Higher brain BDNF gene expression is associated with slower cognitive decline in older adults

Abstract

Objectives: We tested whether brain-derived neurotrophic factor (BDNF) gene expression levels are associated with cognitive decline in older adults.

Methods: Five hundred thirty-five older participants underwent annual cognitive assessments and brain autopsy at death. BDNF gene expression was measured in the dorsolateral prefrontal cortex. Linear mixed models were used to examine whether BDNF expression was associated with cognitive decline adjusting for age, sex, and education. An interaction term was added to determine whether this association varied with clinical diagnosis proximate to death (no cognitive impairment, mild cognitive impairment, or dementia). Finally, we examined the extent to which the association of Alzheimer disease (AD) pathology with cognitive decline varied by BDNF expression.

Results: Higher brain BDNF expression was associated with slower cognitive decline (p < 0.001); cognitive decline was about 50% slower with the 90th percentile BDNF expression vs 10th. This association was strongest in individuals with dementia. The level of BDNF expression was lower in individuals with pathologic AD (p = 0.006), but was not associated with macroscopic infarcts, Lewy body disease, or hippocampal sclerosis. BDNF expression remained associated with cognitive decline in a model adjusting for age, sex, education, and neuropathologies (p < 0.001). Furthermore, the effect of AD pathology on cognitive decline varied by BDNF expression such that the effect was strongest for high levels of AD pathology (p = 0.015); thus, in individuals with high AD pathology (90th percentile), cognitive decline was about 40% slower with the 90th percentile BDNF expression vs 10th.

Conclusions: Higher brain BDNF expression is associated with slower cognitive decline and may also reduce the deleterious effects of AD pathology on cognitive decline.

Figure 1. Brain BDNF expression level and the rate of cognitive decline

To display this association, 3 hypothetical average participants with their estimated rate of cognitive decline based on the complete model with all the cases analyzed in this study are illustrated. Model derived trajectories of cognitive decline for 3 participants with low (red, 10th percentile), average (black, 50th percentile) and high (blue, 90th percentile) brain BDNF expression levels in the dorsal lateral prefrontal cortex. BDNF = brain-derived neurotrophic factor.

Figure 2. Brain BDNF expression level modifies the association of AD pathology and the rate of cognitive decline

To display this association, 3 pairs of hypothetical average participants with their estimated rate of cognitive decline based on the complete model with a 3-way interaction term with all the cases analyzed in this study are illustrated. Model derived trajectories of cognitive decline for participants with low (red, 10th percentile) and high (blue, 90th percentile) brain BDNF gene expression levels with 3 levels of AD pathology: low (10%, solid), median (50%, dashed), and high (90%, dotted). At all levels of AD pathology, the rate of cognitive decline is slower in individuals with high levels of BDNF (blue) vs low BDNF expression levels (red). It is evident that the difference in slopes of cognitive decline between the high levels of BDNF expression (blue) and low levels of BDNF expression (red lines) is much greater for the dashed lines (high AD pathology) as compared to the solid lines (low AD pathology). AD = Alzheimer disease; BDNF = brain-derived neurotrophic factor; path = pathology.