The Tangled Neuron

Dreaming About A Cure, Talking About Care: Part 4 of 4 - New Ideas for Care and Cure

Whether we view Alzheimer’s as a disease, or as part of aging, most of us know from personal experience that the way we deal with it is terribly inadequate. In the past three posts, I’ve written about the growing recognition that Alzheimer’s isn’t a single disease, and the controversy about whether we should spend our limited resources on trying to find a “cure.”

Maybe if we give up our fantasies of a single “cure” for Alzheimer’s, we can start talking about better ways to view and treat dementia. These discussions have already begun in labs, at conferences, on email lists, and in homes around the world. While preliminary, they provide us with a glimpse of how Alzheimer’s care might look in the future.

Dr. Peter Whitehouse’s work is an example. Earlier in his career, he focused on drug development. Now he’s more interested in prevention and in intervention studies aimed at improving quality of life for dementia sufferers.

“We need to re-evaluate what’s important,” he says. “Regardless of cure, care needs more attention. Trying to find a cure is part of caring, but there’s an imbalance. We have a great obligation to think clearly about the condition, then do things to improve it. We need to think about ethical considerations – for example, there are still children whose brains are being damaged by lead. Addressing this problem is important for future generations. And instead of focusing on degeneration, we should be focusing on renaissance and legacy.”

Dr. Whitehouse’s recent work includes research on using electronic aids for reminiscence therapies (LifeBook) and archiving individual stories of people’s experiences with disease (including dementia) and medical treatment (StoryBank). His main intervention studies will be at The Intergenerational School, a Cleveland public school serving learners of all ages. He founded the school with his wife Catherine. “The IG school represents one way of pulling it all together,” he says. “Purpose, a sense of community, remaining cognitively active, leaving a legacy, being engaged and valued - these things are much more important to quality of life.”

In labs and at conferences, other scientists are discussing new approaches to Alzheimer’s research, such as more accurate “sub-typing” for identifying different types of dementia, and focusing on investigating potential causes of dementia other than beta amyloid. I’ll write more about this in another post.

And within DASN, members are talking about how to improve care:

- “I think the 'person-centered' model is the ideal for both the care partner and the person with dementia. Each of us has different needs, so no care plan would suit even the majority of folks touched by this disease.” (Shirl Garnett, western Australia, diagnosed with early onset dementia at 59)

Shirl Garnett

- “The mind-body-spirit approaches developed by new age physicians to address those other diseases must be brought to bear on AD. Further, I believe that new era medicine - consciousness and healing - could inform the research being done in the AD research centers and private laboratories.” (Jay Smith, California, diagnosed with early onset Alzheimer’s)

- “Services in the form of support for caregivers and those of us with dementia can often be provided in part by volunteers. I am convinced that there are many more volunteers who are qualified and would contribute if given the opportunity.” (Charley Schneider, Missouri, diagnosed with early onset Alzheimer’s)

- “I think that the key to finding a better medication for treatment and possibly a cure lies in the minds (no pun intended)of those that ARE diagnosed in their 30's, 40's and 50's. If they were open to allowing us to be a part of research in clinical trials I personally think that this would speed up the process for their goal of a cure. So, so many of us work so diligently with great urgency to make this happen as we don’t have the time that the associations and researchers do to plan this all out as our time is running out. Why not focus on those under 50? They might be surprised how much money is saved in research if they would just broaden their horizons so to speak.” (Tracy Mobley, Missouri, diagnosed with early onset Alzheimer’s disease at the age of 38)

Tracy Mobley

- “What makes the best sense of all is empowering people with dementia to care for themselves as much as possible and for as long as possible. People with dementia absolutely can learn some things far into the disease. I truly believe that people with early dementia can be taught to better understand and manage their own disease and behaviors. I further believe that a society which allows people with dementia to stay involved in their chosen activities also prolongs life and emotional health.” (Carole Mulliken, Missouri, diagnosed with vascular dementia)

Dr. Whitehouse sees hope in this kind of open-minded discussion. “If we can think through Alzheimer’s in a deeper way, will have insights into how the brain works. Underneath Alzheimer’s is a re-thinking about what it means to be human, and science’s role in society.”

Dreaming About A Cure, Talking About Care: Part 3 of 4 - The Fantasy of "Cure"

When Dr. Peter Whitehouse of Case Western Reserve University says we should redirect Alzheimer’s funding to emphasize care over “cure,” the idea isn’t very popular (see previous two posts). But he’s not really suggesting we should stop funding research – it’s just that he doesn’t like how that research is presented to the public. “I’m not saying we don’t need bio research,” he explains. “But using the word “cure” is irresponsible.”

“I’m more of a psycholinguist than a physician, so I’m interested in words,” he continues. “In the discourse about Alzheimer’s, our field needs to be more honest. It’s unlikely we’ll fix the problem in the sense of a cure. Care is more complicated to appreciate than finding a drug that blocks pathways, and it involves ethical and cultural implications. It’s easy to say ‘give me half a billion dollars to find a cure,’ but asking for half a billon for better long term care is more difficult. But we keep saying ‘give us more money to find a cure.’ This is a fantasy – people are starting to realize the emperor has no clothes.”
Looking back, I think my dream of finding a cure for Dad really was a fantasy. I kept reading that we were making great progress towards a cure for Alzheimer’s, but the reality was that my father’s doctors were unsure why he had dementia, and unsure what to do about it.

This is part of the massive information disconnect surrounding Alzheimer’s and dementia, and a source of anger for many persons with dementia and their families. I think most of us dealing with dementia can understand the kind of complexity Dr. Whitehouse talks about. We will continue to support both research and care efforts even when the hype about a cure is replaced by careful discussion about how we should view and treat dementia.

“It’s our obligation to think through what “Alzheimer’s” is and how to address it,” Dr. Whitehouse says.

Dreaming About A Cure, Talking About Care: Part 2 of 4 - More Care, Less "Cure"?

In my last post, I wrote about how researchers are beginning to question whether Alzheimer’s is really one disease. A different view of the definition of Alzheimer’s naturally leads to a different view of what we should do about it:

1. If Alzheimer’s is a disease, we need to continue to try to find the cure for it.

2. If Alzheimer’s is cognitive dysfunction caused by multiple aging-related conditions, we should shift our focus to steps we can take to prevent those conditions.

Dr. Peter Whitehouse, Professor of Neurology at Case Western Reserve University, is one of those who holds the second view. Because he doesn’t think Alzheimer’s is a single disease, he believes it’s unlikely that researchers will find a “cure.” He’s concluded we should focus resources on care and services for people with cognitive impairment, and on prevention, rather than searching for a “magic bullet” cure. “Care needs to be dominant over cure,” he says.

Richard Taylor, a retired psychologist, DASN member and author of the book Alzheimer's from the Inside Out, was diagnosed three years ago with dementia. He agrees there should be a shift in funding.

Richard Taylor, Ph.D

“This disease creates turmoil in 99.9% of the families who are dealing with it,” he says. “While ‘bench’ researchers run around chasing their molecular tails, people who are living with the disease as carers and carriers battle with themselves and each other.

When will more attention be paid to this real problem and less to the conditions of nude mice? I realize both areas need research, lots of research. In the mean time millions of people are struggling with the psycho-social consequences of the disease.

The vision of a world without Alzheimer's is compelling. Shouldn't the cries for help from people confronting it be just as compelling? There needs to be a more equitable split in research dollars between tomorrow's and today's issues.”

As I think through the care versus cure question, I wonder what a decision to shift resources away from research would have meant for my dad, whose cerebral amyloid angiopathy (CAA) caused microbleeds in his brain that led to his dementia and death. I don’t think the preventative measures we talk about now (healthy diets, exercise, staying engaged, etc.) would have made a difference for him. Basic research into the causes of and treatments for CAA and Alzheimer’s would have helped him more.

But in the last few years, research facilities have been forced to delay Alzheimer’s-related experiments and lay off scientists because they can’t get funding. With money already scarce for Alzheimer’s research, do we really want to shift resources from cure to care?

Lisa Genova, the neuroscientist and author mentioned in my earlier post, doesn’t think so. “As a neuroscientist who understands the biology of this disease and as someone who knows the researchers who are driven and dedicated to finding a cure, I honestly believe that a cure for this disease is within grasp, and to take funding away would be a crazy, horrific mistake,” she says.

Jeanne Lee, a DASN member living in Hawaii, and author of the book Just Love Me: A Life Turned Upside-down by Alzheimer’s, doesn’t want research funding reduced, but would like to see it redirected. “I do agree too much money is spent on the later stages of Alzheimer's or dementia,” she says. “The research monies need to go towards the other end of the disease when WE are still capable of knowing what is happening in our lives. We have medicines for early stages of cancer, diabetes and other diseases, and sometimes they’re caught early enough to be cured. This is what we need for Alzheimer’s and dementia, so why would you say research is not necessary?” Jeanne was diagnosed with dementia of the Alzheimer’s type in 1995.

Jeanne Lee

Many scientists agree with Jeanne that research must focus on stopping dementia long before onset. Dr. Whitehouse has specific ideas of how we should address research on early medical interventions. “I’d prefer to see research on healthy aging, and understanding the value of basic preventative measures, such as physical exercise,” he says. “Many of these measures are good for a lot of things besides Alzheimer’s, so the money would be better spent.”

On this aspect, Jay Smith, another DASN member mentioned in my last post, agrees with Dr. Whitehouse. “More research should be done to identify and isolate the various environmental and lifestyle causes of the disease - diet, nutrition, life style, stress, genetics, environmental toxins, etc. - as has been done in diabetes, heart disease and cancer over the past twenty years,” he says.

Wrong Question?

Other DASN members don’t like the care versus cure question. Carole Mulliken, a former teacher and school counselor diagnosed with vascular dementia at 59, says that, “…in most cases, framing a question in ‘either or’ format guarantees a false conclusion. To tie ourselves up in deciding which of the two is more important eliminates the possibility of putting energy in to multi-faceted responses.”

Carole Mulliken

Chuck Jackson another DASN member who has been diagnosed with early onset dementia agrees. “If we have a medical cure,” he says, “or medical treatment that stops progress of the disease in early stages, then we won’t need expensive care facilities after a certain amount of time. The bottom line is how to facilitate both care research and medical research.”

Richard Taylor feels the same way. “It's the wrong question to ask. The crucial question is why are there so few dollars that a choice has to be made. It's tragic, it's irresponsible, and everyone should be ashamed and angry we all aren't doing more to address the consequences of this plague.”

But if the current trend of reduced government spending for Alzheimer’s research continues, and private donors don’t step up with more donations, we’ll have to make a choice between cure and care.

Dreaming About A Cure, Talking About Care: Part 1 of 4 - Is Alzheimer's Really A Disease?

Last night, I dreamed Dad was getting better. He called to say he was back home, and sounded upbeat. He was finding words more easily than when we last had talked. I immediately started thinking about things we could do to speed his recovery: green tea, meditation, maybe even a little red wine. More than a year after Dad died, I'm still dreaming about a cure.

I'm not alone in my dreams. "I really thought that we would have a cure before I had to worry about onset. I was terribly wrong," says Chuck Jackson, a former employment counselor whose mother and nine of her siblings had early onset Alzheimer's. Four of his cousins have died of the disease, and how he, his brother and three of his cousins have been diagnosed with it.

This talk of a cure is echoed around the world in hundreds of labs and millions of homes. But I don't think we're anywhere close.

If you are diagnosed with Alzheimer's today, your doctor may prescribe Aricept, Namenda or other medicines. The most these drugs will do is delay symptoms in some people; they have no effect in others. Treatment won't change the underlying degeneration of your brain, or halt progression. If your family can't care for you, there's little chance you'll get good care in a nursing home, at least in the US.

This bleak reality has prompted Chuck Jackson and other members of the Dementia Support and Advocacy Network (DASN) to speak out about Alzheimer's. The majority of DASN members are persons with dementia or their care partners. Individual members of the group are working with organizations, the media and lawmakers to raise awareness about Alzheimer's.

"If doctors themselves would be more aware, I think they'd find there are a lot more afflicted with Alzheimer's disease than they realize," says Sarah Christianson, a DASN member and former office manager diagnosed with early onset Alzheimer's and frontotemporal dementia.

Sarah Christianson

But Dr. Peter Whitehouse advocates something different: a complete redefinition of Alzheimer's and how we treat it.

Dr. Whitehouse is Director of Integrative Studies and Professor of Neurology at Case Western Reserve University, and author of the forthcoming book The End of Alzheimer's [St. Martin's Press]. He is one of several scientists and doctors who have mentioned to me that they don't think Alzheimer's is a single disease.

Peter J. Whitehouse, M.D., Ph.D

"People suffer enormously from what I used to call Alzheimer's," he says. "But as a clinician, I'm aware of the variability of dementia symptoms and progression, so I'm suspicious of the claim that this is one disease and that it's different than aging."

Expressing doubts about Alzheimer's status as a disease is controversial, both among researchers and among persons with dementia. "Terribly wrong-headed," says Jay Smith, a DASN member from California who is working to organize a conference for people with dementia. "That kind of thinking (simplistic, not based in reality) is just dangerous." Jay was forced to leave his job when he was diagnosed with early onset Alzheimer's.

Jay Smith

Lisa Genova, another DASN member, neuroscientist and author of Still Alice, a novel about a fifty-year-old cognitive psychology professor diagnosed with Alzheimer's. "This IS a disease," she says, "œand not just a normal part of aging."

"Alzheimer's doesn't just happen to people in their 70's and 80's; it happens to people in their 40's & 50's and younger," says Jaye Lander, a Pennsylvania-based former Wall Street executive diagnosed with early onset dementia of the Alzheimer's type. "I turned 60 on Thanksgiving but have had brain tissue atrophy visible in MRI's for several years. As long as our brains start disintegrating on us in our primes, I think it is a terrible disease and not just a normal function of aging."

Many researchers assume early onset and late onset Alzheimer's disease are similar, but Dr. Whitehouse's comments were not meant to address early onset Alzheimer's. "Of course, if people are getting it in their 40s and 50s, it's hard to say that's aging. It's more reasonable to call what these people are suffering from a disease," he says.

He is much less certain about whether late onset dementia is really one disease. "As a clinician, I now avoid using the word Alzheimer's," Dr. Whitehouse says. "But what do I put on a billing form, and what do I say to a patient? The answers are more complicated than we like."

Alzheimer's Plaque-Buster?

For years, Dad had a night job. By day, he ran our family’s retail lumberyard. By night, he ran a mouse relocation program. Our house was full of mice. They scampered through the attic and ran down plumbing and electrical ducts, nabbing cotton balls and Kleenex to build their nests. They got into our food, and left droppings along the baseboard.

The situation came to a head when my mother went into the kitchen to get a plastic bag full of garbage she had left on the counter. “There was a mouse sitting inside the bag, stuffing his face,” she says. She called Dad into the kitchen. He carefully closed the bag, carried it outside, and let the mouse go.

That night, my father brought home a small Havahart trap, baited it with peanut butter, and set it in the laundry room. A quivering brown mouse was in the cage the next morning. On his way to work, Dad drove his passenger down a dirt road, and released him in the woods.

Dad reset the trap that night, and another mouse was there in the morning. This went on for months – almost every morning, another mouse. And almost every morning, Dad would head down the dirt road to his mouse drop-off spot.

“They’ve posted a sign,” he joked, “free peanut butter and a ride.” My parents kept a tally - after four months, Dad had transported 123 mice. They seemed to be multiplying faster than he could clear them out.

Breaking Down Beta Amyloid

Scientists think the same thing may be happening with beta amyloid, the protein that makes up the plaques found in Alzheimer’s. The protein is constantly produced by the body, then cleared from the brain. It may be that in people with Alzheimer’s, the beta amyloid is building up faster than it can be eliminated, and the excess protein is toxic to brain cells.

Researchers have found several enzymes that break down beta amyloid, including insulin degrading enzyme (IDE). Increasing the amount of these substances in the body could help speed up the elimination of excess beta amyloid.

Dr. Jin-Moo Lee, Assistant Professor of Neurology at Washington University School of Medicine in St. Louis has shown that another enzyme called matrix metalloprotease-9 (MMP-9) also degrades beta amyloid. Dr. Lee found that MMP-9 is able to break down the fibrils that make up the plaques found in Alzheimer’s. MMP-9 and other enzymes break down a free-floating kind of beta amyloid that hasn’t formed into plaques. But in Dr. Lee’s lab, the other enzymes didn’t seem to degrade fibrils the way MMP-9 did. These results suggest that MMP-9, already found in the body, may be helpful in clearing plaques from the brain.

Jin-Moo Lee, M.D., Ph.D.

There’s more evidence that the enzyme may help regulate beta amyloid levels. Dr. Lee and his colleagues found that turning off the gene for MMP-9 in mice increased the levels of beta amyloid in their brains.

MMP-9’s Role In Other Diseases

Harnessing MMP-9 to break down beta amyloid will be a delicate task. High levels of the enzyme are associated with cancer and arthritis. Even worse in terms of dementia, Dr. Lee has shown that high levels of MMP-9 near blood vessel walls in the brain are associated with cerebral amyloid angiopathy (CAA). In CAA, beta amyloid is deposited on blood vessel walls in the brain. The walls then thicken, harden and crack, allowing blood to leak out into the surrounding tissue. My father’s autopsy showed severe CAA, and it’s likely that the disease and resulting microbleeds caused his dementia. He died last year of a massive hemorrhagic stroke, probably due to CAA.

So MMP-9 may clear Alzheimer’s plaques, but may also be involved in CAA and brain hemorrhages. Is MMP-9 good or bad for the brain?

“MMP-9 is neither ‘good’ nor ‘bad,’ Dr. Lee says, “but may have different responses and activities in different cells and different locations. We have hypothesized that MMP-9 may play a role in weakening the vessel wall in CAA (though this is far from proven)…. We have shown that MMP-9 and -2 can degrade Abeta [beta amyloid] in the brain. These are two different locations and two different activities.”

The fact that increased levels of MMP-9 have been found in the brains of ischemic stroke patients provided a clue to MMP-9’s role in brain hemorrhages. “MMP-9 is upregulated after ischemic stroke,” Dr. Lee explains, “and likely plays a role in converting an ischemic stroke into a hemorrhagic stroke (by weakening the vessel wall). This is why it is so intriguing that MMP-9 is upregulated in CAA vessels, with the thought that CAA vessels may have increased MMP-9 which might eventually lead to weakened vessels.”

Dr. Lee is working to confirm the role of MMP-9 in CAA. He has a study underway to see if lowering MMP-9 levels in mice with CAA reduces the frequency of brain hemorrhages. “This data will be far more convincing,” he says.

More Research Needed

Adding to the uncertainty of MMP-9’s role in dementia, it’s not clear what effect breaking down the beta amyloid fibrils will have. “Again, this may be "good" or "bad," Dr. Lee explains. “Recent reports suggest that smaller aggregates of Abeta (oligomers) may be toxic or inhibit neurotransmission. It is possible that MMP-9 may break down fibrils into these smaller aggregates, which might be even more toxic than fibrils. On the other hand, it is possible that MMP-9 could degrade both fibrils and oligomers rendering them non-toxic. We are currently investigating this.”

It’s also not clear whether drugs designed to increase or decrease levels of MMP-9 could stop brain degeneration and dementia, or what any side effects would be. One possibility for therapy stems from the fact that MMP-9, like many other enzymes, requires the presence of zinc to work. So in theory, reducing the amount of zinc in the body via chelation therapy might inactivate MMP-9 and reduce damage to blood vessel walls. It’s unclear what this might do to the beta amyloid plaques in other areas of the brain, though, and there could be severe side effects. “Removing zinc would likely be detrimental to other systems,” says Dr. Lee.

The connection of MMP-9 to both Alzheimer’s and CAA is intriguing, but still murky. More research is needed before any treatments can be developed. “I think we are far from therapies at this point,” Dr. Lee says. “One must remember that at this level of research, we are trying to understand molecular mechanisms, and we are somewhat removed from therapies. However, our goal is to identify potential targets for the development of therapies. It’s too early to say whether MMP-9 will provide us with viable targets, but therapies to ameliorate disease are always on our minds.”