Alzheimer’s disease, a condition characterized by an accumulation of beta-amyloid plaques and neurofibrillary tangles in the brain, affects an estimated 5 million Americans; this number is expected to reach 14 million by 2060.1 With no known cure, researchers are scrambling to find treatments, often with a misguided focus on drugs designed to remove excess beta-amyloid in the brain.
Drug development for Alzheimer’s has so far been a dismal failure, with 300 failed trials to date.2 Despite the history of letdowns, the latest failed drug trial is still making waves in the research community because there were high hopes that it would provide a breakthrough treatment for people with gene mutations known to cause Alzheimer’s.
Now, with the experimental drugs failing to lead to improvements, researchers are asking if the focus on drugs to target and neutralize beta-amyloid in the brain is all wrong, and if other potential targets should become the focus of future research.3
Two Experimental Drugs Fail to Improve Alzheimer’s
The study, which was a collaboration between Washington University in St. Louis, drug companies Eli Lilly and Roche, the National Institutes of Health and others, involved 194 participants, of which 52 took Roche’s drug gantenerumab and 52 took Eli Lilly’s solanezumab.
The drugs were intended to remove beta-amyloid from the brain, and while the researchers are still evaluating this outcome, they failed to achieve the primary outcome of the study, which was slowed cognitive decline, as measured by tests on thinking and memory.
The study, Dominantly Inherited Alzheimer Network-Trials Unit (DIAN-TU), involved people with an inherited form of early-onset Alzheimer’s known as dominantly inherited Alzheimer’s disease or autosomal dominant Alzheimer’s disease, which account for less than 1% of Alzheimer’s cases.4
While in most cases Alzheimer’s symptoms begin after the age of 60, and risk increases with increasing age, people with this early-onset Alzheimer’s may begin to experience memory decline in their 30s, 40s or 50s. However, the brain changes that occur are similar in both those with inherited Alzheimer’s and the more common sporadic Alzheimer’s, so a treatment that works in one will likely work in the other.
According to a Washington University School of Medicine in St. Louis news release, a silent phase of Alzheimer’s occurs up to 20 years before symptoms develop. Study participants were expected to develop symptoms within 15 years of enrolling in the study or had very mild symptoms at the beginning of the study. Most also had early signs of the disease in their brains. Researchers explained:5
“People who inherit the mutation are all but guaranteed to develop symptoms at about the same age their parents did. While devastating for families, such mutations allow researchers to identify people in the early stages of the disease before their behavior and memory begin to change.”
The news that the drugs had failed came after an average of five years of follow-up and was a shock even to the researchers. “It was really crushing,” lead study author Dr. Randall Bateman of Washington University St. Louis told The New York Times.6 However, should it have been so shocking, considering both drugs have failed previously?
Experimental Drugs Have Failed in the Past
Researchers with the featured study are still wondering whether the experimental drugs could work at different doses or if they would work better if they were started even earlier. However, past studies suggest the drugs are useless for Alzheimer’s.
In one study of solanezumab, published in The New England Journal of Medicine in 2018, patients with mild dementia due to Alzheimer’s disease received solanezumab or placebo intravenously every four weeks for 76 weeks.7 The drug did not significantly affect cognitive decline, and the researchers even suggested this could be because the target is all wrong:8
“ … [S]olanezumab was designed to increase the clearance of soluble Aβ [amyloid-beta] from the brain, predicated on the Aβ hypothesis of Alzheimer’s disease — that the disease results from the overproduction of or reduced clearance of Aβ (or both).
Although the amyloid hypothesis is based on considerable genetic and biomarker data, if amyloid is not the cause of the disease, solanezumab would not be expected to slow disease progression.”
A study comparing gantenerumab at different doses with placebo came up with similarly disappointing results. A futility analysis was conducted when 50% of the patients had completed two years of treatment, and it found no differences between the drug or placebo, prompting researchers to stop the study early.9
A subsequent study that significantly increased the dose of the drug found it did reduce amyloid-beta plaques in Alzheimer’s patients,10 but how this translates to affecting cognitive decline remains to be seen.
Beta-Amyloid Is a Symptom of Alzheimer’s — Not the Cause
The reason why beta-amyloid drugs continue to fail to improve Alzheimer’s disease is because beta-amyloid is a symptom of Alzheimer’s — not the cause.
Alzheimer’s has many causes, as discussed eloquently by Dr. Dale Bredesen, professor of molecular and medical pharmacology at the University of California, Los Angeles School of Medicine, and author of “The End of Alzheimer’s: The First Program to Prevent and Reverse Cognitive Decline.”11
Bredesen’s ReCODE protocol evaluates 150 factors — including biochemistry, genetics and historical imaging — known to contribute to Alzheimer’s disease. This identifies your disease subtype or combination of subtypes so an effective treatment protocol can be devised.
For instance, Bredesen states that type 1 Alzheimer’s is “inflammatory” or “hot,” and patients present predominantly inflammatory symptoms. Type 2 is atrophic or “cold,” with patients presenting an atrophic response. In type 3, or toxic “vile” Alzheimer’s, patients have toxic exposures.
There’s also a mixed type, type 1.5, which is referred to as “sweet” and is a subtype that involves both inflammation and atrophy processes, due to insulin resistance and glucose-induced inflammation. An algorithm is used to determine a percentage for each subtype based on the variables evaluated, and an individualized treatment protocol is created.
ReCODE Protocol Leads to Improvement in 100 Patients
Bredesen’s most recent publication is a case report of 100 patients using the ReCODE protocol.12,13 He has previously published three case reports, each involving just 10 patients. The fourth case report contains 100 patients treated at 15 different clinics across the U.S., all of which have documented pre- and post-cognitive testing.
Not only did all show improvement in symptoms, some of them also showed improvement in their quantitative electroencephalographs (EEGs). Others who underwent magnetic resonance imaging (MRI) with volumetrics also showed objective improvement.
The results are impressive, to put it mildly. Here’s an example of just one patient’s outcome — a 73-year-old woman with cognitive decline who could not remember recent conversations, mixed up the names of people and pets and forgot the names of books she had read. Her significant other described her memory as “disastrous,” but this changed remarkably for the better:14
“She was treated with the programmatic approach described previously, and over 12 months, her on-line cognitive assessment improved from the 9th percentile to the 97th percentile. Her significant other noted that her memory had improved from “disastrous” to “just plain lousy” and finally to “normal.” She remains on the therapeutic program, and has sustained her improvement.”
Understanding Ketosis and Autophagy for Alzheimer’s
A hallmark of neurodegenerative diseases such as Alzheimer’s is that proteins are aggregated and typically misfolded. By inducing ketosis, improving insulin sensitivity and supporting the mitochondria, you can often regain the ability to refold or proteolyze misfolded proteins.
Likewise, researchers wrote in the International Journal of Neuropsychopharmacology, “Research teams have reported some success in ameliorating the severity of symptoms in neurodegenerative diseases, most notably in patients with mild cognitive impairment or early Alzheimer’s disease [via diet-induced ketosis and/or ingestion of ketone bodies] … ”15
Bredesen’s ReCODE protocol makes use of nutritional ketosis, in which your body produces endogenous ketones (water-soluble fats), but that’s not all. Your body has a mechanism by which misfolded proteins are refolded. Heat-shock proteins play a central role in this process, and if the misfolding is too severe, the heat-shock proteins help remove them altogether.
Heat-shock proteins are a corollary of autophagy, the process by which your body cleans out damaged organelles, which relates to Alzheimer’s because the refolding process is one of several factors that need to work in order for your brain to function. In Medicinal Research Reviews, researchers explained:16
“There are few more neurodegenerative diseases, like amyotrophic lateral sclerosis (ALS), Alzheimer’s, and other dementias that have been investigated for their autophagy interconnection in the last two decades …
Autophagy also clears the aggregates formed by Alzheimer’s and dementia associated proteins tau, β‐secretase, and presenilin 1 for neuronal cells and provide cytoprotection against proteotoxicity caused by these mutant proteins aggregates.
The autophagy pathway participates in amyloid‐beta (Aβ) protein secretion and further clearance of accumulated aggregates of this protein in Alzheimer’s disease.”
Intermittent Fasting for Alzheimer’s
Unfortunately, a vast majority of people do not have well-functioning autophagy, for the simple reason that they’re insulin-resistant. If you’re insulin-resistant, you cannot increase your adenosine 5’ monophosphate-activated protein kinase (AMPK) level, which prevents the inhibition of mammalian target of rapamycin (mTOR), and mTOR inhibition is one of the primary drivers of autophagy.
Ultimately, Bredesen typically recommends an intermittent fasting approach, which helps your body to cycle through autophagy and the rebuilding phase:
“You want to use appropriate fasting and an appropriate diet to activate this autophagy,” Bredesen says. “We recommend … 12 to 14 hours [of fasting] if you are apolipoprotein E4-negative (ApoE4-negative) … If you are ApoE4-positive, you’d want to go longer — 14 to 16 hours. There’s nothing wrong with doing a longer fast …
The reason we suggest longer for the ApoE4-positives [is because] if you are ApoE4-positive, you are better at absorbing fat. It tends to take longer to enter autophagy …
Typically, we recommend it about once a week. But again, a longer fast once a month is a good idea. It depends a lot on your body mass index (BMI). What we found is people who have higher BMIs respond better to this fasting early on. They’re able to generate the ketones.
If you lose both the carbohydrates and the ketones, you end up [feeling] completely out of energy … We are very careful when people are down below 20 on their BMI, especially the ones 18 or below. We want to be very careful to make sure to cycle them [in and out of ketosis] once or twice a week …
These are the ones where, often, exogenous ketones can be very helpful early on … Measure your ketones. It’s simple to do. We want to get you into, ultimately, the 1.5 to 4.0 millimolar [range for] betahydroxybutyrate. That is the goal.”
To test your ketones, I recommend KetoCoachX.17 It’s one of the least expensive testing devices on the market right now. Another good one is KetoMojo. KetoCoach, however, is less expensive, the strips are individually packed and the device is about half as thick as KetoMojo’s, making it easier to travel with.
While drug trials for Alzheimer’s continue to fail, Bredesen’s latest book, “The First Survivors of Alzheimer’s,” contains exciting first-person accounts from patients diagnosed with Alzheimer’s who beat the odds and improved. You can learn more about Bredesen and his work by visiting his website, drbredesen.com.