The brain is a very complex organ, and thus the age-related failures of brain function also tend to be very complex. Alzheimer's disease receives the greatest attention from the research community, but is still only partially understood. The major focus of efforts over the past two decades has been on the clearance of amyloid-β aggregates from the brain, largely via immunotherapies, but a few other approaches have surfaced as well. Only in the past few years has this effort achieved success and resulted in large reductions in amyloid-β in patient brains, but unfortunately this did not result in a reversal of symptoms.
The amyloid cascade hypothesis is the central dogma for the study of Alzheimer's disease: amyloid-β aggregation occurs slowly over time, setting up the conditions for the later, more harmful stage of neuroinflammation and tau aggregation. That amyloid-β clearance fails to help patients may indicate that amyloid-β becomes irrelevant in the later stages of Alzheimer's disease, or it may indicate that it is not actually central to the progression of Alzheimer's disease. Over the years of failure to make meaningful progress with clearance of amyloid-β, and especially now that clearance has failed to help patients, researchers have increasingly turned to other approaches. This is a field in the midst of profound change and loud debate.
Given what has been discovered about the role of senescent cells in the aging brain in recent years, and the growing evidence for chronic inflammation to occupy a central position in the progression of neurodegenerative conditions, it seems likely that clearance of senescent cells is one of the most promising new approaches to Alzheimer's disease currently in the works. Time will tell; the first trial using the senolytic dasatinib and quercetin combination is underway.
The treatments of Alzheimer's disease (AD) fall into two main categories: symptomatic and disease-modifying. The purpose of symptomatic treatments is cognitive improvement or control of neuropsychiatric symptoms, without having an impact on the biological causes leading to neuronal death. By contrast, disease-modifying treatments are designed to induce neuroprotection through changing the neuropathology of AD, often acting on a variety of intermediate mechanisms. Unfortunately, most therapeutic agents developed in the last 15 years have failed.
Despite being such an important disease, the number of drugs in development for AD is much lower than in other diseases with a higher therapeutic arsenal. This reflects the fact that AD's biology is poorly understood, and the availability of biomarkers is a very limited. Moreover, the duration of clinical trials for assessing AD treatments is very long, which increases the risk of failure.
In any case, we may wonder why the treatments in development are failing or are not effective. Based on numerous trials of failed drugs in patients with AD, a plausible explanation could be that amyloid-β (Aβ) therapies are being administered too late, when the disease is completely developed and the effectiveness of the treatments is dramatically reduced. Therefore, an earlier (pre-symptomatic) diagnosis should be made, including a rethinking of the AD diagnostic criteria, which should be based primarily on biomarkers. Following this line of thought, drugs in phase III clinical development are being tested primarily in subjects during the early stages of the disease (mild cognitive impairment), in the preclinical phase of AD or even in asymptomatic subjects at high risk of developing AD.
An additional explanation could be that the initial hypotheses proposed for β-amyloid and tau as the main responsible neurotoxins for AD, are not able to entirely explain the pathophysiology of the disease. Hence, β-amyloid plaques and neurofibrillary tangles would have a secondary role in AD's origin. Indeed, if we review the clinical trials developed during the last 5 years, we find a progressive emphasis on non-amyloid targets, including candidate treatments for inflammation, synapse and neuronal protection, vascular factors, neurogenesis, and epigenetic interventions. There has also been an increase in the study of "reused drugs", that is to say, drugs that are used to treat other pathologies but are also thought to be useful for AD treatment. Two clear examples of these are escitalopram and metformin. In any case, the complexity of AD's etiopathogenesis demands multiple therapeutic strategies that can be proposed according to the molecular and physiological processes involved.
Undoubtedly, the trends in therapeutic strategies for AD will involve an increase in the diversity of non-amyloid or tau targets, including inflammation, insulin resistance, synapse and neuronal protection, cardiovascular factors, neurogenesis and epigenetic interventions. Indeed, some authors consider that AD should no longer be considered a brain disease, since its development is also attributed to peripheral factors as, for instance, intestinal dysbiosis.