Cerebral β-amyloid deposition is augmented by the -491AA promoter polymorphism in non-demented elderly individuals bearing the apolipoprotein E E4 allele

The apoliprotein E E4 allele (APOE, gene; apoE, protein) is widely accepted as a risk factor for Alzheimer's disease (AD). Our previous studies found that APOEE4 promotes AD pathogenesis by fostering the early deposition of the amyloidogenic peptide Aβ in the aging brain. Recent reports suggest that polymorphisms in the upstream promoter region of APOE differentially affect the production of apoE and also may have an important influence on the probability of developing AD. In this study, we asked whether APOE promoter -491 (A/T) variants interact with APOE polymorphisms to modulate the degree of β-amyloid and tau-related pathology in the medial temporal lobe of the non-demented elderly. Our results confirm that APOEE4 is associated with increased formation of senile plaques, cerebrovascular amyloid, and neurofibrillary tangles in the medial temporal lobe. We also found that homozygosity for A at position -491 of the APOE promoter (-491AA) correlates with increased Aβ17-24 and Aβ42 deposition in APOEE4-positive cases, but not in cases lacking the E4 allele. In comparison, Aβ burden is significantly less in E4 carriers with the -491AT and -491TT promoter allelotypes. There was no effect of -491 polymorphisms on Aβ40 deposition (which is relatively sparse in the non-demented elderly), on the number of activated microglia, or an the amount of neurofibrillary tangles. We conclude that the amyloidogenic effects of apoE4 are exacerbated by polymorphisms in the APOE promoter that enhance apoE production.