With population aging, the number of people with dementia is expected to increase over the coming decades. Alzheimer’s disease (AD), the leading cause of dementia worldwide, is characterized by a progressive loss of autonomy leading to dramatic consequences for patients and their caregivers, as well as an increase in health and social care costs. The main physiopathological features of AD include deposition of amyloid plaques and neurofibrillary tau tangles. Disease-related biological changes are detectable before the onset of clinical symptoms. The development of strategies to prevent or delay progression of AD-related cognitive decline has been a major challenge for more than 30 years. Many randomized controlled trials (RCTs) have failed to significantly slow clinical disease progression, but have contributed to improving the understanding of AD physiopathology. Treatment options for AD were limited to symptomatic therapies and improving quality of life, until the early 2020s saw the approval of the first anti-amyloid drugs in the US. Alternative or additional treatments for AD may become available in the future. The aim of this perspective paper is to summarize lessons learned from failed AD trials over the past decades, and to present the state-of-the-art and future direction of research in this field.

 

In 1993, the first AD drug was approved by the Food and Drug Administration (FDA). Cholinesterase inhibitors (tacrine, donepezil, rivastigmine, galantamine) were approved for the treatment of mild to moderate stages of the disease and a NMDA receptor modulator (memantine) in moderate to severe stages. However, these drugs only offer modest symptomatic relief, particularly in early disease stages, and lack AD-specific targets, which has highlighted the need for treatments acting on the physiopathological process of the disease and slowing its progression (i.e., disease-modifying agents).

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