Alzheimer’s Disease: Neurodegeneration the Path to Prevention – Part 4

Alzheimer'sWelcome back to my series on neurodegeneration.  In this series so far, I have provided an introduction to the general idea of neurodegeneration, as well as in depth information on  Frontotemporal Lobar Degeneration and Type 2 Diabetes related neurodegeneration.  Today, I will be focusing on a more well known type of neurodegenerative condition, Alzheimer’s Disease.

What is Alzheimer’s Disease

As it is with Frontotemporal Lobar Degeneration, Alzheimer’s disease is a fatal, progressive, and degenerative disease in which brain cells are destroyed.  Once again, just like many other neurodegenerative conditions, the exact cause and mechanisms of cell death and disease progression are not fully known.  Alzheimer’s is commonly quoted as the most common cause of dementia, and the number of people with Alzheimer’s is only expected to rise significantly over the next decade or so.

The brains of individuals with Alzheimer’s show abnormal tissue changes, or neuropathology, in the form of significant brain atrophy (shrinkage), along with the presence of Beta-amyloid plaques and Tau neurofibril tangles.  Recall my description of the neuropathology of Frontotemporal Lobar Degeneration, the case here is much the same as misfolded or formed proteins basically get stuck inside (in the form of Tau) and outside (in the form of Beta-amyloid) the neuron cells.  It is understood that the formation of these tangles and plaques is not a normal process; however, the controversial part is whether the formation of these tangles and proteins cause the disease, or whether they are simply a byproduct of another underlying cause.  Funny enough, just to make it more confusing, there is no fully accepted consensus on what the actual underlying cause of Alzheimer’s Disease is.

From a genetic perspective, Alzheimer’s Disease has a strong familial link (1); however, the contribution of autosomal dominant forms of the condition are very low; somewhere in the neighbourhood of less than 5% of the total Alzheimer’s population (2, 3).  There are however other identified genetic risk factors related to Alzheimer’s (1, 3); just keep in mind that there is a big difference between autosomal dominance and genetic risk.  Notably, this difference lies in the likelihood that an individual with the genetic risk factor or autosomal dominant inheritance will actually contract the disease (this is called disease penetrance).  Basically, an autosomal dominant genetic inheritance has a much greater penetrance than a genetic risk factor.  Please refer to my article on Frontotemporal Lobar Degeneration for a more indepth explanation of this.  Therefore, with only such a small percentage of Alzheimer’s cases being autosomal dominant, there are clearly more risk factors to consider other than simple genetics, like our environment and lifestyle for instance.

Now that you have a solid understanding of what Alzheimer’s Disease is (classifications, histopathology, and basic genetics), let’s look now to the specifics of what is suggested as causative factors of the condition.

Alzheimer’s Disease – Metabolic Derangement

A connection between metabolic derangement and Alzheimer’s disease is nothing new.  For instance, there is plenty of evidence linking Diabetes with Alzheimer’s and Alzheimer’s like dementia (4).  You may have also heard Alzheimer’s Disease being referred to as Type 3 Diabetes in the media a few times over the past decade.  Convincing evidence supporting this hypothesis is growing and there is even suggestive mechanisms for how impaired glucose metabolism and insulin signalling in the brain can lead to the multiple other suggested causes of Alzheimer’s, some of which I will also discuss below (i.e. Tau and Beta-Amyloid pathology, oxidative damage, inflammation, mitochondrial dysfunction, etc.).

Studies show that the glucose utilization in the brains of Alzheimer’s patients is reduced (4, 5); and thus, energy production is also reduced.  Reduced glucose metabolism (hypometabolism) has even been found to be present well prior to the onset of Alzheimer’s symptoms (4, 5, 6), providing indication that it may in fact be the underlying, or part of the underlying, cause of the condition.  Brain glucose hypometabolism in Alzheimer’s patients is linked to abnormalities in insulin and insulin like growth factors (IGF) levels and expression in the brain.  Recall from my post on Type 2 Diabetes Related Dementia that insulin isn’t simply a hormone signalling glucose storage, it also has important functions in the brain (7). Specific to Alzheimer’s Disease, alterations in insulin and IGF are tied to the following proposed causative mechanisms of Alzheimer’s:

  • The production of Tau tangles and Beta-Amyloid plaques via altered gene expression (5, 6).  I guess it’s important here to note that for Beta-Amyloid formation, there is evidence indicating that Beta-Amyloid plaque formation leads to impaired insulin signalling as well as evidence that impaired insulin signalling leads to Beta-Amyloid Plaque formation.  So once again there is no definite answer on what comes first, but still some good progress.

  • Increased oxidative stress (5, 6).

  • Mitochondrial dysfunction (5, 6). See below for more on this.

  • Pro-inflammatory cytokine activation (i.e over activated immune system in the brain) (5, 6).

Ultimately, all the above mechanisms lead to the death and dysfunction of neurons and the associated symptoms of Alzheimer’s.  Also, as the symptoms progress, so do the levels of brain insulin and IGF abnormalities.

Alzheimer’s Disease – Mitochondrial Dysfunction and Oxidative Stress

As mentioned above, mitochondrial dysfunction has also been tagged as a causative factor in Alzheimer’s disease (6, 8).  Mitochondria are found inside each cell in our body, and are classified as one of many different types of organelle contained in each of our cells.  You can think of organelles within a single cell as similar to organs found in your body, each organelle has a specific function within every individual cell.  Mitochondria themselves play a very important role.  You may have heard of them being referred to as the powerhouse or powerplant of the cell, and this is because they produce the energy (ATP) that our cells need to keep us alive.  Interestingly, because of their energy producing function, they are one of the major producers of Reactive Oxygen Species (ROS) in our body (8).  Basically, while the production of ROS is normal, ROS can ultimately lead to oxidative stress.  Our bodies can normally deal with ROS via our antioxidant system; however, when something isn’t functioning right, bad things happen.  Strangely enough, mitochondria appear to be very sensitive to oxidative damage even though they are a major producer of ROS (8).

So, on the mitochondrial dysfunction front, the argument is that any type of alteration in the regular function of the mitochondria will lead to increases in the production of ROS leading to a level of oxidative stress that our cells just can’t cope with.  There are multiple proposed mechanisms of how mitochondrial dysfunction can happen, including but not limited to: mitochondrial gene mutation (8), irregular fission (splitting) and fusion (joining) of mitochondria (8), and dysregulated glucose metabolism (5, 6).  At the end of the day, what is seen in Alzheimer’s patients is a dysfunction in the mitochondrial function in the brain; as evidenced by, abnormal size and function (8), or mitochondrial gene mutation (8).  Based on the above explanation of the significant role that mitochondria play in energy production, a dysfunction in their ability is bound to have significant impacts on energy availability and the production of ROS, leading to increased oxidative stress.

Alzheimer’s Disease – Systemic Inflammation

I briefly mentioned above that an overactivated immune system is present in Alzheimer’s patient’s brains.  What this means is that the immune system is constantly primed for action in the brain, ultimately leading to a chronic inflammatory state in the brain.  However, what’s interesting is that systemic (not in the central nervous system) inflammation is now being identified as playing a factor in disease progression, and even possibly having a causative role (9, 10, 11) in Alzheimer’s.  As you may recall from my first post of this series, I discussed (with references) how systemic inflammation can influence inflammation in the brain via multiple mechanisms.  So, in a nutshell, the central nervous system isn’t shut off from the rest of the body.

Part of the evidence to support the idea that systemic inflammation crosses the blood brain barrier comes from studies on something called sickness behaviour.  What is suggested here is that systemic inflammatory cytokines cross the the blood brain barrier and activate the immune system in the brain, leading to temporary behaviour changes that ultimately aid in survival/recovery.  In the normal population the immune activation of the central nervous system caused by a systemic infection is only temporary and returns to normal after the infection is gone (9).  However; this does not appear to be the case in Alzheimer’s since the brain’s immune system seems to be in a chronic state of partial activation, and can be influenced more by systemic inflammatory signals than the general population (9).  Evidence in support of this theory comes from some known risk factors for Alzheimer’s; for instance, that fact that certain types of systemic infections can increase the risk for Alzheimer’s disease (9).  However, where I think the strongest argument for this hypothesis lies is in the fact that Alzheimer’s and dementia are definitely tied to other metabolic conditions (Type II Diabetes and Obesity) which are strongly related to systemic inflammation (10).  It is hypothesized that the level of systemic inflammation seen in these diseases could possibly be a causative factor for the development of Alzheimer’s (10).  Furthermore, the above noted metabolic conditions are also associated with Leptin resistance, and there is now evidence indicating that abnormalities in leptin levels can also contribute to inflammation in the brain and periphery (10).  Notwithstanding the above, further support of systemic inflammation as a possible causative factor for Alzheimer’s comes from a study that found markers of systemic inflammation to be elevated even in early clinical Alzheimer’s patients (11).

Alzheimer’s Disease – DNA Methylation

I partly explained epigenetics in my first post in this series when I explained that your actual DNA is not the full story, there are many other factors that affect how and when our specific genes actually express themselves.  You see, we have so many genes making up our DNA, but not every gene is active and expressing itself, it could simply be dormant until some environmental trigger comes along to initiate the expression of the gene.  For instance, think about this: how the heck can humans and chimpanzees have such similar DNA (some sources say up to 98% the same), but remain so different? Well, look no further than epigenetics, or simply the processes and environmental factors affecting the regulation in the expression of our genes. I have obviously simplified this explanation as the processes surrounding gene expression are quite complicated from a biochemical point of view, but the main idea here is that there is growing evidence for the importance of epigenetics in health and disease.

One mechanisms for gene regulation that has been receiving a good deal of attention over the past few years is something called DNA Methylation.  While this is one of those complicated biochemical processes, the long and short of it is that it is a mechanism for the regulation of genes.  This regulation can be in the form of gene expression, gene suppression, gene overexpression, or gene underexpression.  Ultimately, any problems with our body’s ability to appropriately control DNA methylation can clearly have some significant impacts.

I think you have probably guessed where I am going with this, and yes, you guessed it, DNA methylation has been shown to be altered in Alzheimre’s patients (12).  There is yet to be a consensus of how exactly it is altered as some studies have show higher levels of methylation while others have show lower levels of methylation.  Either way, DNA methylation is dysregulated.  Furthermore, in support of dysregulated DNA methylation as a causative factor of the disease, altered markers of the methylation process are present prior to the onset of Alzheimer’s symptoms (12).  Hopefully I will be able to get into more detail on this in a later post, but one of the major factors that regulate DNA methylation is diet.  This is evidenced by the fact that certain vitamin/mineral deficiencies (i.e. B vitamin, choline, betaine, methionine, and Vitamin D) and oxidative stress have been indicated as a cause of altered DNA methylation (12, 13).

Of an important note, and I wish I had come across this when researching FTLD, but by no surprise in light of the above, DNA Methylation also appears to be altered in FTLD Patients (14).

Alzheimer’s Disease – Takeaway

As it is with most neurodegenerative diseases, the final answer on what causes Alzheimer’s disease is still elusive.  However, as more information is discovered, it becomes more apparent that these conditions are heterogeneous (having more than one cause), Alzheimer’s included.  As I have noted above, specific to Alzheimer’s disease, there is evidence to support metabolic derangement, oxidative stress, mitochondrial dysfunction, systemic inflammation, and DNA methylation all as factors that could cause the disease.  While all these suggested causes likely interact in multiple ways (i.e. one causes the other to occur and vice versa), they can no doubt all be influenced by our diet and lifestyle; and, an ancestral approach to health is a great place to start.  Some helpful resources for information on ancestral approaches to eating and living are: The Perfect Health Diet, The Paleo Diet, Primal living, and Weston A Price Foundation.  Some of these may be labelled as diets, but what you will find is that they are most definitely not temporary diets, but ways of living for life.

         

As for my next post in this series I have not yet decided.  I may write about Multiple Sclerosis, or I may jump straight to a post about how ancestral living and eating can be beneficial for reducing neurodegeneration.

Sincerely,

The Barefoot Golfer

References:

1.) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3797601/

2.) http://www.ncbi.nlm.nih.gov/pubmed/23178565

3.) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3437002/

4.) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2769828/

5.) http://www.ncbi.nlm.nih.gov/pubmed/22329651

6.) http://www.sciencedirect.com/science/article/pii/S0301008213000531

7.) http://www.ncbi.nlm.nih.gov/pubmed/22411248

8.) http://www.ncbi.nlm.nih.gov/pubmed/23200807

9.) http://www.ncbi.nlm.nih.gov/pubmed/23046210

10.) http://www.ncbi.nlm.nih.gov/pubmed/22921944

11.) http://www.ncbi.nlm.nih.gov/pubmed/23380586

12.) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3851782/

13.) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3405985/

14.) http://www.ncbi.nlm.nih.gov/pubmed/24252647

 

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