Dementia: A generational challenge

November 27, 2006|By Greg Critser

This month, major scientific and medical societies concerned with Alzheimer's disease marked the central event in the evolution of this modern malady: the centennial of the case of Auguste D as presented by Dr. Alois Alzheimer at a medical conference in November 1906.

Something else will not be marked as loudly: The slow but gradual end of Alzheimer's as we know it - and the Americanization of dementia science.

Germany's Alois Alzheimer gave us the basis of the modern conception of the disease, that of a dementia caused by a buildup of plaque between neurons and fibrous tangles inside brain cells. This he did through his examination of Auguste D, 51, who came to him at a hospital at Frankfurt am Main. He found her anxious, disoriented, apathetic, unable to care for herself, often delusional and unable to remember key personal details of her life. As Auguste told Alzheimer at one point: "I have lost myself." Slices of her brain at autopsy showed that her brain had extensive plaque and tangles.

Yet Auguste D's case was hardly tidy. Yes, she had plaque and tangles; no, she did not have brain lesions (dead areas) and artery problems normally associated with brain dysfunction.

For a century, most of neuroscience used Alzheimer's observations to, essentially, reason backward. What causes the tangles, which seem to starve brain cells? What causes the plaque, which seems to mix up neural communication? And how do such changes lead to dementia? The focus on plaque and tangles has led to important discoveries about how brain disease develops, including inflammation, infection, chromosomal aging and beyond. But that narrow focus also has yielded no major therapeutic advances.

In many ways, it took Ronald Reagan, a perpetually sunny Californian, to wrest the disease from the grim determinism of fin de si?cle Germany's model of Alzheimer's. The late president's candor about his condition, and his wife Nancy's energetic dedication to the cause, helped transform dementia science. The result is a number of new approaches that, while more promising than classic plaque-and-tangles theory, require a leap of faith. Stem cells are one such tack. If you can grow new neurons, you might be able to rewire demented brains.

More radical: What, for example, if one abandoned "reasoning backward" from plaque and tangles altogether? That is the bombshell dropped last summer in the journal Alzheimer's & Dementia. After studying Alzheimer's patients who were given experimental doses of the diabetes drug Avandia, Allen D. Roses, head of the neurological drugs lab at GlaxoSmith- Kline, and Ann M. Saunders theorized that what causes Alzheimer's dementia is not plaque and tangles. Instead, the disease may result from a "dysfunction" in the way brain cells of a certain genetic stripe use glucose, leading to destroyed dendrites, neurons' main way to communicate. Mr. Roses did not leave the implications of his theory hanging. Targeting impaired glucose - not plaque and tangles - should be a priority for early detection and treatment.

On the other end of the new research wave are academic entrepreneurs who are asking: Can we find a public health intervention that can slow the growing dementia rates in large populations? To that end, the National Institutes of Health have begun trials on omega-3 oils.

A number of promising experiments are under way, including the work of Greg Cole, a professor of medicine and neurology at the University of California, Los Angeles, on the use of curcumin, a spice in curry powder, and its ability to retard dementia-linked changes in Alzheimer's-prone rats. The University of Southern California has a number of experiments under way as well, many inspired by the pacesetting work of Caleb Finch, arguably the world's leading gerontological thinker.

Instructively, dementia and cognitive impairment, not Alzheimer's, have been the hot topics at the major Alzheimer's conventions in recent years. And for good reason. Not all dementia is caused by plaque and tangles (stroke is a leading cause), and not all plaque and tangles lead to dementia. Aging does not inevitably lead to dementia either.

Where gerontological wisdom once held that anyone who lived to 110 or older would be demented and/or afflicted with plaque and tangles, such has turned out not to be the case. Jeanne Calment, the Frenchwoman who lived to age 121, was cognitively unimpaired to the end. And gene science and brain scanning are showing that dementia is hardly the linear disease that Alzheimer and his successors proposed. Environment catalyzes genes, and genes catalyze environments. Mr. Reagan's dementia has become a hot topic among researchers for this reason. What role did the environment created by his neglectful alcoholic father and emotionally absent mother play in the origins of his disease? Did the fact that he was easily able to quit smoking indicate a shortage of certain, later critical, brain receptors?

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