Memory function often declines with age¹, and is believed to deteriorate initially because of changes in synaptic function rather than loss of neurons². Some individuals then go on to develop Alzheimer's disease with neurodegeneration. Here we use Tg2576 mice, which express a human amyloid- precursor protein (APP) variant linked to Alzheimer's disease, to investigate the cause of memory decline in the absence of neurodegeneration or amyloid- protein amyloidosis. Young Tg2576 mice (< 6 months old) have normal memory and lack neuropathology, middle-aged mice (6–14 months old) develop memory deficits without neuronal loss, and old mice (> 14 months old) form abundant neuritic plaques containing amyloid- (refs 3–6). We found that memory deficits in middle-aged Tg2576 mice are caused by the extracellular accumulation of a 56-kDa soluble amyloid- assembly, which we term A*56 (A star 56). A*56 purified from the brains of impaired Tg2576 mice disrupts memory when administered to young rats. We propose that A*56 impairs memory independently of plaques or neuronal loss, and may contribute to cognitive deficits associated with Alzheimer's disease.

1. Departments of Neurology and
2. Neuroscience, and
3. Graduate Program in Neuroscience, University of Minnesota Medical School, Minneapolis, Minnesota 55455, USA
4. Department of Psychological and Brain Sciences, Johns Hopkins University, Baltimore, Maryland 21218, USA
5. Geriatric Research Education Clinical Center, Minneapolis VA Medical Center, Minneapolis, Minnesota 55417, USA
6. Department of Molecular Biology and Biochemistry, University of California, Irvine, California 92697, USA
7. Department of Pharmaceutical Sciences, University of Southern California, Los Angeles, California 90089, USA

Correspondence to: Karen H. Ashe^1,2,3,5 Correspondence and requests for materials should be addressed to K.H.A. (Email: hsiao005@umn.edu).

Received 23 November 2005 | Accepted 13 December 2005

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