People that carry the 4 alleles, either one occurrence of it as in 3,4 or in double occurrence as in 4,4, those folks seem to get huge increases in their LDL, especially their small dense LDL, when they eat fat, especially saturated fat, but all fat seems to play a role. 

The maximum amount of fish oil that someone who’s an Apo E4 carrier should take in my opinion is 500 mg of EPA plus DHA.

Even though saturated fat has pretty much been redeemed on the heart disease front, there’s one subset of the population that might genuinely need to limit their intake for the sake of heart-health: ApoE4 carriers!

In the e4-expressing subjects:

Higher saturated fat intake was associated with smaller LDL particles (-2%, P < 0.05) in APOE2 carriers, and larger LDL particles (+2%, P < 0.05) in APOE4 carriers, but the gene-diet interaction was not statistically significant (P = 0.09).

We provide novel evidence of a divergent CRP response to SFA according to APOE genotype, with a significant increase in CRP concentrations after increased SFA intakes evident only in APOE4 carriers.

In conclusion, this study has confirmed previous findings that the APOE genotype is associated with fasting lipid profile and CRP. 

Additionally, serum CRP was lower in E4 carriers, a finding that has also been observed in other studies.

This study finds that a low-fat diet will reduce LDL size and the decrease in size is bigger for APOE 3/4 & 4/4 than 3/3 and that ApoB, however, remained unchanged.

Even though a MUFA-rich diet increases LDL size compared with a CHO-rich diet, this effect is dependent on apoE genotypes. Thus, the replacement of a CHO diet by a MUFA diet increases LDL-size in apoE 3/3, whereas it decreases it in apoE 4/3 subjects.

Diets used in the Moreno Study

... there was evidence of a significant diet x genotype interaction with significantly greater decreases in TC (p = 0.02) and apo B (p = 0.006) among carriers of E4 when SFA was replaced with low GI carbohydrate on a lower-fat diet (TC -0.28 mmol/L p = 0.03; apo B -0.1 g/L p = 0.02), and a relative increase in TC (in comparison to E3/E3) when SFA was replaced with MUFA and high GI carbohydrates (TC 0.3 mmol/L, p = 0.03).

When the response of an E3/3 phenotype was used for comparison, individuals with an E3/2 phenotype had a lower rate of intestinal absorption of cholesterol, while those with an E4/3 phenotype had a higher rate

Following intervention, there was evidence of a significant diet x genotype interaction with significantly greater decreases in TC (p = 0.02) and apo B (p = 0.006) among carriers of E4 when SFA was replaced with low GI carbohydrate on a lower fat diet (TC -0.28 mmol/L p = 0.03; apo B -0.1 g/L p = 0.02), and a relative increase in TC (in comparison to E3/E3) when SFA was replaced with MUFA and high GI carbohydrates (TC 0.3 mmol/L, p = 0.03). 

In E4+, mean plasma [13C]DHA was 31 % lower than that in E4-, and cumulative b-oxidation of [13C]DHA was higher than that in E4- 1–28 d post-dose (P#0·05). A genotype time interaction was detected for cumulative b-oxidation of [13C]DHA (P 0·01). The whole-body half-life of [13C]DHA was 77 % lower in E4+ compared with E4- (P 0·01). 

The preferential binding of APOE4 compared to APOE ε3 (APOE3) and APOE2 alleles (APOE4 > APOE3 > APOE2) with larger fat-containing particles contributes to altered lipid and cholesterol metabolism. For example, DHA and EPA are transported on chylomicrons to the liver following absorption, and APOE4 carriers have faster DHA and EPA clearance from plasma compared to non-carriers

In apoE4 individuals, a significant increase in total cholesterol and a trend toward a reduction in HDL-C relative to the common homozygous E3/E3 profile was evident.

High dose DHA supplementation is associated with increases in total cholesterol in E4 carriers, which appears to be due to an increase in LDL-C and may in part negate the cardioprotective action of DHA in this population subgroup.

Significant gene-EPA interactions were found with HDL-C and particle concentrations of large and total HDL. The lipid targets were positively associated with EPA in the E2 groups, whereas negative trends were observed among the E4 participants. Gene-DHA interactions were noted for small LDL particle concentrations alone, where a positive trend was found among E4 but not E2 or E3 participants.

In contrast with our previous study, in which an effect of genotype on the LDL cholesterol response was evident—7% increases were observed in the group as a whole, and 3%,1%, and 16% increases were observed in E2, E3, and E4 subgroups, respectively, after 3 g EPA DHA/d — there was no significant effect of genotype in the current study ( 0.7g/d & 1.8g/d ). Taken together, these data suggest that the effect of APOE genotype on the LDL- cholesterol response may be dose-dependent.

...the greatest hypotriacylglycerolemic effects were evident in apoE4 males: 15% (P 0.004) and 23% (P 0.001) reductions in TAG concentrations were evident after the 8-wk 0.7FO and 1.8FO intervention periods, respectively, in the male E4 subgroup

At a population level, the overall clinical significance of the 0 –10% TAG, cholesterol, and HDL and LDL size changes may be modest, but, for certain persons, such as males with an APOE4 genotype (11% of whites), the lipid-modulatory effects observed at these EPA-DHA doses are likely to have a significant effect on CVD risk

Also, we have reported that the commonly observed LDL-cholesterol– raising effect of high-dose fish oils, particularly DHA, is most evident in APOE4 carriers. A significant 10% increase in LDL cholesterol was observed in this subgroup after supplementation with a DHA-rich oil (3.7 g DHA/d) as was a modest reduction evident in the wild-type APOE3/E3 group, which was broadly consistent with the findings of an earlier study 

In contrast with our previous findings, in the current study (against a background diet high in total fat and SFA) we observed no increase in total and LDL cholesterol in the APOE3/E4 group after high-dose DHA supplementation

In conclusion, our data indicate that, in normolipidemic individuals, heterozygous APOE4 status is unlikely to be a major population determinant of the fasting cholesterol responses to altered fat intakes, but conferred greater sensitivity to the hypotriglyceridemic actions of DHA

...young E4+ participants already had a tendency toward lower baseline-DHA levels in LDL particles as well as a more atherogenic ω-6/ω-3 PUFA ratio in LDL pre- and post-supplementation.

Our findings indicate that apolipoprotein E genotype and BMI may be important variables that determine the plasma long-chain PUFA response to dietary fat manipulation. APOE4 carriers with BMI ≥25.5 may need higher intakes of DHA for cardiovascular or other health benefits than do noncarriers 

Baseline CSF Aβ42 levels were significantly lower in ɛ4 carriers than in ɛ4 noncarriers (p = 0.01). Participants carrying the ɛ4 allele (n = 25) demonstrated a less pronounced increase in CSF DHA level compared with noncarriers (n = 4), APOE ɛ4 allele and lower CSF Aβ42 levels were associated with less transport of DHA to CSF. 

Interestingly, 6 months of fish-oil supplementation decreased IFN-related gene expression in APOE4 carriers. The increased expression of genes in the IFN signaling pathway and IFN-regulated genes in PBMCs of APOE4 carriers at baseline may point toward a systemic pro-inflammatory state.  

Some studies have found a possible relationship between the presence of an ApoE ε4 allele and the decrease of motor function in healthy older adults. No significant cross-sectional or prospective associations were found between ApoE ε4 status, lower-limb function, and handgrip strength in our study.

There is growing evidence that physical activity, exercise, and aerobic fitness significantly reduce CAD risk and improve cognitive aging and biomarkers of AD pathology in APOE e4 carriers.

Collectively, these results suggest that cognitively normal sedentary APOE ε4-positive individuals may be at augmented risk for cerebral amyloid deposition.

Increasing physical activity may compensate for the potentially deleterious effects of the apoE4 genotype on the lipid profile, at least in western (European) populations. It appears that this protection may be obtained by performing any high-intensity physical activity (ie, expending 4 times the BMR or more), such as brisk walking or sports.

Participants who endorsed one of the two items indicating two or fewer days of low-intensity PA (ranging from no PA to slow walking or light chores) were classified as physically inactive (Low PA). Participants endorsing one of the remaining three items describing moderate to vigorous-intensity PA three or more days per week (ranging from brisk walking, jogging or swimming for 15 min or more, or moderately difficult chores for 45 min, to regular jogging, running, bicycling or swimming for 30 min or more, or playing sports such as handball or tennis for an hour or more) were classified as physically active (High PA).

... change from baseline to 18-month follow-up. A significant interaction was observed between Risk and PA for the hippocampus. Hippocampal volume decreased 3% in the High Risk/Low PA group, whereas the volumetric changes in the remaining three groups were negligible.

Controlling for age and baseline performance, individuals with at least one APOE ε4 allele showed less improvement in executive function with aerobic exercise

It has been found that 40 to 80% of people with AD have at least one APOE4, and it increases the risk of AD in heterozygotes and homozygotes by 3 and 15 times, respectively.

There was no significant effect of APOE or APOE × age interaction on gray matter volume and glucose metabolism, although decreases with age tended to be stronger in noncarriers than in carriers. In contrast, β-amyloid (Aβ) deposition was significantly higher in carriers compared with noncarriers in a largely distributed network, and there was a significant APOE × age interaction such that Aβ deposition increased nonlinearly with age in APOE ε4 carriers only.

There was a 3-fold increase in the epsilon 4 allele frequency in both LBD and AD groups compared with controls. These results indicate that LBD and AD share the epsilon 4 allele of ApoE as a major risk factor for the development of disease and suggest a similarity in disease aetiology. 

The authors found no significant differences in the distribution of genotypes between patients with MS and controls. However, patients with MS with the epsilon4 allele (n = 85) had a significantly higher progression index of disability (0.46 +/- 0.4 versus 0.33 +/- 0.26; p < 0.004) and a worse ranked MS severity score (5.1 +/- 1.9 versus 5.7 +/- 1.7; p = 0.05) than their non-epsilon4 counterparts,

Among 31 prospectively assessed subjects with pathologically confirmed AD (without Lewy bodies), epsilon4+ subjects had a longer duration of disease (by 2.8 years, p = 0.04). Only cell loss in the substantia nigra (p = 0.002) was associated with epsilon4. Neither neurofibrillary tangles nor plaque counts were associated with epsilon4

The epsilon3/epsilon4 participants showed lower gray matter density than the epsilon3/epsilon3 participants in right medial temporal and bilateral frontotemporal regions as well as other areas

The patients with the APOE genotype sigma4/4 had more extensive WMLs in the deep white matter than patients with genotypes sigma3/3 and sigma3/4. There was a correlation with age for WMLs in the deep white matter in patients with the APOE sigma3/3 genotype. In patients carrying at least one sigma4 allele, the WMLs showed no age correlation 

Based on our studies, we hypothesize that the Aβ and plaque-independent effects of apoE4 on neuronal and behavioural deficits are caused by neurotoxic effects of the apoE fragments

But in the TBI group, APOE4 carriers had more focal or global irregular slow wave activities than APOE4 non-carriers. APOE gene did not influence brain electrical activity under normal conditions, but TBI can induce different alterations among different APOE gene carriers, and APOE4 allele enhances the EEG abnormalities at the early stage of TBI