Apolipoprotein E (apoE) alleles determine the age-adjusted relative risk ( 4 > 3) for Alzheimer's disease (AD). ApoE may affect AD pathogenesis by promoting deposition of the amyloid- (A) peptide and its conversion to a fibrillar form. To determine the effect of apoE on A deposition and AD pathology, we compared APPV717F transgenic (TG) mice expressing mouse, human, or no apoE (apoE/). A severe, plaque-associated neuritic dystrophy developed in APPV717F TG mice expressing mouse or human apoE. Though significant levels of Abeta deposition also occurred in APPV717F TG, apoE/ mice, neuritic degeneration was virtually absent. Expression of apoE3 and apoE4 in APPV717F TG, apoE/ mice resulted in fibrillar Abeta deposits and neuritic plaques by 15 months of age and substantially (>10-fold) more fibrillar deposits were observed in apoE4-expressing APPV717F TG mice. Our data demonstrate a critical and isoform-specific role for apoE in neuritic plaque formation, a pathological hallmark of AD.
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