the extent and location of the vascular damage in the brain, according to Snowdon, that appears to be the determining factor.
The implication is that the accumulation of damage to neurons and blood vessels is one unavoidable process of aging. There is a point when the slow accumulation of Alzheimer’s lesions and vascular damage passes some threshold and manifests itself as dementia, and diabetics are always likely to reach that threshold sooner than nondiabetics, if only because they accumulate vascular damage more rapidly, even if the diabetes bestows on them no special predisposition to develop Alzheimer’s plaques and tangles. So whatever dietary factors or lifestyle factors lead to Type 2 diabetes will always increase the likelihood of manifesting dementia.
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
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.
The involvement of insulin in Alzheimer’s can be considered the simplest possible explanation for the slow, relentless development of Alzheimer’s plaques in the aging brain. Insulin (in a test tube) will monopolize the attention of the
Much of the relevant research in humans on insulin and Alzheimer’s has been done by Suzanne Craft, a neuropsychiatrist at the University of Washington. In 1996, Craft and her colleagues reported that boosting insulin levels, at least in the short term, seems to enhance memory and mental prowess, even in Alzheimer’s patients. This linked insulin to the biochemical regulation of memory in the brain, but it said nothing about the long-term, chronic effects of hyperinsulinemia. In 2003, Craft reported that when insulin was infused into the veins of elderly volunteers, the amount of amyloid in their cerebral spinal fluid increased proportionately. This implied that the level of amyloid protein in their brain had increased as well. The older the patient, the greater the increase in amyloid protein. As Craft sees it, if insulin levels are chronically elevated (hyperinsulinemia), then brain neurons will be excessively stimulated to produce amyloid proteins, and IDE will be preoccupied with removing the insulin, so that less will be available to clean up the amyloid. “We’re not saying this is
This evidence linking insulin, amyloid, and Alzheimer’s has now evolved to the point where it has “attendant therapeutic implications,” as the Harvard neurologists Dennis Selkoe and Rudolph Tanzi wrote in a 2004 article. “Compounds that subtly increase IDE activity,” they suggested, “could chronically decrease [amyloid] levels in the human brain.” This implies that anything that decreases insulin levels over the long term (and so increases the amount of IDE available to clean up amyloid)—including such dietary approaches as eating less carbohydrates—will achieve the same effect. This isn’t to say that eating carbohydrate foods to excess is a cause of Alzheimer’s, only that mechanisms have now been identified to make the hypothesis plausible.
To discuss cancer, we need to first return to the subject of cancer in isolated populations eating traditional diets. The modern incarnation of these observations begins with John Higginson, who was the founding director of the World Health Organization’s International Agency for Research on Cancer (IARC), a position he would hold for two decades. In the 1950s, Higginson studied cancer incidence in native African populations and compared them with incidence in the United States and Denmark, the two nations for which equivalent data existed. With a few exceptions, Higginson reported, cancer in African natives was remarkably uncommon. This led Higginson to conclude that
Cancer epidemiologists then tried to establish what proportion of cancers these might be. Higginson suggested 70 to 80 percent of all cancers could be prevented; others said as many as 90 percent. In 1981, the Oxford epidemiologists Richard Doll and Richard Peto published the seminal work on this subject: a 120-page analysis in the
In the quarter-century since Doll and Peto published their analysis, it has been cited in nearly two thousand journal articles, and yet the fundamental implications have been largely lost. The two most important conclusions in their analysis were that man-made chemicals—in pollution, food additives, and occupational exposure—play a minimal role in human cancers, and that diet played the largest role—causing 35 percent of all cancers, though the uncertainties were considered so vast that the number could be as low as 10 percent or as high as 70 percent.
Higginson had repeatedly remarked on these two points during his tenure as director of IARC. In early reports, Higginson and the World Health Organization had referred to “extrinsic factors” and “environmental factors” as the cause of most cancers, by which they meant lifestyle and diet. The public and the environmental movement had perceived this to mean almost exclusively “man-made chemicals”—the “carcinogenic soup,” as it was known in the
