Alzheimer’s disease, the road ahead

Abstract

The failure of all the clinical trials focused on the treatment of Alzheimer’s disease (AD), including the Phase 3 aducanumab trial, is another warning that the field must take a different approach. Some authors have already called for a rejection of the amyloid hypothesis, new and old players like tau-related pathology microglia activation and neuroinflammation are now looming on the horizon, but the core of the issue is that the reductionist approach that has dominated modern medicine should be abandoned. We need an epistemological leap forward, a change in paradigm, and an embrace of a complex view of the disease as a condition resulting from the converging failure of many health-controlling systems and networks, a condition that is shaped, in each subject, by the combination of the individual “omic” lookout and its modulation by the environment. Moreover, we need to leave behind the illusion that a single bullet/intervention can be the cure and adopt a systems-biology approach (Greene and Loscalzo, 2017). The talks will discuss the multifactorial nature of AD, a condition in which, along with Aβ accumulation, the convergence of many genetic, environmental, vascular, metabolic, and inflammatory factors promotes the neurodegenerative process. All these conditions find fertile ground, inside and outside of the central nervous system, provided by the aging process. In that respect, converging approaches targeting co-morbidity factors represent one of the more promising areas of intervention as, at least, we need to remind ourselves that a third of AD cases are strongly dependent on the concerted activity of modifiable factors like low education, midlife hypertension, midlife obesity, diabetes, physical inactivity, smoking, and depression (Brem and Sensi 2018). Thus, in line with a more modern, we need to reconcile ourselves to the fact that complex, nontransmissible chronic conditions must be treated with a multifaceted approach.