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 β‐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 β‐amyloid on cognition and to identify which cognitive domains first become affected. RESULTS: β‐amyloid accumulation was linked to significant cognitive dysfunction in cognitively unimpaired participants with subthreshold levels of β‐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 β‐amyloid, across all measures (P < 0.05). The Free and Cued Selective Reminding Test, a list recall memory test, appeared most sensitive to β‐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 β‐amyloid‐positive individuals will include a large number of individuals where mechanisms downstream from β‐amyloid pathology are already activated. These findings have implications for primary and secondary prevention of Alzheimer’s disease.