The Stealth Solution

After 22 posts about dementia in which I repeatedly inveigh against the all-too prevalent hype about how the cure for Alzheimer’s disease is just around the corner, I finally have some encouraging news. A piece in the “Medical News and Perspectives” section of the Journal of the American Medical Association highlights a radically new approach to preventing dementia.

At the heart of the approach is the recognition, as the JAMA article leads off by saying, that “pathology is not destiny.” We know that this is true in large part because of the nun study, an ingenious epidemiological study that’s been ongoing since 1986. In this study, 678 of the School Sisters of Notre Dame agreed to annual assessments of their cognitive and physical function as well as to blood tests for genetic studies. They also agreed to donate their brains to the researchers upon their deaths. Taken together, these tests allow researchers to uncover the relationship between cognitive function during life (the presence, absence or degree of dementia), biochemical markers in the blood, and pathologic changes in the brain.

The study population is particularly useful because the nuns tend to stay within their order—they don’t move around the way many Americans do—simplifying longitudinal follow-up. Moreover, because they all live in the same order, where they have a similar diet and participate in many of the same activities, they exhibit a degree of environmental homogeneity seldom found in other groups. One of the many things we have learned from the nun study is that there are people with evidence of advanced Alzheimer’s disease at autopsy who clinically had very mild disease and conversely, there are people whose brain pathology is consistent with early Alzheimer’s disease who were clinically quite severely affected. This observation strongly suggests that factors other than the brain plaques and tangles that are the hallmarks of Alzheimer’s can mediate the severity of a person’s symptoms.

One of these mediators is other brain pathology, such as vascular disease, which causes strokes. It turns out that vascular changes plus plaques and tangles are far more devastating than would be expected by simply summing the expected effects of each alone. The implication is that preventing atherosclerosis (what once upon a time was known as hardening of the arteries), which involves smoking cessation and treatment or prevention of high blood pressure, diabetes, and elevated cholesterol, is an effective means of attenuating dementia, even dementia due to Alzheimer’s disease. But another mediator is entirely new and different: recent results from the longitudinal Framingham Heart study point to special proteins that the brain manufactures to protect itself. Remarkably, a stimulus for the body to make more of these magic molecules is social engagement.

One such brain protein has the awkward name of brain-derived neurotrophic factor, abbreviated BDNF. This substance appears to reduce the risk of both dementia and stroke, probably by promoting the growth of new neurons and of synapses, the connections between neurons, as well as by protecting neurons from dying. Another protein, with the equally euphonious name of vascular endothelial growth factor, abbreviated VEGF, may also play a protective role. VEGF promotes the growth of new blood vessels, which may counteract the damage to the brain resulting from amyloid, a principal factor in the development of Alzheimer’s dementia. Just as social networks seem to boost BDNF, exercise seems to increase the levels of VEGF.

So far, no one has found a drug that either mimics the effects of BDNF or VEGF or stimulates the brain to make more of these substances. Or at least, the one such drug that has been studied, davunetide, failed to show any benefit in a clinical trial. It’s conceivable that a combination of pharmacology and life style interventions will be needed to make a clinical difference. But the idea of harnessing the body’s own repair mechanisms is promising; it seems much better than trying to remove amyloid deposits after they’ve formed (by which time the damage has already been done) or to boost levels of the neurotransmitters needed for neuron to neuron communication (which doesn’t work if the neurons that are supposed to communicate are already dead). 

If one way to coax the brain into producing more protective protein is by exercising and remaining socially engaged, both of which have other benefits and almost no side effects, that would be welcome news indeed.

Paradigm Shift?

The most powerful explanatory model in medicine is the germ theory of disease. It’s simple and it’s elegant: find the offending microbe, kill it, and cure the disease. This approach has led to some of the most dramatic and effective advances in medical history: identifying the leading cause of pneumonia (the pneumococcus bacillus), finding a chemical that kills the bacteria without harming people (penicillin), diagnosing disease (by some combination of physical examination, a chest x-ray, and examination of sputum under the microscope), and treating the patient with antibiotics. The result?  Pneumonia cedes its place as the leading cause of death in older people to heart disease. 

Life has turned out to be a bit more complicated than the germ theory suggests. Expose a group of people to exactly the same dose of a microbe and not all of them will get sick. Of those who do become ill, not everyone is equally sick. Other factors proved to matter, ranging from the vigor of the patient’s immune system to socioeconomic status. And pneumococci were not the only causes of pneumonia: all kinds of other bacteria can cause much the same clinical and radiographic picture, as can a whole host of viruses. Even with our enhanced understanding of the causes of disease and of how and why illness develops in different individuals, we haven’t been able to eradicate pneumonia. Together with influenza, it’s still the seventh leading cause of death in older people.

These caveats mean we’ve had to refine the model, to elaborate on it. But the germ theory of disease still stands as the gold standard for all of medicine. Doctors in areas under than infectious disease seek to find a similar master key that unlocks the diseases of their particular organ system. Cardiologists have focused on atherosclerosis as the unifying feature underlying coronary heart disease; neurologists have seized on amyloid as the basis for Alzheimer’s disease. But the reductionist view of the world seems to break down when it comes to geriatric syndromes, problems such as falls and incontinence that are responsible for so much misery in older people. What seems to explain reality more effectively is a multifactorial understanding. Maybe that’s why even though last week’s JAMA includes two reports of failed efforts to stave off Alzheimer’s disease, one with anti-oxidants taken as nutritional supplements, and one with exercise, the editorial accompanying the articles optimistically maintains that we can make a difference. We just have to eat well and exercise and play mind games.

Now there are a number of possible reasons that the JAMA studies may have been unable to find any benefit of their interventions. The anti-oxidant study was carried out in older patients with macular deterioration, a chronic eye disease. Its main hypothesis was that supplements would stave off progressive visual loss—preventing cognitive impairment was a secondary aim. Conceivably, people with macular degeneration are sufficiently different from the general population that what works, or doesn’t work, for them may not be the same as for everyone else. The trial used pills, not diet rich in anti-oxidants, and there are at least some nutritionists who maintain that the purified version of a chemical won’t work the same way as that chemical in combination with food. The exercise study used moderate intensity physical activity such as walking, it used resistance training, and it used flexibility exercises, which it compared to an educational program. It’s at least possible that other kinds of exercise, or exercise of different intensity or duration, would have been more effective. 

The commentary in JAMA, written by a psychiatrist and an internist from Ontario, Canada, mentions these possibilities. But it also seizes on a different study, one of the few encouraging ones in a field littered with negative results. And that is the FINGER trial, a multifaceted intervention involving diet, exercise, and cognitive training in Finland in people aged 60-77. After two years, there were measurable benefits to the study population as determined by psychological testing. So despite the negative findings of the two studies they are charged with reviewing, the editorialists put on their rose-colored glasses and assert that “it is still likely that lifestyle factors such as diet and physical activity have important roles in the prevention of cognitive decline, dementia, and performance of the activities of daily living.”

There is precedent for a multifactorial intervention working when no single approach succeeded. In her path-breaking work on falls, Mary Tinetti of Yale found that fall rates in community dwelling older people could be significantly decreased if they had an evaluation that focused on physical hazards (throw rugs or poor lighting), on a medication review (getting rid of drugs that cause orthostatic hypotension or confusion), and on strength training. Similarly, Sharon Inouye, now at Harvard, recognized that delirium in the hospital is difficult to prevent, but found the most effective strategy involved a multi-component intervention targeting sleep, mobility, vision, hearing, cognition, and fluid intake. 

So maybe we can make a difference in preventing dementia or delaying its onset or slowing its progression. Maybe the recent meta-analysis that was widely quoted in the media (published in the somewhat obscure Journal of Neurology, Neurosurgery, and Psychiatry) as claiming that “modifiable risk factors” are responsible for 2/3 of the risk of Alzheimer’s disease is onto something. Or maybe it’s all wishful thinking and we should redouble our efforts to look for the magic bullet, the switch that we can turn off amyloid deposition in the brain, stopping dementia before it starts. Or maybe we just have to do something. Eating vegetables, going for walks, and doing crossword puzzles won't hurt. They don't cost a lot of money. They won't jack up the cost of American health care. And in combination, they just might help.