P. Aisen1, R. Sperling2
1. Alzheimer’s Therapeutic Research Institute, University of Southern California, San Diego, CA, USA; 2. Center for Alzheimer Research and Treatment, Brigham and Women’s Hospital, Massachusetts General Hospital, Harvard Medical School, Boston, MA USA
Corresponding Author: Paul Aisen, Alzheimer’s Therapeutic Research Institute, University of Southern California, San Diego, CA, USA, paisen@usc.edu
J Prev Alz Dis 2024;4(11):801
Published online July 24, 2024, http://dx.doi.org/10.14283/jpad.2024.118
The A4 (Anti-Amyloid treatment in Asymptomatic Alzheimer’s) Study (1) arose from the recognition that amyloid accumulation in brain, which occurs in about 30% of clinically unimpaired individuals aged 65 and older, is accompanied by evidence of neurodegeneration and cognitive decline that defines the preclinical stage of Alzheimer’s disease (2). A composite cognitive function scale was developed to serve as a primary outcome measure (3), as well as other novel outcome measures appropriate for this very early stage of AD. The A4 trial was launched in 2014 testing an antibody against monomeric amyloid, solanezumab. Solanezumab has only modest effects on fibrillar amyloid deposits but showed promise in initial studies with mild AD dementia participants (though a subsequent Phase 3 trial was negative (4)).
The results from the A4 Study were negative; solanezumab did not slow cognitive decline over the 4.5-year treatment period (5). But the trial confirmed the high prevalence of amyloid in cognitively normal older individuals and demonstrated clear evidence of cognitive, clinical and functional decline in preclinical AD. A companion study, LEARN (Longitudinal Evaluation of Amyloid Risk and Neurodegeneration) (6), with individuals interested in joining A4 but who screen-failed on the basis of normal amyloid PET scan results, followed participants with a similar schedule of assessments to provide a valuable comparator group. Together, A4 and LEARN comprise a rich longitudinal dataset to elucidate the earliest changes related to preclinical AD and the aging brain. In this special issue of JPAD, a series of papers explore this dataset.
In accordance with the Collaboration on Alzheimer’s Prevention guidelines (7), the A4 (and LEARN) pre-randomization datasets were released for public sharing one year after the completion of screening activities (8) [ida.loni.usc.edu]. The data has been downloaded about 1500 times to date by students, trainees and scientists around the world. By the end of June 2024, the full longitudinal A4 and LEARN datasets will be shared. Additional trials in the preclinical AD population have now been launched (9). Preliminary evidence from successful trials of lecanemab (10) and donanemab (11) in symptomatic AD suggest that that aggressive amyloid removal (and perhaps other interventions against AD) will yield the greatest clinical benefits at the earliest stage of disease. It is our hope that continuing scrutiny of the A4 and LEARN data will facilitate further advances in therapy that will reduce the devastating burden of this disease.
Conflict of Interest: Dr. Aisen reports grants from Lilly, Eisai, NIH, Alzhiemer’s Association, personal fees from Merck, Biogen, Abbvie, Genentech, Roche, ImmunoBrain Checkpoint, Arrowhead, outside the submitted work.
References
1. Sperling RA, Rentz DM, Johnson KA, et al. The A4 study: stopping AD before symptoms begin? Sci Transl Med. Mar 19 2014;6(228):228fs13. doi:10.1126/scitranslmed.3007941
2. Sperling RA, Aisen PS, Beckett LA, et al. Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. May 2011;7(3):280-92. doi:10.1016/j.jalz.2011.03.003
3. Donohue MC, Sperling RA, Salmon DP, et al. The preclinical Alzheimer cognitive composite: measuring amyloid-related decline. JAMA Neurol. Aug 2014;71(8):961-70. doi:10.1001/jamaneurol.2014.803
4. Honig LS, Vellas B, Woodward M, et al. Trial of Solanezumab for Mild Dementia Due to Alzheimer’s Disease. N Engl J Med. Jan 25 2018;378(4):321-330. doi:10.1056/NEJMoa1705971
5. Sperling RA, Donohue MC, Raman R, et al. Trial of Solanezumab in Preclinical Alzheimer’s Disease. N Engl J Med. Sep 21 2023;389(12):1096-1107. doi:10.1056/NEJMoa2305032
6. Sperling RA, Donohue MC, Raman R, et al. Association of Factors With Elevated Amyloid Burden in Clinically Normal Older Individuals. JAMA Neurol. Jun 1 2020;77(6):735-745. doi:10.1001/jamaneurol.2020.0387
7. Weninger S, Carrillo MC, Dunn B, et al. Collaboration for Alzheimer’s Prevention: Principles to guide data and sample sharing in preclinical Alzheimer’s disease trials. Alzheimers Dement. May 2016;12(5):631-2. doi:10.1016/j.jalz.2016.04.001
8. ida.loni.usc.edu
9. Rafii MS, Sperling RA, Donohue MC, et al. The AHEAD 3-45 Study: Design of a prevention trial for Alzheimer’s disease. Alzheimers Dement. Apr 2023;19(4):1227-1233. doi:10.1002/alz.12748
10. van Dyck CH, Swanson CJ, Aisen P, et al. Lecanemab in Early Alzheimer’s Disease. N Engl J Med. Jan 5 2023;388(1):9-21. doi:10.1056/NEJMoa2212948
11. Sims JR, Zimmer JA, Evans CD, et al. Donanemab in Early Symptomatic Alzheimer Disease: The TRAILBLAZER-ALZ 2 Randomized Clinical Trial. JAMA. Aug 8 2023;330(6):512-527. doi:10.1001/jama.2023.13239
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