Peter H. St George-Hyslop
Over the past decade, researchers have pinpointed an early and central cause of Alzheimer’s Disease: a rogue substance formed from a common amino acid called amyloid precursor protein, or APP. This dangerous APP derivative, known as amyloid beta-peptide (A-beta), is the main ingredient in small fibers—the amyloid or senile plaque—that accumulate in the spaces between nerve cells in the brains of Alzheimer’s patients. Over time, the buildup of senile plaque causes the nerve cells to malfunction and ultimately kills them; thus the gradual, degenerative course of the disease.
While A-beta is thought to be toxic to nerve cells generally, it appears to be especially dangerous when it assembles itself within these small fibers. Researchers have replicated much of this abnormal biochemical process in laboratory animals, helping them to identify a number of genetic factors underlying Alzheimer’s disease, all of which influence either the rate of production of A-beta or how it arranges itself after its synthesis from APP. Indeed, researchers now believe that, taken together, these factors enable and speed up the accumulation of senile plaque in the brain.
With convincing evidence that the buildup of A-beta is the principal event underlying the onset of Alzheimer’s, several therapies are now being developed to inhibit its production, remove it once it has been produced, or reduce its toxicity. This has, understandably, generated excitement among scientists and the public about the possibility of developing ways to treat and/or prevent the disease. But it is not yet clear which therapeutic approach, if any, will prove effective, or whether a therapy that is effective in treating Alzheimer’s can also be used to prevent its onset.
One strategy, based on research using a version of Alzheimer’s in mice, involves the removal of A-beta by inducing the patient’s immune system to generate antibodies that specifically target it. Several laboratories have shown that as the antibodies alter the way A-beta is processed in the brains of the vaccinated mice, the number of senile plaques plummets, bringing significant improvement in the animals’ cognitive functioning. These results inspire hope that a similar immune-response approach can be used to halt progression of Alzheimer’s in humans—and alleviate some existing symptoms—as nerve cells that are sick (but not dead) recover from the toxic effects of A-beta deposits.
Unfortunately, therapy based on stem-cell replacement is unlikely to produce similar improvement. In contrast to, say, Parkinson Disease, Alzheimer’s affects many different types of nerve cells in many different parts of the brain, making it very difficult to organize their coordinated replacement and re-connection. Moreover, simply replacing lost cells will not restore lost memories and cognitive skills. Moreover, unless over-production of A-beta is stopped, the new cells would eventually be damaged, too.
Other therapeutic strategies are more promising precisely because they take aim at A-beta even before it can damage nerve cells. One of these potential treatments uses what are called, fittingly, amyloid chain busters—compounds designed to prevent A-beta from insinuating itself into the toxic filament whose buildup ultimately causes cell dysfunction and death.
A second, and more radical, approach targets the production of A-peptide itself by inhibiting the two APP enzymes, called beta-secretase and gamma-secretase, from which it is formed. Some compounds that are believed to inhibit gamma-secretase will enter clinical trials at about the same time as the immune-response vaccine that was tested in mice.
Today, however, there is insufficient evidence to support choosing any one of these potential treatments over the others. The main advantage of gamma-secretase or beta-secretase inhibitors is that they are conventional drugs, thus allowing doctors to tailor the dosage to an individual patient’s needs, and discontinue treatment if toxic side effects appear. On the other hand, it is likely that adequate enzyme inhibition will require daily administration of medication—an obvious problem in a patient whose memory has been impaired by the clinical dementia brought on by Alzheimer’s.
Vaccination, by contrast, ostensibly allows for a normal course of immunization followed by periodic (annual, bi-annual, etc.) booster shots. This makes it well suited both for use with demented patients and as a long-term preventive treatment for individuals who have yet to exhibit symptoms of the disease. But these advantages may be outweighed by the risk that long-term vaccination with a human protein could eventually precipitate autoimmune disease in some patients. This risk could be reduced by administering ready-made antibodies to attack the A-beta deposits — an approach that might be particularly useful with elderly people, whose immune systems often mount only weak responses.
If any of these potential treatments prove to be effective and relatively non-toxic, when should they be used? Ideally, they should be administered in the earliest stages of Alzheimer’s, when biochemical abnormalities have been detected but before they have had a chance to cause significant damage to nerve cells. Indeed, high-risk individuals identified by the presence of inherited genetic determinants might be appropriately treated throughout adulthood.
Unfortunately, in all but less than 5% of Alzheimer’s cases (in which there is a strong, recognizable determinant), it is currently impossible to identify unambiguously who will develop the disease within the next several years. This means that scientific research, paradoxically, may be getting ahead of itself. For, no matter how much the treatments now being developed—whether immune-response vaccination or chemical protocols—fulfill their promise, they cannot be widely and effectively applied in the absence of reliable tests to diagnose early, pre-clinical forms of Alzheimer’s.
China’s success in the next five years will depend largely on how well the government manages the tensions underlying its complex agenda. In particular, China’s leaders will need to balance a muscular Communist Party, setting standards and protecting the public interest, with an empowered market, driving the economy into the future.
The preference of some countries to isolate themselves within their borders is anachronistic and self-defeating, but it would be a serious mistake for others, fearing contagion, to respond by imposing strict isolation. Even in states that have succumbed to reductionist discourses, much of the population has not.
When the Bretton Woods Agreement was hashed out in 1944, it was agreed that countries with current-account deficits should be able to limit temporarily purchases of goods from countries running surpluses. In the ensuing 73 years, the so-called "scarce-currency clause" has been largely forgotten; but it may be time to bring it back.
Republican leaders have a choice: they can either continue to collaborate with President Donald Trump, thereby courting disaster, or they can renounce him, finally putting their country’s democracy ahead of loyalty to their party tribe. They are hardly the first politicians to face such a decision.
As the global economic recovery strengthens, and central banks move to raise interest rates, they need to improve their communication with the general public. To do that, they should follow the trail blazed by Donald Trump.
With talks on the UK's withdrawal from the EU stalled, negotiators should shift to the temporary “transition” Prime Minister Theresa May officially requested last month. Above all, the negotiators should focus immediately on the British budget contributions that will be required to make an orderly transition possible.
In recent decades, as President Vladimir Putin has entrenched his authority, Russia has seemed to be moving backward socially and economically. But while the Kremlin knows that it must reverse this trajectory, genuine reform would be incompatible with the kleptocratic character of Putin’s regime.
As a part of their efforts to roll back the 2010 Dodd-Frank Act, congressional Republicans have approved a measure that would have courts, rather than regulators, oversee megabank bankruptcies. It is now up to the Trump administration to decide if it wants to set the stage for a repeat of the Lehman Brothers collapse in 2008.