We demonstrate feasibility of a cognitive composite outcome for clinically normal (CN) elders with evidence of AD pathology: the Alzheimer’s Disease Cooperative Study Preclinical Alzheimer Cognitive Composite (ADCS-PACC). The ADCS-PACC combines tests that assess episodic memory, timed executive function, and global cognition. The ADCS-PACC is the primary outcome for the first clinical trial in preclinical AD: Anti-Amyloid Treatment for Asymptomatic AD (A4). We derive pilot estimates of ADCS-PACC decline using data from three studies. We estimate decline in a preclinical AD “Aß+” placebo group, and compare to an “Aß-” group.

Results: In the first study, Aß+ subjects decline more than Aß- on the ADCS-PACC at 24 months (-1.239, SE=0.522, p=0.018). In second study, the difference is significant at both 18 months (-1.009, SE=0.406, p=0.014) and 36 months (-1.404, SE=0.452, p=0.002). In the third study, APOE-e4 allele carriers performed significantly worse on the ADCS-PACC at 24 months (-0.742, SE=0.294, p=0.012) and 36 months (-1.531, SE=0.469, p=0.001). In the third study, CN who progress from Global CDR 0 are significantly worse on the ADCS-PACC than CN who are stable Global CDR 0 at months 12, 24, and 36 (-4.471, SE=0.702, p<0.001). Using pilot estimates of variance and assuming N=500 per group with 30% attrition and 5% alpha, we project 80% power to detect effects in the range ?=0.473 to 0.742 on ADCS-PACC.

Conclusions: Analyses of at-risk CN populations suggests that we can reliably measure the first signs of cognitive decline with the ADCS-PACC. These analyses also suggest the feasibility of secondary prevention trials.