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M. Canevelli1, N. Vanacore2, A. Blasimme3, G. Bruno1, M. Cesari4

1. Sapienza University, Rome, Italy; 2. National Center for Disease Prevention and Health Promotion, National Institute of Health, Rome, Italy; 3. Department of Health Sciences and Technology, ETH Zürich, Switzerland; 4. IRCCS Istituti Clinici Maugeri, University of Milan, Italy.

Corresponding Author: Matteo Cesari, MD, PhD, Geriatric Unit, IRCCS Istituti Clinici Scientifici Maugeri, Via Camaldoli 64 – 20138 Milan – Italy, Phone: +39 02 50725136, Twitter: @macesari, email:

J Prev Alz Dis 2020;
Published online December 31, 2020,



The management of frailty in older persons is not easy, implying interventions beyond the simple prescription of medications. Biological complexity, multimorbidity, polypharmacy, and social issues often hamper the possibility to directly translate the evidence coming from research into clinical practice. Frailty indeed represents the most relevant cause of the “evidence-based medicine issue” influencing clinical decisions in geriatric care. Today, patients with Alzheimer’s disease (AD) are much older and frailer than some decades ago. They also tend to have more drugs prescribed. In parallel, research on AD has evolved over the years, hypothesizing that anticipating the interventions to the earliest stages of the disease may provide beneficial effects (to date, still lacking). In this article, we argue that, by focusing exclusively on “the disease” and pushing to anticipate its detection (sometimes even before the appareance of its clinical manifestations) may overshadow the person’s values and priorities. Research should be developed for better integrating the concept of aging and frailty in the design of clinical trials in order to provide results that can be implemented in real life. On the other hand, clinicians should be less prone to the easy (but unsupported by evidence) pharmacological prescription.

Key words: Overtreatment, dementia, cognition, geriatrics, prevention.

The management of frailty in older persons is not easy, mainly because it requires interventions beyond the simple prescription of medications (1–5). Biological complexity, multimorbidity, polypharmacy, and social issues often hamper the possibility to translate the evidence coming from research into clinical practice directly. Frailty indeed represents the most relevant cause of the “evidence-based medicine issue”, which has traditionally complicated geriatric medicine (3, 6, 7). Moreover, the outcomes often used in clinical trials conducted in adult and/or non-frail individuals are often meaningless in older persons with frailty (8, 9). What is more, the priorities of older persons with chronic conditions are usually found on aspects that are not necessarily related to the cure of a given disease or the life extension (10, 11). Instead, considerations about the quality of life play a critical role that is routinely neglected in medical decision-making (8). Lack of regard for patient-centered care as well as the absence of evidence specifically supporting the clinical management of frail older persons often lead to the need of making decisions with the addition of a good dose of common sense.
At the same time, the increasing diagnostic capacity and the hyper-specialization of medicine (arguably a correlate of a culture that privileges functional integrity over life quality and emotional fulfillment) (12) have substantially contributed to the widespread phenomena of overdiagnosis and overtreatment (13). In particular, these problems of modern medicine stem from the incapacity to deal with the individual’s multidimensional complexity and the lack of integrated models of care. The former, caused by the heterogeneity of the underlying aging process (14, 15), is responsible for the “one-size-fits-all” paradigm pervasively promoted in medicine. The latter causes an approach to the patient that proceeds by siloes, failing to 1) realize the complexity of the system (16, 17), and 2) adequately integrate available clinical information with the person’s life plans, expectations, and preferences (3). After all, it is well-established that, while the robustness of scientific evidence tends to fade in the oldest and frailest individuals, these are paradoxically the ones who are the most exposed to polypharmacy (18). In this scenario, we cannot ignore the detrimental aspect of the defensive medicine19. Clinicians today identify the prescription of tests and medications as the final goal of their mission, and patients are not aware that sometimes “less is more” (20).
The field of Alzheimer’s disease (AD) has substantially been exposed to these risks. AD is a condition of old age. Today, AD patients are much older and frailer than some decades ago (21). They also tend to have more drugs prescribed. The complexity of the condition is also exemplified by the substantial role played by social factors (e.g., literacy) in its clinical expression (22).
Research on AD has been evolving over the years, hypothesizing that the anticipation of the interventions to the earliest stages of the disease may provide those beneficial effects that, to date, are still lacking. For this reason, a myriad of preclinical conditions has been developed. Constructs as mild cognitive impairment (23), prodromal AD (24), subjective cognitive decline (25)… have been designed for research purposes, in particular for defining conditions to target with experimental drugs. Although sometimes explained the rationale behind the design of these pre-AD conditions, their adoption in the clinical setting has always been quite rapid – a phenomenon known as “diagnostic creep” (26). This leads to an earlier diagnosis of AD (and its different forms), generating a more extended life “with the disease”, more heterogeneity in the biological/clinical profile, more patients to treat, and higher costs for the healthcare systems. By focusing exclusively on “the disease”, the push to anticipate its detection even before its preclinical manifestations appear (27) overshadows the person’s values and priorities.
Furthermore, it also seems that the risk of preciously treating individuals presenting early signs/symptoms of AD is never considered for its potential of reducing the effect size of the intervention. In other words, there is the possibility that an effective molecule might appear less effective than it is simply because administered to a population including false positive (i.e., non-diseased) individuals. Moreover, anticipating the diagnosing of a condition that, to date, has still no disease-modifier treatment is fraught with a host of not yet settled ethical issues (28–30). In particular, does an anticipated AD diagnosis really expand individual autonomy and self-determination (as many seem to argue), or is it instead conducive to self-depreciation, stigmatization, and further social isolation?
Moreover, let us consider some of the implications of treating AD preclinical phases as actual clinical entities. Recently, Egan et al. (31) published the results from a randomized, double-blind, placebo-controlled trial aimed at evaluating the effect of verubecestat, a beta-site amyloid precursor protein-cleaving enzyme-1 (BACE-1) inhibitor, in prodromal AD. Beyond the negative effect of the drug on cognitive function, what stood out from the report was the theoretically unexpected, high proportion of participants (i.e., 46.0 %) taking cholinesterase inhibitors or memantine at the study baseline. Such a high prevalence in the treatment of prodromal AD is unjustified and quite worrisome, given the likely inclusion of many potentially reversible cases among the participants (32). It is furthermore not negligible that this overtreatment occurs with medications that:
1) have proven to be ineffective at delaying/halting the progression to overt dementia (33);
2) may expose the individual to adverse drug reactions and even worsen the person’s functioning (34); and
3) are not approved for such use by international regulatory agencies.
The absence of alternative therapeutic options cannot justify these interventions, which should be considered as ethically, clinically, and economically inappropriate/unsustainable. Research should thus be developed for better integrating the concept of aging and frailty in the design of clinical trials in order to provide results that can be implemented in real life (8, 35–38). On the other hand, clinicians should be less prone to the easy (but unsupported by evidence) pharmacological prescription.


Conflicts of interest: Marco Canevelli is supported by a research grant of the Italian Ministry of Health (GR-2016-02364975) for the project “Dementia in immigrants and ethnic minorities living in Italy: clinical-epidemiological aspects and public health perspectives” (ImmiDem). Matteo Cesari has received honoraria for presentations at scientific meetings and/or research funding from Nestlé. No specific conflict of interest declared by the other authors.



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