A key question in the pathogenesis of Alzheimer's disease is the relation between the accumulation of β-amyloid (Aβ) and the formation of neurofibrillary tangles. Are the two processes entwined or are they independent manifestations of the disease? Two recent papers provide convincing evidence that the two archetypal neuropathological changes seen in Alzheimer's disease are linked. Both papers converge on the idea that the formation of Aβ deposits acts to promote the appearance of tangles.

Lewis et al. generated a long-awaited transgenic animal — a mouse carrying mutant forms of both the amyloid precursor protein (APP) and tau, the main component of neurofibrillary tangles. Mice bearing either one of the two mutant genes fail to recapitulate all of the neuropathological changes found in Alzheimer's disease. It was therefore hoped that the double-transgenic mice would constitute a better model of the pathology. Indeed, these mice showed both amyloid plaques and tangles but, more importantly, the number of tangles in the double mutant was higher than in mice expressing only tau, indicating that the accumulation of Aβ might stimulate the formation of tangles.

But is Aβ responsible for the observed phenotype or is it APP itself? In an independent study, Götz et al. used transgenic mice expressing tau but, instead of generating a double mutant, they injected Aβ directly into the cortex and hippocampus of these animals. They found that this treatment also increased the number of tangles, providing evidence that Aβ is indeed the molecule that stimulates tangle formation.

An intriguing aspect of both studies is that Aβ and tau were spatially segregated. Lewis et al. found that, in contrast to what is found in Alzheimer's disease, amyloid plaques were not surrounded by tau-positive neurites in the double mutants, and Götz et al. found that tangle formation was stimulated in brain regions far from the Aβ injection sites. So, it seems that these models also fail to reproduce every aspect of Alzheimer's disease, although the two of them provide better tools to test more rigorously the benefit of new treatments for this pathology.