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Background: Reductions in brain-derived neurotrophic factor (BDNF) have been implicated in the pathophysiology of Alzheimer's disease (AD). Nevertheless, the factors influencing central and peripheral BDNF levels are still poorly understood. Cerebral microvascular endothelial cells are known to be a major source of BDNF with a rate of production by far exceeding that of cortical neurons. Exposure of these cells to amyloid beta (Ab), results in cell death or injury with significant reductions in BDNF secretion. Moreover, in rodents, infusion of Ab40 into the carotid resulted in a disruption of endothelial cells, which was not observed with Ab42. Plasma Ab40 levels have also been associated with white matter hyperintense lesions (WMHI) on MRI scans in AD, an effect that may be mediated by the toxic effects of soluble Ab40 on small cerebral blood vessels and endothelial cells. Therefore, we hypothesized that concentrations of plasma Ab40, but not Ab42, would have a negative effect on plasma BDNF and on measures of white matter integrity as determined by Diffusion Tensor Imaging (DTI). Methods: To test this hypothesis, we examined BDNF and Ab levels in plasma from 119 subjects with intact cognition (no dementia and a Mini-Mental State Exam score of at least 28) and no gross MRI abnormalities other than white matter hyperintensities. Of these, 88 subjects also had BDNF in plasma determined. Results: Consistent with our prediction, Ab40 was inversely correlated with BDNF concentrations (P <.001), whereas Ab42 was independent (P = .231). Fractional anisotropy (FA; a measure of white matter integrity in DTI) was also inversely correlated with Ab40 (P = .001) and so was performance in delayed recall (P = .029). Conclusions: In cognitively intact individuals, circulating Ab40 results in reduction in plasma BDNF, white matter integrity (FA), and memory performance. As such, it may have prognostic significance