The Fox and the Rabbits—Environmental Variables and Population Genetics (1) Replication Problems in Association Studies and the Untapped Power of GWAS (2) Vitamin A Deficiency, Herpes Simplex Reactivation and Other Causes of Alzheimer's Disease
Classical population genetics shows that varying permutations of genes and risk factors permit or disallow the effects of causative agents, depending on circumstance. For example, genes and environment determine whether a fox kills black or white rabbits on snow or black ash covered islands. Risk promoting effects are different on each island, but obscured by meta-analysis or GWAS data from both islands, unless partitioned by different contributory factors. In Alzheimer's disease, the foxes appear to be herpes, borrelia or chlamydial infection, hypercholesterolemia, hyperhomocysteinaemia, diabetes, cerebral hypoperfusion, oestrogen depletion, or vitamin A deficiency, all of which promote beta-amyloid deposition in animal models—without the aid of gene variants. All relate to risk factors and subsets of susceptibility genes, which condition their effects. All are less prevalent in convents, where nuns appear less susceptible to the ravages of ageing. Antagonism of the antimicrobial properties of beta-amyloid by Abeta autoantibodies in the ageing population, likely generated by antibodies raised to beta-amyloid/pathogen protein homologues, may play a role in this scenario. These agents are treatable by diet and drugs, vitamin supplementation, pathogen detection and elimination, and autoantibody removal, although again, the beneficial effects of individual treatments may be tempered by genes and environment.
If there is one factor common to complex polygenic diseases it is the heterogeneity in both gene and risk factor association studies.
Although these have discovered key genes and risk factors, the results for most are invariably confounded by conflicting data . In the genetic arena, the clear familial component of many diseases has driven the search for major genes using genome-wide association studies (GWAS) with large numbers of patients pooled from different regions . Such studies have been able to discover rare variants that play a major role in a small percentage of patients, for example VIPR2 in schizophrenia . However, in complex diseases, these have failed to find major genes relevant to all patients , instead unearthing yet more genes of small effect, whose risk promoting effects are yet again contested, as is the case with CR1 and PICALM, which have not been confirmed as risk factors for Alzheimer’s disease in Chinese patients  despite extensive evidence in Caucasian studies . GWAS studies have, however, been more successful in uncovering larger numbers of genes of greater effect for simpler traits such as lipid levels .
Viruses and other pathogens have been implicated as risk factors in many diseases, although again, conflicting evidence leads to scepticism in many areas. For example, the involvement of the Epstein-Barr virus in multiple sclerosis is hotly contested [8–10].
Gene-gene and gene-environment interactions may play an important role in such inconsistency. For example, the risk promoting effects of genes can be better explained when using pathway analysis or combining the effects of genes with common function, rather than by studying single genes in isolation [11, 12]. Genes and risk factors can also act together, and in certain cases genes can be linked to environmental variables. For example, many of the genes implicated in schizophrenia or Alzheimer’s disease are involved in the life cycles of the pathogens involved in the diseases [13, 14]. Environment-environment interactions are also apparent. For example, the effects of vitamin E on lifespan, or on resistance to various infections can be null, deleterious, or protective, depending on confounding factors such as age, exercise, smoking, and vitamin C consumption [15–17].
Complex diseases are also composed of many endophenotypes or underlying pathologies, and different genes or risk factors may contribute to any of these. Many different processes contribute to cell death in Alzheimer’s disease, for example, beta amyloid, glutamate, calcium, or free radical mediated toxicity [18, 19]. The efficiency of each of these subprocesses is controlled by genes, many of which have been implicated in association studies (see Table 1).
In genetic association studies, the drive has been to increase statistical power by increasing the numbers of subjects enrolled. This has resulted in the discovery of important genes and rare genetic variants, but has not delivered genes that confer a high degree of risk in the majority of patients. However, as illustrated below, more could perhaps be gained by a reanalysis of existing data in relation to other genetic and risk factor variables that could result in elucidation of the causes rather than the risks.
Alzheimer’s disease susceptibility genes and risk factors are stocked in an online database at http://www.polygenicpathways.co.uk/alzenvrisk.htm. KEGG pathway analysis of over 400 associated genes was performed , and the results of the exercise were posted at http://www.polygenicpathways.co.uk/alzkegg.htm. In these figures, yellow genes have been implicated in Alzheimer’s disease and red genes are also implicated in the herpes simplex life cycle. Other gene-risk factor relationships were identified by literature survey. B cell and T cell epitopes within the beta-amyloid peptide were identified using the immune epitope database server http://tools.immuneepitope.org/main/index.html which predicts the antigenicity of peptide sequences, based on their charge and hydrophobicity properties . Sequence comparisons of the beta-amyloid peptide versus selected bacterial, fungal, or viral proteomes was performed using the NCBI blast server [22, 23].
3. Results and Discussion
3.1. Kegg Pathway Analysis of Alzheimer’s Disease Susceptibility Genes
The overall results of this analysis are shown in Table 1. The pathways include many that are relevant to the known pathologies and risk factors of Alzheimer’s disease, including the Alzheimer’s disease pathway itself, primarily related to beta-amyloid and tau processing, but also to glutamate-related pathways (long-term potentiation and depression), apoptosis, insulin and diabetes pathways, neurotrophin signalling, oxidative stress (glutathione/oxidative phosphorylation), cerebral hypometabolism (oxidative phosphorylation, glycolysis and the Krebs cycle), arginine and proline metabolism (including nitric oxide), and folate, methionine and homocysteine metabolism, and steroid hormone synthesis (together with androgen and oestrogen receptors AR, ESR1, and ESR2). PPAR signalling regulates many lipoprotein-related genes and cholesterol/lipid pathways are dispersed in terpenoid backbone biosynthesis (FDPS, HMGCR, HMGCS2), steroid hormone biosynthesis (HSD11B1), steroid biosynthesis (DHCR24, LIPA, SOAT1), glycerolipid metabolism (ALDH2, LIPC, LPL), and bile acid biosynthesis (CH25H, CYP46A1) pathways. Immune, complement, and cytokine-related pathways figure prominently, as do several pathogen defence pathways including the DNA sensing retinoic acid inducible gene (RIG-1) pathways that react to viral DNA/RNA by increasing the expression of interferons and other antiviral genes, and the Toll receptor and NOD pattern recognition pathway that control immune and cytokine networks [24–26]. Glutathione pathways were also present. Glutathione has potent viricidal and bactericidal properties and is often depleted by infections [27–30]. A number of pathogen entry pathways are also concerned, and although C. Pneumoniae or C. Neoformans pathways are not specifically represented, many of these pathways can be considered as generic pathways relevant to many bacteria and other pathogens. The H. Pylori pathway contains only two genes, IL8 and CSK, but others can be added to this list including all members of the PI 3-kinase/AKT signalling network which is activated by the H. pylori protein CagA  or Toll receptor pathways that are activated by H. Pylori heat shock protein, HSP60 . Similarly, there is no specific HSV-1 viral entry pathway in the KEGG database, but the virus uses actin pathways, endocytosis, protein processing, and DNA repair pathways during its life cycle, which are heavily represented .
3.2. Vitamin-A-Related Genes
These were identified by literature survey and the most directly relevant are shown in Table 2. Of particular interest is a close relationship between cholesterol/lipoprotein-related genes and vitamin A. Both retinols and cholesterol are transported by lipoproteins, and the clusterin receptor, LRP2/megalin, is a key retinol entry point. APOE4 is the isoform least able to bind to retinyl palmitate. ABCA1 is also involved in cholesterol and retinol transport. Several genes (ALDH2, CYP46A1, GSTM1, GSTP1, LIPA, LPL, and LRAT) are involved in Vitamin A metabolism, and 24-s hydroxycholesterol, the product of CYP46A1, is a ligand for retinoic acid receptors (RARA and RARG). Retinoid coreceptors and binding partners include RXRA, ESR1, KLF5 NPAS2, NR1H2, PARP1, PIN1, POU2F1, PPARA, PPARG, THRA, UBQLN1, and VDR. Retinoids modulate APP processing, via regulation of beta and gamma secretases while the RIG-1 pathway is crucial in viral defence. A large number of genes are also regulated by retinoids or retinoid receptors.
3.3. The Fox, the Rabbits, Gene, and Environmental Variables
This is an adaptation of Lees’s classical population genetics example of the peppered moth, whose dark or pale colouring confers advantage or disadvantage depending upon the degree of industrial pollution that covers trees with soot. It has served to illustrate the concept of natural selection where, over time, dark genes become more common in polluted areas, an effect that could eventually lead to speciation .
On two islands one covered in snow and the other in black volcanic ash live an equal number of black and white rabbits and a family of foxes, who will find it easier to trap the black rabbits on the snowy island and the white rabbits on the island covered in black ash. Gene association studies would correctly identify the black and white genes as being protective or risk promoting depending upon the environment. The snow, the ash, or the fox, being equally present on each island, regardless of the toll of dead rabbits, could not be considered as risk factors. Genetic meta-analysis or pooled GWAS data would also rule out any genetic involvement, leaving no susceptibility genes, no risk factors, and no cause. However, a GWAS study, apportioning the genetic data in relation to ash, snow, and fox would be able to correctly surmise that the white gene is a risk factor on the ash-covered island, and the black gene a risk factor on the snowy island, as would have D. R. Lees. Again the fox is undetectable, being present in all compartments.
On other similar islands, live further populations of black and white rabbits with no fox, an equal number of deaths due to old age, and no reason to investigate either genes or risk factors. However, it is only by including this island, again partitioning GWAS data in relation to all variables, that the genes, the risk factors, and the cause can be correctly allotted their respective roles.
In this example, the genes and environmental variable are risk or protective factors for the cause as well as for the deaths, depending on circumstance. The genes or risk factors are not killing the rabbits, but are allowing the cause to do so. Nonstratified association studies would thus seem to be ill-suited to find important genes, risk factors, or causes, and the pursuit of greater statistical power may well be futile, although such strategies can find rare variants that may cause disease in a minority of patients, which is evidently useful. However, for the majority of cases, much could perhaps be gained from a reappraisal of existing data and by partitioning GWAS data in relation to the many known risk factors in each disease.
The situation is evidently more complex in polygenic diseases, where hundreds of interacting genes, many risk factors, and probably many causes are present. This is already appreciated, and several groups have analysed the statistical problems involved due to the mass of genes and risk factors [35–37]. However, it is likely that an appropriate selection of genes and risk factors could markedly affect the degree of risk. For example, the odds ratio for APOE4 was shown to be 1.67 in Alzheimer’s disease patients without cerebral HSV-1 DNA and 16.8 in patients where viral DNA was detected . The population genetics example, and the discussion below, suggests that certain susceptibility genes are restricted to risk factor subsets.
From the above, it would appear that a cause can be present in equal proportion in control and disease populations but should be able to produce the pathological features of the disease, and the disease incidence should be reduced where the causes are few. A cause can kill regardless of the genes (black or white) or risk factors (snow or volcanic ash) but its effects are tempered by a combination of the two (fox + snow + black gene or fox + ash + white gene = death and fox + snow + white gene or fox + ash + black gene, or no fox and any combination = life). The genes and risk factors are, however, both able to influence the cause.
In relation to Alzheimer’s disease, beta-amyloid deposition can be produced by herpes simplex [189–191] or chlamydia pneumoniae infection [192, 193], hypercholesterolemia (which also causes cholinergic neuronal loss and memory deficits in rats [194–197]), by or hyperhomocysteinaemia, an effect reversed by folate and vitamin-B12 , by NGF deprivation , by reduced cerebral perfusion (hypoxia, cerebral ischaemia, or carotid artery occlusion [200–203]), as well as by experimental diabetes and streptozotocin [204, 205], oestrogen depletion , or vitamin A deficiency, which also reduces choline acetyltransferase activity in the forebrain —all without the aid of any variant genes, in animal models. While none of the animal models faithfully reproduce the entire symptomatology of Alzheimer’s disease, in the clinical setting these risk factors coexist to varying degrees, rendering the situation rather more complex.
The risk factors in Alzheimer’s disease include herpes simplex infection  acting in combination with APOE4 , C. Pneumoniae [210, 211] or Helicobacter pylori infection [212, 213], mild hypercholesterolaemia , but declining cholesterol levels from midlife to late life , atherosclerosis of the carotid arteries, leptomeningeal arteries, or the circle of Willis, and stroke, leading to cerebral hypoperfusion [216–219], hyperhomocysteinaemia , type 2 diabetes and modified insulin metabolism , age-related loss of sex steroid hormones in both women and men , but high total oestradiol levels [223, 224], and vitamin A deficiency . These factors may be confounded by interrelationships, and in some cases by the fact that death due to other causes—for example, atherosclerosis-related myocardial infarction or stroke may lead to an apparent paucity of comorbid risk factors in Alzheimer’s disease groups at later ages.
The genes implicated in Alzheimer’s disease are related to the herpes simplex life cycle [13, 226], bacterial and viral entry pathways, viral and pathogen defence (Table 1), and the immune network , cholesterol and lipoprotein pathways [11, 228], folate and homocysteine pathways , and insulin, or neurotrophin signalling pathways, steroid metabolism and receptors (Table 1 and 2), and vitamin A metabolism and function (Table 2).
The genes, risk factors and agents known to increase beta-amyloid deposition all concur, suggesting that Alzheimer’s disease is multifactorial with many foxes, each with their respective genes and risk factors, any of which can lead to beta-amyloid deposition in multifarious ways. Each risk factor can act independently of any gene or other risk factor variant, in animal models—as with the fox. This in turn might suggest that it is not the risk promoting polymorphisms in the Alzheimer’s disease patients that are crucial, as the risk factors can in any case promote beta-amyloid deposition, but the equivalent polymorphisms in the control group, that are providing protection; a subtle distinction that awaits characterisation of the functional effects of many different gene variants. The reasoning also suggests that beta-amyloid deposition is the consequence and not the cause of the many factors able to promote Alzheimer’s disease. Anoxia, ischaemia, hypoglycaemia, hypercholesterolaemia, and vitamin A deficiency are all able to kill neurones, in some cases including cholinergic neurones, without the aid of beta amyloid.
3.4. Low Incidence of Alzheimer’s Disease and Protective Factors
In relation to Alzheimer’s disease, there is an island where longevity is increased, related to the nun study [231–234]. Nuns do not have children, (the number of pregnancies is a risk factor in Alzheimer’s disease ), do not consume high concentrations of saturated fats (low cholesterol), and are unlikely to have sexually transmitted diseases or viral and other common pathogen diseases vectored by childhood infections (Herpes and chlamydia, inter alia). Their vitamin A levels and general health are sustained by a healthy diet, regular fish on Fridays, and exercise.
There are few strategies that have been shown to reduce the severity of Alzheimer’s disease, once established. It has, however, been shown that Helicobacter pylori elimination increases the cognitive abilities and the lifespan of Alzheimer’s disease patients . In addition, two separate case reports have shown complete reversal of dementia in two patients diagnosed with Alzheimer’s disease, by identification and eradication of the fungal pathogen Cryptococcus Neoformans [237, 238].The TNF antagonist, etanercept, has also been reported to produce a striking remedial effect on symptomatology, following perispinal application . However, the use of TNF antagonists is also associated with an increased incidence of opportunistic bacterial, fungal, and viral infestations, including cytomegalovirus, and cryptococcal infections , perhaps a contraindication for their prolonged use.
A number of epidemiological studies have shown that the incidence of Alzheimer’s disease can be reduced, although, once the disease is established, there is little evidence for any curative effects of any treatment other than the above. These protective factors are in most cases the obverse of the risk factors and include diets rich in fish or polyunsaturated fatty acids [241, 242], the Mediterranean diet  and the use of statins , which are counter to the effects of high cholesterol. A diet rich in fruit and vegetables is associated with reduced dementia incidence  and is able to sustain Vitamin A levels and reduce homocysteine levels in the elderly population . High folate intake, which reduces homocysteine levels , and the use of nonsteroidal anti-inflammatories have also been reported to reduce risk . Again these are related to the risk factors and to the genes, which may condition their success (cf. Vitamin E).
3.5. Relevance of These Factors to the Genes Identified in Genome-Wide Association Studies
Four major genes have been discovered prior to and from GWAS studies, APOE4, clusterin, complement receptor 1, and PICALM [6, 249]. The close relationships between these genes and herpes simplex infection have been the subject of a previous article . APOE4 also favours the binding of C. Pneumoniae elementary bodies to host cells . It is also a risk factor for hypercholesterolaemia, per se , and for carotid artery atherosclerosis in men with diabetes . APOE4 is also the isoform least able to promote lipid efflux from neuronal cells , a factor that may enhance the cholesterol dependent cleavage of beta-amyloid by beta and gamma secretase . It is also the least able isoform binding the vitamin A precursor retinyl palmitate  (see below). Complement receptor 1 is a pathogen receptor for both herpes simplex , and C. Neoformans  and also for the atherogenic pathogen, P. Gingivalis , a key cause of periodontitis/gum disease, which has also been implicated as a risk factor in dementia . Both Helicobacter pylori and C. Pneumoniae  use the mannose-6-phosphate IGF2 receptor (inter alia) for entry. This binds to clusterin and its endocytosis is controlled by PICALM . PICALM (phosphatidylinositol binding clathrin assembly protein), as its name implies, is involved in clathrin-mediated endocytosis , a process used by C. Pneumoniae to gain cellular entry , for the internalisation of herpes simplex glycoprotein D  or the cytomegalovirus chemokine receptor  and for the uptake of outer membrane vesicles from certain strains of H. pylori, into gastric epithelial cells . Clathrin also associates with HHV-6 virions . Clusterin is an inhibitor of the membrane attack complex that is inserted into microbial membranes causing death by lysis . It is also a ligand for the retinol/lipoprotein receptor LRP2 , and the gene contains a retinoid response element (Table 2). Thus it would seem that the key role of these genes may be related to their ability to target multiple aspects of diverse risk factor networks.
3.6. Relationships between Risk Factors and a Key Role for Herpes Simplex Activation (Figure 1)
Hypercholesterolaemia can evidently be related to other dietary risk factors such as saturated fat consumption, and to atherosclerosis. Docosahexaenoic acid increases total plasma cholesterol levels in hymans, but only in APOE4 carriers, an effect that may negate the cardioprotective effects of fish oil supplementation . Helicobacter pylori infection also causes malabsorption of vitamin B12 and folate, leading to increased homocysteine levels, that can be restored by H. pylori eradication . Homocysteine metabolism is also related to glutathione synthesis via the transsulfuration pathway (homocysteine→cysteine→glutathione). Increased levels of homocysteine and reduced levels of glutathione in Alzheimer’s disease suggest impairments in the transsulfuration pathway . Glutathione is a potent antiviral and bactericidal agent with effects targeted at herpes simplex and C. Pneumoniae, inter alia both of which also diminish glutathione levels in infected cells [27, 272, 273]. H. pylori expresses an enzyme, gamma-glutamyltranspeptidase that enables it to metabolise the host’s extracellular glutamine and glutathione which are hydrolysed to glutamate, which is fed into the H. pylori Krebs cycle, resulting in diminished glutathione levels that can be restored by H. pylori elimination [27, 273]. Glutathione levels are reduced in Alzheimer’s disease and many others .
In both coronary artery disease and carotid artery atherosclerosis, high plasma levels of homocysteine are positively correlated with C. Pneumoniae seropositivity suggesting a role for the bacterium in promoting high homocysteine levels. [275, 276]. Indeed carotid artery atherosclerosis is correlated with antibodies to C. Pneumoniae, and to a lesser extent with antibodies to H. pylori, but in this case, only in individuals with low social status .
The growth of C. Neoformans is attenuated by diethylstilbestrol and oestradiol but not by progesterone or testosterone . Helicobacter pylori adsorbs a number of steroids including pregnenolone and two androgens (dehydroepiandrosterone and epiandrosterone and 3-hydroxylated oestrogens (oestrone and oestradiol). These are glucosylated and the glucosyl-steroid hormone derivatives used as membrane lipid components . Oestradiol, androstenedione, and progesterone are all able to inhibit the growth of H. pylori .
These complex interactions, of which there are likely many more, suggest that in addition to epistasis and gene-environment interactions, environment-environment interactions have to be factored in to an already complex equation (cf. vitamin E).
Factors known to reactivate herpes simplex include heat , 17-beta oestradiol  and the inflammatory cytokine interleukin 6  where a role for corticosterone has been proposed . NGF deprivation  also reactivates the virus and NGF promotes viral latency via the TrkA receptor  (cf. neurotrophin signalling). Vitamin A supplementation in rats increases the cerebral levels of both NGF and BDNF  while oestrogen deficiency lowers cerebral NGF levels, an effect reversed by 17-beta oestradiol . Transient cerebral ischaemia lowers NGF levels . Hypoxia is also able to increase the replication of herpes simplex .
Fevers induced by diverse infections might thus be expected to reactivate herpes simplex, as well as cerebral hypoperfusion. IL6 plasma and CSF levels have been reported to be increased in Alzheimer’s disease and the secretion of IL6 from monocytes is increased [290–292]. IL6 plasma levels are raised by infection with C. Pneumoniae  or Helicobacter pylori , and IL6 production in monocytes is stimulated by C. Neoformans . Cortisol levels are also increased in the ageing population and in Alzheimer’s disease [296, 297]. High levels of total oestradiol have been reported as a risk factor for Alzheimer’s disease in both women and men [223, 224].
As so many other risk factors seem able to reactivate the virus, this may be a key precipitant for the final curtain. Herpes simplex viral DNA is present in Alzheimer’s disease plaques , and the plaques and tangles in Alzheimer’s disease contain a very high proportion of herpes simplex interacting proteins, as well as immune-related components. The presence of the complement membrane attack complex in neurones suggests that the neuronal destruction in Alzheimer’s disease might well be related to the consequences of battle between the virus and the immune network that has eliminated the virus at a terrible cost of collateral neuronal damage . IgM+ antibodies, which preferentially index HSV-1 reactivation, have been shown to be able to predict the future risk of developing Alzheimer’s disease , and the ability of other risk factors, particularly other infections, to reactivate the virus suggests a complex interplay of genes and risk factors that funnel towards viral reactivation and plaque and tangle formation.
3.7. The Importance of Vitamin A
Low vitamin A levels are a problem in the ageing population, and even in successfully ageing persons can be observed in 50% of the population over the age of 80–85  (cf. the fox). Low vitamin A levels are also a risk factor for Alzheimer’s disease . Vitamin A plays an important role in maintaining the immune system , many genes of which are implicated in Alzheimer’s disease. APP is involved in the vitamin A arena, as a gamma57 gamma secretase cleavage product suppresses retinoid signalling .
The vitamin A derivative, retinoic acid, inhibits herpes simplex replication [301, 302] as well as chlamydial infection and growth . Vitamin A also stunts the growth of Helicobacter pylori . The effects of vitamin A on C. Neoformans do not appear to have been examined. However, glucuronoxylomannan, the polysaccharide component of the capsular material of cryptococcus neoformans, exhibits potent immunosuppressive properties. This compound downregulates TNF-alpha and IL-1beta, and upregulates the inhibitory cytokine IL-10, but also inhibits retinoic receptor (RORG) synthesis . Retinoic acid is also able to lower plasma homocysteine levels via the induction of hepatic glycine N-methyltransferase. Homocysteine in contrast inhibits retinoic acid synthesis [306, 307].
Vitamin A levels are in fact higher in hypercholesterolemia patients . This may perhaps be due to the fact that retinyl palmitate, the vitamin A precursor, like cholesterol, is also transported by lipoproteins in the blood, mainly in the VLDL fraction (which primarily consist of APOC2/APOE) and the LDL fraction (which primarily consists of APOB) . Retinyl palmitate concentrations in the blood are affected by APOE polymorphisms and radiolabelled retinyl palmitate binding in total plasma and nonchylomicron fractions is least in APOE4+/+ carriers . The aortic concentrations of triglycerides, total cholesterol, free and esterified cholesterol, and phospholipids are increased in vitamin A deficient rats, an effect reversed by vitamin A supplementation 
A large number of Alzheimer’s disease genes are related to vitamin A (Table 2), and an even larger number responsive to retinoic acid via the action of RAR or RXR transcriptional control.
3.8. Autoantibodies to the Antimicrobial Peptide Beta Amyloid: Likely Derivation from Antibodies to Pathogens
Beta-amyloid is a potent antimicrobial peptide. Although not tested against C. Neoformans, H. pylori, or C. Pneumoniae, it was found to have broad spectrum activity against a variety of yeasts and bacteria, effects that were attenuated by anti-Aβ antibodies. . Lactotransferrin is also an antimicrobial peptide that colocalises to plaques and tangle in the Alzheimer’s disease brain  and other antimicrobial peptides include the susceptibility gene products cystatin C, defensin DEFB122, myeloperoxidase, and transferrin . beta-amyloid, like acyclovir, also attenuates the stimulatory effects of HSV-1 on miRNA-146a levels in neuronal cells . The antimicrobial and antiviral properties of beta amyloid are, however, likely to be abrogated by the presence of beta-amyloid antibodies in the sera of the ageing population  and in Alzheimer’s disease .
As shown in Table 3, a number of pathogens implicated in Alzheimer’s disease or its attendant risk factors, express proteins with a high degree of homology to beta-amyloid. These include proteins from HSV-1, HHV-6, the cytomegalovirus, C. Neoformans, H. pylori, C. Pneumoniae, B. Burgdorferi and, P. Gingivalis. Antibodies to B. Burgdorferi  and C. Pneumoniae  and Herpes simplex and HHV-6 viral DNA [298, 315] have all been reported in or around Alzheimer’s disease plaques, and antibodies to H. pylori recovered from Alzheimer’s disease serum and cerebrospinal fluid . A recent study showed that P. Gingivalis antibodies, cross-reactive with human HSP60, were observed in 100% of a sample of 20 atherosclerosis patients . The immune system is not designed to raise antibodies to a self-protein, and this high degree of homology suggests that the autoantibodies to beta-amyloid are created by antibodies to homologous pathogens’ proteins.
Several other autoantibodies have been reported in Alzheimer’s disease, including targets such as nerve growth factor , cholinergic neurones , the choroid plexus , and neurofibrillary tangles, inter alia . The very extensive sharing of viral and bacterial protein sequences with the human proteome [230, 322–324] suggests that these too might be derived from cross-reactive microbial antigens. Again the ability to create autoantibodies is conditioned by genes, particularly HLA-antigens [325, 326]. Autoantibodies are often regarded as an epiphenomenon, but their ability to traverse the blood-brain barrier , and the recent recognition of their ability to enter cells  casts them in a new light as pathological immunopharmacological agents able to block the function of their target proteins: this has indeed been shown for Alzheimer’s disease-derived ATP synthase autoantibodies which block ATP synthesis and cause apoptosis in neuroblastoma cells .
The classical population genetics example of the foxes and rabbits illustrates how genes and risk factors can differentially permit or disallow the effects of a causative agent, depending on a permutation of circumstance. Applying this model to Alzheimer’s disease also suggests that many of the environmental risk factors in Alzheimer’s disease are in fact causative agents, at least in terms of an ability to produce beta-amyloid deposition, per se, as shown in nontransgenic animal models. Their effects are also clearly related to other risk factors and genes. This would infer that the susceptibility genes in Alzheimer’s disease permit the actions of these agents but, perhaps more importantly, that polymorphisms in the control population do not. Functional characterisation of these control variants may provide important clues to overall methods of protection.
Many of these risk factors are avoidable or amenable to therapy. Diet is already known to be an important risk/protective factor with regard to the incidence of Alzheimer’s disease. For example there is clear evidence that the omega-3 fatty acid docosahexaenoic acid (DHA), a component of fish and the Mediterranean diet, also protective factors [243, 330], is associated with a reduced risk of dementia , although a recent study with DHA in mild to moderate Alzheimer’s disease, failed to show disease arrest or diminution . However, in agreement with epidemiology, DHA significantly benefited two measures of cognition in mild to moderate non-ApoE4 carriers . High vitamin A and low homocysteine levels are related to a high intake of fruit and vegetables in elderly patients . Fruit and vegetable juice consumption is also associated with reduced Alzheimer’s disease incidence .
Given the fact that the potential causes of Alzheimer’s disease appear to be multifactorial, perhaps a multifactorial therapeutic effort is also needed. Such approaches might include a greater attention to diet, homocysteine and cholesterol levels, vitamin A supplementation where necessary, and the regular detection and elimination of herpes simplex, B. Burgdorferi, C. Pneumoniae, H. pylori, C. Neoformans, and other pathogens in the ageing population. The removal of beta-amyloid antibodies and of others prevalent in Alzheimer’s disease might also be of benefit. These are simple preventive measures, requiring public health attention, whose corporate instigation might markedly reduce the incidence, and perhaps halt or reverse the progression, of Alzheimer’s disease.
L. Bertram and R. E. Tanzi, “Alzheimer's disease: one disorder, too many genes?” Human Molecular Genetics, vol. 13, no. 1, pp. R135–R141, 2004.View at: Google Scholar
B. Bondy, “Genetics in psychiatry: are the promises met?” The World Journal of Biological Psychiatry, vol. 12, no. 2, pp. 81–88, 2011.View at: Google Scholar
H. L. Li, S. S. Shi, Q. H. Guo et al., “PICALM and CR1 variants are not associated with sporadic Alzheimer's disease in Chinese patients”.View at: Google Scholar
D. Franciotta, A. Bestetti, S. Sala et al., “Broad screening for human herpesviridae DNA in multiple sclerosis cerebrospinal fluid and serum,” Acta Neurologica Belgica, vol. 109, no. 4, pp. 277–282, 2009.View at: Google Scholar
A. Papassotiropoulos, M. A. Wollmer, M. Tsolaki et al., “A cluster of cholesterol-related genes confers susceptibility for Alzheimer's disease,” Journal of Clinical Psychiatry, vol. 66, no. 7, pp. 940–947, 2005.View at: Google Scholar
I. L. Ferreira, R. Resende, E. Ferreiro, A. C. Rego, and C. F. Pereira, “Multiple defects in energy metabolism in Alzheimer's disease,” Current Drug Targets, vol. 11, no. 10, pp. 1193–1206, 2010.View at: Google Scholar
M. Facheris, S. Beretta, and C. Ferrarese, “Peripheral markers of oxidative stress and excitotoxicity in neurodegenerative disorders: tools for diagnosis and therapy?” Journal of Alzheimer's Disease, vol. 6, no. 2, pp. 177–184, 2004.View at: Google Scholar
S. Goto, H. Bono, H. Ogata et al., “Organizing and computing metabolic pathway data in terms of binary relations,” Pacific Symposium on Biocomputing, pp. 175–186, 1997.View at: Google Scholar
J. E. Larsen, O. Lund, and M. Nielsen, “Improved method for predicting linear B-cell epitopes,” Immunome Research, vol. 2, article 2, 2006.View at: Google Scholar
A. H. Oijen, M. L. Verhulst, H. M. Roelofs, W. H. Peters, W. A. de Boer, and J. B. Jansen, “Eradication of Helicobacter pylori restores glutathione S-transferase activity and glutathione levels in antral mucosa,” Japanese Journal of Cancer Research, vol. 92, no. 12, pp. 1329–1334, 2001.View at: Google Scholar
R. Takenaka, K. Yokota, K. Ayada et al., “Helicobacter pylori heat-shock protein 60 induces inflammatory responses through the Toll-like receptor-triggered pathway in cultured human gastric epithelial cells,” Microbiology, vol. 150, no. 12, pp. 3913–3922, 2004.View at: Publisher Site | Google Scholar
C. J. Carter, “Alzheimer's disease plaques and tangles: cemeteries of a Pyrrhic victory of the immune defence network against herpes simplex infection at the expense of complement and inflammation-mediated neuronal destruction,” Neurochemistry International, vol. 58, no. 3, pp. 301–320, 2011.View at: Publisher Site | Google Scholar
D. S. Goodman, “Plasma retinol-binding protein,” Annals of the New York Academy of Sciences, vol. 348, pp. 378–390, 1980.View at: Google Scholar
R. Schindler and A. Klopp, “Transport of esterified retinol in fasting human blood,” International Journal for Vitamin and Nutrition Research, vol. 56, no. 1, pp. 21–27, 1986.View at: Google Scholar
M. M. Sousa, L. Berglund, and M. J. Saraiva, “Transthyretin in high density lipoproteins: association with apolipoprotein A-I,” Journal of Lipid Research, vol. 41, no. 1, pp. 58–65, 2000.View at: Google Scholar
S. Smeland, S. O. Kolset, M. Lyon, K. R. Norum, and R. Blomhoff, “Binding of perlecan to transthyretin in vitro,” Biochemical Journal, vol. 326, no. 3, pp. 829–836, 1997.View at: Google Scholar
T. C. Kiorpes, R. S. Anderson, and G. Wolf, “Effect of vitamin A deficiency on glycosylation of rat serum α-macroglobulin,” Journal of Nutrition, vol. 111, no. 12, pp. 2059–2068, 1981.View at: Google Scholar
R. P. Koldamova, I. M. Lefterov, M. D. Ikonomovic et al., “22R-hydroxycholesterol and 9-cis-retinoic acid induce ATP-binding cassette transporter A1 expression and cholesterol efflux in brain cells and decrease amyloid β secretion,” Journal of Biological Chemistry, vol. 278, no. 15, pp. 13244–13256, 2003.View at: Publisher Site | Google Scholar
E. Reboul, D. Trompier, M. Moussa et al., “ATP-binding cassette transporter A1 is significantly involved in the intestinal absorption of alpha- and gamma-tocopherol but not in that of retinyl palmitate in mice,” The American Journal of Clinical Nutrition, vol. 89, no. 1, pp. 177–184, 2009.View at: Google Scholar
S. K. Lee, H. S. Choi, M. R. Song, M. O. Lee, and J. W. Lee, “Estrogen receptor, a common interaction partner for a subset of nuclear receptors,” Molecular Endocrinology, vol. 12, no. 8, pp. 1184–1192, 1998.View at: Google Scholar
E. I. Christensen, J. O. Moskaug, H. Vorum et al., “Evidence for an essential role of megalin in transepithelial transport of retinol,” Journal of the American Society of Nephrology, vol. 10, no. 4, pp. 685–695, 1999.View at: Google Scholar
Y. Wang, N. Kumar, C. Crumbley, P. R. Griffin, and T. P. Burris, “A second class of nuclear receptors for oxysterols: regulation of RORalpha and RORgamma activity by 24S-hydroxycholesterol (cerebrosterol),” Biochimica et Biophysica Acta, vol. 1801, no. 8, pp. 917–923, 2010.View at: Publisher Site | Google Scholar
H. Chen and M. R. Juchau, “Recombinant human glutathione S-transferases catalyse enzymic isomerization of 13-cis-retinoic acid to all-trans-retinoic acid in vitro,” Biochemical Journal, vol. 336, no. 1, pp. 223–226, 1998.View at: Google Scholar
E. H. Harrison, “Lipases and carboxylesterases: possible roles in the hepatic utilization of vitamin A,” Journal of Nutrition, vol. 130, no. 2, pp. 340S–344S, 2000.View at: Google Scholar
A. Woods, C. G. James, G. Wang, H. Dupuis, and F. Beier, “Control of chondrocyte gene expression by actin dynamics: a novel role of cholesterol/Ror-α signalling in endochondral bone growth,” Journal of Cellular and Molecular Medicine, vol. 13, no. 9, pp. 3497–3516, 2009.View at: Publisher Site | Google Scholar
D. R. Johnson, J. M. Lovett, M. Hirsch, F. Xia, and J. D. Chen, “NuRD complex component Mi-2beta binds to and represses RORgamma-mediated transcriptional activation,” Biochemical and Biophysical Research Communications, vol. 318, no. 3, pp. 714–718, 2004.View at: Google Scholar
X. H. Zhang, B. Zheng, M. Han, S. B. Miao, and J. K. Wen, “Synthetic retinoid Am80 inhibits interaction of KLF5 with RARα through inducing KLF5 dephosphorylation mediated by the PI3K/Akt signaling in vascular smooth muscle cells,” FEBS Letters, vol. 583, no. 8, pp. 1231–1236, 2009.View at: Publisher Site | Google Scholar
C. Crumbley, Y. Wang, D. J. Kojetin, and T. P. Burris, “Characterization of the core mammalian clock component, NPAS2, as a REV-ERBalpha/RORalpha target gene,” The Journal of Biological Chemistry, vol. 285, no. 46, pp. 35386–35392, 2010.View at: Google Scholar
M. Gianni', A. Boldetti, V. Guarnaccia et al., “Inhibition of the peptidyl-prolyl-isomerase Pin1 enhances the responses of acute myeloid leukemia cells to retinoic acid via stabilization of RARα and PML-RARα,” Cancer Research, vol. 69, no. 3, pp. 1016–1026, 2009.View at: Publisher Site | Google Scholar
A. Gorla-Bajszczak, C. Juge-Aubry, A. Pernin, A. G. Burger, and C. A. Meier, “Conserved amino acids in the ligand-binding and tau(i) domains of the peroxisome proliferator-activated receptor alpha are necessary for heterodimerization with RXR,” Molecular and Cellular Endocrinology, vol. 147, no. 1-2, pp. 37–47, 1999.View at: Google Scholar
G. E. O. Muscat, L. Mynett-Johnson, D. Dowhan, M. Downes, and R. Griggs, “Activation of myoD gene transcription by 3,5,3'-triiodo-L-thyronine: a direct role for the thyroid hormone and retinoid X receptors,” Nucleic Acids Research, vol. 22, no. 4, pp. 583–591, 1994.View at: Google Scholar
D. Zhu, C. Wang, B. Liu, Y. Wu, L. Zhong, and C. Wang, “Interaction between nuclear localization signal-retinoic acid receptor alpha and Ubiquilin 1,” Journal of Central South University, vol. 35, no. 7, pp. 649–654, 2010.View at: Google Scholar
A. Jämsä, K. Hasslund, R. F. Cowburn, A. Bäckström, and M. Vasänge, “The retinoic acid and brain-derived neurotrophic factor differentiated SH-SY5Y cell line as a model for Alzheimer's disease-like tau phosphorylation,” Biochemical and Biophysical Research Communications, vol. 319, no. 3, pp. 993–1000, 2004.View at: Publisher Site | Google Scholar
C. M. Bliss Jr., D. T. Golenbock, S. Keates, J. K. Linevsky, and C. P. Kelly, “Helicobacter pylori lipopolysaccharide binds to CD14 and stimulates release of interleukin-8, epithelial neutrophil-activating peptide 78, and monocyte chemotactic protein 1 by human monocytes,” Infection and Immunity, vol. 66, no. 11, pp. 5357–5363, 1998.View at: Google Scholar
Y. Ma, Q. Chen, and A. C. Ross, “Retinoic acid and polyriboinosinic: polyribocytidylic acid stimulate robust anti-tetanus antibody production while differentially regulating type 1/type 2 cytokines and lymphocyte populations,” Journal of Immunology, vol. 174, no. 12, pp. 7961–7969, 2005.View at: Google Scholar
A. Yen, D. M. Lin, T. J. Lamkin, and S. Varvayanis, “Retinoic acid, bromodeoxyuridine, and the Δ205 mutant polyoma virus middle T antigen regulate expression levels of a common ensemble of proteins associated with early stages of inducing HL-60 leukemic cell differentiation,” In Vitro Cellular and Developmental Biology, vol. 40, no. 7, pp. 216–241, 2004.View at: Google Scholar
P. Desreumaux, L. Dubuquoy, S. Nutten et al., “Attenuation of colon inflammation through activators of the retinoid X receptor (RXR)/peroxisome proliferator-activated receptor gamma (PPARgamma) heterodimer. A basis for new therapeutic strategies,” The Journal of Experimental Medicine, vol. 193, no. 7, pp. 827–838, 2001.View at: Publisher Site | Google Scholar
U. Lind, T. Nilsson, J. McPheat et al., “Identification of the human ApoAV gene as a novel RORalpha target gene,” Biochemical and Biophysical Research Communications, vol. 330, no. 1, pp. 233–241, 2005.View at: Google Scholar
D. Kardassis, A. Roussou, P. Papakosta, K. Boulias, I. Talianidis, and V. I. Zannis, “Synergism between nuclear receptors bound to specific hormone response elements of the hepatic control region-1 and the proximal apolipoprotein C-II promoter mediate apolipoprotein C-II gene regulation by bile acids and retinoids,” Biochemical Journal, vol. 372, no. 2, pp. 291–304, 2003.View at: Publisher Site | Google Scholar
P. A. Mak, B. A. Laffitte, C. Desrumaux et al., “Regulated expression of the apolipoprotein E/C-I/C-IV/C-II gene cluster in murine and human macrophages: a critical role for nuclear liver X receptors α and β,” Journal of Biological Chemistry, vol. 277, no. 35, pp. 31900–31908, 2002.View at: Publisher Site | Google Scholar
Y. S. Lopez-Boado, M. Klaus, M. I. Dawson, and C. Lopez-Otin, “Retinoic acid-induced expression of apolipoprotein D and concomitant growth arrest in human breast cancer cells are mediated through a retinoic acid receptor RARalpha-dependent signaling pathway,” The Journal of Biological Chemistry, vol. 271, no. 50, pp. 32105–32111, 1996.View at: Google Scholar
G. D. Norata, M. Ongari, P. Uboldi, F. Pellegatta, and A. L. Catapano, “Liver X receptor and retinoic X receptor agonists modulate the expression of genes involved in lipid metabolism in human endothelial cells,” International Journal of Molecular Medicine, vol. 16, no. 4, pp. 717–722, 2005.View at: Google Scholar
S. Georgala, K. H. Schulpis, I. Potouridou, and H. Papadogeorgaki, “Effects of isotretinoin therapy on lipoprotein (a) serum levels,” International Journal of Dermatology, vol. 36, no. 11, pp. 863–864, 1997.View at: Google Scholar
R. Verani, I. Cappuccio, P. Spinsanti et al., “Expression of the Wnt inhibitor Dickkopf-1 is required for the induction of neural markers in mouse embryonic stem cells differentiating in response to retinoic acid,” Journal of Neurochemistry, vol. 100, no. 1, pp. 242–250, 2007.View at: Publisher Site | Google Scholar
A. M. Padovani, M. F. Molina, and K. K. Mann, “Inhibition of liver X receptor/retinoid X receptor-mediated transcription contributes to the proatherogenic effects of arsenic in macrophages in vitro,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 30, no. 6, pp. 1228–1236, 2010.View at: Publisher Site | Google Scholar
M. R. de Oliveira, M. W. S. Oliveira, G. A. Behr, M. A. B. Pasquali, and J. C. F. Moreira, “Increased receptor for advanced glycation endproducts immunocontent in the cerebral cortex of vitamin a-treated rats,” Neurochemical Research, vol. 34, no. 8, pp. 1410–1416, 2009.View at: Publisher Site | Google Scholar
D. P. Gelain, M. A. B. Pasquali, F. F. Caregnato, A. Zanotto-Filho, and J. C. Moreira, “Retinol up-regulates the receptor for advanced glycation endproducts (RAGE) by increasing intracellular reactive species,” Toxicology in Vitro, vol. 22, no. 5, pp. 1123–1127, 2008.View at: Publisher Site | Google Scholar
R. M. Moretti, M. M. Montagnani, A. Sala, M. Motta, and P. Limonta, “Activation of the orphan nuclear receptor RORα counteracts the proliferative effect of fatty acids on prostate cancer cells: crucial role of 5-lipoxygenase,” International Journal of Cancer, vol. 112, no. 1, pp. 87–93, 2004.View at: Publisher Site | Google Scholar
J. Ko, C. Y. Yun, J. S. Lee, J. H. Kim, and I. S. Kim, “p38 MAPK and ERK activation by 9-cis-retinoic acid induces chemokine receptors CCR1 and CCR2 expression in human monocytic THP-1 cells,” Experimental and Molecular Medicine, vol. 39, no. 2, pp. 129–138, 2007.View at: Google Scholar
D. Wågsäter, K. Jatta, P. Ocaya, J. Dimberg, and A. Sirsjö, “Expression of IL-1β, IL-1 receptor type I and IL-1 receptor antagonist in human aortic smooth muscle cells: effects of all-trans-retinoic acid,” Journal of Vascular Research, vol. 43, no. 4, pp. 377–382, 2006.View at: Publisher Site | Google Scholar
S. J. Lee, E. K. Yang, and S. G. Kim, “Peroxisome proliferator-activated receptor-gamma and retinoic acid X receptor alpha represses the TGFbeta1 gene via PTEN-mediated p70 ribosomal S6 kinase-1 inhibition: role for Zf9 dephosphorylation,” Molecular Pharmacology, vol. 70, no. 1, pp. 415–425, 2006.View at: Google Scholar
J. Wang, S. Wu, X. Jin et al., “Retinoic acid-inducible gene-i mediates late phase induction of TNF-α by lipopolysaccharide,” Journal of Immunology, vol. 180, no. 12, pp. 8011–8019, 2008.View at: Google Scholar
F. Fidanza, P. Sarchielli, P. Jordan, E. Lüdin, W. Schalch, and B. J. Weimann, “Vitamin nutritional status and immunocompetence of elderly in Perugia (Italy): an epidemiological approach,” International Journal for Vitamin and Nutrition Research, vol. 61, no. 3, pp. 224–231, 1991.View at: Google Scholar
P. Munoz-Canoves, D. P. Vik, and B. F. Tack, “Mapping of a retinoic acid-responsive element in the promoter region of the complement factor H gene,” Journal of Biological Chemistry, vol. 265, no. 33, pp. 20065–20068, 1990.View at: Google Scholar
S. Thompson, P. L. Stern, M. Webb et al., “Cloned human teratoma cells differentiate into neuron-like cells and other cell types in retinoic acid,” Journal of Cell Science, vol. 72, pp. 37–64, 1984.View at: Google Scholar
F. Lancillotti, V. Giandomenico, E. Affabris, G. Fiorucci, G. Romeo, and G. B. Rossi, “Interferon α-2b and retinoic acid combined treatment affects proliferation and gene expression of human cervical carcinoma cells,” Cancer Research, vol. 55, no. 14, pp. 3158–3164, 1995.View at: Google Scholar
E. Czeczuga-Semeniuk, K. Jarzabek, D. Lemancewicz, and S. Wolczynski, “The vitamin A family can significantly decrease the expression of ERbeta of ERs positive breast cancer cells in the presence or absence of ER ligands and paclitaxel,” Gynecological Endocrinology, vol. 25, no. 5, pp. 287–293, 2009.View at: Google Scholar
H. Odawara, T. Iwasaki, J. Horiguchi et al., “Activation of aromatase expression by retinoic acid receptor-related orphan receptor (ROR) α in breast cancer cells: identification of a novel ROR response element,” Journal of Biological Chemistry, vol. 284, no. 26, pp. 17711–17719, 2009.View at: Publisher Site | Google Scholar
S. Kheirvari, K. Uezu, S. Yamamoto, and Y. Nakaya, “High-dose dietary supplementation of vitamin A induces brain-derived neurotrophic factor and nerve growth factor production in mice with simultaneous deficiency of vitamin A and zinc,” Nutritional Neuroscience, vol. 11, no. 5, pp. 228–234, 2008.View at: Publisher Site | Google Scholar
X. Wan, P. Nass, M. D. Duncan, and J. W. Harmon, “Acidic fibroblast growth factor overexpression partially protects 3T3 fibroblasts from apoptosis induced by synthetic retinoid CD437,” Journal of Molecular Medicine, vol. 79, no. 2, pp. 143–148, 2001.View at: Google Scholar
M. Jaradat, C. Stapleton, S. L. Tilley et al., “Modulatory role for retinoid-related orphan receptor alpha in allergen-induced lung inflammation,” American Journal of Respiratory and Critical Care Medicine, vol. 174, no. 12, pp. 1299–1309, 2006.View at: Google Scholar
J. Zimny, “Mechanisms that protect against homocysteine toxicity,” Postepy biochemii, vol. 54, no. 1, pp. 91–98, 2008.View at: Google Scholar
Y. Y. Xu, D. Y. Guan, M. Yang, H. Wang, and Z. H. Shen, “All-trans-retinoic acid intensifies endoplasmic reticulum stress in N-acetylglucosaminyltransferase V repressed human hepatocarcinoma cells by perturbing homocysteine metabolism,” Journal of Cellular Biochemistry, vol. 109, no. 3, pp. 468–477, 2010.View at: Publisher Site | Google Scholar
D. Fell and R. D. Steele, “Modification of hepatic folate metabolism in rats fed excess retinol,” Life Sciences, vol. 38, no. 21, pp. 1959–1965, 1986.View at: Google Scholar
Y. W. Lin, L. M. Lien, T. S. Yeh, H. M. Wu, Y. L. Liu, and R. H. Hsieh, “9-cis retinoic acid induces retinoid X receptor localized to the mitochondria for mediation of mitochondrial transcription,” Biochemical and Biophysical Research Communications, vol. 377, no. 2, pp. 351–354, 2008.View at: Publisher Site | Google Scholar
W. Samuel, R. K. Kutty, S. Nagineni, C. Vijayasarathy, R. A. S. Chandraratna, and B. Wiggert, “N-(4-hydroxyphenyl)retinamide induces apoptosis in human retinal pigment epithelial cells: retinoic acid receptors regulate apoptosis, reactive oxygen species generation, and the expression of heme oxygenase-1 and Gadd153,” Journal of Cellular Physiology, vol. 209, no. 3, pp. 854–865, 2006.View at: Publisher Site | Google Scholar
T. Cadoudal, M. Glorian, A. Massias, F. Fouque, C. Forest, and C. Benelli, “Retinoids upregulate phosphoenolpyruvate carboxykinase and glyceroneogenesis in human and rodent adipocytes,” Journal of Nutrition, vol. 138, no. 6, pp. 1004–1009, 2008.View at: Google Scholar
Y. Y. Xu, Y. Lu, K. Y. Fan, and Z. H. Shen, “Apoptosis induced by all-trans retinoic acid in N- acetylglucosaminyltransferase V repressed human hepatocarcinoma cells is mediated through endoplasmic reticulum stress,” Journal of Cellular Biochemistry, vol. 100, no. 3, pp. 773–782, 2007.View at: Publisher Site | Google Scholar
S. W. Bahouth, M. J. Beauchamp, and E. A. Park, “Identification of a retinoic acid response domain involved in the activation of the β-adrenergic receptor gene by retinoic acid in F9 teratocarcinoma cells,” Biochemical Pharmacology, vol. 55, no. 2, pp. 215–225, 1998.View at: Publisher Site | Google Scholar
S. M. Salih, M. Jamaluddin, S. A. Salama, A. A. Fadl, M. Nagamani, and A. Al-Hendy, “Regulation of catechol O-methyltransferase expression in granulosa cells: a potential role for follicular arrest in polycystic ovary syndrome,” Fertility and Sterility, vol. 89, no. 5, pp. 1414–1421, 2008.View at: Publisher Site | Google Scholar
S. Sharma and M. F. Notter, “Characterization of neurotransmitter phenotype during neuronal differentiation of embryonal carcinoma cells,” Developmental Biology, vol. 125, no. 2, pp. 246–254, 1988.View at: Google Scholar
M. Nilbratt, L. Friberg, M. Mousavi, A. Marutle, and A. Nordberg, “Retinoic acid and nerve growth factor induce differential regulation of nicotinic acetylcholine receptor subunit expression in SN56 cells,” Journal of Neuroscience Research, vol. 85, no. 3, pp. 504–514, 2007.View at: Publisher Site | Google Scholar
A. Oikarinen, T. Vuorio, J. Makela, and E. Vuorio, “13-cis retinoic acid and dexamethasone modulate the gene expression of epidermal growth factor receptor and fibroblast proteoglycan 40 core protein in human skin fibroblasts,” Acta Dermato-Venereologica, vol. 69, no. 6, pp. 466–469, 1989.View at: Google Scholar
C. Chang, X. H. Chen, P. Y. Kong et al., “In vitro effect of all-trans retinoic acid on cell adhesion molecule expression and adhesion capacity of bone marrow stromal cells in patients received peripheral blood stem cell transplantation,” Journal of experimental hematology / Chinese Association of Pathophysiology, vol. 14, no. 4, pp. 768–772, 2006.View at: Google Scholar
M. R. Davies, L. R. Ribeiro, M. Downey-Jones, M. R. C. Needham, C. Oakley, and J. Wardale, “Ligands for retinoic acid receptors are elevated in osteoarthritis and may contribute to pathologic processes in the osteoarthritic joint,” Arthritis and Rheumatism, vol. 60, no. 6, pp. 1722–1732, 2009.View at: Publisher Site | Google Scholar
J. Liu, A. P. Li, C. P. Li, Z. D. Zhang, and J. W. Zhou, “The role of reactive oxygen species in N-[4-hydroxyphenyl] retinamide induced apoptosis in bladder cancer cell lineT24,” Chinese journal of industrial hygiene and occupational diseases, vol. 23, no. 3, pp. 191–194, 2005.View at: Google Scholar
K. A. Latif, I. Amla, and P. B. Rao, “Urinary excretion of arylsulfatases in malnourished/vitamin A deficient children,” Clinica Chimica Acta, vol. 96, no. 1-2, pp. 131–138, 1979.View at: Google Scholar
K. Kasashima, K. Terashima, K. Yamamoto, E. Sakashita, and H. Sakamoto, “Cytoplasmic localization is required for the mammalian ELAV-like protein HuD to induce neuronal differentiation,” Genes to Cells, vol. 4, no. 11, pp. 667–683, 1999.View at: Google Scholar
A. Kihara, M. Ikeda, Y. Kariya, E. Y. Lee, Y. M. Lee, and Y. Igarashi, “Sphingosine-1-phosphate lyase is involved in the differentiation of F9 embryonal carcinoma cells to primitive endoderm,” Journal of Biological Chemistry, vol. 278, no. 16, pp. 14578–14585, 2003.View at: Publisher Site | Google Scholar
T. M. Chlon, D. A. Taffany, J. Welsh, and M. J. Rowling, “Retinoids modulate expression of the endocytic partners megalin, cubilin, and disabled-2 and uptake of vitamin D-binding protein in human mammary cells,” Journal of Nutrition, vol. 138, no. 7, pp. 1323–1328, 2008.View at: Google Scholar
B. A. Kudriashov, A. M. Ul'ianov, G. G. Bazaz'ian, and N. P. Sytina, “Factor XIII activity in the presence of suppression of the function of the anticoagulant system and its restoration in animals on an atherogenic ration,” Voprosy pitaniia, no. 5, pp. 54–57, 1976.View at: Google Scholar
Y. Chen, R. P. Sharma, R. H. Costa, E. Costa, and D. R. Grayson, “On the epigenetic regulation of the human reelin promoter,” Nucleic Acids Research, vol. 30, no. 13, pp. 2930–2939, 2002.View at: Google Scholar
L. Russell, H. Naora, and H. Naora, “Down-regulated RPS3a/nbl expression during retinoid-induced differentiation of HL-60 cells: a close association with diminished susceptibility to actinomycin D-stimulated apoptosis,” Cell Structure and Function, vol. 25, no. 2, pp. 103–113, 2000.View at: Publisher Site | Google Scholar
J. Zhang, L. P. Song, Y. Huang, Q. Zhao, K. W. Zhao, and G. Q. Chen, “Accumulation of hypoxia-inducible factor-1α protein and its role in the differentiation of myeloid leukemic cells induced by all-trans retinoic acid,” Haematologica, vol. 93, no. 10, pp. 1480–1487, 2008.View at: Publisher Site | Google Scholar
M. Takehashi, S. Tanaka, T. Stedeford et al., “Expression of septin 3 isoforms in human brain,” Gene Expression, vol. 11, no. 5-6, pp. 271–278, 2004.View at: Google Scholar
K. Ono and M. Yamada, “Vitamin A potently destabilizes preformed alpha-synuclein fibrils in vitro: implications for Lewy body diseases,” Neurobiology of Disease, vol. 25, no. 2, pp. 446–454, 2007.View at: Google Scholar
Z. J. Sahab, M. D. Hall, L. Zhang, A. K. Cheema, and S. W. Byers, “Tumor suppressor RARRES1 regulates DLG2, PP2A, VCP, EB1, and Ankrd26,” Journal of Cancer, vol. 1, pp. 14–22, 2010.View at: Google Scholar
R. P. J. Prasanthi, E. Schommer, S. Thomasson, A. Thompson, G. Feist, and O. Ghribi, “Regulation of β-amyloid levels in the brain of cholesterol-fed rabbit, a model system for sporadic Alzheimer's disease,” Mechanisms of Ageing and Development, vol. 129, no. 11, pp. 649–655, 2008.View at: Publisher Site | Google Scholar
C. E. Zhang, W. Wei, Y. H. Liu et al., “Hyperhomocysteinemia increases beta-amyloid by enhancing expression of gamma-secretase and phosphorylation of amyloid precursor protein in rat brain,” The American Journal of Pathology, vol. 174, pp. 1481–1491, 2009.View at: Google Scholar
S. Capsoni, G. Ugolini, A. Comparini, F. Ruberti, N. Berardi, and A. Cattaneo, “Alzheimer-like neurodegeneration in aged antinerve growth factor transgenic mice,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 12, pp. 6826–6831, 2000.View at: Publisher Site | Google Scholar
L. Li, X. Zhang, D. Yang, G. Luo, S. Chen, and W. Le, “Hypoxia increases Abeta generation by altering beta- and gamma-cleavage of APP,” Neurobiology of Aging, vol. 30, pp. 1091–1098, 2009.View at: Google Scholar
C. Zhiyou, Y. Yong, S. Shanquan et al., “Upregulation of BACE1 and β-amyloid protein mediated by chronic cerebral hypoperfusion contributes to cognitive impairment and pathogenesis of Alzheimer's disease,” Neurochemical Research, vol. 34, no. 7, pp. 1226–1235, 2009.View at: Publisher Site | Google Scholar
M. Salkovic-Petrisic, F. Tribl, M. Schmidt, S. Hoyer, and P. Riederer, “Alzheimer-like changes in protein kinase B and glycogen synthase kinase-3 in rat frontal cortex and hippocampus after damage to the insulin signalling pathway,” Journal of Neurochemistry, vol. 96, no. 4, pp. 1005–1015, 2006.View at: Publisher Site | Google Scholar
H. Q. Yang, Z. K. Sun, Q. H. Jiang, Q. Shang, and J. Xu, “Effect of estrogen-depletion and 17beta-estradiol replacement therapy upon rat hippocampus beta-amyloid generation,” Chinese Medical Journal, vol. 89, no. 37, pp. 2658–2661, 2009.View at: Google Scholar
W. R. Lin, D. Shang, and R. F. Itzhaki, “Neurotropic viruses and Alzheimer disease: interaction of herpes simplex type I virus and apolipoprotein E in the etiology of the disease,” Molecular and Chemical Neuropathology, vol. 28, no. 1–3, pp. 135–141, 1996.View at: Google Scholar
M. A. Pappolla, T. K. Bryant-Thomas, D. Herbert et al., “Mild hypercholesterolemia is an early risk factor for the development of Alzheimer amyloid pathology,” Neurology, vol. 61, no. 2, pp. 199–205, 2003.View at: Google Scholar
M. van Oijen, F. J. de Jong, J. C. Witteman, A. Hofman, P. J. Koudstaal, and M. M. Breteler, “Atherosclerosis and risk for dementia,” Annals of Neurology, vol. 61, pp. 403–410, 2007.View at: Google Scholar
J. W. Miller, “Homocysteine and Alzheimer's disease,” Nutrition Reviews, vol. 57, no. 4, pp. 126–129, 1999.View at: Google Scholar
G. Ravaglia, P. Forti, F. Maioli et al., “Endogenous sex hormones as risk factors for dementia in elderly men and women,” Journals of Gerontology Series A, vol. 62, no. 9, pp. 1035–1041, 2007.View at: Google Scholar
F. J. Jimenez-Jimenez, J. A. Molina, F. de Bustos et al., “Serum levels of beta-carotene, alpha-carotene and vitamin A in patients with Alzheimer's disease,” European Journal of Neurology, vol. 6, pp. 495–497, 1999.View at: Google Scholar
D. A. Snowdon, “Healthy aging and dementia: findings from the Nun Study,” Annals of Internal Medicine, vol. 139, no. 5, pp. 450–454, 2003.View at: Google Scholar
D. S. Wolf, M. Gearing, D. A. Snowdon, H. Mori, W. R. Markesbery, and S. S. Mirra, “Progression of regional neuropathology in Alzheimer disease and normal elderly: findings from the Nun Study,” Alzheimer Disease and Associated Disorders, vol. 13, no. 4, pp. 226–231, 1999.View at: Google Scholar
T. A. Ala, R. C. Doss, and C. J. Sullivan, “Reversible dementia: a case of cryptococcal meningitis masquerading as Alzheimer's disease,” Journal of Alzheimer's Disease, vol. 6, no. 5, pp. 503–508, 2004.View at: Google Scholar
B. Wolozin, W. Kellman, P. Ruosseau, G. G. Celesia, and G. Siegel, “Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors,” Archives of Neurology, vol. 57, no. 10, pp. 1439–1443, 2000.View at: Google Scholar
L. M. Bermejo, A. Aparicio, P. Andrés, A. M. López-Sobaler, and R. M. Ortega, “The influence of fruit and vegetable intake on the nutritional status and plasma homocysteine levels of institutionalised elderly people,” Public Health Nutrition, vol. 10, no. 3, pp. 266–272, 2007.View at: Publisher Site | Google Scholar
J. A. Luchsinger, M. X. Tang, J. Miller, R. Green, and R. Mayeux, “Higher folate intake is related to lower risk of Alzheimer's disease in the elderly,” Journal of Nutrition, Health and Aging, vol. 12, no. 9, pp. 648–650, 2008.View at: Google Scholar
P. L. McGeer, M. Schulzer, and E. G. McGeer, “Arthritis and anti-inflammatory agents as possible protective factors for Alzheimer's disease: a review of 17 epidemiologic studies,” Neurology, vol. 47, no. 2, pp. 425–432, 1996.View at: Google Scholar
E. H. Corder, A. M. Saunders, W. J. Strittmatter et al., “Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families,” Science, vol. 261, no. 5123, pp. 921–923, 1993.View at: Google Scholar
H. Xiong, D. Callaghan, A. Jones et al., “Cholesterol retention in Alzheimer's brain is responsible for high beta- and gamma-secretase activities and Abeta production,” Neurobiology of Disease, vol. 29, no. 3, pp. 422–437, 2008.View at: Google Scholar
M. S. Weintraub, S. Eisenberg, and J. L. Breslow, “Dietary fat clearance in normal subjects is regulated by genetic variation in apolipoprotein E,” Journal of Clinical Investigation, vol. 80, no. 6, pp. 1571–1577, 1987.View at: Google Scholar
J. H. Powers, B. L. Buster, C. J. Reist et al., “Complement-independent binding of microorganisms to primate erythrocytes in vitro by cross-linked monoclonal antibodies via complement receptor 1,” Infection and Immunity, vol. 63, no. 4, pp. 1329–1335, 1995.View at: Google Scholar
S. M. Levitz, “Receptor-mediated recognition of Cryptococcus neoformans,” Japanese Journal of Medical Mycology, vol. 43, no. 3, pp. 133–136, 2002.View at: Google Scholar
F. Tebar, S. K. Bohlander, and A. Sorkin, “Clathrin assembly lymphoid myeloid leukemia (CALM) protein: localization in endocytic-coated pits, interactions with clathrin, and the impact of overexpression on clathrin-mediated traffic,” Molecular Biology of the Cell, vol. 10, no. 8, pp. 2687–2702, 1999.View at: Google Scholar
A. Fraile-Ramos, T. A. Kohout, M. Waldhoer, and M. Marsh, “Endocytosis of the viral chemokine receptor US28 does not require beta-arrestins but is dependent on the clathrin-mediated pathway,” Traffic, vol. 4, no. 4, pp. 243–253, 2003.View at: Google Scholar
J. Tschopp, A. Chonn, S. Hertig, and L. E. French, “Clusterin, the human apolipoprotein and complement inhibitor, binds to complement C7, C8β, and the b domain of C9,” Journal of Immunology, vol. 151, no. 4, pp. 2159–2165, 1993.View at: Google Scholar
R. D. Bell, A. P. Sagare, A. E. Friedman et al., “Transport pathways for clearance of human Alzheimer's amyloid beta-peptide and apolipoproteins E and J in the mouse central nervous system,” Journal of Cerebral Blood Flow & Metabolism, vol. 27, no. 5, pp. 909–918, 2007.View at: Publisher Site | Google Scholar
K. Shibayama, J. Wachino, Y. Arakawa, M. Saidijam, N. G. Rutherford, and P. J. Henderson, “Metabolism of glutamine and glutathione via gamma-glutamyltranspeptidase and glutamate transport in Helicobacter pylori: possible significance in the pathophysiology of the organism,” Molecular Microbiology, vol. 64, no. 2, pp. 396–406, 2007.View at: Publisher Site | Google Scholar
Y. Sawayama, M. Tatsukawa, S. Maeda, H. Ohnishi, N. Furusyo, and J. Hayashi, “Association of hyperhomocysteinemia and Chlamydia pneumoniae infection with carotid atherosclerosis and coronary artery disease in Japanese patients,” Journal of Infection and Chemotherapy, vol. 14, no. 3, pp. 232–237, 2008.View at: Publisher Site | Google Scholar
M. Mayr, S. Kiechl, J. Willeit, G. Wick, and Q. Xu, “Infections, immunity, and atherosclerosis: associations of antibodies to Chlamydia pneumoniae, Helicobacter pylori, and cytomegalovirus with immune reactions to heat-shock protein 60 and carotid or femoral atherosclerosis,” Circulation, vol. 102, no. 8, pp. 833–839, 2000.View at: Google Scholar
J. A. Mohr, H. Long, B. A. McKown, and H. G. Muchmore, “In vitro susceptibility of Cryptococcus neoformans to steroids,” Sabouraudia Journal of Medical and Veterinary Mycology, vol. 10, no. 2, pp. 171–172, 1972.View at: Google Scholar
C. Clement, P. S. Bhattacharjee, H. E. Kaufman, and J. M. Hill, “Heat-induced reactivation of HSV-1 in latent mice: upregulation in the TG of CD83 and other immune response genes and their LAT-ICP0 locus,” Investigative Ophthalmology and Visual Science, vol. 50, no. 6, pp. 2855–2861, 2009.View at: Publisher Site | Google Scholar
R. D. Vicetti Miguel, B. S. Sheridan, S. A. K. Harvey, R. S. Schreiner, R. L. Hendricks, and T. L. Cherpes, “17-β estradiol promotion of herpes simplex virus type 1 reactivation is estrogen receptor dependent,” Journal of Virology, vol. 84, no. 1, pp. 565–572, 2010.View at: Publisher Site | Google Scholar
J. D. Kriesel, J. Ricigliano, S. L. Spruance, H. H. Garza Jr., and J. M. Hill, “Neuronal reactivation of herpes simplex virus may involve interleukin-6,” Journal of NeuroVirology, vol. 3, no. 6, pp. 441–448, 1997.View at: Google Scholar
S. Noisakran, W. P. Halford, L. Veress, and D. J. J. Carr, “Role of the hypothalamic pituitary adrenal axis and IL-6 in stress- induced reactivation of latent herpes simplex virus type 1,” Journal of Immunology, vol. 160, no. 11, pp. 5441–5447, 1998.View at: Google Scholar
C. L. Wilcox and E. M. Johnson Jr., “Nerve growth factor deprivation results in the reactivation of latent herpes simplex virus in vitro,” Journal of Virology, vol. 61, no. 7, pp. 2311–2315, 1987.View at: Google Scholar
B. Jiang, E. Y. Liao, L. M. Tan, R. C. Dai, Z. J. Xiao, and H. J. Liao, “Effects of long-term replacement therapy of compound nylestriol tablet or low-dose 17 beta-estradiol on the expression of nerve growth factor in OVX rat hippocampal formation,” Journal of Central South University, vol. 29, no. 5, pp. 529–533, 2004.View at: Google Scholar
Y. X. Sun, L. Minthon, A. Wallmark, S. Warkentin, K. Blennow, and S. Janciauskiene, “Inflammatory markers in matched plasma and cerebrospinal fluid from patients with Alzheimer's disease,” Dementia and Geriatric Cognitive Disorders, vol. 16, no. 3, pp. 136–144, 2003.View at: Publisher Site | Google Scholar
J. Kálmán, A. Juhász, G. Laird et al., “Serum interleukin-6 levels correlate with the severity of dementia in down syndrome and in Alzheimer's disease,” Acta Neurologica Scandinavica, vol. 96, no. 4, pp. 236–240, 1997.View at: Google Scholar
P. Kragsbjerg, T. Vikerfors, and H. Holmberg, “Cytokine responses in patients with pneumonia caused by Chlamydia or Mycoplasma,” Respiration, vol. 65, no. 4, pp. 299–303, 1998.View at: Google Scholar
N. Mehmet, M. Refik, M. Harputluoglu, Y. Ersoy, N. E. Aydin, and B. Yildirim, “Serum and gastric fluid levels of cytokines and nitrates in gastric diseases infected with Helicobacter pylori,” New Microbiologica, vol. 27, no. 2, pp. 139–148, 2004.View at: Google Scholar
D. Delfino, L. Cianci, E. Lupis et al., “Interleukin-6 production by human monocytes stimulated with Cryptococcus neoformans components,” Infection and Immunity, vol. 65, no. 6, pp. 2454–2456, 1997.View at: Google Scholar
K. L. Davis, B. M. Davis, B. S. Greenwald et al., “Cortisol and Alzheimer's disease. I: basal studies,” American Journal of Psychiatry, vol. 143, no. 3, pp. 300–305, 1986.View at: Google Scholar
R. D. Semba, “The role of vitamin A and related retinoids in immune function,” Nutrition Reviews, vol. 56, no. 1, pp. S38–S48, 1998.View at: Google Scholar
M. Puolakkainen, A. Lee, T. Nosaka, H. Fukushi, C. C. Kuo, and L. A. Campbell, “Retinoic acid inhibits the infectivity and growth of Chlamydia pneumoniae in epithelial and endothelial cells through different receptors,” Microbial Pathogenesis, vol. 44, no. 5, pp. 410–416, 2008.View at: Publisher Site | Google Scholar
H. Sjunnesson, E. Sturegård, R. Willén, and T. Wadström, “High intake of selenium, β-carotene, and vitamins A, C, and E reduces growth of Helicobacter pylori in the guinea pig,” Comparative Medicine, vol. 51, no. 5, pp. 418–423, 2001.View at: Google Scholar
K. A. Tanghe, T. A. Garrow, and K. L. Schalinske, “Triiodothyronine treatment attenuates the induction of hepatic glycine N-methyltransferase by retinoic acid and elevates plasma homocysteine concentrations in rats,” Journal of Nutrition, vol. 134, no. 11, pp. 2913–2918, 2004.View at: Google Scholar
D. K. Smith, J. M. Greene, S. B. Leonard, T. T. Kuske, D. S. Feldman, and E. B. Feldman, “Vitamin A in hypercholesterolemia,” American Journal of the Medical Sciences, vol. 304, no. 1, pp. 20–24, 1992.View at: Google Scholar
T. Kawamata, I. Tooyama, T. Yamada, D. G. Walker, and P. L. McGeer, “Lactotransferrin immunocytochemistry in Alzheimer and normal human brain,” American Journal of Pathology, vol. 142, no. 5, pp. 1574–1585, 1993.View at: Google Scholar
J. H. Sohn, J. O. So, H. J. Hong et al., “Identification of autoantibody against beta-amyloid peptide in the serum of elderly,” Frontiers in Bioscience, vol. 14, pp. 3879–3883, 2009.View at: Google Scholar
J. Miklossy, K. Khalili, L. Gern et al., “Borrelia burgdorferi persists in the brain in chronic lyme neuroborreliosis and may be associated with Alzheimer disease,” Journal of Alzheimer's Disease, vol. 6, no. 6, pp. 639–649, 2004.View at: Google Scholar
W. R. Lin, M. A. Wozniak, R. J. Cooper, G. K. Wilcock, and R. F. Itzhaki, “Herpesviruses in brain and Alzheimer's disease,” Journal of Pathology, vol. 197, pp. 395–402, 2002.View at: Google Scholar
B. F. Roy, T. Sunderland, D. L. Murphy, and J. M. Morihisa, “Antibody for nerve growth factor detected in patients with Alzheimer's disease,” Annals of the New York Academy of Sciences, vol. 540, pp. 398–400, 1988.View at: Google Scholar
P. Foley, H. F. Bradford, M. Docherty et al., “Evidence for the presence of antibodies to cholinergic neurons in the serum of patients with Alzheimer's disease,” Journal of Neurology, vol. 235, no. 8, pp. 466–471, 1988.View at: Google Scholar
J. M. Serot, M. C. Bene, B. Gobert, D. Christmann, B. Leheup, and G. C. Faure, “Antibodies to choroid plexus in senile dementia of Alzheimer's disease,” Journal of Clinical Pathology, vol. 45, no. 9, pp. 781–783, 1992.View at: Google Scholar
B. S. Kingsley, F. Gaskin, and S. M. Fu, “Human antibodies to neurofibrillary tangles and astrocytes in Alzheimer's disease,” Journal of Neuroimmunology, vol. 19, no. 1-2, pp. 89–99, 1988.View at: Google Scholar
R. Jonsson, B. Nakken, A. K. Halse, K. Skarstein, K. Brokstad, and H. J. Haga, “Heredity and immunology in Sjogren's syndrome,” Tidsskr Nor Lægeforen, vol. 120, no. 7, pp. 811–814, 2000.View at: Google Scholar
D. Phillips, L. Prentice, M. Upadhyaya et al., “Autosomal dominant inheritance of autoantibodies to thyroid peroxidase and thyroglobulin—studies in families not selected for autoimmune thyroid disease,” Journal of Clinical Endocrinology and Metabolism, vol. 72, no. 5, pp. 973–975, 1991.View at: Google Scholar
D. L. Mallery, W. A. McEwan, S. R. Bidgood, G. J. Towers, C. M. Johnson, and L. C. James, “Antibodies mediate intracellular immunity through tripartite motif-containing 21 (TRIM21),” in Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 46, pp. 19985–19990, November 2010.View at: Publisher Site | Google Scholar
W. B. Grant, “Dietary links to Alzheimer's disease: 1999 Update,” Journal of Alzheimer's Disease, vol. 1, no. 4-5, pp. 197–201, 1999.View at: Google Scholar
L. B. Lopez, D. Kritz-Silverstein, and E. Barrett-Connor, “High dietary and plasma levels of the omega-3 fatty acid docosahexaenoic acid are associated with decreased dementia risk: the Rancho Bernardo study,” Journal of Nutrition, Health and Aging, vol. 15, no. 1, pp. 25–31, 2011.View at: Publisher Site | Google Scholar
S. A. Frautschy and G. M. Cole, “What was lost in translation in the DHA trial is whom you should intend to treat,” Alzheimer's Research & Therapy, vol. 3, article 2, 2011.View at: Google Scholar