Human apoE Isoforms Differentially Regulate Brain Amyloid-β Peptide Clearance

The apolipoprotein E (APOE) epsilon 4 allele is the strongest genetic risk factor for late-onset, sporadic Alzheimer's disease (AD). The APOE epsilon 4 allele markedly increases AD risk and decreases age of onset, likely through its strong effect on the accumulation of amyloid-beta (A beta) peptide. In contrast, the APOE epsilon 2 allele appears to decrease AD risk. Most rare, early-onset forms of familial AD are caused by autosomal dominant mutations that often lead to overproduction of A beta(42) peptide. However, the mechanism by which APOE alleles differentially modulate A beta accumulation in sporadic, late-onset AD is less clear. In a cohort of cognitively normal individuals, we report that reliable molecular and neuroimaging biomarkers of cerebral A beta deposition vary in an apoE isoform-dependent manner. We hypothesized that human apoE isoforms differentially affect A beta clearance or synthesis in vivo, resulting in an apoE isoform-dependent pattern of A beta accumulation later in life. Performing in vivo microdialysis in a mouse model of A beta-amyloidosis expressing human apoE isoforms (PDAPP/TRE), we find that the concentration and clearance of soluble A beta in the brain interstitial fluid depends on the isoform of apoE expressed. This pattern parallels the extent of A beta deposition observed in aged PDAPP/TRE mice. ApoE isoform-dependent differences in soluble A beta metabolism are observed not only in aged but also in young PDAPP/TRE mice well before the onset of A beta deposition in amyloid plaques in the brain. Additionally, amyloidogenic processing of amyloid precursor protein and A beta synthesis, as assessed by in vivo stable isotopic labeling kinetics, do not vary according to apoE isoform in young PDAPP/TRE mice. Our results suggest that APOE alleles contribute to AD risk by differentially regulating clearance of A beta from the brain, suggesting that A beta clearance pathways may be useful therapeutic targets for AD prevention.