Open AccessThe A4 study: β ‐amyloid and cognition in 4432 cognitively unimpaired adults
Author(s) -
Insel Philip S.,
Donohue Michael C.,
Sperling Reisa,
Hansson Oskar,
MattssonCarlgren Niklas
Publication year - 2020
Publication title -
annals of clinical and translational neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.824
H-Index - 42
ISSN - 2328-9503
DOI - 10.1002/acn3.51048
Subject(s) - cognition , medicine , recall , amyloid (mycology) , cued speech , dementia , logical address , cognitive test , alzheimer's disease , disease , episodic memory , effects of sleep deprivation on cognitive performance , audiology , neuroscience , psychology , psychiatry , pathology , cognitive psychology , physical address , computer science , programming language , overlay
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.