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Alzheimer’s disease: The drugs don’t work but this protocol does

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Alzheimer’s drugs aren’t the answer to dementia, says Dr Jerry Thompson. Taking an individualized approach that considers the potential root causes could be instead

New Alzheimer’s drug donanemab has hit the headlines recently and been hailed as a “turning point” in the fight against dementia.1 But is this drug really the answer to Alzheimer’s? And what about the other drugs used to treat the disease?

If you or a family member are affected by Alzheimer’s or another form of dementia (most of the research is on Alzheimer’s disease—the most common form), it’s vital you know about the questionable benefits and downsides of these drugs.

Drugs for Alzheimer’s disease

The available drugs for treating Alzheimer’s are all old—in fact, very old. No new drugs have become available since 2002.

Another drug has recently been licensed in the US but not in the UK or Europe, and further drugs of a similar type may be marketed soon. One drug made it to the market but was withdrawn due to severe liver toxicity (Tacrine).

None of the drugs presently available alter the course of the disease. There are still over 100 drugs in the pipeline, but these are thought to be newer variations of existing drugs.

Initially, things were different. Pharmaceutical companies recognized that dementia was a potentially huge market and invested heavily (spending an estimated $42 billion in 25 years). They knew that people with Alzheimer’s disease had very low levels of the neurotransmitter acetylcholine, which is reduced by as much as 90 percent in dementia.

Acetylcholine is essential for nerve transmission and memory. The race was on to find a drug that could increase acetylcholine and thereby potentially cure dementia.

The drug companies developed cholinesterase inhibitors (cholinesterase breaks down acetylcholine), which they expected to increase the levels of acetylcholine. Unfortunately, these drugs did not live up to expectations and were far from a cure for dementia.

But what of the drugs that made it to market? Four drugs are currently licensed in the UK for treating Alzheimer’s disease. Three are cholinesterase inhibitors: donepezil (Aricept), rivastigmine (Exelon) and galantamine (Reminyl, Acumar or Galasya).

The odd one out is memantine (Ebixa, Maruxa or Nemdatine), an NMDA receptor blocker, which inhibits glutamine, not cholinesterase. However, in reality it acts very much like a cholinesterase inhibitor.

All these drugs have been disappointing in that they provide only minor benefits. None slows the progression of the disease. Although they successfully block cholinesterase, the brain compensates by producing more of the enzyme. This creates a further problem: if the patient stops the drug, symptoms worsen.

Another issue is adverse effects. Cholinesterase inhibitors can cause nausea, vomiting, diarrhea, insomnia, bizarre dreams, cramps and fatigue, while memantine can cause dizziness, drowsiness, agitation and hallucinations. For carers, it’s not easy to distinguish drug side effects from a flare-up of dementia, complicating recognition of the problem.

The drugs may also make dementia worse. In November 2018, a review of 10 studies pooled the data from 2,714 patients who received cholinesterase inhibitors or memantine. It found a significantly greater annual decline in mental function in patients on these drugs compared with those on no drugs. Those on both drugs did the worst.2

The latest drugs

The first new drug in 20 years to be approved in the US (but not in Europe and the UK) was aducanumab (Aduhelm). For many years it was thought Alzheimer’s disease was caused by a buildup of beta-amyloid plaque in the brain. However, 30 unsuccessful trials of drugs that lower amyloid have shown they make no difference in mental function—or even worsen it.

The US Food and Drug Administration (FDA) approved aducanumab for early-stage dementia in June 2021, garnering heavy criticism from neurologists and scientists. Three of the FDA experts resigned within days of the approval.

Aducanumab targets amyloid. Given by infusion, it has been noted to cause brain edema in as many as 35 percent of cases and micro-hemorrhages in 19 percent. This means regular MRI scans need to be done on all patients taking it. Every aspect of this process is difficult with dementia patients.

The drug costs approximately $28,200 (£22,300) a year, half of what it cost when it was initially released. Two trials showed it was ineffective and one showed some benefit.

You may wonder why it hasn’t been approved in the UK or Europe. The controversy surrounding this drug was that it was approved for its benefit on a “surrogate endpoint”—because it removed amyloid, not because it led to any clinical improvement.

Given what we know about amyloid and the unsuccessful results of previous trials of drugs targeting it, aducanumab’s ineffectiveness was hardly a surprise. So the approval was indeed a bizarre decision. However, the European Medicines Agency (EMA) refused to give it a license in December 2021.

While this controversy has been going on, another drug has been developed called lecanemab. It is similar to aducanumab in that it targets amyloid, although a different type of amyloid, and is given by infusion every two weeks.

A trial of lecanemab in 1,795 people caused excitement as it was found to reduce cognitive decline by 27 percent over 18 months. The reality was less striking: the difference between scores of patients taking the drug and those taking placebo was 0.45 on an 18-point clinical scale of dementia.

In other words, this change was small and probably barely noticeable. The drug might have benefits, but it’s far from a cure for dementia. Like aducanumab, it can cause brain edema and bleeding, as it did in 23 percent of trial participants. Despite this danger, the drug has been fast-tracked for approval.

Since then, a third drug targeting amyloid, donanemab, has made the headlines. Like lecanemab, it showed a small benefit in trials, reducing decline in Alzheimer’s dementia by 10 points on a 144-point scale (compared to 13 points with placebo) over 18 months.

However, a quarter of patients developed brain edema or bleeding while on the drug. Infusion reactions occurred in 9 percent, and three people died (one on placebo). As you can see, it’s far from clear whether the benefits of the drug outweigh the risks.

Few people have heard of the fourth drug of this class, solanezumab. It works in the same way, successfully stopping the amyloid burden increase in preclinical Alzheimer’s disease. However, it does not help with cognitive function.

Why are there no new drug discoveries?

Although mainstream medicine has been highly effective in curing acute conditions (infections, fractures, surgical emergencies), it has had almost zero success in treating chronic diseases. Even with cancer, a cure usually results from early surgery rather than drugs. Apart from a few rare conditions, we can say that virtually no chronic disease has been cured.

So perhaps we shouldn’t be too surprised that no cure has been found for dementia.

The strategy of pharmaceutical companies has typically been to create drugs that block pathways in the body—beta-blockers, antihistamines, antidepressants and, in this case, cholinesterase inhibitors. This is good for symptom relief but not useful for curing an illness.

A newer development is to use monoclonal antibodies to target certain body structures. These drugs usually end in “mab,” short for monoclonal antibody, and include the three amyloid-targeting drugs discussed above. Some of these monoclonal antibodies have had major benefits in terms of relieving symptoms when used in other diseases, but none has led to a cure. They are also extremely expensive and alter immunity, predisposing those who take them to serious infections.

An effective alternative

There is another way, one that requires a different way of thinking. It involves looking for the causes of the disease and then maximizing the immune system’s effectiveness by increasing the elements supporting the body (such as good nutrition, exercise and sleep) and removing damaging factors (such as stress, toxicity, allergy and inflammation). Eventually the body reaches a tipping point where recovery occurs.

Dr Dale Bredesen, who spent much of his life researching the brain and established his own laboratory at the University of California, Los Angeles (UCLA) in 1989, came up with an effective protocol for Alzheimer’s after he discovered what he considered the underlying mechanism.

He found Alzheimer’s disease could arise due to a protective mechanism. If the brain doesn’t have enough brain-nourishing substances available, notably brain-derived neurotrophic factor (BNF) and netrin-1, or if it has an excess of toxic substances to deal with, including amyloid and biotoxins, it has to shut down some parts of itself to preserve function in the more essential areas.

It all hinges on a molecule that sits on the nerve receptor called APP (amyloid precursor protein) and the way it breaks down. If all is well, APP breaks down into two nerve-nourishing substances and the brain functions normally.

But if the brain is faced with deficiencies or toxic substances and has to use this protective mechanism, it instead produces four nerve-damaging substances. He also found that, by controlling the various factors that influence APP, it was possible to tip the balance away from nerve destruction and toward nerve creation.

Bredesen discovered 36 key factors that influence the breakdown of APP.3 He developed the Bredesen protocol, called ReCODE (see below), and applied to have it tested like a drug. However, his application was turned down as he was told it was too complex because the protocol is highly individualized.

Despite this negative response, Bredesen went on to do clinical trials of his protocol. In 2014 he published a study of 100 patients from clinics in the US and Australia who went through the protocol. Nine out of 10 patients with early Alzheimer’s disease showed reversal of mental decline.4 These results, which had never been achieved before, have been replicated in two further peer-reviewed studies.5

The ReCODE protocol has now been successfully used in over 1,000 patients in seven countries. While only a minority with advanced Alzheimer’s disease improve, some 50 percent with moderate disease improve and virtually all patients with mild Alzheimer’s disease improve.

It typically takes six months for the pathological brain changes to reverse, but the condition can return within a few weeks of stopping the protocol, so perseverance is essential.

A natural, individualized approach

So why are patients treated with largely ineffective drugs when we have peer-reviewed published evidence of an effective treatment for dementia (at least in the early stages)? A major reason is that the cure involves using natural substances that cannot be patented. This means there is no money to be made by pharmaceutical companies and hence no money to support research.

Another issue is that the treatment is complex because of the need to look at all the possible underlying causes and correct them individually. But it’s this very complexity that explains why no present drug treatment has been successful to this day. The one-size-fits-all drug approach certainly isn’t working.

Alzheimer’s and dementia

Dementia is an umbrella term for various symptoms such as short-term memory loss, perceived personality change and impaired intellectual functions. It may include impaired judgment, difficulties with abstract thinking and loss of communication skills.

The terms dementia and Alzheimer’s disease are often confused, but it’s important to remember that Alzheimer’s disease is just one of the diseases that causes symptoms of dementia. Other forms of dementia include vascular dementia, Lewy body dementia and fronto-temporal dementia.

Adapted from “Drugs and Dementia,” by Dr Jerry Thompson, a chapter in Dodging Dementia: Understanding MCI and Other Risk Factors by Mary Jordan (Hammersmith Health Books, 2024)

The ReCODE protocol

The ReCODE protocol is designed for those with mild cognitive impairment or early-stage Alzheimer’s disease. It’s highly personalized depending on the various factors that may be causing or contributing to a person’s individual symptoms, but seven key strategies form the core of the protocol.

  1. Nutrition. Central to ReCODE is KetoFLEX 12/3—a heavily plant-based, nutrient-rich, whole-foods diet that focuses on local, organic and seasonal non-starchy vegetables combined with adequate protein and generous amounts of healthy fat. In 12/3, the 12 refers to the 12 hours between your last meal at the end of one day and your first snack or meal the next day, and the 3 refers to the three hours you should maintain between your last meal and going to bed. For example, if you go to bed at 10:00 p.m., don’t eat after 7:00 p.m., and hold off on breakfast until at least 7:00 a.m. the next day.
  2. Exercise. Aerobic exercise, strength training and mind-body practices such as yoga and tai chi are all essential parts of the protocol.
  3. Sleep. Seven to eight hours of sleep each night is optimal for brain health. It’s vital that sleep conditions like obstructive sleep apnea are treated effectively.
  4. Stress reduction. Techniques such as mindfulness meditation, qigong and yoga along with stress-management habits like unplugging from technology, using lists and taking time for self-care are encouraged daily.
  5. Brain stimulation. Daily brain training using exercises like those developed by BrainHQ (brainhq.com) is key to keep your brain challenged and promote new neural pathways. You can also stay mentally active by learning a new skill, having a strong purpose in life and being part of a social group.
  6. Detox. Identifying and avoiding the toxic agents that can have a negative effect on brain health is another important part of ReCODE. Heavy metals like mercury and aluminum, plastics chemicals, pesticides and mold are some to watch out for.
  7. Supplements. These are based on individual needs, but some of the specific nutrients recommended are as follows:
  • Vitamin B1 for memory formation, 50 mg daily
  • Vitamin B5 for alertness, 100–200 mg daily
  • Vitamin B6/B12/folate combination
  • Vitamin D, 2,500 IU daily until optimal levels are reached
  • Vitamin K2 as MK7, 100 mcg daily
  • Citicoline for synapse growth and repair, 250 mg twice daily
  • Ubiquinol or coenzyme Q10 to support the mitochondria, 100 mg daily

For more information, see apollohealthco.com and Reversing Alzheimer’s.

References
  1. Psychosom Med, 2005; 67(1): 24–30
  2. JAMA Netw Open, 2018; 1(7): e184080
  3. Dale Bredesen, The End of Alzheimer’s: The First Programme to Prevent and Reverse the Cognitive Decline of Dementia (Vermilion, 2017)
  4. Aging, 2014; 6(9): 707–17
  5. Aging, 2016: 8(6): 1250–58; J Alzheimers Dis Parkinsonism 2018; 8(5): 450
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