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)
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Special Emphasis Panel (ZAG1-ZIJ-7 (02))
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University of California San Diego
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Mormino, Elizabeth C; Betensky, Rebecca A; Hedden, Trey et al. (2014) Amyloid and APOE ?4 interact to influence short-term decline in preclinical Alzheimer disease. Neurology 82:1760-7
Mormino, Elizabeth C; Betensky, Rebecca A; Hedden, Trey et al. (2014) Synergistic effect of ?-amyloid and neurodegeneration on cognitive decline in clinically normal individuals. JAMA Neurol 71:1379-85
Rafii, Michael S; Taylor, Curtis S; Kim, Hyun T et al. (2014) Neuropsychiatric symptoms and regional neocortical atrophy in mild cognitive impairment and Alzheimer's disease. Am J Alzheimers Dis Other Demen 29:159-65
Whitehouse, Peter J (2014) The end of Alzheimer's disease--from biochemical pharmacology to ecopsychosociology: a personal perspective. Biochem Pharmacol 88:677-81
Burstein, Aaron H; Grimes, Imogene; Galasko, Douglas R et al. (2014) Effect of TTP488 in patients with mild to moderate Alzheimer's disease. BMC Neurol 14:12
Donohue, Michael C; Jacqmin-Gadda, Hélène; Le Goff, Mélanie et al. (2014) Estimating long-term multivariate progression from short-term data. Alzheimers Dement 10:S400-10
Samieri, Cécilia; Proust-Lima, Cécile; M Glymour, Maria et al. (2014) Subjective cognitive concerns, episodic memory, and the APOE ?4 allele. Alzheimers Dement 10:752-759.e1
Galasko, Douglas; Bell, Joanne; Mancuso, Jessica Y et al. (2014) Clinical trial of an inhibitor of RAGE-A? interactions in Alzheimer disease. Neurology 82:1536-42
Sperling, Reisa A; Rentz, Dorene M; Johnson, Keith A et al. (2014) The A4 study: stopping AD before symptoms begin? Sci Transl Med 6:228fs13
Papay, Kimberly; Xie, Sharon X; Stern, Matthew et al. (2014) Naltrexone for impulse control disorders in Parkinson disease: a placebo-controlled study. Neurology 83:826-33

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