Untangling the Plaque Mess in Neurological Disorders: “Oh, What a Tangled Web we Weave, When First We Practice to Deceive!”

In 1906, Alois Alzheimer first reported a connection between dementia and plaques after postmortem examination of the brain and medical records of a patient with strange behavioral symptoms. Dementia is a progressive, irreversible brain disease that slowly destroys cognitive skills and memory function. Alzheimer’s disease (AD) is the most common form of dementia accounting for more than half the cases of dementia. AD and dementia are heterogenous diseases and exhibit a high degree of variations in clinical manifestation and symptoms. While this phenotypic variability is recognized by clinicians, researchers, and epidemiologists, no effort is made to subcategorize these neurological diseases, their management, and/or treatments.

Age is the single biggest risk factor for AD. While the average duration of AD is 8 years, people can live for over two decades with this disease. The etiology, symptoms presentation, risk factors, development, and progression of most neurological diseases, including dementia and AD differs between women and men. While the incidence of AD appears to be greater in women, there is no evidence of sex or race effect. Since women on an average live longer than men, there are more women with AD. Reporting bias likely skews the numbers. In most societies, women play a key role in running day-to-day life for the household and even small decline in cognitive skills and memory function will be noticed and impact normal functioning of that household, whereas a similar cognitive decline in men may simply be attributed to old age. Another key sex difference is that the disease progression is faster in men and slower in women. A systematic review of all clinical trials performed so far for AD found that none of the trials/studies reported or analyzed data accounting for biological sex or age as variables on the safety, efficacy, and tolerability of therapeutic interventions.

Brain imaging studies, especially those that compare brain images between AD patients and healthy controls for diagnosis of dementia and AD seldom consider age in data analysis. For example, when age is accounted for before statistical tests are applied for data analysis, substantial differences between young AD patients and healthy control subjects are noted in brain areas showing atrophy (shrinkage). In analysis taking age into account, grey matter atrophy of the right hippocampus and right temporal lobe was far more pronounced in old AD patients, but data were not analyzed by biological sex. The hippocampus plays a key role in memory (both memory formation and retrieval). However, there might be sex differences in affected brain regions or the brain connectome (functional network between brain regions), but studies do not examine or focus on these aspects that can be key in understanding disease progression.

Alzheimer’s disease is divided into two categories: early-onset that develops between ages 30–60 years, is rare and accounts for only 2% of the cases; early onset shows a strong Mendelian inheritance pattern. Second category is late-onset and is the most common form of AD. There is a genetic predisposition to late-onset AD, but several polymorphisms are associated, and inheritance of these mutations does not necessarily result in AD in the children. The course of disease progression for both early- and late-onset is arbitrarily divided into three stages, namely: early/mild, moderate, and severe AD. The initial onset of AD is insidious; memory loss is the earliest and most frequently reported symptom. Unfortunately, there is no precise diagnostic test that confirms the presence of AD. A probable diagnosis of AD is arrived at by excluding other conditions that may also explain the observed symptoms. Neuropsychological and mental status testing tools are used by clinicians for diagnosis. The criteria for diagnosing dementia as per the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV), requires loss of two or more domains, including memory, language, calculation, orientation, and judgment. Neuropsychological tests, such as the Mini-Mental State Examination (MMSE) help provide clinical insights into cognitive changes. Magnetic resonance imaging (MRI) or PET/CT scans can be used to discriminate between other forms of dementia, but imaging is not a definitive test. While an experienced physician can diagnose AD with high accuracy, as of now, a definitive diagnosis of AD requires not only the presence of severe dementia but also postmortem confirmation of two histopathological features, neurofibrillary tangles, and extracellular amyloid plaques.

The scenario is further complicated as there are many people who have plaques but never develop dementia, AD, or memory loss. As stated earlier, genetic mutations associated with AD, dementia, or other neurological diseases, such as Parkinson’s do not guarantee development of frank symptoms or disease. Animal models of these human mutations similarly show high variability in presence of misfolded proteins, tangles, plaques, and behavioral symptoms are even harder to ascertain in animals. If many people with plaques and tangles never develop dementia or AD, could plaques and tangles be only a small part of the story? Could these researchers have been partly wrong? Reports highlight fraudulent data published in the journal Science in 2006 overstating the role of amyloids. Other papers also published cherry-picked data to fit a narrative that is appealing and despite investigation, not much has changed for the scientific field or the scientists involved. The papers with falsified data continue to be cited and research proposed and granted to pursue dead ends. Millions of dollars are being spent in researching hypotheses that appear to be a tangled web of lies. In support of this notion are many failed clinical trials targeting amyloid plaques. One study reporting data from a clinical trial initiated in 2000 by Elan Pharmaceutical with up to 15-year follow-up, found that patients on brain scans showed robust decrease in amyloid plaque accumulation after immunotherapy, but despite disappearance of plaques, there was no effect on disease progression and all patients progressed to severe dementia. Post-mortem brain histopathology confirmed absence of plaques.

The protein composition of human vascular amyloid plaques was first reported in 1984 and Tau was reported to be the predominant protein in neurofibrillary tangles in 1985. The observed link between mutations in the gene coding for the Aβ precursor protein (APP) and early onset familial forms of AD, led to the formulation of the “amyloid cascade hypothesis”. Since the postulation of cascade hypothesis, it has been assumed that the AD pathology is initiated by aggregation of Aβ due to mutations making the peptide more prone to misfolding and accompanied by misfolded tau in the tangles. The role of other proteins or mechanisms has largely been ignored. In 1994, at least 35 proteins were reported present in the senile plaques and the number increased to >450 in 2004. As protein purification and identification techniques have become more advanced and sophisticated, several thousands of proteins have now been identified that are associated with plaques and tangles- some proteins are permanent fixtures of the plaques/tangles, whereas other proteins only show transient interaction and evade being caught in the mess. Thus, the scenario is far more complex than a simple amyloid cascade hypothesis. Some other proteins that play very important role in normal functioning of human physiology are part of this tangle. These include, but are not limited to, apolipoproteins (APOE, APOA-I-IV), blood coagulation factors, heat shock proteins, proteases, protease inhibitors, immunoglobulins, proteins of the complement system, proteins involved in metabolism and molecular transport, cell adhesion and extracellular matrix proteins, and several others.

When one of the co-founders of Biogen, who also is a prominent neurologist actively researching mechanisms and therapeutics for dementia was asked for his opinion on the status of this research in an interview. His response was as follows [sic]: “I’ve been trying to develop drugs to stop Alzheimer’s and Parkinson’s. Now, when I started this, I thought, well, some of these big pharmaceutical companies — we’re talking about big companies with gigantic loads and loads of people, huge staffs — I thought I’ll be competing with all these people, but we’ll see what happens. If they fail, this is an unbelievable mess, and that’s exactly what we’re faced with. Its in the literature now and in the newspapers. It’s everyday. Why the hell has all this failed? We — meaning the American people — have put all of this money into Alzheimer’s disease. I don’t know the number — I was going to look it up the other day, but I didn’t do it — I was going to look up the number of papers with Alzheimer’s disease in the title. You can do this in PubMed. My guess is it’s 100,000 or 200,000. It’s just an enormous number of papers, and we’re nowhere. But I really think we’re getting somewhere. We’re moving in a very positive way, so I’m really excited. I’m really happy about this. I’ve got these groups of people. It’s about marshaling all of the skills you need. This is a little more complicated than prions. You’ve got to kill the prion without killing the person. It’s one failure after another. There’s a drug that we’ve been studying. It’s useful in mice. But Amgen killed the drug because it was putting fatal arrhythmias into the hearts of dogs”.

He continues: “Then, there’s another one that was just announced not long ago by Merck. Merck said, “Well, there’s no efficacy.” That’s probably because, without stopping the tau protein from becoming a prion, it just tried to stop the Aβ peptide from becoming a prion. That’s actually lowering the Aβ level. It doesn’t work, because the tangles are being generated already. It’s fascinating to me. I want to see this scourge stopped. It’s horrible! I’ve listened to one story after another, because everybody wants to talk to me about their Alzheimer’s disease”.

Let’s pause and examine this statement about Merck’s drug not working from co-founder of Biogen because despite lowering Aβ levels and plaques, the tangles are still being generated and the drug is thus not effective treatment. The new Biogen drug, Aduhelm, approved by the FDA in June 2022, well, it apparently does exactly what the Merck drug did- lowers the Aβ level but shows no improvement in memory loss or dementia. So, if in Biogen’s co-founder’s words, this is a failed treatment for Merck, why is this any different for Aduhelm?

On June 7, 2021, the FDA approved Aduhelm (Biogen’s aducanumab) under a process called accelerated approval. That the FDA was planning approval through this process was not disclosed to the advisory committee members who reviewed the data, and the members were taken by surprise when told about FDA’s decision. Dr. Aaron Kesselheim is a world-renowned expert in ethics and health policy related to drug development and was one of the three members of the FDA advisory committee who resigned in protest over the FDA decision to approve this questionable drug. Amongst many objections cited by Dr. Kesselheim, included the fact that the Biogen clinical trials were stopped because despite two trials, there was no evidence that the drug would show any benefit. Biogen subsequently re-analyzed the data and found an absolute reduction of 0.39 points on the cognitive decline scale (the scores are between 0–18 points) which somehow was translated to a 20% improvement. Let’s be clear, according to the clinical data, that so called 20% change is not even perceptible to the patient or to their caregivers/family members. Even worse, 40% of the participants in Biogen clinical trials had brain edema (swelling). The consequences of that brain swelling on patients’ well-being and health are not even highlighted by the media covering the story. However, the end point that was finally taken into account was not symptom improvement, but reduction in levels of amyloid plaques as assessed by patients’ brain scans, an end point that failed in Merck’s trial and that Biogen’s cofounder called a failure!

Why was Aduhelm approved by the FDA in the first place? Why give false hope to so many? Just because the American people have put all this money into AD research, we need to repackage failed therapeutics and sell it for a hefty price of 56,000 US$? Who is recovering that money? The American people or Biogen and the pharmaceutical companies? Q&A about Aduhelm can be found at the Penn Memory Center website.

Dr. Kesselheim and other advisory committee members have stated that the American public should know about the process FDA uses to fast-track drugs. In case of Aduhelm, an investigation has been called for to delve deep into the relationship between Biogen’s Al Sandrock and Billy Dunn at the FDA’s Office of Neuroscience. Trust in the FDA and the approval process is at stake. The number of drugs previously approved by the FDA and being recalled are on the rise. A list of recalled drugs and devices can be found here at the FDA website.

A study published in June 2019 that analyzed results from the another clinical trial for Alzheimer’s disease initiated in 2000 using an immunotherapy vaccine, AN1792 from Elan Pharmaceuticals found that 88% of the patients had clear evidence of plaque removal in a 4 month to 15year follow-up. Despite clear reduction in this clinical biomarker of Alzheimer’s pathology, most patients progressed to severe dementia, including the five with very extensive plaque removal. Whether targeting other misfolded proteins in the plaque, such as tau would have halted progression of the disease or improve lifespan, is questionable. The AN1792 trial was halted in 2002 when 6% of the patients developed toxicity (T cell-mediated meningoencephalitis) and died. How can we have one single drug or vaccine or therapeutic that will work on a disease that is manifested as a spectrum? How can we administer one drug, one dose to people when men and women show different course and symptoms? The tangled web has created enough chaos and memory loss for all. However, trust in science and scientist is also at stake. Integrity should matter.

“Oh, what a tangled web we weave, when first we practice to deceive!” (Sir Walter Scott, 1808, Marmiom).