The isoforms of the APOE gene are of profound importance regarding the onset of Alzheimer's disease (AD), with APOE2 conferring resistance, APOE3 conferring neutral susceptibility, and APOE4 conferring proneness to AD. L-cysteine is an amino acid that has several anti-AD properties, among which are its ability to sequester iron and form glutathione (GSH), a powerful antioxidant. In our experiment, we fed Mus musculus (mice) homozygous for APOE2, APOE3, and APOE4 either a control diet or a diet high in L-cysteine. Using Western blotting analysis, we quantified total APOE proteins extracted from post-mortem brains of APOE2, APOE3, and APOE4 homozygous mice, total Amyloid β (Aβ) protein, and total hyper-phosphorylated Tau (HP-Tau) from mice at 3-, 6-, 9-, and 12-month ages. We found that administration of L-cysteine trends toward lowering levels of Aβ in the APOE3 cohort, but this effect is statistically insignificant. On the other hand, L-cysteine caused a significant increase in APOE4 abundance, but a significant decrease in APOE3 abundance regarding diet [F(6,42) = 5.61, p = 0.01]. Furthermore, administration of L-cysteine revealed trends toward lowering HP-Tau deposition in the APOE2 and APOE3 cohorts, but increasing deposition in the APOE4 cohort, although these effects are statistically insignificant. Moreover, immunohistochemistry analyses on the hippocampus and midsagittal brain revealed no effects of L-cysteine on Aβ. Results also showed a decrease in HP-Tau without regard to APOE genotype, but this was not statistically significant (p = 0.18). Taken together, these data suggest that L-cysteine may serve as a promising intervention for AD pathology, although future studies necessitate increasing statistical power to confirm the effect of diet on Aβ and HP-Tau deposition.

Current theories regarding accumulation of Alzheimer's disease-related deposits of abnormal intra-and extracellular proteins include reactions to inflammation and mitochondrial dysfunction. In this study, we explored whether age, genotype and inflammation via diet have a greater effect on dysregulatory protein accumulation in any particular subfield of the hippocampus. We stained for ferritin, ferroportin, hyperphosphorylated tau and β-amyloid proteins in the hippocampal region of Apolipoprotein E2 (ApoE2), ApoE3 or ApoE4 mice fed a control diet or a hypothesized inflammationinducing methionine diet and euthanized at 3, 6, 9 or 12 months. We analysed stains based on hippocampal subfield and compared the protein accumulation levels within each group. We found significantly decreased ferritin expression in ApoE4 mice in the CA1 and Hi regions and decreased ferroportin expression in ApoE4 mice in the Hi region. There was also a significant effect on hyperphosphorylated tau protein levels based upon a given mouse genotype and diet interaction. Additionally, there were nonsignificant trends in each hippocampal subfield of increasing ferroportin and hyperphosphorylated tau after 6 months of age and decreasing β-amyloid and ferritin with age. This study identified that there are changes in iron regulatory molecules based on genotype in the Hi and CA1 regions. Our findings also suggest a diet-genotype interaction, which affects levels of specific Alzheimer's disease biomarkers in the hippocampus. Additionally, we identified a trend toward increased ability to clear β-amyloid and decreased ability to clear hyperphosphorylated tau with age in all subfields, in addition to evidence of increasing iron load with time.