Abstract
Dear Editor,
Dementia is a medical condition marked by the gradual deterioration of memory, cognitive abilities, language, personality, behavior, and problem-solving skills that affect and interfere with the daily activities of life. Alzheimer’s disease (AD), a multifactorial disease is by far the leading cause of dementia. Approximately 50 million individuals worldwide are currently affected by AD, and the number is estimated to be quadrupled, reaching 152 million by 2050. AD can be described as a gradually advancing neurodegenerative condition marked by the accumulation of neuritic plaques and neurofibrillary tangles in the brain which result from the buildup of amyloid-beta peptide (Aβ) in the regions of the brain that are most severely affected, namely, the medial temporal lobe and neocortical structures. The contributing elements comprise growing age, genetic susceptibility, injuries to the head, vascular disorders, and infections. These risk factors, in conjunction with mutations in genes like APP, PSEN1, and PSEN2, have been found to impact Aβ metabolism, resulting in the aggregation of Aβ and an accelerated neurodegenerative process and neuronal cell death. 1
Only two types of drugs (cholinesterase enzyme inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists) had been approved for the treatment of AD. Several acetylcholinesterase enzyme inhibitors (AChEI)s and NMDA receptor antagonists, including donepezil, rivastigmine, galantamine, and memantine are currently used to treat the manifestation of moderate to severe AD but do not halt disease progression. 1
Moreover, researchers have been intensively working on some disease-modifying drugs that alter the pathophysiological mechanism and reduce the disease progression. 1 One of the disease-modifying drugs called donanemab was recently created to eliminate amyloid plaques. Donanemab (LY3002813) is a monoclonal antibody, specifically a humanized immunoglobulin G1 antibody that targets an N-terminal pyroglutamate amyloid beta (A) epitope found solely in brain amyloid plaques. 2 The drug was experimented on a Phase III randomized placebo-controlled trial and it showed positive results. The trial involved 1736 patients manifesting across a wide age range from 60 to 85 years, every individual among them were in the early stages of symptomatic AD with amyloid pathology and varying levels of tau pathology, categorized as either low/medium or high. The patients received intravenous treatments every 4 weeks, with one group being administered either 700 mg of donanemab for the first three doses and 1400 mg for subsequent doses, while the other group received a placebo. 3
Donanemab treatment had a significant positive impact on patients with AD, slowing down their clinical progression by more than 20% on iADRS and clinical dementia rating sum of boxes (CDR-SB) scales observed in both low/medium tau and combined groups. The possibility of disease progression was reduced by roughly 38.6% as measured by clinical dementia rating global (CDR-G) score. Throughout the 18-month study trial, patients in the low/medium tau group spared 4.4–7.5 months of disease development in contrast with the patients treated with placebo. Notably, the CDR-SB score was found to be static in 47% of the participants receiving donanemab after a year indicating no disease progression compared to 29% seen in the placebo group. Furthermore, participants receiving donanemab therapy also experienced a reduction in brain amyloid plaques, with 88.0 Centiloids in the low/medium tau group and 86.0 Centiloids in the combined group clearing up amyloid plaques at 76 weeks. In an ongoing phase of the study, researchers are studying the effects of clearance beyond 76 weeks, as well as its impact on other AD biomarkers. 3
AD is considered a global health solicitude and a long-term terminal illness causing millions of deaths globally. Although the trial conducted by John R. Sims and Company is a promising advancement in the field of neurology, ARIA (amyloid-related imaging abnormalities) is a possible side effect of treatment. It is usually asymptomatic and resolves within a few weeks, and only a small number of participants experienced slight headache and confusion. In rare cases, ARIA can be severe causing edema, microhemorrhage, and hemosiderin deposits, leading to hospitalization and even death, as seen in three cases in the TRAILBLAZER-ALZ 2 study. Therefore, further research is needed to comprehend the efficacy of the drug and make sure the benefits outweigh the adverse effects. 3
