Molecular Therapeutics in Development to Treat Alzheimer's Disease

Abstract

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.

Fig. 1

Target points for disease-modifying immunotherapies and gene therapies aimed at the amyloid-β (Aβ) and tau aggregation cascades. The three anti-Aβ immunotherapies that have been approved by the US Food and Drug Administration are indicated on the left side of the panel. The three tau immunotherapies displayed on the right were chosen as they have all shown some promise in concluded or ongoing clinical trials. The ongoing anti-sense oligonucleotide (ASO) trials, together with the preclinical gene editing based approaches, all targeting either amyloid precursor protein (APP)/Aβ or tau, are also illustrated. CRISPR clustered regularly interspaced short palindromic repeats, dsDNA double-stranded DNA, mAB monoclonal antibody, mRNA messenger RNA, siRNA small interfering RNA. Image created by Gustavo Grimmer using BioRender

Fig. 2

Agents in clinical trials for treatment of Alzheimer's disease in 2024 (from ClinicalTrials.gov as of the index date of 1 January, 2024). Phase III agents are displayed in the inner ring, phase II agents in the middle ring, and phase I agents in the outer ring. Agents in green areas are biologics; agents in purple areas are disease‐modifying small molecules; agents in orange areas are agents targeting cognitive enhancement or behavioral symptoms; and agents in blue areas target behavioral and neuropsychiatric symptoms. The shape of the icon shows the target population of the trial; the icon color shows the Common Alzheimer’s Disease Research Ontology (CADRO)‐based class of the agent (“Other” category includes CADRO classes that have three or fewer agents in trials). ApoE apolipoprotein E, CBD cannabidiol, DHA docosahexaenoic acid, THC delta-9-tetrahydrocannabinol, Tx treatment. Used with permission from the authors [89] and from Alzheimer’s & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals LLC on behalf of Alzheimer’s Association. (Figure© J Cummings; M de la Flor, created with Illustrator)