Alzheimer's treatment: Aducanumab vs. Bredesen Protocol

 The FDA has recently given accelerated approval for a new drug, aducanumab, to treat mild Alzheimer’s Disease. Unlike other Alzheimer’s drugs currently on the market, which merely “manage symptoms” but do not slow the progress, this drug is said to be “disease-modifying.” However, the risks may outweigh the benefits, necessitating the search for another way to address the problem. Dr. Dale Bredesen says that he has developed a protocol which can actually reverse the disease.

What is Alzheimer’s Disease?

Alzheimer’s Disease is the most prevalent form of dementia affecting adults from 65 years of age and up. Other forms of dementia, as noted by the Cleveland Clinic, include vascular dementia, Lewy bodies dementia, frontotemporal dementia, mixed dementia, dementia due to Parkinson’s disease, and conditions that resemble dementia which are a result of medication side effects or thyroid problems and are reversible. “Dementia: Symptoms, Types, Causes, Treatment & Risk Factors.” Cleveland Clinic, 12 Mar. 2022, https://my.clevelandclinic.org/health/diseases/9170-dementia. [1] Mercury toxicity can also result in dementia.[2] Mutter, Joachim, et al. “Does Inorganic Mercury play a role in Alzheimer’s disease? A systematic review and an integrated molecular mechanism.” Journal of Alzheimer’s Disease, vol. 22, no. 2, 1 Oct. 2010, pp. 357–374, https://doi.org/10.3233/jad-2010-100705.

The Alzheimer’s Association’s “2023 Alzheimer’s Disease Facts and Figures” special report [3] “2023 Alzheimer’s Disease Facts and Figures .” Alzheimer’s Association, 2023, www.alz.org/media/Documents/alzheimers-facts-and-figures.pdf. states that approximately 6.7 million (1 in 9 or 10.8% of) Americans age 65 and over were living with Alzheimer’s dementia in 2023. Most are aged 75 or older. More precisely, the rate of Alzheimer’s, which goes up with age, affects 5% of people between 65-74, 13.1% of those between 75-84, and 33% of individuals 85 and above. 

Conversely, 89.2% of people age 65 and older do not get Alzheimer’s. The good news is that the rate of Alzheimer’s has been decreasing (although the raw numbers may increase as the baby-boomer generation ages). 

According to the report, the disease starts by affecting memory and cognitive function and progresses to mood changes and other emotional challenges:

In Alzheimer’s, the neurons damaged first are those in parts of the brain responsible for memory, language and thinking. As a result, the first symptoms tend to be memory, language and thinking problems. Although these symptoms are new to the individual affected, the brain changes that cause them are thought to begin 20 years or more before symptoms start.

. . . Alzheimer’s disease is a progressive disease, meaning it gets worse with time. How quickly it progresses and what abilities are affected vary from person to person. As time passes, more neurons are damaged and more areas of the brain are affected. Increased help from family members, friends and professional caregivers is needed to carry out activities of daily living, such as dressing and bathing, and to keep the individual safe. 

Individuals with Alzheimer’s may develop changes in mood, personality or behavior. One behavior that is of special concern is wandering, which refers to individuals walking away from a particular location and not being able to retrace their steps. Individuals who wander may become lost, putting them at risk of significant injury and death. 

. . . Studies indicate that people age 65 and older survive an average of four to eight years after a diagnosis of Alzheimer’s dementia, yet some live as long as 20 years. (Emphases added.)

Diagnosing Alzheimer’s

According to the Cleveland Clinic, diagnosing Alzheimer’s Disease may involve laboratory tests, imaging tests, and neurocognitive tests (thinking tests). Laboratory tests can be used to rule out infection, inflammation, underactive thyroid, and vitamin deficiency (especially B12) as causes of this dementia. 

Healthcare providers may order cerebrospinal fluid tests to evaluate autoimmune conditions and neurodegenerative diseases, if necessary.

Treatment options

Drugs to manage symptoms

Although doctors believe there is no cure for Alzheimer’s, medications have been developed to manage symptoms. The Cleveland Clinic explains there are two types of drugs approved by the FDA for symptom relief — cholinesterase inhibitors and NMDA antagonists. “Alzheimer’s Disease: Causes, Symptoms, Treatment & Stages.” Cleveland Clinic, https://my.clevelandclinic.org/health/diseases/9164-alzheimers-disease. [4] 

Cholinesterase inhibitors, which are predominantly used to ameliorate symptoms for mild to moderate disease are Donepezil (Aricept®) approved for moderate to severe disease, Rivastigmine (Exelon®), and Galantamine (Razadyne®).

The Clinic clarifies that these drugs are of limited benefit:

These drugs can improve some memory problems and reduce some behavioral symptoms of Alzheimer’s disease.

These medications don’t cure Alzheimer’s disease or stop the progression of the disease. (Emphasis added.)

Regarding the NMDA antagonist (N-methyl-D-aspartate), Memantine (Namenda®), reported as keeping certain brain cells healthier, the Clinic states that it is FDA-approved for treating moderate to severe Alzheimer’s disease. Studies show that patients perform activities of daily living like eating, walking, toileting, bathing, and dressing themselves better when on this drug.

Clinically significant adverse effects

Dr. James M. Ellison, MD, MPH of the Swank Center for Memory Care and Geriatric Consultation, ChristianaCare, writing for Bright Focus, [5] Ellison, James M, MD, MPH. “Do Alzheimer’s Medications Really Help?” BrightFocus, 10 Aug. 2021, www.brightfocus.org/alzheimers/article/do-alzheimers-medications-really-help. explains that cholinesterase inhibitors have gastrointestinal side effects, as well as “several other side effects that can be clinically significant: disruption of sleep, enhanced risk for bleeding, and slowing of the heart rate to the point of potential danger from fainting or disrupted heart rhythm.” However, Memantine’s side effects, as Ellison explained, “are often minimal, though occasionally Memantine can enhance or initiate confusion, agitation, constipation, or headache.”

A new drug said to slow Alzheimer’s progression

The newest drug, aducanumab (Aduhelm™) developed to treat Alzheimer’s Disease is reported to actually modify the disease and is credited with slowing clinical progression within 18 months for people with early-stage Alzheimer’s. The results of the original investigation, as reported in JAMA (Journal of the American Medical Association)[fn] Sims, John R., MD, et al. “Trial of Donanemab in Early Symptomatic Alzheimer Disease.” JAMA, JAMA Network, 17 July 2023, https://jamanetwork.com/journals/jama/fullarticle/2807533. [6] were significant, showing improved Alzheimer’s rating and Dementia rating scores. Amyloid plaques were shown to have been reduced. It must be noted that, of the 18 authors listed in the paper, 14 were employed by Eli Lilly, the drug’s manufacturer. 

Is the treatment worse than the disease?

Following Eli Lilly’s press release in May 2023 about the success of the stage 3 trials for aducanumab, John Travis, writing for Science, [7] Travis, John. “‘It’s Not a Miracle Drug’: Eli Lilly’s Antibody Slows Alzheimer’s Disease but Safety Issues Linger.” Science, 3 May 2023, www.science.org/content/article/it-s-not-miracle-drug-eli-lilly-antibody-slows-alzheimer-s-disease-safety-issues-linger. reported that while the drug did slow the progression of the disease some, it came with significant adverse effects, similar to those of a similar monoclonal antibody, lecanemab. He wrote:

Clinical trial results released today by Eli Lilly and Co. indicate its antibody donanemabclearly, if perhaps modestly, slows the progression of Alzheimer’s disease. Following on the heels of comparable results for a similar antibody, lecanemab, the data bolster the long-held but contested hypothesis that preventing the accumulation of a protein called beta amyloid in the brain could help the many millions of people who develop the fatal neurodegenerative disorder. (Emphasis added.)

Significantly, Travis also noted that the data showed a risk of brain swelling and hemorrhaging, which Eli Lilly revealed may have been the cause of two to three deaths in the clinical trial:

But Eli Lilly’s preliminary donanemab results also reveal a sobering risk of brain swelling and hemorrhaging, side effects that the company disclosed may be linked to two—perhaps three—deaths in the clinical trial and that echo hazards seen with lecanemab, which is being marketed by Eisai and Biogen. With the U.S. Food and Drug Administration considering full approval for lecanemab next month and Eli Lilly vowing to quickly submit donanemab to the agency for review, many physicians, Alzheimer’s patients, and their caregivers may soon face difficult conversations about whether to risk immediate harm to take these therapies, the first to be clinically proven to somewhat thwart a slow but inexorable destroyer of the brain.

Beyond that debate, Eli Lilly’s results are likely to fuel concerns about the dangers of amyloid-targeting antibodies. Lecanemab has been linked to several deaths and cases of severe brain damage, as well as to less severe brain swelling and hemorrhaging. (Emphases added.)

More side effects? 

Monoclonal antibodies [8] Monoclonal antibodies are laboratory produced antibodies designed to recognise and bind to specific receptors found on the surface of cells. They are derived from natural antibodies, complex proteins derived from a single B cell made by the body's immunological defence system to recognise and fight foreign invaders such as bacteria and viruses. “Monoclonal Antibodies Comprise a Third of All New Drugs.” WhatisBiotechnology.Org, www.whatisbiotechnology.org/index.php/science/summary/mabs/monoclonal-antibodies-comprise-a-third-of-all-new-drugs. [9]

Aducanumab, which received accelerated FDA approval, is from a class of drugs called monoclonal antibodies. In a paper in the journal Antibodies, “Immune- and Non-Immune-Mediated Adverse Effects of Monoclonal Antibody Therapy: A Survey of 110 Approved Antibodies,” Baldo, Brian A. “Immune- and non-immune-mediated adverse effects of monoclonal antibody therapy: A survey of 110 approved antibodies.” Antibodies, vol. 11, no. 1, 25 Feb. 2022, p. 17, https://doi.org/10.3390/antib11010017. author Brian A. Baldo details the four types of adverse events associated with this type of drug, even as it acknowledges that they have improved or provided treatment for many previously neglected diseases or those with poor outcomes. The adverse events include:

• anaphylaxis (a severe allergic reaction that can be life-threatening), 
• blood disorders, 
• potentially fatal skin disorders,
• lung, heart, and liver damage
• severe infusion reactions (antibodies are administered intravenously) are also very common. 
• any of the life-threatening syndromes associated with the antibodies are caused by cytokine storms which occur if the body produces an overabundance of pro-inflammatory molecules. Under ordinary circumstances, they are a normal part of the immune response, but a “sudden release in large quantities may cause multisystem organ failure and death.” 

Does aducanumab even work?

Dr. Andrew E. Budson, an Editorial Advisory Board Member for Harvard Health Publishing reviewed the data. He is not sure that the drug works at all, since two different drug trials had different outcomes, one positive and one negative. He explained:

I reviewed the publicly available data and the daylong FDA hearing on aducanumab. In a nutshell, there were two large clinical trials to assess effectiveness, side effects, safety, and how the drug might be used in clinical practice. One of the studies was positive, meaning that the drug worked to slow down the decline of thinking, memory, and function that is usually impossible to stop in Alzheimer's. The other large study was negative. In my view — and that of the FDA advisory panel — these results mean that we don't know if the drug works or not.

Another factor to consider is that the potential benefit — if the drug works as well as it did in the positive study — was fairly small. Looking at the two objective measures, in the positive trial, the high dose made a 0.6-point change on the 30-point Mini-Mental State Examination. On the 85-point Alzheimer's Disease Assessment Scale–Cognitive Subscale-13, the high dose made a 1.4-point change. (Emphases added.)

Fraud?

Amyloid plaques

In a recent article, “The cost of fraudulent research” by Ann-Marie Roche for publishing house Elsevier, Roche, Ann-Marie. “The Cost of Fraudulent Research.” Www.Elsevier.Com, Elsevier, 29 Sept. 2023, www.elsevier.com/connect/the-cost-of-fraudulent-research. [10] she described the harm caused by fraudulent papers since researchers rely on this false information as the basis for further research. The example given was a fraudulent paper relating to amyloid plaque to Alzheimer’s disease. 

In 2022, a whistleblower revealed that an Alzheimer’s study published 16 years earlier may have contained falsified information. Because this was a key study with critical findings that spurred subsequent avenues of research, the implications are incredibly serious. 

The study had confirmed a theory that the Aβ*56 amyloid protein caused dementia. “Its results inspired a new avenue of scientific research and funding, including pharmaceutical companies developing drugs aiming to break amyloid protein down or prevent its formation to treat Alzheimer’s disease,” wrote Aman Majmudar in The Scientist. “Even as the amyloid-protein theory has gained momentum, studies exploring it have yielded mixed results. Almost half of the funding for research on Alzheimer’s — $1.6 billion — from the National Institutes of Health for this fiscal year went to amyloids-focused research and drug development.”

Medical News Today has reported that the original paper is now being investigated by the editorial team at Nature but also points out that “to date, the paper has been cited in over 2,200 scientific papers and accessed more than 50,000 times.” If information in the study is proven to have been false, that would be thousands of hours wasted by scientists who could have been following more promising leads. It would be millions of dollars in precious research funds that could have been spent getting closer to a real cure. (Emphases added.)

This means that patients using these drugs, which were developed based on possibly fraudulent research, may not only have been given false hope but may have been subjected to serious and perhaps life-threatening adverse events.

Reversing Alzheimer’s 

While drug companies and medical researchers have been looking for one drug to be a magic bullet based on various hypotheses, Dr. Dale Bredesen, over years of research,  has found underlying health and lifestyle issues that may be responsible for the development of Alzheimer’s. Dr. Bredesen, the founding president and CEO of the Buck Institute for Research on Aging and director of the Easton Center for Alzheimer’s Disease Research, UCLA, says that 36 different “holes” that when addressed can prevent or even reverse the disease in people with mild cognitive decline and early dementia: “The Science of Alzheimer’s.” Apollo Health, www.apollohealthco.com/bredesen-protocol/. [11]

Using a twenty-first-century approach, Dr. Bredesen has found that treating Alzheimer’s is analogous to repairing a roof with 36 holes. Treating the disease requires addressing many aspects of the body at one time, as you would when repairing holes in a roof. The more holes you cover, the more success you have at fixing the problem. 

The current pharmaceutical approach is focused on developing a drug to combat Alzheimer’s. If we were to create a single drug specific to Alzheimer’s, it would have to perform so many different functions that it would be unlike any drug ever developed. Therefore, it is not surprising that there have been over 400 failed clinical trials using a monotherapeutic (single drug) approach. While the single-pill approach may not be a viable option, we can address the underlying problem and patch 36 factors or holes as we referred to them in our earlier analogy by knowing the characteristics of the disease. This approach is the cornerstone of the Bredesen Protocol. 

To understand Alzheimer’s and why neurons in the brain degenerate, we need to look at it from a cellular level. Higher organisms (including humans) rely on four developmental processes:

• Proliferation
• Differentiation
• Migration
• Integration 

We also rely on these processes for the repair and regeneration of cells and neurons. This cyclic routine creates a lifelong need for balance among these processes. When this balance is disturbed, it can result in the development of diseases such as cancer or Alzheimer’s. In cancer’s case, an imbalance towards an increase in the proliferation and survival against programmed cell death leads to the development and spread of cancer cells in the body. (Emphases added.)

Listen to Dr. Bredesen in this TedTalk: A precision approach to end Alzheimer's Disease

Listen below to hear Dr. Bredesen's 7-step plan to avoid dementia.

Below Dr. Bredesen speaks at a Grand Rounds to doctors at the Cleveland Clinic which was hosted by the Center for Functional Medicine of the Cleveland Clinic and “presents his innovative protocol for reversing memory loss,” showing "how one goes about developing an effective treatment for an incurable illness."

The following video is a short Q&A with Dr. Bredesen and Dr. Mark Hyman, Head of Strategy and Innovation, Cleveland Clinic, Center for Functional Medicine, following Bredesen's Grand Rounds talk.

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