It’s Time To Rethink the Amyloid Alzheimer’s Theory - Dr. Michael Ruscio, DC

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It’s Time To Rethink the Amyloid Alzheimer’s Theory

How To Keep Your Brain Healthy As You Age

Key Takeaways:

  • The amyloid Alzheimer’s hypothesis has been the leading theory on how Alzheimer’s develops.
  • The amyloid Alzheimer’s hypothesis assumes beta-amyloid is the cause of Alzheimer’s disease.
  • Beta-amyloid is part of a normal protein in the brain, but when it begins to accumulate in the gray matter, plaques are formed, which can downregulate brain function.
  • The amyloid Alzheimer’s theory is being widely questioned for several reasons. For example, research hasn’t been able to connect beta-amyloid plaques to degenerative changes and beta-amyloid is present and seems to have positive functions in healthy people.
  • Beta-amyloid plaques appear to be a protective mechanism, not a cause of Alzheimer’s disease, and drugs targeting them have failed to produce any meaningful improvement.
  • We don’t know the cause of Alzheimer’s, but it likely results from multiple insults to the brain, so preventing and reversing it requires a personalized approach that targets root causes.
  • Chronic inflammation is a likely root cause of Alzheimer’s disease, so addressing it should be at the core of treatment.

 

Contrary to what we’ve been told, memory loss and poor brain function don’t have to be a normal part of aging. Yet Alzheimer’s disease (the most common type of dementia) is the 6th leading cause of death in the United States, and the number of Americans with this disease could more than double over the next 40 years [1, 2]. Why, with all the research that’s been done over the past several decades, are people still dying from this and other neurodegenerative diseases?

A solution may have eluded us thus far based on a faulty amyloid Alzheimer’s research hypothesis, which assumes beta-amyloid (also called amyloid-beta or amyloid-β) is to blame for the devastating effects of this type of dementia. Much of the drug research has been focused on clearing beta-amyloid plaques from the brain. However, beta-amyloid may not be the right target and is likely a normal immune system response to the insult (or multiple insults) occurring in the brains of Alzheimer’s patients.

Our clinical understanding is still limited, but the scientific evidence strongly suggests that there’s a silent but significant underlying theme to the factors that contribute to Alzheimer’s disease — chronic inflammation

Some neuroinflammation (inflammation in the brain) may have genetic and neurotransmitter components, but this new theory of Alzheimer’s that places chronic inflammation at the forefront is a good sign. A condition that previously seemed largely out of our control now has a promising explanation, and since there are many ways to target inflammation levels, we now have hope for effective prevention and treatment of Alzheimer’s disease.

In this article, I’ll share what we know about Alzheimer’s disease and dig into the amyloid Alzheimer’s theory. I’ll also share the highlights from my discussions on the podcast with Dr. Dale Bredesen (a neurologist and neuroscientist), including some practical tips to help you keep your brain healthy for the long haul.

Alzheimer’s Disease – The Basics

Alzheimer’s disease is a gradual, progressive form of dementia affecting 6 million Americans (as of 2022) [1]. It limits a person’s ability to create new memories, think, and carry out simple tasks like cooking or taking a shower.

Alzheimer’s is the most common type of dementia (responsible for two-thirds of dementia cases in people over the age of 64). It usually starts in the hippocampus – a structure in the brain responsible for memory, learning, emotion, and autonomic nervous system function (the system that controls your bodily functions without you noticing) [1].

Alzheimer’s can be broken down into two main categories [1]:

  • Early-onset: Symptoms start before the age of 65.
  • Late-onset: Symptoms start after the age of 65.

Stages of Alzheimer’s

Amyloid Alzheimer’s

Patients with Alzheimer’s disease (and other types of dementia) typically progress through four different stages. Here’s a chart detailing those stages and what patients commonly experience [1]:

Stage Description
Preclinical or Presymptomatic 
  • Periodic short-term memory loss but long-term memory function remains intact
Mild Cognitive Impairment 
  • Slow progressive decline in executive tasks like thinking, problem-solving, and judgment
  • Loss of motivation
  • More disorganized
  • Can generally continue to work and perform activities of daily living but multitasking and abstract thinking (reasoning) are difficult
Dementia 
  • Speech errors
  • Inability to imagine objects, make shapes out of smaller parts, or understand how objects are alike or different from each other
  • Apathy and social withdrawal
  • Impulsive behavior
  • Intense anxiety
  • Wandering
  • Psychosis
Advanced Dementia
  • Inability to perform motor tasks (walking and balancing)
  • Loss of smell
  • Sleep problems
  • Movement disorders
  • Inability to speak
  • Unable to respond to verbal requests
  • Bed bound
  • Show no signs of awareness

It’s so far been difficult to make meaningful improvement once an Alzheimer’s diagnosis has been made. However, when cognitive decline is recognized and treated early on, patients can thrive and may even be able to prevent an Alzheimer’s diagnosis. 

Before we can prevent and reverse cognitive decline, we have to know what’s causing it in the first place. Here are some known risk factors for Alzheimer’s disease [1]:

  • Genetics (having at least one copy of the APOE e4 allele)
  • Down syndrome
  • Older age
  • Head trauma
  • Depression
  • Cardiovascular disease
  • Cerebrovascular disease
  • Type 2 diabetes mellitus
  • Being born to older parents
  • Smoking
  • Family history of dementia
  • High homocysteine level 
  • Being overweight or obese
  • Physical inactivity

It’s important to understand that simply having one or two of these doesn’t necessarily mean you’ll develop the disease. You actually have a lot of control over your current and future brain health just by practicing healthy habits on a daily basis, like eating whole foods, exercising, getting restful sleep, managing stress, and finding purpose. Before we get into specific lifestyle recommendations, let’s take a look at the leading theory on how Alzheimer’s develops. 

What is the Amyloid Alzheimer’s Theory?

The amyloid Alzheimer’s theory arose in 1984 when a pathologist isolated beta-amyloid [3]. Beta-amyloid is a peptide (a short chain of amino acids) that makes up part of a normal protein called an amyloid precursor protein (APP) [1]. Normally, when APP is broken down, various amino acids come off as fragments and they float around without doing harm. 

However, if smaller amino acid peptides (specifically beta-amyloid 42) reach certain levels, the amyloid can become toxic to nerve cells, which encourages more amyloid to form. The amyloid then begins to accumulate and deposit itself outside of neurons (brain cells) and into the gray matter, where amyloid plaques are formed [1]. These plaques are considered a hallmark of Alzheimer’s disease.

Essentially the amyloid Alzheimer’s theory says amyloid is the cause of the disease, so the vast majority of the research has focused on targeting and eliminating amyloid [3]. The problem here is that amyloid-targeting drugs have failed to prevent disease progression, let alone cure Alzheimer’s [3]. Let’s take a look at why we may need to rethink the viability of the amyloid Alzheimer’s theory.

Why the Amyloid Alzheimer’s Hypothesis May Not Hold Up

Since amyloid was isolated in the brains of Alzheimer’s patients, the vast majority of the research has focused on targeting beta-amyloid. 

But part of the issue here is that amyloid deposits may be a protective mechanism against oxidative stress in the brain [4]. Essentially, beta-amyloid is more likely a symptom of Alzheimer’s, rather than a cause

In addition, amyloid plaques have been found in the brain tissue of elderly patients with normal brain function [4], and cognitive decline doesn’t seem to be associated with the amount of amyloid plaque in the brain [5]. 

Probably the most important reason to reconsider the amyloid Alzheimer’s theory is the fact that FDA-approved amyloid-targeting drugs have failed and even caused serious side effects [4]:

  • A 2021 meta-analysis looking at the highest doses of anti-amyloid-beta immunotherapies in Alzheimer’s patients found no effect at all after 12 months of therapy [6]. 
  • Clinical trials of anti-amyloid drugs and immunotherapies designed to prevent the breakdown of APP fragments into beta-amyloid have fared poorly and have, at times, caused increased brain inflammation, worsening cognition, and other damage [3].
  • A meta-analysis of one drug (aducanumab) found a reduction in amyloid plaques but no clinically meaningful improvement in symptoms. In addition, patients experienced cerebral edema and hemorrhage, leading to headaches, confusion, dizziness, and nausea [7].

Other considerations include: 

  • One study linking a certain type of beta-amyloid (amyloid-beta 52) to Alzheimer’s was found to have falsified images to support the author’s conclusion [8].
  • Tau protein tangles (a protein that builds up inside brain cells, eventually forming neurofibrillary tangles) seem to have a stronger association with cognitive decline in Alzheimer’s patients and can develop when no amyloid plaques are present [4].

Alzheimer’s is so poorly understood that the first-line medications used to treat it don’t even target the currently perceived culprit, beta-amyloid, but are purely designed to provide relief through altering acetylcholine or glutamate levels. However, like beta-amyloid therapies, targeting neurotransmitter levels isn’t as successful as we had hoped, and has left us searching for an alternate explanation for what is really at play in Alzheimer’s disease.  

The British National Health Service has proposed to discontinue the use of these medications in Alzheimer’s patients due to the low clinical benefit and high variability in effects. Furthermore, the American College of Physicians and American Academy of Family Physicians no longer promote this type of therapy as first-line for everyone and state it should be used on an individual basis [9].

As Dr. Bredesen and I discussed on the podcast, the amyloid Alzheimer’s theory has led us down a path of creating drugs that target a single concern. Since Alzheimer’s seems to develop from multiple factors, these types of drugs are not likely to lead to an effective solution for most people. And while some patients do find symptomatic relief from the current pharmaceuticals, they shouldn’t be the only treatment option. There are many other treatments that do target inflammation, which is the more likely culprit of Alzhemer’s disease. 

Dr. Bredesen’s research has found that the average person with cognitive decline (and ultimately Alzheimer’s disease) has at least 10 to 25 different contributing factors. This is likely why drugs targeting beta-amyloid plaques alone haven’t been effective. Preventing and reversing this disease requires a comprehensive approach that addresses all (or at least the most important) factors that have led the brain to try to protect itself.

One neuroscience research group is forging ahead though with a new study to test the amyloid Alzheimer’s theory in younger patients with a confirmed genetic variant that causes early-onset Alzheimer’s. The participants will receive an anti-amyloid drug (lecanemab) and be followed for 4 years. The lead researcher, Dr. Randall Bateman, states, “this is the ultimate test of the amyloid hypothesis.” 

If this drug doesn’t prevent amyloid from building up and symptoms from developing in young people who are predisposed to Alzheimer’s, then the amyloid Alzheimer’s theory will likely be debunked once and for all [10, 11]. So if amyloid isn’t the cause of the disease, let’s look at additional research theories of why people may end up with Alzheimer’s.

Potential Alzheimer’s Disease Causes

It would be great if there were one, single cause of Alzheimer’s – that would mean we could develop a drug, vaccine, or lifestyle intervention to prevent and/or reverse it. 

However, we’re more likely looking at a series of contributing factors and events that are unique to each individual. This sheds some light on why the drugs developed thus far haven’t been successful. 

The great news here is that even though we don’t have one individual cause to pinpoint, many of the contributing factors have inflammation as a predominant theme, and that is absolutely something we can target with a variety of proven interventions. 

If the amyloid Alzheimer’s theory is debunked, hopefully more research dollars can be spent on some of the other theories behind the pathogenesis of Alzheimer’s and other types of dementia (like Parkinson’s and Lewy body). Let’s take a look at some of these other theories, and remember, it’s likely not any one of these alone that causes the disease but rather a combination that’s unique to each patient. Here’s a chart detailing possible contributing factors and how they might contribute to Alzheimer’s development.

Contributing FactorMechanism of Action
Loss of synapsesIt’s well-established that losing synapses (a junction between 2 nerve cells that helps pass information from cell to cell) in the human brain is strongly associated with memory loss in Alzheimer’s patients. This could be the result of low acetylcholine levels, which causes neuronal cell (building blocks of the brain) death. Another less likely scenario involves glutamate (an excitatory signaling molecule). When glutamate is high, patients may experience neuronal cell death [12].
Poor metabolic healthThe brains of people with Alzheimer’s are often affected by metabolic dysfunction as evidenced by reduced blood flow and glucose use (despite high levels of glucose in the blood) [12].  One genome-wide study found a strong relationship between Alzheimer’s disease and type 2 diabetes mellitus and shared genetic underpinnings between Alzheimer’s and metabolic dysfunction [13].  
InfectionsInfections like the herpes simplex virus have also been implicated in Alzheimer’s development.  One review of mouse models and human cell studies found this virus to increase the level of amyloid-beta, which begins as a protective mechanism, but ultimately may become harmful, causing brain atrophy.  It may work like this: infections in the gut, mouth, nose, and skin can get into the brain and spinal cord causing inflammation. This inflammation then leads to the death of neurons and immune cells, which ultimately ends in dementia [3, 14].
Chronic inflammationBrain cells called microglia and astrocytes help us get rid of wastes and toxins that make their way across protective membranes into our brains. In people with Alzheimer’s, these cells don’t function normally, which allows waste (like beta-amyloid plaques) to build up in the brain. These cells may also secrete inflammation-causing chemicals that kill neurons. One meta-analysis found increased brain inflammation to be associated with the progression from mild cognitive impairment to Alzheimer’s disease [15, 16].
Genetic mutations or variantsNearly all early Alzheimer’s disease arises from variants in three genes, which account for 5–10% of all Alzheimer’s cases. In the case of late-onset Alzheimer’s, about 50% of people with one APOE-e4 allele develop the disease, while about 90% of people with two copies of this gene develop the disease [1].
Vascular problemsBoth a cause and consequence: Beta-amyloid plaques, mini-strokes, and atherosclerosis impact the brain’s blood vessels, so they’re less able to carry blood and oxygen to the brain [15]. Compromised blood vessels may also affect the blood-brain barrier, which can mean glucose (fuel for the brain) can’t get in and wastes like beta-amyloid can’t be removed. This process then causes inflammation, which further impedes blood flow worsening brain function [15].
Neurofibrillary TanglesWhile beta-amyloid builds up outside of neurons, a protein called tau can form into abnormal neurofibrillary tangles (or fibrils), which inhibit the normal flow of communication between neurons. These tau tangles aggregate, especially in brain regions involved in memory like the hippocampus, and they can spread to other areas [1, 15]. Tau tangles are thought to pose more of a threat than the beta-amyloid but beta-amyloid drives their creation [3].

Receiving an Alzheimer’s diagnosis thus far has meant getting your affairs in order and taking medications that don’t do much to improve brain function. But research is providing hope for patients with cognitive decline. There are a vast number of nutrition and lifestyle options that target some of the potential root causes of Alzheimer’s, like inflammation. Let’s briefly discuss some of the most important ones.

Reducing Alzheimer’s Risk With Nutrition and Lifestyle

In the clinic, we focus on the foundations to create optimal brain health. There’s no one food, magic supplement, or test that will prevent Alzheimer’s disease, rather it’s the combination of daily lifestyle habits that will support great brain function as you age.  

In general, an active, healthy, positive lifestyle reduces your risk of dementia (as well as other chronic diseases) [5]. There’s strong evidence that the following may help prevent Alzheimer’s disease specifically [17]:

  • Keeping your brain active through education and cognitive activities throughout life can help improve neuroplasticity and cognitive reserve [1, 18, 19]
  • Maintaining a healthy weight, especially later in life
  • Managing homocysteine levels
  • Relieving depression
  • Managing stress in a healthy way
  • Avoiding or controlling diabetes
  • Avoiding head trauma
  • Managing your blood pressure, especially in mid-life
  • Reducing orthostatic hypotension (getting dizzy when standing up)

In addition, it’s a great idea to get enough high-quality sleep, avoid smoking, and maintain your strength as you age [17]. Let’s look more closely at what exercise, nutrition, and probiotics can do for your brain.

Exercise For Brain Health

We all know exercise is great for improving our cardiovascular health and overall physical function, but it’s also one of the most important lifestyle components for preventing [17] and even improving cognitive decline. Meta-analyses have found:

  • Exercise improves cognition in people with both Alzheimer’s and mild cognitive impairment [20, 21].
  • Resistance exercise (strength training) largely improves brain-derived neurotrophic factor (BDNF – a protein that helps create new brain cells and synapses) in those with neurodegenerative disorders (22).
  • 30–45 minutes of physical activity routinely improves cognition and activities of daily living in people with Alzheimer’s disease [23, 24].

It’s important to create a consistent exercise routine, and it’s never too late to start moving your body. Simply walking every day is the perfect way to build a foundation of physical activity. Ideally, you’ll work your way up to three days of full-body strength training and three days of cardiovascular training per week. It’s also a great idea to filter in mobility exercises like stretching and yoga. 

Food is also a huge factor when it comes to improving brain health. Inflammatory foods can disrupt gut health, creating body-wide inflammation that can be harmful to your brain. Let’s look at some nutrition-related guidelines.

Nutrition For Brain Health

There’s no one perfect diet for everyone, so finding what works best for you is important. In general, diets high in fruits, whole grains, and vegetables have been found to reduce the symptoms of and your overall risk of developing Alzheimer’s disease [25]. And adequate amounts of choline can improve memory and behavior, limit dementia progression, and reverse dementia symptoms [26, 27]. 

In addition, one systematic review found promising results with low carbohydrate and ketogenic diets for people with all types of neurological diseases as they have an anti-inflammatory effect, which can protect brain health [28].  

Any meal plan that offers a wide variety of nutrients and supports great gut health will likely also protect your brain (Paleo and Mediterranean diets fit this description), so there’s no need to try to fit into one category when it comes to diet. If you’re already experiencing cognitive decline though, it’s worth investigating specific nutrition-related options. Since poor gut health is often a center for inflammation in the body, probiotics can also be a wonderful addition when you’re trying to optimize or improve brain function.

Probiotics for Brain Health

One meta-analysis found probiotics may be very useful for patients with Alzheimer’s disease since they can improve cognitive function, acute memory, and the ability to perform activities of daily living [29]. Probiotics are very safe and effective, so they’re worth trying. In the clinic, I recommend the triple therapy probiotic approach, which incorporates the three main categories of probiotics: a lacto-bifido blend, soil-based, and Saccharomyces boulardii.  

Target Inflammation to Help Prevent Alzheimer’s Disease

The amyloid Alzheimer’s theory assumes that beta-amyloid is the cause of Alzheimer’s disease. However, treatments designed to remove amyloid plaques have failed and can even cause serious side effects. Instead of being the cause of the disease, research suggests beta-amyloid plaques may be a natural immune response.  Essentially, the brain is trying to protect itself from multiple insults like toxins and inflammation, but this comes at the expense of brain function.

Preventing and possibly reversing Alzheimer’s disease takes a personalized approach that targets all of the factors leading the brain to try to protect itself. The underlying theme of many of these factors is chronic neuroinflammation. This silent inflammation is something we can target with  nutrition and lifestyle changes like exercise, an anti-inflammatory diet, and probiotics. These therapies can be very effective, and they place the power of healing back in your hands. 

Healthy Gut, Healthy You is a great do-it-yourself resource that targets your brain indirectly by lowering inflammation and improving your gut health. If you work through the Great-In-8 Action Plan in the book but still struggle with negative symptoms or just want to fine-tune your plan, please reach out to the Ruscio Institute for Functional Health.

The Ruscio Institute has developed a range of high-quality formulations to help our patients and audience. If you’re interested in learning more about these products, please click here. Note that there are many other options available, and we encourage you to research which products may be right for you.

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