International Journal of Alzheimer’s Disease, 2012

 Abstract

The amyloid cascade hypothesis remains a robust model of AD neurodegeneration. However, amyloid deposits contain proteins besides Aβ, such as apolipoprotein E (apoE). Inheritance of the apoE4 allele is the strongest genetic risk factor for late-onset AD. However, there is no consensus on how different apoE isotypes contribute to AD pathogenesis. It has been hypothesized that apoE and apoE4 in particular is an amyloid catalyst or “pathological chaperone”. Alternatively it has been posited that apoE regulates Aβ clearance, with apoE4 been worse at this function compared to apoE3. These views seem fundamentally opposed. The former would indicate that removing apoE will reduce AD pathology, while the latter suggests increasing brain ApoE levels may be beneficial. Here we consider the scientific basis of these different models of apoE function and suggest that these seemingly opposing views can be reconciled. The optimal therapeutic target may be to inhibit the interaction of apoE with Aβ rather than altering apoE levels. Such an approach will not have detrimental effects on the many beneficial roles apoE plays in neurobiology. Furthermore, other Aβ binding proteins, including ACT and apo J can inhibit or promote Aβ oligomerization/polymerization depending on conditions and might be manipulated to effect AD treatment.

http://www.hindawi.com/journals/ijad/2012/489428/

There is a more simple and perhaps better explanation for this.  Low density lipid receptors are g-protein coupled receptors.  When slightly stimulated by Apoe2 for instance, amyloid is cleared via the phosphatidylinositol 3-kinase/Akt.  When overstimulated by Apoe4, it leads to the formation of peroxynitrites and the aggregation of amyloid.

Functional interaction between APOE4 and LDL receptor isoforms in Alzheimer's disease

Conclusion: These results imply a functional interaction between ApoE and LDL receptor proteins that determines risk for Alzheimer's disease.

Part of the key is oxidative stress.  For those with the Apoe4 gene it is critical to avoid other factors that can increase oxidative stress (salt, sugar, carbohydrates, high fructose corn syrup, smoking, excessive alcohol consumption, sedentary lifestyle, etc.).

Impact of apoE genotype on oxidative stress, inflammation and disease risk.

Abstract

Although in developing countries an apolipoprotein E4 (apoE4) genotype may offer an evolutionary advantage, as it has been shown to offer protection against certain infectious disease, in Westernised societies it is associated with increased morbidity and mortality, and represents a significant risk factor for cardiovascular disease, late-onset Alzheimer's disease and other chronic disorders. ApoE is an important modulator of many stages of lipoprotein metabolism and traditionally the increased risk was attributed to higher lipid levels in E4 carriers. However, more recent evidence demonstrates the multifunctional nature of the apoE protein and the fact that the impact of genotype on disease risk may be in large part due to an impact on oxidative status or the immunomodulatory/anti-inflammatory properties of apoE. An increasing number of studies in cell lines, targeted replacement rodents and human volunteers indicate higher oxidative stress and a more pro-inflammatory state associated with the epsilon4 allele. The impact of genotype on the antioxidant and immunomodulatory/anti-inflammatory properties of apoE is the focus of the current review. Furthermore, current information on the impact of environment (diet, exercise, smoking status, alcohol) on apoE genotype-phenotype associations are discussed with a view to identifying particular lifestyle strategies that could be adapted to counteract the 'at-risk' E4 genotype.

 

Interesting, Apoe deficiency also increases oxidative stress without apparently producing amyloid.

Free Radic Biol Med. 2002 Oct 15;33(:1115-20.

Apolipoprotein E deficiency promotes increased oxidative stress and compensatory increases in antioxidants in brain tissue.

Shea TB1, Rogers E, Ashline D, Ortiz D, Sheu MS.

Author information

Abstract

The epsilon 4 allele of the apolipoprotein E gene (ApoE) is associated with Alzheimer's disease (AD). The extent of oxidative damage in AD brains correlates with the presence of the E4 allele of ApoE, suggesting an association between the ApoE4 genotype and oxygen-mediated damage in AD. We tested this hypothesis by subjecting normal and transgenic mice lacking ApoE to oxidative stress by folate deprivation and/or excess dietary iron. Brain tissue of ApoE-deficient mice displayed increased glutathione and antioxidant levels, consistent with attempts to compensate for the lack of ApoE. Folate deprivation and iron challenge individually increased glutathione and antioxidant levels in both normal and ApoE-deficient brain tissue. However, combined treatment with folate deprivation and dietary iron depleted antioxidant capacity and induced oxidative damage in ApoE-deficient brains despite increased glutathione, indicating an inability to compensate for the lack of ApoE under these conditions. These data support the hypothesis that ApoE deficiency is associated with oxidative damage, and demonstrate a combinatorial influence of genetic predisposition, dietary deficiency, and oxidative stress on oxidative damage relevant to AD.

I am still sorting through this article, but there may be some important clues here:

Transgenic mice expressing apoE4 in astrocytes have impairment of working memory, despite the absence of significant neuropathological changes in the brain [81]. Furthermore, human apoE4 knock-in mice, in which the mouse apoE gene is replaced with the human apoE gene, develop spatial learning and memory deficits not seen in human apoE3 knock-in mice [78,79,81,82]. Since Aβ does not accumulate in any of these apoE isoform transgenic mouse models, these data strongly suggest Aβ-independent roles of apoE4 in causing neuronal and behavioral deficits in vivo.

So maybe the fact that Apoe4 knockout mice don't develop amyloid is irrelevant.  Apoe deficiency is very rare in human beings, and unfortunately few if any of the people with this deficiency live very long lives.

Interestingly, exercise, which stimulates hippocampal neurogenesis, improves cognition and hippocampal plasticity in apoE4 transgenic mice [99].

ApoE4 and its fragments impair mitochondrial function. Mitochondrial dysfunction has been reported in AD, which is modulated by apoE genotype, with a greater effect in apoE4 than in apoE3 carriers [121-124,125]. In both AD patients and age-matched nondemented subjects, apoE4 is associated with decreased cerebral glucose metabolism [126-135], an effect that occurs decades before cognitive impairment become apparent [126,127,136] and, probably, also before significant Aβ deposition. Thus, apoE4 may cause mitochondrial dysfunction at very early stages in life. Mitochondrial dysfunction is clearly coupled with production of reactive oxygen species and increased oxidative damage, which in turn further impair mitochondrial activity. Temporary or sustained loss of mitochondrial function impairs cellular defenses and repair mechanisms, decreasing the ability of neurons to mount an appropriate stress response and causing cellular injury.

Concluding remarks and potential therapeutic strategies
In addition to its well-documented Aβ-dependent roles [157], apoE4 has Aβ-independent roles in the pathogenesis of AD [43,47,48,158]. Independently of Aβ, apoE4 has detrimental effects on neuronal plasticity, undergoes aberrant proteolysis that generates neurotoxic fragments, stimulates tau phosphorylation and disrupts the cytoskeleton, and impairs mitochondrial function (Figure 3). In humans, the Aβ-dependent and Aβ-independent effects of apoE4 can act in concert to exacerbate the pathological and clinical phenotypes of AD.

http://labs.gladstone.ucsf.edu/huang/pages/apoe-research

Here is a link between Apoe4 and p38 Mapk and from there it is just one more step to peroxynitrites.

Inheritance of the three different alleles of the human apolipoprotein (apo) E gene (APOE) are associated with varying risk or clinical outcome from a variety of neurologic diseases. ApoE isoform-specific modulation of several pathogenic processes, in addition to amyloid β metabolism in Alzheimer's disease, have been proposed: one of these is innate immune response by glia. Previously we have shown that primary microglia cultures from targeted replacement (TR) APOE mice have apoE isoform-dependent innate immune activation and paracrine damage to neurons that is greatest with TR by the ε4 allele (TR APOE4) and that derives from p38 mitogen-activated protein kinase (p38MAPK) activity.

http://www.jneuroinflammation.com/content/3/1/10

Activation of p38 MAPK induced peroxynitrite generation in LPS plus IFN-gamma-stimulated rat primary astrocytes via activation of iNOS and NADPH oxidase.

The Absence of ABCA1 Decreases Soluble ApoE Levels but Does Not Diminish Amyloid Deposition in Two Murine Models of Alzheimer Disease

Now it is my turn to sort through things.  In the meantime, here is a possible route that explains the benefit of DHA: the activation of Akt (perhaps in part through SorLA) and the induction of the brain's master antioxidant: glutathione.

Docosahexaenoic acid: A positive modulator of Akt signaling in neuronal survival

(cannot find a direct DHA/Akt/glutathione reference).

ApoE can activate the phosphatidylinositol 3/Akt kinase through low density lipid receptors, but the increased binding of very low density lipids to these receptors by ApoE4 results in the production of peroxynitrites and Alzheimer's disease.

These results suggest that inheritance of apoE4 is associated with an increased affinity of VLDL particles for LDL receptors on hepatocytes and may partly explain the influence of the E4 isoform on lipid metabolism.

http://www.ncbi.nlm.nih.gov/pubmed/10070023

Apolipoprotein E activates Akt pathway in neuro-2a in an isoform-specific manner.

This is good stuff. Could this be evidence for a low-fat diet increasing the risk for AD? What if:

ApoE4 + healthy fat in the diet (DHA) = lower risk for AD

and

ApoE2(3) + low-fat diet = higher risk for AD

Because we have to address why all with the E4 gene don't get AD, and many with the beneficial E2 gene do get AD

Also, the young blood mouse study and anecdotal blood transfusion evidence sticks in my mind as being important. The link to lipids might explain that.

This may very well be right.  DHA is likely protective regardless of the Apoe4 status, but saturated fats effects may vary depending on Apoe status.  In regards to the new blood study, I have a feeling something significant is there as well, but would like to know precisely what the new blood contains that the old blood does not that may make it an effective treatment. 

The question of fats gets further complicated by polyphenols and carbohydrates.  Many saturated fats coming from plants and dairy products contain polyphenols which help protect the brain against Alzheimer's disease. On the other hand, when people go on a low fat diet they often replace the calories with sugar and carbohydrates which increases the risk for Alzheimer's disease. 

I think that changes in the way we consume and process food has significantly increased the incidence of Alzheimer's disease.  Before fructose or sugar may have come in the form of fruits or cocoa rich in polyphenols. Breads and pastas used to contain higher levels of polyphenols and lower levels of gluten.  And then we started consuming products that combined the worse of both such as high fructose corn syrup.  And finally there are environmental contaminants (pesticides, for instance) added to our food.