The A4 study: β-amyloid and cognition in 4432 cognitively unimpaired adults

Objective To clarify the preclinical stage of Alzheimer's disease by estimating when beta-amyloid accumulation first becomes associated with changes in cognition. Methods Here we studied a large group (N = 4432) of cognitively unimpaired individuals who were screened for inclusion in the A4 trial (age 65-85) to assess the effect of subthreshold levels of beta-amyloid on cognition and to identify which cognitive domains first become affected. Results beta-amyloid accumulation was linked to significant cognitive dysfunction in cognitively unimpaired participants with subthreshold levels of beta-amyloid in multiple measures of memory (Logical Memory Delayed Recall, P = 0.03; Free and Cued Selective Reminding Test, P < 0.001), the Preclinical Alzheimer's Cognitive Composite (P = 0.01), and was marginally associated with decreased executive function (Digit Symbol Substitution, P = 0.07). Significantly, decreased cognitive scores were associated with suprathreshold levels of beta-amyloid, across all measures (P < 0.05). The Free and Cued Selective Reminding Test, a list recall memory test, appeared most sensitive to beta-amyloid -related decreases in average cognitive scores, outperforming all other cognitive domains, including the narrative recall memory test, Logical Memory. Interpretation Clinical trials for cognitively unimpaired beta-amyloid-positive individuals will include a large number of individuals where mechanisms downstream from beta-amyloid pathology are already activated. These findings have implications for primary and secondary prevention of Alzheimer's disease.