1. In this randomized controlled trial, over a period of 240 weeks, solanezumab did not slow cognitive decline as compared to placebo in patients with preclinical Alzheimer’s disease.
2. Solanezumab did not change the levels of amyloid levels in the brain as compared to placebo in persons with preclinical Alzheimer’s disease.
Evidence Rating Level: 1 (Excellent)
Study Rundown: The pathophysiology of Alzheimer’s disease involves the accumulation of amyloid-beta (Aβ) into fibrillar plaques and hyperphosphorylated tau. This results in neurofibrillary tangles that can often begin a decade before clinically evident cognitive impairment. Thus, it has been proposed that cognitively unimpaired geriatric patients represent a preclinical, or asymptomatic, stage of Alzheimer’s disease and thus could be candidates for intervention. Solanezumab is an immunoglobulin G1 monoclonal antibody that binds to the mid-domain of the Aβ monomer. There is a gap in knowledge as to understanding whether solanezumab as compared with placebo has an impact on slowing cognitive decline in patients with preclinical Alzheimer’s disease without cognitive impairment. Overall, this study found that solanezumab did not slow the progression of cognitive and functional decline in persons with preclinical Alzheimer’s disease as compared with placebo over a period of 4.5 years. This study was limited by having few Black participants and having a midtrial dose increase, as well as participants not being representative of older persons at risk for cognitive decline. Nevertheless, these study’s findings are significant, as they demonstrate that solanezumab does not slow cognitive and functional decline in persons with preclinical Alzheimer’s disease.
Click to read the study in NEJM
Relevant Reading: Trial of Solanezumab for Mild Dementia Due to Alzheimer’s Disease
In-Depth [randomized controlled trial]: This phase three randomized controlled trial randomly assigned participants to receive solanezumab at a dose of up to 1600 mg intravenously every four weeks compared to a placebo in a 1:1 ratio. Persons who were 65 to 85 years of age and were living independently without a diagnosis of mild cognitive impairment or dementia with the absence of cognitive impairment were included. This was confirmed by a global Clinical Dementia Rating (CDR) score of 0, by a Mini–Mental State Examination (MMSE) score of 25 to 30, and by a Wechsler Memory Scale Logical Memory Delayed Recall (LMDR) score of 6 to 18. Patients who had LMDR scores greater than 18 (>1.5 SD above normal values for this age range) were excluded to enhance the likelihood of enrolling persons with elevated brain amyloid levels, as well as patients with unstable medical conditions. The primary outcome measured was the change in the Preclinical Alzheimer’s Cognitive Composite (PACC) score at 4.5 years. Outcomes in the primary analysis were assessed by comparing changes in mean differences in the change in the PACC score. Based on the primary analysis, at 240 weeks, the mean change in PACC score was −1.43 in the solanezumab group and −1.13 in the placebo group (difference, −0.30; 95% confidence interval, −0.82 to 0.22). Amyloid levels on brain PET increased by a mean of 11.6 centiloids in the solanezumab group and 19.3 centiloids in the placebo group. In summary, this study demonstrates that solanezumab did not slow cognitive decline as compared to placebo over 240 weeks in persons with preclinical Alzheimer’s disease.
Image: PD
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