Treat Alzheimers failed to show dramatic benefit

The third try wasn’t the charm for Eli Lilly’s Alzheimer’s drug solanezumab. In EXPEDITION3, the third test of the drug since it was developed in 2006, the compound failed once again to show significant benefit for people with mild forms of the disease.

“The results of the solanezumab EXPEDITION3 trial were not what we had hoped for and we are disappointed for the millions of people waiting for a potential disease-modifying treatment for Alzheimer’s disease,” said John Lechleiter, chairman, president and chief executive officer of Lilly, in a statement. The company will not continue to pursue approval of the drug for treatment of mild Alzheimer’s.

Solanezumab is among the first of a new group of treatments that are designed to address the brain disorder at its root cause, rather than just relieve symptoms. Had it been successful, it would have been the first so-called disease-modifying treatment, or therapy that slowed progression of Alzheimer’s. The compound sticks to the free-floating forms of the protein amyloid, which build up into damaging plaques in the brain. Lilly scientists had hoped that their agent, an amyloid antibody, would soak up enough of the circulating amyloid so that there weren’t enough fragments around to aggregate into the toxic plaques. “By increasing the rate of clearance of amyloid with solanezumab, we are making the brain younger in a sense,” Dr. Eric Siemers, medical director of the Alzheimer’s Disease Team at Lilly, told TIME earlier while describing the compound.

In the study, 2,100 people with mild dementia and evidence of amyloid in the brain confirmed by PET scans were randomly assigned to solanezumab or placebo. After 18 months, there was no significant difference between them on measures of cognitive decline.

“It’s clearly disappointing for all of us [in the Alzheimer’s field],” says Dr. Dennis Selkoe, co-director of the center for neurology at Brigham and Women’s Hospital. Selkoe was not involved in the study but has patients who are enrolled in it.

The company came under fire over the summer when it changed the endpoint of the trial. Originally, Lilly was going to determine the success of solanezumab by looking at two measures: how it affected thinking skills such as memory and reasoning, and whether it changed a person’s ability to function independently and perform daily activities such as dressing, bathing and feeding. But just before the final data on the last patient was collected in October, Lilly changed the outcomes so that the drug’s success would rest solely on the cognitive changes, with the functional ones as a secondary measure of success. Critics pointed out that functional changes tend to be more challenging to show and that the company made the change to maximize the chances of a positive outcome.

The company maintains that the shift simply reflected better understanding of how Alzheimer’s affects the brain; cognitive declines happen before functional ones, so detecting the latter would take a longer, more expensive study than an 18-month trial.

EXPEDITION3 was Lilly’s third chance to show that solanezumab was worth approving. In the previous two studies, people with either mild or moderate Alzheimer’s participated and the results were similarly negative. As knowledge about the disease improved, researchers learned that amyloid starts to build up years, perhaps even decades, before the first symptoms of memory and cognitive problems start. In response, Lilly launched EXPEDITION3, limiting the participants to people with mild forms of the disease. The company also took advantage of better imaging techniques that could document the presence of amyloid in the brain; in the previous two studies, anywhere from 20% to 30% of the volunteers did not actually have amyloid. (At the time, doctors were diagnosing people based only on their symptoms and performance on cognitive tests.)

The fact that the trial did not show benefit even among people with mild Alzheimer’s doesn’t necessarily spell the end of anti-amyloid approaches. It could simply mean that the drug treatment wasn’t started early enough in the disease to make a difference. Other anti-amyloid compounds, including one developed by Biogen, for example, have recently shown encouraging results in reducing amyloid plaques as well as improving cognitive skills. That agent, aducanumab, is designed to bind preferentially to the early clumps of amyloid as they form plaques, and therefore may be more useful in mild or moderate patients who are already showing signs of memory loss and other cognitive problems. “I don’t think we will abandon attempts to slow down Alzheimer’s with amyloid-lowering,” says Selkoe. “We’ve always known that solanezumab is a weak antibody, which is why it also doesn’t have many side effects. There is a balance between efficacy and safety, and while solanezumab was not that powerful, the idea was that the Food and Drug Administration, in approving the first disease-modifying Alzheimer’s treatment, needs to have a drug that can be used safely, and first do no harm.”

Symptoms of the memory-robbing disorder

Everyone struggles to come up with a name once in a while. But how can you tell if it’s more serious?

“One symptom alone does not necessarily indicate that a person has Alzheimer’s or dementia,” says Raj C. Shah, MD, of the Rush Memory Clinic at Rush University Medical Center, in Chicago. (Dementia is chronic loss of cognition, usually affecting memory, and Alzheimer’s causes 50% to 80% of dementia cases.)

There are many other causes of memory loss, including vitamin B12 deficiency, and brain, thyroid, kidney, or liver disorders. However, having several other symptoms could be a sign of Alzheimer’s disease (AD). Recognizing the signs of dementia can help lead to a quicker diagnosis.

Serious memory loss and confusion are not a normal part of aging. But forgetfulness caused by stress, anxiety, or depression can be mistaken for dementia, especially in someone who is older.

“We all forget the exact details of a conversation or what someone told us to do, but a person with AD will forget what just happened, what someone just said, or what he or she just said and therefore repeat things over and over again,” says Lisa P. Gwyther, co-author of The Alzheimer’s Action Plan: A Family Guide ($9-20; amazon.com).

Memory loss isn’t consistent, and people with AD may forget the dog’s name one day and remember it the next. “Nothing is certain or predictable with most dementias except they do progress,” says Gwyther.

It’s common for someone suffering from AD to seem anxious or agitated.

They may constantly move around and pace, get upset in certain places, or become fixated on specific details. Agitation usually results from fear, confusion, fatigue, and feeling overwhelmed from trying to make sense of a world that no longer makes sense, explains Gwyther.

Certain circumstances can also make the individual more anxious, such as relocating to a nursing home. In addition to agitation, rapid and seemingly unprovoked mood swings are another sign of dementia—going from calm to tearful to angry for no apparent reason.

Be Careful of Contraception

When it comes to birth control, many people want to just set it and forget it. It’s there, it does its job, who wants to think about it, right?

But bungling birth control is all too common. In fact, half of all pregnancies in the United States are unintended. Yikes.

To make sure you can count on your contraceptive, here are the potential pitfalls.

It’s no secret that birth control is a touchy subject, particularly in the US. Political and religious leaders fight about it endlessly, and it’s all tangled up in personal choices about—shhhh!—sex.

But the bottom line is if you’re sexually active, and now isn’t a great time to start a family, you should select a type of birth control that works for you. Luckily, there are a ton of birth control options out there.

The antibiotic rifampin can undermine hormonal contraception, including the pill, the patch (Ortho Evra), or the vaginal ring (NuvaRing).

Some anticonvulsants, oral medications for yeast infections, HIV drugs, and the herbal supplement St. John’s wort can also be a problem for these types of birth control, as well as for contraceptive implants (Implanon), according to Planned Parenthood.

Bottom line? Check with your doctor about possible interactions and medications that can make your birth control less effective.

Help Save Your Memory

Healthy eating lowers your risk of diabetes, hypertension, and heart disease, but it’s not yet clear if that’s true for Alzheimer’s disease as well.

“I can’t write a prescription for broccoli and say this will help—yet,” says Sam Gandy MD, PhD, the associate director of the Mount Sinai Medical Center Alzheimer’s Disease Research Center, in New York City.

(The National Institutes of Health has said there is insufficient evidence that food, diet, or lifestyle will prevent Alzheimer’s disease.)

It’s not a lost cause though. Here are 9 foods that researchers think will keep your whole body—including your brain—healthy.

“The data support eating foods that are high in vitamin E and this includes healthy vegetable oil-based salad dressings, seeds and nuts, peanut butter, and whole grains,” says Martha Clare Morris, ScD, director of the section on nutrition and nutritional epidemiology in the Department of Internal Medicine at Rush University, in Chicago.

The benefit has been seen with vitamin-E rich foods, but not supplements, she says.

A potent antioxidant, vitamin E may help protect neurons or nerve cells. In Alzheimer’s disease, neurons in certain parts of the brain start to die, which jump-starts the cascade of events leading to cognitive deterioration.

Salmon, mackerel, tuna, and other fish are rich in heart-healthy omega-3 fatty acids, including docosahexaenoic acid (DHA).

“In the brain, DHA seems to be very important for the normal functioning of neurons,” Morris says.

Another plus: Eating more fish often means eating less red meat and other forms of protein that are high in artery-clogging saturated fats.

Help Reverse Memory Loss in People

A small new study—just 10 people—suggests that an intense and personalized approach may help reverse memory loss in people with signs of early Alzheimer’s disease.

The researchers, from the Buck Institute on Aging at UCLA and led by Dale Bredesen, MD, report in the journal Aging, that the 10 patients improved so much that some were able to return to work and “those struggling at work were able to improve their performance.”

The MEND (Metabolic Enhancement for Neurodegeneration) program contains 36 items which are tailored to individual patients. The regimen incorporates some of the lifestyle measures long recommended to preserve brain function, such as diet, exercise, good sleep, and stimulating the brain, along with drugs and vitamins to enhance brain chemistry.

The authors did MRI scans and neuropsychological testing on the patients, who had a variety of signs and symptoms of Alzheimer’s disease, including memory trouble, a family history of dementia, and in many cases, a risk-boosting genetic variation called ApoE-e4. The paper consists of a series of case studies.

One 66-year-old man who had had “senior moments” for two years, shed 18 pounds after three months on the protocol and stopped forgetting things. When he went off the program for three weeks, the senior moments, such as leaving the car idling in the driveway, returned. This man also showed a large increase in the volume of the hippocampus, which is a part of the brain connected with memory.

Another man who was shutting down his business after 11 years of memory loss, regained not only his memory but also his work abilities, including his knack for doing mathematical calculations in his head. Rather than close his business, he expanded it.

Other participants were able to work again, picked up playing guitar again, and even regained foreign language abilities.

In addition to increases in the volume of the hippocampus, a part of the brain that can shrink in Alzheimer’s patients, the study authors noted other biological changes, including improvements in CRP, a marker of inflammation, as well as glucose metabolism and insulin levels.

Jessica Zwerling, MD, associate director of the Montefiore Einstein Center for the Aging Brain in New York City, notes that the people in the study were clearly very motivated to take charge of their health. It’s not clear how well this protocol would work with other groups of people. “Statistics [show] a growing population of individuals that may have poor health literacy,” she says. “[The patient group in this study] does represent a niche.”

Given the success of the MEND protocol in this study, the authors suggest that more widespread genetic testing of ApoE-e4 is in order. However, ApoE-e4 is very common—82 million Americans carry one or two copies of the gene, inherited from one or both parents—and having it doesn’t mean you will necessarily get the memory-robbing condition.