White matter lesions, also termed White Matter Hyperintensities (WMH), on T2-weighted MR images, are common in the elderly population. Of note, their presence is often accompanied with
cognitive decline and the risk of
dementia. Even though previous
brain ischemia and WM lesion studies have been conducted and indicated that
brain-derived neurotrophic factor (
BDNF) might protect against neuronal cell death, the interaction between regional WMH volume and the
BDNF Val66Met polymorphism on the cognitive performance of healthy elderly population remains unclear. To investigate the genetic effect of
BDNF on cognitive function and regional WMH in the healthy elderly population, 90 elderly men, without
dementia, with a mean age of 80.6 ± 5.6 y/o were recruited to undergo cognitive tests, structural magnetic resonance imaging (MRI) scans, and genotyping of
BDNF alleles. Compared with Met homozygotes, Val homozygotes showed significantly inferior short-term memory (STM) performance (P = .001). A tendency toward dose-dependent effects of the Val allele on WMH volume was found, and Val homozygotes showed larger WMH volume in the temporal (P = .035), the occipital (P = .006), and the global WMH volume (P = .025) than others. Significant interaction effects of
BDNF genotypes with temporal WMH volume on STM performance was observed (F1,89 = 4.306, P = .041). Val homozygotes presented steeper negative correlation compared to Met carriers. Mediation analysis also demonstrated that WMH in temporal, limbic, and subcortical regions might mediate the relationship between
BDNF's genetic effect and STM performance. Our findings supported the hypothesis that the
BDNF Val66Met polymorphism may affect susceptibility to regional WMH volume and such genotype-by-WMH interaction effect is correlated with
cognitive decline in non-demented elderly males, in which the Met allele plays a protective role.