Brain-derived neurotrophic factor (BDNF) levels increase with exercise, and BDNF is believed to at least partly mediate exercise's probrain effects. The BDNF gene harbors a common polymorphism; one version deposits valine at the amino acid 66 position, while the other deposits methionine. Previous work suggests that in normal brain aging, the valine-containing version may be functionally advantageous, and Val/Val homozygotes may enjoy a degree of “neuroprotection” that heterozygotes (Val/Met) or methionine homozygotes (Met/Met) do not.1 To further explore this possibility, this study analyzed brain volume and physical activity levels in a cohort of aged, cognitively normal individuals.2 The authors hypothesized that if the BDNF Val/Val genotype is truly advantageous and physical activity increases BDNF levels, then Val/Val carrier brains would benefit more from physical activity than Val/Met or Met/Met carrier brains.
While the data essentially support this hypothesis, the overall findings were complex. For BDNF Val/Val homozygotes, MRI-determined temporal, medial temporal, and hippocampal volumes did positively correlate with physical activity levels (as quantified by a physical activity questionnaire). However, it was further found that participants with at least one methionine allele showed the inverse; relatively active methionine carriers had relatively smaller temporal lobe volumes than less active methionine carriers.
Does this mean the methionine-containing BDNF isoform is harmful? This interpretation seems premature, and as the authors point out, although some studies suggest that Val/Met and Met/Met individuals are disadvantaged, other studies argue the opposite.3 Does this mean Val/Val individuals should exercise in order to fully enjoy the salubrious effects of BDNF, while Val/Met and Met/Met carriers should avoid vigorous exercise? In the absence of interventional data, this conclusion also seems premature. While this well-done cross-sectional study raises provocative questions, results such as these emphasize the limitations of using correlation to infer causality and conclude molecular mechanisms.
Footnotes
Study funding: No targeted funding reported.
Disclosure: Dr. Swerdlow is supported by the NIH. He has received an honorarium from Medscape. Go to Neurology.org for full disclosures.
References
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