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...
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| Published in | Annals of clinical and translational neurology Vol. 7; no. 5; pp. 776 - 785 |
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| Main Authors | , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
John Wiley & Sons, Inc
01.05.2020
John Wiley and Sons Inc Wiley |
| Subjects | |
| Online Access | Get full text |
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| Summary: | 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. |
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| Bibliography: | Work at the authors’ laboratory was supported by the Wallenberg Center for Molecular Medicine, The Knut and Alice Wallenberg Foundation, The Medical Faculty at Lund University, Region Skåne, the European Research Council, the Swedish Research Council, the Marianne and Marcus Wallenberg foundation, the Strategic Research Area MultiPark (Multidisciplinary Research in Parkinson’s disease) at Lund University, the Swedish Alzheimer Foundation, the Swedish Brain Foundation, the Parkinson foundation of Sweden, The Parkinson Research Foundation, the Swedish Medical Association, the Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse, the Skåne University Hospital Foundation, and the Swedish Federal Government under the ALF agreement. The A4 study is a secondary prevention trial in preclinical Alzheimer’s disease, aiming to slow cognitive decline associated with brain amyloid accumulation in clinically normal older individuals. The A4 study is funded by a public‐private‐philanthropic partnership, including funding from the National Institutes of Health‐National Institute on Aging (U19AG010483; R01AG063689), Eli Lilly and Company, Alzheimer’s Association, Accelerating Medicines Partnership, GHR Foundation, an anonymous foundation and additional private donors, with in‐kind support from Avid, Cogstate, Albert Einstein College of Medicine, US Against Alzheimer’s disease, and Foundation for Neurologic Diseases. The companion observational Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) study is funded by the Alzheimer’s Association and GHR Foundation. The A4 and LEARN Studies are led by Reisa Sperling at Brigham and Women’s Hospital, Harvard Medical School and Paul Aisen at the Alzheimer’s Therapeutic Research Institute (ATRI), University of Southern California. The A4 and LEARN Studies are coordinated by ATRI at the University of Southern California, and the data are made available through the Laboratory for Neuro Imaging at the University of Southern California. The participants screening for the A4 study provided permission to share their de‐identified data in order to advance the quest to find a successful treatment for Alzheimer’s disease. We would like to acknowledge the dedication of all the participants, the site personnel, and all of the partnership team members who continue to make the A4 and LEARN Studies possible. The complete A4 study team list is available on: a4study.org/a4‐study‐team. Funding Information ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 |
| ISSN: | 2328-9503 2328-9503 |
| DOI: | 10.1002/acn3.51048 |