What is the Purpose of Medicine When Dealing with Incurable Alzheimer’s Disease?

by Jack de la Torre, MD, PhD on 21 April 2021

It is fair to ask this consequential question in the title above since it is seldom, if ever, discussed at dementia or neurology conferences. A follow-up question may be asked: Has medicine and its medical practitioners created a reasonable and consistent plan of action in dealing with an incurable disease such as Alzheimer’s disease (AD)?

This last question has no clear-cut answer but does raise a Pandora’s box of moral, ethical and scientific dilemmas that go well beyond the guidelines of the Hippocratic Oath.

Because effective therapy for Alzheimer’s disease (AD) is presently an unmet medical need, my own soul-searching view of this conundrum was expressed in a previous publication, as follows: “The main goal of medicine is to provide the ill with hope for healing, and when there is no hope, to offer understanding.” [1]

As simplistic as this observation appears, it raises an important issue that modern medicine as yet to resolve. This issue centers on the conduct of medical practitioners in providing not hope for healing, but false hope, by prescribing clinically unproven and ineffective drug medicaments (see below).

There is little need to illustrate examples of this “pseudotherapeutic” cop-out since classically, such ‘false hope’ remedies are standard practice at the present time in any medical setting and have been standard practice for decades.

A medical practitioner’s dubious justification to engage in this practice is often, “hey, no good treatment is available for AD so a useless pill is as good as it gets…”, and even better, “I need to prescribe something or these people will march out of here until they find a prescriber somewhere else,” or finally, “…some top medical professionals report that anti-abeta drugs or passive immunotherapy for AD may provide “modest” improvement of daily living (brushing teeth, feeding, bathing) especially in patients that can tolerate the high side-effects of these medications.” Nonetheless, the word “modest improvement” is seldom measurably defined using evidence-based medicine or meta-analyses of current AD treatments, and instead, slips under type ll error components, trial inaccuracies and data fabrication, making it difficult to ascertain drug-placebo group differences [2].

A word about providing false hope from inadequate remedies. At the present time, only 5 FDA-approved medicines for AD are available in the USA; 4 anticholinesterase inhibitors and one NMDA blocker. These drugs make up a multi-billion dollar market for their manufacturers and shareholders, with the bewildering help of licensed prescribers and primary care physicians.

One wonders, however, whether there is some other way to offer understanding of AD rather than using sham medicines that for the most part don’t work and generally have side serious side-effects that can harm the patient?

The most charitable value-judgment that can be said about these 5 FDA-approved products is that they “may” provide a clinically marginal feeling of temporary symptom improvement, which is neither consistent or sustainable. However, their daily use is not innocuous and may be responsible for the high drop-out rate among its takers [3].

For example, none of the 5 FDA approved AD medicines or anti-Abeta immunotherapy vaccines, given individually or in combination used in numerous human trials have been able to measurably assess AD improvement in behavior or alter the course of neurodegenerative progression characteristics of AD [4].

My thinking of an unremitting trend to overplay the public trust using high- power medical advertisements or questionable conjectures from so-called, paid “experts” that solely subscribe to anti-Alzheimer medications, can backfire by ignoring the progressive neurodegenerative pathology unfolding in AD brain. It also serves little purpose to create understanding when hope vanishes from the therapeutic framework. Such practice and competent application that rejects medical phoniness and charlatanism is what makes medicine and its expert personnel a true and esteemed science.

Understanding a complex disease such as AD can identify the at-risk AD patient who can benefit from tailor-made interventions targeting selective lifestyle factors, such as physical, and mental exercise, a nutritious diet and treatment to manage known AD risk factors, hypertension, diabetes, high body mass index and heart disease. Minimizing these risks is potentially useful in therapeutic strategies that may be effective in delaying AD onset [5]. This approach may require some extra effort by the AD clinician but the satisfaction of not whipping out the prescription pad, underlines the value of William Osler’s dictum: “The good physician treats the disease, the great physician treats the patient who has the disease”. Osler is widely considered the father of modern medicine.

In my judgment, a paradigm shift is needed to replace “false hope” medicaments that are more likely to harm the patient. Instead, preventive strategies must be found and quickly applied before the incurability of AD onset implodes.

References
[1] de la Torre JC (2016) Alzheimer’s Turning Point: A Vascular Approach to Clinical Prevention. Springer AG Switzerland.
[2] Becker RE, Greig NH (2008) Why do so many drugs for Alzheimer's disease fail in development? Time for new methods and new practices? J Alzheimers Dis 15, 303-325.
[3] Rochon PA, Gruneir A (2018) Initial cholinesterase Inhibitor therapy dose and serious events in older women and men. J Am Geriatr Soc 66, 1692-1699.
[4] Salloway S, Sperling R, Fox NC (2014) Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer’s disease. N Engl J Med 370 322–333.
[5] Barnard ND, Bush AI, Ceccarelli A (2014) Dietary and lifestyle guidelines for the prevention of Alzheimer's disease. Neurobiol Aging 35 Suppl 2, S7.

Last comment on 25 April 2021 by Patrizia Mecocci, MD, PhD

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Comments

There is some fundamental food for thought in this blog. The question of the role of a physician for a not curable disease is a key one, as we are forced to think about Osler's vision of patient-centered, value-based medicine. This is the paradigm shift needed:  moving from the one cause - one mechanism - one therapy approach to the conscious avoidance of the Ockham's razor. While razors in medicine can be very important because of their ability to shave off complex problems using heuristics to enable better decisions, they can be - as every razor - extremely dangerous: in this case, if used in the frame of "one size fits all" in a disease afftecting old and very old persons in over 2/3 of the cases. In other words, evidence, recommendations, and guidelines help to orientate diagnosis in cognitive impairment with and without dementia, but do not disentangle complexity. There are no "too complex" problems in the medicine of the aged, rather problems exists, which base on age-related physiologic changes and need to be uncovered.   
Geriatric medicine, which was first described (also in highest impact journals) by a british female surgeon, Marjory Warren, uses since its foundation a patient-centered approach based on functions, measured with the cornestone of this discipline - the comprehensive assessment. During the performance of the multidimensional assessment, the doctor disentangles complexity and puts together the puzzle of the real-life patient with dementia: old-old or oldest-old, female, multimorbid, frail - quite different from the typical RCT participant. And it is also (mainly?) due to the obsessive fixation on the one cause - one mechanism - one therapy spotlight that so many trials don't work. I started as a physician and researcher now 30 years ago to work on cognitive impairment. And it is frankly quite a pity that the medical scene did not show any substantial innovative, resilient, sustainable approach to this dramatic condition in such a long time. 

Looking back to the last thirty years in the field of AD we can see how the amyloid cascade hypothesis has permeated most of the researches and dominated the clinical and therapeutic approach. Unfortunately, as it often happens—but it should not—in the world of science, the landscape of research became narrower and narrower and many other hypotheses, and so possibilities to understand and offer new chances to efficacious treatments, have been discarded.

The attitude to walk all together in the mainstream can be comfortable but not useful to open further views in sciences. And this is what happened in the AD world.

Now we are still waiting for disease-modifying drugs and the approved drugs (the last one twenty years ago) have limited efficacy.

What did go wrong? Probably a pervasive “street light effect”, looking at what it is easier to see, caused a too long-lasting shortcut that, as a final result, offers no effective treatments to an increasing number of patients.

Maybe we should start again, of course accepting amyloid and tau as characteristics of AD, but looking up to the main risk factor of dementia: aging [1]. The aging brain is the battlefield where protein aggregation, inflammatory factors, mitochondrial alterations, energy reduction, oxidative stress are the resulting paths due to conditions that start many years before: diabetes, hypertension, heart diseases, metabolic problems, hypoxia due to pulmonary diseases, pollution, psychological stress and whatever can happen in your life.

So starting to act more strenuously for prevention is the first action that we must consider and new studies have recently shown how the incidence rate of dementia in Europe and North America has declined by 13% per decade over the past 25 years [2] suggesting that probably a more controlled lifestyle is protective against dementia, one of the several age-related diseases.

It is conceivable that acting for maintaining a good health status along with life and acting for healthy aging is the main action to defeat dementia. Cells, tissue, organs are built up to self-guarantee their survival for a certain time. In the last century, humans have created the opportunity to live much longer than biologically established. Now we need to learn how to slow the biological decline due to aging [3]. Acting against the many diseases that we face during life, i.e., acting to prevent and not to cure, is the main chance we have to avoid, or almost postpone, dementia in old age. What we still called AD, in old age, when its prevalence steeply increases, is not a one-cause disease but the convergence of many factors that we need to manage with a healthier lifestyle.
Furthermore, allowing exploring pathogenetic hypotheses other than the amyloid cascade  is fundamental to broaden the horizons of research since, quoting the philosopher Karl Popper  “Whenever a theory appears to you as the only possible one, take this as a sign that you have neither understood the theory nor the problem which it was intended to solve”  

REFERENCES
[1] Mecocci P, Boccardi V (2021) The impact of aging in dementia: It is time to refocus attention on the main risk factor of dementia. Ageing Res Rev 65, 101210.
[2] Wolters FJ et al., (2020) Twenty-seven-year time trends in dementia incidence in Europe and the United States: The Alzheimer Cohorts Consortium. Neurology 95, e519-e531.
[3] Mecocci P, Baroni M, Senin U, Boccardi V (2018) Brain aging and late-onset Alzheimer's disease: a matter of increased amyloid or reduced energy? J Alzheimers Dis 64 (s1), S397-S404.

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