Metals That Might Make You Mental

I've said it once. I've said it a million times. They haven't found a cure for Alzheimer's Disease because they don't know what causes Alzheimer's Disease. They don't know the cause of AD because there is no cause, per say. There are genes that make you more prone to the disease (such as ApoE), but there is no AD gene. There is no vitamin deficiency, toxicity, gene or one thing that causes AD. Instead, it appears that AD is a multifactorial disease that is caused by a different mix of things in each individual person. The only true cause that continues to have overwhelming evidence confirming it's role in causation of AD is inflammation... But that's where the multifactorial thing comes in. Weather it be a bad diet, head injury, drugs, infections, thoughts, toxins or autoimmunity, many things cause inflammation. Therefore, many things can contribute to one developing Alzheimer's Disease. The Alzhimer's Disease brain is a brain on fire, and research continually shows us that the fire starts many, many years before we see the smoke. There is no magic bullet to prevent Alzheimer's Disease; you just have to live a healthy life.

Everybody has heard of heavy metals. The bad guys of the periodic table, heavy metals such as mercury and lead have been associated with a wide range of diseases and disorders. But what about other metals? What about the metals we thought all along were good for us? In comes Iron (Fe) and Copper (Cu), two transition metals that may be new culprits in the AD puzzle and inflammation in general. But everybody knows we need iron to make hemoglobin, so having too much couldn't possibly be a bad thing, right? Wrong. The type of Iron or Copper dictates how it functions in the body, and having too much of the "bad" kind can wreak all sorts of havoc on the body.

Transition metals are unique because they exhibit two or more oxidant states (for example, Fe+2 and Fe+3). This is what makes able to participate in chemical reactions and makes them particularly useful in day to day bodily functions. This characteristic also makes them remarkably able to bind with stuff we don't want them to bind to and create free radicals. Free radicals like the hydroxyl ion are then able to scamper about the body binding to molecules and altering their function... This is the hallmark of inflammation- free radical damage that alters the body's normal molecules, and subsequently alters the function of those molecules.

For simplicity's sake, there are two basic types of metals: free metals (inorganic) and metals that are bound to other stuff (organic). Weather or not these metal ions are bound to a molecule (such as a protein) will affect how they are absorbed and processed by the body. Organic Copper and Iron compounds are absorbed a little slower by the intestinal tract, but more importantly they are processed differently than their inorganic brethren. Food Copper (and Iron) must go through additional processing in the liver before it is allowed into systemic circulation (the blood stream). Typically the body keeps most of it's Copper bound to proteins and keeps the more unstable, inflammatory free Copper to a minimum (5-15% total Cu in the blood). When inorganic Copper is absorbed it immediately contributes to the free Copper pool in the blood steam, bypassing the liver and increasing the risk of inorganic Copper induced oxidative stress [1]. Similar is true of Iron's story.

The proposed mechanisms of how inorganic Copper and Iron contribute to the inflammation in AD are numerous, but here are a few.

Copper has been shown to bind with homocysteine (an inflammatory molecule that is related to one's intake of B vitamins) and increase the oxidation of LDL- the so-called "bad" cholesterol [1, 2]. Cu, unlike Zinc, Nickel, Aluminum, or Cadmium, has been shown to compromise the stability of Ubiquitin. The Ubiquitin-Proteasome System (UPS.. haha) is the main pathway by which we eliminate misfolded proteins from our cells such as the notorious Beta Amyloid of Alzheimer's Disease and the Lewy bodies that are seen in Parkinson's Disease [5]. This may result in decreased clearance of these proteins in the brain, eventually leading to a build-up, cellular toxicity and death. Even the so-called AD gene may be related to Cu metabolism! The three different ApoE Alleles differ in the number of cysteine binding sites they posses- the part of the molecule that is able to bind to Copper. ApoE 2 has two binding sites, ApoE3 has one and ApoE 4 has none. This correlates with the risk of AD associated with each of those alleles (2 is protective against AD, 3 is neutral and 4 increases your risk). It has now been postulated that the risk associated with the ApoE alleles is due to ApoE 4's inability to bind and remove Copper from the brain [2].

Like Copper, Iron is necissary for human life, but an excess of inorganic Iron may be one of the inflammatory triggers in the AD cascade. Several studies have shown that Fe accumulates in Beta Amyloid plaques [3]. Not only that, but the presence of Iron during plaque formation not only increases the synthesis of Beta Amyloid by it's interaction with PACE, but it has been shown to favor the more toxic form of the plaques [4].

As in all things in life, your current inflammatory status will play a role in how you handle further stressors. Inflammation disrupts the blood brain barrier (BBB) and alters it's ability to regulate the transport of Fe to and from the brain [4]. HAMP, the gene that is responsible for the production of Hepcidin (THE Iron homeostasis hormone in our bodies) is directly influenced by inflammatory cytokines such as IL-1B and IL-6 [4]. Similarly, the mechanism I mentioned above of how Copper binds to homocysteine to produce inflammation would probably not be that big of a deal if you didn't have high homocysteine levels in the first place!

So what can we do to avoid the damage caused by inorganic Copper and Iron?

1. Decrease your inflammatory burden. I've said it once. I've said it a thousand times. This is highly individual, since no two of us have the same health problems. Weather it be being overweight, not exercising, a crappy diet, diabetes, gastrointestinal issues, an autoimmune disease, or whathaveyou, get healthier. If you're not inflamed it appears that these pesky metals won't hurt you as much.

2. Avoid inorganic Copper and Iron. Brewer et al [1] and several others have identified the two major sources of inorganic Copper and Iron as being Copper in our drinking water from Copper pluming and multivitamins (like Centrum). Interestingly, Brewer et al [2] points out in his paper that all of the industrialized countries are dealing with increased rates of AD- Except Japan. This is noteworthy, because Japan is the only industrialized country that does not use Copper pluming. In contrast, about 85% of US homes have Copper pluming [2]. Here's what you can do to minimize the amount of Copper that leaches into your water and avoid inorganic Copper and Iron:
     A. Filter your water. Brita.com does state that their filters filter Copper, but I can not say to what extent. Reverse osmosis is the best at
     filtering things like Cu and Fe, but is more expensive.
     B. Do not get hot water from the tap- Hot water will leach more Cu from the pipes than cold water- Warm the water after it comes out of the
     faucet.
     C. Check the acidity of your water. The more acidic your water, the more it will etch the Copper pipes.
     D. Avoid multivitamins like Centrum. They look like a big ol' piece of metal that they painted red anyway, so who are we fooling when we
     take those? There is no substitute for the vitamins and minerals you get from a healthy diet. Period.

 3. Zinc has been shown to lower levels of free Copper in the blood [2], so making sure you have adequate Zinc levels may be a good idea if you think you're at risk of ingesting too much Copper (perhaps people who have really acidic water at home and can not afford to install a reverse osmosis system).

Healthfully yours,

Nikki

References:
[1] Brewer, G. Risks of Copper and Iron Toxicity during Aging in Humans. Chem Res Toxicol 2010, 23, 319-326 (PMID 19968254)
[2] Brewer, G. Copper Toxicity in Alzheimer's Disease: Cognitive Loss from Ingestion of Inorganic Copper. J of trace elements in medicine and biology 26 (2012) 89-92. (PMID 22673823)
[3] Batista-Nascimento, L. et al. Iron and Neurodegeneration: From Cellular Homeostasis to Disease. Oxidative Medicine and Cellular Longevity, May 2012 (PMID 22701145)
[4] Mesquita, S. et al. Modulation of Iron Metabolism in Aging in Alzheimer's Disease: Relevance of the Choroid Plexus. Frontiers in Cellular Neurosci. May 2012 (PMID 22661928)
[5] Arnesano, F. et al. Copper-Triggered Addregation of Ubiquitin. PLoS ONE 2009 Sept 16; 4(9) e7052 (PMID 19756145)

Alzheimer's Disease: An Ounce of Prevention

Ben Franklin said it best when he said "an ounce of prevention is worth a pound of cure". This is especially true of Alzheimer's Disease (AD). There is overwhelming evidence that the neurofibrillary tangles and beta-amyloid plaques (AB) seen in AD are not a cause, but an effect of the disease process. Similarly, there is evidence that AB deposits themselves are not a signature of neurotoxicity, per se, but of oxidative imbalance and an oxidative stress response in the brain (1).

The reason we haven't been able to find a cause for AD is because there is no cause... Or rather, there is no one cause. AD is a multifactorial disease, each case having it's own causative factors and unique set of symptoms and story. The real kicker is that inflammatory diseases like AD actually cause changes in gene expression and protein function and further perpetuate the inflammatory state. In other words, the inflammation seen in AD can be induced by numerous things by our environment and then maintaned by the body without any further insult, creating a vicious cycle.

So, my friends, the time to act is now. Not tomorrow. Not next week. Right now.
I have already written about ways to reduce your inflammatory burden (ex: losing weight). Let's talk about what we can do to try to shut off the vicious cycle and get rid of the inflammation we already have.. Of course, all of these supplements would be great for someone who already has AD, but they will be the most effective and protective in people who are not yet afflicted with the full-blown disease.

Inflammation is mediated by many receptors, proteins and enzymes. One example of such a receptor is RAGE, the receptor for advanced glycation end-products. The most well known AGE today is HbA1C, the marker for glycosylated hemoglobin used to track blood sugar in diabetic patients. HbA1C is a marker of inflammatory stress and high AGEs, and therefore the higher your HbA1C, the more critical it is that you get that blood sugar under control. RAGE has been implicated to play an important role in AD.

Interestingly, all of these pathways eventually feed back into one major loop that is mediated by the Nuclear Factor Kappa Beta (NF-KB). For example, RAGE triggering leads to activation of NF-KB and it's pro-inflammatory signals, which in turn stimulates RAGE and leads to a vicious cycle of inflammation (2). The major inhibitor of NF-KB is NRF-2, known as the keeper of redox homeostasis. Therefore, effective methods to get the core of inflammation would and should include foods and supplements that 1. stimulate NRF2 2. Inhibit NF-KB and 3. Boost antioxidants such as glutathione.

Curcumin, a component of the yellow curry spice tumeric, is a hot topic these days- and it's no wonder why. Not only is curcumin a NF-KB inhibitor, but it has several neuroprotective effects that make it uniquely suited for the prevention of AD. Among it's many antioxidant and protective effects, curcumin has been shown to bind AB and increase it's uptake by white blood cells (3), making it an enticing treatment for AD. Curcumin has been shown to be a potent free radical scavenger- more so than vitamin E. Curcumin has been shown to chelate metals such as Iron and Copper, excess of both of which have been implicated in the pathogenesis of AD (4). Unfortunately, curcumin has relatively low bioavailability on it's own. There are quality products available today that are readily absorbed (I personally like the one from Apex Energetics), but these products need to be ordered by a physician. Many functional medicine doctors are familiar with this company and can help you determine if this product is for you (it is). : )

Resvertrol, a flavanoid in red wine, has been shown to have many effects similar to curcumin. Resvertrol is a potent inhibitor of the NF-KB pathway, and it has been shown to increase the clearance of AB (4). It also protects DNA, decreases cell death, and decreases inflammation. Resvertrol is also not very bioavailable on it's own, but like curcumin, there are products available today that are better absorbed by the body.

Omega-3 fatty acids (fish oils) are another hot topic in nutrition these days. Generally, omega-3s are known to decrease inflammation, but one particular omega-3, DHA, has been shown to be especially neuroprotective. DHA has been shown to stimulate transthyretin, a protein possibly involved in the clearance of AB (4).

EGCG, the major component of green tea flavanoids, is another great source of antioxidants that may show particular benefit in AD. EGCG has been shown to chelate iron and copper, function as an antioxidant, and elevate and up-regulate enzymes that produce other antioxidants such as superoxide dimutase and catalase (4). Green tea is a great, easy way to get antioxidants into your daily routine. To get the most out of your green tea (and make it taste WAY better), check out this website for green tea brewing tips: http://www.thefragrantleaf.com/brewingtips.html

Glutathione is the body's most important antioxidant- particularly in the brain. Glutathione is also critically important in detoxification in the liver, so anyone who has or is taking a lot of drugs (medications or illegal) or alcohol should consider boosting their stores. While the body does make it's own glutathione, taking precursors such as N-Acetyl Cysteine can help give you a boost in times of stress. Quite frankly, in the world we live in now I think we are literally surrounded by stressors and should be taking some of this every day. Naturopathic doctors (NDs) may offer IV glutathione in their practices, which is a great way to get a boost of this important antioxidant (as long as you're not afraid of needles, that is)..

There are many, many supplements that are being studied for their benefits in AD... Honestly, this is just the tip of the iceberg! Of course, I know nobody wants to take a zillion pills a day, weather they be medications or supplements, so this list is the ones I deem the most important and effective at this time.

May your oxidants be neutralized, followers!

Nikki

Resources:
(1) Siddharatha Mondragon-Rodrigues et al "Causes versus effects: the increasing complexities of Alzheimer's disease pathogenesis" Expert Rev Neurother 2010 May; 10(5): 683-691 (PMID: 20420489)
(2) Lorena Perrone "The complexity of sporadic Alzheimer's Disease pathogenesis: the role of RAGE as a therapeutic target to promote neuroprotection by inhibiting neurovascular dysfunction" Int J of Alzheimer's D March 11, 2011 (PMID: 22482078)
(3) Dumont Magali "Mitochondria and antioxidant targeted therapeutic strategies for Alzheimer's Disease" J Alz Dis 2010; 20(2) (PMID: 20421689)
(4) Ramesh Balenahalli et al "Neuronutrition and Alzheimer's Disease" J Alz Dis Jan 2010; 19(4): 1123-1139 (PMID: 20308778)

Special note: I have started including citations with a PubMed ID number, PMID. Now all you have to do to read my references (or at least the abstracts), is go to pubmed.gov and type the PMID number in the search field!

Alzheimer's Disease: Current Medical Treatment

As we have discussed before, the best way to fix Alzheimer's Disease (AD) is to not get it in the first place. There is no cure for Alzheimer's Disease, but two classes of drugs have been approved by the FDA to treat the cognitive decline seen in AD. However, as I am about to show you, their effectiveness is questionable.

There are two types of drugs that are FDA approved to treat AD, cholinesterase inhibitors and namenda (1). Lets examine them both.

Cholinesterase inhibitors act by slowing down the re-uptake of a neurotransmitter (acetylcholine) by nerve cells, allowing it act on the neuron for a longer period of time. in 2005 a meta-analysis was done on 22 clinical trials of cholinesterase inhibitors to investigate the effectiveness of this class of drugs in AD patients. The conclusion of the study was:
"CONCLUSION: Because of flawed methods and small clinical benefits, the scientific basis for recommendations of cholinesterase inhibitors for the treatment of Alzheimer's disease is questionable." (2)
The authors go on to state that doctors often argue that CI's are beneficial in approximately 10-20% of patients with AD, and that since this sub-group can not be identified before treatment that every patient with AD should be treated. The authors make a good point and argue that perhaps further research should be conducted to help identify that sub-group, rather than medicate every AD patient with drugs that (like all drugs) can cause dangerous side-effects. I think they make an excellent point- why do those 10-20% of people respond to this class of drugs, and how can we identify them in advance? This would cut the cost of AD medications by- oh wait, that's why there's no pharmaceutical sponsored research on this. We wouldn't want to cut down on drug costs, now would we?

Namenda is a class of drugs that are NMDA-receptor antagonists. In 2011 a meta-analysis was conducted that evaluated three clinical trials on Memantine (Namenda) in over 1,000 patients with mild to moderate AD. Their conclusion was similarly unimpressive:

"CONCLUSIONS: Despite its frequent off-label use, evidence is lacking for a benefit of memantine in mild AD, and there is meager evidence for its efficacy in moderate AD. Prospective trials are needed to further assess the potential for efficacy of memantine either alone or added to cholinesterase inhibitors in mild and moderate AD." (3)

Would you want to take your chances with this kind of results? Let's prevent cognitive decline before it sets in, rather than rely on questionably effective pharmaceuticals. Once again I make the arguement you can't unscramble a scrambled egg.

Until next time, gang.

Nikki

References
(1) http://www.alz.org/alzheimers_disease_standard_prescriptions.asp
(2) Kaduszkiewicz H "Cholinesterase inhibitors for patients with Alzheimer's disease: systematic review of randomised clinical trials." BMJ. 2005 Aug 6;331(7512):321-7.
(3)  Schneider LS "Lack of evidence for the efficacy of memantine in mild Alzheimer disease"

Arch Neurol. 2011 Aug;68(8):991-8. Epub 2011 Apr 11.

Prevent Alzheimer's Disease, Remove the Source of Inflammation

 As we discussed in the previous post, research is pointing more and more toward Alzheimer's Disease (AD) being a disease of inflammation (aka oxidative stress) and mitochondrial dysfunction. We also discussed previously that while there is no cure for AD, there is much that can be done to prevent or delay its onset. Inflammation is present in the AD brain long before symptoms show up- and by the time a person becomes symptomatic it is generally too late to make a big difference. Think of it this way- you can't unscramble a scrambled egg.

Combating inflammation is a two step process: you need to REMOVE the source of inflammation as well as beef-up your ability to combat inflammation. You can take all the omega-3s in the sea, but if your diet and lifestyle are otherwise unhealthy it's not going to do a lick of good.

Step 1: Removing the source of inflammation

A. Obesity, particularly central obesity, has been linked with decreased volume in the hippocampus, the part of the brain that is primarily affected by AD, as well as cognitive impairment (1). The authors of this particular study make note that adipose tissue (fat) actually produces inflammatory molecules called cytokines, meaning that obesity in and of itself is an inflammatory process in and of itself. There has been research into the gastric bypass playing a role in AD prevention (as well as diabetes), but ideally it shouldn't come down to that. I will write posts about weight loss and bariatric surgery in the future, but the thing to know from this post is that obesity is a risk factor for AD. Similarly influcenced factors such as hypertension and abnormal lipid profiles also have been shown to increase your risk for AD.

B. Diabetes and insulin resistance is undoubtedly a risk factor for AD, however in recent years the link has been shown to be so strong that they are starting to call AD "type 3 diabetes" (2). Handling type 1 diabetes comes down to managing and calming down the immune system as we discussed before. Type 2 diabetes can be REVERSED by eating a healthy, low sugar, anti-inflammatory diet and physical exercise. Particularly in the case of type 2 diabetes, doctors will frequently check a blood marker called "HbA1C", or glycosylated hemoglobin. Basically, when this marker is high it indicates that the persons glucose level was so high, that the body started trying to do something with the sugar- so it bound a protein to it. HbA1C is not only a marker for how high your blood sugar has been recently, but more importantly it is a marker of inflammation. Not surprisingly, studies have shown that the higher your HbA1C is, the more you lose brain volume (particularly in the hippocampus) as you age (3).

C. Traumatic brain injury (TBI) such as concussion ignite a mean inflammatory cascade in the brain, as well as the gut (more on that later). Interestingly, research on former NFL players have been shown to be more prone to AD and mild cognitive impairment (MCI) compared to age-matched controls (4). The most important window of opportunity for trying to mitigate the inflammation associated with TBI is the first few months after the injury. During that time I recommend patients to eat a super anti-inflammatory diet which includes avoiding dietary antigens such as gluten and dairy (more on why later), take anti-oxidant supplements such as N-Acetyl Cysteine and DHA (an omega-3), and try to get enough physical exercise to increase blood flow to the brain. That last bit of information is in direct conflict to what most doctors would recommend, but there has been some interesting research that shows that concussion patients who exercise within their symptomatic tolerance (aka exercise that does not provoke symptoms) actually heal faster (5). Also interestingly enough, there has been research that shows that mice who were fed a diet high in omega-3 fatty acids ("fish oils") for several weeks prior to TBI were actually protected from the harmful, inflammatory effects seen in TBI (6). Once again we see that an ounce of prevention goes a long way!

D. Stress is no joke, folks. Stress has been shown to disrupt the hypothalamus-pituitary-adrenal axis (HPA axis) and put stress on the brain. This is particularly true of the hippocampus- the part of the brain that is generally most involved in AD (1). Things such as meditation and relaxation techniques, new hobbies, physical activity, quality relationships (friends, family), certain "adaptogen" supplements, and pets can all help you deal with stress- don't let stress age you prematurely.

E. Lack of physical exercise is not only related to obesity, heart disease, hypertension and diabetes, but it is an independent risk factor for AD in and of itself. Weather your goal is to lose weight or to just stay healthy and age gracefully, everybody should strive to get at least 30-60 minutes of physical activity a day. My biggest advice is to find an activity that you truly enjoy- if you have to drag yourself to the gym and force the work out it's not going to do much for your stress level and HPA axis.

F. Other hidden sources of inflammation include autoimmune diseases, infections, leaky gut, and food sensetivities. Remember, it has been estimated that 23 million Americans or 8+% of the population have an autoimmune disease (see previous post), so this is no joke.

Stay tuned for Part 2: Supplements!

Nikki

References!
(1) Jagust W et al "Central Obesity and the Aging Brain" Archives of Neurology Oct 2005; vol 62
(2) http://www.time.com/time/health/article/0,8599,1673236,00.html

(3) Enzinger, C er al "Risk factors for progression of brain atrophy in aging: six-year follow-up of normal subjects" Neurology 64: 1704-11; May 24, 2005

(4) http://healthland.time.com/2011/07/18/nfl-players-may-be-more-vulnerable-to-alzheimers-disease/

(5) Leddy J et al "Regulatory and autoregulatory physiological dysfunction as a primary characteristic of post concussion syndrome: Implications for treatment" Neurorehabilitation 22 (2007) 199-205
(6) Reference to come- The article is back home on my desk!

What causes Alzheimer's Disease?

Alzheimer's Disease (AD) is the most common form of dementia in the US, affecting approximately 5.4 million Americans. One in eight people over the age of 65 have AD, or nearly half (45%) of people over 85 years old (1). As the baby-boomers move ever-closer toward their golden years, these numbers are expected to increase drastically in the years to come. Health care costs for AD are expected to soar from an estimated 200 Billion in 2012 to 1.1 Trillion dollars annually by 2050 (1). As a country on the brink of bankruptcy largely due to our staggeringly high health care costs, this is a road we simply can not afford to go down. 

If you asked people off the street what disease they feared most, I'm sure many people would say Alzheimer's. The thought of losing our marbles some day, losing your memories and your personality that makes you you, is literally terrifying. But we're not going to get anywhere by crossing our fingers and hoping we don't get it. So let's talk about Alzheimer's Disease and, more importantly, what we can do to protect ourselves from getting it.

So what causes Alzheimer's Disease? Most people will tell you that it's the Beta-amyloid plaques and neurofibrillary tangles that are the causative agent behind AD. While these are indeed part of the AD pathogenesis, they are a most likely a result of the disease process, not a cause. As such, our question can be rephrased to ask "why would our brain lay down beta-amyloid plaques and neurofibrillary tangles?" The short answer is that there is no official answer yet, but there is a large body of research pointing toward one mechanism: Inflammation.

Everybody utters the phrase "I'm getting too old for this" at some point in their life. But while we all talk about the act of getting old, nobody ever talks about what happens to the body as we age. Aging is generally accompanied by an increase in oxidative stress (aka inflammation), which is most likely due to waning antioxidant defenses (2). Unfortunately, the part of the cell that is most vulnerable to oxidative stress is the mitochondria- the organelle in charge of making the cell's ATP (energy source). Mitochondrial dysfunction and damage has been implicated to play an important, possibly causative role in AD pathology (3). Without an adequate source of fuel, the cell can not repair itself and maintain function, and eventually will die. It is now believed that beta-amyloid (BA) plaque is actually an anti-oxidant, and my in fact be the cell's last futile attempt to quench the inflammation that is killing it from the inside-out (4). There has also been evidence to show that BA is an anti-microbial peptide, and may be a by-product of immune activation in the brain (5).

Before you know it you have a vicious cycle of inflammation that eventually takes out enough neurons that you experience symptoms. Only after symptoms appear will your doctor be able to make the diagnosis of AD, Parkinson's, ALS, etc... However, by this point there is often so much damage to the involved structures that it's too late to make any substantial changes. That's not to say that these patients can't benefit from the treatments I am sharing with you, but they are not a cure. With few exceptions, neurons do not regenerate. More importantly, the rate at which you are losing neurons every day far out-paces your brain's ability to make new neurons. Therefore, it is MUCH easier and FAR more effective to prevent diseases of this nature, rather than trying to fix it once the disease has set in.

Stay tuned for Part 2: Prevention soon!

Nikki

References:

(1) http://www.alz.org/downloads/facts_figures_2012.pdf

(2)  Galasko, Douglas. Biomarkers of oxidative damage and inflammation in Alzheimer’s disease. Biomark med. 2010 February: 4 (1): 27-36

(3) Bonda, David. Mitochondrial dynamics in Alzheimer’s disease opportunities for future treatment strategies. Drugs aging 2010 March 1; 27 (3): 181-192.

(4) Mondragon-Rodriguez, Siddhartha. Causes versus effects: the increasing complexities of Alzheimer’s disease pathogenesis. Expert rev neurother 2010 May: 10 (5): 683-691

(5) Soscia, Stephanie. The Alzheimer’s disease-associated amyloid B-protein is an antimicrobial peptide. 2010; PLoS ONE 5(3): e9505