Although a number of promising anti-amyloid (ABeta) agents are currently in large-scale clinical trials, unfortunately, none of the trials at the stages of mild to moderate Alzheimer's disease (AD) dementia has yet demonstrated clear evidence of clinical benefit. Given the mounting evidence that neurodegeneration is well entrenched even by the stage of MCI, there is growing concern in the field that we may need to institute antiamyloid therapies at a much earlier stage of AD to fully impact the course of the disease. Recent imaging, biomarker, and autopsy studies are remarkably consistent in the finding that approximately 1/3 of clinically normal older individuals harbor ABeta pathology, and many of these individuals already demonstrate functional and structural brain imaging abnormalities consistent with preclinical AD. The """"""""A4"""""""" (Anti-Amyloid treatment in Asymptomatic Alzheimer's disease) study is a secondary prevention trial in clinically normal older subjects with biomarker marker evidence of AD pathology, who at increased risk for progression to AD dementia. The A4 trial will be a 3-year, double-blinded, placebo-controlled trial of a monoclonal anti-ABeta antibody in 1000 older individuals who are ABeta-positive on screening PET amyloid imaging. The primary outcome will be rate of decline on a cognitive composite, heavily weighted towards episodic memory and executive function tests. Secondary biomarker outcomes will include PET amyloid imaging, cerebrospinal fluid levels of tau/phosphotau, and volumetric MRI measures. We will also develop a novel computerized test battery and task-free functional MRI as exploratory outcomes. The A4 study will also include a natural history arm of age and education matched ABeta-negative individuals (n=500) who will undergo longitudinal clinical and cognitive assessments. The A4 study should provide critically needed evidence to support (or refute) ABeta as a promising strategy for disease-modifying therapy in very early AD, and will serve to greatly enhance the efficiency of future prevention studies as additional therapies, including anti-tau agents, become available.

Public Health Relevance

Converging evidence suggests that the pathophysiological process of Alzheimer's disease (AD) begins many years prior to the emergence of clinically evident cognitive impairment. The A4 trial will treat clinically normal older individuals who have evidence that the process of AD has already begun in their brain, in the hope that we can delay the onset of memory problems and progression to AD dementia.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program--Cooperative Agreements (U19)
Project #
Application #
Study Section
Special Emphasis Panel (ZAG1-ZIJ-7 (02))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Diego
La Jolla
United States
Zip Code
Rentz, Dorene M; Dekhtyar, Maria; Sherman, Julia et al. (2016) The Feasibility of At-Home iPad Cognitive Testing For Use in Clinical Trials. J Prev Alzheimers Dis 3:8-12
Graff-Radford, Jonathan; Madhavan, Malini; Vemuri, Prashanthi et al. (2016) Atrial fibrillation, cognitive impairment, and neuroimaging. Alzheimers Dement 12:391-8
Johnson, Keith A; Schultz, Aaron; Betensky, Rebecca A et al. (2016) Tau positron emission tomographic imaging in aging and early Alzheimer disease. Ann Neurol 79:110-9
Kennedy, Richard E; Cutter, Gary R; Wang, Guoqiao et al. (2016) Post Hoc Analyses of ApoE Genotype-Defined Subgroups in Clinical Trials. J Alzheimers Dis 50:1205-15
Reiman, Eric M; Langbaum, Jessica B; Tariot, Pierre N et al. (2016) CAP--advancing the evaluation of preclinical Alzheimer disease treatments. Nat Rev Neurol 12:56-61
Raman, Mekala R; Schwarz, Christopher G; Murray, Melissa E et al. (2016) An MRI-Based Atlas for Correlation of Imaging and Pathologic Findings in Alzheimer's Disease. J Neuroimaging 26:264-8
Gauthier, Serge; Feldman, Howard H; Schneider, Lon S et al. (2016) Efficacy and safety of tau-aggregation inhibitor therapy in patients with mild or moderate Alzheimer's disease: a randomised, controlled, double-blind, parallel-arm, phase 3 trial. Lancet 388:2873-2884
Le, Michelle H; Weissmiller, April M; Monte, Louise et al. (2016) Functional Impact of Corticotropin-Releasing Factor Exposure on Tau Phosphorylation and Axon Transport. PLoS One 11:e0147250
Tarrant, Sarah D; Bardach, Shoshana H; Bates, Kendra et al. (2016) The Effectiveness of Small-group Community-based Information Sessions on Clinical Trial Recruitment for Secondary Prevention of Alzheimer's Disease. Alzheimer Dis Assoc Disord :
Zhang, Cheng; Kuo, Ching-Chang; Moghadam, Setareh H et al. (2016) Corticotropin-releasing factor receptor-1 antagonism mitigates beta amyloid pathology and cognitive and synaptic deficits in a mouse model of Alzheimer's disease. Alzheimers Dement 12:527-37

Showing the most recent 10 out of 402 publications