Category Archives: Neurological

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Natural Compounds That Promote Anti-Aggregation And Clearance of Amyloid Beta

Alzheimer’s disease is the most prevalent neurodegenerative disease in the growing population of elderly people. A hallmark of Alzheimer’s disease is the accumulation of plaques in the brain of Alzheimer’s disease patients. The plaques predominantly consist of aggregates of amyloid-beta generated in vivo by specific, proteolytic cleavage of the amyloid precursor protein. There is a growing body of evidence that amyloid-beta aggregates are ordered oligomers and the cause rather than a product of Alzheimer’s disease.

There are a number of studies that state that the accumulation of amyloid beta within the brain arises from an imbalance of the production and clearance of amyloid beta.  Most of the time in the case of Alzheimer’s disease, amyloid beta clearance is impaired.  1

The process of creating amyloid beta in the brain has multiple roles in the brain, including:  2

  • antioxidant activity
  • calcium homeostasis
  • metal ion sequestration
  • modulation of synaptic plasticity
  • neurogenesis
  • neurotrophic activity

This controlled homeostatic regulation allows for the normal functions of amyloid beta but also prevents accumulation of excess amyloid beta as a metabolic waste product. 

An imbalance in this homeostasis results in pathological and neurotoxic accumulations of cerebral amyloid beta.  3

Scientists have developed a number of therapeutic strategies as possible interventions against amyloid beta, two of which include:

  • Anti-aggregations agents
  • Clearance of amyloid beta

Anti-aggregations agents

Anti-aggregation prevent amyloid beta fragments from aggregating or clear aggregates once they are formed.  4

Clearance of amyloid beta

Impaired clearance of amyloid beta is now widely identified as a contributing factor towards Alzheimer’s disease progression.  5   In order to prevent pathological accumulations of amyloid beta in the brain, amyloid beta clearance from the cerebral milieu into periphery and out of the system is of prime importance. Improving amyloid beta clearance from the brain across the blood–brain barrier (BBB) and into blood plasma.

Clearance of amyloid beta is so important that recent evidence in humans suggests that impaired amyloid beta clearance is the main cause of pathological accumulations of cerebral amyloid beta in late onset Alzheimer’s disease and not the overproduction of amyloid beta.  6 

The purpose of this article is to examine and identify the natural compounds that act as either anti-aggregation agents or an agents for the clearance of amyloid beta, or both.  

Researchers have identified a number of natural compounds that have been effective as therapeutics for Alzheimer’s disease whether as an anti-aggregation agent and/or an agent for clearance of amyloid beta.  7 

These natural compounds include:

  • Baicalein
  • Curcumin
  • Ellagic acid
  • (−)-Epigallocatechin-3-gallate (EGCG)
  • Ferulic acid
  • Fisetin
  • Kaempferol
  • Luteolin
  • Malvidin
  • Melatonin
  • Myricetin
  • Nordihydroguaiaretic acid (NDGA)
  • Oleuropein Aglycone (OLE)
  • Proline Rich Polypeptide (Colostrinin™)
  • Quercetin
  • Resveratrol
  • Rosmarinic acid
  • Rutin
  • Vitamin A

Natural Compounds That Promote Anti-Aggregation And Clearance of Amyloid Beta

Natural CompoundAbstractReferences
BaicaleinOur data showed that baicalein inhibited the formation of α-syn oligomers in SH-SY5Y and Hela cells, and protected SH-SY5Y cells from α-syn-oligomer-induced toxicity. We also explored the effect of baicalein on amyloid-β peptide (Aβ) aggregation and toxicity. We found that baicalein can also inhibit Aβ fibrillation and oligomerisation, disaggregate pre-formed Aβ amyloid fibrils and prevent Aβ fibril-induced toxicity in PC12 cells. Our study indicates that baicalein is a good inhibitor of amyloid protein aggregation and toxicity. 1
CurcuminWhen fed to aged Tg2576 mice with advanced amyloid accumulation, curcumin labeled plaques and reduced amyloid levels and plaque burden. Hence, curcumin directly binds small beta-amyloid species to block aggregation and fibril formation in vitro and in vivo. These data suggest that low dose curcumin effectively disaggregates Abeta as well as prevents fibril and oligomer formation, supporting the rationale for curcumin use in clinical trials preventing or treating AD.2 2a
Ellagic acidHere, we tested the effects of ellagic acid (EA), a polyphenolic compound, on Abeta42 aggregation and neurotoxicity in vitro. EA promoted Abeta fibril formation and significant oligomer loss, contrary to previous results that polyphenols inhibited Abeta aggregation. 3
(−)-Epigallocatechin-3-gallate (EGCG)Here, we show that EGCG has the ability to convert large, mature α-synuclein and amyloid-β fibrils into smaller, amorphous protein aggregates that are nontoxic to mammalian cells. Mechanistic studies revealed that the compound directly binds to β-sheet-rich aggregates and mediates the conformational change without their disassembly into monomers or small diffusible oligomers. These findings suggest that EGCG is a potent remodeling agent of mature amyloid fibrils.4
The polyphenol (-)-epigallocatechin gallate efficiently inhibits the fibrillogenesis of both alpha-synuclein and amyloid-beta by directly binding to the natively unfolded polypeptides and preventing their conversion into toxic, on-pathway aggregation intermediates. Instead of beta-sheet-rich amyloid, the formation of unstructured, nontoxic alpha-synuclein and amyloid-beta oligomers of a new type is promoted, suggesting a generic effect on aggregation pathways in neurodegenerative diseases.5
Ferulic acidFerulic acid dose-dependently inhibited fAbeta formation from amyloid beta-peptide, as well as their extension. Moreover, it destabilized preformed fAbetas. The overall activity of the molecules examined was in the order of: Cur > FA > rifampicin = tetracycline. FA could be a key molecule for the development of therapeutics for AD.6
Chronic (for 6 months from the age of 6 to 12 months) oral administration of ferulic acid at a dose of 5.3 mg/kg/day significantly enhanced the performance in novel-object recognition task, and reduced amyloid deposition and interleukin-1 beta (IL-1β) levels in the frontal cortex. These results suggest that ferulic acid at a certain dosage could be useful for prevention and treatment of AD.7
FisetinFisetin (3,3',4',7-tetrahydroxyflavone) has been found to be neuroprotective, induce neuronal differentiation, enhance memory, and inhibit the aggregation of the amyloid beta protein (Abeta) that may cause the progressive neuronal loss in Alzheimer's disease. 8
The natural flavonoid fisetin (3,3',4',7-tetrahydroxyflavone) is neurotrophic and prevents fibril formation of amyloid β protein (Aβ). It is a promising lead compound for the development of therapeutic drugs for Alzheimer's disease.  9
KaempferolKaempferol was shown to have protective effects against oxidative stress-induced cytotoxicity in PC12 cells. Administration of kaempferol also significantly reversed amyloid beta peptide (Abeta)-induced impaired performance in a Y-maze test.10
Luteolin These results indicated that luteolin from the Elsholtzia rugulosa exerted neroprotective effects through mechanisms that decrease AβPP expression, lower Aβ secretion, regulate the redox imbalance, preserve mitochondrial function, and depress the caspase family-related apoptosis.11
MalvidinWe have identified four novel polyphenols which could be efficient fibril inhibitors in Alzheimer's disease: malvidin and its glucoside and curculigosides B and D. We suggest that molecules with the particular C(6)-linkers-C(6) structure could be potent inhibitors. From the results reported for the flavan-3-ol family, their anti-amyloidogenic effects against whole peptides (1-40 and 1-42) could involve several binding sites.12
MelatoninWe report that melatonin, a hormone recently found to protect neurons against Abeta toxicity, interacts with Abeta1-40 and Abeta1-42 and inhibits the progressive formation of beta-sheets and amyloid fibrils. In sharp contrast with conventional anti-oxidants and available anti-amyloidogenic compounds, melatonin crosses the blood-brain barrier, is relatively devoid of toxicity, and constitutes a potential new therapeutic agent in Alzheimer's disease.13
Inhibition of beta-sheets and fibrils could not be accomplished in control experiments when a free radical scavenger or a melatonin analog were substituted for melatonin under otherwise identical conditions. In sharp contrast with conventional anti-oxidants and available anti-amyloidogenic compounds, melatonin crosses the blood-brain barrier, is relatively devoid of toxicity, and constitutes a potential new therapeutic agent in Alzheimer's disease.14
MyricetinMyricetin was the most potent compound myricetin to the neurotoxic oligomers rather than monomers. These findings suggest that flavonoids, especially Myricetin, exert an anti-amyloidogenic effect in vitro by preferentially and reversibly binding to the amyloid fibril structure of fAbeta, rather than to Abeta monomers.15
Nordihydroguaiaretic acid (NDGA)In cell culture experiments, fAbeta disrupted by NDGA were less toxic than intact fAbeta, as demonstrated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Although the mechanisms by which NDGA inhibits fAbeta formation from Abeta, as well as breaking down pre-formed fAbetain vitro, are still unclear, NDGA could be a key molecule for the development of therapeutics for AD.16
Oleuropein Aglycone (OLE)Here we report that oleuropein aglycon also hinders amyloid aggregation of Aβ(1-42) and its cytotoxicity, suggesting a general effect of such polyphenol. We also show that oleuropein aglycon is maximally effective when is present at the beginning of the aggregation process; furthermore, when added to preformed fibrils, it does not induce the release of toxic oligomers but, rather, neutralizes any residual toxicity possibly arising from the residual presence of traces of soluble oligomers and other toxic aggregates. The possible use of this polyphenol as anti-aggregation molecule is discussed in the light of these data.17
Proline Rich Polypeptide (Colostrinin™)Colostrinin™ is a mixture of proline-rich polypeptides (PRP) from ovine (sheep) colostrums. Colostrinin inhibits amyloid beta aggregation and facilitates disassembly of existing aggregates by disrupting beta-sheets bonding.18
QuercetinQuercetin is an effective amyloid aggregation inhibitor and inhibits amyloid beta fibrillization, but not its toxic oligomerization19
ResveratrolHere we show that resveratrol (trans-3,4',5-trihydroxystilbene), a naturally occurring polyphenol mainly found in grapes and red wine, markedly lowers the levels of secreted and intracellular amyloid-beta (Abeta) peptides produced from different cell lines. Resveratrol does not inhibit Abeta production, because it has no effect on the Abeta-producing enzymes beta- and gamma-secretases, but promotes instead intracellular degradation of Abeta via a mechanism that involves the proteasome. 20
In conjunction with the concept that Abeta oligomers are linked to Abeta toxicity, we speculate that aside from potential antioxidant activities, resveratrol may directly bind to Abeta42, interfere in Abeta42 aggregation, change the Abeta42 oligomer conformation and attenuate Abeta42 oligomeric cytotoxicity. 21
Rosmarinic acidRosmarinic acid had especially strong anti-amylid beta aggregation effects in vitro22
Rosmarinic acid reduced a number of events induced by Abeta. These include reactive oxygen species formation, lipid peroxidation, DNA fragmentation, caspase-3 activation, and tau protein hyperphosphorylation. Moreover, rosmarinic acid inhibited phosphorylated p38 mitogen-activated protein kinase but not glycogen synthase kinase 3beta activation. These data show the neuroprotective effect of sage against Abeta-induced toxicity, which could validate the traditional use of this spice in the treatment of AD. Rosmarinic acid could contribute, at least in part, for sage-induced neuroprotective effect.23
RutinHere, we show that the common dietary flavonoid, rutin, can dose-dependently inhibit Aβ42 fibrillization and attenuate Aβ42-induced cytotoxicity in SH-SY5Y neuroblastoma cells. 24
Vitamin A (beta-carotene)In this study, we used fluorescence spectroscopy with thioflavin T (ThT) and electron microscopy to examine the effects of vitamin A (retinol, retinal, and retinoic acid), beta-carotene, and vitamins B2, B6, C, and E on the formation, extension, and destabilization of beta-amyloid fibrils (fAbeta) in vitro. Among them, vitamin A and beta-carotene dose-dependently inhibited formation of fAbeta from fresh Abeta, as well as their extension. Moreover, they dose-dependently destabilized preformed fAbetas.25
Withanolides (Withania somnifera)The researchers found that using Withania somnifera extracts, comprising 75% withanolides and 20% withanosides, reversed plaque pathology and reduced the amyloid beta burden in middle-aged and old APP/PS1 mice through up-regulation of liver LRPI, leading to increased clearance of amyloid beta.26

Cover Photo:  Rosemary plant and flower

Can a Spoonful of Ceylon Cinnamon Make the Parkinson’s Go Down?

Parkinson’s disease is a degenerative disorder of the central nervous system in which dopamine generating cells in the substantia nigra die.  This then affects the motor system with regards to movement related activities, such as, shaking, rigidity, difficulty in walking and slowness in walking.

Two proteins in the brain act to protect neurons in the substantia nigra from cell death.  The first is Protein deglycase DJ-1 (DJ-1) which protects neurons against oxidative stress and cell death   The second is Parkin which helps degrade one or more proteins toxic to dopaminergic neurons.  The loss of function of the Parkin protein leads to dopaminergic cell death, which then can lead to Parkinson’s disease. Parkin and DJ-1 are known to stimulate and support the survival of existing dopaminergic neurons. It has been identified that Parkin and Protein deglycase DJ-1 decrease in the brain of Parkinson’s patients.  1

An interesting article published in the Journal of Neuroimmune Pharmacology in September 2014 entitled Cinnamon Treatment Upregulates Neuroprotective Proteins Parkin and DJ-1 and Protects Dopaminergic Neurons in a Mouse Model of Parkinson’s Disease explored a novel use of cinnamon in upregulating Parkin and DJ-1 and protecting dopaminergic neurons in a MPTP mouse model of Parkinson’s.

The authors from Rush University Medical Center’s Department of Neurological Sciences, Kalipada Pahan and Saurabh Khasnavis found that after oral feeding, ground cinnamon (Ceylon cinnamon (Cinnamonum verum)) is metabolized into sodium benzoate, which then enters into the brain, which then:  2

  • Stops the loss of Parkin and Protein deglycase DJ-1
  • Protects neurons
  • Normalizes neurotransmitter levels
  • Improves motor functions in mice with Parkinson’s

The authors also found that the oral treatment of MPTP-intoxicated mice with cinnamon powder and sodium benzoate:  3

  • Reduces the nigral expression of iNOS
  • Blocks nigral loss of Parkin and DJ-1
  • Protects the nigrostriatal axis
  • Restores locomotor activities

They suggested that cinnamon may be used to protect dopaminergic neurons in the nigra of Parkinson’s patients.

The authors of the study used True Cinnamon or Ceylon cinnamon (Cinnamonum verum) rather than using Chinese cinnamon (Cinnamomum cassia).  They stated that “Although both types of cinnamon are metabolized into sodium benzoate, by mass spectrometric analysis, we have seen that Ceylon cinnamon is much more pure than Chinese cinnamon as the latter contains coumarin, a hepatotoxic molecule.”  4

The use of Ceylon cinnamon could potentially be one of the safest approaches to halt disease progression in Parkinson’s patients.”  5

Ceylon cinnamon contains a major compound named cinnamaldehyde, which is converted into cinnamic acid by oxidation. In the liver, this cinnamic acid is β-oxidized to benzoate that exists as sodium salt (NaB) or benzoyl-CoA.   6

The authors concluded their study by stating, “Now we need to translate this finding to the clinic and test ground cinnamon in patients with PD. If these results are replicated in PD patients, it would be a remarkable advance in the treatment of this devastating neurodegenerative disease.”  7


It is important to note that if one is to consume a teaspoon or less of Ceylon cinnamon or True cinnamon (Cinnamonum verum) daily, it should be consumed in liquid or in food, and never in its dry form directly in the mouth as this could cause choking

Also make sure that you consume Ceylon cinnamon or True cinnamon (Cinnamonum verum or Cinnamomum Zeylanicum) and not Chinese cinnamon (Cinnamomum cassia or Cinnamomum Aromaticum) or Indonesian cinammon (Cinnamomum Burmanni) or Saigon cinammon (Cinnamomum Loureiroi), as these three cassia cinnamons can be hepatotoxic (damaging to the liver) in large quantities and on a frequent basis.

A common method of consuming Ceylon cinnamon or True cinnamon (Cinnamonum verum or Cinnamomum Zeylanicum) is to mix it in a smoothie with vegetables/fruit and protein powder.


Resources:

Cinnamon Vogue – CEYLON CINNAMON POWDER USDA ORGANIC

Ceylon cinnamon or True cinnamon (Cinnamonum verum)

Modulating the Genetic Factors (ApoE) of Alzheimer’s Disease With Positive Behaviors and Natural Substances

Causitive Factors of Dementia and Alzheimer’s Disease

It is generally believed that the onset of dementia and Alzheimer’s disease is the consequences of complex interactions among:  1

  • genetic factors
  • environmental factors
  • lifestyle factors

The main features of dementia and Alzheimer’s disease are the presence of:

  • extracellular amyloid beta protein plaques
  • intracellular neurofibrillary tangles of tau proteins (NFTs)
  • loss of neurons and synapses in the cerebral cortex and certain subcortical regions in the brain

Image result for amyloid beta plaques

Figure 1.  Amyloid beta protein plaques and intracellular neurofibrillary tangles of tau proteins  (Source)

Image result for loss of neurons and synapses in the cerebral cortex

Figure 2.  Loss of neurons and synapses in the cerebral cortex  (Source)

This article focuses on the genetic factors as a potential cause for the late-onset of Alzheimer’s disease and what actions can be taken to modulate these genetic factors as it related to the most important genetic factor known as apolipoprotein E (ApoE).

Genetic Factors

Studies have demonstrated that Alzheimer’s disease is related to polymorphisms of at least four (4) genes:

  • amyloid precursor protein (APP)
  • presenilin (PS-1)
  • presenilin (PS-2)
  • apolipoprotein E (ApoE)

Polymorphisms in the three genes, amyloid protein precursor (APP), presenilin (PS)-1 and PS-2, is estimated to be the cause of early-onset (which is less than 60 years of age) autosomal dominant Alzheimer’s disease, which accounts for less than 1% of Alzheimer’s disease cases.  2

There are multiple genetic, environmental and lifestyle factors involved in late-onset Alzheimer’s disease, yet impairment in amyloid-beta clearance by ApoE is a major contributor to development of the disease.

Apolipoprotein E (ApoE)

Apolipoprotein E (ApoE) is a class of apolipoprotein found in the chylomicron and Intermediate-density lipoprotein (IDLs) that is essential for the normal catabolism of triglyceride-rich lipoprotein constituents. 

ApoE is mainly produced by astrocytes, and transports cholesterol to neurons via ApoE receptors, which are members of the low density lipoprotein receptor gene family.  ApoE is the principal cholesterol carrier in the brain and encodes for a protein that transports cholesterol, fats and fat-soluble vitamins through the blood.  

ApoE also contributes to the maintenance and repair of nerve cells.

PBB Protein APOE.jpg

Figure 3.  Apolipoprotein E (ApoE)  (Source)

There are three (3) major polymorphisms or alleles in the ApoE gene:

  • ApoE-ε2  (good one)
  • ApoE-ε3  (neutral)
  • ApoE-ε4  (problematic)

Since we carry two copies of the APOE gene, one from our mother and one from our father, the combination of alleles determines our ApoE3 genotype, for which there are six possible genotypes:

  • E2/E2
  • E3/E3
  • E4/E4
  • E2/E3
  • E2/E4
  • E3/E4

The ApoE-ε2 polymorphism, the most desirable to have, is associated with lower cholesterol levels and it actually may protect against Alzheimer’s disease in some populations and may decrease the risk.  3  

The ApoE-ε3 allele has a frequency of approximately 79 percent and is considered the “neutral” Apo E genotype. This means that for 79% of the population, a genetic polymorphism of this gene does not cause dementia or heart disease.  

The E2 allele is the one that is the most efficient in clearing and removing the amyloid-beta plaques from the brain.  The second most efficient allele is the E3 version, which does an average job of removing amyloid-beta plaques.

The E4 allele is the least efficient version in removing and clearing amyloid-beta plaques from the brain.  This results in more plaques building up and creating a much greater risk of developing Alzheimer’s disease.

The best genotype to have is E2/E2.

The worst genotype to have is E4/E4.

There are certain percentages of the population that carry certain genotypes:

  • Around 55% of the population have the E3/E3 genotype, which is the most common, equating to average risk  
  • Around 25% of the population have the E3/E4 genotype
  • Around 15% of the population have the E2/E3 genotype

ApoE-ε4 Allele

ApoE-ε4 is a major genetic risk factor for late-onset Alzheimer’s disease.  

Individuals carrying the E4 allele are at an increased risk of Alzheimer’s disease.  Having one allele of ApoE4 increases the risk of Alzheimer’s disease, and if two ApoE4 alleles are present, the risk is even higher.  15

However, many individuals with the ApoE-ε4 allele never develop the disease and many patients with Alzheimer’s disease do not have the ApoE-ε4 allele.  

With an allele frequency of approximately 14%, the ApoE-ε4 polymorphism has been implicated in the following diseases:

  • atherosclerosis  4
  • Alzheimer’s disease  5
  • impaired cognitive function  6
  • reduced hippocampal volume  7 
  • HIV  8 
  • faster disease progression in multiple sclerosis  9
  • unfavorable outcome after traumatic brain injury  10 
  • ischemic cerebrovascular disease  11 
  • sleep apnea  12
  • accelerated telomere shortening  13
  • reduced neurite outgrowth  14  

Image result for Apolipoprotein E

Figure 4.  Apolipoprotein E and Alzheimer disease  (Source)

Those patients with two ε4 alleles of the APOE gene have up to 20 times the risk of developing Alzheimer’s disease.  16  The lifetime risk estimate of developing Alzheimer’s disease for individuals with one copy of the apoE4 allele (approximately 25% of the population) is approximately 30%. 17

According to the National Institute of Health, inheriting a single copy of ApoE4 from a parent increases the risk of Alzheimer’s disease by about three-fold. Inheriting two copies, one from each parent, increases the risk by about 12-fold.

ApoE generally is an anti-inflammatory and is able to break down the amyloid beta proteins that are a cause of Alzheimer’s disease.  The ApoE-ε4 allele is limited in its ability to function as an anti-inflammatory and to break down amyloid beta proteins. 18

Increasing the Production and Function of ApoE-ε4

If a person has one E4 allele or two E4 alleles (E4/E4, which is the worst and carries the highest risk for Alzheimer’s disease), then they can and should take proactive and aggressive preventive action to increase the production and function of the ApoE-ε4 allele.

You ultimately want your ApoE working effeciently to help control and remove the harmful buildup of amyloid-beta plaques.

Since the ApoE-ε4 allele does not function as efficiently as the ApoE-ε2, there are certain behaviors that can be done and substances that can be taken to increase its production and function. 

Behavioral Actions

There are certain behavioral actions that can be taken to increase to production and function of the ApoE, such as:

  • Eat a Ketogenic diet  19
  • APOE Stabilization by Exercise  20
  • Reduce elevated total cholesterol level and blood pressure 21
  • Learning and education (allowing the brain to constantly learn new and interesting in-depth subjects)  
  • 22

Natural Substances that Increase the Production and Function of ApoE-ε4

There are also natural substances that be consumed that have shown to increase the production and function of ApoE, especially in the case of a low functioning E4 single of double allele.  

These substances are listed in the Table below:

Increasing the Production and Function of ApoE-ε4

CategorySubstanceReference
Fatty Acids
DHA Ref.
Butyrate Ref.
Polyphenols
Curcumin Ref.   Ref.
Vitamins
Vitamin A (Retinol)   Ref.
Citicoline (cytidine diphosphate-choline (CDP-Choline) Ref.

Resources:

In order to see what your genotype in the ApoE gene, especially if your have the ApoE-ε4 polymorphism, you need to order a DNA and Genetic Test.  There are a number of testing companies.  The most popular are:

23andMe

Ancestry

Genos

Once you have ordered and received your DNA and Genetic Test from the testing company, you can then download your data to one of a number of websites that will analyze your genetic data and provide information on the polymorphisms of the ApoE gene and your specific genotype. 

A number of companies will analyze your genetic data and include:

SelfDecode

Livewello

Infinome

Promethease

Codegen.eu

All of the 5 companies above will receive the 23andMe genetic data.

Another way to test for your genotype and the ApoE-ε4 polymorphism can be done by ordering the following test from Life Extension:

Life Extension – ApoE Genetic Test for Alzheimer’s and Cardiac Risk

Sample Report (PDF)

Videos:

Dr. Ben Lynch – Alzheimer’s Dirty Gene APOE4

AHS16 – Steven Gundry – Dietary Management of the Apo E 4

NutritionFacts.org – The Alzheimer’s Gene: Controlling ApoE

Apo E Gene’s connection with Alzheimer’s Disease, Heart Disease and more

Do you have Apo E 4 Dementia risk, Heart Attack diet risk; Apo(e) 4 and alcohol