Conversely, we demonstrated in a previous study that some nonagenarian individuals with a heavy load of amyloid, similar to those commonly observed in the final stages of AD, likewise did not manifest cognitive impairment and dementia. This apparent paradox implies that amyloid accumulation may be critically important in the development of cognitive failure in some individuals but might not represent the sole decisive factor for the induction of clinically manifested AD. These issues are further complicated by the recent recognition of a third group classified as suspected non-amyloid pathology cases in which clinical symptoms and signs of neurodegeneration are present while amyloid Methoxamine hydrochloride accumulations remain undetectable by imaging methods. The cognitive failure of AD occurs when the burden of both amyloid and tangles is widespread. Some observations insinuate that AD etiology is mechanistically heterogeneous and that other complicating causal conditions related to aging, in addition to Ab, are necessary and sometimes sufficient for dementia emergence. It has been recently shown that the development of AD may be linked to the nuclear loss of the repressor element 1-silencing transcription factor, a molecule associated with cognitive preservation and longevity, in some GSK J4 hydrochloride neurodegenerative disorders. In understanding the role of Ab in the pathogenesis of AD, two important questions remain unanswered: 1) what are the triggering mechanisms that primarily induce Ab deposition? and 2) why does Ab relentlessly accumulate in such a destructive manner? The first question has not been fully addressed, although some interesting hypotheses have been advanced. In relation to the second, recent data suggest that Ab deposits self-propagate through the continuous accretion of misfolded and degradation-resistant molecules. These toxic Ab molecules may result from structurally altered conformations, possibly induced or stabilized by posttranslational modifications common in the AD brain. Furthermore, once nucleated, noxious Ab molecules may propagate in a timedependent fashion through cell-to-cell transmission as proposed for tau and a-synuclein.