Mary Christian-Madden's motherwas diagnosed with Alzheimer's in her late 70s, and four of her cousins, now all deceased, also developed the disease.
"So I already know that it's there on the maternal side of the family," said Christian-Madden, 56, a former principal at Killingly High School who now teaches chemistry at Quinebaug Valley Community College in Danielson. "I understand that I'm at increased risk."
She's glad for the knowledge.
"It gives me a modicum of control over the last decades of my life, if I'm making some plans," said Christian-Madden, who lives in East Greenwich, R.I. "You need to plan to the best of your ability in the last portion of your life and to make it least tragic for members should I develop the disease."
Today, almost 100 years after Dr. Alois Alzheimer identified the disease, diagnosing it is still difficult. But researchers are getting closer, and they're detecting the signs earlier.
The use of PET scans and cerebrospinal fluid has allowed researchers to detect the protein plaques and tangles strongly associated with Alzheimer's, years before any outward symptoms appear. With genetic tests, people have a better idea of their risk for Alzheimer's.
The next step for researchers is to capitalize on these advancements to treat and even prevent the disease, for which there is no cure.
According to research published this year in the New England Journal of Medicine, total health care costs for Alzheimer's disease was $215 billion in 2010. The researchers, from the RAND Corp., predict twice that amount within 30 years.
Earlier this year at StemCONN — an annual gathering in the state of stem cell researchers — Larry Goldstein of the University of California, San Diego compared the amount spent on caring for Alzheimer's patients to researching the disease itself to spending $1,000 a year on a leaky roof and only $1 to find the origin of the leak.
Dr. Adam Fleisher of the University of California, San Diego and director of imaging at the Banner Alzheimer's Institute said the search for this leak continues. Catching Alzheimer's and effectively treating the disease before the patient is suffering its effects increases the chances of thwarting it.
As it is now, he said, treatment begins too late.
"If you go to a doctor and he finds a lump with no symptoms, it would be silly to say, 'Well, you don't have any symptoms, so we're not going to treat it,'" he said. "But that's what we do with Alzheimer's."
"We started with the low-hanging fruit," he said. "The stage we could most easily identify is the dementia. Treating that first is like trying to treat cancer stage 4 metastatic disease. It makes no sense."
But we do that, he said, because there is no proven treatment.
"We want to get to the point where you can identify the pathology and the disease, so we can treat it," he said.
Yale In Major Study
One study with that aim is set to begin early next year, and is known as the Anti-Amyloid Treatment in Asymptomatic AD , or A4. It will involve 1,000 participants whose PET scans reveal amyloid accumulation in their brains — a biological indicator of Alzheimer's — but do not have any symptoms of Alzheimer's. Half of the participants will be given a placebo, the other half will be given a drug called solanezumab.
The drug, which clears away the protein plaques on brains, was found in an earlier trial to have no effect on people in the advanced stages of Alzheimer's, but it slowed the progression of the disease by 34 percent in people with mild Alzheimer's (the disease is generally classified in three stages: mild, moderate and severe). The thinking behind the A4 trial is that if the drug is somewhat effective on people with mild Alzheimer's, perhaps it will be even more so when given to people at an earlier stage of the disease, ideally staving off symptoms altogether.
The study is led by researchers at Harvard, with recruitment and testing centers around the U.S. The biggest is at Yale, led by Dr. Chris Dyck, director of the Alzheimer's Disease Research Unit at the Yale School of Medicine.
"The hoped-for effect would be a slowing of ongoing symptoms and the onset of symptoms," Van Dyck said, "and then to see what the placebo group sees in its onset of symptoms."
It is one of four Alzheimer's-related studies that will an $11 million federal grant. Whether the drug will meet the researchers' hopes will take some time to determine. A rough estimate is that people develop Alzheimer's symptoms about 15 years after the plaques develop. The grant is for three years, but Van Dyck said he thinks the money will be renewed indefinitely, being one of the largest and most promising trials out there.
The two proteins tau and amyloid are considered the most prominent culprits in the development of the disease. The Alzheimer's brain is riddled with tangles of tau and plaques of amyloid. These tangles and plaques kill cells and cause surviving cells to lose their connections to each other and the brain to lose mass.
A brain that weighed 1,300 grams (or about 2.87 pounds) while healthy can shrink to as little as 900 grams (a little under 2 pounds) by the time the disease has run its course. The majority of researchers in the field suspect that the amyloid plaques are the initial insult to the brain and the tau tangles are a secondary result.
There is still a lot that isn't known about the disease. Its cause, for one. In rare cases, a person's genetic makeup plays a very strong role in determining whether Alzheimer's is in their future. For others, researchers suspect genetics plays some role, but in combination with lifestyle choices that possibly include exercise and diet.
Rare Genetic Curse
Mutations to three genes known as presenilin-1 (PS-1), presenilin-2 (PS-2) and Amyloid precursor protein (APP) all lead to early onset Alzheimer's. Someone carrying a dominantly inherited mutation of one of these genes — a very rare occurrence — will likely get Alzheimer's at an early age. In these people, researchers believe, an overproduction of amyloid causes the disease. In typical Alzheimer's cases, amyloid production is normal but the ability to clear away the protein has diminished.
In both cases, the result is the development of amyloid plaques on the brain. And even though carriers of the mutated genes develop the disease much earlier in life, the trajectory of symptoms is the same.
The value of studying these people is that researchers can explore closely any physiological changes that lead up to the disease — insights that can probably be applied to Alzheimer's cases in the general population.
Most of the people with the gene develop the disease in their 40s. "Some are converting in their 20s, and I have to tell you that it's the saddest thing you've seen in your life," said Dorene Rentz, co-director of the Center for Alzheimer Research and Treatment at Harvard Medical School.
Rentz is part of an international team of researchers studying people who carry the rare gene mutation with the hope of learning more about the root causes of the disease and the physiological mechanisms that trigger its symptoms. That effort, known as the Dominantly Inherited Alzheimer Network (DIAN), is currently enrolling people.
"We're following people with PS1 here in the U.S. and looking at whether we can detect the tipping point of people who convert to Alzheimer's," Rentz said. Besides tracking the trajectory of the disease, she said, the study will have a prevention trial.
Carriers of a gene known as APOE-e4, a modified form of APOE, have an increased risk of developing Alzheimer's. The increased risk of those with one copy of the gene is five-fold; 10-fold for those with two copies of the gene. Those with two copies stand a 50 percent chance of developing Alzheimer's after age 55. For research purposes, genetically testing for this gene mutation plays a crucial role in learning more about Alzheimer's.
But for individuals, the question of whether there is any benefit to knowing whether you have the APOE-e4 genetic mutation is "widely discussed" among Alzheimer's researchers, said Fleisher, of the Banner Alzheimer's Institute.
"This gets into the ethical question," he said. "It's available for clinical use, but it's rarely used in a clinical way because, for one, we don't have treatment. If you have a cognitively normal person and you know they have a 50 percent chance of getting it, that's a pretty scary thing."
On the other hand, such knowledge could push the person to exercise more, change their diet — both of which may stave off Alzheimer's — or get involved in clinical studies. "And they can make plans, make sure they have power of attorney and make plans for the future — so there are definite reasons to know," Fleisher said.
Exactly what role exercise plays in staving off Alzheimer's is unknown. Dr. Sara Gregory at Hartford Hospital is leading a study exploring that question. Nine people between 40 and 60 years old with at least one parent with Alzheimer's will take part in a six-month exercise program. Before and after the six-month period, the hippocampus region of the participants' brains will be measured by MRI and they will take a series of cognitive tests. Another group of nine people in the same age group and with a parent who has Alzheimer's will perform the cognitive tests and undergo measurements of their hippocampi, but will not take part in the exercise.
Why She's Signing Up
Christian-Madden, the former Killingly principal, has signed onto the Banner Institute's Alzheimer's Prevention Initiative registry, a program that connects people with Alzheimer's studies and clinical trials of drugs. She's gotten a few leads, but so far hasn't been matched up with a study.
"My main focus is not that I'm not looking to get anything for myself," she said. "I want to make a contribution to research, finding the causality and how it's prevented because my background is science."
She has never had genetic testing, but because of the medical history on her mother's side, she said, "it's an increased risk — it's there." That means working out a lot of particulars.
"You have a very detailed, comprehensive estate plan and all of those powers of attorney and protocols of health, you plan for that," she said. "You make your wishes known to your spouse and to your children. And that goes right down to brain autopsy. I do not want to be cremated and I want my brain to be autopsied after death. That has to be formalized."
Beyond figuring out the practicalities, Christian-Madden said knowing her medical history changes the way she thinks about the big things.
"Do I live differently? You bet. Every day is an absolute blessing and I make sure not to bitch about the rainy weather we've had for the last few weeks," she said, laughing. "It's even more apparent that you appreciate every single thing."
For more information about taking part in the A4 study, call the Alzheimer's Disease Research Unit at the Yale School of Medicine at (203) 764-8100.
For information about enrolling in the study at Hartford Hospital, call (860) 545-1507.
To sign up for the Banner Institute's Alzheimer's Prevention Initiative registry, go to http://endalznow.org/.