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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AG010483-23
Application #
8601652
Study Section
Special Emphasis Panel (ZAG1-ZIJ-7)
Project Start
Project End
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
23
Fiscal Year
2014
Total Cost
$4,604,811
Indirect Cost
$774,810
Name
University of California San Diego
Department
Type
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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