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Alzheimer’s brain tangles offer clue to worsening


WASHINGTON – That sticky substance coating Alzheimer’s patients’ brains gets all the notoriety, but another culprit is gaining renewed attention: Protein tangles that clog brain cells and just might determine how fast patients go downhill.

Nobody knows what causes Alzheimer’s, although the disease’s hallmark plaque – that gooey stuff called beta-amyloid – is the main suspect. Yet repeated attempts at anti-amyloid treatments have failed, the latest disappointment last month when Eli Lilly and Co. abandoned an experimental drug that wound up doing harm, not good.

Now comes a different clue: A second protein called tau seems to signal how aggressive the mind-robbing disease will be. Researchers discovered that patients with mild Alzheimer’s and high levels of tau also harbored a genetic alteration that in turn predicted they would worsen faster.

That suggests if scientists could figure out how to lower tau levels, it might slow dementia, says senior researcher Alison Goate of Washington University in St. Louis.

More than 5 million Americans are estimated to be living with Alzheimer’s, as many as half in the disease’s early stages. The only available medications temporarily ease symptoms but don’t slow the disease.

How quickly a loved one will deteriorate is a big question for families struggling to plan for care — and Goate’s work is a first step at identifying genetic markers to help predict how long someone may function independently and when they might require a nursing home.

Do not look for a genetic test for tau any time soon. This is first-step research that needs to be validated by other laboratories, and Goate says it is likely just one genetic marker among many to be discovered.

Already, a handful of drug companies are focusing on the protein. Singapore-based TauRx Therapeutics tells The Associated Press it has begun planning an advanced research trial of its experimental anti-tau drug known as LMTX. It is a second-generation version of a drug named Rember that generated excitement in early-stage testing a few years ago.

And the genetic finding promises to increase interest.

“We’ve been saying for years, ‘Hedge your bets guys, you don’t know what’s going to pay off,’” says Dr. John Trojanowski of the University of Pennsylvania, which this spring began collaborating with drugmaker AstraZeneca to hunt anti-tau compounds.

The work opens an important window into the neurobiology of Alzheimer’s, but doesn’t negate the long-standing focus on amyloid plaque, cautions dementia specialist Dr. Paul Aisen of the University of California, San Diego.

“Both amyloid and tau are clearly important, and both represent plausible areas for drug development,” Aisen says.

Researchers have been measuring amyloid in hopes of learning to diagnose Alzheimer’s at its earliest stages. But autopsies find amyloid buildup in lots of elderly people who had no memory problems, so harboring amyloid alone doesn’t mean pending dementia.

The newest thinking is that the two proteins play a tandem role, with amyloid-run-amok the trigger for disease to start brewing years before it becomes apparent. Tau makes its entrance later, as symptoms appear.

Strings of an abnormal form of tau build up inside dying nerve cells. It is called ptau, or phosphorylated tau. When the cells die, the ptau is released into spinal fluid, where it can be measured. Goate knew that spinal tap studies show healthy people have low ptau levels and people with Alzheimer’s disease have higher but also variable ptau levels.

In people with particularly high ptau levels in their spinal fluid, her team uncovered a variation in a gene involved in producing the abnormal tau. Then they had to test if that mattered.

Tracking records of several hundred Alzheimer’s patients, they found up to a sevenfold difference in how quickly people declined if they had the abnormal genetic marker.    

“What you predict from this data is people with lowest levels of tau progress the slowest,” said Goate, who reported the work last week in the journal PLoS Genetics.

This genetic work may help the hunt for better Alzheimer’s drugs in a different way, by allowing researchers to test experimental therapies in patients who may show an effect the soonest, says William Thies of the Alzheimer’s Association. He cautions that spinal taps for now are reserved for research studies.

TauRx is thought to have the drug farthest along in development for breaking up tau tangles, but the company did not say how soon its next-phase testing could begin. At an international Alzheimer’s meeting in Hawaii last summer, other researchers reported that new ways of targeting amyloid might in turn lower tau levels, too — and that vaccine-like therapies to attack tau are just beginning to be tested in mice.

Associated Press