The Multiple Pathways and Causative Factors of Alzheimer’s and Dementia

Written by Neal Rouzier, MD

Every year I struggle with the decision as to what topic would be the most appropriate for the next APIM Annual Summit. Three years ago, at Hormones & Beyond Symposium 2019, we reviewed diabetes, fasting, treatment options, and pathophysiology. Two years ago, we covered How Estrogenics are making you Fat, Sick, and Infertile. Last year, we reviewed cancer, hormones, cardiovascular disease, and prostate cancer. So, now what? Fortunately, the FDA has recently approved the first and only treatment for Alzheimer’s Disease.  This was extremely political and controversial. Also recently, I attended a lecture by Dale Bredesen from U.C.L. A., a world’s expert on dementia and Alzheimer’s Disease. As a result of the foregoing, the topic for this year’s symposium was easy. And as usual, and as I did with hormones and cancer, diabetes, CVD, and prostate cancer, I will disagree with the current treatments and strategies purported in the literature to be beneficial. However, I base my opinion on current medical literature that is seemingly ignored, missed, or not appreciated by medical societies and our peer medical specialists. I plan to present that which is so obvious and scientific yet ignored just like the elephant in the room.

The Multiple Pathways of Dementia

By way of introduction, Dr. Bredesen states that dementia is a complex disease process, oftentimes being many separate disease states all resulting in some form of dementia. There can be multiple pathologies that can result in many different types of dementia, and these can be additive. Dale relates the analogy of a leaky roof with many different leaks all requiring a different type of patch to fix each leak.  He relates that the pharmaceutical industry has thrown over 40 billion dollars at trying to fix Alzheimer’s dementia and yet we still are no farther ahead in treating and reversing the disease process than we were 20 years ago. This is due to the fact that dementia is not due to just one factor as there are now many known factors and pathways to many different types of dementia. As a result, there are multiple contributors, multiple theories, multiple proposed treatments, and multiple failures. AD is stated to be a metabolic disorder, an inflammatory mediator disorder, a mitochondrial disorder, a hormonal deficiency disorder, a nutrient disorder, an environmental disorder, a toxicity disorder, and an iatrogenic disorder caused by us clinicians prescribing various medications. Diagnosing the toxic players and removing them has also been challenging. However, multiple toxic medications that can increase dementia are alarming and can be simple to remove. Our ignorance as to the medical literature demonstrating iatrogenic harm of everyday medical treatments and our reluctance to stop these medications is unconscionable. “Yes, but the benefits outweigh the risks!” Well, no they don’t.

All of the above multiple mechanistic factors can be simultaneously additive in this multifactorial disease process. We are well aware of the deposition of beta-amyloid plaque on neurons as well as the neurofibrillary tangles of tau protein as the main pathological insults that result in neuronal cell death. However, we still don’t know what exactly causes this pathology or why. (I do). We do understand the pathophysiology of vascular dementia related to atherosclerotic plaque in blood vessels. However, dementia can be due to a little of both, and even due to the third most common cause of dementia which is LATE (Limbic-predominant age-associated TDP-43 encephalopathy where a protein TDP-43 accumulates within neurons resulting in cell death). So, is it the AD, VD, or LATE that took precedence in causing the signs and symptoms of dementia? Could the different pathologies (one is plaque inside of blood vessels and the other is plaque on the outside of neurons) be driven by the same cause/mechanism? (I think it is). Both result in similar clinical dementias by the same mechanism but with different pathological changes on autopsy. Ultimately, path reports indicate that the causation might be the same, but the response is different in different tissues. If we can simply remove the major contributors to the disease process, then we can stop the initiation and disease progression. And that is exactly what the literature supports but is ignored. The data and studies from multiple therapies proving benefit are impressive. What is not impressive is how this data and the outcome studies are ignored. My analogy is that we are trying to put out the fire once the house has burned down as opposed to preventing the fire from starting in the first place. We should not be throwing monoclonal antibodies at the fire once there is no structure left to the house. Monoclonal antibodies do nothing to prevent the disease in the first place and everyone ignores the elephant in the room that is responsible for the disease process. And monoclonal antibodies do not address the cause of the disease process. If the inside of the house gets cooked, throwing flame retardant on the outside is meaningless. How to treat, prevent, and reverse AD that starts inside the neuron is the theme for this year’s upcoming 7th Academic Summit: Breakthroughs in Brain Health, CVD, and Autoimmunity.

Non-Patentable Drugs and Therapies in Dementia

If we know and understand that the pathology of AD involves deposition of the beta-amyloid plaque and neurofibrillary tangles of tau protein, then it makes more sense to sort out the initial cause of this pathology. The data and literature of successful prevention and treatment of AD is tremendous, whereas I continue to see claims that there is no treatment or prevention for AD. Well, there are many treatment modalities but none that is an FDA-approved patented medication. Nevertheless, the pharmaceutical world struggles to develop that billion-dollar patentable drug that will fix AD. We’ll spend several hours examining these outcome studies of non-patentable drugs and therapies that demonstrate a decrease in AD plaque and metabolic changes seen in the neurons on FDG-PET scans. We will also review all the data demonstrating improvement in clinical signs and symptoms which, unfortunately, has not been demonstrated in any study with monoclonal antibodies. Should we not embrace the literature demonstrating protection and reversal of disease rather than chase monoclonal antibodies that have failed in so many studies to provide improvement in symptomatic dementia? Great, so the PET scans showed mild decrease in beta-amyloid plaque with monoclonal antibodies, but the house still burned down. And the patient is still clinically demented.

The FDA Approved Drug for Dementia

It is the tau tangles and aggregates inside the cell that are resulting in the cell death. The tangles and aggregates found outside the cell are the result of the insults inside the cell that eventually get pushed/transported to outside the cell. Removing this extracellular trash/tau and beta-amyloid tangles/aggregates seems meaningless if there is no improvement clinically. Out of the 3 studies of aducanumab, none demonstrated any overall improvement clinically (symptomatically) after removal of extracellular plaque. Perhaps with time we will discover the proper dose given at the right time will help, but we await long-term studies. However, upon further review and data mining, there was slight clinical improvement in beta-amyloid plaque removal from the outside of the neuron, but only with the high dose aducanumab (Aduhelm). Based on this finding in only one of the three studies, the FDA issued a controversial FDA approval for Aduhelm. Aducanumab is the first and only FDA approved drug that treats/removes extra-cellular plaque in AD patients. Perhaps there is hope for AD patients. But what about the disease inside the neuron that is destroying the cell during the 30 years prior to the onset of clinical symptoms?

The Causative Factors of Alzheimer’s Dementia

The best way to fully address health problems is to treat their root causes. This may be surprising to some but one way to do this is through hormone replacement therapy. Simply stated, hormone replacement therapy replaces hormones that decline as we age. In essence, it treats the root cause of many age-related ailments.

The current FDA treatment with aducanumab is similar to the treatment of CVD with statins. Although statins have an enormous benefit in secondary prevention studies, their effectiveness is weak in primary prevention studies averaging 2-3% risk reduction in men and no benefit to women in the majority of studies for primary disease prevention. IR, dyslipidemia with high triglycerides and low HDL, and obesity seem to be more causative in CVD than elevated cholesterol. (Statins’ main benefit is in converting echolucent plaque to echogenic safe plaque, but so does E2). Similarly, once the disease has been allowed to destroy neurons for 30 years, removing the plaque formed on the outside of the neuron by monoclonal antibodies does not make sense and this is evidenced by failure so far of all the AD monoclonal antibody drugs. Once the house has burned down, once the neuron has been destroyed, it makes no sense to remove the plaque from the outside of the house if the inside of the house has been destroyed. Bredesen addresses that there are multiple causative factors that can be additive to this multifactorial disease process causing different types of dementia. Is it the vascular dementia that is primary, or the AD that is primary, or some other disease process? In addition, Bredesen points out that there are an infinite number of possibilities that can be causative as well as many different pathologies seen on autopsy. Bredesen stresses that the onset of AD occurs 30 years before clinical signs are manifest as evidenced by AD plaque seen on PET scans in younger individuals.  What Bredesen failed to emphasize was prevalent causative factors that can and should be diagnosed and treated so that AD can be prevented. We should be looking for horses and not zebras. Based on the literature that I will present, the cause of AD is no different than any other disease process seen in all other tissues and organs. However, Bredesen fails to stress this and leaves us hanging just like an Alfred Hitchcock movie. I plan to present the data and literature as to the cause, prevention, and treatment of the most common types of dementia and it does not involve the use of monoclonal antibodies.

Similar to CVD, dementia can be due to many common causes, many zebras. Bredesen addresses many of the zebras that can cause dementia. Heavy metals, excess iron and copper, EDCs, fungus, nutritional deficiencies, mitochondrial dysfunction, inflammatory disorders, medications, genetics, all contributing to a toxic insult to the brain. However, I feel that all the foregoing causes only a small percentage of major contributors to the disease initiation and progression. Sure, we should put back in what is missing and remove the inciting/causative agent that should not be there. But what is the most important causative factor resulting in beta-amyloid plaque deposition and intercellular tau tangles? It has been demonstrated that the process of plaque formation found outside the cell actually starts inside the cell from some inciting agent that is responsible for the cell death. It is not necessarily the plaque that forms outside the cell but rather the tangles and aggregates found inside the cell that get pushed/transported to outside the cell. And there is some indication that it may be a defect in the microglia that is responsible for the cleanup of cellular debris that may also be causative. In addition, over 20% of patients with significant beta-amyloid plaque seen on PET scans have no evidence of AD dementia. And removing that plaque with monoclonal antibodies has not resulted in any improvement clinically in those that are severely affected. Hmmm. 

Upon further review of the study that demonstrated no improvement with aducanumab, and along with some data mining, high dose aducanumab did demonstrate removal of plaque on PET scans. However, there were some significant side effects and intracranial hemorrhage with the high dose aducanumab. Nevertheless, based on this re-evaluation of one study, the FDA approved aducanumab as the first and only drug that treats/removes extracellular beta-amyloid protein plaque. The FDA decision to approve aducanumab came with great controversy as many FDA members did not agree to approving the medication wherein many resigned from the FDA as the result. Although there was significant disagreement among the FDA members, the FDA approval was heralded as a “gamechanger” for the neurological world. Recently the enthusiasm has waned with many neurological centers refusing to administer the medication. In addition, Medicare has restricted use to only patients that are enrolled in the IRB studies (which they should have been anyway). Unfortunately, the patient that resides in a rural area won’t have access to treatment centers and family PMDs won’t be able to administer the medication. On the other hand, patients should only be treated by expert neurologists that are specially trained in prescribing and monitoring these complex and problematic medications. Whether these medications will result in disease regression and symptomatic improvement remains to be seen.

Collateral Damage – Why Do We Ignore It?

Bredesen ended his lecture with much excitement. There is evidence that AD starts 30 years before AD becomes symptomatic and clinical. He stated that AD is entirely a preventable disease whereby the year 2050, AD will not be a disease that we encounter, rather a disease that we only read about in medical history books (thundering audience applause). Early signs of AD are evident that will enable us to intervene long before clinical disease becomes manifest. (That’s what they said about CVD which continues to accelerate every year despite all the drugs we throw at it). So then, how does one diagnose, treat, and remove the multiple disease drivers? How can we prevent and treat the disease before the house burns down? Doesn’t anyone else see the elephant in the room? What Bredesen failed to mention/address in detail is the iatrogenic disease that we clinicians cause that is well referenced in our literature but simply ignored. And that will also be a major focus of mine in this conference. It will be entitled “Collateral Damage – Why Do We Ignore It?” 

Stay tuned for more discussion as to upcoming topics and agenda for WLM Academic Summit.

Respectfully, Neal