Neuroimaging Results and A4 in the Context of the LEARN Study.

Background: The A4 Study was a 240‐week, double‐blind, placebo‐controlled Phase 3 secondary prevention trial in cognitively unimpaired adults (ages 65‐85) with elevated amyloid on PET testing solanezumab, a monoclonal antibody targeting soluble amyloid‐beta. The companion LEARN Study enrolled participants who were otherwise eligible for A4 but did not show elevated amyloid. Method: Entry criteria included CDR‐Global Scale (CDR‐GS) = 0, MMSE≥25, WMS Logical Memory = 6‐18, and elevated amyloid on florbetapir PET (for A4). The primary outcome measure was the Preclinical Alzheimer Cognitive Composite (PACC) with key secondary functional measures: Cognitive Function Index (CFI), Activities of Daily Living Scale (ADL), and CDR‐GS. A subset of participants underwent flortaucipir Tau PET. Result: For A4, 1169 randomized: 578 to solanezumab and 591 to placebo. Treatment groups were well matched. Solanezumab did not slow cognitive decline on the PACC (mean change (95% CI): placebo ‐1.13 (‐1.45,‐0.81); solanezumab ‐1.43 (‐1.83,‐1.03); p =.260). Secondary clinical outcomes were consistent, numerically favoring placebo. Across both arms, 36.1% progressed to symptomatic AD, defined as CDR‐GS> 0 at two consecutive visits or final visit. Higher baseline amyloid levels were strongly associated with faster cognitive decline and greater risk of progression to symptomatic AD across both groups (p<.001). Amyloid continued to accumulate in both placebo (65.9 centiloid baseline, 19.3 increase) and solanezumab (66.2 centiloid baseline, 11.6 increase) groups. Tau PET showed similar increases in placebo and solanezumab groups in medial temporal lobe and neocortical composites, that were negatively correlated with PACC decline. No serious safety signals for solanezumab were identified, with only one case of ARIA‐E. ARIA‐H rates were similar across groups. LEARN participants (N = 538, 4.2 centiloid baseline on amyloid PET) did not demonstrate cognitive decline. Conclusion: The A4 Study demonstrated the feasibility of conducting a large‐scale trial in preclinical AD, with cognitive and functional measures sensitive to decline. Solanezumab did not slow cognitive decline or clinical progression. Baseline amyloid PET was among the strongest predictors of decline across both placebo and solanezumab. LEARN participants did not demonstrate decline. These results suggest that amyloid plaque removal may be necessary even at this very early stage of AD. [ABSTRACT FROM AUTHOR]