Evidence suggests that the progression of Alzheimer’s disease (AD) begins more than a decade before the clinical stage we now recognize as AD dementia. The A4 Study, Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Study, was the first trial to test an intervention in clinically normal older individuals with biomarker evidence of AD pathology. The overall goal of the A4 Study was to test the hypothesis that decreasing “upstream” Aβ burden in the preclinical stages of AD would impact biomarkers of “downstream” neurodegeneration and slow the rate of cognitive decline towards MCI and AD dementia.
The A4 Study was a Phase 3 blinded study with individuals between 65 and 85 years of age. A public private partnership with National Institute on Aging (NIA) at the National Institutes of Health (NIH) and Eli Lilly and Co. was established to carry out the trial, with additional funding contributed by philanthropic groups, and in-kind support from multiple partners. A companion to the A4 study is the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) study. The LEARN study is a first of its kind study that will follow individuals who do not have elevated levels of amyloid-beta plaque in order to identify other biological changes related to cognitive decline. The A4 Open Label Extension (A4 OLE) allowed for active treatment continuation of all participants enrolled into the study until top line study results were available. Novel design features included Tau PET imaging and a pilot of retinal imaging and actigraphy.
The A4 Study clinical trial results were announced in March 2023, and published in the New Journal of Medicine in July 2023. Very disappointingly, no beneficial treatment effects were observed with solanezumab compared to placebo. Together, the A4 and LEARN Studies have allowed us to better understand the role that amyloid has in driving cognitive change, even in very early stages.
Key publications
Sperling et al. Trial of Solanezumab in Preclinical Alzheimer’s Disease. N Engl J Med. 2023 Sep 21;389(12):1096-1107. doi: 10.1056/NEJMoa2305032. Epub 2023 Jul 17. PMID: 37458272; PMCID: PMC10559996.
Donohue et al. Natural cubic splines for the analysis of Alzheimer’s clinical trials. 10 January 2023 https://doi.org/10.1002/pst.2285
Raman R, et al. Disparities by Race and Ethnicity Among Adults Recruited for a Preclinical Alzheimer Disease Trial. JAMA Netw Open. 2021 Jul 1;4(7):e2114364. doi:
10.1001/jamanetworkopen.2021.14364. PMID: 34228129; PMCID: PMC8261604.
Sperling RA et al. Association of Factors With Elevated Amyloid Burden in Clinically Normal Older Individuals in the A4 Study Screening Cohort. JAMA Neurol. 2020 Apr 6 doi:10.1001/jamaneurol.2020.0387
Sperling RA, et al. The A4 study: stopping AD before symptoms begin? Sci Transl Med. 2014 Mar 19;6(228):228fs13. doi: 10.1126/scitranslmed.3007941. PMID: 24648338; PMCID: PMC4049292.
ACTC Affiliation
The A4 Study became affiliated with ACTC in 2015. ACTC helped navigate the study through many challenges, including the COVID-19 pandemic. A key contribution of ACTC was the novel analysis method utilizing splines, where time is treated as a continuous, rather than categorical, variable (see Donohue et al above). The A4/LEARN screening dataset is the largest cohort of cognitively unimpaired older individuals with amyloid imaging and detailed cognitive testing available to date and has been requested by over 1500 investigators from around the world. In a first for a Phase 3 trial, A4 pre-randomization data and LEARN data were publicly released within one year after completion of randomization, and includes 4,486 Amyloid PET scans. The full dataset will be available early summer 2024. Learn more about data sharing and how to access the dataset here.