Molecular Therapeutics in Development to Treat Alzheimer's Disease.

Until recently, only symptomatic therapies, in the form of acetylcholine esterase inhibitors and NMDA-receptor antagonists, have been available for the treatment of Alzheimer's disease. However, advancements in our understanding of the amyloid cascade hypothesis have led to a development of disease-modifying therapeutic strategies. These include immunotherapies based on an infusion of monoclonal antibodies against amyloid-β, three of which have been approved for the treatment of Alzheimer's disease in the USA (one of them, lecanemab, has also been approved in several other countries). They all lead to a dramatic reduction of amyloid plaques in the brain, whereas their clinical effects have been more limited. Moreover, they can all lead to side effects in the form of amyloid-related imaging abnormalities. Ongoing developments aim at facilitating their administration, further improving their effects and reducing the risk for amyloid-related imaging abnormalities. Moreover, a number of anti-tau immunotherapies are in clinical trials, but none has so far shown any robust effects on symptoms or pathology. Another line of development is represented by gene therapy. To date, only antisense oligonucleotides against amyloid precursor protein/amyloid-β and tau have reached the clinical trial stage but a variety of gene editing strategies, such as clustered regularly interspaced short palindromic repeats/Cas9-mediated non-homologous end joining, base editing, and prime editing, have all shown promise on preclinical disease models. In addition, a number of other pharmacological compounds targeting a multitude of biochemical processes, believed to be centrally involved in Alzheimer's disease, are currently being evaluated in clinical trials. This article delves into current and future perspectives on the treatment of Alzheimer's disease, with an emphasis on immunotherapeutic and gene therapeutic strategies.