International Conference on Alzheimer's Disease (ICAD) 2008

Summary:  the majority of presentations at ICAD focused on Alzheimer's as a disease, and what we can do to cure it.  But the presentations on healthy brain aging (even in people with Alzheimer's plaques and tangles in their brains) were just as interesting.  From my layperson's point of view, we may learn as much from exploring healthy brain aging as we do from looking for an Alzheimer's cure.

It's hard to summarize ICAD 2008, held last week in Chicago.  The majority of the hundreds of oral presentations and thousands of poster presentations focused on molecular biology (genes, proteins, etc.), and on amyloid protein in particular.  But the three presentations in the plenary session on the last day highlighted that there are at least two ways to look at Alzheimer's: 

1. as a disease, with the focus on what can we do to cure it
2. as the opposite of successful aging, with the focus on what keeps our brains healthy as we age.

Paul Aisen, MD, now at University of California - San Diego, gave a presentation called "The Evolution of Alzheimer's Disease Clinical Trial Design."  His presentation was from the view of Alzheimer's as a disease, and what we can do to cure it.

Dr. Aisen argued that the Newsweek article "The Scandal That is Alzheimer's Research" [detailing questions about the amyloid hypothesis and the failure of Flurizan in Phase 3 trials] did not reach a "reasonable conclusion."   Instead, he said, recent failures of anti-amyloid drugs in trials "represent methodological issues."

There was a lot of discussion at ICAD about the size and duration of clinical trials needed.  If the benefit from potential Alzheimer's drugs can only be measured by a slower rate of decline on cognitive tests, and if there isn't a rapid decline in trial participants taking a placebo, then it's difficult to prove these new drugs work.  Some researchers say larger and longer trials are required to show an effect, and that would mean increased costs to bring a drug to market.

With the current trial designs, Dr. Aisen said, if Phase 2 trials only hint that a disease-modifying drug might work, then the chances of success in a Phase 3 trial are low - maybe 10 to 20 percent.

To improve chances of success, "we must change the current FDA regulatory pathway," he said.  According to Dr. Aisen, the key is using biomarkers (perhaps beta amyloid in spinal fluid, brain atrophy, or amyloid detected via new imaging techniques) to prove that a drug is effective.  For the FDA to accept biomarkers as a "surrogate" of clinical improvement, he says, researchers must establish that these biomarkers are related to:

1. the neurobiology of disease progression
2. cognitive improvement (this must be established for multiple drugs in multiple trials).

He believes preliminary data from the Alzheimer's Disease Neuroimaging Initiative and other studies are encouraging, and indicate that the size [and cost] of drug trials could be reduced by 80 to 90 percent if biomarkers were used.

David Bennett, MD, Director of the Rush Alzheimer's Disease Center at Rush University, gave a talk more focused on the healthy aging view of Alzheimer's.  His presentation, "Brain Reserve:  The Epidemiological Perspective," was a readout of results from two ongoing population studies on aging and dementia at Rush:  the Religious Orders Study (1100+ participants) and the Rush Memory and Aging Project (1200+ participants).

Eighty-five percent of elderly people living in the community have brain pathology (including Alzheimer's plaques and tangles, Lewy bodies, and damage from strokes) according to a study conducted by Dr. Bennett and his colleagues.  In this study, most people with dementia had mixed pathologies - Alzheimer's plaques and tangles, plus "something else."  But people without cognitive impairment had about the same level of Alzheimer's plaques and tangles, with much lower levels of "something else." 

According to Dr. Bennett, this suggests that it's possible to accumulate a lot of Alzheimer's pathology without having cognitive impairment, and indicates that some people's brains have the capacity to withstand the effects of the Alzheimer's pathology thought to be harmful.  This capacity has recently been labeled "brain reserve." 

Researchers at Rush have been working to identify what factors seem to affect this brain reserve that theoretically contributes to healthy brain aging.  Using data from the Religious Orders Study and the Rush Memory and Aging Project, they've found the following factors seem to contribute to brain reserve and healthy brain aging:

1. a tendency to be conscientious
2. education
3. social networks
4. lifetime participation in cognitively stimulating activities.

On the other hand, there are factors that seem to work against healthy brain aging and to reduce brain reserve:

1. distress proneness
2. depression
3. loneliness

These factors may all feed on each other, and may also actually alter brain structures.  If the researchers at Rush are correct, maybe making changes in our lives (enhancing our social lives, for example) will increase our chances of healthy brain aging.

The last presentation, "Role of Plasticity in Aging and Dementia," was given by Marsel Mesulam, MD, Director of the Cognitive Neurology and Alzheimer's Disease Center at Northwestern University.  He focused on healthy brain aging, but also presented a non-mainstream molecular biology theory. 

According to Dr. Mesulam, you can think of late life as a race between dementia and death [I know, it's much more fun to talk about healthy aging].  At some point, he said, maybe on average around age 70, your brain is no longer able to repair itself.  But the genes for brain aging are not the same as those for overall longevity, and some of us live to be 100 or older.  So, at least theoretically, there's a window of about thirty years where we have an increased risk of dementia.

What causes that dementia?  "I'll make the semi-provocative statement that we still do not fully understand the causes of Alzheimer's disease, and there is plenty of room for alternative theories to the dominant amyloid hypothesis," Dr. Mesulam said.  I'll try to write more about his theory in another post, but for now you should know he thinks Alzheimer's starts when risk factors decrease the brain's capacity to repair and rearrange itself (neuroplasticity).  The problem is, we don't really understand these risk factors.  But there are some hints on healthy brain aging in existing research, he says. 

His suggestions to the audience:  "seek as enriched an environment as possible, get good exercise, eat fresh fruits and vegetables and a little bit of fish, solve crossword puzzles, and don't forget some good red wine.  I can't guarantee you'll prevent Alzheimer's, but the side effects will be mild, and you may enjoy the experience!"

The scientists I met at ICAD are working very hard to cure Alzheimer's and this aspect of Alzheimer's research is well-reported in the media.  But from my layperson's point of view, we don't hear enough about research into healthy brain aging.

Comments

[Manfred Brockhaus]

Even professional Alzheimer's researchers do not understand more than a layperson - and this after spending billions of dollars on AD research. The advice to get good exercise etc. can't be so wrong. Let me point out that there is an often overlooked factor triggering the disease with several years delay: A short loss of consciousness after falling. It is is very frequent in the elder age group and it is often not even reported by the family. Even a slight brain damage may put so much stress on the brain repair system (= neuroplasticity) that the biochemical system (= beta-amyloid ?) gets overly activated. It's a common picture seen also in other diseases that the repair stress leads the way to a collaps of the whole system and finally to the death of the individual. AD in my view is the fatal consequence out of attemps to repair damaged brain tracks. My advice to the >50y is: Don't play football, soccer, or hockey. Keep your brain as something precious and vulnerable as it is.

[Don Moyer]

So, now Mesulam and Bennett are saying out loud and in public what persons living with memory challenges have been saying for years. Fascinating!

[Gail Rae Hudson]

Completely off topic: Good word, "plenary"!
Really workable, promising stuff, here, despite the appearance that, as Brockhaus says, "Even professional Alzheimer's researchers do not understand more than a layperson..."
The idea that failure in drug trials needs to be redefined is, to my mind, very on point. Reminds me of something I believe was attributed to Edison (forgive me if I'm not remembering it exactly): That if he failed 99 times he was 99 trials closer to success.
There's lots in this for me to ponder, specifically (but not completely): The "something else" theory; considering one's brain a vulnerable organ; the emphasis on social networks...which leads me to wonder, what about people (like me, for instance) who don't actually know what loneliness is because their preference is for being alone; what about when a normally social person hits the stage where my mother's at when socializing in very small, occasional doses is preferred; is this actually a symptom of something being wrong...or is it a natural social progression for some people?
Anyway, I'm very glad you went to this conference, Mona...I'm eating up your reports, and ever grateful that you have "at least two years" worth of material to write about!
Carry on!