Anti-Amyloid Treatment in Asymptomatic Alzheimer’s (A4) Study and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) Study

The amyloid hypothesis of AD postulates that the accumulation of amyloid-β peptide (Aβ) is an early and necessary event in the pathogenesis of AD. This hypothesis suggests that treatments that slow the accumulation of Aβ in the brain or increase clearance of Aβ may be able to slow the progression of the AD clinical syndrome. 

Converging evidence from both genetic at-risk and age at-risk cohorts suggests that the pathophysiological process of AD begins well more than a decade before the clinical stage now recognized as AD dementia, and that neurodegeneration is already apparent by the stage of mild cognitive impairment (MCI)/prodromal AD. Recent clinical trial results in mild-to-moderate AD dementia, as well as evidence from transgenic animal experiments, suggest that earlier intervention may be most beneficial to fully impact the clinical progression of the disease, particularly with therapies targeted at Aβ reduction. 

Data from autopsy cohorts and cerebrospinal fluid (CSF) and positron emission tomography (PET) scan amyloid imaging studies demonstrate that approximately 30% of individuals over the age of 65 have evidence of amyloid pathology. Clinically “normal” older individuals with biomarker evidence of elevated amyloid pathology demonstrate AD-like abnormalities on functional and structural imaging, perform less well on cognitive tests compared to amyloid-negative older individuals, are more likely to report subjective memory concerns, and are at increased risk for cognitive decline and progression to MCI and AD. Recent academic consensus workgroups focused on developing guidelines for earlier diagnosis of AD and research diagnostic criteria have defined a stage of “preclinical AD,” based on biomarker evidence of AD pathology before the stage of clinically evident symptoms of cognitive impairment. 

The Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease “A4” study was a Phase 3, double-blind, placebo-controlled study in subjects with preclinical AD. The A4 trial preclinical AD study population was defined as subjects with evidence of brain amyloid pathology on PET amyloid imaging who were still clinically normal but at high risk for cognitive decline. The A4 study was designed to test the hypothesis that solanezumab, a monoclonal antibody that binds Aβ, would slow decline on a cognitive composite measure designed to be sensitive to early decline in the preclinical stages of AD. This study collected additional data on the long-term safety and efficacy of solanezumab, including computerized cognitive outcomes, as well as self and study partner reports of daily-life cognitive function outcomes, a brief resource utilization inventory, and biomarker and imaging measures.