So what if tangles precede plaques?

Abstract

As proposed by Hardy and Higgins in 1992 [8], the amyloid hypothesis had two tenets. First, that deposition of -amyloid (A ) is the causative agent of Alzheimer’s disease (AD) pathology, and secondly that other lesions (tangles, dystrophic neurites, synaptic and cell loss, vascular degeneration) follow directly from this deposition. In their paper analyzing early formation of amyloid plaques and neurofibrillary tangles, Schonheit et al. aim to refute the second tenet, arguing that tangles form without or prior to the presence of plaques, and therefore that A cannot be the causative agent for neurofibrillary lesions. As discussed below, their argument is consistent with earlier observations that at least the initial formation of tangles is independent of A . On the other hand, the first tenet of the amyloid hypothesis is now supported so strongly by several lines of evidence that it is difficult to refute it. The challenge is how to reconcile these seemingly contradictory conclusions. Probably, the most compelling evidence that A is the causative agent of AD comes from observations on genetic mutations or other conditions that cause familial forms of AD, all of which produce an elevation in A or its more toxic form, A 1–42 [21,22]. These mutations occur directly in the gene for amyloid precursor protein (APP), and produce excess A , or occur in the genes for the Presenilin proteins, which form an important part of the -secretase complex that cuts APP to liberate A . Down’s Syndrome, with triplication of chromosome 21, also results almost invariably in AD, beginning at ages at which AD is extremely rare. Because the gene for APP is on the chromosome 21, an excess amount of A is generated. Amyloid plaques develop in Down’s Syndrome brains at about the age of 20–30 years, and large numbers of tangles appear in these cases during the third to fifth decades of life [9,11,12,26]. Although these genetic conditions account for only a small fraction of the total number of AD cases, the associated pattern of