Cancer research provides a model for advancing clinical trials in dementia in the era of disease-modifying Alzheimer’s-type dementia therapies

Abstract

Abstract Dementia and cancer are multifactorial, widely-feared, age-associated clinical syndromes that are increasing in prevalence. There have been major breakthroughs in clinical cancer research leading to some effective treatments, whereas the field of dementia has achieved comparatively limited success in clinical research. The lessons of cancer research may help those in the dementia research field in confronting some of the dilemmas faced when the clinical care regimen is not entirely safe or efficacious. Cancer clinical trials have assumed that untreated individuals with cancer are at high risk for morbidity and mortality after primary diagnoses. Thus, patients deserve a choice of clinical interventions, either standard of care or experimental, even if the benefits are not certain and the therapy’s side effects are potentially severe. The prognosis for many individuals at risk for dementia carries a correspondingly high level of risk for both mortality and severe morbidity, particularly if one focuses on “health-span” rather than lifespan. Caregivers and patients can be strongly impacted by dementia and the many troubling associated symptoms that often go well beyond amnesia. Polls, surveys, and a literature on “dementia worry” strongly underscore that the public fears dementia. While there are institutional and industry hurdles that complicate enrollment in randomized trials, the gravity of the future morbidity and mortality inherent in a dementia diagnosis may require reconsideration of the current protective stance that limits the freedom of at-risk individuals (either symptomatic or asymptomatic) to participate and potentially benefit from ongoing clinical research. There is also evidence from both cancer and dementia research that individuals enrolled in the placebo arms of clinical trials have unexpectedly good outcomes, indicating that participation in clinical trial can have medical benefits to enrollees. To highlight aspects of cancer clinical research that may inform present and future dementia clinical research, this review highlights three main themes: the risk of side effects should be weighed against the often dire consequences of non-treatment; the desirability of long-term incremental (rather than “magic bullet”) clinical advances; and, the eventual importance of combination therapies, reflecting that the dementia clinical syndrome has many underlying biological pathways.

Keywords

• Lecanemab
• Donanemab
• Epidemiology
• Immunotherapy
• Alzheimer’s disease
• Neuropathology