling (AAL) atlas (areas 91-108) and masked inclusively with subjectspecific GM maps, with the threshold for masking set at > 0.3 [16,17]. This reference region was used both for 18 F-flutemetamol and for 11 C-PIB images.…”