Association of BACE1 Gene Polymorphism with Cerebellar Volume but Not Cognitive Function in Normal Individuals

β-Site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) is a biological and positional candidate gene for Alzheimer's disease (AD). Previous studies found that BACE1-null mice had impaired performance on cognition and neurodegeneration during the aging process. Additionally, a synonymous polymorphism of BACE1 (rs638405) in exon 5 has been reported to be associated with risk for AD. We hypothesized that this BACE1 gene variant might influence regional brain volumes and cognitive tests in normal individuals.

Participants were 330 normal volunteers between 21 and 92 years of age (mean age 56.3 ± 22.0 years; 191 males, 139 females). Cognitive tests (the Mini-Mental State Examination and Digit Spans), magnetic resonance imaging, and genotyping of BACE1 rs638405 were examined for each subject. The differences in regional gray matter (GM) volumes between G homozygotes and C-allele carriers were tested using optimized voxel-based morphometry.

Compared to C-allele carriers, G homozygotes exhibited significantly larger GM volumes in the left cerebellar culmen and right cerebellar lingual area, but no significant differences on cognitive function tests.

The findings suggest that the BACE1 rs638405 polymorphism may affect cerebellar morphology, but not cognitive function in healthy humans.