We demonstrate that folate and vitamin E can compensate for the diminished oxidative buffering capacity of brains of apolipoprotein E-deficient mice. Normal and ApoE(tmlUne) homozygous 'knockout' mice were maintained for 1 month on a diet either lacking or supplemented with folate, vitamin E or iron as a pro-oxidant after which brain tissue was harvested and analyzed for for thiobarbituric acid-reactive substances (TBARs) as an index of oxidative damage. Normal mice exhibited no significant difference in TBARs following iron challenge in the presence or absence of vitamin E, folic acid or both. Similarly, ApoE knockout mice exhibited no significant differences following dietary iron challenge in the presence or absence of vitamin E. However, ApoE knockout mice accumulated significantly increased TBARs following iron challenge when folic acid was withheld, and accumulated even more TBARs when both folic acid and vitamin E were withheld. These findings demonstrate that ApoE knockout mice during vitamin deficiency are less capable of buffering the consequences of dietary iron challenge than are normal mice. Since the apolipoprotein E4 allele, which exhibits diminished oxidative buffering capacity, is linked to Alzheimer's disease (AD), these data underscore the possibility that critical nutritional deficiencies may modulate the impact of genetic compromise on neurodegeneration in AD.