In Preventing Alzheimer’s, Mutation May Aid Drug Quest

By GINA KOLATA

Published: July 11, 2012

A study of a rare gene mutation that protects people against Alzheimer’s disease provides the strongest evidence yet that excessive levels of a normal brain substance, beta amyloid, are a driving force in the disease — bolstering hopes that anti-amyloid drugs already under development might alter the disease’s course or even prevent it.

DeCode Genetics stored blood samples from its research on genomes and Alzheimer’s disease.

So far, the drugs have not succeeded. But scientists not connected with the new study said it suggested that the drug companies’ big bets on anti-amyloid treatments could yet pay off.

The implication for drug development “is hugely important,” said Dr. David Altshuler, a genomics expert at Harvard Medical School and the Broad Institute of Harvard and M.I.T. 

And Dr. Samuel Gandy, an Alzheimer’s researcher who directs the Mount Sinai Center for Cognitive Health, called the finding the most significant in the field in two decades, since researchers first reported a mutation that leads to the disease. 

The protective mutation, whose discovery was reported online Wednesday in the journal Nature, is highly uncommon — it is not the reason most people do not develop Alzheimer’s. But what intrigues researchers is how it protects the brain. 

Mutations that cause Alzheimer’s lead to excessive amounts of beta amyloid in the brain; by contrast, the protective mutation slows beta amyloid production, so people make much less.

“This paper provides strong evidence that it would work in the general population if you did it right,” Dr. Altshuler said. 

Scientists at the drug companies agreed. “We are thrilled,” said Ryan Watts, one of the authors of the new paper and head of the neurodegeneration labs at Genentech, which is developing two drugs to reduce brain amyloid levels. 

Dr. Richard Mohs, leader of neuroscience early clinical development at Eli Lilly, said the company was “very encouraged by these study results.” They show, he said, that despite an initial failure, the strategy of focusing on drugs to reduce beta amyloid levels is “a logical path for the development of effective therapies that may slow disease progression.” 

Many questions remain, of course. Most people do not have the protective gene mutation, but as common as Alzheimer’s is, most people do not get it. It is not clear why. And most who develop Alzheimer’s do not have one of the rare gene mutations that cause it. The reasons for their disease are unclear. 

The discovery of the protective gene mutation, a product of the revolution that has taken place in genetics, arose when researchers scanned the entire DNA of 1,795 Icelanders. 

About 1 in 100 had a mutation in the gene for a large protein that is sliced to form beta amyloid. Then the investigators studied people who had been given an Alzheimer’s diagnosis, and a group of people 85 and older. Those with the mutation appeared to be protected from Alzheimer’s disease.

The investigators, led by Dr. Kari Stefansson, chief executive at DeCode Genetics, an Icelandic company, looked at genomes of North Americans and found the gene mutation in only about 1 in 10,000 people. That indicates, Dr. Stefansson said, that the mutation arose relatively recently in Scandinavia. 

The protective gene even appears to override a very strong risk factor for Alzheimer’s disease in old age — two copies of a gene known as ApoE4. Ninety percent of people with two ApoE4 genes get Alzheimer’s by age 80. But Dr. Stefansson says there are 25 people in his study with two copies of ApoE4. None have Alzheimer’s disease. 

The research “is obviously right,” said John Hardy, an Alzheimer’s researcher at University College London and a discoverer of the first gene mutation found to cause the disease. “The statistics and the finding are pretty secure.” 

The discovery is part of a continuing story that implicates beta amyloid as a central and crucial player in this destructive brain disease. The idea began two decades ago with the discovery of very rare gene mutations that always cause Alzheimer’s in those who inherit them, usually by middle age. The mutations were different in different families, but all had the same effect: They increased the amount of beta amyloid in the brain. That meant that a buildup of amyloid was sufficient to cause the disease.

Elderly people with Alzheimer’s — who typically do not have these gene mutations — also had excess amyloid in the brain. So researchers reasoned that might mean that excess amyloid was causing the disease in them, too. 

Additional evidence of the role of beta amyloid was reported on Wednesday in The New England Journal of Medicine. Using spinal taps and brain scans to track the protein, investigators found that people with one of the Alzheimer’s-causing mutations start making too much beta amyloid as long as 20 years before they have symptoms of the disease. 

Researchers and drug companies focused on the amyloid hypothesis to the extent that almost every experimental drug being tested to slow or halt Alzheimer’s disease is designed to reduce the amount of amyloid in the brain. Most of those drugs are still being tested in clinical trials, but a Lilly drug that failed spectacularly in 2010, semagacestat, actually made people with Alzheimer’s worse and gave rise to soul-searching in the field. 

It emphasized a crucial question that hung over the endeavor. Was amyloid really causing Alzheimer’s in elderly people? Might the protein instead be a bystander, accumulating, for example, as part of the brain’s response to damage? 

The discovery of the protective gene mutation provides strong clues. People with the mutation make substantially less beta amyloid, but other than that they are no different from anyone else. And they do not get Alzheimer’s. 

People could be tested to see if they have the protective mutation, Dr. Stefansson said, but he added, “The benefits of doing so are not obvious to me.” He explained that since the gene is so rare, chances that a person being tested would have it — especially if that person is not Scandinavian — are extremely low. Almost everyone would end up with the same uncertainty they have now. There is as yet no way to prevent Alzheimer’s and, outside of families with one of the rare disease-causing gene mutations, no way to know who is going to get it. 

Still, Dr. Hardy noted, as provocative as the discovery of the protective gene mutation is, the strategy of reducing amyloid levels — the ultimate test of the amyloid hypothesis — still must be evaluated in typical Alzheimer’s disease. For example, perhaps people need to have lower levels of beta amyloid from birth to really be protected. 

Researchers and companies explain away the failure of the first few experimental drugs to reduce beta amyloid levels or to block the protein by saying they were not powerful enough and were studied in people who already had the disease and clear symptoms of mental decline. By then it might be too late to make any difference. When brain cells have died, nothing can bring them back.

The strategy now is to use new brain scans and other methods to find and treat people before they have symptoms of mental decline. 

“The idea is that treatment has to start early to make a difference,” Dr. Watts said.

Of course, people with the newly discovered mutation have lower levels of beta amyloid for their entire lives. 

“You couldn’t start earlier than that,” Dr. Watts said.

Women and Finance

Money Matters | Women just don’t get it

By SANDI WEAVER

The topic assigned for today was women’s issues. Since I’ve intensely enjoyed financial planning for 30 years, I felt my perspective may be skewed even though I’m female. So I sent a survey. Twenty women revealed a stunning (to me) “state of the sexes”. When asked what women should do better in planning their finances, the overwhelming response was to quit ducking it and be an active participant.

One woman lost her husband at age 49, and emailed a heartfelt message to “learn now while your partner is here and … wants to help you.” She felt that handling finances side-by-side with her husband would have helped her understand why budgeting was important, to “own some of the worry” when times were tight, how to teach their two college boys to handle money better during school, and to avoid the massive anxiety she has faced when dealing with finances since his death.

How do women get in this spot? It’s easy. For couples, a division of labor makes life easier. I’ll do the wash if you’ll do the lawn. I’ll cook, if you’ll handle the money. Both sides become comfortable in the roles.

Do you see yourself in these other comments?

Some don’t get involved because “they perceive themselves to be too stupid – a mistake.”

Some women in their 60’s “don’t know even how to pay the bills. They should start small … and learn the process.”

“Women need to know where all their assets are, and make sure they’re jointly titled or not, depending on circumstances. Are they in a second marriage?”

Even “professional women cannot turn finances over to their husbands without keeping close tabs. We think we’re too busy with work to pay attention to it.”

That’s the No. 1 tip for women and money. Based on my 30 years in this field, here’s my list along with the survey’s other comments, to round out the top 10.

Increase your earning capacity with education and savvy career transitions. Women typically have lower income due to less education, plus they earn less than men for the same positions.

Many women don’t like numbers, or are big spenders. Don’t manage your cashflow blindly. Use software such as Quicken, or online services like Mint. One woman who wanted to curb spending recently made a deal with herself that she could not get her hair cut until she paid off her credit card. That worked!

Don’t give money you need to your adult children unless they’ve promised to house you in your retirement years. You’re responsible for your financial needs. Help by teaching them to be responsible for theirs. One woman said friends agonized over decisions on whether to help a child.

You make 77% of what a man does, so start saving early. Women generally are more concerned about the present: money issues surrounding their children, home, and parents, but fail to be concerned about their retirement.

Save smart. To get the biggest bang for your buck, first save that 3% or 6% of salary to snare your employer’s company match in the pension, then contribute to a Roth, then go back and maximize savings into your pension. If you can’t qualify to use a Roth, then use a deductible IRA if possible, otherwise save in a non-deductible IRA. If you need to save more, next consider a low-cost annuity if your marginal tax rate is high, or save in a plain vanilla taxable brokerage account.

When investing, don’t be too conservative. Two women wrote “I feel that women, through years of practice, are already good at finding bargains and savings on household expenditures. We need more practice on investing and "growing the money.” “….women could do a better job of taking calculated risks so that their money could grow sufficiently to provide for their future needs.”

Get powers of attorney for financial decisions and for healthcare decisions in case you’re incapacitated. Women live long, but those years may be fraught with difficulties.

Long-term care insurance is a needed safety net for most women, unless you’re in the low income or upper income strata.

When age 62, research if you can use your work record to start social security and later switch to 50% of your husband’s, or a divorced spouse’s, work record if it yields a higher benefit. Otherwise, it’s usually more beneficial to wait until full retirement age or later, if you expect a normal life span.

I’ve paraphrased another woman’s conclusion. Women often taken time off to care take - whether it's children or parents, to be underemployed, to work part time, to be underpaid compared to males counterparts. All of those decisions we make, which we usually don't regret, can have a huge impact on what's available for retirement whether it's a 401k or social security income.

Life is such a balancing act for women, but if we use a smart approach, we can have it all.