Here’s what we’ll cover in this blog post:
- How Alzheimer’s is historically understood
- What the amyloid hypothesis is
- How new studies are changing our approach to Alzheimer’s
- The different subtypes of Alzheimer’s
Alzheimer’s disease (AD) is the fifth leading cause of death in individuals 65 years and older and reported deaths have increased by 146.2% in the past 20 years. In contrast, reported deaths from cardiovascular disease (the #1 cause of death in America) have decreased in that same time frame.
Our ability to therapeutically address and mitigate the progression of Alzheimer’s disease has been abysmal despite significant advances in therapeutics to address heart disease, cancer, and diabetes. This begs the question, “What are we missing and where did we go wrong?”
A significant part of the issue is that we are only paying attention when individuals present with mild cognitive impairment or significant brain atrophy–both late-stage markers. By then, it seems to be too late to make any significant impact on disease progression. This is reflected by the fact that despite hundreds of billions of dollars being poured into Alzheimer’s care, there are no effective therapeutics to date.
Given the abysmal state of affairs in this realm, the next logical questions become clear. Do we truly understand what Alzheimer’s is…and isn’t? What factors really drive Alzheimer’s pathology and neurodegeneration? Does our current understanding offer hope for prevention and reversal? These nagging questions implore us to go back to the basics. Well, basic biology, that is.
Alzheimer’s: A Classic Aging Pathology
We know that age is a major risk factor for developing Alzheimer’s. The risk and incidence of Alzheimer’s increases with age, with 1 in 3 US seniors dying of Alzheimer’s each year.
This sobering fact is not due to the excess cake and ice cream we consume on birthdays (although, as we’ll show later, sugar spikes do play a role).
Aging is characterized by gradual damage accumulation over time—in fact, several decades. As we age, various stressors compromise our intrinsic quality control systems tasked with clearing away cellular damage. When that happens in our brain, we eventually experience cellular dysfunction, brain atrophy, and death.
One form of cellular damage is misfolded proteins, which is one of the hallmarks of aging. Our cells normally regulate protein synthesis, folding, and degradation through a process called proteostasis. As we grow older, our cells slowly lose this ability, allowing misfolded or damaged proteins to accumulate.
The accumulation of misfolded proteins (amyloid beta) has long been correlated with Alzheimer’s disease. The popular view is that amyloid beta is a major hallmark and driver of Alzheimer’s. This theory is called the amyloid hypothesis.
Naturally, tracking and clearing away amyloid beta has been a major focus of Alzheimer’s therapeutics. It makes sense, until you take a closer look at the data.
The Amyloid Hypothesis: Chasing a Red Herring
More recent studies have revealed that, in many cases, amyloid beta isn’t present at abnormal levels in Alzheimer’s patients. Where abnormal levels were detected, the amount of amyloid beta was often insufficient to drive neurodegeneration. In some cases, amyloid beta seemed to delay the onset of Alzheimer’s.
Other studies show that amyloid beta is produced as an immune response resulting from stress to the brain. This suggests that amyloid beta has a more complex role than simply driving neurodegeneration: they also chelate pathogens, toxins, and other chemical insults, containing them from spreading across the brain.
Though these studies challenge the amyloid hypothesis, it’s still true that amyloid plays a role in Alzheimer’s pathogenesis. In some cases, amyloid beta accumulation reduces valuable neural real estate in our brain, limiting its functional capacity. But these may only represent a minority of Alzheimer’s cases, according to these new studies.
So where does that leave us today? These studies challenge a theory that has largely defined Alzheimer’s therapy to date, but it turns out scientists may have spent several decades chasing a red herring. This may explain why the US invests $231 billion to caring for those with Alzheimer’s, with another $3.8 billion dedicated to research. Meanwhile, the FDA has only approved five drugs for Alzheimer’s and these only partially mitigate symptoms in some patients.
A Personalized Approach to Alzheimer’s
But there is a silver lining. As researchers shift focus away from the amyloid hypothesis, they now have a new opportunity to reframe Alzheimer’s and discover the true drivers of this disease.
Now, research is showing that Alzheimer’s exists as various subtypes, like diabetes. In other words, Alzheimer’s isn’t a one-size-fits-all disease that can be addressed with a single therapy. Rather, Alzheimer’s seems to be a group of diseases.
Further, each Alzheimer’s subtype is characterized by neuronal hypometabolism, which is when metabolic activity slows, and the brain can’t use insulin or glucose for energy as efficiently.
By this view, we can effectively prevent Alzheimer’s by characterizing the subtypes, finding biomarkers indicative for each, and targeting the disease based on an individual’s unique pathological hallmarks.
| Subtype | Pathological Hallmarks | Neuronal Hypometabolism |
| Glycolytic | High blood glucose and insulin; insulin resistance; Comorbidity: type 2 diabetes | Glucose can’t get into neurons |
| Vascular | High blood pressure; vascular damage (arterial stiffness, occlusion, ischemia); Comorbidity: cardiovascular disease and traumatic brain injury | Glucose can’t get to brain or particular locations in brain |
| Inflammatory | High C-reactive protein, cytokines, chronic inflammation; Comorbidity: multiple age-related chronic diseases | Glucose intercepted by energetically demanding inflammatory process |
| Pathogen | Microbial infection (fungal, bacterial), chronic inflammation | Glucose intercepted by pathogen and energy demanding inflammatory process |
| Toxin | Metallotoxin: High copper to zinc ratio Organotoxin: DDT Biotoxin from molds | Glucose gets into neurons but mitochondria impaired by toxin |
| Atrophic | Hormone factor deficiency Neurotrophic factor deficiency | Glucose can’t get to particular location in brain without proper signaling in place |
How Does Metabolism Affect Alzheimer’s?
The brain primarily relies on glucose as an energy source. Multiple studies have shown cerebral insulin resistance and high glucose levels precede all other pathological hallmarks of Alzheimer’s. That may explain why type 2 diabetes and cardiovascular disease are the most prevalent comorbidities of Alzheimer’s disease. This isn’t a unique feature of Alzheimer’s. In fact, impaired glucose metabolism is a hallmark of many neurodegenerative disorders.
But how does neuronal hypo-metabolism drive the various subtypes of Alzheimer’s? Think of a mailman delivering a bad report card to different homes in the neighborhood. The children don’t want their parents to read their report card, so they go to various lengths to stop the mail delivery.
In this analogy, the mail is glucose, while the homes are various neurons of the brain, and the children are the subtypes of Alzheimer’s. To stop the mail, the children will either:
- Block the delivery path (Vascular)
- Remove the mailbox (Glycolytic, Atrophic)
- Intercept the mail en route (Inflammatory, Pathogen)
- Impair ability to open the envelope (Toxin)
Currently, these are the only troublemakers we know of, but there could be more subtypes waiting to be discovered.
But recognizing the multifaceted nature of Alzheimer’s and characterizing it this way helps us distill its inherent complexity into actionable insights that can be used to build a personalized approach for disease prevention. This renewed understanding of Alzheimer’s pathology may very well hold the answer to the most expensive and debilitating disease our world has known, unlocking a path that could help millions live longer, healthier lives.
Note: The above statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease.