Good Calories, Bad Calories (39 page)

DEMENTIA, CANCER, AND AGING

The bottom line is pretty irrefutable: What is good for the heart is good for the brain.

RUDOLPH TANZI AND ANN PARSON, Decoding Darkness: The Search for the Genetic Causes of Alzheimer’s Disease, 2000

WHEN IT COMES TO THE CAUSE of chronic disease, as we discussed earlier, the carbohydrate hypothesis rests upon two simple propositions. First, if our likelihood of contracting a particular disease increases once we already have Type 2 diabetes or metabolic syndrome, then it’s a reasonable assumption that high blood sugar and/or insulin is involved in the disease process. Second, if blood sugar and insulin are involved, then we have to accept the possibility that refined and easily digestible carbohydrates are as wel .

This applies to Alzheimer’s disease and cancer, too, since both diabetes and metabolic syndrome are associated with an increased incidence of these two il nesses. In both cases, critical steps in the disease process have been linked unambiguously to insulin and blood sugar, and the relevant research is now beginning to influence the mainstream thinking in these fields.

Though the characteristic dementia and brain lesions of Alzheimer’s were first described a century ago, the disease only recently captured the attention of the research community. In 1975, when the NIH was supporting hundreds of research projects on atherosclerosis and cholesterol metabolism, it was funding fewer than a dozen on Alzheimer’s and what was then cal ed senile dementia. This number rose gradual y through the end of the 1970s. Between 1982 and 1985, the number of Alzheimer’s-related research projects funded by the NIH quintupled.

It took another decade for researchers to begin reporting that heart disease and Alzheimer’s seem to share risk factors: hypertension, atherosclerosis, and smoking are al associated with an increased risk of Alzheimer’s, as is the inheritance of a particular variant of a gene cal ed apolipoprotein E4 (apo E4) that also increases the risk of cardiovascular disease.*59 This in turn led to the notion that what’s good for the heart is good for the brain, but that, of course, depends on our understanding of what exactly is good for the heart. Because Alzheimer’s researchers, like diabetologists, assume that Keys’s fat-cholesterol hypothesis is supported by compel ing evidence, they wil often suggest that cholesterol and saturated fat play a role in Alzheimer’s as wel .

But if coronary heart disease is mostly a product of the physiological abnormalities of metabolic syndrome, as the evidence suggests, then this implicates insulin, blood sugar, and refined carbohydrates instead, a conclusion supported by several lines of research that began to converge in the last decade.

A handful of studies have suggested that Alzheimer’s is another disease of civilization, with a pattern of distribution similar, if not identical, to heart disease, diabetes, and obesity. Japanese Americans, for instance, develop a pattern of dementia—the ratio of Alzheimer’s dementia to the stroke-related condition known as vascular dementia—that is typical y American; when Japanese immigrate to the United States, their likelihood of developing Alzheimer’s disease increases considerably, while their risk of developing vascular dementia decreases. The incidence of Alzheimer’s dementia in African Americans, according to research published in JAMA in 2001, is twice that of rural Africans, and they are three times as likely to suffer vascular dementia, again suggesting that dietary or lifestyle factors play a role in both dementias.

Studies in large populations—6,000 elderly subjects in Rotterdam, 1,500 in Minnesota, 1,300 in Manhattan, 800 Catholic nuns, priests, and brothers in the American Midwest, and 2,500 Japanese Americans in Honolulu—have suggested that Type 2 diabetics have roughly twice as much risk of contracting Alzheimer’s disease as nondiabetics. Diabetics on insulin therapy, according to the Rotterdam study, had a fourfold increase in risk.

Hyperinsulinemia and metabolic syndrome are also associated with an increased risk of Alzheimer’s disease. And so one interpretation of these results, as the Rotterdam investigators noted in 1999, is that “direct or indirect effects of insulin could contribute to the risk of dementia.”

One complicating factor in this research is that the underlying cause of dementia is exceedingly difficult to diagnose, even on autopsy. For this reason, it’s possible that the research linking diabetes to a higher incidence of Alzheimer’s does so because it confuses the consequences of a known complication of diabetes—vascular dementia—with an apparently increased incidence of Alzheimer’s dementia. These are the two most common causes of dementia, but the actual diagnoses are not clear-cut.

Alzheimer’s dementia is typical y perceived as a slow, insidious process that can be identified on autopsy by the presence of neurofibril ary tangles, which are twisted protein fibers located within neurons, and amyloid plaques, which accumulate outside the neurons. Vascular dementia, a recognized complication of diabetes, is perceived as a more abrupt cognitive decline that is caused by smal strokes in the blood vessels of the brain. Vascular dementia is usual y diagnosed because the dementia appeared shortly after a stroke, or because an autopsy revealed the characteristic stroke-related signs of vascular damage. That vascular dementia is a complication of diabetes means that diabetics are far more likely to be diagnosed someday with vascular dementia than nondiabetics.

In cases of dementia, however, the determination of the actual cause is likely to be arbitrary. Most of us, if we live long enough, wil accumulate both vascular damage and Alzheimer’s plaques and tangles in our brains, even if we don’t manifest any perceptible symptoms of dementia. (Similarly, most of us wil have plaques in our arteries even if we don’t manifest clinical signs of heart disease.) Vascular dementia and Alzheimer’s dementia appear to coexist frequently, a condition known as mixed dementia. When dementia is present, the diagnosis of its ultimate cause is a matter of clinical judgment.

This gray zone of mixed dementia was examined in a seminal study of nearly seven hundred elderly members of the Sisters of Notre Dame congregation, led by the University of Kentucky epidemiologist David Snowdon. The results suggest that, the less vascular damage we have in our brains, the more easily we can tolerate the lesions of Alzheimer’s without exhibiting signs of dementia. It’s 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 wil 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 a s 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 natural y 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 cel ular 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 ideal y 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 occasional y, 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 eventual y become advanced glycation end-products. Al 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 cel 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) wil monopolize the attention of the insulin-degrading enzyme (IDE), which normal y degrades and clears both amyloid proteins and insulin from around the neurons. The more insulin available in the brain, by this scenario, the less IDE is available to clean up amyloid, which then accumulates excessively and clumps into plaques. In animal experiments, the less IDE available, the greater the concentration of amyloid in the brain. Mice that lack the gene to produce IDE develop versions of both Alzheimer’s disease and Type 2 diabetes.*60

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 col eagues 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 wel . The older the patient, the greater the increase in amyloid protein. As Craft sees it, if insulin levels are chronical y elevated (hyperinsulinemia), then brain neurons wil be excessively stimulated to produce amyloid proteins, and IDE wil be preoccupied with removing the insulin, so that less wil be available to clean up the amyloid.

“We’re not saying this is the mechanism for al of Alzheimer’s disease,” Craft says. But “it may have a role in a significant number of people.”

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 chronical y 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—wil 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 most human cancers were caused by environmental factors, and that diet and lifestyle factors were the primary suspects. “It would seem, therefore, that the majority of human cancer is potential y preventable,” as the World Health Organization concluded in 1964, a view that evolved into the new orthodoxy.

Cancer epidemiologists then tried to establish what proportion of cancers these might be. Higginson suggested 70 to 80 percent of al cancers could be prevented; others said as many as 90 percent. In 1981, the Oxford epidemiologists Richard Dol and Richard Peto published the seminal work on this subject: a 120-page analysis in the Journal of the National Cancer Institute that reviewed the existing evidence on changes in cancer incidence over time, changes upon migration from one region of the world to another, and differences in cancer rates between communities and nations. (Colon cancer, for example, was ten times more common in rural Connecticut than in Nigeria; breast cancer was diagnosed eight times more often in British Columbia than in the non-Jewish population of Israel.) Based on this evidence, Dol and Peto concluded that at least 75 to 80 percent of cancers in the United States might be avoidable with appropriate changes in diet and lifestyle.

In the quarter-century since Dol 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 pol ution, food additives, and occupational exposure—play a minimal role in human cancers, and that diet played the largest role—causing 35 percent of al cancers, though the uncertainties were considered so vast that the number could be as low as 10 percent or as high as 70 percent.