HORSEMAN #4: ALZHEIMER’S AND OTHER NEURODEGENERATIVE DISEASES

Well after a very long delay, one month, this week we will delve into Dr. Peter Attia’s research on Alzheimer’s and other neurodegenerative diseases.  As he notes:

“Alzheimer’s disease is perhaps the most difficult, most intractable of the Horsemen diseases.  We have a much more limited understanding of how and why it begins, and how to slow or prevent it, than we do with atherosclerosis.  Unlike with cancer, we currently have no way to treat it once symptoms begin.  And unlike type 2 diabetes and metabolic dysfunction, it does not appear to be readily reversible.”

This is why I, like most of Dr. Attia’s patients, fear dementia more than any other consequence of aging, including death.  I would rather die than lose my mind, which I consider to be living death.

THE BRAIN

Where a computer is powered by electricity, the beautiful machine that is the human brain depends on a steady supply of glucose and oxygen, delivered via a huge and delicate network of blood vessels.  Even slight disruptions to this vascular network can result in a crippling or even fatal stroke.

But what exactly is the mind, the brain.  Here is what Dr. Attia tells us in Outlive:

“The brain is a greedy organ.  It makes up just 2% of our body weight, yet it accounts for about 20% of our total energy expenditure.  Its eighty-six billion neurons each have between one thousand and ten thousand synapses connecting them to other neurons or target cells, creating our thoughts, our personalities, our memories, and the reasoning behind both our good and bad decisions.  There are computers that are bigger and faster, but no machine yet made by man can match the brain’s ability to intuit and learn, much less feel, or create.  No computer possesses anything approaching the multidimensionality of the human self.  Where a computer is powered by electricity, the beautiful machine that is the human brain depends on a steady supply of glucose and oxygen, delivered via a huge and delicate network of blood vessels.  Even slight disruptions to this vascular network can result in a crippling or even fatal stroke.

On top of this, brain cells metabolize glucose in a different way from the rest of the body; they do not depend on insulin, instead absorbing circulating glucose directly, via transporters that essentially open a gate in the cell membrane.  This enables the brain to take top priority to fuel itself when blood glucose levels are low.  If we lack new sources of glucose, the brain’s preferred fuel, the liver converts our fat into ketone bodies, as an alternative energy source that can sustain us for a very long time, depending on the extent of our fat stores.  (Unlike muscle or liver, the brain itself does not store energy.)  When our fat runs out, we will begin to consume our own muscle tissue, then our other organs, and even bone, all in order to keep the brain running at all costs.  The brain is the last thing to shut off.”

NEURODEGENERATIVE DISEASES

Dr. Attia notes that:

“Alzheimer’s disease is the most common, but there are other neurodegenerative diseases that concern us.  The most prevalent of these are Lewy body dementia and Parkinson’s disease, which are distinct conditions that share some pathological features.  The primary difference between these two is that Lewy body dementia … affects cognition, while Parkinson’s disease is considered primarily (but not entirely) a movement disorder, although it does also result in cognitive decline. … Beyond that, there are a variety of less common but also serious neurodegenerative conditions such as amyotrophic lateral sclerosis (ALS, or Lou Gehrig’s disease) and Huntington’s disease.  … In the United States, about 6 million people are diagnosed with Alzheimer’s disease, while about 1.4 million have Lewy body dementia, and 1 million have been diagnosed with Parkinson’s, which is the fastest-growing neurodegenerative disease.”

Alzheimer's

Just as most of an iceberg lies beneath the surface of the ocean, dementia can progress unnoticed for years before any symptoms appear.

Alzheimer's is a progressive brain disorder that gradually impairs memory, thinking skills, and eventually the ability to carry out even the simplest tasks.  Symptoms include memory loss, such as forgetting recent events or misplacing items; a struggle finding the right words or understanding language; difficulties with spatial awareness and navigation; decline in decision-making abilities; and behavioural changes including becoming worried, angry, or violent as the disease progresses.  It is the most common cause of dementia among older adults and its risk increases with age.

Like the other Horsemen, dementia has an extremely long gestation period.  As Dr. Attia notes:

“Its beginnings are so subtle that very often the disease isn’t recognized until someone is well into its early stages.  This is when their symptoms go beyond occasional lapses and forgetfulness to noticeable memory problems such as forgetting common words and frequently losing important objects….  Friends and loved ones notice changes, and performance on cognitive tests begins to slip.”

This is recognized as the early clinical stage of Alzheimer’s, known as mild cognitive impairment (MCI).  But Dr. Attia suggests that MCI is not the first stage on the long road to dementia.  He believes that subtler signs of cognitive changes, called stage I preclinical Alzheimer’s disease, often become apparent well before patients meet the criteria for MCI, and over 46 million people in the United States alone are estimated to be in this stage, but major symptoms are still largely absent.  He notes that:

“While it’s not clear how many of these patients will go on to develop Alzheimer’s, what is clear is that just as most of an iceberg lies beneath the surface of the ocean, dementia can progress unnoticed for years before any symptoms appear.”

CAUSES OF NEURODEGENERATIVE DISEASES

The Amyloid Hypothesis

The “amyloid hypothesis” has been the dominant theory of Alzheimer’s disease since the 1980s.  Dr. Attia shares the initial research, which revealed that a patient’s degree of cognitive impairment seemed to correlate with the extent of plaques found in the brain.  He also notes that subsequent research identified the substance in the plaques as a peptide called amyloid-beta which also triggers the aggregation of another protein called tau, which in turn leads to neuronal inflammation and, ultimately, brain shrinkage.  Since it is often found at the scene of the crime, amyloid-beta was immediately suspected to be a primary cause of Alzheimer’s disease and on the basis of available evidence, it was easy to conclude that Alzheimer’s is caused directly by this accumulation of amyloid-beta in the brain.

However, as Dr. Attia shares:

“… several dozen drugs have been developed that target amyloid-beta in one way or another.  But even when they succeed in clearing amyloid or slowing its production, these drugs have yet to show benefit in improving patients’ cognitive function or slowing the progression of the disease.  Every single one of them failed.”

In addition to the drug failures, he also shares other evidence calling into question the causal relationship between amyloid and neurodegeneration, including the following:

• Autopsy studies have found that more than 25% of cognitively normal people nevertheless had large deposits of amyloid in their brains when they died—some of them with the same degree of plaque build-up as patients who died with severe dementia.  But for some reason, these people displayed no cognitive symptoms.  This was not actually a new observation: Blessed, Tomlinson, and Roth noted back in 1968 that other researchers had observed “plaque formation and other changes [that] were sometimes just as intense in normal subjects as in cases of senile dementia.
• Some patients with all the symptoms of Alzheimer’s disease, including significant cognitive decline, have little to no amyloid in their brains.

 Dr. Attia therefore suggests that the presence of amyloid-beta plaques may be neither necessary for the development of Alzheimer’s disease nor sufficient to cause it.

Blood Flow Theory

Alzheimer’s is primarily a vascular disorder of the brain, i.e., it is caused when the vessels or ducts that supply blood to the brain are compromised, reducing blood flow.

As noted above:

“… the human brain depends on a steady supply of glucose and oxygen, delivered via a huge and delicate network of blood vessels.  Even slight disruptions to this vascular network can result in a crippling or even fatal stroke.”

Therefore, robust blood flow seems to be critical to maintaining brain health.

Dr. Attia seems to subscribe to neurologist’s Jack de la Torre’s theory that Alzheimer’s is primarily a vascular disorder of the brain, i.e., it is caused when the vessels or ducts that supply blood to the brain are compromised, reducing blood flow. 

He believes that:

“The dementia symptoms that we see result from a gradual reduction in blood flow, which eventually triggers a cascade of unfortunate events that harms the neurons and ultimately causes neurodegeneration.  The amyloid plaques and tangles come later, as a consequence, rather than a cause.”

He also cites the following in support of this theory:

• Alzheimer’s is more likely to be diagnosed in patients who have suffered a stroke, which typically results from a sudden blockage of blood flow in specific regions of the brain.  In these cases, symptoms emerge abruptly, as if a switch has been flipped.
• It has been established that people with a history of cardiovascular disease are at a higher risk of developing Alzheimer’s disease.
• Evidence also demonstrates a linear relationship between cognitive decline and increased intimal media thickness in the carotid artery, a major blood vessel that feeds the brain.
• Some two dozen known risk factors for Alzheimer’s disease also happen to reduce blood flow, including high blood pressure, smoking, head injury, and depression.
• A drop in blood flow seems to predict when a person will transition from preclinical Alzheimer’s disease to MCI, and on to full-fledged dementia. 

Metabolic Dysfunction

Finally, Dr. Attia’s research suggests that there may be a connection between Alzheimer’s disease and metabolic dysfunction.  He notes that:

“Having type 2 diabetes doubles or triples your risk of developing Alzheimer’s disease…. chronically elevated blood glucose can directly damage the vasculature of the brain.  But insulin resistance alone is enough to elevate one’s risk.

Insulin resistance appears to play to play a key role in memory function and a causal role in the development and progression of Alzheimer’s disease.  Several studies have found that spraying insulin right into subjects’ noses—administering it as directly as possible into their brains—quickly improves cognitive performance and memory, even in people who have already been diagnosed with Alzheimer’s disease.

The signal event here (again) appears to be a drop in energy delivery to the brain, like what is seen in the onset of vascular dementia.…  Just like reduced blood flow, reduced glucose metabolism essentially starves these neurons of energy, provoking a cascade of responses that include inflammation, increased oxidative stress, mitochondrial dysfunction—and ultimately neurodegeneration itself.”

Next week I will share Dr. Attia’s research and advice on what we can do to prevent Alzheimer’s and Other Neurodegenerative Diseases.  Again, I strongly urge you to read Outlive and I hope that these excerpts will help convince you to do so.

Please accept my very best wishes for a happy Christmas and holiday season.  If you find this advice helpful, please share with your friends and colleagues.  As usual, I look forward to your questions and comments.  Be safe.  Take good care, and if you can, help someone in need.

Cheers, Nigel

Nigel Romano,

Senior Director, Moore Trinidad & Tobago, Chartered Accountants