Two other lines of evidence linking insulin and high blood sugar to Alzheimer’s disease are directly related to the amyloid-plaque buildup that is now thought to result in the degeneration and death of neurons in the Alzheimer’s-affected brain. The primary component of these plaques is a protein known as beta-amyloid—or just amyloid, for short—and this protein is what’s left after a larger protein, a precursor protein, is cleaved in two. The amyloid precursor protein exists naturally in brain neurons, according to the Harvard neurologist Rudolph Tanzi, and the act of cutting it down in size to the amyloid protein appears to be a normal cellular process. A healthy brain, however, clears away amyloid efficiently after the cleavage occurs; this does not happen in Alzheimer’s. The question is, why not?

One phenomenon now implicated in the process of amyloid-plaque accumulation is the accumulation of AGEs, the conglomerations of haphazardly linked proteins and sugars that are found to excess in the organs and tissues of diabetics. Because neurons ideally last a lifetime, they seem to be prime candidates for the slow accumulation of AGEs and the toxic damage they inflict. The proteins that make up the plaques and tangles of Alzheimer’s are particularly long-lived themselves and so particularly susceptible. And AGEs can indeed be found buried in both the plaques and tangles of Alzheimer’s and even in immature plaques, suggesting that they are involved from the very beginning of the process.

Investigators studying AGEs have proposed that Alzheimer’s starts with glycation—the haphazard binding of reactive blood sugars to these brain proteins. Because the sugars stick randomly to the fine filaments of the proteins, this in turn causes the proteins to stick to themselves and to other proteins. This impairs their function and, at least occasionally, leaves them impervious to the usual disposal mechanisms, causing them to accumulate in the spaces between neurons. There they cross-link with other nearby proteins, and eventually become advanced glycation end-products. All of this would then be exacerbated by the fact that the glycation process itself generates more and more toxic reactive oxygen species (free radicals), which in turn causes even more damage to the neurons. In theory, this is what causes the amyloid plaques and leads to the degeneration of neurons, the cell loss, and the dementia of Alzheimer’s. The theory is controversial, but the identification of AGEs in the plaques and tangles of Alzheimer’s is not.