Parkinson's, Alzheimer's, and the New Science of Hope

Metabolic similarities offer a path to preventing neurodegenerative disorders.

Posted Jun 29, 2019

lightwise/123RF
Source: lightwise/123RF

June is Alzheimer’s and Brain Awareness Month. One could argue that awareness of neurodegenerative disorders like Alzheimer’s disease and Parkinson’s disease—which gradually destroy brain cells as we age—is already at a fever pitch. Who among us hasn’t yet been personally affected by these thieves of intellect and dignity?

Now a global epidemic, Alzheimer’s disease already plagues nearly six million Americans and 50 million people worldwide.

Parkinson’s disease, the second most common neurodegenerative disorder, afflicts approximately one million people in the United States and as many as 10 million people worldwide. 

Is greater awareness really the answer? We are told that there are no good treatments for these scourges and that the risk factors are things we can’t do anything about: how old we are, our family history, and which genes we happen to possess. Hopelessness and helplessness inevitably ensue, as we wait passively to see who will be stricken next.

In most cases, these disorders are considered “sporadic” (random) and “idiopathic” (mysterious in origin). While there remains great uncertainty about underlying causes, both of these diagnoses feature telltale microscopic abnormalities that make tempting targets for pharmaceutical-minded researchers.

In the case of Alzheimer’s disease, popular drug targets have included its notorious beta-amyloid plaques and neurofibrillary tangles.

In the case of Parkinson’s disease, the potentially poisonous protein du jour is alpha-synuclein, a molecule needed for normal brain synapse function. In the vast majority of Parkinson’s cases, this protein clumps into misfolded “toxic fibrils” which accumulate inside abnormal structures called Lewy bodies.

Unfortunately, countless desperate dollars have fueled decades of sophisticated drug research, taking aim at these and other potential culprits, leading to exactly zero medications with the potential to make any meaningful difference in the course of these conditions thus far.

Yet hope exists . . . if we know where to look for it. What if visual peculiarities like plaques, tangles, and Lewy bodies aren’t the real villains in the story? In the hunt for true root causes, could these tempting pathological tidbits be throwing curious scientists off the scent? In the case of Parkinson's disease, a brand-new review paper published this week by an international group of European neuroscientists argues that alpha-synuclein is nothing more than a red herring—an innocent bystander that only appears guilty by association. 

Instead of allowing ourselves to be distracted by the shiny objects under the microscope, we would likely be better served by standing back and looking at the big picture to re-orient ourselves.

As different as these diseases may seem, they have many things in common that deserve our attention. By far, the most important one to keep in mind is this:

Brain Cells Are Dying

In Alzheimer’s disease—which gradually destroys the entire brain—it is the cells of the hippocampus, the brain’s memory center, which are among the first to go.

In Parkinson’s disease, the death and destruction appear to begin with the dopamine-producing cells of the substantia nigra—the brain’s movement coordination center. As these precious cells gradually fall by the wayside, classic symptoms of motor dysfunction emerge, including tremor, rigidity, bradykinesia (slowed movement), and changes in speech and gait. While Parkinson’s symptoms can be lessened by a drug called L-dopa, which the brain can use to make more dopamine, no medication has yet been developed that can slow or stop the progression of this debilitating disease.

Bruce Blaus/Medical gallery of Blausen Medical 2014
Source: Bruce Blaus/Medical gallery of Blausen Medical 2014

Why Are Brain Cells Dying?

Are we to simply accept that it is normal and natural for so many of us to begin randomly losing cells in our hippocampus and/or substantia nigra as we age? If we understood what was killing them, perhaps we could do something about it.

Multiple lines of quality evidence have convincingly established that insulin resistance (aka pre-diabetes) is a key driving force behind most cases of Alzheimer’s disease, leading some to refer to Alzheimer’s as “type three diabetes.” (Learn more in my Psychology Today post “Avoiding Alzheimer’s Disease Could Be Easier than You Think.”)

The majority of Americans now have insulin resistance—a metabolic problem that can cause insulin levels in the blood to run too high too often—particularly in response to carbohydrates in the diet.

Suzi Smith, used with permission
Source: Suzi Smith, used with permission

In people with insulin resistance, glucose (blood sugar) continues to waltz into the brain, no questions asked; it is insulin that struggles to cross the blood-brain barrier. Since brain cells can't turn glucose into energy without adequate insulin, people with insulin resistance face a brain energy crisis.

If you are insulin-resistant, your brain cells can be swimming in a sea of glucose and yet be starving to death.

Parkinson’s Disease as a Metabolic Disorder

As a psychiatrist with clinical experience in treating people with Alzheimer’s disease, I’ve been writing and speaking about Alzheimer’s for some time now, but it wasn’t until I was invited to give a presentation about insulin resistance and neurodegenerative diseases at the first annual Keto-Live conference in Bergün, Switzerland, earlier this month that I delved into the Parkinson’s disease research for the first time. What I discovered was a cornucopia of striking metabolic similarities between Parkinson’s and Alzheimer’s:

  • Brain glucose utilization problems
  • Mitochondrial dysfunction
  • Protein misbehavior
  • Increased apoptosis (cell suicide)
  • Inflammation
  • Glutamate toxicity
  • Oxidative damage
  • Slowed brain cell conduction
  • Formation of Advanced Glycation End products (AGEs)

It just so happens that low brain insulin levels can lead to the first four phenomena listed above, while the last five can be driven by high brain glucose levels. This suggests that, like Alzheimer’s disease, Parkinson’s disease may be intimately tied to insulin resistance of the brain.

For example, just as insulin resistance helps to explain the accumulation of plaques and tangles in Alzheimer’s brains, it also helps to explain the formation of the Lewy bodies lurking within the vast majority of Parkinson’s brains. This is because insulin activates the enzyme responsible for preventing alpha-synuclein from forming the toxic fibrils found inside Lewy bodies in the first place. 

How many people with Parkinson’s disease have insulin resistance?

A 2018 study of 154 non-diabetic Parkinson’s patients conducted at Cedars-Sinai Hospital in Los Angeles found that 58 percent of them had insulin resistance. All of these people had normal fasting glucose levels and—in many cases—normal hemoglobin A1C levels and normal body weight as well. In fact, a surprising 42 percent of normal-weight people with Parkinson’s had insulin resistance [determined by a HOMA index of 2.0 or above and/or a hemoglobin A1C of 5.7 or above]. These data underscore the fact that routine diabetes testing and body weight measurements often fail to detect insulin resistance, fooling people into thinking they are metabolically healthy and don’t need to make lifestyle changes.

Other studies have shown that people with Parkinson’s disease who also have insulin resistance are more likely to have severe symptoms, faster disease progression, and Parkinson’s-related dementia

So, while insulin resistance is certainly not the only player in the development of Parkinson’s disease, it is clearly a force to be reckoned with in the majority of cases.

Location, Location, Location

If insulin resistance is a general metabolic problem that affects the glucose and insulin levels of the whole brain, why is it that Parkinson’s disease appears to originate in the substantia nigra?

The substantia nigra demands much more energy than most other regions of the brain. This is because it is densely packed with highly-interconnected, dopamine-producing neurons, many of which are poorly insulated or completely uninsulated. Myelin, the white matter that wraps around nerve cells and makes electrical conduction more energy-efficient, is largely absent in this area of the brain, meaning that these cells use more energy when sending their electrical messages. These cells also possess pacemaker properties which contribute to their hunger for energy. Together, these features render dopamine-producing neurons exquisitely vulnerable to the brain energy deficits caused by insulin resistance.

In fact, a newly published paper raises the fascinating possibility that the earliest and most fundamental problem underlying both Alzheimer’s and Parkinson’s may be the loss of dopamine-producing neurons throughout the brain. Only three areas of the brain synthesize dopamine: the substantia nigra (movement coordination), the locus coeruleus (attention/arousal/stress response), and the ventral tegmental area or VTA (emotion, cognition, motivation, pleasure). This dopamine deficit hypothesis may help to explain why it is so common for Alzheimer’s and Parkinson’s patients alike to experience psychiatric symptoms such as attention, mood and motivation problems, even rather early in the course of the disease.

It would seem that anything we could do to preserve the exposed, energy-hungry neurons of our dopamine circuitry would be a very good idea indeed.

Ketogenic Diets for Parkinson’s Disease

If Parkinson’s disease in many cases is partly due to an energy crisis in which the low-insulin brain struggles to process glucose, then providing the brain with an alternative fuel source should be helpful.

Fortunately, ketones serve as an excellent fuel source for most brain cells, and they burn beautifully in a low-insulin environment. The body naturally generates ketones from fat whenever blood insulin levels are low enough to switch the body into fat-burning mode. Ketogenic diets—very low carbohydrate diets—lower blood glucose and insulin levels to the point that ketones are produced that can be measured in the bloodstream.

Thus far there have only been two human clinical studies of ketogenic diets in Parkinson’s disease, but the results look promising.

Suzi Smith, used with permission
Source: Suzi Smith, used with permission

The first was a small 2005 pilot study of five overweight patients instructed to eat a diet composed of 90 percent fat, 8 percent protein and 2 percent carbohydrates. All patients achieved ketosis, with blood ketone levels ranging from 1.13 mM to 8.0 mM. All patients lost weight and experienced a reduction in symptoms as measured by the Unified Parkinson’s Disease Rating Scale. The main criticism of this study was that four of the five patients were taking L-dopa, which enters the brain more easily under low-protein conditions. Thus, it is possible that the clinical improvements seen may have been due to improved medication delivery to the brain rather than to ketosis, as this particular research diet was designed to be relatively low in protein.  

The second study was a 2018 randomized trial of 38 people with Parkinson’s disease that compared a low-fat diet to a ketogenic diet for eight weeks. Both diets were designed to contain adequate (rather than low) protein (75 g/day) and the same number of calories (1750/day). The low-fat diet contained 42 grams of fat and 246 grams of carbohydrate per day. The ketogenic diet contained 152 grams of fat and 16 grams of carbohydrate per day. People in the ketogenic group achieved blood ketone levels of 1.15 ± 0.59 mM.

Both groups showed small but significant improvements in motor and nonmotor symptoms; however, the ketogenic group showed much greater improvements (41 percent) in nonmotor symptoms. This is important, because nonmotor symptoms, such as urinary problems, pain, fatigue, daytime sleepiness, and cognitive impairment, are among those least likely to respond to L-dopa.

Suzi Smith, used with permission
Source: Suzi Smith, used with permission

Wake Up and Smell the Insulin

Just as Alzheimer’s disease does not happen overnight, Parkinson’s disease begins long before symptoms appear. By the time a person notices the symptoms of Parkinson’s, at least 50 percent of the dopamine-producing neurons in the substantia nigra have already been destroyed. 

Fortunately, you don’t have to stand idly by while your brain quietly deteriorates from the inside-out. Insulin resistance is a major risk factor for this devastating condition that you can do something about right away.

Many of my patients think that the best way to boost brain energy is by eating more carbohydrates. While this sounds logical, the paradoxical truth is that the more sugar you eat, the more insulin-resistant your brain can become, making it increasingly difficult for your brain cells to turn sugar into energy. 

If you discover that you have insulin resistance, you can take steps right now to lower your insulin levels and reduce your risk for neurodegenerative conditions. Learn more about how to figure out whether you have insulin resistance, improve your metabolism, and protect your insulin-signaling system using simple lifestyle strategies in my post “How to Diagnose, Prevent and Treat Insulin Resistance” which includes a (free) downloadable PDF of simple insulin resistance tests you can bring to your next medical visit and an infographic of ways to eat healthier that you can use right away to improve your metabolism.

It is common for awareness campaigns to solicit donations for research, most of which is focused on medications, all of which have failed. Raising awareness of the important connection between metabolic health and neurodegenerative diseases could inspire much-needed nutrition and lifestyle-oriented research and, in the meantime, empower individuals to invest in lifestyle changes that could change the course of their future.